title: Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions.
abstract: 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 drug's 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.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Yuejie
authors.initials: Y
authors.lastname: Chen
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Ching
authors.initials: C
authors.lastname: Su
authors.forename: Michael
authors.initials: M
authors.lastname: Hageman
authors.forename: Munir
authors.initials: M
authors.lastname: Hussain
authors.forename: Roy
authors.initials: R
authors.lastname: Haskell
authors.forename: Kevin
authors.initials: K
authors.lastname: Stefanski
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
mesh_terms: D003460:Crystallization; D015736:Felodipine / Q000737:chemistry; D006118:Griseofulvin / Q000737:chemistry; D007654:Ketoconazole / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D011108:Polymers / Q000737:chemistry*; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014867:Water / Q000737:chemistry*
chemical_list: D011108:Polymers; D014867:Water; D006118:Griseofulvin; D015736:Felodipine; D007654:Ketoconazole
keywords: FT-IR; Flory−Huggins interaction parameter; NMR; amorphous solid dispersion; crystallization; dissolution; drug−polymer interaction; dynamic vapor sorption