Isothermal Crystallization Monitoring and Time-Temperature-Transformation of Amorphous GDC-0276: Differential Scanning Calorimetric and Rheological Measurements.

Abstract

Cold crystallization of amorphous pharmaceuticals is an important aspect in the search to stabilize amorphous or glassy compounds used as amorphous pharmaceutical ingredients (APIs). In the present work, we report results for the isothermal crystallization of the compound GDC-0276 based on differential scanning calorimetric and rheometric measurements. The kinetics of isothermal crystallization from the induction time to the completion of crystallization can be described by the classic Johnson-Mehl-Avrami (JMA) equation. The time-temperature-transformation (TTT) diagrams were constructed for two time points-that of induction and that of completion of crystallization. The results show that the rheological measurement for GDC-0276 has a better overall sensitivity in detection of the early stage nucleation and, consequently, detects the onset of crystallization sooner than does the differential scanning calorimetry. Rheological measurements were also used to obtain the temperature dependence of the viscosity of GDC-0276 and the relevant parameters were used in a modified form of the JMA model to describe the temperature dependence of the crystal induction and completion times, that is, the TTT diagram for the material. In the modification, we assumed that the kinetics followed the viscosity to the 0.75 power as suggested by the recent work of Huang et al. (Huang, C., et al., J. Chem. Phys.2018,149, 054503). The relationship and the possible impact on crystallization kinetics of the break-down of the Stokes-Einstein relation in glass-forming liquids are discussed. From the crystallization kinetics modeling, the solid-liquid interfacial surface tension σSL was obtained for GDC-0276 and was compared with that obtained from the melting point depression measurements of the material confined in nanoporous glasses. The differences between the values from the two methods are discussed.