Stephen 205 (1)

1Department of Pharmaceutical Analysis, Oriental College of Pharmacy.Navi Mumbai,India.

Online Published (2011) ISSN: 0976-7908 Selvan et al

www.pharmasm.com IC Value – 4.01 1756

PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

REVIEW ON IMPURITIES: A REGULATORY OVERVIEW

M.Arulselvan1*, B.Stephen Rathinaraj2,Sirajudeen.M.A.3, Md. Fareedullah2, Farsiya

Fatima2, Fatima Shiree2

Department of Pharmaceutical Analysis, Oriental College of Pharmacy.Navi Mumbai,India

2Department of Pharmaceutics, Vaagdevi College of Pharmacy, Hanamkonda, Warangal, Andhrapradesh, India. 3Department of Pharmaceutical Biotechnology, Omega College of Pharmacy, Hyderabad, Andhrapradesh, India

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 material4. 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]

Figure 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

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



can be justified on the basis of a risk--benefit assessment2. 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 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 impurities5. 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 sensitivity3. 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 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 avoided-

Known human carcinogens, strongly suspected human carcinogens, and

environmental hazards.

Class 2 solvents: Solvents to be limited-

Nongenotoxic animal carcinogens or possible causative agents of other

irreversible toxicity such as neurotoxicity or teratogenicity.

Class 3 solvents: Solvents with low toxic potential-

Solvents 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 [7].

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 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].

LIMITS OF RESIDUAL SOLVENTS:

A. Solvents to Be Avoided

Solvents in Class 1 (Table 1) should not be employed in the manufacture of drug

substances, excipients, and drug products because of their unacceptable toxicity or their

deleterious environmental effect. However, if their use is unavoidable in order to produce

a drug product with a significant therapeutic advance, then their levels should be

restricted as shown in Table 1, unless otherwise justified. The solvent 1, 1, 1-

Trichloroethane is included in Table 1 because it is an environmental hazard. The stated

limit of 1,500 ppm is based on a review of the safety data.

TABLE 1: CLASS 1 SOLVENT (SOLVENTS THAT SHOULD BE AVOIDED)

Concentration limit (ppm)

Concern

Benzene 2 Carcinogen Carbon tetrachloride 4 Toxic and

environmental hazard

1,2-Dichloroethane 5 Toxic 1,1 - Dichloroethane 8 Toxic

1,1,1 - Trichloroethane 1500 Environmental hazard

B. Solvents to Be Limited

Solvents in Class 2 (Table 2) should be limited in pharmaceutical products

because of their inherent toxicity. PDEs are given to the nearest 0.1 mg/day, and



concentrations are given to the nearest 10 ppm. The stated values do not reflect the

necessary analytical precision of determination. Precision should be determined as part of

the validation of the method [7].

TABLE 2: CLASS 2 SOLVENTS (SOLVENTS TO BE LIMITED)

Solvent PDE (mg/day) Concentration limit (ppm)

Acetonitrile 4.1 410 Chlorobenzene 3.6 360

Chloroform 0.6 60 Cyclohexane 38.8 3880

1,2-Dichloroethane 18.7 1870 Dichloromethane 6.0 600

1,2-Dimethoxyethane 1.0 100 N,N-Dimethylacetamide 10.9 1090 N,N-Dimethylformamide 8.8 880

1,4-Dioxane 3.8 380 2-Ethoxyethanol 1.6 160 Ethyleneglycol 6.2 620

Formamide 2.2 220 Hexane 2.9 290

Methanol 30.0 3000 2-Methoxyethanol 0.5 50

Methylbutyl ketone 0.5 50 Methylcyclohexane 11.8 1180

N-Methylpyrrolidone 48.4 4840 Nitromethane 0.5 50

Pyridine 2.0 200 Sulfolane 1.6 160 Tetralin 1.0 100 Toluene 8.9 890

1,1,2-Trichloroethene 0.8 80 Xylene* 21.7 2170

* Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene

C. Solvents with Low Toxic Potential

Solvents in Class 3 (Table 3) may be regarded as less toxic and of lower risk to

human health. Class 3 includes no solvent known as a human health hazard at levels

normally accepted in pharmaceuticals. However, there are no long-term toxicity or

carcinogenicity studies for many of the solvents in Class 3. Available data indicate that

they are less toxic in acute or short-term studies and negative in genotoxicity studies. It is

considered that amounts of these residual solvents of 50 mg per day or less



(corresponding to 5,000 ppm or 0.5 percent under Option 1) would be acceptable without

justification. Higher amounts may also be acceptable provided they are realistic in

relation to manufacturing capability and good manufacturing practice (GMP) [7].

D. Solvents for which no adequate toxicological data were found

The solvents listed in Table 4 may also be of interest to manufacturers of

excipients, drug substances, or drug products. However, no adequate toxicological data

on which to base a PDE were found. Manufacturers should supply justification for

residual levels of these solvents in pharmaceutical products[7].

TABLE 3: CLASS 3 SOLVENTS (SOLVENTS WITH LOW TOXIC POTENTIAL)

Acetic acid Acetone Anisole 1-Butanol 2-Butanol Butyl acetate tert-Butylmethyl ether Cumene Dimethyl sulfoxide Ethanol Ethyl acetate Ethyl ether Ethyl formate Formic acid

Heptane Isobutyl acetate Isopropyl acetate Methyl acetate 3-Methyl-1-butanol Methylethyl ketone Methylisobutyl ketone 2-Methyl-1-propanol Pentane 1-Pentanol 1-Propanol 2-Propanol Propyl acetate Tetrahydrofuran

TABLE 4: SOLVENTS FOR WHICH NO ADEQUATE TOXICOLOGICAL

DATA WERE FOUND

1,1-Diethoxypropane 1,1-Dimethoxymethane 2,2-Dimethoxypropane Isooctane Isopropyl ether Methylisopropyl ketone Methyltetrahydrofuran Petroleum ether Trichloroacetic acid Trifluoroacetic acid



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]. USP <467>

recommends testing for seven organic volatile impurities is listed in Table 5 [9].

TABLE 5: ORGANIC VOLATILE IMPURITIES (OVI)

OVI Limit

Benzene

Chloroform

1, 4-Dioxane

Methylene Chloride

Trichloroethylene

2 ppm max

60 ppm max

380 ppm max

600 ppm max

80 ppm max

The compounds were chosen based on relative toxicity and only applied to drug

substances and some excipients [8]. 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 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].

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 co-crystallising 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 [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

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>

[14].

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.

A Comparison of residual solvents content reported by Pfizer and ICH Guideline is listed

in Table 6 [14].



TABLE 6: COMPARISON OF RESIDUAL SOLVENTS CONTENT REPORTED

BY PFIZER AND ICH GUIDELINE

Solvent Pfizer specification* ICH class and specification

Residual solvents (total) NMT 0.5%

Ethyl acetate No individual specification 3 / NMT 0.5%

Methylene chloride NMT 600 ppm 2 / NMT 600 ppm

Tetrahydrofuran No individual specification 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 [5].

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.

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[15].

TABLE 7: LIST OF PHARMACEUTICAL SAMPLE NAMES AND CONTAINED

RESIDUAL SOLVENTS [16].

Pharmaceutical sample Residual solvent Class

Lidocain Heptane 3

Ethyl aminoben Toluene 2

Antipyrine Methanol 2

Phenacetin Methanol, toluene 2, 2

Cimetidine Ethanol 3

Famotidine Methanol 2

carbamazepine Acetone 3

Residual solvent analysis can be performed with a large array of analytical

techniques [17]. The most popular, and the most appropriate, specific solvent analysis is

testing by gas chromatography (GC). Modern capillary-column 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 [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]. List of pharmaceutical sample names and

contained residual solvents is reported in Table 8 [18].

TABLE 8: LIST OF PHARMACEUTICAL SAMPLE NAMES AND CONTAINED

RESIDUAL SOLVENTS

Pharmaceutical sample Residual solvent Class

Lidocain Heptane 3

Ethyl aminoben Toluene 2

Antipyrine Methanol 2

Phenacetin Methanol, toluene 2, 2

Cimetidine Ethanol 3

Famotidine Methanol 2

carbamazepine Acetone 3

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.

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For Correspondence: M.Arul Selvan Email: [email protected]

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