Residual solvents in pharmaceutical products: acceptable limits, influences on physicochemical properties, analytical methods and documented values

Abstract

Residual solvents in pharmaceutical products, known as a potential toxic risk but actually only limited officially by the USP XXIII, have attracted considerable interest during the last years, with demands for international harmonisation of limits. In this sense, the limits proposed by the International Committee for Harmonisation (ICH) will most probably be adopted by the pharmacopoeias of USA, Japan and Europe. Beside the glass transition temperature, several other physicochemical parameters as the dissolution properties, the permeability and the crystallinity of substances have been reported to be affected by residual solvents. For the quantitative and the qualitative analysis of residual solvents, the official methods (USP 23 〈467〉 Organic Volatile Impurities and Eur. Ph. V.3.3.9 chapters) and other gas chromatography methods, especially static and dynamic headspace chromatography, are the most appropriate methods of all those reviewed. The importance of a drying step during the preparation process of pharmaceutical products is underlined by the literature-documented residual solvent values, presented in this article.