Journal
MOLECULAR PHARMACEUTICS
Volume 14, Issue 1, Pages 264-273Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.6b00866
Keywords
pharmaceutical glass; solid dispersion; crystallization; stability; pair distribution function
Funding
- Health Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan
- World Premier International Research Center (WPI) Initiative on Materials Nanoarchitectonics from MEXT, Japan
- JSPS, Japan [15K04614]
- Grants-in-Aid for Scientific Research [15K04614] Funding Source: KAKEN
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Amorphous solid dispersions (ASDs) play a key role in the pharmaceutical industry through the use of high-energy amorphous state to improve solubility of pharmaceutical agents. Understanding the physical stability of pharmaceutical glasses is of great importance for their successful development. We focused on the anti-HIV agent, ritonavir (RTV), and investigated the influence of annealing at temperatures below the glass transition temperature (sub-T-g) on physical stability, and found that the sub-T-g annealing effectively stabilized RTV glasses. Through the atomic structure analyses using X-ray pair distribution functions and infrared spectroscopy, we ascertained that this fascinating effect of the sub-T-g annealing originated from strengthened hydrogen bonding between molecules and probably from a better local packing associated with the stronger hydrogen bonds. The sub-T-g annealing is effective as a physical stabilization strategy for some pharmaceutical molecules, which have relatively large energy barrier for nucleation.
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