ULTRA-TRACE DETERMINATION OF METHYL METHANE SULFONATE IN APIS USING A VALIDATED ANALYTICAL METHOD BY AUTO LIQUID SAMPLER MODE IN GC-FID CHROMATOGRAPHIC TECHNIQUE

Abstract

Methyl Methane Sulfonate (MMS) is a potential genotoxic impurity, which could be generated during the synthesis of an active pharmaceutical ingredient (API) and therefore requires sensitive and reliable analytical methods for patient safety and regulatory compliance. For MMS determination, a number of techniques based on liquid chromatography mass spectrometry (LC–MS/MS) and gas chromatography–mass spectrometry (GC–MS) have been reported. A simple, rapid, sensitive and cost-effective gas chromatography–flame ionisation detection (GC–FID) technique by ALS mode of injection has been developed and validated for the assessment of MMS in calcium dobesilate API utilising an Auto Liquid Sampler (ALS). Optimization of the chromatographic conditions was performed systematically by trying different stationary phases, injection modes, carrier gas flow rates and oven temperature programs. The DB-624 capillary column was found to give the best chromatographic performance in the separation of MMS from residual solvents and API-related matrix components, with good peak symmetry and reproducibility. The established technique has been validated in accordance with ICH Q2(R2) recommendations for specificity, linearity, limit of detection, limit of quantification, precision, accuracy, and system adaptability. The approach demonstrated an excellent linear range (R² = 0.9997), high sensitivity for trace-level measurement, commendable precision (RSD < 2%), and satisfactory recovery, making it appropriate for quantitative analysis. The validated approach was effectively utilised for the examination of many production batches of Calcium Dobesilate API, in which MMS was undetected. The novelty of this study is the development of a validated GC–FID method through ALS mode of injection, which represents a practical and economical alternative method to mass spectrometry-based methods for routine monitoring of MMS, which is a time-saving process. The proposed method can be adopted for pharmaceutical quality control, process monitoring, batch release testing and regulatory compliance to ICH M7 recommendations.