Xie Tian, Gao Wei, Taylor Lynne S
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN 47907, United States.
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN 47907, United States.
Int J Pharm. 2017 Oct 5;531(1):313-323. doi: 10.1016/j.ijpharm.2017.08.099. Epub 2017 Aug 24.
The purpose of this work was to evaluate the impact of polymer(s) on the dissolution rate, supersaturation and precipitation of indomethacin amorphous solid dispersions (ASD), and to understand the link between precipitate characteristics and redissolution kinetics. The crystalline and amorphous solubilities of indomethacin were determined in the absence and presence of hydroxypropylmethyl cellulose (HPMC) and/or Eudragit EPO to establish relevant phase boundaries. At acidic pH, HPMC could maintain supersaturation of the drug by effectively inhibiting solution crystallization while EPO increased both the crystalline and amorphous solubility of the drug, but did not inhibit crystallization. The HPMC dispersion dissolved relatively slowly without undergoing crystallization while the supersaturation generated by rapid dissolution of the EPO ASD was short-lived due to crystallization. The crystals thus generated underwent rapid redissolution upon pH increase, dissolving faster than the reference crystalline material, and at a comparable rate to the amorphous HPMC dispersion. A ternary dispersion containing both EPO and HPMC dissolved rapidly, generating an apparent drug concentration that exceeded the amorphous solubility of indomethacin, leading to the formation of a new nanosized droplet phase. These nanodroplets dissolved virtually immediately when the pH was increased. In conclusion, the concentration-time profiles achieved from indomethacin ASD dissolution are a complex interplay of drug release rate, precipitation kinetics and outcome, and precipitate redissolution rate, whereby each of these processes is highly dependent on the polymer(s) employed in the formulation.
这项工作的目的是评估聚合物对吲哚美辛无定形固体分散体（ASD）的溶解速率、过饱和度和沉淀的影响，并了解沉淀特性与再溶解动力学之间的联系。在不存在和存在羟丙基甲基纤维素（HPMC）和/或丙烯酸树脂EPO的情况下测定吲哚美辛的结晶和无定形溶解度，以建立相关的相边界。在酸性pH值下，HPMC可通过有效抑制溶液结晶来维持药物的过饱和度，而EPO则增加了药物的结晶和无定形溶解度，但不抑制结晶。HPMC分散体溶解相对较慢且未发生结晶，而EPO ASD快速溶解产生的过饱和度由于结晶而短暂存在。由此产生的晶体在pH值升高时迅速再溶解，溶解速度比参比结晶材料快，且与无定形HPMC分散体的溶解速度相当。含有EPO和HPMC的三元分散体迅速溶解，产生的表观药物浓度超过吲哚美辛的无定形溶解度，导致形成新的纳米液滴相。当pH值升高时，这些纳米液滴几乎立即溶解。总之，吲哚美辛ASD溶解所获得的浓度-时间曲线是药物释放速率、沉淀动力学和结果以及沉淀再溶解速率之间复杂相互作用的结果，其中每个过程都高度依赖于制剂中使用的聚合物。
