Dissolution mechanisms of amorphous solid dispersions: Role of polymer molecular weight and identification of a new failure mode.

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL
Alexandru Deac, Chailu Que, Michelle L Cousineau, Anura S Indulkar, Yi Gao, Geoff G Z Zhang, Lynne S Taylor
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Abstract

The mechanisms of drug release from amorphous solid dispersions (ASDs) are complex and not fully explored, making it difficult to optimize for in vivo performance. A recurring behavior has been the limit of congruency (LoC), a drug loading above which the ASD surface forms an amorphous drug-rich barrier in the presence of water, which hinders release, especially in non-sink conditions. Drug-polymer interactions and drug glass transition temperature were reported to affect the LoC. However, the effect of polymer molecular weight has not been explored. ASDs of clotrimazole and different molecular weight grades of poly (vinylpyrrolidone) (PVP) were studied for their release to obtain their LoC drug loadings. Failure modes underpinning the LoC were investigated using fluorescence confocal microscopy to analyze the ASD/solution interface and phase behavior of ASD films at high relative humidity. ASDs with good release formed stable drug-rich nanodroplets at the ASD/solution interface, while ASDs with poor release were limited by one of two failure modes, depending on PVP molecular weight. In Failure Mode I the nanodroplets quickly agglomerated, while in Failure Mode II the system underwent phase inversion. This work highlights the importance of identifying the mechanisms underlying the LoC to improve the release of higher drug loading ASDs.

无定形固体分散体的溶解机理:聚合物分子量的作用和新失效模式的鉴定。
无定形固体分散体(ASD)的药物释放机制十分复杂,而且尚未得到充分探索,因此很难对其体内性能进行优化。一个经常出现的现象是同质性极限(LoC),即药物负载量超过这一极限时,无定形固体分散体表面在有水存在的情况下会形成富含药物的无定形屏障,从而阻碍药物的释放,尤其是在非沉降条件下。据报道,药物与聚合物的相互作用和药物的玻璃化温度会影响 LoC。然而,聚合物分子量的影响尚未得到探讨。对克霉唑的 ASD 和不同分子量等级的 PVP 进行了释放研究,以获得其 LoC 药物负载量。使用荧光共聚焦显微镜分析了 ASD/溶液界面和 ASD 薄膜在高相对湿度下的相行为,研究了 LoC 的失效模式。释放效果好的 ASD 在 ASD/溶液界面上形成了稳定的富含药物的纳米液滴,而释放效果差的 ASD 则受限于两种失效模式之一,具体取决于 PVP 的分子量。在失效模式 I 中,纳米液滴会迅速团聚,而在失效模式 II 中,系统会发生相反转。这项工作强调了确定 LoC 的基本机制以改善高药物负载 ASD 释放的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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