Investigation into the Stability, Crystallization Kinetics, and Heating Rate Dependent Crystallization of Amorphous Posaconazole
Poor aqueous solubility is a major challenge for formulation scientists as more than 40% of new chemical entities developed in the pharmaceutical industry are insoluble in water. The high energy amorphous form offers enhanced solubility and eventually bioavailability of BCS class II drugs. Because of the high thermodynamic properties, the amorphous form tends to lower its internal energy via crystallization and exhibit instability. Knowledge of crystallization tendency and kinetics is of key importance in the design and development of amorphous systems.
In this study, the stability, fragility, critical cooling rate for amorphization, crystallization kinetics, and effect of moisture on stability of the amorphous posaconazole (POS) were investigated. The glass forming ability (GFA) was calculated, and the relevance of fragility and GFA to crystallization of amorphous POS was studied. The crystallization kinetics of amorphous POS was investigated using isothermal and non-isothermal models. The fragility, GFA, and crystallization kinetic studies exhibited correlation. The non-isothermal crystallization studies also led to the discovery of a previously unknown heating rate dependent crystallization of amorphous POS. This study contributed toward an integrated approach to establish fragility, GFA, and crystallization kinetics as stability predictors for amorphous drug systems.
Shahab Ud Din, Helen Hughes, Niall J. O’Reilly, Helen Cathcart, Thomas O’Ceallaigh, Elias Ndzie, and Peter McLoughlin
ACS, Cryst. Growth Des. 2020, 20, 8, 5129–5142
https://doi.org/10.1021/acs.cgd.0c00312