Download ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES

Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Available online at www.ordonearresearchlibrary.com
ISSN 2249 - 4898
Review Article
ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH
ORGANIC VOLATILE IMPURITIES: A REGULATORY OVERVIEW
Poonam Kushwaha*
Faculty of Pharmacy, Integral University
Lucknow-226026, INDIA
Received: 21 April 2011; Revised: 14 may 2011; Accepted: 20 June 2011; Available online: 25 June 2011
ABSTRACT
Increasing demands of consumers and higher competition in the market emphasize the importance of drug analysis. The
accurate assessment of quality and freshness is especially important to ease anxiety and to benefit consumers. The quality
and stability of pharmaceutical substances can be affected by the presence of volatile impurities. Volatile impurities in
pharmaceutical products are often residual solvents used in the synthesis, crystallization that escapes during drying or in
extraction. This paper reviews the residual solvents found in the pharmaceuticals, identifying different sources, as well as
providing examples and demonstrating possible measures regarding the control of these organic volatile impurities in
pharmaceuticals.
Keywords: Residual solvents; sources of residual solvents; ICH guideline; analysis of residual solvents;
INTRODUCTION
Residual solvents in pharmaceuticals, commonly known as organic volatile impurities (OVIs), are chemicals
that are either used or produced during the manufacture of active pharmaceutical ingredients (APIs), excipients
and drug products [1, 2].
Organic solvents play an essential role in drug-substance and excipient manufacture (e.g., reaction, separation
and purification) and in drug-product formulation (e.g., granulation and coating) [3]. Some organic solvents are
often used during the synthesis of active pharmaceutical ingredients and excipients or during the preparation of
drug products to enhance the yield, increase solubility or aid crystallization [2]. These process solvents cannot
be completely removed by practical manufacturing practices such as freeze–drying and drying at high
temperature under vacuum. Therefore, some residual solvents may remain in drug substance material [4].
Typically, the final purification step in many pharmaceutical drug-substance processes involves a crystallization
step, and the crystals thus formed can entrap a finite amount of solvent from the mother liquor that may cause
degradation of the drug, OVIs may also contaminate the products during packaging, storage in warehouses
and/or during transportation [3].
1
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Sources of residual solvents
Used as vehicle
during synthesis
may remain as
residue
Dissolution during
purification or
crystallization may
remain as residue
Used during
granulation, coating
or any other unit
operation
Fig. 1 sources of residual solvents
While solvents play a key role in the production of pharmaceuticals, there is also a downside, as many of the
solvents used have toxic or environmentally hazardous properties. Complete removal of residual levels of
solvents is impractical from a manufacturing standpoint, so it is inevitable that traces will remain in the final
product. The presence of these unwanted chemicals even in small amounts may influence the efficacy, safety
and stability of the pharmaceutical products. Because residual solvents have no therapeutic benefits but may be
hazardous to human health and the environment, it must be ensured that they are either not present in products
or are only present below recommended acceptable levels. It is a drug manufacturer's responsibility to ensure
that any OVIs present in the final product are not harmful to humans and that medicinal products do not contain
levels of residual solvents higher than recommended safety limits. Solvents known to cause unacceptable
toxicity should be avoided unless their use can be justified on the basis of a risk--benefit assessment [2].
Because of their proven or potential toxicity the level of residual solvents is controlled through national and
international guidelines, for example through the FDA and International Conference on Harmonization.
"All drug substances, excipients, and products are subject to relevant control of residual solvents, even when no
test is specified in the individual monograph."
REGULATORY AND COMPLIANCE ENVIRONMENT:
One of the essential aspects of pharmaceutical manufacturing is regulatory compliance, which typically
encompasses two aspects. The first is compliance with private sets of standards based on an applicant filing
with a regulatory agency, which requires the applicant to report the determined residual solvent levels in a
number of representative batches of pharmaceutical product to establish typical levels of solvent contamination
that can routinely be achieved. Based on a statistical evaluation of the reported data, a specification is agreed for
solvents used in the final step of the process and a decision made on whether testing is required for solvent used
at earlier stages in the process. To arrive at a specification that is a measure of the routine performance of the
process, regulatory agencies require numerical data rather than reporting compliance with a limit test.
Internationally, there has been a need to establish regulatory standard guidelines. In 1997, The International
Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
(ICH), through its Q3C Expert working group formed by regulators from the three ICH regions, industry
representatives and interested parties/observers, finalized the Q3C guideline on residual solvents. Essentially,
ICH has consistently proposed that limits on organic solvents be set at levels that can be justified by existing
2
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
safety and toxicity data, and also kept proposed limits within the level achievable by normal manufacturing
processes and within current analytic capabilities.
The second aspect is compliance with public standards set by Pharmacopoeias from the three ICH regions
(United States Pharmacopoeia (USP), European Pharmacopoeia (Ph. Eur.) and Japanese Phamacopoeia (JP))
and also with local pharmacopoeias from countries outside the ICH regions. In the recent past, guidelines for
organic residual solvents for public standards have generally been vague and not up to date. The
pharmacopoeial approach was typically a limit test for residual solvents, employing standard addition [3]. The
USP set the official limits in USP 23rd edition in the general chapter<467> organic volatile impurities [5]. Very
early on, the Ph. Eur. employed the ICH Q3C regulatory approach and updated the acceptance limits but kept
the methodology as a limit test based on standard addition. The general method in Ph. Eur. for Identification
and Control of Residual Solvents in drug substances defines a general procedure and describes two
complementary gas chromatography (GC) conditions for identifying unknown solvents. ‘‘System A’’ is
recommended for general use and is equivalent to ‘‘Methods IV and V’’ of the USP for analysis of volatile
organic impurities ‘‘System B’’ is used to confirm identification and to solve co-elutions. Implementation of
this general method is a subject of debate in the pharmaceutical industry due to its limited selectivity and
sensitivity [3]. Historically, until its 27th edition, the USP restricted its listing of residual solvents to those of
Class 1 and neglected to consider the wide range of organic solvents used routinely in the pharmaceutical
industry. Furthermore, the limits stated for Class 1 solvents benzene, chloroform, 1, 4-dioxane, methylene
chloride, and 1, 1, 1-trichloroethane are in the range 2–600 (ppm) and are therefore not in concordance with the
ICH guideline. Residual solvent testing using GC has been included in the pharmacopeias for almost 20 years,
while residual solvent-test methods have been reported in the literature since before that. With USP 28, the
public standard for residual solvents was updated to comply with the ICH Q3C guideline, but the methodology
(the same limit-test approach as Ph. Eur.) and the targeted monographs were not considered appropriate by
industry and regulators, leading to a notice postponing implementation in USP 29 [6].
ICH GUIDELINE:
The objective of this guidance is to recommend acceptable amounts for residual solvents in pharmaceuticals for
the safety of the patient. The guidance recommends use of less toxic solvents and describes levels considered to
be toxicologically acceptable for some residual solvents.
Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in
the manufacture of drug substances or excipients, or in the preparation of drug products. This guidance does not
address solvents deliberately used as excipients nor does it address solvates. However, the content of solvents in
such products should be evaluated and justified.
Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent
possible to meet product specifications, good manufacturing practices, or other quality-based requirements.
Drug products should contain no higher levels of residual solvents than can be supported by safety data. Some
solvents that are known to cause unacceptable toxicities (Class 1) should be avoided in the production of drug
substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment.
Some solvents associated with less severe toxicity (Class 2) should be limited in order to protect patients from
potential adverse effects. Ideally, less toxic solvents (Class 3) should be used where practical [7].
SCOPE OF THE GUIDANCE:
Residual solvents in drug substances, excipients, and drug products are within the scope of this guidance.
Therefore, testing should be performed for residual solvents when production or purification processes are
3
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
known to result in the presence of such solvents. It is only necessary to test for solvents that are used or
produced in the manufacture or purification of drug substances, excipients, or drug products. Although
manufacturers may choose to test the drug product, a cumulative method may be used to calculate the residual
solvent levels in the drug product from the levels in the ingredients used to produce the drug product. If the
calculation results in a level equal to or below that recommended in this guidance, no testing of the drug product
for residual solvents need be considered. If, however, the calculated level is above the recommended level, the
drug product should be tested to ascertain whether the formulation process has reduced the relevant solvent
level to within the acceptable amount. Drug product should also be tested if a solvent is used during its
manufacture.
This guidance does not apply to potential new drug substances, excipients, or drug products used during the
clinical research stages of development, nor does it apply to existing marketed drug products.
The guidance applies to all dosage forms and routes of administration. Higher levels of residual solvents may be
acceptable in certain cases such as short-term (30 days or less) or topical application. Justification for these
levels should be made on a case-by-case basis [7].
CLASSIFICATION OF RESIDUAL SOLVENTS:
OVIs are classified into three classes on the basis of their toxicity level and the degree to which they can be
considered an environmental hazard. The list provided in the guideline is not exhaustive, and one should
evaluate the synthesis and manufacturing processes for all possible residual solvents.
The term tolerable daily intake (TDI) is used by the International Program on Chemical Safety (IPCS) to
describe exposure limits of toxic chemicals and the term acceptable daily intake (ADI) is used by the World
Health Organization (WHO) and other national and international health authorities and institutes. The new term
permitted daily exposure (PDE) is defined in the present guidance as a pharmaceutically acceptable intake of
residual solvents to avoid confusion of differing values for ADI's of the same substance [7].
Residual solvents are classified on the basis of risk assessment:
Class 1 solvents: Solvents to be avoidedKnown human carcinogens, strongly suspected human carcinogens, and environmental hazards.
Class 2 solvents: Solvents to be limitedNongenotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as
neurotoxicity or teratogenicity.
Class 3 solvents: Solvents with low toxic potentialSolvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDE's
of 50 milligrams (mg) or more per day.
Class 4 solvents: Solvents for which no adequate toxicological data was found
No adequate toxicological data on which to base a PDE (permitted dose exposure) was found.
ENVIRONMENTAL REGULATION OF ORGANIC VOLATILE SOLVENTS
Several of the residual solvents frequently used in the production of pharmaceuticals are listed as toxic
chemicals in Environmental Health Criteria (EHC) monographs and in the Integrated Risk Information System
(IRIS). The objectives of such groups as the International Programme on Chemical Safety (IPCS), the U.S.
Environmental Protection Agency (EPA), and the U.S. Food and Drug Administration (FDA) include the
determination of acceptable exposure levels. The goal is protection of human health and maintenance of
4
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
environmental integrity against the possible deleterious effects of chemicals resulting from long-term
environmental exposure. The methods involved in the estimation of maximum safe exposure limits are usually
based on long-term studies. When long-term study data are unavailable, shorter term study data can be used
with modification of the approach such as use of larger safety factors. The approach described therein relates
primarily to long-term or lifetime exposure of the general population in the ambient environment (i.e., ambient
air, food, drinking water, and other media) [7].
THE CURRENT STATUS OF USP, EP AND JP:
Although the ICH guideline regarding residual solvents in pharmaceuticals became official in July 1997, USP
has not fully adopted it. The current status of each pharmacopeia is different [2].
United States Pharmacopoeia (USP):
In 1988, the United States Pharmacopoeia (USP) provided control limits and testing criteria for seven organic
volatile impurities (OVIs) under official monograph <467> [8]. According to USP, testing should be conducted
only if a manufacturer has indicated the possible presence of a solvent in a product. Testing may be avoided
when a manufacturer has assurance, based on the knowledge of the manufacturing process and controlled
handling, shipping, and storage of the product, that no potential exists for specific solvents to be present and
that the product, if tested, will comply with the accepted limit. Items shipped in airtight containers (such as
those used for food additives) can be considered not to have acquired any solvents during transportation [2].
The compounds were chosen based on relative toxicity and only applied to drug substances and some
excipients8. In addition; a test for ethylene oxide is conducted if specified in the individual monograph. Unless
otherwise specified in the individual monograph, the acceptable limit for ethylene oxide is 10 ppm. USP does
not address all other solvents mentioned in the ICH guideline [2].
In an effort to harmonize with the International Conference for Harmonization (ICH), the USP has proposed the
adoption of a slightly modified version of ICH (Q3C) methodology, which has been scheduled for
implementation on July 1, 2007. The ICH Q3C methodology provides a risk-based approach to residual solvent
analysis that considers a patient’s exposure to a solvent residue in the drug product. Solvents have been
classified based on their potential health risks into three main classes:
• Class 1: Solvents should not be used because of the unacceptable toxicities or deleterious environmental
effects
• Class 2: Solvents should be limited because of inherent toxicities
• Class 3: Solvents may be regarded as less toxic and of lower risk to human health
Testing is only required for those solvents used in the manufacturing or purification process of drug substances,
excipients or products. This allows each company to determine which solvents it uses in production and develop
testing procedures that address their specific needs. It is the responsibility of the drug manufacturer to qualify
the purity of all the components used in the manufacturing of the drug product. This would pertain to items such
as excipients, of which some contain residual levels of Class 1 solvents by nature of the manufacturing process
and/or nature of the starting materials (e.g. ethyl cellulose). The new <467> monograph provides an optional
method to determine when residual solvent testing is required for Class 2 solvents. Each Class 2 solvent is
assigned a permitted daily exposure (PDE) limit, which is the pharmaceutically acceptable intake level of a
residual solvent.
The USP has provided a method for the identification, control, and quantification of Class 1 and 2 residual
solvents. The method calls for a gas chromatographic (GC) analysis with flame ionization detection (FID) and a
headspace injection from either water or organic diluent. The monograph has suggested two procedures:
Procedure A G43 (Zebron ZB-624) phase and Procedure B G16 (Zebron ZB-WAXplus) phase. Procedure A
should be used first. If a compound is determined to be above the specified concentration limit, then Procedure
5
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
B should be used to confirm its identity. Since there are known co-elutions on both phases, the orthogonal
selectivity ensures that co-elutions on one phase will be resolved on the other. Neither procedure is quantitative,
so to determine the concentration the monograph specifies Procedure C, which utilizes whichever phase will
give the fewest co-elutions. Class 3 solvents may be determined by <731> Loss on Drying unless the level is
expected to be >5000 ppm or 50 mg. If the loss on drying is >0.5 %, then a water determination should be
performed using <921> Water Determination.
One of the most important considerations is that once implemented, the new method will pertain to all currently
marketed drug products as well as those in development and clinical trials [8, 9].
European Pharmacopoeia (EP):
EP has fully adopted the ICH guideline regarding residual solvents in 1997. In 2000, they started requiring that
all currently marketed drug products, as well as those in development or clinical trial, meet the ICH guidelines
[8]. Section 2.4.24 of the 4th edition of EP describes how to identify and quantify Class 1 and Class 2 residual
solvents. The test methods can be used to identify the majority of Class 1 and Class 2 solvents when they are
unknown and as limit tests for Class 1 and Class 2 solvents. The methods also can be used for the quantification
of Class 2 solvents when the limits are ≥ 1000 ppm (0.1%) or for the quantification of Class 3 solvents when
required [2].
In 2005 (EP 5th edition) it has been agreed that acceptance criteria for Class II solvents would not be mentioned
in the European Pharmacopoeia monographs and that Class I solvents would be included only where it was
known that their use was unavoidable in the manufacturing process for the drug substance using the acceptance
criteria laid down in the ICH guidelines. Finally, it is also recognized that some specific substances produce
solvated forms for which there are frequently higher levels of solvents, for example, Class III solvents cocrystallising with the active substances for which higher limits than the normal general 0.5% limit may have to
be applied. These higher-level Class III solvents would then be named individually on a case-by-case basis
where their presence at such levels is considered to be unavoidable. It should be stressed that there is no safety
issue relating to such levels since they are low toxicity solvents and the 0.5% threshold is merely a nominal
limit [10, 11 & 12].
Japanese Pharmacopoeia (JP):
The current JP (14th) has adopted the ICH guideline. This pharmacopeia defines residual solvents as those
residual organic solvents in pharmaceuticals that should be tested using gas chromatography to comply with the
limits specified in the ICH Harmonized Tripartite Guideline [2, 13].
CASE STUDIES: LIMITS OF RESIDUAL SOLVENT PRESENT IN PFIZER PRODUCTS AS
COMPARED TO ICH LIMITS.
Product (Pfizer centre source)
Triamcinolone USP
C21H27FO6
MW 394.43
6
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Organic Volatile Impurities
Of the solvents targeted in USP 26 General Chapter <467>, only methylene chloride may appear in bulk
pharmaceutical products manufactured by Pfizer at the Kalamazoo plant. For those products where OVI testing
is required, our material will meet the compendial limits for methylene chloride and other solvents that may be
added to the target list in the future.
No OVI requirement exists in the USP 26 monograph for Triamcinolone, but Triamcinolone from Pfizer meets
the requirements of USP 26 General Chapter <467>.
ICH Residual Solvents
As of 01 July 2000, Pfizer’s laboratories began to internally report all solvents that are present above the assay
detection limit. During the review of the batch data, it is verified that no solvents are present above the ICH
limits. Therefore, all lots of Triamcinolone released after 01 July 2000 will meet the ICH residual solvent
guidance [14].
Table 5: Comparision of residual solvents content reported by Pfizer and ICH Guideline [14]
Solvent
Pfizer
specificatio
n*
Residual
solvents
(total)
Ethyl acetate
NMT 0.5%
Methylene
chloride
Tetrahydrofur
an

No
individual
specification
NMT 600
ppm
No
individual
specification
ICH class
and
specificatio
n
Class/NM
T 0.5%
3 / NMT
0.5%
2 / NMT
600 ppm
3 / NMT
0.5%
Pfizer does not have Registered Specifications for residual solvents, only quality controls Targets.
ANALYSIS OF RESIDUAL SOLVENT IN PHARMACEUTICALS:
The analysis of residual solvents is an essential part in the quality control of drug substances used in preclinical
or clinical trials as well as for use in commercial drug products. Residual solvent analysis of bulk drug
substance and finished pharmaceutical products is necessary for a number of reasons:




High levels of residual organic solvents represent a risk to human health because of their toxicity
Residual organic solvents also play a role in the physicochemical properties of the bulk drug substance.
Crystallinity of the bulk drug substance can be affected. Differences in the crystal structure of the bulk
drug may lead to changes in dissolution properties and problems with formulation of the finished
product.
Finally, residual organic solvents can create odor problems and color changes in the finished product
and, thus, can lead to consumer complaints.
Often, the main purpose for residual solvent testing is in its use as a monitoring check for further drying
of bulk pharmaceuticals or as a final check of a finished product.
7
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011



Testing for solvent content in intermediates may need to be performed if a critical amount of residual
solvent(s) remaining in the intermediate can alter the next step of the process.
Knowledge of the solvent content in the starting materials may help to the development chemist to
understand the synthetic routes and predict potential process related impurities.
Knowing the solvents used in the process allows the development chemist to look for possible
compound- solvent interactions which can lead to the formation of impurities [5, 15].
Residual solvent analysis can be performed with a large array of analytical techniques [16]. The most popular,
and the most appropriate, specific solvent analysis is testing by gas chromatography (GC). Modern capillarycolumn gas chromatographs can separate a large number of volatile components, permitting identification
through retention characteristics and detection at ppm levels using a broad range of detectors [5].Gas
chromatographic testing can be categorized into three main procedures according to the means of introducing
the sample into the instrument. A direct gas chromatographic procedure is one in which a portion of the actual
drug substance or formulation is injected into a GC system. The drug substance is usually dissolved in an
appropriate solvent and loaded into a syringe and injected. Headspace analysis, on the other hand, is an indirect
testing procedure. The analysis is conducted when a volume of gas above the drug substance or formulation is
collected and analyzed by a gas chromatograph. Finally, solid-phase microextraction (SPME) is making much
progress in recent years for residual solvent testing. In SPME, a silica fiber coated with a sorbent is used to
collect and concentrate the volatile solvents. The volatiles are then thermally desorbed in the inlet of the gas
chromatograph and analyzed [17, 18].
Many alternatives to gas chromatography have been used to determine the level of residual solvent in
pharmaceutical products. Many of these procedures are either nonspecific—that is, the solvents are not
identified—or they have high detection limits, so they are inappropriate for the detailed product characterization
required for a regulatory submission. The oldest and simplest method for determining the quantity of volatile
residue is measuring the weight loss of a sample during heating. LOD method is widely used, particularly for
Class 3 solvents, due to its simplicity and ease of introduction into even the most basic analytical laboratory [5].
Another approach is to use thermogravimetric analysis (TGA), which is a well-known method for the
quantitative analysis of the loss of volatile components from a sample [18]. Spectroscopic and spectrometric
methods have generally lacked the low detection limits needed for toxic residual solvents, although the
detection limits would be applicable for ICH class 2 and 3 solvents. In the case of infrared spectroscopy (IR), a
detection limit above 100 ppm and lack of accuracy at low concentrations of residual solvent have been
reported. For NMR also high detection limit has been reported [5].
CONCLUSION:
Whenever organic solvents are used in the production of pharmaceutical products, especially in the last
processing steps, the content of residual solvent in the final product should be analyzed. The complete removal
of residual level of these solvents is impracticable and traces always remain in the final products. The presence
of these residual solvents even in small amounts has a negative influence not only on the quality of products but
also on human health. Acceptability of residual solvents seems to be best judged following the ICH residual
solvent guideline which is adopted by the USP, EP and JP; it classifies the solvent into four groups. In class 1
are included the most toxic solvents which, unless strongly justified, should be avoided. For the toxic solvents
of class 2, the limits are expressed as concentrations (ppm) and additionally in the case of known daily drug
intake, by the very important ‘permitted daily exposure’ (PDE). The class 3 includes the solvents with low toxic
potential for which the general limit is set at 0.5%. The class 4 includes solvents for which no adequate
toxicological data was found.
8
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011
REFERENCES
1. Michulec M., Wardenki, W. Development of headspace solid- phase microextraction-gas chromatography
method for the determination of solvent residues in edible oils and pharmaceuticals. J. Chromatogr 2005;
1071: 119-124.
2. Dwivedi A. M. Residual solvent analysis in pharmaceuticals. Pharmaceutical technology 2002; 42-46.
3. Camarasu C. Unknown residual solvents identification in drug products by headspace solid phase
microextraction gas chromatography- mass spectroscopy. Chromatographia 2002; 56: S131-S135.
4. Rocheleau M J. Measuring residual solvents in pharmaceutical samples using fast gas chromatography
techniques. J. Chromatogr. B 2004; 805: 77-86.
5. B’Hymer C. Residual solvent testing: A review of gas chromatographic and alternative techniques, Pharm.
Res. 2003; 20, 337-343.
6. Otero, R., Carrera, G., Static headspace gas chromatographic method for quantitative determination of
residual solvents in pharmaceutical drug substances according to European pharmacopoeia requirements. J.
Chromatogr. A 2004; 1057: 193-201.
7. ICH Q3(C). Impurities: residual solvents 1997.
8. Countrymen, S. Understanding the revision to USP monograph <467>: residual solvents, phenomenex Inc.
Torrance, CA, USA, 2007.
9. General chapters <466>. "Ordinary impurities" and <1086>, "Impurities in official articles," in USP 28-NF 23. US Pharmacopoeia. 12601 Twin brook Parkway, Rockville, Maryland 20852, USA, 2004.
10. European pharmacopoeia. Identification and control of residual solvents (2.4.24), directorate for the quality
of medicines of the council of Europe, Strasbourg, France, 2005, 5th edition, pp. 96.
11. European Pharmacopoeia. General chapter 5.10, Control of impurities in substances for pharmaceutical use
and general monograph: 2034, substances for pharmaceutical use, 2005, 5th edition. pp 559-561, 586-587.
12. Morris, J. M . Regulation of residual solvents in medicinal products in the European Union, Irish medicines
board, 2007.
13. Japanese Pharmacopoeia. Residual solvent testing, society of Japanese pharmacopoeia, 14th edition.
14. Pfizer centre source. Triamcinalone, Pfizer.inc 2004.
15. Ahuja S. Residual solvents. Handbook of modern pharmaceutical analysis. Marcel Dekker publications,
2003. pp. 86-87.
16. Ahuja S. Gas chromatography, Handbook of modern pharmaceutical analysis. Marcel Dekker publications,
2003, pp.375-377.
17. Madichie C., Camarasu C. Recent progress in the determination of volatile impurities in pharmaceuticals.
Trends in analytical chemistry 2006; 25: 768-777.
18. Wood, D. C., Miller, J. M. Headspace liquid microextraction. LC-GC Europe 2004; 17: 573-579.
9
Kushwaha et al. / AJPSR volume 1 issue 1, June 2011