Temperature-Dependent Crystallization Pathways of the Curcumin-Magnolol Coamorphous System: A Mechanistic Study Integrating Thermodynamics and Kinetics

Abstract

Coamorphous drug systems have received increasing interest owing to their potential to improve the solubility, dissolution, and bioavailability of insoluble drugs. However, coamorphous systems exist in a high-energy state, making them prone to crystallization into stable forms. In this study, the curcumin-magnolol coamorphous (CUR-MAG CA) system was found to crystallize into different phases, with different crystallization kinetics, depending on temperature: (1) MAG crystal at 30–40 °C, (2) CUR-MAG cocrystal at 50–80 °C, and (3) CUR crystal at 90–100 °C. By integrating thermodynamic and kinetic analyses, we propose a mechanistic framework for the crystallization pathways of the CUR-MAG CA system. At lower temperatures (T < Tf (41.1 °C), Tf is the critical point where molecular mobility significantly increases, determined by dynamic mechanical analysis (DMA)), crystallization is associated with a high degree of undercooling and high viscosity, and the CUR-MAG CA system preferentially transforms into the kinetically favored phase. At moderate temperatures (Tf < T < Tm-MAG (101.4 °C)), molecular mobility becomes sufficient, enabling the system to preferentially transform into the thermodynamically stable phase. At higher temperatures (T > Tm-MAG), the thermodynamic driving force for MAG crystallization vanishes in the absence of supercooling, thereby favoring crystallization of CUR, which possesses the higher melting point (Tm-CUR = 181.9 °C). This study provides insight into the temperature-dependent crystallization behavior of coamorphous systems and may contribute to the development of more stable pharmaceutical formulations.