Study on the regulation mechanism of effective glass transition temperature on the crystallization of crystalline solid dispersion.

Abstract

The focus of this investigation was to determine the mechanism of effective glass transition temperature (TgE) on the crystallization behavior and microstructure of drugs in crystalline solid dispersion (CSD). CSDs were prepared by rotary evaporation using ketoconazole (KET) as a model drug and the triblock copolymer poloxamer 188 as a carrier. The pharmaceutical properties of CSDs, such as crystallite size, crystallization kinetics, and dissolution behavior, were investigated to provide a foundation for studying the crystallization behavior and the microstructure of drugs in CSDs. According to classical nucleation theory, the relationship of treatment temperature-drug crystallite size-TgE of CSD was investigated. Voriconazole, a compound that is structurally similar to KET but with different physicochemical properties, was used to verify the conclusions. The dissolution behavior of KET was significantly enhanced compared to the raw drug due to smaller crystallite size. Crystallization kinetic studies revealed a two-step crystallization mechanism for KET-P188-CSD, in which P188 crystallized first and KET crystallized later. When the treatment temperature was near TgE, the drug crystallite size was smaller and more numerous, which suggests nucleation and slow growth. With the increase of temperature, the drug changed from nucleation to growth, and the number of crystallites decreased and the size of the drug increased. This result suggests it is possible to prepare CSDs with higher drug loading and smaller crystallite size by adjusting the treatment temperature and TgE, so as to maximize the drug dissolution rate. The VOR-P188-CSD maintained a relationship between treatment temperature, drug crystallite size, and TgE. The findings of our study demonstrate that TgE and the treatment temperature can be used to regulate the drug crystallite size and improve the drug solubility and dissolution rate.