Quantitative Analysis of Physical Stability Mechanisms of Amorphous Solid Dispersions by Molecular Dynamic Simulation.

Autor: Zhong H; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 999078, Macau, China., Lu T; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 999078, Macau, China.; Institute of Applied Physics and Materials Engineering, University of Macau, 999078, Macau, China., Wang R; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 999078, Macau, China., Ouyang D; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 999078, Macau, China. defangouyang@um.edu.mo.; Faculty of Health Sciences, University of Macau, 999078, Macau, China. defangouyang@um.edu.mo.
Jazyk: angličtina
Zdroj: The AAPS journal [AAPS J] 2024 Dec 05; Vol. 27 (1), pp. 9. Date of Electronic Publication: 2024 Dec 05.
DOI: 10.1208/s12248-024-01001-w
Abstrakt: Amorphous solid dispersions (ASDs) represent a promising strategy for enhancing the solubility of poorly soluble drugs. However, the mechanisms underlying the physical stability of ASDs remain insufficiently understood. This study aims to investigate these mechanisms and propose quantitative thresholds to predict the maximum stable drug loading using molecular dynamics simulations. Poly(vinylpyrrolidone) (PVP) and poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA64) are selected as polymeric carriers, while naproxen and acetaminophen serve as model drugs, resulting in the formulation of 18 distinct ASDs across four types for comparison with experimental results. Our findings indicate that the molecular mobility of active pharmaceutical ingredients (APIs) is the primary determinant of solid dispersion stability. High polymer concentrations limit drug molecular mobility through spatial structural constraints and ASD viscosity. As drug loading increases, the polymer concentration reaches a critical threshold (C*), beyond which drug-rich regions form, leading to potential aggregation, rearrangement, and recrystallization of drug molecules into more energetically stable forms. Notably, both the interaction energy and diffusion coefficient show sharp fluctuations at the maximum stable drug loading, which can serve as predictive indicators for ASD stability. Additionally, a search strategy is used to identify potential pre-crystalline sites. By integrating kinetic, thermodynamic, and pre-crystalline analyses through molecular dynamics simulations, this study provides a foundation for more accurate predictions of ASD stability, significantly aiding future formulation development.
Competing Interests: Declarations. Competing Interest: None of the authors have any competing interests.
(© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)
Databáze: MEDLINE
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