Physicochemical changes in unit-dose packaging of generic olmesartan medoxomil tablets and metformin hydrochloride tablets

Unit-dose packaging is widely used in clinical pharmacy practice to support medication adherence; however, physicochemical interactions between co-packaged drugs may result in visual changes such as tablet discoloration, affecting patient acceptance. Generic formulations may differ in excipient composition and manufacturing processes, influencing stability under stressed storage conditions. This study evaluated physicochemical stability and visual changes during unit-dose packaging of multiple formulations of metformin hydrochloride (brand-name and generics) and olmesartan medoxomil (OLMMD), and explored formulation-dependent factors contributing to these differences. Brand-name and generic metformin hydrochloride tablets (MET-A–H) were co-packaged with OLMMD orally disintegrating tablets (OLMOD-A–C) or standard tablets (OLM-A–B) and stored under accelerated conditions (40°C, 75% relative humidity) for 28 days. MET discoloration was evaluated by visual inspection. Tablet hardness was measured using a portable tester. The contents of OLMMD and its degradation product, olmesartan, were quantified by high-performance liquid chromatography. Excipient compositions were compared among formulations. MET discoloration varied markedly by formulation: MET-B showed prominent pinking, whereas MET-H showed no change. These differences did not correlate with hardness or excipient types, suggesting manufacturing factors. OLMMD degradation remained below 2% in all products, with OLMOD-B and OLM-B showing lower levels. OLMOD-B, which caused minimal MET discoloration, uniquely contained acesulfame potassium and fragrance, suggesting stabilizing effects. Although degradation was clinically negligible, visible discoloration may influence patient adherence. Co-packaging MET with OLMOD/OLM can induce visible discoloration without clinically meaningful degradation. Identifying formulations with better stability may support safer and more acceptable unit-dose dispensing.