Analysis of residual solvents in pharmaceuticals

A medicine is, in most cases, a combination of one or more active ingredients with constituents called excipients.

While the purpose of a drug is to cure or prevent a disease, we also know that any truly active pharmaceutical molecule may intrinsically present a certain toxicity. Every effort must therefore be made to avoid introducing other sources of toxicity, such as impurities in the active ingredient, excipients or in the manufacture of the final pharmaceutical product or galenic form (tablets, capsules, oral and injectable solutions, etc.).

Since the 1950s, the health authorities responsible for granting marketing authorization (MA) have consistently raised the quality standards required to obtain this authorization. The active ingredients, excipients and pharmaceutical forms themselves are subject to extremely thorough quality control. All impurities, whatever they may be, are researched, quantitatively determined and maximum levels proposed, based on toxicological assessments known globally as the toxicological qualification process.

The main categories of impurities concerned include :

• impurities related to the active ingredient from the synthesis process;

• impurities caused by the degradation and interaction of the active ingredient with excipients, or even with the drug's primary packaging;

• residual impurities originating from the reagents used and not completely removed during the purification stages. In addition to trace metals and catalysts, this last category includes residual solvents (SR) from the processes used to obtain the active ingredients, excipients and pharmaceutical products themselves.

As these products may themselves carry a certain toxicity, it is important to research and quantify them in pharmaceutical products. Toxicity is not the only reason, however, and the presence of residual solvents in pharmaceutical substances has other consequences. From this point of view, the case of water, a solvent very often used in the pharmaceutical industry, can also be considered where appropriate.

Among the analytical methods for determining the presence of trace solvents (including water), gas chromatography is the method of choice, frequently combined with headspace extraction of the analyte. The work carried out by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceutical Products (ICH) has made it possible to assess the health impact of residual solvents in terms of toxicity, with a view to defining tolerance standards.