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.
Methods: 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.
Results: 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.
The apparent co-elution of pharmacopoeial-specified impurities D and E was shown to result from acid-induced
interconversion of impurity E into impurity D during analysis, rather than from insufficient chromatographic
resolution.
Conclusion: 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.