Metrolab Blog

THERMO Scientific | Simplified, cost-effective headspace GC method for residual solvents analysis in pharmaceutical products

Organic solvents are often used in the manufacturing and purification of drug substances but due to their potential toxicity their absence/presence must be verified in the pharmaceutical products to ensure patient safety. The United States Pharmacopeia (USP) method <467> provides detailed procedures for screening, confirmation and quantitation of residual solvents, including sample preparation and analytical conditions.
Gas chromatography (GC) coupled with headspace (HS) sampling technique and flame ionization detection (FID) as detector is the analytical method specified in USP <467> for this application, as most of the target compounds are organic solvents with relatively low boiling points and good thermal stability.
Since a chromatographic resolution (Rs)≥1.0 between the critical pair acetonitrile/dichloromethane is required as a system performance criterion, an initial isothermal condition of the GC column followed by a slow heating rate is recommended by the USP <467> method, in order to avoid peak co-elution and to achieve a baseline peak separation. However, those conditions typically lead to a long analysis time (60 minutes).
The USP General Notices and Requirements allow for the use of alternative methods but they shall be validated as described in the general chapter <1225> Validation of Compendial Procedures and must be shown to give equivalent or better results compared to the USP standard methods.
In this technical note, the USP <467> method for Class 2A solvent was modified as an example of how the residual solvent analysis can be improved with a faster and cost-effective alternative method.

Read the detailed technical note.