Simultaneous quantitation of water and residual solvents in pharmaceuticals by rapid headspace gas chromatography with thermal conductivity detection (GC-TCD)

Abstract

In the pharmaceutical industry, an array of analytical testing is performed to demonstrate the safety and efficacy of drug substance and drug products. Among the most critical attributes of release testing are quantitation of residual solvents from the manufacturing process, which pose toxicity concerns, and determination of water content, which can impact potency and shelf life. Residual solvent determination in pharmaceuticals is most commonly performed using headspace capillary gas chromatography (GC) with flame ionization detection (FID), a robust technique that incorporates a mode of detection noteworthy for its sensitivity and wide dynamic range. However, FID responds exclusively to combustible organic species, and does not produce any signal for common gases such as carbon dioxide, ammonia, and notably water. While thermal conductivity detection (TCD) is an alternate, universal mode of detection that has a known response to all GC-appropriate compounds, including water, its use among pharmaceutical companies is uncommon due to the ubiquity of the more sensitive FID and the availability of other techniques for water quantitation such as Karl Fischer titrations (KF). In this work, the use of headspace GC-TCD was successfully demonstrated for the development of a 7.5-minute method for simultaneous quantitation of water, over 25 common residual solvents, and other volatile impurities in small molecule pharmaceutical samples. By carefully controlling sample preparation to minimize the impact of residual water from the diluent, the results for residual solvents and water obtained by this technique were found to be comparable to those of GC-FID and KF, respectively. Headspace GC-TCD improves the throughput of drug testing by greatly reducing the need for KF testing and associated expensive reagents, and helps to conserve samples that are often limited in early stages of development. The technique has desired sensitivity, precision, accuracy and linear dynamic range suitable for pharmaceutical analysis.