Non-Sink Dissolution Behavior and Solubility Limit of Commercial Tacrolimus Amorphous Formulations

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• 作者：Niraj S. Trasi¹ ; Hitesh S. Purohit¹ ; Hong Wen² ; Dajun D. Sun² ; Lynne S. Taylor¹ ; ^{lstaylor@purdue.edu}
• 关键词：amorphous ; solubility ; dissolution ; tacrolimus ; solid dispersion
• 刊名：Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：106
• 期：1
• 页码：264-272
• 全文大小：1145 K
• 卷排序：106

文摘

An increasing number of drugs with low aqueous solubility are being formulated and marketed as amorphous solid dispersions because the amorphous form can generate a higher solubility compared to the crystalline solid. The amorphous solubility of a drug can be determined experimentally using various techniques. Most studies in this area investigate the drug in its pure form and do not evaluate any effects from other formulation ingredients. In this study, we use 6 marketed amorphous oral drug products, capsules containing 5 mg of tacrolimus, and various excipients, consisting of 1 innovator product and 5 generics. The amorphous solubility of tacrolimus was evaluated using different techniques and was compared to the crystalline solubility of the drug. Dissolution of the different products was conducted under non-sink conditions to compare the maximum achieved concentration with the amorphous solubility. Diffusion studies were performed to elucidate the maximum flux across a membrane and to evaluate whether there was any difference in the thermodynamic activity of the drug released from the formulation and the pure drug. The amorphous solubility of tacrolimus was found to be a factor of 35 higher than the crystalline solubility. The maximum concentration obtained after dissolution of the capsule contents in non-sink conditions was found to match the experimentally determined amorphous solubility of the pure drug. Furthermore, the membrane flux of tacrolimus following dissolution of the various formulations was found to be similar and maximized. This study demonstrates a link between key physicochemical properties (amorphous solubility) and in vitro formulation performance.