Gedeon Richter Plc., Formulation R&D, Gyömrői Str. 19-21, Budapest, Hungary.
J Pharm Biomed Anal. 2011 Mar 25;54(4):730-4. doi: 10.1016/j.jpba.2010.11.005. Epub 2010 Nov 11.
The aim of the present study was to predict the structural changes of polymeric excipients in the course of storage causing undesired changes in drug release stability of tablets containing different polymers. Matrix tablets were formulated with metronidazole as a model drug, using polyvinylpyrrolidone and carbopol as matrix materials. Dissolution tests were carried out before and after storing the tablets under stress conditions for different time intervals. Parameters characterizing the release kinetics of matrix tablets, just as difference and similarity factors, were calculated to compare the release profiles as a function of storage time. FT-IR measurements were carried out to track the structural changes of the physical mixtures of metronidazole and polymers during storage. The changes of the characteristic peaks of the FT-IR spectra of metronidazole-polymer mixtures were in good correlation with the significant changes of release parameters of tablets. The latter was confirmed by ab initio calculations. The work showed that the combination of ab initio calculations with structural examinations could predict the possible instability of drug release and, thus, enables the screening of polymeric excipients of undesired physical stability.
本研究旨在预测聚合物辅料在储存过程中的结构变化，这些变化可能导致含有不同聚合物的片剂的药物释放稳定性发生不良变化。采用甲硝唑作为模型药物，以聚乙烯吡咯烷酮和卡波姆为基质材料，制备了基质片剂。在不同的时间间隔下，对片剂在应激条件下储存前后进行了溶出度试验。计算了表征基质片剂释放动力学的参数，如差异因子和相似因子，以比较作为储存时间函数的释放曲线。进行了 FT-IR 测量，以跟踪甲硝唑和聚合物的物理混合物在储存过程中的结构变化。甲硝唑-聚合物混合物的 FT-IR 光谱的特征峰的变化与片剂释放参数的显著变化密切相关。这一点通过从头算计算得到了证实。这项工作表明，将从头算计算与结构研究相结合，可以预测药物释放可能的不稳定性，从而能够筛选出物理稳定性不理想的聚合物辅料。
