Residual solvent in pharmaceuticals is defined as organic volatile chemical which is used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products or dietary supplement products.
The solvents may not completely removed by practical manufacturing techniques but must be in controlled as per regulatory guidelines or other quality-based requirements. Because residual solvents do not provide any therapeutic benefit.
Classification of Residual Solvent
Based on potential toxicity, carcinogenicity and environmental hazard and solvents are classified into three (03) categories –
Class 1 solvents: Solvents to be avoided—known human carcinogens, strongly suspected human carcinogens, and environmental hazards.
Class 2 solvents: Solvents to be limited—on-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.
Class 3 solvents: Solvents with low toxic potential—solvents with low toxic potential to man; no health-based exposure limit is needed. Control to 50 mg/day or less for each of these solvents is acceptable without justification.
Potential sources
There are three potential sources of residual solvents in the pharmaceutical drug products and dietary supplement products that should be considered:
1. Drug substance or dietary active ingredient
2. Excipients and/or dietary ingredient
3. Formulation
Class 1 Residual Solvents
List of class 1 solvents with concentration limit
- Benzene (2 ppm) - Carcinogen
- Carbon tetrachloride (4 ppm) - Toxic and environmental hazard
- 1,2-Dichloroethane (5 ppm) - Toxic
- 1,1-Dichloroethene (8 ppm) - Toxic
- 1,1,1-Trichloroethane (1500 ppm) - Environmental hazard
Class 2 Residual Solvents
List of class 2 solvents with concentration limit
- Acetonitrile (410 ppm)
- Chlorobenzene (360 ppm)
- Chloroform (60 ppm)
- Cumene (70 ppm)
- Cyclohexane (3880 ppm)
- 1,2-Dichloroethene (1870 ppm)
- 1,2-Dimethoxyethane (100 ppm)
- N,N-Dimethylacetamide (1090 ppm)
- N,N-Dimethylformamide (880 ppm)
- 1,4-Dioxane (380 ppm)
- 2-Ethoxyethanol (160 ppm)
- Ethylene glycol (620 ppm)
- Formamide (220 ppm)
- Hexane (290 ppm)
- Methanol (3000 ppm)
- 2-Methoxyethanol (50 ppm)
- Methylbutylketone (50 ppm)
- Methylcyclohexane (1180 ppm)
- Methylene chloride (600 ppm)
- Methylisobutylketone (4500 ppm)
- N-Methylpyrrolidone (530 ppm)
- Nitromethane (50 ppm)
- Pyridine (200 ppm)
- Sulfolane (160 ppm)
- Tetrahydrofuran (720 ppm)
- Tetralin (100 ppm)
- Toluene (890 ppm)
- Trichloroethylene (80 ppm)
- Xylenea (2170 ppm)
- Cyclopentyl Methyl Ether (1500 ppm)
- Tertiary Butyl Alcohol (3500 ppm)
Class 3 Residual Solvents
It is considered that amounts of these residual solvents of 50 mg/day or less of each solvent (corresponding to 5000 ppm or 0.5% w/w in Option 1, which is described below) would be acceptable for each solvent without justification. Higher amounts may also be acceptable, provided that they are realistic in relation to manufacturing capability and good manufacturing practice. If a Class 3 solvent limit in an individual monograph is greater than 0.5%, that residual solvent should be identified and quantified.
- Acetic acid
- Isobutyl acetate
- Acetone
- Isopropyl acetate
- Anisole Methyl acetate
- 1-Butanol
- 3-Methyl-1-butanol
- 2-Butanol
- Methylethylketone
- Butyl acetate
- tert-Butylmethyl ether
- 2-Methyl-1-propanol
- Dimethyl sulfoxide
- Pentane
- Ethanol
- 1-Pentanol
- Ethyl acetate
- 1-Propanol
- Ethyl ether
- 2-Propanol
- Ethyl formate
- Propyl acetate
- Formic acid
- Triethylamine
- Heptane
- 2-Methyltetrahydrofuran
Control Strategy
- Analysis of Drug Product or Substances
- Confirmation of Compliance with General Guidelines
- Control of Solvent used in manugacturing Process