Integrated RP-HPLC-FTIR investigation of impurity interconversion and excipient-mediated degradation of venlafaxine tablets

Background: Mechanistically informed stability assessment is essential for reliable impurity interpretation and regulatory compliance. Conventional forced degradation studies often overlook analytical-condition-induced interconversion and excipient-mediated effects. This study aimed to establish an integrated RP-HPLC-FTIR analytical framework for forced degradation profiling and drug-excipient compatibility assessment of venlafaxine hydrochloride tablets. Venlafaxine hydrochloride active substance and finished tablets were subjected to hydrolytic, oxidative, thermal, and photolytic stress conditions in accordance with ICH guidelines. Binary mixtures with individual excipients were evaluated under accelerated and exaggerated thermal conditions. Impurity profiling was performed using stability-indicating RP-HPLC with PDA detection, supported by peak purity and mass balance assessment. FTIR spectroscopy was applied to investigate solid-state interactions. The RP-HPLC method demonstrated adequate selectivity, peak purity, and mass balance values close to 100% for most stress conditions. Venlafaxine hydrochloride showed high stability under photolytic and accelerated storage conditions, while significant degradation occurred under oxidative and severe thermal stress (105°C). Binary mixture studies identified microcrystalline cellulose as the only excipient promoting impurity formation under exaggerated thermal conditions. FTIR results supported the presence of solid-state interactions. Apparent co-elution pharmacopoeial-specified impurities (D and E) was shown to result from acid-induced interconversion of impurity E into impurity D during analysis, rather than insufficient chromatographic resolution. The integrated RP-HPLC-FTIR approach enables mechanistic differentiation between intrinsic degradation, excipient-mediated effects, and analytical-condition-induced impurity interconversion, providing a robust framework for stability evaluation.