Mechanistic Study on Transformation of Coamorphous Baicalein-Nicotinamide to Its Cocrystal Form

Recently, coamorphization and cocrystal technologies are of particular interest in the pharmaceutical industry due to their ability to improve the solubility/dissolution and bioavailability of poorly water-soluble drugs, while the coamorphous system often tends to convert into the stable crystalline form usually crystalline physical mixture of each component during formulation preparation or storage. In this paper, BCS II drug baicalein (BAI) along with nicotinamide (NIC) were prepared into a single homogeneous coamorphous system with a single transition temperature at 42.5 °C. Interestingly, instead of the physical mixture of crystalline BAI and NIC, coamorphous BAI-NIC would transform to its cocrystal form under stress of temperature and humidity. The transformation rate under isothermal condition was temperature-dependent, since the crystallinity of the cocrystal enhanced as the temperature increased. Further mechanic studies showed the activation energy for the transformation under non-isothermal condition was calculated to be 184.52 kJ/mol. Additionally, water vapor sorption tests with further solid characterizations indicated the transformation was faster under higher humidity condition due to the faster nucleation process of cocrystal BAI-NIC. This research not only discovered the mechanism of transformation from coamorphous BAI-NIC to cocrystal form, but also provided an unusual method for cocrystal preparation from its coamorphous form.