Various organic solvents are used in the synthesis of complex drug products (for example, nanomedicines) and in the manufacturing/purification of drug substances and other excipients. Residual organic solvents may originate from the purification of drug materials and cleaning/maintenance of equipment used to manufacture the drug products. These residual organic solvents are considered drug product impurities having no therapeutic benefit. High or inconsistent concentrations of these volatile residual impurities not only pose health risks for patients but also affect the product’s quality. In addition, residual organic solvents can affect the physicochemical properties of therapeutics, such as particle size, dissolution and wettability [1].
The amount of residual organic solvent tolerated in final drug products is well-described in pharmacopeias such as United States Pharmacopeia (USP) and European Pharmacopeia (EP), and is closely monitored by regulatory agencies. The International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and the US Food and Drug Administration (FDA) have released a guideline for Residual Solvents Q3C approach for their classification [2]. The residual solvents were evaluated for their possible risk to human health and were placed into one of three classes based on their toxicity data and environmental impact.
Class 1 solvents such as benzene, carbon tetrachloride, dichloroethane, and trichloroethane are highly suspected human carcinogens and must be completely avoided. Class 2 solvents such as acetonitrile, chlorobenzene, chloroform, cyclohexane, hexane, and methanol produce non-genotoxic carcinogens and induce neurotoxicity. Class 3 solvents such as acetone, ethanol, ethyl acetate, formic acid, heptane, and propanol have low toxic potential. Class 3 solvents are typically limited to 5000 ppm or 0.5% (w/w). Class 2 solvents have their own individual limits; the acceptable levels of residual solvents are specified by ICH Q3C [2].
Headspace-Gas Chromatography (HS-GC) is the preferred technique for analysis of residual organic solvents in nanoformulations/drug products because it offers several advantages over direct injection GC. In using HS, only volatile components are introduced into the GC system, resulting in extended column lifetime and reduced instrument maintenance, providing superior sensitivity and reproducibility. Headspace sampling is conducted by placing a liquid or solid sample in a sealed vial until a thermodynamic equilibrium between the sample and gas phase is reached. A known aliquot of the gas phase analyte is then transferred to the gas chromatograph for analysis.
This protocol outlines procedures for quantitative determination of various residual organic solvents using headspace-gas chromatography.