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.
Friday 30 July 2010
Compendium of Pharmaceutical Excipients for Vaginal Formulations
Human Serum Albumin as a Pharmaceutical Excipient
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).
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
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
* 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
Saturday 22 August 2009
Monographs: Pharmaceutical substances: Dinitrogenii oxidum - Dinitrogen oxide 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.
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
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.
Saturday 1 August 2009
Silicone Excipients in Drug Development
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
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)
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