Application of GC–MS in Analytical Method Development for Volatile Drug Substances: A Comprehensive Review

Abstract

Gas Chromatography–Mass Spectrometry (GC–MS) is a powerful and widely employed analytical technique for the identification, separation, and quantification of volatile drug substances in pharmaceutical analysis. Volatile compounds, characterized by low molecular weight, high vapor pressure, and low boiling points, require specialised analytical approaches due to their susceptibility to evaporation and degradation. This review highlights the fundamental principles of GC–MS, including gas chromatographic separation and mass spectrometric detection, along with key instrumental components and ionisation techniques such as electron ionisation and chemical ionisation. The article comprehensively discusses method development strategies, emphasising sample preparation techniques such as liquid–liquid extraction, solid-phase extraction, headspace analysis, and solid-phase microextraction. Optimisation of chromatographic conditions and mass spectrometric parameters is also addressed to achieve enhanced sensitivity, resolution, and reproducibility. Method validation based on ICH guidelines ensures the reliability and regulatory compliance of analytical procedures. Furthermore, the review explores diverse applications of GC–MS, including impurity profiling, residual solvent analysis, pharmacokinetic studies, and bioanalysis. Stability studies under thermal, oxidative, and photolytic conditions are discussed, highlighting the role of GC–MS in identifying degradation products. The advantages, limitations, regulatory aspects, recent advancements, and challenges associated with GC–MS are critically evaluated.