Residual Solvents

Residual solvent analysis in raw materials and end products

The determination of residual solvents for all pharmaceutical substances and products has been mandatory since 01/07/2008. This is regulated in the almost harmonised chapters “Residual Solvents” of the European and American Pharmacopoeias (Ph. Eur. chapter 5.4 and USP chapter 467). The ICH regulations also apply for GMP compliant testing.

According to the rules and regulations, testing should basically be performed for all solvents that could be contained within a substance or a product due to their origin or due to manufacturing.
Testing can be omitted only when the presence can be excluded taking into consideration the complete manufacturing or extraction process.

Often, exact production details for all of the chemicals and excipients used are not known. As a result, screening and validation of the content determination is necessary.

Do you ask yourself what differences there still are between the Ph. Eur. and USP despite the extensive harmonisation? Would you like to know whether product-specific validation is necessary for the analysis to conform with GMP? With our technical expertise and experience, we can find the perfect solution for you.

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René Wicki

GRADUATE CHEMIST HTL

Tel. +41 58 434 42 00

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Where do solvent residues come from?

Often, the usage of a solvent enables a reaction, be that through heat and material transfer, stabilisation of a transition state of a reaction or dilution for the prevention of secondary reactions. Cleaning steps such as precipitation, (re)crystallisations, extractions or chromatographic separations are only made possible by the solvents. Often however, the solvents enter into finished products such as tablets unexpectedly, as solvents from the lacquer or marking.

Three toxicity classes

The pharmacopoeias define limit values for the concentration of solvents in finished products. Depending on their dangerousness (toxicity), they are divided into three different toxicity classes.

Class 3 residual solvents (solvents of low toxicity)
Class 2 residual solvents (limited solvents)
Class 1 residual solvents (solvents to be avoided)

The requirements on the analysis methods increase with the increasing potential for danger.

Class 3 residual solvents

Depending on their toxicity, these solvents can be defined as sum parameters by investigation using loss on drying. Because the loss on drying test is an unspecific test, the limit here is taken to be the total limit of all class 3 solvents, i.e. the total of all class 3 solvents must be < 5000 ppm. There are also further limitations in the use of the loss on drying test, in most cases, a specific method is unavoidable.

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
Methylethylketone
Methylisobutylketone
2-Methyl-1-propanol
Pentane
1-Pentanol
1-Propanol
2-Propanol
Propyl acetate

Class 2 and class 1 residual solvents

Identification and/or quantification are mandatory here. The method of choice is headspace gas chromatography (HS-GC). The pharmacopoeias describe different methods for sample preparation (water soluble or water insoluble samples) and for chromatographic determination (various HS-GC parameters).

Class 2 residual solvents (limited solvents)

Solvent	PDE (mg/day)	Concentration Limit (ppm)
Xylene*	21.7	2170
Acetonitrile	4.1	410
Chlorobenzene	3.6	360
Chloroform	0.6	60
Cyclohexane	38.8	3880
1,2-Dichloroethene	18.7	1870
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
Ethylene glycol	6.2	620
Formamide	2.2	220
Hexane	2.9	290
Methanol	30.0	3000
2-Methoxyethanol	0.5	50
Methylbutylketone	0.5	50
Methylcyclohexane	11.8	1180
Methylene chloride	6.0	600
N-Methylpyrrolidone	5.3	530
Nitromethane	0.5	50
Pyridine	2.0	200
Sulfolane	1.6	160
Tetrahydrofuran	7.2	720
Tetralin	1.0	100
Toluene	8.9	890
Trichloroethylene	0.8	80

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

Class 1 residual solvents (solvents to be avoided)

Solvent	Concentration Limit (ppm)	Concern
Benzene	2	Carcinogen
Carbon tetrachloride	4	Toxic and environmental hazard
1,2-Dichloroethane	5	Toxic
1,1-Dichloroethene	8	Toxic
1,1,1-Trichloroethane	1500	Environmental hazard

Analytical challenges and general trends

A number of different measurement methods are used because of the large number of matrices and analytes. The solubility of the analyte, the type and boiling point of the solvent, limit values and also the difference between the USP and the Ph. Eur. determine the amount of effort required for residual solvent analysis. As a result of the ever more complex formulations, complicated active ingredient structures and higher requirements for product safety, quality conscious companies more and more often commission a complete screening programme for residual solvents and allow the methods to be validated.

The main differences in the evaluation of the results between the Ph. Eur. and USP

The limits are valued in the Ph. Eur. Content determination is only included when the limit is greater than 1000 ppm, otherwise the sample either complies with or doesn’t comply with the requirements. To take account of this uncertainty, the Ph. Eur. takes account of a safety factor of 2.

In contrast, in the USP, one is allowed to make a statement about the contents - with the same limit values - no matter how high or low the limit is. Here, a safety factor of 2 doesn't need to be taken into account.

In borderline cases, this could lead to a situation where after similar implementation, a sample meets the requirements of the USP but does not however comply with the criteria of the Ph. Eur.

When is validation necessary?

When it deviates from the statutory limit values - either above or below.
Ph. Eur.: If the sample is not completely dissolved and so another solvent is used.
If an unlisted residual solvent is to be determined.
If a non-established Head-Space-GC solvent is being investigated.
If a method that has not been described is to be used.
If a class-3 solvent is to be analysed with the described GC methods, because determination using loss on drying is either not possible or is not permitted.

What are the arguments for method development and a product-specific validation of methods?

The methods are reliable as they have been matrix-specific validated.
The methods are optimised for the product and the analysis.
There are cost savings due to regular receipt of samples and often lower limits of determination from the optimised methods.