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.

Isothermal Crystallization and Time–Temperature Transformation of Amorphous Nifedipine: A Case of Polymorphism Formation and Conversion

“…The dynamic moduli were measured using an oscillatory shear experiment with the rheometer used for this measurement being the same instrument as described above. All the experiments were performed with an 8 mm parallel plate geometry, the initial gap between the two plates was measured to be between 0.9 and 1.2 mm, and the value of the gap at the test temperature was corrected based on the thermal expansion coefficient of the instrument which is 2.516 μm/ o C. The experimental condition used was adapted from our previous study 12 where a dynamic time sweep is applied to the sample at the temperature of interest. The tests were carried out at a frequency of 10 rad/s.…”

“…46,47 The apparent crystallization time t app is correlated to the combination of the nucleation rate I and the crystal growth rate U c , as t app ∼ 1/U app ∼ (I•Uc 3 ) −1/4 . 12 3. RESULTS 3.1.…”

“…Of course, any heterogeneous nucleation contribution to the induction time would tend to decrease the value of the estimated interfacial energy. 61 Finally, the TTT diagram of NIF here is compared to that of the GDC-0276, 12 and the respective induction/completion times are plotted in Figure 8. It can be seen that compared to the GDC-0276, the NIF has a larger error bar for the induction times and this is due to the polymorphism.…”

“…18,31,62−65 While there is some disagreement on details of this polymorphism, 16,27,30,31 it is generally recognized that there are three polymorphs in bulk nifedipine: the α-form, which is the most stable crystal polymorph, with a T m of 170− 172 °C and ΔH f = 114 J/g; the β′-form, a metastable The data for the GDC-0276 are from our prior study. 12 The light color/square points are for the induction times, and the darker color/ triangle points represent the measured completion times. The glass line for the two materials is estimated from the VFT equation.…”

“…The results from both methods were presented in the TTT-diagram framework, showing the induction and completion times for crystallization. 12 A modification of the classical model of homogeneous nucleation and crystal growth theory was used to describe the TTT behavior. In the present study, a similar methodology has been used to characterize the crystallization response of nifedipine (NIF), and the results are discussed and compared with those from the study of the GDC-0276.…”