When we are sick, we take medicines to relieve symptoms and cure our ailments. But when we take a drug, we never take it in a pure form. The active pharmaceutical ingredient (API) has typically been formulated with excipients and binders, each with their own manufacturing impurities such as residual solvents from the manufacture and formulation process.
Residual solvents are more than just a smelly inconvenience. They can be carcinogenic and/or genotoxic at very low exposure levels. This is worrying because medicines are given to the sick while they are at their most vulnerable.
Now I’m Scared. Who’s Responsible for This?
It is the responsibility of the drug manufacturer to ensure that these residues are removed, or are present only in limited concentrations. Thankfully, regulatory agencies, which have been established to protect consumers, work on ensuring that drug manufacturers deliver on their responsibilities.
Class 1 compounds are carcinogenic compounds that pose a risk to both the consumer and the environment. The use of these solvents is to be avoided, but if they are used, they must be tightly controlled.
Class 2 compounds are non-genotoxic animal carcinogens and concentrations of these compounds should be limited. Chromatographic analysis is needed for both the Class 1 and Class 2 residual solvents.
Class 3 compounds have low toxic potential and may be assayed by nonspecific techniques.
Each solvent has a maximum permissible concentration limit in the drug product based on its toxicology and tolerable daily exposure, for example, benzene being amongst the most toxic solvent has a maximum permissible limit of 2 ppm. As an organic chemist, at university I remember sloshing benzene into test tubes to dissolve dyestuffs without much thought to its toxicity. Benzene is great stuff for cleaning, but an acknowledged carcinogen. The European Medicines Agency has also adopted the same guidelines and limits as those of the ICH. Munish Garg et al. give an excellent summary on residual solvents regulations for various regulatory agencies in this journal article (downloadable PDF).
So, How do We Analyze for Residual Solvents in Pharmaceutical Products?
The United States Pharmacopeia (USP) general chapter <467> Residual Solvents provides a widely used method for identifying and quantifying residual solvents when no information is available on what solvents are likely to be present.
The USP <467> method consists of a headspace extraction coupled with a gas chromatographic separation and flame ionization detection; although there are revisions that account for the increasing popularity of detection by mass spectrometry.
Polar gas chromatography columns for volatiles separation, typically cyanopropyl GC columns (Thermo Scientific TRACE TR-V1) or wax phase GC columns (Thermo Scientific TraceGOLD TG 624SilMS). Check out this downloadable application note using the cyanopropyl columns:
Over 60 solvents are included in USP <467> but limits are given only for finished products. However, testing for residual solvents in raw materials may be highly recommended as this solvent may be carried through the process and remain in the finished product. Thankfully, help is at hand. We have compiled a number of resources to assist you in implementing residual solvents testing: