Drug鈥揚olymer鈥揥ater Interaction and Its Implication for the Dissolution Performance of Amorphous Solid Dispersions

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• 作者：Yuejie Chen ; Chengyu Liu ; Zhen Chen ; Ching Su ; Michael Hageman ; Munir Hussain ; Roy Haskell ; Kevin Stefanski ; Feng Qian
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：February 2, 2015
• 年：2015
• 卷：12
• 期：2
• 页码：576-589
• 全文大小：792K
• ISSN：1543-8392

文摘

The in vitro dissolution mechanism of an amorphous solid dispersion (ASD) remains elusive and highly individualized, yet rational design of ASDs with optimal performance and prediction of their in vitro/in vivo performance are very much desirable in the pharmaceutical industry. To this end, we carried out comprehensive investigation of various ASD systems of griseofulvin, felodipine, and ketoconazole, in PVP-VA or HPMC-AS at different drug loading. Physiochemical properties and processes related to drug鈥損olymer鈥搘ater interaction, including the drug crystallization tendency in aqueous medium, drug鈥損olymer interaction before and after moisture exposure, supersaturation of drug in the presence of polymer, polymer dissolution kinetics, etc., were characterized and correlated with the dissolution performance of ASDs at different dose and different drug/polymer ratio. It was observed that ketoconazole/HPMC-AS ASD outperformed all other ASDs in various dissolution conditions, which was attributed to the drug鈥檚 low crystallization tendency, the strong ketoconazole/HPMC-AS interaction and the robustness of this interaction against water disruption, the dissolution rate and the availability of HPMC-AS in solution, and the ability of HPMC-AS in maintaining ketoconazole supersaturation. It was demonstrated that all these properties have implications for the dissolution performance of various ASD systems, and further quantification of them could be used as potential predictors for in vitro dissolution of ASDs. For all ASDs investigated, HPMC-AS systems performed better than, or at least comparably with, their PVP-VA counterparts, regardless of the drug loading or dose. This observation cannot be solely attributed to the ability of HPMC-AS in maintaining drug supersaturation. We also conclude that, for fast crystallizers without strong drug鈥損olymer interaction, the only feasible option to improve dissolution might be to lower the dose and the drug loading in the ASD. In this study, we implemented an ASD/water Flory鈥揌uggins parameter plot, which might assist in revealing the physical nature of the drug鈥損olymer interaction. We also introduced supersaturation parameter and dissolution performance parameter as two quantitative measurements to compare the abilities of polymers in maintaining drug supersaturation, and the dissolution performance of various solid dispersions, respectively.