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Contract
Laboratory Services (CLS)
> Pharmaceutical Analysis
>> Residual
Solvents Analysis / Organic
Volatile Impurities >>> Residual Solvents Page 2
More
information on ICH Q3C Guideline on Residual Solvents:
ICH
Q3C defines RESIDUAL solvents as organic volatile chemicals that
are used or produced in the manufacture of drug substances or
excipients, or in the preparation of drug products.
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. Class 1, Table 1) should be avoided.
Table
1. - Class 1 Solvents in Pharmaceutical Products (solvents
that should 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
|
Table
2. - Class 2 Solvents in Pharmaceutical Products
(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-Dichloroethene
|
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.
Table
3. - Class 3 Solvents Which Should Be Limited by GMP or Other
Quality-Based Requirements
|
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
|
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