Analysis of spironolactone polymorphs in active pharmaceutical ingredients and their effect on tablet dissolution profiles

ABSTRACT Spironolactone (SPR) is a steroidal drug administered as a potassium-sparing diuretic for high blood pressure treatment. The drug shows incomplete gastrointestinal absorption due to its poor aqueous solubility. The physicochemical properties of SPR in crystal forms I and II suggest that differences in their aqueous solubility may lead to a lack of bioequivalence between solid-state formulations. In this study, SPR polymorphs in five batches of active pharmaceutical ingredients (APIs) from three manufacturers were characterized using powder X-ray diffraction, infrared spectroscopy, thermal analysis, and solubility measurements. SPR tablets (50 mg) were manufactured in our laboratory using API in pure form II, and API in form II contaminated with form I, which was found in a commercial batch. Physicochemical quality evaluations of the manufactured tablets, along with five SPR tablets marketed in Brazil, were performed, and results indicated differences in their dissolution profiles. In the manufactured tablets, differences were associated with the increased solubility of API in form II contaminated with form I compared to API in pure form II. In the marketed SPR tablets, the formulation composition demonstrated an important role in the dissolution rate of the drug, leading to lack of pharmaceutical equivalence among the drug products.

摘要：螺内酯（Spironolactone, SPR）是一种甾体类药物，作为保钾利尿剂用于高血压治疗。该药物水溶性较差，导致其胃肠道吸收不完全。晶型I与晶型II的螺内酯理化性质差异提示，二者水溶性的不同可能会造成固体制剂间生物等效性缺失。本研究采用粉末X射线衍射、红外光谱法、热分析以及溶解度测定，对来自3家厂商的5批活性药物成分（Active Pharmaceutical Ingredients, APIs）中的螺内酯多晶型进行了表征。本实验室分别以纯晶型II的API，以及某商业批次中检出的混有晶型I的晶型II API为原料，制备了50mg规格的螺内酯片剂。对本实验室制备的片剂以及在巴西上市的5款螺内酯片剂开展了理化质量评价，结果显示不同样品的溶出曲线存在差异。在实验室制备的片剂中，溶出差异与混有晶型I的晶型II API较纯晶型II API溶解度提升有关。而在上市的螺内酯片剂中，制剂处方组成对药物溶出速率具有显著影响，导致各药品间无法达到药学等效性。