Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism,Microstructure, and Its Impact on Dissolution Performance |
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Authors: | Huijun Chen Yipshu Pui Chengyu Liu Zhen Chen Ching-Chiang Su Michael Hageman Munir Hussain Roy Haskell Kevin Stefanski Kimberly Foster Olafur Gudmundsson Feng Qian |
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Institution: | 1. School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China;2. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Lawrenceville, New Jersey 08648;3. Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047;4. Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08901;5. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Wallingford, Connecticut 06492 |
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Abstract: | Amorphous phase separation (APS) is commonly observed in amorphous solid dispersions (ASD) when exposed to moisture. The objective of this study was to investigate: (1) the phase behavior of amorphous solid dispersions composed of a poorly water-soluble drug with extremely low crystallization propensity, BMS-817399, and PVP, following exposure to different relative humidity (RH), and (2) the impact of phase separation on the intrinsic dissolution rate of amorphous solid dispersion. Drug-polymer interaction was confirmed in ASDs at different drug loading using infrared (IR) spectroscopy and water vapor sorption analysis. It was found that the drug-polymer interaction could persist at low RH (≤75% RH) but was disrupted after exposure to high RH, with the advent of phase separation. Surface morphology and composition of 40/60 ASD at micro-/nano-scale before and after exposure to 95% RH were also compared. It was found that hydrophobic drug enriched on the surface of ASD after APS. However, for the 40/60 ASD system, the intrinsic dissolution rate of amorphous drug was hardly affected by the phase behavior of ASD, which may be partially attributed to the low crystallization tendency of amorphous BMS-817399 and enriched drug amount on the surface of ASD. Intrinsic dissolution rate of PVP decreased resulting from APS, leading to a lower concentration in the dissolution medium, but supersaturation maintenance was not anticipated to be altered after phase separation due to the limited ability of PVP to inhibit drug precipitation and prolong the supersaturation of drug in solution. This study indicated that for compounds with low crystallization propensity and high hydrophobicity, the risk of moisture-induced APS is high but such phase separation may not have profound impact on the drug dissolution performance of ASDs. Therefore, application of ASD technology on slow crystallizers could incur low risks not only in physical stability but also in dissolution performance. |
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Keywords: | amorphous solid dispersion physical stability drug-excipient interaction dissolution rate |
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