Residual Solvents in Pharmaceuticals

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Background:

Numerous organic solvents were utilized in the synthesis of drug substances or drug products. These organic solvents have poisonous properties also harmful to the environment. During manufacturing, it’s very difficult to get rid of organic solvents completely from the finished product. If organic solvents aren’t removed completely from the finished product then the quality and safety of the product is at risk and finally unsafe to the consumer.

What is Residual Solvent?

Residual solvents in pharmaceuticals are those organic volatile compounds which are used during the manufacturing of drug product or formed during the manufacturing of drug substances or excipients.

Classification of Residual Solvents by Risk Assessment:

There are certain guidelines issued by the regulatory authority to make sure that it’s safe to use of organic solvents. Permitted daily exposure (PDE) is defined as a pharmaceutically suitable consumption of residual solvents.

Class 1 SolventsClass 2 SolventsClass 3 Solvents
Class-1 solvents to be avoided because of its predictable and assumed to human carcinogens and environmental risks.Class-2 solvents is a smaller amount genotoxic carcinogens agent of other irrevocable toxicity like neurotoxicity.Class-3 solvents with less poisonous and lesser risk to human health.
Class-1 solvent should be avoided within the manufacture of drug substances, excipients, and drug products.Class-2 solvents assumed as further substantial but revocable toxicities. PDEs are stated to the adjacent 0.1 mg/day, and concentrations are given around 10ppm.Class-3 solvents are safe to human with it’s generally accepted limit in drugs. PDEs are specified as 50 mg per day (5000ppm) would be acceptable without justification.
e.g. Benzene, Carbon tetrachloride, 1,2-Dichloroethane 1,1-Dichloroethene, 1,1,1-Trichloroethanee.g. Acetonitrile, Chlorobenzene, Cyclohexane, Dichloromethane, Hexane, Methanol, N-Methylpyrrolidone, Tetrahydrofuran, Toluene, Xylenee.g. Acetic acid, Acetone, Anisole, 1-Butanol, 2-Butanol, Butyl acetate, tert-Butylmethyl ether, 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.

Recently International Council for Harmonisation (ICH) published draft guideline ICH Q3C(R8) for establishing new permitted daily exposures (PDEs) for three residual solvents.
 2-methyltetrahydrofuran (Class-3), Cyclopentyl methyl ether (Class-2) and Tertiary butyl alcohol (Class-2).

References:

  1. ICH, Q3C(R6) Impurities: Guideline for Residual Solvents,
  2. ICH, Q3C(R8) Impurities: Guideline for Residual Solvents, PDE for 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether and Tertiary-Butyl Alcohol, Draft Version,
  3. The United States Pharmacopeia (USP) general chapter <467> Residual Solvents,
  4. Poseva Panovska; Acevska J; Stefkov G; Breszovska K; Petkovska R; Drimitrovska.A, Optimization of HS-GC-FID-MS Method for Residual Solvent Profiling in Active Pharmaceutical Ingredients Using DoE, Journal of Chromatographic Science, 54, 2016,

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