pharmaceuticalexcipients.blogspot.com

Compendium of Pharmaceutical Excipients for Vaginal Formulations

2010-07-30T00:57:00.001-07:00

Excipients

Global research in pharmaceutical sciences will acquire
new dimensions in the post-GATT (General Agreement
in Trade and Tariff) era. The pharmaceutical industry
currently is focused on the identification and
development of novel leads from areas such as biotechnology,
combinatorial chemistry,molecular modeling, and genetic engineering.
The leads coming from these varied sources will require
specialized formulation techniques and ingredients. At
the same time, the process of discovering new drugs is a costly
proposition and requires input from the basic as well as applied
sciences. Research organizations that do not have adequate expertise
or vision tend to fall out rapidly. The alternative approach
for such organizations would be to develop new dosage
forms or formulations using novel excipients for the existing
drugs that offer distinct benefits over the conventional formulations.
Recent developments in pharmaceutical legislation, regulatory
guidelines, and licensing policies have led to increased
awareness of the properties and roles of excipients in formulations.
A careful use of excipients can lead to the development of novel delivery systems that are both effective and economical.
These innovative formulations also may offer life extension
to drugs in the form of new patents, extending the product life
cycle and adding to the market share of the company.
A formulation can be regarded as a system comprising an active
molecule along with some inert ingredients (see Figure 1).
According to the definition given by the International Pharmaceutical
Excipients Council (IPEC), “Excipients are substances,
other than the active drug substance or finished dosage
form, which have been appropriately evaluated for safety and
are included in drug delivery systems for specific functions” (1).
This definition indicates that excipients are to render easy processing
of the drug delivery systems, to protect, support, or enhance
stability, bioavailability, and patient compliance. They
also assist in product identification and are important for overall
safety and effectiveness of the drug delivery system during
storage or use. These ingredients render specific properties to
a formulation and thus represent an important aspect of formulation
design and optimization. Selection of the type and
amount of excipient is dictated by the target formulation profile
and is a major challenge for the pharmaceutical scientist.
Traditionally the ingredients of a formulation “other than
active ingredient” were known as inactive ingredients. In the
present day, where these inactive ingredients are known to play
a crucial role in designing a formulation and to provide desirable
characteristics, the term excipient is more commonly used.
The equivalent of activity in an excipient is functionality, which
refers to special attributes that the ingredient can provide to a
formulation. Developing a new excipient is as complicated as
developing a new drug molecule; therefore, excipients manufacturers
tend to opt for an easier route for value-added specialty
excipients. Knowledge and understanding of the ingredients
are extremely useful to a product development scientist.

Human Serum Albumin as a Pharmaceutical Excipient

2010-07-30T00:50:00.000-07:00

INTRODUCTION

Human serum albumin (HSA) is one of the most widely used and characterized proteins in the pharmaceutical field. It occurs naturally in the body, as a plasma protein, with a concentration of 50 mg/mL. At this concentration, HSA regulates the colloidal osmotic pressure of blood. HSA is also responsible for transporting endogenous and exogenous compounds, which might be toxic in the unbound state, but non-toxic as albumin-bound. Human serum albumin purified from plasma is used for therapeutic applications, as a plasma expander, in situations involving severe blood loss. HSA is also widely used as an excipient, especially for biotechnology products. While the albumin used in marketed products is derived from plasma, recombinant versions of the protein are being investigated. Recombinant albumin can also alleviate any theoretical concerns of disease transmissivity associated with the human plasma-derived protein. This article provides a brief review of the use of albumin as a pharmaceutical excipient, and provides an update on the development of recombinant albumin.

USE OF HSA AS AN EXCIPIENT

Human serum albumin is a 66-kD protein, with no glycosylation. The protein has molecular dimensions of 8 nm X 3.8 nm, and a half-life of 15 to 20 days. Due to its high concentration in plasma, HSA is not associated to significant extents with safety or immunogenicity concerns. A 5% albumin solution has an osmolarity of 265 mOsm/kg. Human serum albumin is a remarkably stable protein - it is the only therapeutic protein that is stable as a liquid at room temperature over the shelf life of the product. This is primarily due to the presence of 17 disulfide linkages present in the molecule. The intrinsic stability of the protein also allows it to be heated at 60�C for 10 hours to facilitate virus inactivation during manufacturing. This process has demonstrated elimination of both lipid-enveloped and certain non-lipid-enveloped viruses in validation experiments. The stability of albumin makes its storage and handling easier than typical proteins, thus lending itself well toward the use as an excipient.

Due to its established safety profile and unique properties, HSA is frequently used as a stabilizer for proteins. The protein has amphiphilic properties, which makes it suitable as an additive to inhibit adsorption of the active protein to the container, via competitive adsorption mechanisms. The surface-active character of the protein also makes it suitable for use as a surfactant to prevent protein aggregation. HSA also has a high glass transition temperature, which in combination with its amphiphilic nature, makes it an ideal excipient for cryoprotection. For some proteins, the dual functionality (surfactant and cryoprotectant) results in better cryoprotection for albumin than disaccharides, as was observed by Liu, for Lactate dehydrogenase.1 Table 1 lists representative commercial protein products that contain Albumin as an excipient.

Albumin is also being used as a carrier for microparticles and nanoparticles for sustained-release injectable drugs. A nanoparticulate formulation of paclitaxel containing albumin as the carrier was recently approved by the FDA. A number of researchers have also used albumin for sustained release of small molecules and proteins. Albumin's capacity to adsorb hydrophobic molecules makes it a unique carrier for controlled release because the drug gets released via desorption without significant burst effects. Albumin's adsorption capacity has also been exploited in development of magnetic microparticles. Such particles were used for targeted delivery of chemotherapeutic agents, such as doxorubicin. The particles consisted of albumin for binding of drug and iron for magnetic behavior to facilitate targeting.2 Albumin microspheres have also been used in diagnostic applications to detect intravascular susceptibility.3

In recent years, albumin's long plasma circulation characteristics have been exploited to develop albumin-conjugated protein drugs that have longer half-lives as compared to the unconjugated protein. Albumin-fusion proteins are produced via recombinant techniques, and this concept has been used to extend the half-lives of a number of proteins including interferon-a4, interleukin-2, and G-CSF.5

RECOMBINANT ALBUMIN

Although there has been no case of disease transmission for the use of HSA, a theoretical or perceived risk exists, due to which recombinant human albumin is currently being explored.6 While this recombinant version is currently being explored as a therapeutic, its use as an excipient may be a logical progression, if the product gets approved.

A yeast-derived recombinant version was tested by Bosse and co-workers in a Phase I comparability study with human serum albumin.7 The two proteins were compared side-by-side for both intravenous and intramuscular injections, involving more than 500 volunteers. No serious or potentially allergic events, or immunological response were reported with either product in the IV study. Serum albumin, colloid osmotic pressure changes, and hematocrit ratio were also similar. The authors concluded that rHA and HSA exhibited similar safety, tolerability, and pharmacokinetic/pharmacodynamic profiles, with no evidence of any immunological response. Tarelli and co-workers investigated the use of recombinant albumin as a cryoprotectant for thyroid-stimulating hormone (TSH), interleukin 15 (IL-15), and granulocyte colony-stimulating factor (G-CSF).8 It was observed that the recombinant albumin was equivalent in its functionality to HSA, for stabilization of the proteins as well as binding of fatty acids.

SUMMARY

Albumin is a well characterized protein and serves important needs as a therapeutic, diagnostic agent, as well as an excipient. While use of albumin as an excipient has met some resistance due to perceived risk of disease transmission, recombinant albumin is being developed to address any such concerns. Recombinant albumin may also serve as a useful case study for follow-on biologics.9 However, use of recombinant albumin as an excipient, would depend on the efficiency of the manufacturing process, to allow for reasonable cost of goods.

______________

REFERENCES

1. Liu W. The impact of formulation composition on the stability of freeze dried proteins. Doctoral Dissertation, Purdue University, 2000.
2. Rudge S, Peterson C, Vessely C, Koda J, Stevens S, Catterall L. Adsorption and desorption of chemotherapeutic drugs from a magnetically targeted carrier (MTC). J Control Release. 2001 Jul 6;74(1-3):335-40.
3. Wong KK, Huang I, Kim YR, Tang H, Yang ES, Kwong KK, Wu EX. In vivo study of microbubbles as an MR susceptibility contrast agent. Magn Reson Med. 2004 Sep;52(3):445-52.
4. Sung C, Nardelli B, LaFleur DW, Blatter E, Corcoran M, Olsen HS, Birse CE, Pickeral OK, Zhang J, Shah D, Moody G, Gentz S, Beebe L, Moore PA. An IFN-beta-albumin fusion protein that displays improved pharmacokinetic and pharmacodynamic properties in nonhuman primates. J Interferon Cytokine Res. 2003 Jan;23(1):25-36.
5. Halpern W, Riccobene TA, Agostini H, Baker K, Stolow D, Gu ML, Hirsch J, Mahoney A, Carrell J, Boyd E, Grzegorzewski KJ. Albugranin, a recombinant human granulocyte colony stimulating factor (G-CSF) genetically fused to recombinant human albumin induces prolonged myelopoietic effects in mice and monkeys. Pharm Res. 2002 Nov;19(11):1720-9.
6. Chuang VT, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharm Res. 2002 May;19(5):569-77.
7. Bosse D, Praus M, Kiessling P, Nyman L, Andresen C, Waters J, Schindel F. Phase I Comparability of Recombinant Human Albumin and Human Serum Albumin. The Journal of Clinical Pharmacology, 2005; 45:57-67.
8. Tarelli E, Mire-Sluis A, Tivnann HA, Bolgiano B, Crane DT, Gee C, Lemercinier X, Athayde ML, Sutcliffe N, Corran PH, Rafferty B. Recombinant human albumin as a stabilizer for biological materials and for the preparation of international reference reagents. Biologicals. 1998 Dec;26(4):331-46.
9. Morioka H. Considerations about generic biologics. Business Briefings: Pharmagenerics 2004 (http://www.bbriefings.com/pdf/955/ACFB481.pdf).

PQRI Survey of Pharmaceutical Excipient Testing

2010-07-30T00:46:00.000-07:00

he Product Quality Research Institute (PQRI) conducted an open, publicly available, electronic survey of current excipient-control strategies among pharmaceutical excipient manufacturers, excipient distributors, and drug-product manufacturers (excipient users). Among the major findings are:

* the majority of respondents supply their products for global markets, and thus must meet substantially different test requirements for different regions;
* the majority of respondents use reduced-testing strategies employing equivalent methods;
* a large majority of respondents perform tests on the excipients beyond those given in pharmacopeias to determine physical and chemical properties necessary for their intended use;
* drug-product manufacturers typically follow their own company procedures to qualify excipient manufacturers and suppliers.

Figure 1: Respondents selling products both in the United States and abroad.
The survey results provide insights about the decisions of excipient manufacturers and drug-product manufacturers regarding testing excipient quality and using excipients in pharmaceutical manufacturing.

Background

When the European Agency for the Evaluation of Medicinal Products (1) and US Food and Drug Administration (2) issued excipients guidances in 2003, industry predicted that they would have the unintended result of causing additional paperwork and excessive testing for excipient control strategies, without adding benefits. In addition, industry believed the guidances effectively eliminated generally accepted and common excipient control strategies.

Figure 2: Respondents testing excipient according to USP–NF monograph/general chapter methods
FDA's interpretation of International Conference on Harmonization (ICH) common technical document (CTD) language used in section P.4, "Control of Excipients" required that manufacturers specify each method used for routine excipients testing, unless the method is exactly that of the pharmacopeia and full monograph testing is performed.

Often, a drug-product manufacturer has methods used internally that are shown to produce equivalent results to those in a pharmacopeia. In addition, many manufacturers with global markets seek to eliminate redundant testing of the same property by selecting a single method shown to be capable of ensuring compliance with requirements of many pharmacopeias. The United States Pharmacopeia (USP) has been clear that alternate methods are acceptable to demonstrate compliance with USP–National Formulary (NF) requirements (3).

Figure 3: Respondents´ frequency of accepting excipient based on process controls, not on Certificate of Analysis.
FDA recently announced its Guidance for Industry on Chemistry, Manufacturing, and Controls Information; Withdrawal and Revision of Seven Guidances (4). By focusing on the Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century (CGMP Initiative) and ICH Guidelines, FDA has strategically reduced industry's regulatory and paperwork concerns, and changed the regulatory focus to concentrate on those aspects of manufacturing that pose the greatest risk to product quality. Although excipients constitute a large portion of most drug products, they have been viewed as a low-risk aspect of drug-product safety. They are, however, a key aspect of product Quality by Design (QbD).

Survey results

Figure 4: Respondents reporting difficulty finding manufacturer of USP–NF grade excipients.
The PQRI Excipient Working Group developed three surveys to gather responses from each of three respondent groups: excipient manufacturers, excipient distributors, and drug-product manufacturers. The surveys gathered information about excipient-control strategies used by companies that manufacture, distribute, and sell prescription-only and over-the-counter drug products for US-only or US-and-world markets. The anonymous surveys could be completed electronically by individuals belonging to the PQRI member organizations (http://www.pqri.org) and other interested persons. The survey period was from June 13, 2005 to Oct.14, 2005.

Figure 5: Obstacles to labeling excipients as USP–NF.
PQRI received responses from 180 drug-product manufacturers, 26 excipient manufacturers, and 6 distributors of pharmaceutical excipients. It should be recognized that PQRI is a unique US-based organization and that the survey questions were developed in the United States. Some survey responses may, however, have come from companies that manufacture their products for distribution and sale outside, as well as within, the United States.

This report presents findings of the three surveys and an analysis of survey responses. For the purposes of this report, the terms "excipient user" and "drug-product manufacturer" mean the same, and are used interchangeably throughout the document.

Figure 6: Respondents reporting inspections or visits by FDA (for either drug excipient or food use).
The survey clearly indicates that the majority of excipient manufacturers, excipient distributors, and drug-product manufacturers make their products for global distribution (see Figure 1). They test their excipients according to USP–NF monographs and general chapter methods (see Fig. 2). Almost all (97%) drug-product manufacturers perform more than just the identification test when receiving excipients from their vendors along with Certificates of Analysis (C of A). The additional tests include analyses for desired physical and chemical properties.

Less than 20% of drug-product manufacturers accept some or most material based on the excipient manufacturer's process controls and on in-process tests. These controls and tests are not mentioned on C of A, but provide assurance of conformity with USP–NF requirements (see Figure 3). This area offers opportunities for excipient manufacturers and drug-product manufacturers to research and subsequently use information and knowledge that lies in the excipient-maker's "manufacturing process-controls" and "in-process test results" domain. Assessment of such information could also confirm (or otherwise indicate) certain physicochemical quality aspects of an excipient batch, or qualities of an excipient produced under continuous manufacturing conditions.

Figure 7: Respondents reporting familiarity with requirements of Food Drug and Cosmetic Act and 21 CFR Part 211.84.
Drug-product manufacturers qualify new sources of excipients by vendor audits and complete testing according to the compendial monograph. According to the survey, 40% of drug-product manufacturers had difficulty finding a manufacturer of at least one USP–NF grade excipient (see Figure 4). In such a situation, they would use the best grade available, test the excipient according to the compendial monograph, and conduct an audit of the excipient manufacturer. Approximately 75% of drug-product manufacturers indicated they test and perform site audits to confirm compliance (for "a few" to "all" excipients) with compendial-grade standards. In 80% of the cases, respondents used validated test procedures to confirm the compliance of noncompendial grade excipients with compendial grade standards, or confirm that products conforming with one compendial grade also met standards from other compendia.

Figure 8: Respondents testing excipients by Ph.Eur. or JP methods instead of USP–NF.
Only a minority of responding excipient manufacturers and distributors cited specific reasons for not labeling their products as USP–NF compendial grade. Approximately one-third cited low demand for compendial grade products; just under 30% cited restrictive GMP requirements, the prospect of FDA inspection, or the time and resources needed to perform required audits. Only a handful expressed doubts about being able to meet compendial monograph requirements (see Figure 5). Nearly 80% of excipient manufacturers and drug-product manufacturers, and 60% of distributors, have been inspected or visited by FDA for either drug excipient or food use (see Figure 6).

Among drug-product manufacturers, 89% have five or more excipients in reduced-testing programs, and do not perform complete monograph testing after vendor qualification and receipt of C of A.

Figure 9: Respondents applying harmonized monographs and general chapters across all sites.
Excipient manufacturers, distributors, and drug-product manufacturers all responded that they feel adequately familiar with the applicable FDA and compendial requirements and recommendations related to testing of excipients used in a drug product (see Figure 7).

Among manufacturers, distributors, and users of USP–NF excipients, 70% or more perform additional functionality or processability testing that is not part of any USP–NF,European Pharmacopoeia (Ph.Eur.), or Japanese Pharmacopoeia (JP) compendial monograph. Of these, 87% perform the tests because of processing concerns. Most additional testing was performed for solid oral dosage forms (87%), and 24% of drug-product manufacturers have products for which excipient variability is a problem in spite of such extra-compendial testing.

Appendix: Excipient Working Group Recommendations for a PQRI Workshop
At least half of excipient manufacturers, distributors and drug-product manufacturers test some, most, or all of their excipients by alternate international (Ph.Eur., JP) compendial methods instead of USP–NF (see Figure 8).

Nearly 60% of excipient and drug-product manufacturers conduct excipient testing per harmonized monographs, and reduce redundant testing by either demonstrating multiple compendial specification equivalence or using the most stringent method or specification for confirming compliance with more than one compendium. Approximately 50% of both excipient manufacturers and drug-product manufacturers have applied harmonized excipient monographs and harmonized general chapters across all their sites (see Figure 9).

The PQRI and its Excipient Working Group encourage active participation by stakeholders from excipient manufacturers, excipient distributors, drug-product manufacturers, compendia, and regulatory agencies in discussing the current issues and for developing possible solutions to problems faced by pharmaceutical excipient manufacturers, distributors, and drug-product manufacturers (5).

References

1. European Agency for the Evaluation of Medicinal Product (EMEA), Note for Guidance on Excipients, Antioxidants and Antimicrobial Preservatives in the Dossier for Application for Marketing Authorisation of a Medicinal Product (CPMP/QWP/419/03) (EMEA, London, UK, Feb. 20, 2003).

2. US Food and Drug Administration, Guidance for Industry, Drug Product: Chemistry, Manufacturing, and Controls Information (FDA, Rockville, MD, Jan. 2003), now withdrawn, Fed. Reg. 71 (105), 31194–31195 (June 1, 2006).

3. United States Pharmacopeia 29–National Formulary 4, General Notices, section Tests and Assays under Procedures (United States Pharmacopeia Convention, Rockville, MD, 2006).

4. FDA, "Guidance for Industry on Chemistry, Manufacturing, and Controls Information; Withdrawal and Revision of Seven Guidances," Fed. Reg. 71 (105), 31194–31195 (June 1, 2006).

5. Details are posted online at http://www.pqri.org/workshops/Excipient/Excipient06.asp

6. Product Quality Research Institute (PQRI) workshop on Excipient Testing and Control Strategies, Oct. 10–11, 2006, Marriott Bethesda North Conference Center in Maryland.

The authors are members of the Pharmaceutical Quality Research Institute's Excipient Working

Monographs: Pharmaceutical substances: Dinitrogenii oxidum - Dinitrogen oxide N2O

2009-08-22T02:16:00.000-07:00

Relative molecular mass. 44.01

Chemical name. Nitrous oxide; CAS Reg. No. 10024-97-2.

Other name. Nitrous oxide.

Description. A colourless gas; odourless.

Solubility. One volume dissolves in about 1.5 volumes of water at a pressure of 101.3 kPa and a temperature of 20 °C.

Category. Inhalational anaesthetic gas.

Storage. Dinitrogen oxide should be kept as compressed gas or liquid at very low temperatures, in appropriate containers complying with the safety regulations of the national authority. Valves or taps should not be lubricated with oil or grease.

Labelling. An ISO standard1 requires that cylinders containing Dinitrogen oxide intended for medical use should bear the name of the contents in legible and permanent characters and, preferably, also the molecular formula N2O.

1 International Standard 32. Gas cylinders for medical use - marking for identification content. International Organization for Standardization, Switzerland, 1977.

Additional information. In the analysis of medicinal gases certain tests are not intended for hospital pharmacists. They are applicable solely by laboratories equipped with specialized apparatus.

Requirements

Dinitrogen oxide contains not less than 98.0% v/v of N2O in the gaseous phase, when sampled at 15 °C.

Note: If the analysis is performed on a cylinder, keep the cylinder of the gas to be examined at room temperature for at least 6 hours before carrying out the tests. Keep the cylinder in the vertical position with the outlet valve uppermost.

The test for carbon monoxide should be carried out on the first portion of gas drawn from the container and the tests for nitrogen monoxide and nitrogen dioxide immediately thereafter.

Identity tests

• Either test A alone or tests B, C, and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the reference spectrum of dinitrogen oxide.

B. Place a glowing splinter of wood into the gas; the splinter bursts into flame.

C. Shake the gas with alkaline pyrogallol TS; it is not absorbed and the solution does not become brown (distinction from oxygen).

D. Mix the gas with an equal volume of nitrogen monoxide R; no red fumes are produced (distinction from oxygen).

Carbon monoxide

• Either test A, test B, or test C may be applied.

• The tests should be carried out on the first portion of gas released from the container.

A. The apparatus (Fig. 6) consists of the following parts connected in series:

- a U-tube (U1) containing desiccant silica gel R impregnated with chromium trioxide R;

- a wash bottle (F1) containing 100 ml of potassium hydroxide (~400 g/l) TS;

- a U-tube (U2) containing pellets of potassium hydroxide R;

- a U-tube (U3) containing phosphorus pentoxide R dispersed on previously granulated, fused pumice;

- a U-tube (U4) containing 30 g of recrystallized iodine pentoxide R in granules, previously dried at 200 °C and kept at a temperature of 120°C (T) during the test. The iodine pentoxide is packed in the tube in 1-cm columns separated by 1-cm columns of glass wool to give an effective length of 5 cm;

- a reaction tube (F2) containing 2.0 ml of potassium iodide (160 g/l) TS and 0.15 ml of starch TS.

Flush the apparatus with 5.0 litres of argon R. If necessary, discharge the blue colour in tube F2 containing potassium iodide (160 g/l) TS by adding a sufficient volume of freshly prepared sodium thiosulfate (0.002 mol/l) VS. Continue flushing with argon R until not more than 0.045 ml of sodium thiosulfate (0.002 mol/l) VS is required after the passage of 5.0 litres of argon R. Pass 5.0 litres of the test gas from the container through the apparatus. Flush the last traces of liberated iodine into the reaction tube by passing 1.0 litre of argon R through the apparatus. Titrate the liberated iodine with sodium thiosulfate (0.002 mol/l) VS. Repeat the procedure using 5.0 litres of argon R.

Figure 6.

Apparatus for the determination of carbon monoxide in medicinal gases

Measurements in mm.

Reproduced with the permission of the European Pharmacopoeia Commission, European Directorate for the Quality of Medicines, Council of Europe.

The difference between the volumes of sodium thiosulfate (0.002 mol/l) VS used in the titrations is not more than 0.25 ml (5μl/l).

B. Carry out the test as described under 1.14.5 Gas chromatography, using a stainless steel column (2m × 4mm) packed with a 0.5-nm molecular sieve (e.g. X13, obtainable from a commercial source). Maintain the column at 80 °C, and the injection port and the detector at room temperature. Use helium R as the carrier gas at a flow rate of 60 ml per minute, and a helium ionization detector.

Use the following gases: (1) the test gas; and (2) a mixture containing 5μl of carbon monoxide R in 1 litre of dinitrogen oxide R as the reference gas.

Inject a suitable volume of both gases (1) and (2). Adjust the volume, as well as the conditions specified above, to produce a peak response for carbon monoxide obtained with the reference gas (2) that gives a height of not less than 5% on the recorder.

Measure the areas of the peak responses obtained in the chromatograms from injections 1 and 2 and calculate the content of carbon monoxide in the test gas (1) by comparing with the peak response for carbon monoxide obtained from the reference gas (2); not more than 5μl/l.

C. Determine the content using a carbon monoxide detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the carbon monoxide detector tube to the metering pump according to the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and pump a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 5μl/l.

Note: For the following tests - Nitrogen monoxide and nitrogen dioxide, Carbon dioxide Test A, Halogens and hydrogen sulfide, and Acidity and alkalinity - pass the gas to be tested through the appropriate reagent contained in a hermetically closed flat-bottomed glass cylinder, with dimensions such that 50ml of liquid reaches a height of 12-14 cm, that is fitted with (a) a delivery tube terminated by a capillary 1 mm in internal diameter and placed within 2mm of the bottom of the cylinder; and (b) an outlet tube.

Prepare the reference solutions in identical cylinders.

Nitrogen monoxide and nitrogen dioxide

• Either test A or test B may be applied.

• This test should be performed after release of the 5.0 litres of gas as described above under "Carbon monoxide, test A".

A. Pass the test gas through two of the cylinders connected in series as described above under "Carbon monoxide, test A". To obtain the liquid phase invert the gas cylinder; the liquid vaporizes on leaving the valve.

To 50 ml of water add 1.2 ml of sulfuric acid (~1760 g/l) TS and dilute with sufficient water to produce 100 ml. To 15 ml of this solution add 375mg of potassium permanganate R, mix, and transfer to the first cylinder (solution A).

Dissolve 1 g of sulfanilic acid R in a mixture of 180 ml of water and 10ml of glacial acetic acid R (solution 1). Separately dissolve 0.2g of N-(1- naphthyl)ethylenediamine hydrochloride R in a mixture of 4 ml of glacial acetic acid R and 5 ml of water, heat gently, and dilute to 200 ml with water (solution 2). Mix 1 volume of solution 2 with 9 volumes of solution 1 and transfer 20 ml of this mixture to the second cylinder (solution B).

Connect the outlet tube of the first cylinder to the delivery tube of the second cylinder containing solution B. Pass 2.5 litres of the test gas through the reagents at a rate of 15.0 litres per hour.

Prepare a reference solution by adding 0.25 ml of a solution containing 61.6μg/ml of sodium nitrite R in water to 20 ml of solution B as prepared above. Allow the test solution and reference solution to stand for 10 minutes.

Examine the gaseous and the liquid phases separately.

For both gaseous and liquid phases, any red colour produced from the solution of the test gas is not more intense than that from the reference solution (2μl/l of NO + NO2).

B. Determine the content using a nitrogen monoxide and nitrogen dioxide detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the nitrogen monoxide and nitrogen dioxide detector tube to the metering pump following the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and pump a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 2μl/l.

Carbon dioxide

• Either test A, test B, or test C may be applied.

A. Pass 1.0 litre of the test gas through 50 ml of a clear solution of barium hydroxide (0.15 mol/l) VS. Similarly prepare a reference solution by adding 1.0 ml of a 1.1 mg/ml solution of sodium hydrogen carbonate R in carbondioxide- free water R to 50 ml of barium hydroxide (0.15 mol/l) VS.

Any turbidity in the solution after the passage of the the test gas is not more intense than that of the reference solution (300μl/l).

B. Carry out the test as described under 1.14.5 Gas chromatography, using a stainless steel column (3.5m × 2mm) packed with ethylvinyl-benzenedivinylbenzene copolymer. Maintain the column at 40 °C and the detector at 90 °C. Use helium R as the carrier gas at a flow rate of 15 ml per minute, and a thermal conductivity detector.

Use the following gases: (1) the test gas; and (2) a mixture containing 300μg of carbon dioxide R in 1 litre of dinitrogen oxide R as the reference gas.

Inject a suitable volume of both gases (1) and (2). Adjust the volume, as well as the conditions specified above, to obtain a peak response for carbon dioxide obtained with the reference gas (2) of a height of not less than 35% on the recorder.

Measure the areas of the peak responses obtained in the chromatograms from the injections of gases 1 and 2 and calculate the content of carbon dioxide in the test gas (1) by comparing with the peak response for carbon dioxide obtained from the reference gas (2); not more than 300μl of CO2 per litre.

C. Determine the content using a carbon dioxide detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a suitable pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the carbon dioxide detector tube to the metering pump according to the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and pump a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 300μl/l.

Halogens and hydrogen sulfide. Pass 20.0 litres of the test gas through a mixture of 1 ml of silver nitrate (40 g/l) TS and 49 ml of water at a flow rate not exceeding 15 litres per hour.

Prepare the reference solution as follows: to 1.0 ml of silver nitrate (40 g/l) TS add 40 ml of chloride standard (5μg/ml) TS and 0.15 ml of nitric acid (~130 g/l) TS, dilute to 50 ml with water, and allow to stand protected from light for 5 minutes. For the blank solution, repeat the procedure passing the test gas through 50 ml of water.

Compare a 100-mm layer of the solution as described under 1.11 Colour of liquids.

The solution of the test gas does not darken when compared with the blank. Any opalescence is not more intense than that of the reference solution (10μg Cl per litre of dinitrogen oxide).

Water

• Either test A or test B may be applied.

A. The apparatus consists of either an electrolytic hygrometer as described below, an appropriate humidity detector tube, or a capacity hygrometer.

The measuring cell consists of a thin film of phosphoric anhydride placed between two coiled platinum wires which act as electrodes. The water vapour in Dinitrogen oxide is absorbed by the phosphoric anhydride to form phosphoric acid which acts as an electrical conductor.

Before introducing the test gas into the device, allow the gas to stabilize at room temperature and make sure that the temperature is constant throughout the apparatus. Apply a continuous voltage across the electrodes to produce electrolysis of the water and regeneration of phosphoric anhydride. Measure the resulting electric current, which is proportional to the water content in the test gas. (This is a self-calibrating system that obeys Faraday's law.)

Calculate the content of water; not more than 60μg/l.

B. Determine the content using a water vapour detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a suitable pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the water vapour detector tube to the metering pump according to the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and pump a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 60μl/l.

Acidity and alkalinity. Pass 2.0 litres of the test gas through a mixture of 0.10 ml of hydrochloric acid (0.01 mol/l) VS and 50 ml of carbon-dioxide-free water R.

For reference solution 1, use 50 ml of carbon-dioxide-free water R. For reference solution 2, use a mixture of 0.20 ml of hydrochloric acid (0.01 mol/l) VS and 50ml of carbon-dioxide-free water R.

To each solution add 0.1 ml of methyl red/ethanol TS; the intensity of the colour in the test gas solution is between that of reference solutions 1 and 2.

Assay. Determine as described under 1.14.5 Gas chromatography, using a stainless steel column (2m × 2mm) packed with silica gel for chromatography R (250-355μm). Maintain the column at 60 °C and the detector at 130°C. Use helium R as the carrier gas at a flow rate of 50 ml per minute, and a thermal conductivity detector.

Use the following gases: (1) the test gas; and (2) dinitrogen oxide R as the reference gas.

Inject a suitable volume of both gases (1) and (2). Adjust the volume, as well as the conditions specified above, to produce a peak response for dinitrogen oxide obtained with reference gas (2) that gives a height of not less than 35% on the recorder.

Measure the areas of the peak responses obtained in the chromatograms from the injections of gases (1) and (2), and calculate the percentage content of dinitrogen oxide.

Monographs: Pharmaceutical substances: Dinatrii edetas - Disodium edetate

2009-08-22T02:10:00.000-07:00

C₁₀H₁₄N₂Na₂O₈,2H₂O

Relative molecular mass. 372.2

Chemical name. Disodium dihydrogen (ethylenedinitrilo)tetraacetate dihydrate; N,N'-1,2-ethanediylbis[N-(carboxymethyl)glycine] disodium salt, dihydrate; CAS Reg. No. 6381-92-6.

Other name. Edetate disodium.

Description. A white, crystalline powder; odourless.

Solubility. Soluble in water; slightly soluble in ethanol (~750 g/l) TS; practically insoluble in ether R.

Category. Stabilizer; chelating agent.

Storage. Disodium edetate should be kept in a well-closed container.

Additional information. Solutions of disodium edetate should not come into contact with metal.

Requirements

Disodium edetate contains not less than 98.5% and not more than the equivalent of 101.0% of C₁₀H₁₄N₂Na₂O₈,2H₂O.

Identity tests

• Either test A alone or tests B, C, and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from disodium edetate R or with the reference spectrum of disodium edetate.

B. To 3 drops of ferric chloride (25 g/l) TS add 3 drops of ammonium thiocyanate (75 g/l) TS; to the deep red solution produced add 0.05 g of Disodium edetate; the colour is discharged, leaving a yellowish solution. (Keep this solution for test D.)

C. Dissolve 2 g in 25 ml of water, add 2 ml of lead nitrate (100 g/l) TS, shake, and add 6 ml of potassium iodide (80 g/l) TS; no yellow precipitate is observed.

D. To the solution from test B, add ammonia (~100 g/l) TS, drop by drop, until an alkaline reaction is obtained with pH-indicator paper R. Add 5 ml of ammonium oxalate (25 g/l) TS; no precipitate is produced (distinction from sodium calcium edetate).

Heavy metals. Use 1.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 20 μg/g.

pH value. pH of a 0.05 g/ml solution, 4.0-5.5.

Assay. Dissolve 0.5 g, accurately weighed, in sufficient water to produce 300 ml. Add 2 g of methenamine R and 2 ml of hydrochloric acid (~70 g/l) TS. Titrate with lead nitrate (0.1 mol/l) VS to which 50 mg of xylenol orange indicator mixture R has been added.

Each ml of lead nitrate (0.1 mol/l) VS is equivalent to 37.22 mg of C₁₀H₁₄N₂Na₂O₈,2H₂O.

Silicone Excipients in Drug Development

2009-08-01T10:10:00.001-07:00

A versatile ingredient works in excipient applications

By Gerald K. Schalau II and Katherine L. Ulman

Silicones have a range of applications in the pharmaceutical industry, from active ingredients in antacids to tubing used in drug processing. They also are used as excipients in topical pharmaceutical creams, ointments and lotions. These applications depend on the versatility and distinctive physicochemical and performance properties of silicone fluids, gums, and gels, which can offer combinations of formulating solutions not available with other ingredients. Low surface tension, improved aesthetics, substantivity, high permeability, nonstaining properties, and the ability to protect and deliver active ingredients allow contract manufacturers expanded formulating opportunities to meet the evolving needs of their customers.

An Expanding Role for Silicones

As the functional properties of excipients become more critical to the performance of pharmaceutical products — for example, their impact on bioavailability of drugs — contract manufacturers can benefit from considering excipients with versatility to fill a number of roles. Although silicones can function as active ingredients, they are more often used as excipients. Examples include siliconization (lubrication of syringe barrels, pistons, needles or stoppers), skin adhesives in transdermal patches (based on their adaptability for drug permeability), volatile or nonvolatile agents to improve spreading and aesthetic properties, or carriers for active ingredients. With silicone excipients, a key factor for success is selecting from a range of materials to provide specific functionalities and performance characteristics throughout the shelf life of the drug product.

The use of silicones to improve a pharmaceutical application or its aesthetics might be considered a form of technology transfer from the personal care industry. Silicones have been incorporated into skin care products since the early 1950s, and today at least 50% of newly launched skin care products contain at least one silicone. However, many silicones also have been used in healthcare applications, as evidenced by the number of silicone materials listed on the FDA’s inactive ingredient list. The silicones used in healthcare applications are among the most extensively tested materials for safety, and they are known to provide a pleasant silky, nongreasy and dry feel on skin.

Aiding Patient Compliance

The sensory properties of silicone excipients can be important factors in assisting patients who do not comply with treatment regimens because their prescribed medications have poor aesthetics. Poor patient compliance and its impact on treatment failure is a growing concern. A recent publication estimated the economic impact in the U.S. at $100 billion annually due to excessive use of healthcare resources in response to medication noncompliance¹. Because of its chronic nature and the need for topical treatments, psoriasis has been a focus of the dermatology community in an effort to understand the causes of medication noncompliance. It has been reported that more than one-third of psoriatic patients are not compliant with their prescribed medication².

Another study of psoriatic patients links medication compliance and successful patient outcomes³. The vehicle-related factor that the “medication felt unpleasant” was rated as important, while the “medication stained clothing” factor and the convenience of application (“application was time-consuming”) factor were rated as some of the most important issues. The authors stated, “Choosing a fast-drying vehicle that is easy to apply may improve usage in patients concerned about inconvenience of application.” Of note, the authors indicated that compliance did not vary with prescribed application frequency (once- versus twice-daily application), nor was there a significant difference between high-potency steroid use compared to medium and low-potency steroids.

Versatile Options

Whether selection of excipients focuses primarily on patient compliance or on other functional issues, the distinctive chemical and structural characteristics of silicones play a significant role. The silicones used in healthcare applications are typically based on the polydimethylsiloxane (PDMS) polymer, with its silicon-oxygen backbone and attached methyl pendants. Based on the requirements of individual applications, chain length, cross-linking or substitution by various functional groups can result in a variety of useful materials. Among the most important silicone forms in healthcare applications are volatile and nonvolatile silicone fluids, waxes, emulsifiers, or polymer blends such as elastomers and gums.

Volatile silicone fluids are used in a variety of personal care applications because of their easy spreading, fast evaporation rates, nonstaining properties, smooth and nongreasy feel, noncooling and nonstinging characteristics, and their safety profile. The chemical characteristics of these high purity fluids also make them useful in topical pharmaceutical products. They are compatible with a broad range of lipophilic products such as mineral oil, petrolatum, esters, and lipophilic sun filters, and can be incorporated into the oil phase of emulsions and easily dispersed into hydrogels. Some volatile silicones can be used as volatile excipients in spray pump systems for topical applications. Their low surface tension improves skin coverage and may increase bioavailability of active ingredients, while the low heat of vaporization allows films to dry quickly.

Nonvolatile silicone fluids offer high water repellency through nonocclusive films, good lubrication characteristics and low surface tension for improved spreading. They can also provide substantivity and lubrication, while reducing tackiness and residue on the skin.

As hydrophobic lubricants, nonvolatile silicone fluids can serve as emollients to improve the aesthetics of lotions and creams, and as excipients in transdermal drug delivery systems. At use levels of 1% to 30%, some silicone fluids, depending upon viscosity, appear as active ingredients with skin protectant claims. These products fit the description of “a drug product that temporarily protects injured or exposed skin or mucous membrane surfaces from harmful or annoying stimuli, and may help provide relief to such surfaces,” as described in the FDA skin protectant monograph⁴.

Figure 1 illustrates the use of two viscosities of PDMS delivered at 5% from an isododecane carrier and measured on the skin using a wash-off simulator. After three washes, results show the higher viscosity material has a higher level of substantivity.

Figure 1: Substantivity of 5% PDMS in isododecane on skin after three washings.

Silicone elastomer blends, a mixture of fluid and cross-linked nonfunctional silicone elastomer, can also be used to improve the substantivity of topical pharmaceutical formulations. They provide a more matte appearance on the skin compared to silicone fluids and leave a drier and more powdery feel — an effect that is enhanced by their ability to absorb oil and sebum. In formulations, they can act as rheology modifiers to offer distinctive sensory and textural effects, and recent studies show they can function as carriers for the release of active ingredients⁵. They also offer enhanced delivery and stabilization of volatile or unstable ingredients such as vitamins and pharmaceutical actives. Silicone elastomers can aid in the formation of emulsions or anhydrous gels, and they are optimum thickeners for silicone-based formulations. Upon application, their shear-thinning properties translate to smooth, even application for good coverage, and a “rebuild” of viscosity to remain substantive on the skin.

Figure 2 shows results of sensory evaluations of two ointments, one containing 100% petrolatum, and the other containing 70% petrolatum, 15% volatile silicone and 15% silicone elastomer. The ointment containing silicone was easier to spread and less tacky before and after application than the 100% petrolatum ointment. After application, a perceptible film was present on the skin for both formulations, but the silicone-containing ointment was less greasy, silkier and more slippery (showing better lubrication) than the ointment containing petrolatum. The perception of higher wetness for the silicone formulation was attributed to its lower oiliness.

Figure 2: Sensory evaluation (paired comparison) of an all-petrolatum
ointment versus an ointment containing petrolatum and silicones. Percentages indicate level of confidence, and the ratings for absorption were based on panelists’ perceptions, not biological skin absorption.

The addition of silicones to petrolatum resulted in a net improvement in the sensory profile of the ointment. This improvement is important in the case of ointments, which traditionally are linked to poor patient compliance due to their lack of spreadability and their tacky and greasy feel.

Silicone gums are high molecular weight silicone polymers that may be linear or branched and can be delivered onto the skin in volatile or nonvolatile silicone fluids. Like nonvolatile silicone fluids, these materials can enhance film cohesion on the skin, for greater substantivity and prolonged effectiveness of active ingredients. Improved substantivity of UV sunscreens on the skin has been demonstrated in the presence of very high molecular weight (Mw = 700,000) silicone gums⁶.

Silicone gums have been shown to improve substantivity of ketoprofen, a nonsteroidal anti-inflammatory drug, on skin when dispensed from a volatile-based silicone spray⁷. After eight hours, the presence of ketoprofen was detected on the skin surface using formulations containing a silicone gum, while ketoprofen was no longer detected in the control after six hours. It is not clear if the improved substantivity was a result of improved abrasion resistance or whether the gum had an influence on the skin penetration rate by acting as a reservoir to delay penetration. Abrasion resistance was certainly improved. Consecutive attempts to remove the film with adhesive tape immediately after spraying indicated the presence of silicone gum made removal more difficult, and drug-loaded films were even more resistant to removal⁷.

Silicone gums are very substantive on their own.In one evaluation, more than 25% of the silicone gum tested remained on the skin after eight hours⁷. Improved substantivity was observed even when very low concentrations of silicone gum (1% to 3% by weight) were used, thus providing a low viscosity formulation that could easily be applied by spraying, and which would not unreasonably increase drying time⁷.

Silicone waxes improve the aesthetic properties of topical pharmaceutical formulations, allowing application of very thin occlusive to semi-occlusive films that are neither too oily, tacky, nor dry. While silicones such as these are used for their biocompatibility and aesthetic benefits, studies also suggest they may improve the bioavailability of active ingredients over less occlusive formulations. Silicone waxes can also be used to impart moisturization, reduce tackiness and increase the viscosity of emulsions, and they have good compatibility with organic ingredients. Figure 3 shows the thickening effect of a silicone wax on three emulsion types.

Figure 3: Viscosity of emulsions with and without silicone wax.

While PDMS materials are highly permeable to moisture, some silicones such as stearoxytrimethylsilane wax display occlusive properties while still maintaining the silky feel usually associated with silicones. The following listcompares the occlusivity of oil-in-water petrolatum and stearoxytrimethylsilane wax emulsions on gelatin membranes.

Comparison of Oil-in-Water Emulsion Occlusivity

Oily Ingredient / Occlusivity (%)

Petrolatum Emulsion:93.4

Petrolatum/Silicone Wax, 50:50 Emulsion:84.7

Silicone Wax Emulsion:72.9

Silicone emulsifiers are designed for preparation of water-in-oil and water-in-silicone emulsions with excellent stability, flexibility and aesthetics. They are completely soluble in the water phase and dispersible in water solutions, but soluble in detergent systems. The presence of electrolytes (e.g., NaCl, or MgSO4 at 0.7% to 2%) helps reduce the interfacial surface and so reduce particle size, while increasing viscosity, stability and freeze resistance. At levels of 1% to 3%, silicone emulsifiers deliver the benefits of skin protection and water resistance, and they allow formulation of creams and lotions at room temperature, resulting in lower processing costs and faster processing times.

Product Registration Support

When selecting a silicone excipient, the source of the excipients may be in question, and compendial monographs do not exist to describe all potential silicone excipients. It may be preferable to select excipients that are manufactured, packaged, or tested in a dedicated facility that is registered and inspected by the FDA, or similar agencies in other geographies, that apply appropriate GMPs or similar standards for the intended healthcare applications.

Many of the silicone chemistries discussed in this article have already been used in such applications and are listed on the FDA’s Inactive Ingredient List. Using materials on this list may expedite product registration times and reduce costs. The flexibility of silicone excipient options can also be enhanced by selecting a supplier who can provide documentation to help expedite and simplify the regulatory approval process and support customer requests. Filings with global authorities may include Drug Master Files (in the U.S.) and Technical Files (in Europe) or similar filings in other geographies. Other assistance may include Letters of Authorization that provide customer access to Drug Master Files without disclosing proprietary information, while FDA inspection reports can show how well suppliers are conforming to regulatory requirements.

Access to filings of this type can expedite the regulatory application process. In addition, if a contract manufacturer has access to toxicologists and toxicological data via its excipient supplier, the process of determining suitability of silicone excipients for specific applications can go more smoothly. In effect, the expertise of the supplier can help serve as a screening process for potential excipients.

As a complement to regulatory support, availability of formulation expertise to illustrate prototype formulations in a variety of product forms can help contract manufacturers screen multiple formulations without the need to develop them from scratch. This may in turn support their customers by speeding the process for getting products to market.

Silicones have a history of more than 50 years of safety and efficiency in healthcare-related applications, and polydimethylsiloxanes are globally recognized both for their proven biocompatibility as well as for being one of the most tested materials for their safety.

As excipients, many of the unique properties of PDMS have been capitalized upon in controlled release drug delivery systems due to their chemical stability, high level of purity, ease of use and high permeability to many active drugs. Because of their distinctive physicochemical properties, silicones are especially suitable for providing aesthetics and bioavailability of actives for topical formulations.

References

1 R. Balkrishnan, C.L. Carroll, F.T. Camancho and S.R. Feldman, J. Am. Acad. Dermatol., 49, 651-4 (2003).

2 P.C. van de Kerkhof, D. de Hoop, J. De Korte, S.A. Cobelens, and M.V. Kuipers, Dermatology, 200, 292-8 (2000).

3 C.L. Carroll, S.R. Feldman, F.T. Camancho and R. Balkrishnan, Br. J. Dermatol., 151, 895-7 (2004).

4 Skin Protectant Drug Products for Over-the-Counter Human Use; Final Monograph, FDA Monograph 21 CRF Part 347, June 4, 2003.

5 A. Etienne and L. Aguadisch, EP 0 475 664 (1992).

6 G. Chandra and H. Klimisch, J. Soc. Cosmet Chem., 37:2 73 (1986).

7 L. Aguadisch et al., EP 0 966 972 (1999)

Silicone Excipients in Drug Development

2009-08-01T10:10:00.000-07:00

A versatile ingredient works in excipient applications

By Gerald K. Schalau II and Katherine L. Ulman

An Expanding Role for Silicones

Aiding Patient Compliance

Versatile Options

Figure 1: Substantivity of 5% PDMS in isododecane on skin after three washings.

Figure 3: Viscosity of emulsions with and without silicone wax.

Product Registration Support

Monographs: Pharmaceutical substances: Diphenoxylati hydrochloridum - Diphenoxylate hydrochloride

2009-08-01T10:00:00.000-07:00

Molecular formula. C₃₀H₃₂N₂O₂,HCl

Relative molecular mass. 489.1

Graphic formula.

Chemical name. Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotate monohydrochloride; ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylate monohydrochloride; CAS Reg. No. 3810-80-8.

Description. A white or almost white, crystalline powder; odourless.

Solubility. Sparingly soluble in water, acetone R and ethanol (~750 g/l) TS; practically insoluble in ether R.

Category. Antidiarrhoeal drug.

Storage. Diphenoxylate hydrochloride should be kept in a well-closed container.

Requirements

Definition. Diphenoxylate hydrochloride contains not less than 98.0% and not more than 101.0% of C₃₀H₃₂N₂O₂,HCl, calculated with reference to the dried substance.

Identity tests

• Either tests A and E or tests B, C, D and E may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from diphenoxylate hydrochloride RS or with the reference spectrum of diphenoxylate hydrochloride.

B. The absorption spectrum of a 0.50 mg/ml solution in a mixture of 1 volume of hydrochloric acid (1 mol/l) VS and 99 volumes of methanol R, when observed between 230 nm and 350 nm, exhibits maxima at about 252 nm, 258 nm, and 265 nm; the absorbances of a 1-cm layer at these wavelengths are about 0.55, 0.65 and 0.50, respectively.

C. Dissolve 25 mg in 5 ml of water and add 0.1 ml of potassio-mercuric iodide TS; a cream-coloured precipitate is produced.

D. Melting temperature, about 223 °C.

E. A 20 mg/ml solution yields reaction B described under 2.1 General identification tests as characteristic of chlorides.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 5.0 mg/g.

Related substances. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R1 as the coating substance and a mixture of 92 volumes of chloroform R, 3 volumes of methanol R, and 5 volumes of glacial acetic acid R as the mobile phase. Apply separately to the plate 10 μl of each of 2 solutions in chloroform R containing (A) 50 mg of the test substance per ml and (B) 0.50 mg of the test substance per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, expose it to the vapour of iodine, and examine the chromatogram in daylight. Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B.

Assay. Dissolve about 0.4 g, accurately weighed, in 40 ml of glacial acetic acid R1, add 10 ml of mercuric acetate/acetic acid TS and titrate with perchloric acid (0.1 mol/l) VS as described under 2.6 Non-aqueous titration. Method A. Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 48.91 mg of C₃₀H₃₂N₂O₂,HCl.

Monographs: Pharmaceutical substances: Dinitrogenii oxidum - Dinitrogen oxide

2009-08-01T09:59:00.000-07:00

N₂O

Relative molecular mass. 44.01

Chemical name. Nitrous oxide; CAS Reg. No. 10024-97-2.

Other name. Nitrous oxide.

Description. A colourless gas; odourless.

Solubility. One volume dissolves in about 1.5 volumes of water at a pressure of 101.3 kPa and a temperature of 20 °C.

Category. Inhalational anaesthetic gas.

Storage. Dinitrogen oxide should be kept as compressed gas or liquid at very low temperatures, in appropriate containers complying with the safety regulations of the national authority. Valves or taps should not be lubricated with oil or grease.

Labelling. An ISO standard¹ requires that cylinders containing Dinitrogen oxide intended for medical use should bear the name of the contents in legible and permanent characters and, preferably, also the molecular formula N₂O.

¹ International Standard 32. Gas cylinders for medical use - marking for identification content. International Organization for Standardization, Switzerland, 1977.

Additional information. In the analysis of medicinal gases certain tests are not intended for hospital pharmacists. They are applicable solely by laboratories equipped with specialized apparatus.

Requirements

Dinitrogen oxide contains not less than 98.0% v/v of N₂O in the gaseous phase, when sampled at 15 °C.

Note: If the analysis is performed on a cylinder, keep the cylinder of the gas to be examined at room temperature for at least 6 hours before carrying out the tests. Keep the cylinder in the vertical position with the outlet valve uppermost.

The test for carbon monoxide should be carried out on the first portion of gas drawn from the container and the tests for nitrogen monoxide and nitrogen dioxide immediately thereafter.

Identity tests

• Either test A alone or tests B, C, and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the reference spectrum of dinitrogen oxide.

B. Place a glowing splinter of wood into the gas; the splinter bursts into flame.

C. Shake the gas with alkaline pyrogallol TS; it is not absorbed and the solution does not become brown (distinction from oxygen).

D. Mix the gas with an equal volume of nitrogen monoxide R; no red fumes are produced (distinction from oxygen).

Carbon monoxide

• Either test A, test B, or test C may be applied.

• The tests should be carried out on the first portion of gas released from the container.

A. The apparatus (Fig. 6) consists of the following parts connected in series:

- a U-tube (U1) containing desiccant silica gel R impregnated with chromium trioxide R;

- a wash bottle (F1) containing 100 ml of potassium hydroxide (~400 g/l) TS;

- a U-tube (U2) containing pellets of potassium hydroxide R;

- a U-tube (U3) containing phosphorus pentoxide R dispersed on previously granulated, fused pumice;

- a U-tube (U4) containing 30 g of recrystallized iodine pentoxide R in granules, previously dried at 200 °C and kept at a temperature of 120°C (T) during the test. The iodine pentoxide is packed in the tube in 1-cm columns separated by 1-cm columns of glass wool to give an effective length of 5 cm;

- a reaction tube (F2) containing 2.0 ml of potassium iodide (160 g/l) TS and 0.15 ml of starch TS.

Flush the apparatus with 5.0 litres of argon R. If necessary, discharge the blue colour in tube F2 containing potassium iodide (160 g/l) TS by adding a sufficient volume of freshly prepared sodium thiosulfate (0.002 mol/l) VS. Continue flushing with argon R until not more than 0.045 ml of sodium thiosulfate (0.002 mol/l) VS is required after the passage of 5.0 litres of argon R. Pass 5.0 litres of the test gas from the container through the apparatus. Flush the last traces of liberated iodine into the reaction tube by passing 1.0 litre of argon R through the apparatus. Titrate the liberated iodine with sodium thiosulfate (0.002 mol/l) VS. Repeat the procedure using 5.0 litres of argon R.

Figure 6.	Apparatus for the determination of carbon monoxide in medicinal gases
	Measurements in mm.

Reproduced with the permission of the European Pharmacopoeia Commission, European Directorate for the Quality of Medicines, Council of Europe.

The difference between the volumes of sodium thiosulfate (0.002 mol/l) VS used in the titrations is not more than 0.25 ml (5μl/l).

B. Carry out the test as described under 1.14.5 Gas chromatography, using a stainless steel column (2m × 4mm) packed with a 0.5-nm molecular sieve (e.g. X13, obtainable from a commercial source). Maintain the column at 80 °C, and the injection port and the detector at room temperature. Use helium R as the carrier gas at a flow rate of 60 ml per minute, and a helium ionization detector.

Use the following gases: (1) the test gas; and (2) a mixture containing 5μl of carbon monoxide R in 1 litre of dinitrogen oxide R as the reference gas.

Inject a suitable volume of both gases (1) and (2). Adjust the volume, as well as the conditions specified above, to produce a peak response for carbon monoxide obtained with the reference gas (2) that gives a height of not less than 5% on the recorder.

Measure the areas of the peak responses obtained in the chromatograms from injections 1 and 2 and calculate the content of carbon monoxide in the test gas (1) by comparing with the peak response for carbon monoxide obtained from the reference gas (2); not more than 5μl/l.

C. Determine the content using a carbon monoxide detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the carbon monoxide detector tube to the metering pump according to the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and pump a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 5μl/l.

Note: For the following tests - Nitrogen monoxide and nitrogen dioxide, Carbon dioxide Test A, Halogens and hydrogen sulfide, and Acidity and alkalinity - pass the gas to be tested through the appropriate reagent contained in a hermetically closed flat-bottomed glass cylinder, with dimensions such that 50ml of liquid reaches a height of 12-14 cm, that is fitted with (a) a delivery tube terminated by a capillary 1 mm in internal diameter and placed within 2mm of the bottom of the cylinder; and (b) an outlet tube.

Prepare the reference solutions in identical cylinders.

Nitrogen monoxide and nitrogen dioxide

• Either test A or test B may be applied.

• This test should be performed after release of the 5.0 litres of gas as described above under "Carbon monoxide, test A".

A. Pass the test gas through two of the cylinders connected in series as described above under "Carbon monoxide, test A". To obtain the liquid phase invert the gas cylinder; the liquid vaporizes on leaving the valve.

To 50 ml of water add 1.2 ml of sulfuric acid (~1760 g/l) TS and dilute with sufficient water to produce 100 ml. To 15 ml of this solution add 375mg of potassium permanganate R, mix, and transfer to the first cylinder (solution A).

Dissolve 1 g of sulfanilic acid R in a mixture of 180 ml of water and 10ml of glacial acetic acid R (solution 1). Separately dissolve 0.2g of N-(1- naphthyl)ethylenediamine hydrochloride R in a mixture of 4 ml of glacial acetic acid R and 5 ml of water, heat gently, and dilute to 200 ml with water (solution 2). Mix 1 volume of solution 2 with 9 volumes of solution 1 and transfer 20 ml of this mixture to the second cylinder (solution B).

Connect the outlet tube of the first cylinder to the delivery tube of the second cylinder containing solution B. Pass 2.5 litres of the test gas through the reagents at a rate of 15.0 litres per hour.

Prepare a reference solution by adding 0.25 ml of a solution containing 61.6μg/ml of sodium nitrite R in water to 20 ml of solution B as prepared above. Allow the test solution and reference solution to stand for 10 minutes.

Examine the gaseous and the liquid phases separately.

For both gaseous and liquid phases, any red colour produced from the solution of the test gas is not more intense than that from the reference solution (2μl/l of NO + NO₂).

B. Determine the content using a nitrogen monoxide and nitrogen dioxide detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the nitrogen monoxide and nitrogen dioxide detector tube to the metering pump following the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and pump a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 2μl/l.

Carbon dioxide

• Either test A, test B, or test C may be applied.

A. Pass 1.0 litre of the test gas through 50 ml of a clear solution of barium hydroxide (0.15 mol/l) VS. Similarly prepare a reference solution by adding 1.0 ml of a 1.1 mg/ml solution of sodium hydrogen carbonate R in carbondioxide- free water R to 50 ml of barium hydroxide (0.15 mol/l) VS.

Any turbidity in the solution after the passage of the the test gas is not more intense than that of the reference solution (300μl/l).

B. Carry out the test as described under 1.14.5 Gas chromatography, using a stainless steel column (3.5m × 2mm) packed with ethylvinyl-benzenedivinylbenzene copolymer. Maintain the column at 40 °C and the detector at 90 °C. Use helium R as the carrier gas at a flow rate of 15 ml per minute, and a thermal conductivity detector.

Use the following gases: (1) the test gas; and (2) a mixture containing 300μg of carbon dioxide R in 1 litre of dinitrogen oxide R as the reference gas.

Inject a suitable volume of both gases (1) and (2). Adjust the volume, as well as the conditions specified above, to obtain a peak response for carbon dioxide obtained with the reference gas (2) of a height of not less than 35% on the recorder.

Measure the areas of the peak responses obtained in the chromatograms from the injections of gases 1 and 2 and calculate the content of carbon dioxide in the test gas (1) by comparing with the peak response for carbon dioxide obtained from the reference gas (2); not more than 300μl of CO₂ per litre.

C. Determine the content using a carbon dioxide detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a suitable pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the carbon dioxide detector tube to the metering pump according to the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and pump a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 300μl/l.

Halogens and hydrogen sulfide. Pass 20.0 litres of the test gas through a mixture of 1 ml of silver nitrate (40 g/l) TS and 49 ml of water at a flow rate not exceeding 15 litres per hour.

Prepare the reference solution as follows: to 1.0 ml of silver nitrate (40 g/l) TS add 40 ml of chloride standard (5μg/ml) TS and 0.15 ml of nitric acid (~130 g/l) TS, dilute to 50 ml with water, and allow to stand protected from light for 5 minutes. For the blank solution, repeat the procedure passing the test gas through 50 ml of water.

Compare a 100-mm layer of the solution as described under 1.11 Colour of liquids.

The solution of the test gas does not darken when compared with the blank. Any opalescence is not more intense than that of the reference solution (10μg Cl per litre of dinitrogen oxide).

Water

• Either test A or test B may be applied.

A. The apparatus consists of either an electrolytic hygrometer as described below, an appropriate humidity detector tube, or a capacity hygrometer.

The measuring cell consists of a thin film of phosphoric anhydride placed between two coiled platinum wires which act as electrodes. The water vapour in Dinitrogen oxide is absorbed by the phosphoric anhydride to form phosphoric acid which acts as an electrical conductor.

Before introducing the test gas into the device, allow the gas to stabilize at room temperature and make sure that the temperature is constant throughout the apparatus. Apply a continuous voltage across the electrodes to produce electrolysis of the water and regeneration of phosphoric anhydride. Measure the resulting electric current, which is proportional to the water content in the test gas. (This is a self-calibrating system that obeys Faraday's law.)

Calculate the content of water; not more than 60μg/l.

B. Determine the content using a water vapour detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a suitable pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the water vapour detector tube to the metering pump according to the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and pump a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 60μl/l.

Acidity and alkalinity. Pass 2.0 litres of the test gas through a mixture of 0.10 ml of hydrochloric acid (0.01 mol/l) VS and 50 ml of carbon-dioxide-free water R.

For reference solution 1, use 50 ml of carbon-dioxide-free water R. For reference solution 2, use a mixture of 0.20 ml of hydrochloric acid (0.01 mol/l) VS and 50ml of carbon-dioxide-free water R.

To each solution add 0.1 ml of methyl red/ethanol TS; the intensity of the colour in the test gas solution is between that of reference solutions 1 and 2.

Assay. Determine as described under 1.14.5 Gas chromatography, using a stainless steel column (2m × 2mm) packed with silica gel for chromatography R (250-355μm). Maintain the column at 60 °C and the detector at 130°C. Use helium R as the carrier gas at a flow rate of 50 ml per minute, and a thermal conductivity detector.

Use the following gases: (1) the test gas; and (2) dinitrogen oxide R as the reference gas.

Inject a suitable volume of both gases (1) and (2). Adjust the volume, as well as the conditions specified above, to produce a peak response for dinitrogen oxide obtained with reference gas (2) that gives a height of not less than 35% on the recorder.

Measure the areas of the peak responses obtained in the chromatograms from the injections of gases (1) and (2), and calculate the percentage content of dinitrogen oxide.

Monographs: Pharmaceutical substances: Dinatrii edetas - Disodium edetate

2009-08-01T09:58:00.001-07:00

C10H14N2Na2O8,2H2O

Relative molecular mass. 372.2

Chemical name. Disodium dihydrogen (ethylenedinitrilo)tetraacetate dihydrate; N,N'-1,2-ethanediylbis[N-(carboxymethyl)glycine] disodium salt, dihydrate; CAS Reg. No. 6381-92-6.

Other name. Edetate disodium.

Description. A white, crystalline powder; odourless.

Solubility. Soluble in water; slightly soluble in ethanol (~750 g/l) TS; practically insoluble in ether R.

Category. Stabilizer; chelating agent.

Storage. Disodium edetate should be kept in a well-closed container.

Additional information. Solutions of disodium edetate should not come into contact with metal.

Requirements

Disodium edetate contains not less than 98.5% and not more than the equivalent of 101.0% of C10H14N2Na2O8,2H2O.

Identity tests

• Either test A alone or tests B, C, and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from disodium edetate R or with the reference spectrum of disodium edetate.

B. To 3 drops of ferric chloride (25 g/l) TS add 3 drops of ammonium thiocyanate (75 g/l) TS; to the deep red solution produced add 0.05 g of Disodium edetate; the colour is discharged, leaving a yellowish solution. (Keep this solution for test D.)

C. Dissolve 2 g in 25 ml of water, add 2 ml of lead nitrate (100 g/l) TS, shake, and add 6 ml of potassium iodide (80 g/l) TS; no yellow precipitate is observed.

D. To the solution from test B, add ammonia (~100 g/l) TS, drop by drop, until an alkaline reaction is obtained with pH-indicator paper R. Add 5 ml of ammonium oxalate (25 g/l) TS; no precipitate is produced (distinction from sodium calcium edetate).

Heavy metals. Use 1.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 20 μg/g.

pH value. pH of a 0.05 g/ml solution, 4.0-5.5.

Assay. Dissolve 0.5 g, accurately weighed, in sufficient water to produce 300 ml. Add 2 g of methenamine R and 2 ml of hydrochloric acid (~70 g/l) TS. Titrate with lead nitrate (0.1 mol/l) VS to which 50 mg of xylenol orange indicator mixture R has been added.

Each ml of lead nitrate (0.1 mol/l) VS is equivalent to 37.22 mg of C10H14N2Na2O8,2H2O.

Monographs: Pharmaceutical substances: Dimercaprolum - Dimercaprol

2009-08-01T09:55:00.000-07:00

Molecular formula. C3H8OS2

Relative molecular mass. 124.2

Graphic formula.

Chemical name. 2,3-Dimercapto-1-propanol; CAS Reg. No. 59-52-9.

Description. A clear, colourless or slightly yellow liquid, with an unpleasant, mercaptan-like odour.

Miscibility. Miscible with 20 parts of water; miscible with ethanol (~750 g/l) TS and methanol R.

Category. Antidote for arsenic, gold, and mercury poisoning.

Storage. Dimercaprol should be kept in a small, well-filled and tightly closed container, protected from light, and stored at a temperature not exceeding 5°C.

Requirements

Definition. Dimercaprol contains not less than 98.5% w/w and not more than 101.5% w/w of C3H8OS2.

Identity tests

A. Mix 0.05 ml of cobalt(II) chloride (30 g/l) TS with 5 ml of water and add 0.05 ml of the test liquid; a yellow-brown colour is produced.

B. Dissolve 0.1 ml in 4 ml of water and add a few drops of lead acetate (80 g/l) TS; a yellow precipitate is formed.

Refractive index. .

Relative density. .

Halides. Dissolve 2.0 g in 25 ml of potassium hydroxide/ethanol TS1 and heat under a reflux condenser for 2 hours. Evaporate the ethanol in a current of warm air, add 20 ml of water, and cool. Add a mixture of 10 ml of hydrogen peroxide (~330 g/l) TS and 40 ml of water, boil gently for 10 minutes, cool, and filter rapidly. Add 10 ml of nitric acid (~130 g/l) TS and 5 ml of silver nitrate (0.1 mol/l) VS and titrate with ammonium thiocyanate (0.1 mol/l) VS, using ferric ammonium sulfate (45 g/l) TS as indicator. Repeat the operation without the test liquid being examined. The difference between the titrations does not exceed 1.0 ml.

pH value. pH of a 0.5 g/ml solution in carbon-dioxide-free water R, 4.6-6.8.

Assay. Dissolve about 0.12 g, accurately weighed, in 20 ml of hydrochloric acid (0.1 mol/l) VS and titrate rapidly with iodine (0.05 mol/l) VS, using starch TS as indicator. Repeat the operation without the test liquid being examined and make any necessary corrections. Each ml of iodine (0.05 mol/l) VS is equivalent to 6.211 mg of C3H8OS2.

Additional requirement for Dimercaprol for parenteral use

Monographs: Pharmaceutical substances: Diloxanidi furoas - Diloxanide furoate

2009-08-01T09:52:00.000-07:00

Molecular formula. C₁₄H₁₁Cl₂NO₄

Relative molecular mass. 328.2

Graphic formula.

Chemical name.

2,2-Dichloro-4'-hydroxy-N-methylacetanilide 2-furoate (ester); 4-[(dichloroacetyl)methylamino]phenyl 2-furancarboxylate; 2,2-dichloro-N-(4-hydroxyphenyl)-N-methylacetamide 2-furoate; CAS Reg. No. 3736-81-0.

Description. A white or almost white, crystalline powder; odourless.

Solubility. Very slightly soluble in water; soluble in 100 parts of ethanol (~750 g/l) TS and in 130 parts of ether R.

Category. Antiamoebic drug.

Storage. Diloxanide furoate should be kept in a well-closed container, protected from light.

Requirements

Definition. Diloxanide furoate contains not less than 98.0% and not more than 102.0% of C₁₄H₁₁Cl₂NO₄, calculated with reference to the dried substance.

Identity tests

• Either test A alone or tests B and C may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from diloxanide furoate RS or with the reference spectrum of diloxanide furoate.

B. The absorption spectrum of a 7.0 μg/ml solution in ethanol (~750 g/l) TS, when observed between 240 nm and 350 nm, exhibits a maximum at about 258 nm; the absorbance of a 1-cm layer at this wavelength is about 0.49.

C. Carry out the combustion as described under 2.4 Oxygen flask method, using 20 mg of the test substance and 10 ml of sodium hydroxide (1 mol/l) VS as the absorbing liquid. When the process is complete, acidify with nitric acid (~130 g/l) TS; the solution yields reaction A, described under 2.1 General identification tests as characteristic of chlorides.

Melting range. 114-116 °C.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 5.0 mg/g.

Free acidity. Shake 3.0 g with 50 ml of carbon-dioxide-free water R, filter and wash the residue with 3 quantities, each of 20 ml of carbon-dioxide-free water R. Titrate the combined filtrate and washings with sodium hydroxide (0.1 mol/l) VS, phenolphthalein/ethanol TS being used as indicator; not more than 1.3 ml is required.

Related substances. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R2 as the coating substance and a mixture of 24 volumes of dichloromethane R and 1 volume of methanol R as the mobile phase. Apply separately to the plate 5 μl of each of 2 solutions in chloroform R containing (A) 0.10 g of the test substance per ml and (B) 2.5 mg of the test substance per ml. After removing the plate from the chromatographic chamber, allow it to dry in air and examine the chromatogram in ultraviolet light (254 nm). Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B.

Assay. Dissolve about 0.3 g, accurately weighed, in 50 ml of anhydrous pyridine R and titrate with tetrabutylammonium hydroxide (0.1 mol/l) VS determining the end-point potentiometrically as described under 2.6 Non-aqueous titration, Method B. Each ml of tetrabutylammonium hydroxide (0.1 mol/l) VS is equivalent to 32.82 mg of C₁₄H₁₁Cl₂NO₄.

Monographs: Pharmaceutical substances: Digitoxinum - Digitoxin

2009-08-01T09:48:00.001-07:00

Molecular formula. C₄₁H₆₄O₁₃

Relative molecular mass. 765.0

Graphic formula.

Chemical name.

3β-[(O-2,6-Dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribo-hexopyranosyl)-oxy]-14-hydroxy-5β-card-20(22)-enolide; CAS Reg. No. 71-63-6.

Description. A white or almost white, microcrystalline powder; odourless.

Solubility. Practically insoluble in water; slightly soluble in ethanol (~750 g/l) TS.

Category. Cardiotonic.

Storage. Digitoxin should be kept in a well-closed container, protected from light.

Additional information. CAUTION: Digitoxin is extremely poisonous and should be handled with care.

Requirements

Definition. Digitoxin contains not less than 95.0% and not more than 105.0% of C₄₁H₆₄O₁₃, calculated with reference to the dried substance.

Identity tests

• Either tests A, B and D or tests B, C and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from digitoxin RS or with the reference spectrum of digitoxin.

B. Carry out the test as described under 1.14.1 Thin-layer chromatography, using kieselguhr R1 as the coating substance and a mixture of 10 volumes of formamide R and 90 volumes of acetone R to impregnate the plate, dipping it about 5 mm beneath the surface of the liquid. After the solvent has reached a height of at least 15 cm, remove the plate from the chromatographic chamber and allow to stand for at least 5 minutes. Use the impregnated plate within 2 hours, carrying out the chromatography in the same direction as the impregnation. As the mobile phase, use a mixture of 50 volumes of xylene R, 50 volumes of ethylmethylketone R and 4 volumes of formamide R. Apply separately to the plate 3 μl of each of 2 solutions (A) of the test substance, and (B) of digitoxin RS, each prepared by dissolving 50 mg in a mixture of equal volumes of chloroform R and methanol R to produce 10 ml and then diluting 1 ml to 5 ml with methanol R. Develop the plate for a distance of 12 cm. After removing the plate from the chromatographic chamber, allow it to dry at 115 °C for 20 minutes, cool, spray with a mixture of 15 volumes of a solution of 25 g of trichloroacetic acid R in 100 ml of ethanol (~750 g/l) TS and 1 volume of a freshly prepared 30 mg/ml solution of tosylchloramide sodium R, and then heat the plate at 115°C for 5 minutes. Allow to cool, and examine the chromatogram in daylight and in ultraviolet light (365 nm). The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.

C. Dissolve 1 mg in 1 ml of ethanol (~750 g/l) TS by heating gently. Cool the solution and add 1 ml of dinitrobenzene/ethanol TS and 1 ml of potassium hydroxide (1 mol/l) VS; a violet colour develops and then fades.

D. Dissolve 1 mg in 2 ml of a solution prepared by mixing 0.5 ml of ferric chloride (25 g/l) TS and 100 ml of glacial acetic acid R; cautiously add 1 ml of sulfuric acid (~1760 g/l) TS to form a lower layer; a brown ring, but no red colour, is produced at the junction of the two liquids, and after some time the acetic acid layer acquires a blue colour (distinction from allied glycosides).

Specific optical rotation. Use a 10 mg/ml solution in chloroform R and calculate with reference to the dried substance;

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 20 mg/g.

Gitoxin. Dissolve about 5 mg, accurately weighed, in 1 ml of methanol R and dilute to 25 ml with a mixture of equal volumes of hydrochloric acid (~250 g/l) TS and glycerol R. Allow to stand for 1 hour. The absorbance of a 1-cm layer of this solution at 352 nm, when measured against a solvent cell containing a mixture of equal volumes of hydrochloric acid (~250 g/l) TS and glycerol R, is not more than 0.28 (preferably use 2-cm cells for the measurement and calculate the absorbance of a 1-cm layer); the gitoxin content is about 50 mg/g.

Assay. Dissolve about 0.05 g, accurately weighed, in sufficient methanol R to produce 25 ml; dilute 5.0 ml of this solution to 100 ml with methanol R. Place 5.0 ml of the dilute solution to be tested in a 25-ml volumetric flask, add 15 ml of alkaline trinitrophenol TS, and dilute to 25 ml with methanol R. Set aside for 30 minutes, protected from light, and measure the absorbance in a 1-cm layer at the maximum at about 490 nm against a solvent cell containing a solution prepared by diluting 15 ml of alkaline trinitrophenol TS to 25 ml with methanol R. Calculate the amount of C₄₁H₆₄O₁₃ in the substance being tested by comparison with digitoxin RS, similarly and concurrently examined.

Additional requirements for Digitoxin for parenteral use

Complies with the monograph for "Parenteral preparations".

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 111.0 IU of endotoxin RS per mg.

Monographs: Pharmaceutical substances: Digitoxinum - Digitoxin

2009-08-01T09:48:00.000-07:00

Molecular formula. C₄₁H₆₄O₁₃

Relative molecular mass. 765.0

Graphic formula.

Chemical name.

Description. A white or almost white, microcrystalline powder; odourless.

Solubility. Practically insoluble in water; slightly soluble in ethanol (~750 g/l) TS.

Category. Cardiotonic.

Storage. Digitoxin should be kept in a well-closed container, protected from light.

Additional information. CAUTION: Digitoxin is extremely poisonous and should be handled with care.

Requirements

Definition. Digitoxin contains not less than 95.0% and not more than 105.0% of C₄₁H₆₄O₁₃, calculated with reference to the dried substance.

Identity tests

• Either tests A, B and D or tests B, C and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from digitoxin RS or with the reference spectrum of digitoxin.

B. Carry out the test as described under 1.14.1 Thin-layer chromatography, using kieselguhr R1 as the coating substance and a mixture of 10 volumes of formamide R and 90 volumes of acetone R to impregnate the plate, dipping it about 5 mm beneath the surface of the liquid. After the solvent has reached a height of at least 15 cm, remove the plate from the chromatographic chamber and allow to stand for at least 5 minutes. Use the impregnated plate within 2 hours, carrying out the chromatography in the same direction as the impregnation. As the mobile phase, use a mixture of 50 volumes of xylene R, 50 volumes of ethylmethylketone R and 4 volumes of formamide R. Apply separately to the plate 3 μl of each of 2 solutions (A) of the test substance, and (B) of digitoxin RS, each prepared by dissolving 50 mg in a mixture of equal volumes of chloroform R and methanol R to produce 10 ml and then diluting 1 ml to 5 ml with methanol R. Develop the plate for a distance of 12 cm. After removing the plate from the chromatographic chamber, allow it to dry at 115 °C for 20 minutes, cool, spray with a mixture of 15 volumes of a solution of 25 g of trichloroacetic acid R in 100 ml of ethanol (~750 g/l) TS and 1 volume of a freshly prepared 30 mg/ml solution of tosylchloramide sodium R, and then heat the plate at 115°C for 5 minutes. Allow to cool, and examine the chromatogram in daylight and in ultraviolet light (365 nm). The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.

C. Dissolve 1 mg in 1 ml of ethanol (~750 g/l) TS by heating gently. Cool the solution and add 1 ml of dinitrobenzene/ethanol TS and 1 ml of potassium hydroxide (1 mol/l) VS; a violet colour develops and then fades.

D. Dissolve 1 mg in 2 ml of a solution prepared by mixing 0.5 ml of ferric chloride (25 g/l) TS and 100 ml of glacial acetic acid R; cautiously add 1 ml of sulfuric acid (~1760 g/l) TS to form a lower layer; a brown ring, but no red colour, is produced at the junction of the two liquids, and after some time the acetic acid layer acquires a blue colour (distinction from allied glycosides).

Specific optical rotation. Use a 10 mg/ml solution in chloroform R and calculate with reference to the dried substance;

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 20 mg/g.

Additional requirements for Digitoxin for parenteral use

Complies with the monograph for "Parenteral preparations".

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 111.0 IU of endotoxin RS per mg.

CMC Process testing

2009-07-31T08:57:00.000-07:00

The development of a pharmaceutical product requires a broad spectrum of scientific expertise to lead it through the complex pathway from discovery through characterization of quality, efficacy and safety, which are the hallmarks of a successful drug product. A company must be highly proactive in setting targets for appraising and selecting a compound that has the highest probability of success. In addition, the compound and its therapeutic use must be consistent with the research and marketing goals of the company in order to leverage existing resources and experience. To ensure scientific and commercial success, it is critical to understand the drug development process (Figure 1) and the myriad tasks and milestones that are vital to a comprehensive development plan.

Although the primary purpose of a well-designed pathway is to assure an efficient process for providing new, high quality and effective drugs for patients, it is also essential to effectively maximize the return on investment. In this context, some primary drivers contributing to maximizing return on investment include the cost of development, market price, product life cycle and competition (Table 1). Each step along the path from discovery to commercialization is important. However, if material cannot be manufactured, the drug development process cannot proceed. As a result, an effective chemistry, manufacturing and controls (CMC) process plays an integral role in the success of a therapeutic compound.

CMC Process
The ability to assure, over time, the physical and chemical properties of an active pharmaceutical ingredient, drug product or nutraceutical is critical for regulatory approval and therapeutic success. The CMC process is necessary for an efficient and comprehensive development strategy. The major challenges for the manufacturing and control component of drug development is to assure the chemical and physical properties of the compound and product are monitored at all critical phases of the pathway. This process matches the scientific and analytical tasks to the manufacturing and commercialization strategy (Table 2).

In recent years, the International Conference on Harmon-isation of Technical Requirements for Registration of Pharma-ceuticals for Human Use (ICH) has adopted scientific standards for quality control monitoring. These standards are the basis of most regulatory guidelines, including those published by the FDA. Key steps on the path include pharmaceutical analysis and stability studies that are required to determine and assure the identity, potency and purity of ingredients, as well as those formulated products. Stability testing facilitates the establishment of recommended storage conditions, determination of retest periods and definition of acceptable shelf life. These data play a key role in determining labeling requirements, as well as in the development and monitoring process.

A Continuous Process
Stability testing is performed on drug substances and products at various stages of product development (Table 3). In early stages, accelerated stability testing (at relatively high temperatures and/or humidities) is used as a "worst case" evaluation to determine what types of degradation products may be found after long-term storage. In preformulation studies, interactions between excipients and the drug substance are studied under stress conditions to access compatibility.

The design of a complete stability testing program for a drug or nutraceutical product is based upon an understanding of the behavior, properties and stability of the drug substance or active ingredient and the experience gained from preformulation studies and early clinical formulations. Products are analyzed at specific intervals to evaluate a variety of parameters, such as the identity of the active ingredient, potency, measurement of degradation products, dissolution time, physical properties and appearance. Samples from production lots of approved products are retained for stability testing and for comparison testing in the case of product failure. Testing of retained samples alongside returned samples is key to ascertaining whether the product failure was manufacturing or storage related.

The objective of analytical testing during preclinical evaluation and Phase I clinical development is to evaluate the stability of the investigational formulations used in initial clinical trials, to obtain information needed to develop a final formulation, and to select the most appropriate container and closure (e.g., compatibility studies of potential interactive effects between a drug substance and other components). Information from the experiments listed in Table 3 under Discovery to Phase I is summarized in the Investigational New Drug application (IND) with the initiation of Phase I clinical trials. When the delivery mechanism of the drug is an integral part of creating the therapeutic effect and must be used in the Phase I trials, formulation data, container closure data and corresponding short-term accelerated stability data should be included in the IND prior to Phase I trials.

Analysis studies on formulations should be underway by the end of Phase II and the stability protocol for study of both the drug substance and drug product should be defined. This will help assure that analytical chemistry data generated during Phase III are appropriate for submission. Prior to Phase I, stability of the drug substance and the formulation to be used must be evaluated. Impurities from the manufacturing and degradants that form are quantitated and tracked to ensure safety prior to moving into the Phase I clinical trials and continuity of material used for laboratory safety testing and clinical trials.

Stability testing done during Phase III studies focuses on testing final formulations in the proposed packaging produced at the manufacturing site. It is recommended that the stability protocol is defined prior to the initiation of Phase III studies. In this regard, consideration should be given to establish appropriate linkage between the non-clinical and clinical batches of the drug substance and drug product and those of the primary stability batches in support of the proposed expiration dating period. Factors to be considered include the source, quality and purity of various components of the drug product, manufacturing process and production facility for the drug substance and the drug product, as well as use of same containers. Data obtained on tests done under controlled conditions replicating conditions recommended for long-term storage and slightly elevated temperatures are used to determine a product's shelf life and expiration dates. In some cases, comprehensive stability testing must also be conducted after approval (Table 4).

A Focus on Stability
The stability of a product may be defined as the extent to which a product retains, within specified limits, throughout its period of storage and use, the same properties and characteristics possessed at the time of its packaging. Stability testing provides evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. These studies are designed to determine if a drug substance will remain within specifications during its shelf life if stored under recommended storage conditions.

Stability testing focuses on the chemical (i.e., integrity, potency, degradation) and physical properties (e.g., appearance, hardness, particle size, solubility) of active pharmaceutical ingredients (API) and products (Table 5). In addition, microbiological testing is done to ensure the substance and product maintain their resistance to microbial and bacterial growth. Assuring the physical/chemical properties and effectiveness properties of a pharmaceutical is critical for labeling and marketing purposes. A wide range of testing is used to evaluate and verify the identity, potency and availability of the API in the product (Table 6). Stability testing is done at all phases of the development, production and marketing process for quality control and monitoring purposes. A wide scope of analytical methodologies is used, including high-performance liquid, gas and thin-layer chromatography (HPLC, GC, TLC) as well as IR and LC/mass spectrometry.

Stability testing requires the use of specialized environmental chambers that can simulate long-term storage conditions. The stress conditions in the chambers include heat, humidity and light. These chambers enable researchers to evaluate product stability based on real-time, accelerated and long-term protocols and are available in both walk-in and reach-in styles. Chambers are engineered and qualified to ensure uniform exposure of the stress conditions to all material in the chamber. Early in the development of the drug product, purposeful degradation studies are done as a means to predict possible degradation pathways of an API. This information is used in the validation of stability indicating analytical methods and in pre-formulation studies. Degradation studies include stress conditions such as heat, oxidative, light, acidic conditions, basic conditions and heat/humidity.

Physical-Chemical Properties
The physical-chemical properties of the substance are analyzed to verify the identity/structure of the drug substance or product API. Many of these tests require specialized instrumentation and laboratory expertise. In addition, the organoleptic properties—including appearance, hardness and moisture—are evaluated. For quality control purposes, the potency, availability and microbial quality are monitored. All of these factors are key ingredients in stability evaluations.

Testing to assure that products meet specifications for the presence of degradation and impurities are usually intensive chromatographic separations with detection down to the 0.01% levels. Typically, impurities and degradation products that are 0.1% and above need to be evaluated for identity and chemical structure. The level of the impurities allowed depends on the toxicity of the impurity and the daily dose levels of the drug.

Identity information on the stability of a drug substance under defined storage conditions is an integral part of the systematic approach to stability evaluation. Stress testing helps to determine the intrinsic stability characteristics of a molecule by establishing degradation pathways to identify the likely degradation products and to validate the stability indicating power of the analytical procedures used.

Microbiological
Along with chemical and physical testing, a number of microbiological tests must be performed based on the dosage form. For sterile products, the microbiological tests performed include sterility, bioburden and bacterial endotoxins. These tests must be validated to show that the compendial tests are suitable. For example, to validate sterility, the test for bacteriostasis and fungistasis (BF) is performed at time of set down. The BF test ensures that any BF activity does not adversely affect the reliability of the sterility test. Bioburden requires validation to show that the test article will not adversely affect the growth of positive controls.

Non-sterile products have different testing requirements depending on if preservatives are used. Orally administered suspensions or liquids with a preservative are evaluated for microbial limits, total yeasts and molds and antimicrobial preservative effectiveness test. The variations of container closure systems will determine the frequency of testing during the stability study. For example, the sterility of a formulation in a sealed glass ampule need not be tested after sterility is established. For most container closure systems, microbiological testing is performed initially, at 12 months and annually thereafter. For accelerated conditions, testing is minimally performed at end of the storage time.

Stress Testing
The severe conditions encountered during distribution are covered by stress testing of definitive batches of the drug substance. Stress testing provides data on forced decomposition products and mechanisms. These studies establish the inherent stability characteristics of the molecule (e.g., degradation pathways) and lead to identification of degradation products and support the suitability of the proposed analytical procedures. The detailed nature of the studies will depend on the individual drug substance and type of drug product.

Testing is carried out on a single batch of a drug substance and includes the effects of temperatures in 10°C increments above the accelerated temperature test condition and humidity, where appropriate (e.g., 75 % or greater). In addition, one must evaluate oxidation and photolysis on the drug substance, plus its susceptibility to hydrolysis across a wide range of pH values when in solution or suspension.

Photostability (i.e., light) testing is an integral part of stress testing. Some degradation pathways can be complex and, under forced conditions, decomposition products may be observed that are unlikely to be formed under accelerated or long-term testing. This information is useful in developing and validating suitable analytical methods, but may not be necessary to examine specifically for all degradation products if it has been demonstrated that in practice these are not formed. Information obtained from photostability is key in choosing appropriate container/closure systems.

Dosage Form/Delivery System Requirements
The route of administration and delivery system used are key components to the successful development of new drugs and therapies. In addition, these choices have a significant impact on the scientific and regulatory aspects of a stability protocol. The diversity of testing needed for all dosage forms and delivery systems requires a broad range of expertise and methodologies.

In general, all dosage forms are evaluated for appearance, assay and degradation products. Additional tests (i.e., potency) are needed for specific dosage forms. For example, sterility is needed for sterile products but not for tablets or capsules. In addition, not every test will be performed at each time point.

The evaluation of inhalation powders includes aerodynamic particle size distribution of the emitted dose, microscopic evaluation, microbial limit, moisture content, foreign particulates, content uniformity of the emitted dose and number of medication doses per device that meets content uniformity of the emitted dose (metered dose products). The unique characteristics of metered-dose and dry-powder inhalers can affect the product's efficacy as well as the ability of the product to deliver reproducible doses. These factors must be considered during development with respect to formulation, stability, manufacturing, container and closure system and quality control (Table 7).

Stability data for products supplied in closed-end tubes should support the maximum anticipated use period after the tube seal is punctured, allowing product contact with the cap. Ointments, pastes, gels and creams in large containers, including tubes, should be assayed by sampling at the surface, top, middle and bottom of the container. In addition, tubes should be sampled near the crimp.

Evaluation of ophthalmic or optic products (e.g., creams, ointments, solutions and suspensions) includes sterility, particulate matter and extractables. Evaluation of nonmetered topical aerosols includes appearance, assay, degradation products, pressure, weight loss, net weight dispensed, delivery rate, microbial limits, spray pattern, water content and particle size distribution (for suspensions).

Studies of drugs for injection (i.e., parenterals) include monitoring for appearance, clarity, color, reconstitution time and residual moisture content. The stability of drug for injection products must also be evaluated after reconstitution, according to the recommended labeling. Small volume parenterals (SVPs) are a wide range of injection products (e.g., drugs for injection, drugs for injectable suspension and drugs for injectable emulsion). Large volume parenterals (LVPs) studies include evaluation of product stability following exposure to at least the maximum specified process lethality. Interaction of administration sets and dispensing devices are considered to ensure that absorption and adsorption during dwell time do not occur. In veterinary applications, some LVPs are designed for multiple use. These products are evaluated for stability after opening with part of the content removed. The "in-use" studies last from seven days to four weeks.

The functionality and integrity of parenterals in prefilled syringe delivery systems needs to be evaluated throughout the expiration dating period with regard to factors, such as the applied extrusion force, syringeability, pressure rating and leakage. Continued assurance of sterility for products is by a variety of means, including evaluation of the container and closure integrity.

Specific parameters to be examined for reconstituted drug products include appearance, clarity, color, pH, assay (i.e., potency), preservative, degradation products/aggregates, sterility, pyrogenicity and particulate matter. Studies for drug injectable suspension and drug for injectable suspension also include particle size distribution, redispersibility and rheological properties. The studies for drug injectable emulsion products also include phase separation, viscosity and mean size and distribution of dispersed phase globules.

When a drug product or dilutent is intended for use as an additive to another product, the potential for incompatibility exists. In these cases, the drug product labeled to be added to another (e.g., parenterals, inhalation solutions) should be evaluated for stability and compatibility in the mixture both in upright and inverted/on-the-side orientations. The tests should provide for tests to be conducted at appropriate time points over the intended use period at the recommended storage and use conditions.

Package Extraction and Migration
A widely overlooked factor in pharmaceutical analysis testing is the determination of potential impurities resulting from migration from packaging components. This includes testing for nitrosamine residue testing as well as both quantitative and qualitative techniques for nitrosamines and olefin polymers used in packages and closures. The 1998 draft stability guidance recommends performing extractable studies on the container/closure (C/C) system using sensitive and quantitative methods even if the C/C system meets compendial suitability tests. Concern over extractables/leachables from the C/C system depends on the route of administration and the likelihood of a packaging component-dosage form interaction. For example, routes of adminstration such as inhalation aerosals and injectables are of highest concern, whereas orally administered solid dosage forms are of lower priority.

An Integral Component
Although stability is an integral component of a CMC program, a comprehensive testing regimen includes a broad scope of analytical evaluations. The importance of assuring the physical and chemical properties throughout the development and commercialization of a compound is key to effectively managing resources and costs. The inclusion of a well-designed chemistry, manufacturing and controls process in the development pathway can help alleviate devastating pitfalls and facilitate a cost-effective process.

References

1. U.S. Department of Health and Human Services, "Guidance for Industry: Q1A Stability Testing of New Drug Substances and Products." Food and Drug Administration, August 2001.

2. International Conference on Harmonisation of Technical Requirements for Registration of Pharamceuticals for Human Use (ICH), "Stability Testing of New Drug Substances and Products (ICH Q1A)." ICH, September 1993.

3. Gallanger, Maxine M.; A Comparative Analysis of International Regulations and Guidances presented at PDA Scientific Forum: The Extractables Puzzle, November 2001

Excipient Quality in Pharmaceutical Development

2009-07-31T08:56:00.000-07:00

Understanding their functions benefits process control

By Lokesh Bhattacharyya, Ph.D.
US Pharmacopeia

Excipients interact with the actives in the final formulated dosage form and/or provide a matrix that affects the critical quality attributes of the actives, including stability and bioavailability.

Is compliance with compendial monographs sufficient for complete characterization of an excipient, particularly for understanding its processability?

Excipients are the materials (components)—other than the active ingredient(s)—intentionally incorporated into pharmaceutical dosage forms to play specific functional roles. Almost all pharmaceutical dosage forms include excipients. Indeed, in most dosage forms the amounts of one or more excipients are greater than the amounts of the active pharmaceutical ingredients (APIs) present in them. As with APIs, excipients are derived from natural sources, synthesized chemically, or prepared semisynthetically starting from a natural-sourced materials, and range from simple, usually well-characterized, organic or inorganic molecules to highly complex materials that are difficult to fully characterize.

Excipients play a wide variety of functional roles in pharmaceutical dosage forms, including:

• modulating solubility and bioavailability of APIs,

• increasing the stability of active ingredients in dosage forms,

• helping active ingredients maintain preferred polymorphic forms or conformations,

• maintaining the pH and/or osmolarity of liquid formulations,

• acting as antioxidants, emulsifying agents, aerosol propellants, tablet binders, and tablet disintegrants,

• preventing aggregation or dissociation (e.g., of protein and polysaccharide actives),

• modulating immunogenic responses of active ingredients (e.g., adjuvants), and more.

USP 29–NF 24 includes more than 40 functional categories of excipients in pharmaceuticals, and many more may be added over time to meet the needs of new drug delivery systems and biotechnology-derived products.1 The large number of functional categories represents the variety of applications of excipients in both pharmaceutical and biotechnological products.

More than 800 excipients are used currently in marketed pharmaceutical products in the U.S. This number is expected to grow rapidly as new drug delivery technologies are developed to address challenges of drug development such as poor solubility, permeability and bioavailability, along with the growth of the biotechnology industry, including gene and cell therapy products that have different drug delivery requirements compared to traditional small-molecule pharmaceuticals. Thus, there is a significant need to enhance awareness about new excipient development.

Excipient Selection and Use

An excipient is selected and used because it contributes one or more functional attributes to the product characteristics. The excipient interacts with the active in the final formulated dosage form and/or provides a matrix that affects the critical quality attributes of the actives, including stability and bioavailability. It follows logically that the quality of an excipient and its function play critical roles in the effectiveness, safety, potency, purity, and quality of a product. Thus, it is necessary to understand the function of an excipient in order to fully characterize, understand, and control the process as well as the product quality, particularly in the new era of Quality by Design.2 The lack of understanding of the function of an excipient may lead to a situation in which process control—and hence product quality—may be compromised, particularly when the impact of normal variation of the excipient quality on process control has not been established. The need for complete characterization of an excipient and understanding its functional role in the formulated product is far greater when the excipient is used in a more complex product, such as a monoclonal antibody, a vaccine, or a gene therapy/cell therapy product, or in a new/novel drug delivery system such as an inhalation product.

Excipients also influence the safety and effectiveness of drugs depending on the route of administration, so qualitative and quantitative understanding of the excipient’s composition is critically important to the understanding of a dosage form’s bioavailability and bio-equivalence. For orally administered dosage forms, excipients can affect safety and effectiveness outcomes by promoting or delaying gastrointestinal release. The same appears to be true also for certain injections, for which excipients can modify release patterns in much the same way they do for orally administered modified-release dosage forms. For locally acting products—topical applications, products for oral inhalation, nasal administrations, otic products, and ophthalmic dosage forms—excipients are also widely acknowledged to modify the effectiveness outcomes by influencing the pharmacodynamic properties of the actives. Adjuvants, which are excipients required for protein and conjugate vaccines, play a critical role in the immunologic characteristics of vaccines.

Because excipients can affect the safety and effectiveness of dosage forms, manufacturers should understand the functional contributions of the excipients, that is, their “processability.” Unless manufacturers have a good understanding of the processability of the excipients used in their products, it is difficult to see how the manufacturers can reliably demonstrate pharmaceutical equivalence among product(s) synthesized or perhaps formulated differently at different manufacturing sites, using excipients that possibly are sourced from different suppliers or vendors. Such excipients are likely to have been manufactured by different processes, with starting materials whose qualities may be different from and/or sourced differently than those referenced in the original New Drug Application (NDA). Thus, it is likely that the quality of the excipients used by different product manufacturers or at different manufacturing sites of the same product manufacturer may be different, particularly if the manufacturer engages in multisourcing. In the latter case, interchangeability of excipients cannot necessarily be taken for granted. These factors, together with the potential variation in equipment, processing operations, and personnel who may have different backgrounds, training, and levels of expertise, may present a complex multivariate situation that may render very difficult adequate control of the product quality. The variation could range from minor to significant depending upon the function of the excipient used in the product, excipient interaction with the actives(s), and the characteristics of the product, including its route of administration and other factors.

Legal Factors and Release Testing

The US Code of Federal Regulations (CFR) indicates the requirements for excipient (component) release testing in 21 CFR 211.84(6)(d)(2) as follows:

Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.

The second sentence of the CFR requirement above for release testing of excipients is clearly deficient in addressing excipient quality and processibility issues. The concept and the recognition of the need to understand the processability of an excipient and its relation to the quality of a product are relatively recent and require further discussion. In theory, an excipient manufacturer could perform suitable tests to demonstrate appropriate quality and processability of its excipients, provided the company knew the appropriate tests. However, it is not clear how excipient manufacturers would know what the appropriate tests should be, because the tests depend on the nature of the excipient, the characteristics of the active, nature of the product (e.g., solid, liquid, aerosol; therapeutic, prophylactic), the route of administration of the dosage form, and other factors.

In addition, it is conceivable that the same excipient may have different processabilities and functional contributions in different types of dosage forms. For example, the knowledge of the particle size distribution of lactose, a frequently used excipient, is critical for tablets but is unnecessary for an injectable product. Consequently, the tests that are appropriate for one type of product may not be appropriate for another type. For more common types of products (e.g., solid oral, parenteral), one solution to these quandaries is an excipient qualification agreement concluded between excipient vendors and manufacturers according to which vendors agree to make no process changes or other alterations that would affect the specifications of the finished excipient or its impurity profile, and/or to notify the manufacturer of such changes—or some variation of such agreements.

There is general agreement that if there is a pharmacopeial monograph (USP–NF, European Pharmacopoeia, and Japanese Pharmacopoeia) for an excipient, the tests described in the monograph should be performed. This is consistent with the CFR requirements mentioned above because the compendial monographs have written specifications for identity, purity, strength and quality. Therefore, it is critical to examine the roles and limitations of USP–NF (and other pharmacopeial) monographs in excipient testing. USP–NF standards are authoritative, science-based, and are established by a transparent and credible process with established integrity.3

The transparency and credibility of the monographs come from the open review and comment process that takes place when proposed monographs are published in Pharmacopeial Forum, USP’s bimonthly journal of standards development and compendial revision. Anyone interested can provide scientific and regulatory comments regarding the new monographs or revisions to existing monographs published in Pharmacopeial Forum. The quality standards and any public comments are evaluated by the members of the Expert Committees of the USP Council of Experts, who are unpaid volunteers and are recognized experts in their respective fields. Expert Committee members participate in the USP process as individual scientists and not as representatives of their employers or any trade association, thereby providing unbiased, authoritative, and science-based quality standards. Expert Committee members may agree with public comments regarding monographs published in Pharmacopeial Forum and may decide to revise and republish the monographs for further public review and comment. If the monograph is approved, it is published in and becomes official in USP–NF or in the next semiannual Supplement of USP–NF. Therefore, the quality values of monographs for excipients and other materials expressed in USP–NF are indisputable.

However, the question remains if compliance with compendial monographs is sufficient for complete characterization of an excipient, particularly for understanding its processability. This point is critical not only to their functionalities but also to the impurities that may be present in an excipient, which could under certain circumstances affect the quality, safety, and effectiveness of the dosage forms. An example may help clarify the point. A manufacturer changed the vendor of an excipient, and the product showed adverse reactions. However, the materials from both vendors complied with the USP–NF monograph of the excipient. Subsequent investigation showed that the impurity profiles of the excipients from two vendors were different.

Due considerations also need to be given to the concomitant components, i.e., the impurities that are necessary and desired components required to ensure the proper performance of an excipient in a drug formulation. The role and regulation of the concomitant components must be distinguished from other impurities, which are not intended to be present in the finished product, but are present because it is not possible, and often not necessary, in practice to remove them completely through the manufacturing process steps.

The previous example clearly illustrates the need for characterization and qualification of excipients, including evaluation of the processability. A USP–NF monograph, however authoritative and science-based, does not (and cannot) provide any information about the processability of an excipient. Processability depends on the nature of the active and its interaction with the excipient, the manufacturing process, and the route of administration of the dosage form. Neither USP–NF nor any other pharmacopeia has any knowledge of the manufacturing process used by a manufacturer. Furthermore, different manufacturers may use the same excipient to manufacture different dosage forms, so the processability of the excipient may be different.

Thus, the excipient user (product manufacturer) should develop a comprehensive and scientifically sound excipient characterization/qualification program to ensure purity, quality, strength, consistency, suitability, safety, traceability, and processability of the excipient. Although USP–NF monographs ensure purity, quality, strength, consistency, and freedom from bacteria, fungi, mycoplasma, and certain other adventitious agents, they do not ensure the processability and safety of the excipients, and their contributions to the effectiveness of drug products.

At present new excipients are allowed for use either as a part of an NDA process or via adoption of Generally Recognized as Safe (GRAS) status. Excipient standards are set by regional organizations such as USP, EP, and JP. The subtle differences in the requirements of the individual standards have resulted in added challenges for excipient manufacturers. Because the excipient supply chain is global and somewhat less regulated than that for finished pharmaceuticals, the increasing awareness of bioterrorism caused by product tampering has also enhanced the need for guidance for excipient manufacturing and supply chain control.

All these concerns have resulted in a strong need for additional information and guidelines (or guidances) about the development, characterization, and qualification of new excipients and new applications of current excipients. The importance of regulatory guidance for excipients is a concept that has emerged only in recent years. Hence very few standards (or guidances) are available that treat the subject in the manner outlined here. The pharmacopeias (USP, EP, and JP) and International Pharmaceutical Excipient Council (IPEC) have spearheaded some efforts to develop and harmonize the standards, as well as provide guidelines on good manufacturing and distribution practices for excipients.4 However, additional efforts are necessary to develop comprehensive and authoritative standards (or guidances) to promote innovation in the area of excipients, to improve understanding of the importance of excipients, and to forge new avenues for global regulatory review and approval. The pharmaceutical industry is globalizing. With the development of new concepts and new approaches to drugs and drug-delivery technologies, such standards (and guidances) are critical to the development of new excipients, sustaining excipient quality standards, and safe and optimum use of excipients in diverse types of drugs.

Acknowledgment

The author would like to thank Stefan Schuber, Ph.D., director of scientific reports at USP, for his editorial contributions to this paper.

References

1. United States Pharmacopeial Convention. USP 29–NF 24. Rockville, MD: United States Pharmacopeial Convention, Inc.; 2006.

2. Hussain, AS. Engineering a proactive decision system for pharmaceutical quality: integrating science of design, process analytical technology, and quality system. Available at: www.fda.gov/cder/OPS/hussain_1_2005.pdf. Accessed March 29, 2006.

3. Bhattacharyya, L. et al. The value of USP public standards for therapeutic products. Pharm. Res. 2004;21:1725–1731.

Infrared reference spectra: Amoxicillin trihydrate (RS006)

2009-07-31T01:30:00.001-07:00

Instrument: Fourier Transform
Phase: Potassium bromide disc

Infrared reference spectra: Amodiaquine hydrochloride (RS005)

2009-07-31T01:29:00.002-07:00

Instrument: Fourier Transform
Phase: Potassium bromide disc

Infrared reference spectra: Amitriptyline hydrochloride (RS004)

2009-07-31T01:29:00.001-07:00

Instrument: Fourier Transform
Phase: Potassium bromide disc

Infrared reference spectra: Amidotrizoic acid (RS003)

2009-07-31T01:28:00.002-07:00

Instrument: Fourier Transform
Phase: Potassium bromide disc

Infrared reference spectra: Allopurinol (RS002)

2009-07-31T01:28:00.001-07:00

Instrument: Fourier Transform
Phase: Potassium bromide disc

Infrared reference spectra: Acetazolamide (RS001)

2009-07-31T01:26:00.004-07:00

Instrument: Fourier Transform
Phase: Potassium bromide disc

Monographs: Pharmaceutical substances: Diethyltoluamidum - Diethyltoluamide

2009-07-31T01:26:00.003-07:00

C₁₂H₁₇NO

Relative molecular mass. 191.3

Chemical name. N,N-Diethyl-m-toluamide; N,N-diethyl-3-methylbenzamide; CAS Reg. No. 134-62-3.

Description. Colourless or faintly yellow liquid.

Solubility. Practically immiscible in water and glycerol R; miscible with ethanol (~750 g/l) TS and ether R.

Category. Insect repellent.

Storage. Diethyltoluamide should be kept in a tightly closed container.

Additional information. CAUTION: Diethyltoluamide is an irritant to eyes and mucous membranes.

Requirements

Diethyltoluamide contains not less than 97.0% and not more than 103.0% of C₁₂H₁₇NO, calculated with reference to the anhydrous substance.

Identity tests

• Either test A alone or tests B, C, and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from diethyltoluamide RS or with the reference spectrum of diethyltoluamide.

B. Refractive index,

C. To about 2 ml, add 25 ml of hydrochloric acid (~250 g/l) TS and heat under a reflux condenser for 1 hour. Neutralize the solution with sodium hydroxide (~200 g/l) TS, cool, and extract with three quantities, each of 30 ml, of ether R. (Keep the aqueous layer for test D.) Carefully evaporate the ether layer to dryness on a water-bath, and dissolve the residue in 5ml of sodium nitrite (100 g/l) TS. Allow to stand at 5 °C for 10 minutes, add 10 ml of water, and extract with 20 ml of ether R. Evaporate the ether layer and add to the residue 1.0 g of phenol R. Cool and add about 1 ml of sulfuric acid (~1760 g/l) TS; an intense green solution is produced. Pour the mixture into water; the colour turns to red. Add sodium hydroxide (~80 g/l) TS; the colour changes to green.

D. Acidify the aqueous layer obtained in test C with hydrochloric acid (~70 g/l) TS, extract with two quantities, each of 20 ml of ether R, and carefully evaporate the ether layer. Dry the residue at 60 °C; the melting temperature of the residue is about 108 °C.

Mass density. ρ₂₀ = 0.996-1.002.

Sulfated ash. Not more than 1.0 mg/g.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 0.5 g of the substance; the water content is not more than 5.0 mg/g.

Acidity. Dissolve 10.0 g in 50 ml of neutralized ethanol TS, titrate with sodium hydroxide (0.01 mol/l) VS using phenolphthalein/ethanol TS as indicator; not more than 4.0 ml of sodium hydroxide (0.01 mol/l) VS is required to obtain the midpoint of the indicator (pink).

Assay. Carry out Method A as described under 2.10 Determination of nitrogen, using about 0.3 g, accurately weighed, and 7 ml of nitrogen-free sulfuric acid (~1760 g/l) TS, and proceed with the distillation. Titrate with sulfuric acid (0.05 mol/l) VS using methyl red/ethanol TS as indicator. Repeat the procedure without the Diethyltoluamide being examined and make any necessary corrections.

Each ml of sulfuric acid (0.05 mol/l) VS is equivalent to 19.13mg of C₁₂H₁₇NO.

Monographs: Pharmaceutical substances: Diethylcarbamazini dihydrogenocitras - Diethylcarbamazine dihydrogen citrate

2009-07-31T01:26:00.001-07:00

Molecular formula. C₁₀H₂₁N₃O,C₆H₈O₇ or C₁₆H₂₉N₃O₈

Relative molecular mass. 391.4

Graphic formula.

Chemical name. N,N-Diethyl-4-methyl-1-piperazinecarboxamide citrate (1:1); N,N-diethyl-4-methyl-1-piperazinecarboxamide 2-hydroxy-1,2,3-propanetricarboxylate (1:1); CAS Reg. No. 1642-54-2.

Description. A white, crystalline powder; odourless or almost odourless.

Solubility. Very soluble in water; soluble in 35 parts of ethanol (~750 g/l) TS; practically insoluble in ether R.

Category. Filaricide.

Storage. Diethylcarbamazine dihydrogen citrate should be kept in a tightly closed container, protected from light.

Additional information. Diethylcarbamazine dihydrogen citrate is hygroscopic; it has an acid and bitter taste. Even in the absence of light, Diethylcarbamazine dihydrogen citrate is gradually degraded on exposure to a humid atmosphere, the decomposition being faster at higher temperatures.

Requirements

Definition. Diethylcarbamazine dihydrogen citrate contains not less than 98.0% and not more than 101.0% of C₁₀H₂₁N₃O,C₆H₈O₇, calculated with reference to the anhydrous substance.

Identity tests

• Either tests A and D or tests B and C may be applied.

A. Dissolve 0.05 g in 25 ml of water. Add 1 ml of sodium hydroxide (~80 g/l) TS and 4 ml of carbon disulfide R, and shake for 2 minutes. Separate the aqueous layer. Centrifuge the lower layer if necessary, and filter through a dry filter, collecting the filtrate in a small flask provided with a glass stopper. Carry out the examination of the filtered solution using carbon disulfide R as the blank as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from diethylcarbamazine dihydrogen citrate RS treated similarly or with the reference spectrum of diethylcarbamazine base.

B. Dissolve 0.5 g in 10 ml of water, add 10 ml of sodium hydroxide (1 mol/l)VS, and extract with 4 successive quantities, each of 5 ml of chloroform R. Retain the aqueous layer for test C. Wash the combined chloroform extracts with water, filter through a plug of cotton wool, and evaporate the chloroform. Add 1 ml of ethyl iodide R to the residue, and heat gently under a reflux condenser for 5 minutes. Cool, separate the viscous yellow oil, and dissolve it in ethanol (~750 g/l) TS. Add, with continuous stirring, sufficient ether R to precipitate the quaternary ammonium salt, and filter. Dissolve the precipitate in ethanol (~750 g/l) TS, reprecipitate with ether R, and dry at 105°C; melting temperature, about 152°C (1-diethylcarbamoyl-4-methylpiperazine ethiodide).

C. The aqueous layer from test B yields reaction B described under 2.1 General identification tests as characteristic of citrates.

D. Melting temperature, after drying at 80°C, about 137°C.

Heavy metals. Use 1.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 1; determine the heavy metals content according to Method A; not more than 20 μg/g.

Sulfated ash. Not more than 1.0 mg/g.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 1 g of the substance; the water content is not more than 10 mg/g.

pH value. pH of a 30 mg/ml solution, 3.5-4.5.

N -Methylpiperazine. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R1 as the coating substance and a mixture of 6 volumes of ethanol (~750 g/l) TS, 3 volumes of glacial acetic acid R and 1 volume of water as the mobile phase. Apply separately to the plate 5 μl of each of 2 solutions in methanol R containing (A) 50 mg of the test substance per ml and (B) 0.050 mg of N-methylpiperazine R per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, spray with a mixture of 3 volumes of platinic chloride (60 g/l) TS, 97 volumes of water and 100 volumes of potassium iodide (60 g/l) TS, and examine the chromatogram in daylight. The spot obtained with solution B is more intense than any spot, corresponding in position and appearance, obtained with solution A.

Assay. Dissolve about 0.35 g, accurately weighed, in 30 ml of glacial acetic acid R1, and titrate with perchloric acid (0.1 mol/l) VS as described under 2.6 Non-aqueous titration, Method A. Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 39.14 mg of C₁₀H₂₁N₃O,C₆H₈O₇.

Monographs: Pharmaceutical substances: Didanosinum - Didanosine

2009-07-31T01:25:00.000-07:00

C₁₀H₁₂N₄O₃

Relative molecular mass. 236.2

Chemical name. 9-[(2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1,9-dihydro-6H-purin-6-one; 9-(2,3-dideoxy-β-D-glycero-pentofuranosyl)-1,9-dihydro-6H-purin-6-one; 2',3'-dideoxyinosine (DDI); CAS Reg. No. 69655-05-6.

Description. A white to almost white powder.

Solubility. Sparingly soluble in water; slightly soluble in methanol R and ethanol (95 per cent) R

Category. Antiretroviral (Nucleoside Reverse Transcriptase Inhibitor).

Storage. Didanosine should be kept in a tightly closed container.

Requirements

Didanosine contains not less than 98.5% and not more than 101.0% of C₁₀H₁₂N₄O_3,calculated with reference to the dried substance.

Identity test

• Either tests A and B, or test C may be applied.

A. Carry out test A.1. or, where UV detection is not available, test A.2.

A.1. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 67 volumes of dichloromethane R, 20 volumes of acetonitrile R, 10 volumes of methanol R and 3 volumes of ammonia (~260 g/l) TS as the mobile phase. Apply separately to the plate 5 μl of each of 2 solutions in methanol containing (A) 5 mg of the test substance per ml and (B) 5 mg of didanosine RS per ml. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air. Examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.

A.2. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R5 as the coating substance and a mixture of 67 volumes of dichloromethane R, 20 volumes of acetonitrile R, 10 volumes of methanol R and 3 volumes of ammonia (~260 g/l) TS as the mobile phase. Apply separately to the plate 5 μl of each of 2 solutions in methanol containing (A) 5 mg of the test substance per ml and (B) 5 mg of didanosine RS per ml. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air. Spray with vanillin/sulfuric acid TS1. Heat the plate for a few minutes at 120°C. Examine the chromatogram in daylight.

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.

B. The absorption spectrum of a 10 μg/ml solution in methanol R, when observed between 210 nm and 300 nm, exhibits one maximum at about 250 nm; the specific absorbance () is between 435 to 485.

C. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from didanosine RS or with the reference spectrum of didanosine.

If the spectra are not concordant, use didanosine RS. Dissolve the sample in a small amount of methanol R, evaporate to dryness and carry out the IR spectrum with the residue as mentioned above. Treat didanosine RS in the same way. The infrared absorption spectrum is concordant with the spectrum obtained from didanosine RS.

Specific optical rotation. Use a 10 mg/ml solution and calculate with reference to the dried substance; .

Heavy metals. Use 1.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 20 μg/g.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry for 4 hours at 105°C; it loses not more than 5.0 mg/g.

Related substances

Prepare fresh solutions and perform the tests without delay.

Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25cm x 4.6mm), packed with octadecylsilyl base-deactivated silica gel for chromatography R (5μm).

Maintain the column temperature at 20 - 25°C.

The mobile phases for gradient elution consist of a mixture of aqueous phase (Mobile phase A) and methanol (Mobile phase B), using the following conditions:

Mobile phase A: A 0.05 M solution of ammonium acetate R adjusted to pH 8.0 using ammonia (~100 g/l) TS.

Mobile phase B: Methanol R.

Time (min)	Mobile phase A (% v/v)	Mobile phase B (% v/v)
0	92	8
18	92	8
25	70	30
45	70	30
50	92	8
60	92	8

Prepare the following solutions in a mixture of 92 volumes of mobile phase A and 8 volumes of mobile phase B (dissolution solvent).

For solution (1) dissolve 5.0 mg of hypoxanthine R in the dissolution solvent and dilute to 100.0 ml with the same solvent. Dilute 1.0 ml to 20.0 ml with the same solvent. For solution (2) dissolve 5 mg of didanosine for system suitability RS (containing impurities A to F) in the dissolution solvent and dilute to 10 ml with the same solvent. For solution (3) dissolve 25 mg of the test substance in the dissolution solvent and dilute to 50.0 ml with the same solvent. For solution (4) dilute 5.0 ml of solution (3) to 50.0 ml with the dissolution solvent. Then dilute 5.0 ml of this solution to 50.0 ml with the same solvent.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of about 254 nm.

Use the chromatogram supplied with didanosine for system suitability RS and the chromatogram obtained with solution (2) to identify the peaks due to impurities A to F.

Inject 20μl of solution (2). The test is not valid unless the resolution factor between the peaks due to impurity (C) (2'-deoxyinosine) and impurity D (3'-deoxyinosine) is greater than 2.5, if necessary reduce the amount of methanol in the mobile phase and adjust the proportion of aqueous phase pH 8.0 accordingly.

Inject separately 20μl of solution (4) in replicate injections in the chromatographic system. The relative standard deviation for peak areas of didanosine in replicate injections of solution (4) is not more than 5.0%.

Inject separately 20μl each of solutions (1) and (3) and 20ml of dissolution solvent in the chromatographic system. Examine the mobile phase chromatogram for any extraneous peaks and disregard the corresponding peaks observed in the chromatogram obtained with solution (3).

In the chromatogram obtained with solution (2), the following peaks are eluted at the following relative retention with reference to didanosine (retention time about 13-15 min): impurity A about 0.3; impurity B about 0.4; impurity C about 0.44; impurity D about 0.48; impurity E about 0.5; impurity F about 0.8; impurity I about 1.4; impurity G about 1.6; impurity H about 2.0.

In the chromatogram obtained with solution (3) the area of any peak corresponding to impurity A (hypoxanthine) is not greater than the area of the principal peak obtained with solution (1) (0.5%). The area of any individual peak corresponding to impurities B, C, D, E, F or G is not greater than 0.2 times the area of the principal peak obtained with solution (4) (0.2%). The area of any other impurity peak is not greater than 0.1 times the area of the principal peak obtained with solution (4) (0.1%). The sum of the areas of all peaks, other than the principal peak, is not greater than the area of the principal peak obtained with solution (4) (1.0%). Disregard any peak with an area less than 0.05 times the area of the principal peak obtained with solution (4) (0.05%).

Assay

Dissolve about 0.200 g, accurately weighed, in 50 ml of glacial acetic acid R1 and titrate with perchloric acid (0.1 mol/l) VS as described under 2.6 Non-aqueous titration; Method A determining the end point potentiometrically.

Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 23.62 mg of C₁₀H₁₂N₄O₃.

Impurities

The following list of known and potential impurities that have been shown to be controlled by the tests in this monograph is given for information.

A. 1,7-dihydro-6H-purin-6-one (hypoxanthine)

B. R1 = R2 = OH, R3 = H

9-β-D-ribofuranosyl-1,9-dihydro-6H-purin-6-one (inosine)

C. R1 = R3 = H, R2 = OH

9-(2-deoxy-β-D-erythro-pentofuranosyl)-1,9-dihydro-6H-purin-6-one (2'-deoxyinosine)

D. R1 = OH, R2 = R3 = H

9-(3-deoxy-β-D-erythro-pentofuranosyl)-1,9-dihydro-6H-purin-6-one (3'-deoxyinosine)

E. R1 + R2 = O, R3 = H

9-(2,3-anhydro-β-D-ribofuranosyl)-1,9-dihydro-6H-purin-6-one (2',3'-anhydroinosine)

F. R = H

9-(2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl]-1,9-dihydro-6H-purin-6-one; (2',3'-didehydro-2',3'-dideoxyinosine)

G. R = OH

9-(2,3-dideoxy-β-D-glycero-pentofuranosyl)-9H-purin-6-amine (2',3'-dideoxyadenosine)

H. R = H

9-(2,3,5-trideoxy-β-D-glycero-pentofuranosyl)-9H-purin-6-amine (2',3',5'-trideoxyadenosine)

I. 9-(2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)-9H-purin-6-amine (2',3'-dideoxy-2',3'-didehydroadenosine)

J. structure as shown for impurities B to E where R1= R2 = H, R3 = CO-CH₃

9-(5-O-acetyl-2,3-dideoxy-β-D-glycero-pentofuranosyl)-1,9-dihydro-6H-purin-6-one (didanosine acetate)

K. structure as shown for impurity F where R = CO-CH₃

9-(5-O-acetyl-2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)-1,9-dihydro-6H-purin-6-one (2',3'-didehydrodidanosine acetate)

L.9-[2,3-O-[(1RS)-1-methoxyethylene]-β-D-ribofuranosyl]-1,9-dihydro-6H-purin-6-one (2',3'-O-(1-methoxyethylidene)inosine;("dioxalane")

M. mixture of 9-(3,5-di-O-acetyl-2-bromo-2-deoxy-β-D-arabinofuranosyl)-1,9-dihydro-6H-purin-6-one and 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)-1,9-dihydro-6H-purin-6-one ("bromoesters")

Monographs: Pharmaceutical substances: Dicoumarolum - Dicoumarol

2009-07-31T01:24:00.002-07:00

Molecular formula. C₁₉H₁₂O₆

Relative molecular mass. 336.3

Graphic formula.

Chemical name. 3,3'-Methylenebis[4-hydroxycoumarin]; 3,3'-methylenebis[4-hydroxy-2H-1-benzopyran-2-one]; CAS Reg. No. 66-76-2.

Description. A white or creamy white, crystalline powder; odour, characteristic, faint.

Solubility. Practically insoluble in water, ethanol (~750 g/l) TS and ether R.

Category. Anticoagulant.

Storage. Dicoumarol should be kept in a well-closed container, protected from light.

Requirements

Definition. Dicoumarol contains not less than 98.5% and not more than 101.0% of C₁₉H₁₂O₆, calculated with reference to the dried substance.

Identity tests

• Either test A alone or tests B and C may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from dicoumarol RS or with the reference spectrum of dicoumarol.

B. Fuse 0.2 g with 0.2 g of potassium hydroxide R, cool, stir with 5 ml of water, filter and acidify the filtrate with hydrochloric acid (~250 g/l) TS; a white, crystalline precipitate is obtained (salicylic acid). Retain the filtrate for test C.

C. To 1 ml of the filtrate from test B add 5 ml of water and a mixture of 1 drop of ferric chloride (25 g/l) TS and 2 drops of hydrochloric acid (~70 g/l) TS; a violet colour is produced.

Sulfated ash. Not more than 2.5 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 5.0 mg/g.

Acidity. Shake 0.5 g with 10 ml of carbon-dioxide-free water R for 1 minute and filter; titrate the filtrate with sodium hydroxide (0.1 mol/l) VS, methyl red/ethanol TS being used as indicator; not more than 0.1 ml is required to obtain the midpoint of the indicator (orange).

Assay. Dissolve about 0.35 g, accurately weighed, in 40 ml of 1-butylamine R, add 5 drops of azo violet TS and titrate with lithium methoxide (0.1 mol/l) VS to a deep-blue end-point, as described under 2.6 Non-aqueous titration, Method B. Each ml of lithium methoxide (0.1 mol/l) VS is equivalent to 16.82 mg of C₁₉H₁₂O₆.

Monographs: Pharmaceutical substances: Dicloxacillinum natricum - Dicloxacillin sodium

2009-07-31T01:24:00.001-07:00

Molecular formula. C₁₉H₁₆Cl₂N₃NaO₅S,H₂O

Relative molecular mass. 510.3

Graphic formula.

Chemical name. Monosodium (2S,5R,6R)-6-[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarboxamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate monohydrate; monosodium [2S-(2α,5α,6β)]-6-[[[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl]carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate monohydrate; monosodium [3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl]penicillin monohydrate; CAS Reg. No. 13412-64-1 (monohydrate).

Description. A white or almost white, crystalline powder.

Solubility. Freely soluble in water and methanol R; soluble in ethanol (~750 g/l) TS.

Category. Antibacterial drug.

Storage. Dicloxacillin sodium should be kept in a tightly closed container, protected from light.

Additional information. Even in the absence of light, Dicloxacillin sodium is gradually degraded on exposure to a humid atmosphere, the decomposition being faster at higher temperatures.

Requirements

Definition. Dicloxacillin sodium contains not less than 88.0% of total penicillins calculated as dicloxacillin free acid (C₁₉H₁₇Cl₂N₃O₅S) and with reference to the anhydrous substance.

Identity tests

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from dicloxacillin sodium RS or with the reference spectrum of dicloxacillin sodium.

B. To 10 mg of paraformaldehyde R dissolved in 1 ml of sulfuric acid (~1760 g/l) TS add about 1 mg of the test substance; a colourless solution is produced. Heat the solution in a water-bath for 2 minutes and cool; the solution remains colourless (distinction from cloxacillin sodium).

C. Ignite 20 mg and dissolve the residue in acetic acid (~60 g/l) TS. The solution yields reaction B described under 2.1 General identification tests as characteristic of sodium.

Specific optical rotation. Use a 10 mg/ml solution, and calculate with reference to the anhydrous substance; .

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 0.25 g of the substance; the water content is not less than 30 mg/g and not more than 50 mg/g.

pH value. pH of a 10 mg/ml solution, 4.5-7.5.

Chlorine. Carry out the combustion as described under 2.4 Oxygen flask method, but using 25 mg of the test substance and 10 ml of sodium hydroxide (0.1 mol/l) VS as the absorbing liquid. When the process is complete, transfer the resulting solution to a titration vessel, heat on a water-bath for 30 minutes, cool to room temperature, add 20 ml of nitric acid (~130 g/l) TS, and titrate with silver nitrate (0.01 mol/l) VS, determining the end-point potentiometrically using a silver/silver chloride electrode system. Repeat the operation without the substance being tested. Each ml of silver nitrate (0.01 mol/l) VS is equivalent to 0.3546 mg of Cl. Calculate the total content of chlorine in mg/g and subtract from it the content of free chlorides as determined below; the content of chlorine is between 130 mg/g and 142 mg/g.

Free chlorides. Dissolve about 0.12 g, accurately weighed, in 10 ml of sodium hydroxide (0.1 mol/l) VS, add 20 ml of water, and heat on a water-bath for 30 minutes. Cool to room temperature, add 20 ml of nitric acid (~130 g/l) TS, and titrate with silver nitrate (0.01 mol/l) VS, determining the end-point potentiometrically using a silver/silver chloride electrode system. Repeat the operation without the substance being tested. Each ml of silver nitrate (0.01 mol/l) VS is equivalent to 0.3546 mg of Cl; the content of free chlorides is not more than 5 mg/g.

Assay. Dissolve about 50 mg, accurately weighed, in sufficient water to produce 1000 ml. Transfer two 2.0-ml aliquots of this solution into separate stoppered tubes. To one tube add 10.0 ml of imidazole/mercuric chloride TS, mix, stopper the tube and place in a water-bath at 60 °C for exactly 25 minutes. Cool the tube rapidly to 20 °C (solution A). To the second tube add 10.0 ml of water and mix (solution B).

Without delay measure the absorbance of a 1-cm layer at the maximum at about 343 nm against a solvent cell containing a mixture of 2.0 ml of water and 10.0 ml of imidazole/mercuric chloride TS for solution A and water for solution B.

From the difference between the absorbance of solution A and that of solution B, calculate the amount of C₁₉H₁₆Cl₂N₃NaO₅S in the substance being tested by comparison with dicloxacillin sodium RS, similarly and concurrently examined.

Monographs: Pharmaceutical substances: Diazoxidum - Diazoxide

2009-07-31T01:23:00.000-07:00

Molecular formula. C₈H₇ClN₂O₂S

Relative molecular mass. 230.7

Graphic formula.

Chemical name. 7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide; CAS Reg. No. 364-98-7.

Description. A white, or almost white, crystalline powder; odourless.

Solubility. Practically insoluble in water and ether R; freely soluble in dimethylformamide R; slightly soluble in ethanol (~750 g/l) TS.

Category. Antihypertensive.

Storage. Diazoxide should be kept in a well-closed container.

Requirements

Definition. Diazoxide contains not less than 98.0% and not more than 101.0% of C₈H₇ClN₂O₂S, calculated with reference to the dried substance.

Identity tests

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from diazoxide RS or with the reference spectrum of diazoxide.

B. See the test described below under "Related substances". The principal spot obtained with solution B corresponds in position, appearance, and intensity with that obtained with solution C.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 5.0 mg/g.

Related substances. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R2 as the coating substance and a mixture of 17 volumes of ethyl acetate R, 4 volumes of methanol R, and 3 volumes of ammonia (~260 g/l) TS as the mobile phase. Apply separately to the plate 10 μl of each of 3 solutions in sodium hydroxide (0.1 mol/l) VS containing (A) 15 mg of the test substance per ml, (B) 0.15 mg of the test substance per ml and (C) 0.15 mg of diazoxide RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air until the odour of ammonia is no longer detectable, and examine the chromatogram in ultraviolet light (254 nm). Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B.

Assay. Dissolve 0.45 g, accurately weighed, in 100 ml of a mixture of 2 volumes of dimethylformamide R and 1 volume of water, and titrate with sodium hydroxide (0.1 mol/l) VS, determining the end-point potentiometrically. Each ml of sodium hydroxide (0.1 mol/l) VS is equivalent to 23.07 mg of C₈H₇ClN₂O₂S.

Monographs: Pharmaceutical substances: Diazepamum - Diazepam

2009-07-31T01:22:00.000-07:00

Molecular formula. C₁₆H₁₃ClN₂O

Relative molecular mass. 284.7

Graphic formula.

Chemical name. 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; CAS Reg. No. 439-14-5.

Description. A white or almost white, crystalline powder; odourless or almost odourless.

Solubility. Very slightly soluble in water; soluble in ethanol (~750 g/l) TS.

Category. Tranquillizer.

Storage. Diazepam should be kept in a well-closed container, protected from light.

Requirements

Definition. Diazepam contains not less than 99.0% and not more than 101.0% of C₁₆H₁₃ClN₂O, calculated with reference to the dried substance.

Identity tests

• Either tests A and D or tests B, C and D may be applied.

• For tests B and C use low-actinic glassware and measure within 30 minutes.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the reference spectrum of diazepam.

B. The absorption spectrum of an 8.0 μg/ml solution in hydrochloric acid (0.1 mol/l) VS, when observed between 230 nm and 350 nm, exhibits maxima at about 241 nm and 286 nm; the absorbances of a 1-cm layer at the maximum wavelengths of 241 nm and 286 nm are about 0.80 and 0.38, respectively (preferably use 2-cm cells for the measurements and calculate the absorbances for 1-cm layers).

C. The absorption spectrum of a 0.030 mg/ml solution in hydrochloric acid (0.1 mol/l) VS, when observed between 325 nm and 400 nm, exhibits a maximum at about 362 nm; the absorbance of a 1-cm layer at this wavelength is about 0.44 (preferably use 2-cm cells for the measurement and calculate the absorbance of a 1-cm layer).

D. Carry out the combustion as described under 2.4 Oxygen flask method, using 20 mg of the test substance and 5 ml of sodium hydroxide (~80 g/l) TS as the absorbing liquid. When the process is complete, acidify with sulfuric acid (~100 g/l) TS and boil gently for 2 minutes; the solution yields reaction A, described under 2.1 General identification tests as characteristic of chlorides.

Melting range. 131-135°C.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 50°C under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury); it loses not more than 5.0 mg/g.

Related substances. Carry out the test in subdued light as described under 1.14.1 Thin-layer chromatography, using silical gel R2 as the coating substance and a mixture of 1 volume of dehydrated ethanol R and 24 volumes of ethyl acetate R as the mobile phase. Apply separately to the plate 10 μl of each of 2 freshly prepared solutions in chloroform R containing (A) 0.20 g of the test substance per ml and (B) 0.10 mg of 5-chloro-2-methylaminobenzophenone RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, and examine the chromatogram in ultraviolet light (254 nm). Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B.

Assay. Dissolve about 0.55 g, accurately weighed, in 30 ml of glacial acetic acid R1, and titrate with perchloric acid (0.1 mol/l) VS, determining the end-point potentiometrically as described under 2.6 Non-aqueous titration, Method A. Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 28.47 mg of C₁₆H₁₃ClN₂O.

Additional requirements for Diazepam for parenteral use

Complies with the monograph for "Parenteral preparations".

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 11.6 IU of endotoxin RS per mg.

Monographs: Pharmaceutical substances: Dexamethasoni natrii phosphas - Dexamethasone sodium phosphate

2009-07-30T23:24:00.001-07:00

Molecular formula. C₂₂H₂₈FNa₂O₈P

Relative molecular mass. 516.4

Graphic formula.

Chemical name. 9-Fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione 21-(dihydrogen phosphate) disodium salt; 9-fluoro-11β,17-dihydroxy-16α-methyl-21-(phosphonooxy)pregna-1,4-diene-3,20-dione disodium salt; CAS Reg. No. 2392-39-4.

Description. A white or almost white, crystalline powder; odourless or with a slight odour of ethanol.

Solubility. Freely soluble in water; slightly soluble in ethanol (~750 g/l) TS; practically insoluble in ether R.

Category. Adrenal hormone.

Storage. Dexamethasone sodium phosphate should be kept in a tightly closed container, protected from light.

Additional information. Dexamethasone sodium phosphate is very hygroscopic. Even in the absence of light, it is gradually degraded on exposure to a humid atmosphere, the decomposition being faster at higher temperatures.

Requirements

Definition. Dexamethasone sodium phosphate contains not less than 96.0% and not more than 103.0% of C₂₂H₂₈FNa₂O₈P, calculated with reference to the anhydrous and ethanol-free substance.

Identity tests

A. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R1 as the coating substance and a freshly prepared mixture of 3 volumes of 1-butanol R, 1 volume of acetic anhydride R, and 1 volume of water as the mobile phase. Apply separately to the plate 2 μl of each of 4 solutions in methanol R containing (A) 2.5 mg of the test substance per ml, (B) 2.5 mg of dexamethasone sodium phosphate RS per ml, (C) a mixture of equal volumes of solutions A and B, and (D) equal volumes of solution A and a solution of 2.5 mg of prednisolone sodium phosphate RS per ml of methanol R. After removing the plate from the chromatographic chamber, allow it to dry in air until the solvents have evaporated, spray it with a mixture of 10 ml of sulfuric acid (~1760 g/l) TS and 90 ml of ethanol (~750 g/l) TS, heat it at 120°C for 10 minutes, allow it to cool, and examine the chromatogram in ultraviolet light (365 nm). The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B. The principal spot obtained with solution C appears as a single compact spot, whereas the chromatogram of solution D shows 2 closely running spots.

B. Place 0.5 ml of chromic acid TS in a small test-tube and heat in a water-bath for 5 minutes; the solution wets the sides of the tube but there is no greasiness. Add about 3 mg of the test substance and again heat in a water-bath for 5 minutes; the solution no longer wets the sides of the tube.

C. Heat carefully 0.04 g with 2 ml of sulfuric acid (~1760 g/l) TS until white fumes are evolved, add drop by drop nitric acid (~1000 g/l) TS until oxidation is complete, and cool. Add 2 ml of water, heat until white fumes are again evolved, cool, add 10 ml of water, and neutralize with ammonia (~100 g/l) TS, using pH-indicator paper R. Keep half of the solution for test D. The remaining solution yields reaction A described under 2.1 General identification tests as characteristic of orthophosphates.

D. The solution prepared in test C yields reaction B described under 2.1 General identification tests as characteristic of sodium.

Specific optical rotation. Use a 10 mg/ml solution and calculate with reference to the anhydrous and ethanol-free substance; .

Clarity of solution. A solution of 0.10 g in 10 ml of carbon-dioxide-free water R is clear.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, method A, using about 0.3 g of the substance. The sum of the contents of water and ethanol (described below), both calculated in mg/g, is not more than 160 mg/g.

Ethanol. Carry out the test as described under 1.14.5 Gas chromatography, using 3 solutions in water containing (1) a mixture of 10 μl of 1-propanol R per ml serving as an internal standard and 10 μl of dehydrated ethanol R per ml, (2) 0.10 g of the test substance per ml, and (3) a mixture of 0.10 g of the test substance and 10 μl of the internal standard per ml. It may be necessary to adjust the content of dehydrated ethanol R in solution (1) to produce a peak of similar height to the corresponding peak in the chromatogram obtained with solution (2).

For the procedure use a column 1.5 m long and 4 mm in internal diameter packed with porous polymer beads (particle size 80-100 μm from a commercial source, is suitable). Maintain the column at 135 °C, use nitrogen R as the carrier gas and a flame ionization detector.

Calculate the content of ethanol in mg/g, assuming the weight per ml at 20 °C to be 0.790 g; not more than 80 mg/g.

pH value. pH of a 10 mg/ml solution in carbon-dioxide-free water R, 7.5-10.5.

Free dexamethasone and other related substances. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R1 as the coating substance and methanol R as the mobile phase. Apply separately to the plate 2 μl of each of 2 solutions in methanol R containing (A) 10 mg of the test substance per ml, and (B) 0.20 mg of dexamethasone RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air for 5 minutes, spray it with a solution of 3 g of zinc chloride R in 10 ml of methanol R, heat it at about 125°C for 1 hour, and examine the chromatogram in ultraviolet light (365 nm). Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B.

Assay. Dissolve about 0.2 g, accurately weighed, in sufficient water to produce 200 ml. Dilute 5 ml to 250 ml with water and measure the absorbance of this solution in a 1-cm layer at the maximum at about 241 nm. Calculate the content of C₂₂H₂₈FNa₂O₈P, using the absorptivity value of 29.7 .

Additional requirements for Dexamethasone sodium phosphate for parenteral use

Complies with the monograph for "Parenteral preparations".

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 31.3 IU of endotoxin RS per mg.

Monographs: Pharmaceutical substances: Dexamethasoni acetas - Dexamethasone acetate

2009-07-30T23:22:00.002-07:00

Dexamethasone acetate, anhydrous

Dexamethasone acetate monohydrate

Molecular formula. C₂₄H₃₁FO₆ (anhydrous); C₂₄H₃₁FO₆,H₂O (monohydrate).

Relative molecular mass. 434.5 (anhydrous); 452.5 (monohydrate).

Graphic formula.

Chemical name. 9-Fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione 21-acetate; 21-(acetyloxy)-9-fluoro-11β,17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione; CAS Reg. No. 1177-87-3 (anhydrous).

9-Fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione 21-acetate monohydrate; 21-(acetyloxy)-9-fluoro-11β,17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione monohydrate; CAS Reg. No. 55812-90-3 (monohydrate).

Description. A white or almost white powder, odourless.

Solubility. Practically insoluble in water; soluble in 40 parts of ethanol (~750 g/l) TS; slightly soluble in ether R.

Category. Adrenoglucocorticoid.

Storage. Dexamethasone acetate should be kept in a tightly closed container, protected from light.

Labelling. The designation on the container of Dexamethasone acetate should state whether the substance is the monohydrate or is in the anhydrous form.

Requirements

Definition. Dexamethasone acetate contains not less than 96.0% and not more than 104.0% of C₂₄H₃₁FO₆, calculated with reference to the dried substance.

Identity tests

• Either tests A, B, C and E, or tests B, C, D and E may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. For the anhydrous form the infrared absorption spectrum is concordant with the spectrum obtained from dexamethasone acetate RS or with the reference spectrum of dexamethasone acetate. For the monohydrate the infrared absorption spectrum is concordant with the spectrum obtained from dexamethasone acetate monohydrate RS or with the reference spectrum of dexamethasone acetate monohydrate.

B. Dissolve 22 mg in 20 ml of ethanol (~750 g/l) TS and dilute 2 ml to 20 ml with the same solvent. To 2 ml of this solution placed in a stoppered test-tube add 10 ml of phenylhydrazine/sulfuric acid TS, mix, heat in a water-bath at 60°C for 20 minutes and cool immediately. The absorbance of a 1-cm layer at the maximum at about 423 nm is not less than 0.42 (preferably use 2-cm cells for the measurement and calculate the absorbance of a 1-cm layer).

C. See the test described below under "Related steroids". The principal spots obtained with solutions A and C correspond in position with that obtained with solution B. In addition the appearance and intensity of the principal spot obtained with solution A corresponds with that obtained with solution B.

D. Carry out the combustion as described under 2.4 Oxygen flask method, using 7 mg of the test substance and a mixture of 0.5 ml of sodium hydroxide (0.01 mol/l) VS and 20 ml of water as the absorbing liquid. When the process is complete, add 0.1 ml to a mixture of 0.1 ml of freshly prepared sodium alizarinsulfonate (1 g/l) TS and 0.1 ml of zirconyl nitrate TS; the red colour of the solution changes to clear yellow.

E. Heat 0.05 g with 2 ml of potassium hydroxide/ethanol (0.5 mol/l) VS in a water-bath for 5 minutes. Cool, add 2 ml of sulfuric acid (~700 g/l) TS, and boil gently for 1 minute; ethyl acetate, perceptible by its odour (proceed with caution), is produced.

Specific optical rotation. Use a 10 mg/ml solution in dioxan R;

Sulfated ash. Weigh 0.1 g and use a platinum dish; not more than 5.0 mg/g.

Loss on drying. Dry to constant weight at 100°C under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury). For the anhydrous form use about 0.5 g of the substance; it loses not more than 5.0 mg/g. For the monohydrate use about 0.15 g of the substance; it loses not less than 35 mg/g and not more than 45 mg/g.

Related steroids. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R1 as the coating substance and a mixture of 77 volumes of dichloromethane R, 15 volumes of ether R, 8 volumes of methanol R, and 1.2 volumes of water as the mobile phase. Apply separately to the plate 1 μl of each of 2 solutions in a mixture of 9 volumes of chloroform R and 1 volume of methanol R containing (A) 15 mg of the test substance per ml and (B) 15 mg of dexamethasone acetate RS per ml; also apply to the plate 2 μl of a third solution (C) composed of a mixture of equal volumes of solutions A and B and 1 μl of a fourth solution (D) containing 0.15 mg of the test substance per ml in the same solvent mixture as used for solutions A and B. After removing the plate from the chromatographic chamber, allow it to dry in air until the solvents have evaporated and heat at 105°C for 10 minutes; allow to cool, spray with blue tetrazolium/sodium hydroxide TS, and examine the chromatogram in daylight. Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution D.

Assay

• The solutions must be protected from light throughout the assay.

Dissolve about 20 mg, accurately weighed, in sufficient aldehyde-free ethanol (~750 g/l) TS to produce 100 ml. Dilute 20 ml of this solution with sufficient aldehyde-free ethanol (~750 g/l) TS to produce 100 ml. Transfer 10.0 ml of the diluted solution to a 25-ml volumetric flask, add 2.0 ml of blue tetrazolium/ethanol TS and displace the air with oxygen-free nitrogen R. Immediately add 2.0 ml of tetramethylammonium hydroxide/ethanol TS and again displace the air with oxygen-free nitrogen R. Stopper the flask, mix the contents by gentle swirling and allow to stand for 1 hour in a water-bath at 30°C. Cool rapidly, add sufficient aldehyde-free ethanol (~750 g/l) TS to produce 25 ml, and mix. Measure the absorbance of a 1-cm layer at the maximum at about 525 nm against a solvent cell containing a solution prepared by treating 10 ml of aldehyde-free ethanol (~750 g/l) TS in a similar manner. Calculate the amount of C₂₄H₃₁FO₆ in the substance being tested by comparison with dexamethasone acetate RS, similarly and concurrently examined.

Monographs: Pharmaceutical substances: Dehydroemetini dihydrochloridum - Dehydroemetine dihydrochloride

2009-07-30T23:22:00.001-07:00

Molecular formula. C₂₉H₃₈N₂O₄,2HCl

Relative molecular mass. 551.6

Graphic formula.

Chemical name. (±)-2,3-Didehydroemetine dihydrochloride; (±)-2,3-didehydro-6',7',10,11-tetramethoxyemetan dihydrochloride; (±)-(11bR*)-3-ethyl-1,6,7,11b-tetrahydro-9,10-dimethoxy-1-[[(1bS*)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl]methyl]-4H-benzo[a]quinolizine dihydrochloride; CAS Reg. No. 3317-75-7.

Description. A white to yellowish, crystalline powder; odourless.

Solubility. Sparingly soluble in water; soluble in methanol R.

Category. Antiamoebic drug.

Storage. Dehydroemetine dihydrochloride should be kept in a tightly closed container.

Requirements

Definition. Dehydroemetine dihydrochloride contains not less than 98.0% and not more than 101.0% of C₂₉H₃₈N₂O₄,2HCl, calculated with reference to the dried substance.

Identity tests

A. The absorption spectrum of a 0.040 mg/ml solution in hydrochloric acid (0.1 mol/l) VS, when observed between 240 nm and 350 nm, exhibits a maximum at about 282 nm. The absorbance of a 1-cm layer at this wavelength is about 0.49.

B. Sprinkle a small quantity of the powdered substance on the surface of 1 ml of sulfuric acid (~1760 g/l) TS containing 5 mg of molybdenum trioxide R; a bright green colour is produced.

C. A 0.1 g/ml solution yields reaction B described under 2.1 General identification tests as characteristic of chlorides.

Clarity and colour of solution. A solution of 0.30 g in 10 ml of water is clear and not more intensely coloured than standard colour solution Yw2 when compared as described under 1.11 Colour of liquids.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 70 mg/g.

pH value. pH of a 30 mg/ml solution, 3.5-5.0.

Related substances. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R4 as the coating substance and a mixture of 9 volumes of ethyl acetate R and 1 volume of diethylamine R as the mobile phase. Apply separately to the plate 5 μl of each of 3 solutions in methanol R containing (A) 20 mg of the test substance per ml, (B) 0.10 mg of the test substance per ml, and (C) 0.10 mg of emetine hydrochloride RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, spray it with mercuric acetate/acetic acid TS, heat it at 120 °C for 10 minutes, and examine the chromatogram in ultraviolet light (365 nm). Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B or solution C, as appropriate.

Assay. Dissolve about 0.4 g, accurately weighed, in 75 ml of glacial acetic acid R1, add 10 ml of mercuric acetate/acetic acid TS, and titrate with perchloric acid (0.1 mol/l) VS as described under 2.6 Non-aqueous titration, Method A. Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 27.58 mg of C₂₉H₃₈N₂O₄,2HCl.

Monographs: Pharmaceutical substances: Deferoxamini mesilas - Deferoxamine mesilate

2009-07-30T23:20:00.000-07:00

Molecular formula. C₂₅H₄₈N₆O₈,CH₄O₃S

Relative molecular mass, 656.8

Graphic formula.

Chemical name. N-[5-[3-[(5-Aminopentyl)hydroxycarbamoyl]propionamido]pentyl]-3-[[5-(N-hydroxyacetamido)pentyl]carbamoyl]propionohydroxamic acid monomethanesulfonate (salt); N'-[5-[[4-[[5-(acetylhydroxyamino)pentyl]amino]-1,4-dioxobutyl]hydroxyamino]pentyl]-N-(5-aminopentyl)-N-hydroxybutanediamide monomethanesulfonate (salt); CAS Reg. No. 138-14-7.

Other name. Desferrioxamine mesylate.

Description. A white to yellowish white powder; odourless or almost odourless.

Solubility. Soluble in 5 parts of water; soluble in ethanol (~750 g/l) TS; slightly soluble in methanol R; practically insoluble in ether R.

Category. Antidote to iron poisoning.

Storage. Deferoxamine mesilate should be kept in a well-closed container, protected from light, and stored at a temperature not exceeding 4 °C.

Requirements

Definition. Deferoxamine mesilate contains not less than 98.0% and not more than 102.0% of C₂₅H₄₈N₆O₈,CH₄O₃S, calculated with reference to the anhydrous substance.

Manufacture. The production method must be evaluated to determine the potential for formation of alkyl mesilates, which is particularly likely to occur if the reaction medium contains lower alcohols. Where necessary, the production method is validated to demonstrate that alkyl mesilates are not detectable in the final product.

Identity tests

A. Dissolve 5 mg in 5 ml of water, add 2 ml of trisodium orthophosphate (2 g/l) TS, mix, then add 1 ml of sodium 1,2-naphthoquinone-4-sulfonate (5 g/l) TS; a blackish brown colour is produced.

B. The titrated solution obtained in the assay is reddish brown in colour. To 5 ml of the titrated solution add 2 ml of benzyl alcohol R and shake; the colour is extracted. To a further 5 ml of the titrated solution add 2 ml of ether R and shake; the colour is not extracted.

Chlorides. Dissolve 0.7 g in a mixture of 2 ml of nitric acid (~130 g/l) TS, and proceed as described under 2.2.1 Limit test for chlorides; the chloride content is not more than 0.35 mg/g.

Sulfates. Dissolve 0.85 g in 40 ml of water, and proceed as described under 2.2.2 Limit test for sulfates; the sulfate content is not more than 0.6 mg/g.

Clarity and colour of solution. A solution of 1.0 g in 10 ml of water is clear; measure the absorbance of the solution in a 1-cm layer at 420 nm; not more than 0.10.

Sulfated ash. Not more than 1.0 mg/g.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 1 g of the substance; the water content is not more than 20 mg/g.

pH value. pH of a 0.10 g/ml solution in carbon-dioxide-free water R, 3.5-6.0.

Assay. Dissolve about 0.3 g, accurately weighed, in 15 ml of water and add 2 ml of sulfuric acid (0.05 mol/l) VS. Titrate slowly with ferric ammonium sulfate (0.1 mol/l) VS, determining the end-point potentiometrically using a platinum electrode and a calomel reference electrode. Each ml of ferric ammonium sulfate (0.1 mol/l) VS is equivalent to 65.68 mg of C₂₅H₄₈N₆O₈,CH₄O₃S. (Keep the titrated solution for identity test B.)

Monographs: Pharmaceutical substances: Dapsonum - Dapsone

2009-07-27T00:07:00.001-07:00

Molecular formula. C₁₂H₁₂N₂O₂S

Relative molecular mass. 248.3

Graphic formula.

Chemical name. 4,4'-Sulfonyldianiline; 4,4'-sulfonylbis[benzenamine]; 4,4'-diaminodiphenylsulfone; CAS Reg. No. 80-08-0.

Description. A white or creamy white, crystalline powder; odourless.

Solubility. Soluble in 7000 parts of water and in 30 parts of ethanol (~750 g/l) TS; soluble in acetone R.

Category. Antileprotic.

Storage. Dapsone should be kept in a tightly closed container, protected from light.

Additional information. Even in the absence of light, Dapsone is gradually degraded on exposure to a humid atmosphere, the decomposition being faster at higher temperatures.

Requirements

Definition. Dapsone contains not less than 99.0% and not more than 101.0% of C₁₂H₁₂N₂O₂S, calculated with reference to the dried substance.

Identity tests

A. The absorption spectrum of a 5.0 μg/ml solution in methanol R, when observed between 230 nm and 350 nm, exhibits maxima at about 260 nm and 295 nm; the absorbances of a 1-cm layer at the maximum wavelength of 260 nm and 295 nm are about 0.72 and 1.20, respectively.

B. See the test described below under "Related substances". The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.

C. About 0.1 g yields the reaction described for the identification of primary aromatic amines under 2.1 General identification tests, producing a vivid red precipitate.

D. Melting temperature, about 178°C.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 15 mg/g.

Related substances. Carry out the test as described under 1.14.1 Thin-layer chromatography, but using an unlined chamber, silica gel R3 as the coating substance, and a mixture of 8 volumes of toluene R and 4 volumes of acetone R saturated with water as the mobile phase. Apply separately to the plate 10 μl of each of 5 solutions in methanol R containing (A) 10 mg of the test substance per ml, (B) 10 mg of dapsone RS per ml, (C) 0.15 mg of the test substance per ml, (D) 20 μg of the test substance per ml and (E) 0.10 mg of 4,4'-thiodianiline RS per ml. The solution of 4,4'-thiodianiline RS should be freshly prepared. Pour the mobile phase into the chamber and insert the plate immediately, to avoid prior saturation of the chamber. After removing the plate from the chromatographic chamber, spray it with 4-dimethylaminocinnamaldehyde TS2. Heat the plate at 100°C and examine the chromatogram in daylight. The spot obtained with solution C is more intense than any spot obtained with solution A, other than the principal spot, and in addition, not more than 2 among those secondary spots are more intense than the spot obtained with solution D. Moreover, there is no visible spot corresponding in position and appearance with that obtained with solution E.

Assay. Carry out the assay as described under 2.7 Nitrite titration, using about 0.25 g, accurately weighed, dissolved in a mixture of 15 ml of water and 15 ml of hydrochloric acid (~70 g/l) TS and titrate with sodium nitrite (0.1 mol/l) VS. Each ml of sodium nitrite (0.1 mol/l) VS is equivalent to 12.42 mg of C₁₂H₁₂N₂O₂S.

Monographs: Pharmaceutical substances: Dactinomycinum - Dactinomycin

2009-07-27T00:06:00.000-07:00

C₆₂H₈₆N₁₂O₁₆

Relative molecular mass. 1255

Chemical name. Actinomycin D; CAS Reg. No. 50-76-0.

Description. An orange-red to red, crystalline powder.

Solubility. Soluble in water at 10 °C and slightly soluble in water at 37 °C; freely soluble in ethanol (~750 g/l) TS and methanol R; very slightly soluble in ether R.

Category. Cytotoxic drug.

Storage. Dactinomycin should be kept in a tightly closed container, protected from light, and stored at a temperature not exceeding 40 °C.

Additional information. Dactinomycin is hygroscopic and is affected by light and heat.

CAUTION. Dactinomycin must be handled with care, avoiding contact with the skin and inhalation of airborne particles.

Requirements

Dactinomycin contains not less than 95.0% and not more than the equivalent of 103.0% of C₆₂H₈₆N₁₂O₁₆, calculated with reference to the dried substance.

Identity tests

A. The absorption spectrum of a 25 μg/ml solution in methanol R, when observed between 220 nm and 500 nm, exhibits 2 maxima at about 240 nm and 445 nm. The absorbance of a 1-cm layer at the maximum wavelength of 445 nm is about 0.83; the ratio of the absorbance at 240 nm to that at 445 nm is between 1.30 and 1.50.

B. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R4 as the coating substance and a mixture of 4 volumes of 1-butanol R, 2 volumes of water, and 1 volume of methanol R as the mobile phase. Apply separately to the plate 10 μl of each of two solutions in acetone R containing (A) 10 mg of Dactinomycin per ml and (B) 10 mg of dactinomycin RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, and examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.

C. Add 1 mg to a solution of 10 mg of paraformaldehyde R in 1 ml of sulfuric acid (~1760 g/l) TS; a red-violet colour is produced.

Melting range. 235-237 °C.

Specific optical rotation. Use a 1.0 mg/ml solution in methanol R and calculate with reference to the dried substance;.

Sulfated ash. Not more than 5.0 mg/g.

Loss on drying. Dry at 60 °C under reduced pressure (not exceeding 0.6 kPa or 5 mm of mercury) for 3 hours; it loses not more than 50 mg/g.

pH value. pH of a saturated solution, 5.5-7.0.

Assay. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a column, length 30 cm, internal diameter 3.9 mm, packed with porous silica gel or ceramic microparticles having a diameter of 5-10 μm, the surface of which has been modified with chemically bonded octadecylsilyl groups.

As the mobile phase, use a mixture of 46 volumes of acetonitrile R, 25 volumes of sodium acetate (0.04 mol/l) VS and 25 volumes of acetic acid (0.07 mol/l) VS, filter through a membrane filter (porosity of 1 μm or finer) and degas the resulting solvent mixture. (Note: The concentration of acetonitrile may have to be adjusted to provide a suitable chromatogram and elution time.)

Prepare the following solutions immediately before use in the above-mentioned mobile phase, and store them protected from light. Weigh accurately for solution (A) about 1.2 mg of Dactinomycin per ml, and for solution (B) about 1.2 mg of dactinomycin RS per ml.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer at a wavelength of about 254 nm. Make three replicate injections of solution B, each of 20 μl, to determine the peak responses. The relative standard deviation of the peaks is not more than 1.0%. Inject 20 μl of each of solutions A and B.

Measure the areas of the peak responses. (The retention time for dactinomycin is about 25 minutes.) Calculate the content in % of C₆₂H₈₆N₁₂O₁₆ using the following formula: (M₂/M₁) (A₁/A₂) 100, in which M₁ and M₂ are the concentrations , in mg per ml, of Dactinomycin being examined and the reference solution, and A₁ and A₂ are the areas of the peak responses of Dactinomycin and the reference substance, respectively.

Additional requirements for Dactinomycin for parenteral use

Complies with the monograph for "Parenteral preparations".

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 100.0 IU of endotoxin RS per mg.

Sterility. Complies with 3.2.2 Sterility testing of antibiotics, applying the membrane filtration test procedure and using a solution in sterile water R containing 20 mg of Dactinomycin per ml.

Monographs: Pharmaceutical substances: Dacarbazinum - Dacarbazine

2009-07-27T00:05:00.000-07:00

Monographs: Pharmaceutical substances: Dacarbazinum - Dacarbazine

C₆H₁₀N₆O

Relative molecular mass. 182.2

Chemical name. 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide; 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide; CAS Reg. No. 4342-03-4.

Description. A colourless or pale yellow, crystalline powder.

Solubility. Slightly soluble in water and ethanol (~750 g/l) TS.

Category. Cytotoxic drug.

Storage. Dacarbazine should be kept in a tightly closed container, protected from light, and stored at a temperature not exceeding 8 °C.

Additional information. CAUTION: Dacarbazine must be handled with care, avoiding contact with the skin and inhalation of airborne particles.

Requirements

Dacarbazine contains not less than 97.0% and not more than 102.0% of C₆H₁₀N₆O, calculated with reference to the dried substance.

Identity tests

• Either test A alone or tests B, C, and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from dacarbazine RS or with the reference spectrum of dacarbazine.

B. The absorption spectrum of a 6μg/ml solution in hydrochloric acid (0.1mol/l) VS, when observed between 230nm and 350nm, exhibits a maximum at about 323nm and a pronounced shoulder at 275nm. The absorbance of a 1-cm layer at the maximum wavelength of 323 nm is about 0.64.

C. Dissolve 25 mg in 5 ml of water, add 1 drop of cobalt(II) chloride (30 g/l) TS and 1 drop of ammonia (~100 g/l) TS; a violet-red solution is produced.

D. Dissolve 25mg in 5ml of hydrochloric acid (~70 g/l) TS, add about 0.2 g of zinc R powder and allow to stand for 5 minutes. Filter, and to the filtrate add 3 drops of sodium nitrite (10 g/l) TS and 0.5ml of ammonium sulfamate (5 g/l) TS. After the reaction has subsided add 5 drops of N-(1-naphthyl)ethylenediamine hydrochloride/ethanol TS; a deep red solution is produced.

Clarity and colour of solution. A solution of 0.20 g in 10 ml of citric acid (20 g/l) TS is clear and not more intensely coloured than standard colour solution Yw2 when compared as described under 1.11 Colour of liquids.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry at 60 °C to constant mass under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury); it loses not more than 5 mg/g.

Related substances. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R2 as the coating substance and 5 volumes of 1-butanol R, 2 volumes of water and 1 volume of acetic acid (~300 g/l) TS as the mobile phase. Apply separately to the plate 5μl of each of the 3 following solutions in methanol R containing (A) 0.04 g of Dacarbazine per ml, (B) 0.4 mg of dacarbazine related compound A RS per ml, and (C) 0.4 mg of dacarbazine related compound B RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, and examine the chromatogram in ultraviolet light (254 nm).

Any spot obtained with solution A, other than the principal spot, is not more intense or greater in size than that obtained with solution B (1%) and solution C (1%).

Assay

• The solutions must be protected from light throughout the assay.

Dissolve about 30 mg, accurately weighed, in sufficient hydrochloric acid (0.1 mol/l) VS to produce 50 ml of stock solution. For solution S₁ dilute 1.0ml of the stock solution to 100 ml with hydrochloric acid (0.1 mol/l) VS. For solution S₂ dilute a further 1.0 ml aliquot of the stock solution to 100ml with phosphate buffer, pH 7.0, TS. Measure the absorbance of a 1-cm layer of solution S₁ at the maximum at about 323nm against a solvent cell containing hydrochloric acid (0.1 mol/l) VS. Measure the absorbance of a 1-cm layer of solution S₂ at the maximum at about 329nm against a solvent cell containing phosphate buffer, pH 7.0, TS. Calculate the percentage content of C₆H₁₀N₆O.

Monographs: Pharmaceutical substances: Chloramphenicoli natrii succinas - Chloramphenicol sodium succinate

2009-07-23T08:14:00.000-07:00

C₁₅H₁₅Cl₂N₂NaO₈

Relative molecular mass. 445.2

Chemical name. A mixture in variable proportions of (2R,3R)-2-(2,2- dichloroacetamido)-3-hydroxy-3-(4-nitrophenyl)propyl succinate (3 isomer) and of sodium (1R,2R)-2-(2,2-dichloroacetamido)-3-hydroxy-1-(4-nitrophenyl) propyl succinate (1 isomer); [R-(R*,R*)]-mono[2-[(2,2-dichloroacetyl)amino]-3-hydroxy-3-(4-nitrophenyl)propyl] ester, butanedioic acid, monosodium salt; D-threo-(-)-2,2-dichloro-N-[β-hydroxy-α-(hydroxymethyl)-p-nitrophenethyl] acetamide α-(sodium succinate); CAS Reg. No. 982-57-0.

Description. A white or yellowish white powder.

Solubility. Very soluble in water; freely soluble in ethanol (~750 g/l)TS.

Category. Antibacterial drug.

Storage. Chloramphenicol sodium succinate should be kept in a tightly closed container, protected from light.

Labelling. The designation Chloramphenicol sodium succinate for parenteral use indicates that the substance complies with the additional requirements and may be used for parenteral administration. Expiry date.

Additional information. Chloramphenicol sodium succinate is hygroscopic. Even in the absence of light, Chloramphenicol sodium succinate gradually degrades when exposed to a humid atmosphere; decomposition is more rapid at higher temperatures.

Requirements

Chloramphenicol sodium succinate contains not less than 98.0% and not more than the equivalent of 102.0% of C₁₅H₁₅Cl₂N₂NaO₈, calculated with reference to the anhydrous substance.

Identity tests

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from chloramphenicol sodium succinate RS or with the reference spectrum of chloramphenicol sodium succinate.

B. See the test described below under "Chloramphenicol and chloramphenicol disodium disuccinate, test B". The two principal spots obtained with solution A correspond in position and appearance with those obtained with solution B. The positions of the spots obtained with solutions A and B are different from that of the principal spot obtained with solution C.

C. Dissolve 10 mg in 2.0 ml of ethanol (~750 g/l) TS, add 0.2 g of zinc R powder, 1.0 ml of sulfuric acid (~100 g/l) TS, and allow to stand for 10 minutes. Filter. To the filtrate add 0.5 ml of sodium nitrite (10 g/l) TS, and allow to stand for 2 minutes. Then add 1.0 g of urea R and a solution containing 10mg of 2-naphthol R in 2ml of sodium hydroxide (~80 g/l) TS; a red colour is produced. Repeat the test omitting the zinc R powder; no red colour is produced.

D. Dissolve 5 mg in 5 ml of water and add a few drops of silver nitrate (40 g/l) TS; no precipitate is produced. Heat 0.05g with 2.0ml of potassium hydroxide/ethanol TS1 on a water-bath for 15 minutes, add 15mg of charcoal R, shake, and filter. The filtrate yields reaction A described under 2.1 General identification tests as characteristic of chlorides.

E. When tested for sodium as described under 2.1 General identification tests, it yields the characteristic reactions. If reaction B is to be used, prepare a 20 mg/ml solution.

Specific optical rotation. Use a 50 mg/ml solution and calculate with reference to the anhydrous substance;

Clarity of solution. A solution of 1.0 g in 3.0 ml of carbon-dioxide-free water R is clear.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 0.5 g of Chloramphenicol sodium succinate; the water content is not more than 0.20 g/g.

pH value. pH of a 0.25 g/ml solution in carbon-dioxide-free water R, 6.4-7.0.

Chloramphenicol and chloramphenicol disodium disuccinate

• Either test A or test B may be applied.

A. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25cm × 4.6mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5μm). As the mobile phase, use a mixture of 55 volumes of water, 40 volumes of methanol R, and 5 volumes of phosphoric acid (~20 g/l) TS.

Prepare the following solutions in the mobile phase: solution (A) 0.25mg of Chloramphenicol sodium succinate per ml; solution (B) 5.0 μg of chloramphenicol RS per ml; solution (C) 5.0 μg of chloramphenicol disodium disuccinate RS per ml; and for solution (D) dissolve 25mg of Chloramphenicol sodium succinate in the mobile phase, add 0.5 mg of chloramphenicol RS and 0.5 mg of chloramphenicol disodium disuccinate RS and dilute to 100ml with the mobile phase.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of about 275nm.

Using a 20-μl loop injector inject solution D. Inject alternately solutions A, B, C, and D. The test is not valid unless the two peaks in the chromatogram obtained with solution D, corresponding to those in the chromatograms obtained with solutions B and C, are clearly separated from the peaks corresponding to the two principal peaks in the chromatogram obtained with solution A. If necessary, adjust the methanol content of the mobile phase.

Measure the areas of the peak responses obtained in the chromatograms from solutions A, B, and C, and calculate the content of the related substances as a percentage. In the chromatogram obtained with solution A, the area of any peak corresponding to chloramphenicol is not greater than that of the principal peak obtained with solution B (2.0%). The area of any peak corresponding to chloramphenicol disodium disuccinate is not greater than that of the principal peak obtained with solution C (2.0%).

B. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R4 as the coating substance and a mixture of 85 volumes of dichloromethane R, 14 volumes of methanol R, and 1 volume of acetic acid (~60 g/l) TS as the mobile phase. Apply separately to the plate 2 μl of each of 3 solutions in acetone R containing (A) 10mg of Chloramphenicol sodium succinate per ml, (B) 10 mg of chloramphenicol sodium succinate RS per ml, and (C) 10 mg of chloramphenicol RS per ml. Then apply separately 10 μl of solution (A) as prepared above and 1 μl of solution (D) containing 0.20 mg of chloramphenicol RS per ml of acetone R. After removing the plate from the chromatographic chamber, allow it to dry in air until the solvents have evaporated, and examine the chromatogram in ultraviolet light (254 nm).

Any spot obtained with the second application of solution A, other than the principal spot, is not more intense than that obtained with solution D (2.0%).

Assay. Dissolve about 0.2 g, accurately weighed, in sufficient water to produce 500 ml; dilute 5.0 ml of this solution to 100 ml with water. Measure the absorbance of the diluted solution in a 1-cm layer at the maximum at about 276nm and calculate the percentage content of C₁₅H₁₅Cl₂N₂NaO₈ using the absorptivity value of 22.0 , and with reference to the anhydrous substance.

Additional requirements for Chloramphenicol sodium succinate for parenteral use

Complies with the monograph for "Parenteral preparations".

Storage. Sterile Chloramphenicol sodium succinate should be kept in a sterile, tightly closed, and tamper-evident container, protected from light.

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 0.2 IU of endotoxin RS per mg.

Sterility. Complies with 3.2.2 Sterility testing of antibiotics, Membrane filtration test procedure.

Monographs: Pharmaceutical substances: Chlorambucilum - Chlorambucil

2009-07-23T08:12:00.000-07:00

Molecular formula. C₁₄H₁₉Cl₂NO₂

Relative molecular mass. 304.2

Graphic formula.

Chemical name. 4-[p-[Bis(2-chloroethyl)amino]phenyl]butyric acid; 4-[bis(2-chloroethyl)amino]benzenebutanoic acid; CAS Reg. No. 305-03-3.

Description. A white or almost white, crystalline or slightly granular powder.

Solubility. Practically insoluble in water; freely soluble in ethanol (~750 g/l) TS and acetone R.

Category. Cytotoxic drug.

Storage. Chlorambucil should be kept in a well-closed container, protected from light.

Additional information. CAUTION: Chlorambucil must be handled with care, avoiding contact with the skin and inhalation of airborne particles.

Requirements

Definition. Chlorambucil contains not less than 98.0% and not more than 101.0% of C₁₄H₁₉Cl₂NO₂, calculated with reference to the anhydrous substance.

Identity tests

A. Place 20 mg in a test-tube, add 0.20 ml of potassium dichromate TS2, cover the tube with a piece of filter-paper moistened with sodium nitroprusside (8.5 g/l) TS and 0.05 ml of piperidine R. Heat the tube over a small flame; a blue spot appears on the filter-paper.

B. Dissolve 0.05 g in 5 ml of acetone R, and dilute with water to 10 ml. Add 0.05 ml of sulfuric acid (~100 g/l) TS, then add 0.20 ml of silver nitrate (0.1 mol/l) VS; no opalescence is observed immediately (absence of chloride ion). Warm the solution on a water-bath; an opalescence develops (presence of ionizable chlorine).

C. Mix 0.4 g with 10 ml of hydrochloric acid (~70 g/l) TS and allow to stand for 30 minutes, shaking occasionally. Filter, wash the residue with 2 quantities, each of 10 ml of water, and dry at ambient temperature under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury) over phosphorus pentoxide R for 3 hours; melting temperature, about 146°C.

Melting range. 64-69 °C.

Sulfated ash. Not more than 1.0 mg/g.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 0.5 g of the substance; the water content is not more than 5.0 mg/g.

Related substance. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R2 as the coating substance and allowing the coated plate to dry at room temperature for 24 hours. Use as the mobile phase a mixture of 8 volumes of toluene R, 5 volumes of methanol R, 4 volumes of heptane R, and 4 volumes of ethylmethylketone R. Apply separately to the plate 10 μl of each of 2 solutions in acetone R containing (A) 20 mg of the test substance per ml and (B) 0.40 mg of the test substance per ml. After removing the plate from the chromatographic chamber, allow it to dry in air and examine the chromatogram in ultraviolet light (254 nm). Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B.

Assay. Dissolve about 0.2 g, accurately weighed, in 10 ml of acetone R, add 10 ml of water, and titrate with carbonate-free sodium hydroxide (0.1 mol/l) VS using phenolphthalein/ethanol TS as indicator. Repeat the operation without the substance being examined and make any necessary corrections. Each ml of carbonate-free sodium hydroxide (0.1 mol/l) VS is equivalent to 30.42 mg of C₁₄H₁₉

Monographs: Pharmaceutical substances: Chlorali hydras - Chloral hydrate

2009-07-23T08:10:00.000-07:00

C₂H₃Cl₃O₂

Relative molecular mass. 165.4

Chemical name. 2,2,2-Trichloroethane-1,1-diol; CAS Reg. No. 302-17-0.

Description. Colourless, transparent or white crystals; odour, aromatic, pungent and characteristic.

Solubility. Very soluble in water; freely soluble in ethanol (~750 g/l) TS and ether R.

Category. Premedication.

Storage. Chloral hydrate should be kept in a tightly closed container.

Additional information. Melting temperature, about 55 °C; when exposed to air it slowly volatilizes.

Requirements

Chloral hydrate contains not less than 98.5% and not more than 101.0% of C₂H₃Cl₃O₂.

Note: Prepare the following test solution for use in "Identity tests A and B", and for "Clarity and colour". Dissolve 2.5 g in sufficient carbon-dioxide-free water R to produce 25 ml.

Identity tests

A. To 1.0 ml of the test solution add 2.0 ml of sodium sulfide TS; a yellow colour develops which quickly becomes reddish brown. On standing, a red precipitate may be produced.

B. Transfer 10 ml of the test solution to a conical flask and add 10 ml of 1- ethylquinaldinium iodide (15 g/l) TS that has previously been filtered through a 0.45-μm filter. Then add 60ml of 2-propanol R, 5ml of monoethanolamine (0.1 mol/l) VS, and 15 ml of water. Mix, and heat in a water-bath at 60 °C for 15 minutes; a blue colour develops.

Chlorides. Dissolve 2.5 g in a mixture of 2 ml of nitric acid (~130 g/l) TS and 20 ml of water, and proceed as described under 2.2.1 Limit test for chlorides; the chloride content is not more than 0.1 mg/g.

Chloral alcoholate. Warm 1.0 g with 10 ml of sodium hydroxide (~80 g/l) TS. Filter the upper layer and add iodine (0.05 mol/l) VS a drop at a time until a yellow colour is obtained; no precipitate is produced within 1 hour.

Clarity and colour of solution. The test solution is clear and colourless.

Sulfated ash. Not more than 1.0 mg/g.

pH value. pH of a 0.10 g/ml solution in carbon-dioxide-free water R, 3.5-5.5.

Assay. Dissolve about 4 g, accurately weighed, in 10 ml of carbon-dioxide-free water R and add 30.0ml of carbonate-free sodium hydroxide (1 mol/l) VS. Allow the mixture to stand for 2 minutes and titrate with sulfuric acid (0.5 mol/l) VS, using phenolphthalein/ethanol TS as indicator. Repeat the procedure without the Chloral hydrate being examined and make any necessary corrections.

Each ml of carbonate-free sodium hydroxide (1 mol/l) VS is equivalent to 0.1654 g of C₂H₃Cl₃O₂.

Monographs: Pharmaceutical substances: Cetrimidum - Cetrimide

2009-07-17T07:15:00.000-07:00

Chemical name. Trimethyltetradecylammonium bromide mixture with dodecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide; cetrimide; CAS Reg. No. 8044-71-1.

Description. A white or almost white, voluminous, free-flowing powder; odour, slight, characteristic.

Solubility. Freely soluble in water and ethanol (~750 g/l) TS; practically insoluble in ether R.

Category. Antimicrobial preservative.

Storage. Cetrimide should be stored in a well-closed container.

Requirements

Definition. Cetrimide is a mixture consisting mainly of tetradecyltrimethylammonium bromide together with smaller amounts of dodecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide.

Cetrimide contains not less than 96.0% and not more than the equivalent of 101.0% of alkyltrimethylammonium bromides, calculated as C₁₇H₃₈BrN (relative molecular mass = 336.4) and with reference to the dried substance.

Identity tests

A. Dissolve 5 mg in 5 ml of phosphate buffer, pH 8.0, TS. Dip a strip of methyl green/iodomercurate paper R into the solution. Similarly prepare a blank solution without the Cetrimide being examined. After 5 minutes withdraw the strip of paper from the tube; the solution to be tested shows a darker greenish blue colour than the blank solution.

B. Dissolve 0.2 g in 10 ml of carbon-dioxide-free water R and shake; a voluminous froth is produced. (Keep the mixture for test C.)

C. The solution prepared above yields reaction A described under 2.1 General identification tests as characteristic of bromides.

Amines and amine salts. Dissolve 5 g in 30 ml of a mixture of 1 volume of hydrochloric acid (1 mol/l) VS and 99 volumes of methanol R and add 100 ml of 2-propanol R. Slowly pass a stream of nitrogen R through the solution. Gradually add 15 ml of tetrabutylammonium hydroxide (0.1 mol/l) VS and titrate potentiometrically, recording a titration curve; the volume of titrant added between the two points of inflexion is not larger than 2.0 ml.

Sulfated ash. Not more than 5.0 mg/g.

Loss on drying. Dry at 105 °C for 2 hours; it loses not more than 20 mg/g.

Acidity or alkalinity. Dissolve 1 g in 50 ml of carbon-dioxide-free water R and add 0.1 ml of bromocresol purple/ethanol TS; not more than 0.1 ml of hydrochloric acid (0.1 mol/l) VS or 0.1 ml of sodium hydroxide (0.1 mol/l) VS is required to obtain the midpoint of the indicator (grey).

Assay. Dissolve about 2 g, accurately weighed, in 100 ml of water. Transfer 25 ml to a separating funnel, add 25 ml of chloroform R, 10 ml of sodium hydroxide (0.1 mol/l) VS, and 10 ml of a freshly prepared solution containing 5 g of potassium iodide R in 100 ml of water. Shake well, allow to separate, and discard the chloroform layer. Shake the aqueous layer with three quantities, each of 10 ml, of chloroform R, and discard the chloroform layers. Add 40 ml of hydrochloric acid (~420 g/l) TS, allow to cool, and titrate with potassium iodate (0.05 mol/l) VS until the deep brown colour is almost discharged. Add 2 ml of chloroform R and continue the titration, shaking vigorously, until the colour of the chloroform layer no longer changes. Repeat the procedure with a mixture of 10 ml of the above freshly prepared solution of potassium iodide, 20 ml of water, and 40 ml of hydrochloric acid (~420 g/l) TS and make any necessary corrections.

Each ml of potassium iodate (0.05 mol/l) VS is equivalent to 33.64 mg of C₁₇H₃₈BrN.

Monographs: Pharmaceutical substances: Cetomacrogolum 1000 - Cetomacrogol 1000

2009-07-17T07:14:00.002-07:00

(C₂H₄O)nC₁₆H₃₄O

Chemical name. Polyethylene glycol monohexadecyl ether; α-hexadecyl-ω-hydroxypoly(oxy-1,2-ethanediyl); CAS Reg. No. 9004-95-9.

Description. A cream-coloured, waxy, unctuous mass, pellets, or flakes; when heated, it melts to a brownish yellow, clear liquid; odourless or almost odourless.

Solubility. Soluble in water, ethanol (~750 g/l) TS, and acetone R; practically insoluble in light petroleum R.

Category. Nonionic surfactant.

Storage. Cetomacrogol 1000 should be kept in a well-closed container, protected from heat.

Requirements

Definition. Cetomacrogol 1000 is a condensation product of linear fatty alcohols with ethylene oxide, prepared under controlled conditions in order to obtain the required ether with the polyethylene glycol of the desired molecular mass.

Identity tests

A. Dissolve 0.1 g in 5 ml of water and add 10 ml of hydrochloric acid (~70 g/l) TS, 10 ml of barium chloride (50 g/l) TS, and 10 ml of phosphomolybdic acid (80 g/l) TS; a greenish yellow precipitate is produced.

B. Dissolve 0.1 g in 5 ml of water and add gradually tannic acid (50 g/l) TS; a precipitate is formed which dissolves on further addition of tannic acid solution.

Melting point. Not lower than 38 °C.

Refractive index. At 60 °C,

Acid value. Not more than 0.5.

Alkalinity. Dissolve 2 g in 20 ml of carbon-dioxide-free water R, add 1 drop of phenolphthalein/ethanol TS, and titrate with hydrochloric acid (0.1 mol/l) VS; not more than 0.5 ml is required to obtain a pink colour.

Hydroxyl value. Use 10 g, Method A; 40.0-52.5.

Saponification value. Use 10 g; not more than 1.0.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using 2.5 g; the water content is not more than 10 mg/g.

Monographs: Pharmaceutical substances: Cera cetyla - Cetyl esters wax

2009-07-17T07:14:00.001-07:00

Chemical name. C_14-18 Fatty acids C_14-18 alkyl esters; CAS Reg. No. 85566-24-1.

Other name. Synthetic spermaceti.

Description. White to almost white, somewhat translucent flakes (5 μm to several millimetres in the largest dimension), with a crystalline structure and a pearly lustre when caked; odour, faint, mild, aromatic.

Solubility. Practically insoluble in water and ethanol (~750 g/l) TS; soluble in ether R; slightly soluble in hexane R.

Category. Stiffening agent.

Storage. Cetyl esters wax should be kept in a well-closed container, protected from heat.

Additional information. Cetyl esters wax has a mass density of about 0.83 g/ml at 50 °C.

Requirements

Definition. Cetyl esters wax is a mixture consisting primarily of esters of saturated fatty alcohols (C₁₄ to C₁₈) and saturated fatty acids (C₁₄ to C₁₈).

Melting range. 43-47 °C.

Acid value. Not more than 5.

Iodine value. Not more than 1.

Saponification value. 109-120.

Paraffin. To 1 g add 50 ml of boiling ethanol (~750 g/l) TS; the wax is completely

Monographs: Pharmaceutical substances: Cera carnauba - Carnauba wax

2009-07-17T07:13:00.001-07:00

Chemical name. Carnauba wax; CAS Reg. No. 8015-86-9.

Description. Pale yellow to light brown, moderately coarse powder, flakes, or irregular lumps of hard, brittle wax; odour, characteristic and free from rancidity.

Solubility. Practically insoluble in water; soluble in toluene R; slightly soluble in boiling ethanol (~750 g/l) TS.

Category. Polishing agent for coated tablets; viscosity-increasing agent for ointments; release-rate modifier for oral formulations.

Storage. Carnauba wax should be kept in a well-closed container.

Requirements

Definition. Carnauba wax is obtained from the leaves of Copernicia cerifera Mart. (Fam. Palmae).

Melting range. 78-85 °C.

Ash. Weigh 2.0 g and use an open porcelain or platinum dish. Heat over a flame; it volatilizes without emitting an acrid odour. Ignite; the residue weighs not more than 2.5 mg/g.

Acid value. Use 3 g; not more than 8.

Saponification value. Use about 3 g, accurately weighed, add 25 ml of xylene R, and dissolve by warming. To this solution add 50 ml of ethanol (~750 g/l) TS and proceed with the determination of saponification. Attach a reflux condenser and heat for 2 hours; 75-95.

Iodine value. 5-14.

Monographs: Pharmaceutical substances: Cellulosum microcrystallinum - Microcrystalline cellulose

2009-07-17T07:12:00.002-07:00

Chemical name. Cellulose; CAS Reg. No. 9004-34-6.

Description. A white or almost white, fine crystalline or granular powder; odourless.

Solubility. Practically insoluble in water and most organic solvents; slightly soluble in dilute solutions of sodium hydroxide.

Category. Tablet and capsule diluent; suspending agent; disintegrant.

Storage. Microcrystalline cellulose should be kept in a well-closed container.

Additional information. Microcrystalline cellulose is usually defined by its particle size which ranges between 20 and 150 μm.

Requirements

Definition. Microcrystalline cellulose is partially depolymerized cellulose prepared from alpha cellulose.

Identity tests

A. Place 20 g on an air-jet sieve with a screen having a nominal aperture of 38 μm and shake for 5 minutes. If more than 1 g is retained on the screen, mix 30 g with 270 ml of water; otherwise, mix 45 g with 255 ml of water. Perform the mixing in a high-speed blender (18 000 rev/min) for 5 minutes. Transfer 100 ml of the mixture to a 100-ml graduated cylinder and allow to stand for 3 hours; a white, opaque, bubble-free dispersion is obtained without any supernatant liquid.

B. Dissolve 0.05 g in 10 ml of copper tetramine hydroxide TS; it dissolves completely without any residue. Add 5 ml of ethanol (~750 g/l) TS; a precipitate is produced.

Heavy metals. To 1.0 g add 4 ml of magnesium sulfate/sulfuric acid TS, mix, and heat cautiously to dryness on a water-bath. Progressively heat to ignition, not exceeding a temperature of 800 °C, and continue to heat until a white to greyish residue is obtained. Moisten the residue with 1 drop of hydrochloric acid (~250 g/l) TS and continue as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 10 μg/g.

Water-soluble substances. Shake 5 g with 80 ml of water for 10 minutes. Filter into a tared dish, evaporate to dryness on a water-bath, dry at 105 °C for 1 hour, and weigh; the residue weighs not more than 2.0 mg/g.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry for 5 hours at 105 °C; it loses not more than 60 mg/g.

pH value. Shake 2 g with 100 ml of carbon-dioxide-free water R for 5 minutes; pH of the supernatant liquid, 5.0-7.5.

Organic impurities. Place 10 mg on a watch-glass and add 0.05 ml of a freshly prepared solution of 0.1 g of phloroglucinol R in 5 ml of hydrochloric acid (~420 g/l) TS; no red colour appears.

Starch and dextrins. Shake 0.1 g with 5 ml of water and add 0.2 ml of iodine (0.05 mol/l) VS; no blue or red-brown colour develops.

Monographs: Pharmaceutical substances: Cellacefatum - Cellacefate

2009-07-17T07:12:00.001-07:00

Chemical name. Cellulose acetate phthalate; cellulose acetate 1,2-benzenedicarboxylate; CAS Reg. No. 9004-38-0.

Other names. Cellulose acetate phthalate; cellacephate.

Description. A white, free-flowing powder or colourless flakes; odourless or with a faint odour of acetic acid.

Solubility. Practically insoluble in water and ethanol (~750 g/l) TS; freely soluble in acetone R; soluble in dioxan R; dissolves in dilute solutions of alkali.

Category. Enteric coating agent for solid oral dosage forms.

Storage. Cellacefate should be kept in a well-closed container, and stored in a cool and dry place.

Additional information. Cellacefate is hygroscopic.

Requirements

Definition. Cellacefate is a cellulose, some of the hydroxyl groups of which are esterified by phthaloyl groups and others by acetyl groups.

Cellacefate contains not less than 30.0% and not more than the equivalent of 40.0% of phthaloyl groups (C₈H₅O₃, relative molecular mass = 149.1) and not less than 17.0% and not more than the equivalent of 26.0% of acetyl groups (C₂H₃O, relative molecular mass = 43.05), both calculated with reference to the anhydrous substance.

Identity tests

A. To 10 mg add 1.0 ml of ethanol (~750 g/l) TS and 1 ml of sulfuric acid (~1760 g/l) TS, and warm; ethyl acetate, perceptible by its odour (proceed with caution), is produced.

B. Transfer 10 mg to a small test-tube, add 10 mg of resorcinol R and 0.5 ml of sulfuric acid (~1760 g/l) TS, and mix. Heat in a liquid bath at 160 °C for 3 minutes. Cool and pour the solution into a mixture of 25 ml of sodium hydroxide (1 mol/l) VS and 200 ml of water; a vivid green fluorescence is observed in the solution.

C. Dissolve 0.1 g in 1 ml of acetone R and pour onto a clear glass plate; as the solvent evaporates, a glossy, clear film remains.

Free acid. Shake 1.0 g of finely powdered material with 100 ml of carbon-dioxide-free water R for 5 minutes and filter. Wash the flask and the filter with two quantities, each of 10 ml, of carbon-dioxide-free water R. Combine the filtrate and washings, add 0.1 ml of phenolphthalein/ethanol TS, and titrate with carbonate-free sodium hydroxide (0.1 mol/l) VS until a faint pink colour is obtained. Repeat the procedure without the Cellacefate being examined and make any necessary corrections.

Each ml of carbonate-free sodium hydroxide (0.1 mol/l) VS is equivalent to 8.306 mg of phthalic acid. Not more than 60 mg/g (6.0%) is found, calculated as phthalic acid and with reference to the anhydrous substance.

Sulfated ash. Not more than 1.0 mg/g.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using 0.5 g and 20 ml of a mixture of equal volumes of dehydrated methanol R and chloroform R; the water content is not more than 50 mg/g (5.0%).

Assays

A. Phthaloyl groups . Dissolve about 0.4 g, accurately weighed, in 20 ml of ethylene glycol monomethyl ether R previously neutralized using 0.1 ml of phenolphthalein/ethanol TS. Titrate with carbonate-free sodium hydroxide (0.1 mol/l) VS until a faint pink colour is obtained.

Calculate the content of phthaloyl groups in %:

where n is the number of ml of carbonate-free sodium hydroxide (0.1 mol/l) VS used, a is the content of water in %, m is the mass of Cellacefate in g, and S is the content of free acid in %.

B. Acetyl groups . To about 0.1 g, accurately weighed, add 25 ml of carbonate-free sodium hydroxide (0.1 mol/l) VS and heat on a water-bath under a reflux condenser for 30 minutes. Cool, add 0.1 ml of phenolphthalein/ethanol TS, and titrate with hydrochloric acid (0.1 mol/l) VS until the colour is discharged. Repeat the procedure without the Cellacefate being examined and make any necessary corrections.

Calculate the content of acetyl groups in %:

where n₂ is the number of ml of hydrochloric acid (0.1 mol/l) VS used for the blank, n₁ is the number of ml of hydrochloric acid (0.1 mol/l) VS used for Cellacefate, a is the content of water in %, m is the mass of Cellacefate in g, P is the content of phthaloyl groups in %, and S is the content of free acid in %.

Monographs: Pharmaceutical substances: Carmellosum natricum - Carmellose sodium

2009-07-17T07:11:00.001-07:00

Chemical name. Cellulose carboxymethyl ether, sodium salt; CAS Reg. No. 9004-32-4.

Other name. Carboxymethylcellulose sodium.

Description. A white to faintly yellowish powder or granules; odourless.

Solubility. Easily dispersed in water giving a colloidal solution; practically insoluble in acetone R, ethanol (~750 g/l) TS, ether R, and toluene R.

Category. Suspending agent; tablet binder and disintegrant; viscosity-increasing agent.

Storage. Carmellose sodium should be kept in a tightly closed container.

Labelling. The designation on the container of Carmellose sodium should state its viscosity.

Additional information. Carmellose sodium is hygroscopic after drying. This substance is not necessarily suitable for the manufacture of parenteral preparations.

Requirements

Definition. Carmellose sodium is the sodium salt of a partially substituted polycarboxymethyl ether of cellulose.

Carmellose sodium contains not less than 6.5% and not more than the equivalent of 10.8% of Na, calculated with reference to the dried substance.

Identity tests

A. Sprinkle 1.0 g of powdered Carmellose sodium onto 90 ml of carbon-dioxide-free water R at 40-50 °C, stir vigorously until a colloidal solution is produced, cool, and dilute to 100 ml with carbon-dioxide-free water R. Transfer 0.5 ml to a test-tube (keep the remaining solution for "Chlorides", "Clarity and colour of solution", and "pH value"), add 1 ml of water and 5 drops of 1-naphthol TS1, mix, and carefully introduce down the side of the tube 2 ml of sulfuric acid (~1760 g/l) TS to form a lower layer; a red-violet colour develops at the interface.

B. To the sulfated ash, add 1 ml of hydrochloric acid (~420 g/l) TS, evaporate to dryness on a water-bath, and dissolve the residue in 20 ml of water. Use 5 ml, keeping the remaining solution for "Heavy metals"; it yields reaction B described under 2.1 General identification tests as characteristic of sodium.

Heavy metals. Use 12 ml of the solution remaining from identity test B and determine the heavy metals content as described under 2.2.3 Limit test for heavy metals, Method A; not more than 40 μg/g.

Chlorides. Use 10 ml of the solution prepared for identity test A and proceed as described under 2.2.1 Limit test for chlorides; the chloride content is not more than 2.5 mg/g.

Clarity and colour of solution. The solution prepared in identity test A is not more opalescent than opalescence standard TS3 and not more intensely coloured than standard colour solution Yw2 when compared as described under 1.11 Colour of liquids.

Sulfated ash. Use 1.0 g and a mixture of equal volumes of sulfuric acid (~1760 g/l) TS and water. Calculate the result with reference to the dried substance; 0.200 g/g - 0.333 g/g corresponding to a content of Na equivalent to 6.5-10.8%. (Keep the residue for identity test B.)

Loss on drying. Dry to constant mass at 105 °C; it loses not more than 100 mg/g.

pH value. pH of the solution prepared for identity test A, 6.0-8.5.

Monographs: Pharmaceutical substances: Carbomerum - Carbomer

2009-07-17T07:07:00.000-07:00

Chemical name. Acrylic acid polymer with sucrose polyalkyl ether; carbomer; CAS Reg. No. 9007-20-9.

Description. A white, fluffy powder; odour, slight, characteristic.

Solubility. After neutralization with alkali hydroxides or amines, soluble in water, ethanol (~750 g/l) TS, and glycerol R.

Category. Suspending agent.

Storage. Carbomer should be kept in a tightly closed container.

Additional information. Carbomer is very hygroscopic.

Requirements

Definition. Carbomer is a synthetic high molecular mass polymer of allyl acid copolymerized with polysucrose.

Carbomer contains not less than 56.0% and not more than the equivalent of 68.0% of carboxylic acid groups (-COOH), calculated with reference to the dried substance.

Identity tests

A. Disperse 0.5 g in 50 ml of water. To 10 ml add a few drops of thymol blue/ethanol TS; the colour of the dispersion is orange. To a further 10 ml add a few drops of cresol red/ethanol TS; the colour is yellow. (Keep the dispersion for test B.)

B. Adjust the pH of the dispersion from test A to about 7.5 with sodium hydroxide (1 mol/l) VS; a very viscous gel is produced.

Yield value. Prepare a gel as follows: Carefully add 2.5 g to 500 ml of water containing 0.25 g of sodium chloride R in a 1000-ml beaker, stirring continuously at 990-1010 revolutions per minute, the stirrer shaft set to one side of the beaker and near to the bottom at an angle of 60° from the vertical. Add Carbomer being examined slowly at a uniform rate over 45-90 seconds, ensuring that any loose aggregates of powder are broken up. Continue to stir for 15 minutes, remove the stirrer, and allow the beaker containing the dispersion to stand in a water-bath at a temperature of 24.8-25.2 °C for 30 minutes. Insert the stirrer to a depth such that air is not drawn into the dispersion and, while stirring at 290-310 revolutions per minute, add 0.2 ml of phenolphthalein/ethanol TS and 1.5 ml of bromothymol blue/ethanol TS. Add rapidly below the surface 5 ml of sodium hydroxide (~200 g/l) TS and stir for 2-3 minutes until neutralization is reached, indicated by a uniform blue colour. Adjust the pH to 7.3-7.8 potentiometrically, using glass and calomel electrodes, either adding more sodium hydroxide (~200 g/l) TS or preparing a new mucilage using less sodium hydroxide for the neutralization. Return the neutralized mucilage to the water-bath maintained at 25 °C for 1 hour.

The apparatus consists of two clear soda-glass plates, 100 mm × 100 mm × 3 mm. Rub together by hand fine carborundum paste using two opposing faces of the plates to obtain an even and matt surface. With a diamond marker engrave the plates to show centre and corner alignments and four sample location points equidistant from the plate centre and the four corners.

Place the plates in a water-bath at 24.8-25.2 °C to settle, and dry them rapidly before use. Apply 0.1 g of the mucilage to the matt surface of one of the plates at each location for the sample. Align the second plate and lower it carefully, matt side downwards, onto the lower plate. Top the apparatus with a weight so that the combined mass applied equals 100 g. Allow the assembly to stand for 10 minutes and measure the diameters of the 4 zones of each sample using a strip of paper calibrated in mm; the mean diameter of the zones does not exceed 2.0-2.2 cm.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry at 80 °C for 1 hour; it loses not more than 20 mg/g.

Assay. Slowly add 0.4 g, accurately weighed and previously dried at 80 °C for 1 hour, to 400 ml of water while mixing with a magnetic stirrer until completely dissolved. At reduced stirring speed, titrate potentiometrically, using glass and calomel electrodes, with sodium hydroxide (0.2 mol/l) VS. After each addition of sodium hydroxide and before recording the pH of the solution, allow to stir for 1 minute.

Each ml of sodium hydroxide (0.2 mol/l) VS is equivalent to 9.004 mg of carboxylic acid groups (-COOH).

Monographs: Pharmaceutical substances: Carbo activatus - Charcoal, activated

2009-07-17T01:19:00.000-07:00

Description. Fine, black powder, free from grittiness; odourless.

Solubility. Practically insoluble in water and in all usual solvents.

Category. General-purpose antidote; pharmaceutic aid.

Storage. Activated Charcoal should be kept in a well-closed container.

Additional information. Activated Charcoal is a tasteless powder.

Requirements

Identity test. Heat a small quantity of the test substance to redness; it burns slowly without a flame.

Heavy metals. Boil 1 g with a mixture of 20 ml of hydrochloric acid (~70 g/l) TS and 5 ml of bromine TS1 for 5 minutes, filter, and wash with 50 ml of boiling water. Evaporate the combined filtrates to dryness on a water-bath and add to the residue 1 ml of hydrochloric acid (1 mol/l) VS, 20 ml of water, and 5 ml of sulfurous acid TS. Boil the solution until all the sulfur dioxide has been expelled, filter if necessary, and dilute with water to 50 ml. Use 10 ml as the test solution and determine the content of heavy metals as described under 2.2.3 Limit test for heavy metals, according to Method A; not more than 100 μg/g.

Cyanides. In a distillation apparatus, heat 5 g carefully with 50 ml of water and 2 g of tartaric acid R. Collect about 25 ml of distillate in a mixture of 10 ml of water and 2 ml of sodium hydroxide (1 mol/l) VS and dilute to 50 ml with water. To 25 ml add 0.05 g of ferrous sulfate R and heat until boiling starts. Cool in a water-bath at 70°C and acidify with 10 ml of hydrochloric acid (~250 g/l) TS; no green or blue colour develops.

Sulfides. To 1 g in a small conical flask, add 20 ml of water and 5 ml of hydrochloric acid (~250 g/l) TS; the escaping vapours do not darken a strip of filter paper moistened with lead acetate (80 g/l) TS.

Zinc. To 1 g add 25 ml of nitric acid (~130 g/l) TS and heat to boiling for 5 minutes; filter through sintered glass and wash with 10 ml of hot water. Determine the content of zinc either by a dithizone method (A) or by atomic absorption spectrophotometry (B):

A. To 10 ml of the clear solution obtained as described above add successively 3.0 ml of water, 3.0 ml of sodium acetate (60 g/l) TS, 5.0 ml of cyanide/oxalate/thiosulfate TS, and 5.0 ml of a freshly prepared 30 mg/ml solution of dithizone R in carbon tetrachloride R, Mix thoroughly for 2-3 minutes. Separate the dithizone-layer and place in a suitable comparison tube. To 0.5 ml of zinc standard (20 μg/ml Zn) TS add 9.5 ml of water and treat it in the same manner as above. The solution of the test substance shows by reflection a more intense violet colour and, by transmitted light, a not more intense violet colour than the reference solution.

B. Dilute appropriately the solution obtained as described above and proceed as described under 1.8 Atomic spectrometry: emission and absorption.

Fluorescent substances. In an apparatus for intermittent extraction, treat 10 g with 100 ml of cyclohexane R1 for 2 hours. Collect the cyclohexane extract, adjust the volume to 100 ml, and examine in ultraviolet light (365 nm). The fluorescence of the solution is not more intense than that of a solution containing 0.083 mg of quinine R in 1000 ml of sulfuric acid (0.005 mol/l) VS.

Ethanol-soluble substances. In a flask fitted with a reflux condenser, heat 2 g with 50 ml of ethanol (~750 g/l) TS. Boil for 10 minutes, filter immediately, cool, and readjust the volume to 50 ml with ethanol (~750 g/l) TS; the filtrate is not more intensely coloured than reference solution Yw1. Evaporate 40 ml of the filtrate, dry the residue at 105°C, and weigh; not more than 8 mg (5 mg/g).

Acid-soluble substances. Boil 1 g with a mixture of 20 ml of water and 5 ml of hydrochloric acid (~420 g/l) TS for 5 minutes, filter into a tared porcelain crucible, and wash the residue with 10 ml of hot water, adding the washings to the filtrate. To the combined filtrate and washings add 1 ml of sulfuric acid (~1760 g/l) TS, evaporate to dryness, and ignite to constant weight; not more than 35 mg/g.

Alkali-soluble coloured matter. Heat 0.25 g with 10 ml of sodium hydroxide (~80 g/l) TS for 1 minute, cool and filter. Dilute the filtrate to 10 ml with water; the colour is not more intense than reference solution Gn2.

Sulfated ash. Not more than 50 mg/g.

Loss on drying. Dry for 4 hours at 120°C; it loses not more than 150 mg/g.

Acidity or alkalinity. To 2 g add 40 ml of water and heat to boiling for 5 minutes. Cool, restore to the original volume with freshly boiled and cooled water and filter. Reject the first 20 ml of filtrate. The filtrate does not induce any colour change in red or blue litmus paper R. To 10 ml of the filtrate add 0.25 ml of bromothymol blue/ethanol TS and 0.25 ml of sodium hydroxide (0.02 mol/l) VS; the solution is blue. Add 0.75 ml of hydrochloric acid (0.02 mol/l) VS; the solution turns yellow.

Adsorbing power

A. Place 1 g, previously dried at 120°C for 4 hours, in a solution of 100 mg of strychnine sulfate R in 50 ml of water and shake for 5 minutes; filter, rejecting the first 10 ml of filtrate. To a 10-ml portion of the filtrate add 1 drop of hydrochloric acid (~420 g/l) TS and 5 drops of potassio-mercuric iodide TS; no turbidity is produced.

B. To each of two glass-stoppered 100-ml flasks transfer 50 ml of methylthioninium chloride (1 g/l) TS. To one of the flasks add 0.25 g, accurately weighed, of the test substance, insert the stopper in the flask and shake for 5 minutes. Filter the contents of each flask, rejecting the first 20 ml of each filtrate. Transfer 25-ml portions of the filtrates to two 250-ml volumetric flasks. Add to each flask 50 ml of sodium acetate (60 g/l) TS, mix, and add from a burette 35.0 ml of iodine (0.05 mol/l) VS, swirling the mixture during the addition. Stopper the flasks and allow them to stand for 50 minutes, shaking them vigorously at 10-minute intervals. Dilute each mixture with water to volume, mix, allow to stand for 10 minutes, and filter, rejecting the first 30 ml of each filtrate. Titrate the excess iodine in a 100-ml aliquot of each filtrate with sodium thiosulfate (0.1 mol/l) VS, adding 3 ml of starch TS towards the end of the titration. Calculate the number of ml of iodine (0.05 mol/l) VS consumed in each titration; the difference between the two volumes is not less than 0.7 ml.

Monographs: Pharmaceutical substances: Carbidopum - Carbidopa

2009-07-17T01:18:00.002-07:00

Molecular formula. C₁₀H₁₄N₂O₄,H₂O

Relative molecular mass. 244.2

Graphic formula.

Chemical name. (-)-L-α-Hydrazino-3,4-dihydroxy-α-methylhydrocinnamic acid monohydrate; (S)-α-hydrazino-3,4-dihydroxy-α-methylbenzenepropanoic acid monohydrate; CAS Reg. No. 38821-49-7 (monohydrate).

Description. A white to creamy white powder; odourless or almost odourless.

Solubility. Slightly soluble in water; very slightly soluble in ethanol (~750 g/l) TS; practically insoluble in ether R.

Category. Antiparkinsonism drug.

Storage. Carbidopa should be kept in a well-closed container, protected from light.

Requirements

Definition. Carbidopa contains not less than 99.0% and not more than 101.0% of C₁₀H₁₄N₂O₄, calculated with reference to the anhydrous substance.

Identity tests

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from carbidopa RS or with the reference spectrum of carbidopa.

B. To 5 mg add 1 ml of water, 1 ml of pyridine R, and 5 mg of 4-nitrobenzoyl chloride R, mix and allow to stand for 3 minutes; the solution remains colourless, but after boiling changes to a pale yellow colour. While shaking, add 0.1 ml of sodium carbonate (200 g/l) TS; an orange colour is produced.

Specific optical rotation. Use a 10 mg/ml solution in aluminium chloride TS and calculate with reference to the anhydrous substance; .

Sulfated ash. Not more than 1.0 mg/g.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 0.5 g of the substance; the water content is not less than 69 mg/g and not more than 79 mg/g.

Methyldopa and 3-O-Methylcarbidopa. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column 20 cm long and 4 mm in internal diameter packed with particles of silica gel, 10 μm in diameter, the surface of which has been modified with chemically bonded octylsilyl groups. As the mobile phase, use a mixture of 98 volumes of potassium dihydrogen phosphate (13.6 g/l) TS and 2 volumes of methanol R at a flow rate of 1.5 ml per minute. As detector use an ultraviolet spectrophotometer at a wavelength of about 282 nm, fitted with a low-volume flow cell (10 μl is suitable).

Prepare the following solutions in hydrochloric acid (0.1 mol/l) VS containing (A) 0.050 mg of methyldopa RS, 0.050 mg of (-)-3-(4-hydroxy-3-methoxyphenyl)-2-hydrazino-2-methylalanine RS and 0.10 mg of (-)-3-(4-hydroxy-3-methoxyphenyl)-2-methylalanine RS per ml, the last serving as an internal standard, (B) 10 mg of the test substance per ml, and (C) 10 mg of the test substance and 0.10 mg of the internal standard per ml.

In the chromatogram obtained with solution A the peaks, excluding the solvent peak, are due to (a) methyldopa, (b) (-)-3-(4-hydroxy-3-methoxyphenyl)-2-methylalanine and (c) (-)-3-(4-hydroxy-3-methoxyphenyl)-2-hydrazino-2-methylalanine in order of their emergence. The ratios of the areas of the peaks (a) and (c) to the area of the peak due to the internal standard are greater than the corresponding ratios in the chromatogram obtained with solution C.

Assay. Dissolve about 0.3 g, accurately weighed, in 25.0 ml of perchloric acid (0.1 mol/l) VS with the aid of a minimum of heat. Titrate the excess perchloric acid with sodium acetate/glacial acetic acid (0.1 mol/l) VS, determining the end-point potentiometrically as described under 2.6 Non-aqueous titration, Method A. Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 22.62 mg of C₁₀H₁₄N₂O₄.

Monographs: Pharmaceutical substances: Carbamazepinum - Carbamazepine

2009-07-17T01:18:00.001-07:00

Molecular formula. C₁₅H₁₂N₂O

Relative molecular mass. 236.3

Graphic formula.

Chemical name. 5H-Dibenz[b,f]azepine-5-carboxamide; CAS Reg. No. 298-46-4.

Description. A white to yellowish white, crystalline powder; odourless or almost odourless.

Solubility. Practically insoluble in water and ether R; soluble in ethanol (~750 g/l) TS.

Category. Antiepileptic drug.

Storage. Carbamazepine should be kept in a tightly closed container.

Requirements

Definition. Carbamazepine contains not less than 98.0% and not more than 102.0% of C₁₅H₁₂N₂O, calculated with reference to the dried substance.

Identity tests

• Either test A or tests B, C and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum obtained from the test substance without pretreatment is concordant with the spectrum obtained from carbamazepine RS or with the reference spectrum of carbamazepine.

B. See the test described below under "Related substances". The principal spot obtained with solution C corresponds in position, appearance, and intensity with that obtained with solution D.

C. Expose a small amount of the test substance to ultraviolet light (365 nm); an intense blue fluorescence is observed.

D. Heat 0.1 g with 2 ml of nitric acid (~1000 g/l) TS in a water-bath for 3 minutes; an orange-red colour is produced.

Melting range. 189-193 °C.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 5.0 mg/g.

Acidity or alkalinity. Stir 1.0 g with 20 ml of carbon-dioxide-free water R for 15 minutes and filter. To 10 ml of the filtrate add 0.1 ml of phenolphthalein/ethanol TS and titrate with carbonate-free sodium hydroxide (0.01 mol/l) VS; not more than 0.5 ml is required to obtain a pink colour. Add 0.15 ml of methyl red/ethanol TS and titrate with hydrochloric acid (0.01 mol/l) VS; not more than 1.0 ml is required to obtain a red colour.

Related substances. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 86 volumes of toluene R and 14 volumes of methanol R as the mobile phase. Apply separately to the plate 2 μl of each of 5 solutions in a mixture of equal volumes of ethanol (~750 g/l) TS and chloroform R containing (A) 0.050 g of the test substance per ml, (B) 0.050 mg of iminodibenzyl R per ml, (C) 5.0 mg of the test substance per ml, (D) 5.0 mg of carbamazepine RS per ml, and (E) 5.0 μg of carbamazepine RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, spray it with potassium dichromate TS3, and examine the chromatogram in daylight. Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B. Then heat the plate at 140 °C for 15 minutes and examine the chromatogram in ultraviolet light (254 nm). Any additional spot obtained with solution A is not more intense than that obtained with solution E.

Assay. Dissolve about 0.1 g, accurately weighed, in sufficient ethanol (~750 g/l) TS to produce 100 ml. Dilute 10 ml of this solution to 100 ml with the same solvent, and again dilute 10 ml of this dilution to 100 ml with ethanol (~750 g/l) TS. Measure the absorbance of a 1-cm layer of the resulting solution at the maximum at about 285 nm. Calculate the amount of C₁₅H₁₂N₂O in the substance being tested by comparison with carbamazepine RS, similarly and concurrently examined. In an adequately calibrated spectrophotometer the absorbance of the reference solution should be 0.49 ± 0.02.

Monographs: Pharmaceutical substances: Captoprilum - Captopril

2009-07-17T01:17:00.002-07:00

C₉H₁₅NO₃S

Relative molecular mass. 217.3

Chemical name. 1-[(2S)-3-Mercapto-2-methylpropionyl]-L-proline; 1-[(2S)-3- mercapto-2-methyl-1-oxopropyl]-L-proline; CAS Reg. No. 62571-86-2.

Description. A white or almost white, crystalline powder.

Solubility. Freely soluble in water, dichloromethane R, and methanol R.

Category. Cardiovascular agent; angiotensin-converting enzyme inhibitor.

Storage. Captopril should be kept in a tightly closed container, protected from light.

Additional information. Captopril may exist in different polymorphic forms.

Requirements

Captopril contains not less than 98.0% and not more than 102.0% of C₉H₁₅NO₃S, calculated with reference to the dried substance.

Identity tests

• Either tests A and D or tests B, C, and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from captopril RS or with the reference spectrum of captopril.

B. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R4 as the coating substance and a mixture of 75 volumes of toluene R, 25 volumes of glacial acetic acid R, and 1 volume of methanol R as the mobile phase. Apply separately to the plate 2 μl of each of 2 solutions in dichloromethane R containing (A) 5.0 mg of Captopril per ml, and (B) 5.0 mg of captopril RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, and spray with 5,5¢- dithiobis-2-nitrobenzoic acid/methanol TS. Examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.

C. Dissolve 25 mg in 2 ml of ethanol (~750 g/l) TS, add a few crystals of sodium nitrite R and 10 ml of sulfuric acid (~100 g/l) TS, and shake; a red colour is produced.

D. Melting temperature, about 107 °C.

Specific optical rotation. Use a 10 mg/ml solution in dehydrated ethanol R and calculate with reference to the dried substance;

Sulfated ash. Not more than 2.0 mg/g.

Loss on drying. Dry at 60°C under reduced pressure (not exceeding 0.6kPa or about 5mm of mercury) for 3 hours; it loses not more than 10 mg/g.

Related substances. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (12.5cm × 4mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5 μm). Prepare the following solution to be used as the mobile phase: mix 0.05 volumes of phosphoric acid (~1440 g/l) TS with 50 volumes of methanol R and 50 volumes of water.

Prepare the following solutions in the mobile phase: solution (A) 0.5 mg of Captopril per ml; solution (B) 10μg of Captopril per ml; and for solution (C) dissolve 10 μg of Captopril in the mobile phase, add 1 ml of iodine (0.05 mol/l) VS, and dilute to 100 ml with the mobile phase; further dilute 10 ml of this solution to 100 ml with the mobile phase.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of about 220nm.

Inject 20 μl of solution B and adjust the sensitivity of the system so that the height of the principal peak is not less than 40% of the full scale of the recorder. Inject 20 μl of solution C. The test is not valid unless three peaks are obtained and the resolution between the last two eluting principal peaks is at least 2.0.

Inject alternately 20 μl each of solutions A and B. Continue the chromatography for three times the retention time of the principal peak obtained with solution A.

Measure the areas of the peak responses obtained in the chromatograms from solutions A and B, and calculate the content of the related substances as a percentage. In the chromatogram obtained with solution A, the area of any peak, other than the principal peak, is not greater than half the area of the principal peak obtained with solution B (1.0%). The sum of the areas of all the peaks, other than the principal peak, is not greater than the area of the peak obtained with solution A (2.0%). Disregard any peak with a retention time of less than 1.4 minutes or with an area less than 0.1 times that of the peak obtained with solution B.

Assay. Dissolve about 0.3 g, accurately weighed, in 100 ml of water, add 10ml of sulfuric acid (~190 g/l) TS and 1 g of potassium iodide R. Mix and titrate with potassium iodate (0.01 mol/l) VS, using starch TS as indicator. Repeat the operation without the substance being examined. The difference between the titrations represents the amount of potassium iodate required.

Each ml of potassium iodate (0.01 mol/l) VS is equivalent to 13.04mg of C₉H₁₅NO₃S.

Monographs: Pharmaceutical substances: Calcii sulfas - Calcium sulfate

2009-07-17T01:17:00.001-07:00

CaSO₄,2H₂O

Relative molecular mass. 172.2

Chemical name. Calcium sulfate (1:1) dihydrate; CAS Reg. No. 10101-41-4.

Description. A white to almost white, fine powder; odourless or almost odourless.

Solubility. Slightly soluble in water; more soluble in dilute mineral acids; practically insoluble in most organic solvents.

Category. Tablet and capsule diluent.

Storage. Calcium sulfate should be kept in a well-closed container.

Requirements

Calcium sulfate contains not less than 98.0% and not more than the equivalent of 101.0% of CaSO₄, calculated with reference to the dried substance.

Identity tests

Dissolve 1 g in 20 ml of a solution prepared by mixing equal volumes of water and hydrochloric acid (~420 g/l) TS. Heat to boiling for 2 minutes, cool, and filter if necessary. Use this solution for the following tests:

A. The solution yields the reactions described under 2.1 General identification tests as characteristic of calcium.

B. The solution yields the reactions described under 2.1 General identification tests as characteristic of sulfates.

Heavy metals. To 1.0 g add 10 ml of water and 20 ml of hydrochloric acid (~70 g/l) TS, heat to boiling until dissolved, cool, and adjust the pH as described under 2.2.3 Limit test for heavy metals, Procedure 1; determine the heavy metals content according to Method A; not more than 20 μg/g.

Clarity of solution. Dissolve 1 g in a mixture of 45 ml of water and 5 ml of hydrochloric acid (~420 g/l) TS, heating to 50 °C for 5 minutes; the solution is clear.

Loss on drying. Dry to constant mass at a temperature not lower than 250 °C; it loses not less than 190 mg/g and not more than 230 mg/g.

pH value. Slurry 20 g with 80 ml of carbon-dioxide-free water R, allow to settle, and filter, 6.0-7.6.

Assay. To about 0.3 g, accurately weighed, add a mixture of 100 ml of water and 6 ml of hydrochloric acid (~70 g/l) TS, heat to boiling until dissolved, and allow to cool. Proceed with the titration as described under 2.5 Complexometric titrations for calcium.

Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 6.807 mg of CaSO₄.

Monographs: Pharmaceutical substances: Calcii stearas - Calcium stearate

2009-07-17T01:16:00.001-07:00

C₃₆H₇₀CaO₄

Chemical name. Calcium stearate; calcium octadecanoate; CAS Reg. No. 1592-23-0.

Description. A white to yellowish white, fine, bulky powder; odour, slight, characteristic.

Solubility. Practically insoluble in water, ethanol (~750 g/l) TS, acetone R, and ether R.

Category. Tablet and capsule lubricant.

Storage. Calcium stearate should be kept in a well-closed container.

Additional information. The degree of lubrication depends on the particular form and size of the material.

Requirements

Definition. Calcium stearate consists of calcium salts mainly of stearic acid and palmitic acid in variable proportions.

Calcium stearate contains not less than 9.0% and not more than the equivalent of 10.5% of CaO, calculated with reference to the dried substance.

Identity tests

A. Heat 1 g with a mixture of 25 ml of water and 5 ml of hydrochloric acid (~420 g/l) TS; fatty acids are liberated and float as an oil on the surface of the liquid. The aqueous layer yields the reactions described under 2.1 General identification tests as characteristic of calcium.

B. Mix 25 g with 200 ml of hot water, add 60 ml of sulfuric acid (~100 g/l) TS, and heat the mixture until the separated fatty acids layer is clear. Wash it with boiling water until free from sulfates, transfer it to a beaker, and warm on a water-bath until the water separates and the fatty acids are clear. Allow to cool, pour off the water layer, melt the fatty acids, and filter into a dry beaker. Dry at 105 °C for 20 minutes; congealing temperature, not lower than 54 °C.

Loss on drying. Heat at 105 °C for 2 hours and weigh; repeat the heating using 2-hour increments until a constant mass is obtained; not more than 40 mg/g.

Assay. To about 1.2 g, accurately weighed, add 50 ml of hydrochloric acid (0.1 mol/l) V, and heat to boiling for 10 minutes or until the separated fatty acids layer is clear, adding water if necessary to maintain the original volume. Cool, filter, and wash the filter and the flask thoroughly with water until the washing is free from acid when tested with litmus paper R. Neutralize the filtrate with sodium hydroxide (1 mol/l) VS against litmus paper R and proceed with the titration as described under 2.5 Complexometric titrations for calcium.

Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 2.804 mg of CaO

Monographs: Pharmaceutical substances: Calcii phosphas - Calcium phosphate

2009-07-17T01:15:00.002-07:00

Chemical name. Calcium phosphate (3:2) mixture with calcium phosphate (1:1); CAS Reg. No. 7758-87-4 [Ca₃(PO₄)₂]; CAS Reg. No. 7757-93-9 (CaHPO₄).

Other name. Tribasic calcium phosphate.

Description. A white, amorphous powder; odourless or almost odourless.

Solubility. Practically insoluble in water and ethanol (~750 g/l) TS; soluble in hydrochloric acid (~70 g/l) TS and nitric acid (~130 g/l) TS.

Category. Tablet diluent.

Storage. Calcium phosphate should be kept in a well-closed container.

Additional information. At relative humidities between 15% and 65%, the equilibrium moisture content at 25 °C is about 2%, but at relative humidities above 75% small additional amounts of moisture are absorbed.

Requirements

Definition. Calcium phosphate is a mixture consisting mainly of Ca₃(PO₄)₂together with CaHPO₄.

Calcium phosphate contains not less than 34.0% and not more than the equivalent of 40.0% of calcium, Ca, calculated with reference to the ignited substance.

Identity tests

A. Dissolve 0.05 g in 1 ml of hydrochloric acid (~70 g/l) TS by gentle warming and add 4 ml of water and 0.5 g of sodium acetate R. It yields reaction A described under 2.1 General identification tests as characteristic of calcium.

B. To 0.5 g add 2 ml of nitric acid (~130 g/l) TS and heat gently. This solution yields reaction A described under 2.1 General identification tests as characteristic of orthophosphates.

Heavy metals. For the preparation of the test solution use 1.0 g dissolved in 10 ml of hydrochloric acid (~70 g/l) TS. Heat to boiling, cool, dilute to 40 ml with water, and mix. Determine the heavy metals content as described under 2.2.3 Limit test for heavy metals, Method A; not more than 30 μg/g.

Arsenic. Use a solution of 3.3 g in 35 ml of hydrochloric acid (~70 g/l) TS, heat to dissolve and proceed as described under 2.2.5 Limit test for arsenic; the arsenic content is not more than 3 μg/g.

Barium. Mix 0.5 g with 10 ml of water, heat, and add, drop by drop, hydrochloric acid (~420 g/l) TS until solution is effected. Add an excess of 2 drops of acid, filter, and to the filtrate add 1 ml of potassium sulfate (0.1 g/l) TS; no turbidity appears within 15 minutes.

Carbonates. Suspend 5 g in 30 ml of carbon-dioxide-free water R and add slowly 10 ml of hydrochloric acid (~70 g/l) TS; not more than a slight effervescence is observed. (Keep the solution for "Acid-insoluble substances".)

Chlorides. Dissolve 0.2 g in a mixture of 2 ml of nitric acid (~130 g/l) TS and 20 ml of water, and proceed as described under 2.2.1 Limit test for chlorides; the chloride content is not more than 1.4 mg/g.

Fluorides. Prepare and store all solutions in plastic containers.

Weigh 2.0 g of the test sample into a beaker, add 20 ml of water and 3 ml of hydrochloric acid (~250 g/l) TS. Using a magnetic stirrer and a plastic-coated stirring bar, stir until the sample has dissolved. Then add 50 ml of sodium citrate (250 g/l) TS and dilute to 100 ml with water. Use a fluoride-ion-sensitive electrode and a silver/silver chloride reference electrode system, connected to a potentiometer capable of indicating reproducibly a minimum of ±0.2 mV. Insert the previously rinsed and dried electrodes into the solution, stir for 5 minutes, and read the potential in mV.

Prepare a standard solution of fluoride ion containing 1.1052 mg sodium fluoride R per ml. To 20 ml of this solution add 50 ml of sodium citrate (250 g/l) TS and dilute with sufficient water to produce 100 ml (100 μg F/ml). For the establishment of a standard curve, place 50 ml of sodium citrate (250 g/l) TS in a beaker, add 3 ml of hydrochloric acid (~250 g/l) TS, and dilute to 100 ml with water. Stir as described above for 15 minutes, insert the electrodes, and read the potential in mV. Continue to stir, and at 5-minute intervals add 100 μl, 100 μl, 300 μl, 500 μl, and 500 μl of fluoride ion standard solution (100 μg F/ml), equivalent to the cumulative fluoride ion concentration of 0.1, 0.2, 0.5, 1.0, and 1.5 μg/ml, reading the potential 5 minutes after each addition. Plot the logarithms of the cumulative fluoride ion concentration versus potential.

Determine the concentration of fluoride ion in the solution being examined, reading off from the standard curve the value of mV correlating with the μg of F/ml, and divide by the sample mass taken to obtain the content in the sample; not more than 75 μg/g.

Sulfates. Dissolve 0.1 g in 5 ml of hydrochloric acid (~70 g/l) TS, and proceed as described under 2.2.2 Limit test for sulfates; the sulfate content is not more than 8 mg/g.

Acid-insoluble substances. Filter the solution prepared for "Carbonates", wash the residue with water, and dry to constant mass at 105 °C; the residue weighs not more than 15 mg (0.3%).

Loss on ignition. Ignite 1.0 g at 800 °C for 30 minutes; it loses not more than 80 mg/g.

Assay. To about 0.15 g, accurately weighed, add a mixture of 5 ml of hydrochloric acid (~420 g/l) TS and 3 ml of water, use gentle heat to dissolve, and add 125 ml of water. Proceed with the titration as described under 2.5 Complexometric titrations for calcium.

Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 2.004 mg of Ca.

Monographs: Pharmaceutical substances: Calcii hydrogenophosphas - Calcium hydrogen phosphate

2009-07-17T01:15:00.001-07:00

Calcium hydrogen phosphate, anhydrous

Calcium hydrogen phosphate dihydrate

CaHPO₄ (anhydrous)

CaHPO₄,2H₂O (dihydrate)

Relative molecular mass. 136.1 (anhydrous); 172.1 (dihydrate).

Chemical name. Calcium phosphate (1:1); CAS Reg. No. 7757-93-9 (anhydrous).

Calcium phosphate (1:1) dihydrate; CAS Reg. No. 7789-77-7 (dihydrate).

Other name. Dibasic calcium phosphate.

Description. A white or almost white powder; odourless.

Solubility. Practically insoluble in cold water and ethanol (~750 g/l) TS; soluble in dilute acids.

Category. Tablet and capsule diluent.

Storage. Calcium hydrogen phosphate should be kept in a well-closed container.

Labelling. The designation on the container of Calcium hydrogen phosphate should state whether it is the dihydrate or the anhydrous form.

Requirements

Calcium hydrogen phosphate contains not less than 30.9% and not more than the equivalent of 31.7% of calcium, Ca, calculated with reference to the ignited substance.

Identity tests

A. To 0.2 g add a mixture of 10 ml of hydrochloric acid (~70 g/l) TS and 10 ml of water, and heat to dissolve. To 10 ml of this solution add 2.5 ml of ammonia (~100 g/l) TS (keep the remaining solution for test B); it yields reaction A described under 2.1 General identification tests as characteristic of calcium.

B. Acidify the remaining solution from test A with nitric acid (~130 g/l) TS; it yields reaction A described under 2.1 General identification tests as characteristic of orthophosphates.

Heavy metals. For the preparation of the test solution use 1.0 g dissolved in 10 ml of hydrochloric acid (~70 g/l) TS, filter if necessary, and add ammonia (~100 g/l) TS until a precipitate is formed. Add just sufficient hydrochloric acid (~70 g/l) TS to dissolve the precipitate and determine the heavy metals content as described under 2.2.3 Limit test for heavy metals, Method A; not more than 40 μg/g.

Arsenic. Use a solution of 1.0 g in 35 ml of hydrochloric acid (~70 g/l) TS and proceed as described under 2.2.5 Limit test for arsenic; the arsenic content is not more than 3 μg/g.

Barium. Dissolve 1.25 g in 10 ml of hydrochloric acid (~70 g/l) TS, filter if necessary, and add ammonia (~100 g/l) TS until a precipitate is formed. Add just sufficient hydrochloric acid (~70 g/l) TS to dissolve the precipitate and dilute with water to 25 ml. Place a 10-ml portion in each of two separate matched tubes. To one portion add 0.5 ml of sulfuric acid (~100 g/l) TS, and to the other 0.5 ml of water; the solutions remain equally clear when viewed after 15 minutes.

Carbonates. To 1 g add 5 ml of carbon-dioxide-free water R and 2 ml of hydrochloric acid (~420 g/l) TS and shake; no effervescence is produced.

Chlorides. Dissolve 0.1 g in a mixture of 2 ml of nitric acid (~130 g/l) TS and 20 ml of water, and proceed as described under 2.2.1 Limit test for chlorides; the chloride content is not more than 2.5 mg/g.

Fluorides. Prepare and store all solutions in plastic containers.

Weigh 2.0 g of the test sample into a beaker and add 20 ml of water and 2.0 ml of hydrochloric acid (~250 g/l) TS. Using a magnetic stirrer and a plastic-coated stirring bar, stir until the sample has dissolved. Then add 50 ml of sodium citrate (250 g/l) TS and dilute to 100 ml with water. Use a fluoride-ion-sensitive electrode and a silver/silver chloride reference electrode system, connected to a potentiometer capable of indicating reproducibly a minimum of ±0.2 mV. Insert the previously rinsed and dried electrodes into the solution, stir for 5 minutes, and read the potential in mV.

Prepare a standard solution of fluoride ion containing 1.1052 mg sodium fluoride R per ml. To 20 ml of this solution add 50 ml of sodium citrate (250 g/l) TS and dilute with sufficient water to produce 100 ml (100 μg F/ml). For the establishment of a standard curve, place 50 ml of sodium citrate (250 g/l) TS in a beaker, add 2 ml of hydrochloric acid (~250 g/l) TS, and dilute to 100 ml with water. Stir as described above for 15 minutes, insert the electrodes, and read the potential in mV. Continue to stir, and at 5-minute intervals add 100 μl, 100 μl, 300 μl, and 500 μl of fluoride ion standard solution (100 μg F/ml), equivalent to the cumulative fluoride ion concentration of 0.1, 0.2, 0.5, and 1.0 μg/ml, reading the potential 5 minutes after each addition. Plot the logarithms of the cumulative fluoride ion concentration versus potential.

Sulfates. Dissolve 0.10 g in 5 ml of hydrochloric acid (~70 g/l) TS, and proceed as described under 2.2.2 Limit test for sulfates; the sulfate content is not more than 5 mg/g.

Acid-insoluble substances. To 5 g add a mixture of 40 ml of water and 10 ml of hydrochloric acid (~420 g/l) TS, heat until no more dissolves, and dilute to 100 ml with water. Filter any residue, wash with hot water until the washing is free of chlorides, dry the residue at 105 °C for 1 hour, and weigh; not more than 2 mg/g.

Loss on ignition. Ignite 1.0 g to constant mass between 800 and 825 °C. The anhydrous form loses not less than 66 mg/g and not more than 85 mg/g. The dihydrate loses not less than 0.245 g/g and not more than 0.265 g/g.

Assay. To about 0.2 g, accurately weighed, add a mixture of 1 ml of hydrochloric acid (~420 g/l) TS and 5 ml of water, use gentle heat to dissolve, and add 125 ml of water. Proceed with the titration as described under 2.5 Complexometric titrations for calcium.

Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 2.004 mg of Ca.

Monographs: Pharmaceutical substances: Calcii gluconas - Calcium gluconate

2009-07-17T01:14:00.002-07:00

Molecular formula. (C₆H₁₁O₇)₂Ca,H₂O

Relative molecular mass. 448.4

Graphic formula.

Chemical name. Calcium D-gluconate (1:2) monohydrate; CAS Reg. No. 299-28-5.

Description. White, crystalline granules or a white, crystalline powder; odourless.

Solubility. Slowly soluble in water; freely soluble in boiling water; practically insoluble in dehydrated ethanol R and ether R.

Category. Calcium source.

Storage. Calcium gluconate should be kept in a tightly closed container, protected from light.

Additional information. Even in the absence of light, Calcium gluconate is gradually degraded on exposure to a humid atmosphere, the decomposition being faster at higher temperatures.

Requirements

Definition. Calcium gluconate contains not less than 98.0% and not more than 102.0% of (C₆H₁₁O₇)₂Ca,H₂O, calculated as the monohydrate.

Identity tests

A. A 20 mg/ml solution yields the reactions described under 2.1 General identification tests as characteristic of calcium.

B. To 1 ml of a 30 mg/ml solution add 1 drop of ferric chloride (25 g/l) TS; a yellow colour is produced.

C. To 5 ml of a warm 0.1 g/ml solution add 0.7 ml of glacial acetic acid R and 1 ml of freshly distilled phenylhydrazine R, heat on a water-bath for 30 minutes, allow to cool, and scrape the inner surface of the tube to induce crystallization. Collect the crystals, dissolve in 10 ml of hot water, add a small amount of charcoal R, and filter. Allow the filtrate to cool, and scrape the inner surface of the tube; a white, crystalline precipitate is produced; melting temperature, about 200°C with decomposition (phenylhydrazide of gluconic acid).

Chlorides and other halides. Dissolve 0.50 g in a mixture of 2 ml of nitric acid (~130 g/l) TS and 20 ml of water, and proceed as described under 2.2.1 Limit test for chlorides; the chloride content is not more than 0.5 mg/g.

Magnesium and alkaline metals. Dissolve 1.0 g in 100 ml of boiling water, add 10 ml of ammonium chloride (100 g/l) TS, 1 ml of ammonia (~260 g/l) TS and, drop by drop, 50 ml of hot ammonium oxalate (25 g/l) TS. Allow to stand for 4 hours, dilute to 200 ml with water and filter. Evaporate 100 ml of the filtrate to dryness and ignite; the residue weighs not more than 2.0 mg.

Sulfates. Dissolve 5.0 g in 40 ml of boiling water, cool and filter. Proceed with the filtrate as described under 2.2.2 Limit test for sulfates; the sulfate content is not more than 0.1 mg/g.

Glucose and sucrose. Dissolve 0.5 g in 10 ml of hot water, add 2 ml of hydrochloric acid (~70 g/l) TS, and boil for about 2 minutes. Cool, add 15 ml of sodium carbonate (50 g/l) TS, allow to stand for 5 minutes, and filter. Add 5 ml of the clear filtrate to about 2 ml of potassio-cupric tartrate TS, and boil for 1 minute; neither a red turbidity nor any precipitate is produced.

Clarity and colour of solution. A solution of 0.50 g in 10 ml of water is clear and not more intensely coloured than standard colour solution Yw1 when compared as described under 1.11 Colour of liquids.

Assay. Dissolve about 0.5 g, accurately weighed, in 20 ml of hot water containing 2 ml of hydrochloric acid (~70 g/l) TS, allow to cool and dilute to 100 ml with water. Proceed with the titration as described under 2.5 Complexometric titrations for calcium. Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 22.42 mg of (C₆H₁₁O₇)₂Ca,H₂O.

Additional requirements for Calcium gluconate for parenteral use

Complies with the monograph for "Parenteral preparations".

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 167 IU of endotoxin RS per g.

Monographs: Pharmaceutical substances: Calcii folinas - Calcium folinate

2009-07-17T01:14:00.001-07:00

Molecular formula. C₂₀H₂₁CaN₇O₇,5H₂O

Relative molecular mass. 601.6

Graphic formula.

Chemical name.

Calcium N-[p-[[(2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl)methyl]amino]benzoyl]-L-glutamate (1:1) pentahydrate; calcium N-[4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)-methyl]amino]benzoyl]-L-glutamate (1:1) pentahydrate; CAS Reg. No. 6035-45-6 (pentahydrate).

Other name. Leucovorin calcium.

Description. A white or creamy white powder; odourless.

Solubility. Very soluble in water; practically insoluble in ethanol (~750 g/l) TS.

Category. Cytotoxic drug.

Storage. Calcium folinate should be kept in a well-closed container, protected from light.

Additional information. CAUTION: Calcium folinate must be handled with care, avoiding contact with the skin and inhalation of airborne particles.

Requirements

Definition. Calcium folinate contains not less than 95.0% and not more than 105.0% of C₂₀H₂₁CaN₇O₇, calculated with reference to the anhydrous substance.

Identity tests

• Either tests A and C or tests B, C and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from calcium folinate RS or with the reference spectrum of calcium folinate.

B. Dissolve 20 mg in 3.0 ml of water, add 0.5 ml of hydrochloric acid (~70 g/l) TS and 0.5 ml of sodium nitrite (100 g/l) TS. Shake for 2 minutes and add 1.5 ml of 2-naphthol TS1; a yellow-brown precipitate appears and the solution turns green.

C. Dissolve 20 mg in 2.0 ml of water and add 1.0 ml of ammonium oxalate (25 g/l) TS; a white precipitate is produced, which is insoluble in acetic acid (~300 g/l) TS and ammonia (~260 g/l) TS, but is soluble in hydrochloric acid (~70 g/l) TS.

D. Dissolve 20 mg in 5 ml of water and add 1.0 ml of silver nitrate (40 g/l) TS; a white, curdy precipitate is produced. Add a few drops of nitric acid (~130 g/l) TS; the precipitate dissolves.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 0.2 g of the substance; the water content is not less than 0.080 g/g and not more than 0.150 g/g.

Assay

• Use freshly deionized water throughout the procedure, and perform the assay in low-actinic glassware or protect the solutions containing calcium folinate from light. Complete the assay without prolonged interruption.

Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a column 30 cm long and 4 mm in internal diameter, packed with particles of porous silica gel or ceramic, 5-10 μm in diameter, the surface of which has been modified with chemically bonded octadecylsilyl groups.

As the mobile phase, use a mixture of 15 ml of tetrabutylammonium hydroxide/methanol TS with 835 ml of water, add 125 ml of acetonitrile R, adjust the pH to 7.5 ± 0.1 with sodium dihydrogen phosphate (275 g/l) TS, dilute with water to 1000 ml, and filter. Adjust the concentration of acetonitrile, if necessary.

Dilute the following solution for use in the preparation of the test solutions: To 15 ml of tetrabutylammonium hydroxide/methanol TS add 900 ml of water, adjust the pH to 7.5 ± 0.1 with sodium dihydrogen phosphate (275 g/l) TS, dilute with water to 1000 ml, and mix. Weigh accurately a quantity of calcium folinate RS, dissolve it in the above solution and dilute with the same solution to contain about 175 μg per ml (solution A). Dissolve 20 mg of the substance to be examined in a sufficient volume of the above solution to produce 100 ml, and mix (solution B). For the system suitability test, dissolve a quantity of folic acid RS in the above solution and dilute with the same solution to contain about 175 μg per ml. Mix 1 part of this solution with 4 parts of solution A (solution C).

Operate at a flow rate of 1-2 ml per minute. As detector use an ultraviolet spectrophotometer at a wavelength of about 254 nm, fitted with a suitable recorder.

Make 6 replicate injections, each of 15 μl of solution C. The resolution factor between calcium folinate and folic acid should be not less than 3.6, with a relative standard deviation for the calcium folinate peak of not more than 2.0%. The relative retention times for calcium folinate and folic acid are 1.0 and about 1.6, respectively.

Then inject 15 μl of each of solutions A and B. Measure the peak responses at the corresponding retention times and calculate the quantity, in %, of C₂₀H₂₁CaN₇O₇, using the following formula: 100(0.1C)(r_U/r_S) in which C is the concentration in μg per ml of calcium folinate RS in solution A, and r_U and r_S are the peak responses obtained from solutions B and A, respectively.

Additional requirements for Calcium folinate for parenteral use

Complies with the monograph for "Parenteral preparations".

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 0.5 IU of endotoxin RS per mg.

Monographs: Pharmaceutical substances: Calcii carbonas - Calcium carbonate

2009-07-17T01:13:00.002-07:00

Molecular formula. CaCO₃

Relative molecular mass. 100.1

Chemical name. Calcium carbonate (1:1); CAS Reg. No. 471-34-1.

Description. A white, fine, microcrystalline powder; odourless.

Solubility. Practically insoluble in water and ethanol (~750 g/l) TS. It dissolves with effervescence in acetic acid (~60 g/l) TS, hydrochloric acid (~70 g/l) TS, and nitric acid (~130 g/l) TS.

Category. Antacid.

Storage. Calcium carbonate should be kept in a well-closed container.

Requirements

Definition. Calcium carbonate contains not less than 98.0% and not more than 100.5% of CaCO₃, calculated with reference to the dried substance.

Identity tests

A. Dissolve 20 mg in 0.3 ml of hydrochloric acid (~70 g/l) TS and 2 ml of water, and filter. The filtrate yields the reactions described under 2.1 General identification tests as characteristic of calcium.

B. To 0.10 g add 1.0 ml of acetic acid (~300 g/l) TS; a gas evolves that is colourless and odourless. Pass the evolved gas into calcium hydroxide TS; a white precipitate is produced immediately.

Heavy metals. Dissolve 5 g in 80 ml of acetic acid (~60 g/l) TS; when effervescence ceases, boil the solution for 2 minutes, allow to cool, dilute to 100 ml with acetic acid (~60 g/l) TS and, if necessary, filter through a sintered glass filter (retain the filter for the test of substances insoluble in acetic acid). Determine the heavy metals content in 20 ml of the filtrate (keep the remaining filtrate for the limit test for barium), as described under 2.2.3 Limit test for heavy metals, according to Method A; not more than 30 μg/g.

Arsenic. Use a solution of 3.3 g in 35 ml of hydrochloric acid (~70 g/l) TS and proceed as described under 2.2.5 Limit test for arsenic; the arsenic content is not more than 3 μg/g.

Barium. To 10 ml of the filtrate retained from the limit test for heavy metals add 10 ml of calcium sulfate TS (solution A). Mix a further 10 ml of the filtrate with 10 ml of water (solution B). After not less than 15 minutes, solution A is not more opalescent than solution B.

Iron. Dissolve 0.20 g in 10 ml of hydrochloric acid (~70 g/l) TS and dilute to 40 ml with water. Proceed with the 2.2.4 Limit test for iron; not more than 200 μg/g.

Magnesium and alkali metals. Dissolve 1.0 g in 10 ml of hydrochloric acid (~70 g/l) TS, boil for 2 minutes and add 20 ml of water, 1 g of ammonium chloride R, and 0.1 ml of methyl red/ethanol TS. Add ammonia (~100 g/l) TS drop by drop until the solution changes colour, and then add a further 2 ml. Heat to boiling and add 40 ml of hot ammonium oxalate (50 g/l) TS. Allow to stand for 4 hours, dilute to 100 ml with water and filter. To 50 ml of the filtrate add 0.25 ml of sulfuric acid (~100 g/l) TS and evaporate to dryness on a water-bath. Ignite the residue to constant weight at 600 °C; not more than 5 mg.

Substances insoluble in acetic acid. Wash the filter retained from the test for heavy metals with 4 successive quantities, each of 5 ml of hot water, and dry at 105 °C for 1 hour; the residue weighs not more than 10 mg.

Loss on drying. Dry to constant weight at 200 °C; it loses not more than 20 mg/g.

Assay. Dissolve about 0.15 g, accurately weighed, in a mixture of 3 ml of hydrochloric acid (~70 g/l) TS and 20 ml of water, boil for 2 minutes, allow to cool, and dilute to 50 ml with water. Proceed with the titration as described under 2.5 Complexometric titrations for calcium. Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 5.004 mg of CaCO₃.

Monographs: Pharmaceutical substances: Calaminum - Calamine

2009-07-17T01:13:00.001-07:00

Chemical name. Calamine; CAS Reg. No. 8011-96-9.

Description. A fine, amorphous pink or reddish brown powder; odourless.

Solubility. Practically insoluble in water; soluble with effervescence in mineral acids.

Category. Antipruritic drug.

Storage. Calamine should be kept in a well-closed container.

Additional information. Attention should be paid to the microbiological quality since Calamine is of natural origin.

Requirements

Definition. Calamine is zinc oxide with a small proportion of ferric oxide.

Calamine contains not less than 98.0% and not more than the equivalent of 100.5% of ZnO, calculated with reference to the ignited substance.

Identity tests

A. Shake 1 g with 10 ml of hydrochloric acid (~70 g/l) TS and filter. To 5 ml of the filtrate add 0.3 ml of sodium hydroxide (~80 g/l) TS; a white precipitate is formed. Add a further 2 ml of sodium hydroxide (~80 g/l) TS; the precipitate dissolves. Add 10 ml of ammonium chloride (100 g/l) TS; the solution remains clear. Add 0.1 ml of sodium sulfide TS; a white, flocculent precipitate is formed.

B. To 1 g add 10 ml of hydrochloric acid (~70 g/l) TS, heat to boiling, and filter. To the filtrate add a few drops of ammonium thiocyanate (75 g/l) TS; a reddish colour is produced.

Calcium or magnesium. Digest 1 g in 25 ml of hydrochloric acid (~70 g/l) TS for 30 minutes and filter. To the filtrate, add slowly ammonia (~100 g/l) TS until the precipitate first formed redissolves, then add an excess of 5 ml of ammonia (~100 g/l) TS. To 10 ml of this solution add 2 ml of ammonium oxalate (25 g/l) TS; not more than a slight turbidity is produced. To a further 10 ml portion add 2 ml of disodium hydrogen phosphate (100 g/l) TS; not more than a slight turbidity is produced.

Lead. Dissolve 2 g in a mixture of 20 ml of water and 5 ml of glacial acetic acid R, filter, and add 0.1 ml of potassium chromate (100 g/l) TS to the filtrate; the solution remains clear for 5 minutes.

Acid-insoluble substances. Dissolve 2.0 g in 50 ml of hydrochloric acid (~70 g/l) TS, and filter. Wash the residue with water and dry to constant mass at 105 °C; the residue weighs not more than 40 mg (2.0%).

Alkaline substances. Digest 1 g with 20 ml of water and warm on a water-bath for 15 minutes. Filter and add 2 drops of phenolphthalein/ethanol TS to the filtrate; if a red colour is produced, titrate with sulfuric acid (0.05 mol/l) VS; not more than 0.2 ml of acid is required to discharge the colour.

Ethanol-soluble dyes. Shake 1 g with 10 ml of ethanol (~710 g/l) TS and filter; the filtrate is colourless.

Water-soluble dyes. Shake 1 g with 10 ml of water and filter; the filtrate is colourless.

Loss on ignition. Weigh 2.0 g and ignite at 500 °C to constant mass; it loses not more than 20 mg/g.

Assay. Add to about 1.5 g, accurately weighed, 50 ml of sulfuric acid (0.5 mol/l) VS, heat gently until no further precipitation occurs, and filter. Wash the residue with hot water until the last washing is neutral to litmus paper R. Combine the wash liquid and the filtrate, add 2.5 g of ammonium chloride R, cool, and back-titrate with sodium hydroxide (1 mol/l) VS using methyl orange/ethanol TS as indicator.

Each ml of sulfuric acid (0.5 mol/l) VS is equivalent to 40.69 mg of ZnO.

Monographs: Pharmaceutical substances: Butylhydroxytoluenum - Butylated hydroxytoluene

2009-07-16T23:52:00.000-07:00

C₁₅H₂₄O

Relative molecular mass. 220.4

Chemical name. 2,6-Di-tert-butyl-p-cresol; 2,6-bis(1,1-dimethylethyl)-4-methyl-phenol; CAS Reg. No. 128-37-0.

Other name. BHT.

Description. Colourless crystals or a white or almost white, crystalline powder; odour, faint and characteristic.

Solubility. Practically insoluble in water; freely soluble in ethanol (~750 g/l) TS, acetone R, ether R, and arachis oil R.

Category. Antioxidant.

Storage. Butylated hydroxytoluene should be kept in a well-closed container, protected from light.

Requirements

Identity tests

A. Dissolve 0.1 g in 10 ml of ethanol (~750 g/l) TS and add 4 ml of sodium tetraborate (10 g/l) TS and a few crystals of 2,6-dichloroquinone chlorimide R; no more than a faint blue colour is produced (distinction from butylated hydroxyanisole).

B. Dissolve 10 mg in 2 ml of ethanol (~750 g/l) TS. Add 1 ml of testosterone propionate/ethanol TS and 2 ml of sodium hydroxide (~80 g/l) TS. Warm in a water-bath at 80 °C for 10 minutes, and allow to cool; a blue colour is produced.

Congealing temperature. Not lower than 69.2 °C.

Sulfated ash. Not more than 1.0 mg/g.

Acid value. Not more than 0.05.

Monographs: Pharmaceutical substances: Butylhydroxyanisolum - Butylated hydroxyanisole

2009-07-16T23:51:00.002-07:00

C₁₁H₁₆O₂

Relative molecular mass. 180.3

Chemical name. tert-Butyl-4-methoxyphenol; (1,1-dimethylethyl)-4-methoxyphenol; CAS Reg. No. 25013-16-5.

Other name. BHA.

Description. A white or almost white, crystalline powder or a yellowish white solid; odour, faint and characteristic.

Solubility. Practically insoluble in water; freely soluble in ethanol (~750 g/l) TS, ether R, propylene glycol R, and arachis oil R; dissolves in solutions of alkali hydroxides.

Category. Antioxidant.

Storage. Butylated hydroxyanisole should be kept in a well-closed container, protected from light.

Requirements

Definition. Butylated hydroxyanisole contains a variable amount of 3-tert-butyl-4-methoxyphenol.

Identity tests

A. Dissolve 0.1 g in 10 ml of ethanol (~750 g/l) TS and add 4 ml of sodium tetraborate (10 g/l) TS and 1 ml of 2,6-dichloroquinone chlorimide/ethanol TS; a blue colour is produced (distinction from butylated hydroxytoluene).

B. Dissolve a few crystals in 10 ml of ethanol (~750 g/l) TS and add 0.1 ml of potassium ferricyanide (10 g/l) TS and 0.5 ml of ferric ammonium sulfate TS2; a green to blue colour is produced.

Solution in methanol. A solution of 1 g in 10 ml of methanol R is clear and not more intensely coloured than standard colour solution Yw3 when compared as described under 1.11 Colour of liquids.

Sulfated ash. Not more than 1.0 mg/g.

Hydroquinone. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R1 as the coating substance and a mixture of 4 volumes of chloroform R and 1 volume of ethyl acetate R as the mobile phase. Apply separately to the plate 3 ml of each of two solutions in ether R containing (A) 50 mg of Butylated hydroxyanisole per ml, and (B) 0.10 mg of hydroquinone R per ml. After removing the plate from the chromatographic chamber, allow it to dry in air for a few minutes, spray with phosphomolybdic acid/ethanol TS, and while still damp expose it to the vapours of ammonia (~260 g/l) TS. Examine the chromatogram in daylight as soon as the yellow background has disappeared.

The spot obtained with solution B is more intense than any corresponding spot obtained with solution A.

3-tert-Butyl-4-methoxyphenol. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R1 as the coating substance and chloroform R as the mobile phase. Apply separately to the plate 2 μl of each of three solutions in ether R containing (A) 25 mg of Butylated hydroxyanisole per ml, (B) 2.5 mg of Butylated hydroxyanisole per ml, and (C) 0.125 mg of Butylated hydroxyanisole per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, spray it with ferric chloride/potassium ferricyanide TS, and examine the chromatogram in daylight.

The blue-violet spot at R_f ~35 obtained with solution A is not more intense than the principal spot obtained with solution B. Any other spot obtained with solution A is not more intense than the spot obtained with solution C.

Monographs: Pharmaceutical substances: Busulfanum - Busulfan

2009-07-16T23:51:00.001-07:00

Molecular formula. C₆H₁₄O₆S₂

Relative molecular mass. 246.3

Graphic formula.

Chemical name. 1,4-Butanediol dimethanesulfonate; tetramethylene dimethanesulfonate; CAS Reg. No. 55-98-1.

Other name. Myelosanum.

Description. A white, crystalline powder.

Solubility. Very slightly soluble in water; sparingly soluble in acetone R; slightly soluble in ethanol (~750 g/l) TS.

Category. Cytotoxic drug.

Storage. Busulfan should be kept in a well-closed container, protected from light.

Additional information. CAUTION: Busulfan must be handled with care, avoiding contact with the skin and inhalation of airborne particles.

Requirements

Definition. Busulfan contains not less than 98.5% and not more than 100.5% of C₆H₁₄O₆S₂, calculated with reference to the dried substance.

Identity tests

A. Heat 0.1 g with 10 ml of water and 5 ml of sodium hydroxide (1 mol/l) VS until a clear solution is obtained; an intense odour of methanesulfonic acid is perceptible. Cool the solution and divide it into two equal portions for test B.

B. To one portion of the solution prepared in test A add 0.05 ml of potassium permanganate (10 g/l) TS; the purple colour changes to violet, then to blue, and finally to emerald-green. Acidify the second portion of the solution prepared in test A with 2 ml of sulfuric acid (~100 g/l) TS, add 0.05 ml of potassium permanganate (10 g/l) TS and shake; the colour of the permanganate is slowly discharged.

C. To a test-tube transfer 0.10 g of the test substance, suspend it in 1.0 ml of copper edetate TS and 0.5 ml of ammonia (~260 g/l) TS, then add 0.5 ml of hydrogen peroxide (~60 g/l) TS; this constitutes solution 1. Similarly, prepare a blank without the test substance; this constitutes solution 2. Place both tubes in a water-bath for 5 minutes, cool and add 1.0 ml of hydrochloric acid (~70 g/l) TS and 4.0 ml of barium chloride (50 g/l) TS; solution 2 remains clear and an opalescence is produced in solution 1, which changes to a white precipitate after a few minutes.

Melting range. 115 - 118 °C.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 60 °C under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury); it loses not more than 20 mg/g.

Assay. To about 0.25 g, accurately weighed, add 25 ml of water and boil gently under reflux for 30 minutes. Wash the condenser with a small quantity of water, cool, and titrate with carbonate-free sodium hydroxide (0.1 mol/l) VS, using phenolphthalein/ethanol TS as indicator. Repeat the operation without the substance being examined and make any necessary corrections. Each ml of carbonate-free sodium hydroxide (0.1 mol/l) VS is equivalent to 12.32 mg of C₆H₁₄O₆S₂.

pharmaceuticalexcipients.blogspot.com

Compendium of Pharmaceutical Excipients for Vaginal Formulations

Human Serum Albumin as a Pharmaceutical Excipient

PQRI Survey of Pharmaceutical Excipient Testing

Monographs: Pharmaceutical substances: Dinitrogenii oxidum - Dinitrogen oxide N2O

Monographs: Pharmaceutical substances: Dinatrii edetas - Disodium edetate

Silicone Excipients in Drug Development

A versatile ingredient works in excipient applications

By Gerald K. Schalau II and Katherine L. Ulman

An Expanding Role for Silicones

Aiding Patient Compliance

Versatile Options

Product Registration Support

Silicone Excipients in Drug Development

A versatile ingredient works in excipient applications

By Gerald K. Schalau II and Katherine L. Ulman

An Expanding Role for Silicones

Aiding Patient Compliance

Versatile Options

Product Registration Support

Monographs: Pharmaceutical substances: Diphenoxylati hydrochloridum - Diphenoxylate hydrochloride

Monographs: Pharmaceutical substances: Dinitrogenii oxidum - Dinitrogen oxide

Monographs: Pharmaceutical substances: Dinatrii edetas - Disodium edetate

Monographs: Pharmaceutical substances: Dimercaprolum - Dimercaprol

Monographs: Pharmaceutical substances: Diloxanidi furoas - Diloxanide furoate

Monographs: Pharmaceutical substances: Digitoxinum - Digitoxin

Monographs: Pharmaceutical substances: Digitoxinum - Digitoxin

CMC Process testing

Excipient Quality in Pharmaceutical Development

Understanding their functions benefits process control

By Lokesh Bhattacharyya, Ph.D.US Pharmacopeia

Excipient Selection and Use

Legal Factors and Release Testing

Acknowledgment

References

Infrared reference spectra: Amoxicillin trihydrate (RS006)

Infrared reference spectra: Amodiaquine hydrochloride (RS005)

Infrared reference spectra: Amitriptyline hydrochloride (RS004)

Infrared reference spectra: Amidotrizoic acid (RS003)

Infrared reference spectra: Allopurinol (RS002)

Infrared reference spectra: Acetazolamide (RS001)

Monographs: Pharmaceutical substances: Diethyltoluamidum - Diethyltoluamide

Monographs: Pharmaceutical substances: Diethylcarbamazini dihydrogenocitras - Diethylcarbamazine dihydrogen citrate

Monographs: Pharmaceutical substances: Didanosinum - Didanosine

Monographs: Pharmaceutical substances: Dicoumarolum - Dicoumarol

Monographs: Pharmaceutical substances: Dicloxacillinum natricum - Dicloxacillin sodium

Monographs: Pharmaceutical substances: Diazoxidum - Diazoxide

Monographs: Pharmaceutical substances: Diazepamum - Diazepam

Monographs: Pharmaceutical substances: Dexamethasoni natrii phosphas - Dexamethasone sodium phosphate

Monographs: Pharmaceutical substances: Dexamethasoni acetas - Dexamethasone acetate

Monographs: Pharmaceutical substances: Dehydroemetini dihydrochloridum - Dehydroemetine dihydrochloride

Monographs: Pharmaceutical substances: Deferoxamini mesilas - Deferoxamine mesilate

Monographs: Pharmaceutical substances: Dapsonum - Dapsone

Monographs: Pharmaceutical substances: Dactinomycinum - Dactinomycin

Monographs: Pharmaceutical substances: Dacarbazinum - Dacarbazine

Monographs: Pharmaceutical substances: Dacarbazinum - Dacarbazine

Monographs: Pharmaceutical substances: Chloramphenicoli natrii succinas - Chloramphenicol sodium succinate

Monographs: Pharmaceutical substances: Chlorambucilum - Chlorambucil

Monographs: Pharmaceutical substances: Chlorali hydras - Chloral hydrate

Monographs: Pharmaceutical substances: Cetrimidum - Cetrimide

Monographs: Pharmaceutical substances: Cetomacrogolum 1000 - Cetomacrogol 1000

Monographs: Pharmaceutical substances: Cera cetyla - Cetyl esters wax

Monographs: Pharmaceutical substances: Cera carnauba - Carnauba wax

Monographs: Pharmaceutical substances: Cellulosum microcrystallinum - Microcrystalline cellulose

Monographs: Pharmaceutical substances: Cellacefatum - Cellacefate

Monographs: Pharmaceutical substances: Carmellosum natricum - Carmellose sodium

Monographs: Pharmaceutical substances: Carbomerum - Carbomer

Monographs: Pharmaceutical substances: Carbo activatus - Charcoal, activated

Monographs: Pharmaceutical substances: Carbidopum - Carbidopa

Monographs: Pharmaceutical substances: Carbamazepinum - Carbamazepine

Monographs: Pharmaceutical substances: Captoprilum - Captopril

Monographs: Pharmaceutical substances: Calcii sulfas - Calcium sulfate

Monographs: Pharmaceutical substances: Calcii stearas - Calcium stearate

Monographs: Pharmaceutical substances: Calcii phosphas - Calcium phosphate

Monographs: Pharmaceutical substances: Calcii hydrogenophosphas - Calcium hydrogen phosphate

Monographs: Pharmaceutical substances: Calcii gluconas - Calcium gluconate

Monographs: Pharmaceutical substances: Calcii folinas - Calcium folinate

Monographs: Pharmaceutical substances: Calcii carbonas - Calcium carbonate

Monographs: Pharmaceutical substances: Calaminum - Calamine

Monographs: Pharmaceutical substances: Butylhydroxytoluenum - Butylated hydroxytoluene

By Lokesh Bhattacharyya, Ph.D.
US Pharmacopeia