Drug-Polymer-Water Interaction and Its Implication for the Dissolution Performance of Amorphous Solid Dispersions

被引:142
作者
Chen, Yuejie [1 ,2 ]
Liu, Chengyu [1 ,2 ]
Chen, Zhen [1 ,2 ]
Su, Ching [3 ]
Hageman, Michael [3 ]
Hussain, Munir [4 ]
Haskell, Roy [5 ]
Stefanski, Kevin [3 ]
Qian, Feng [1 ,2 ]
机构
[1] Tsinghua Univ, Sch Med, Dept Pharmacol & Pharmaceut Sci, Beijing 100084, Peoples R China
[2] Tsinghua Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, Beijing 100084, Peoples R China
[3] Bristol Myers Squibb Co, Pharmaceut Candidate Optimizat, Lawrenceville, NJ 08648 USA
[4] Bristol Myers Squibb Co, Drug Prod Sci & Technol, New Brunswick, NJ 08903 USA
[5] Bristol Myers Squibb Co, Pharmaceut Candidate Optimizat, Wallingford, CT 06492 USA
关键词
amorphous solid dispersion; drug-polymer interaction; Flory-Huggins interaction parameter; dynamic vapor sorption; dissolution; FT-IR; NMR; crystallization; SOLUBILITY ADVANTAGE; MOLECULAR MOBILITY; CRYSTALLIZATION TENDENCY; PRECIPITATION BEHAVIOR; PHARMACEUTICAL SYSTEMS; PHYSICAL STABILITY; VAPOR ABSORPTION; PHASE-SEPARATION; FELODIPINE; POLYVINYLPYRROLIDONE;
D O I
10.1021/mp500660m
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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-polymer-water interaction, including the drug crystallization tendency in aqueous medium, drug-polymer 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 drugs 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-polymer 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-Huggins parameter plot, which might assist in revealing the physical nature of the drug-polymer 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.
引用
收藏
页码:576 / 589
页数:14
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