The impact of nanoconfinement on the crystallization and glass transition behaviors of nifedipine (NIF) has been investigated using differential scanning calorimetry. Nanoconfinement was provided by imbibing the NIF into a porous medium (controlled pore glass, CPG), and results were compared with the unconfined bulk material. Consistent with previous results from the literature, both glass transition temperature T g and melting temperature T m decrease with decreasing pore size. The melting temperature was found to decrease with the reciprocal of pore diameter and could be analyzed with the Gibbs–Thomson equation. In addition, for confinement sizes of 7.5 and 12 nm, it was found that no cold-crystallization occurs upon heating from the glassy state to above the expected melting transition. Finally, at intermediate confinements we find evidence of a possible new, confinement-induced polymorph of NIF.

Crystallization of active pharmaceutical ingredients (APIs) from the supercooled liquid state is an important issue in determining the stability of amorphous pharmaceutical dispersions. In the present study, the isothermal crystallization from the supercooled liquid state of the pharmaceutical compound nifedipine was investigated by both rheological and differential scanning calorimetry (DSC) measurements, and the crystallization kinetics was fitted to the Johnson–Mehl–Avrami (JMA) equation. Both the crystallization induction time and completion time from the two methods were used to construct the time–temperature-transformation (TTT) diagram for nifedipine. A model based on a modification of classical homogeneous nucleation and crystal growth theory was employed to fit the induction and completion time curves. Both DSC and rheological methods give similar results for the crystallization kinetics of the nifedipine. From the crystallization kinetics modeling, the solid–liquid interfacial surface tension σSL of nifedipine was estimated and the value was found to be consistent with prior results obtained from melting point depression measurements as a function of crystal size. Evidence is shown that for temperatures below 110 °C, at the early stage of nucleation, NIF first nucleates into the metastable β′-form and later converts into the stable α-form during the isothermal crystallization. We are also able to report the heat of fusion of the γ′-NIF based on the calorimetric experiments.

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.

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The glass transition temperature (T g) of a binary miscible mixture of molecular glasses, termed a coamorphous glass, is often synergistically increased over that expected for an athermal mixture due to the strong interactions between the two components. This synergistic interaction is particularly important for the formulation of coamorphous pharmaceuticals since the molecular interactions and resulting T g strongly impact stability against crystallization, dissolution kinetics, and bioavailability. Current models that describe the composition dependence of T g for binary systems, including the Gordon–Taylor, Fox, Kwei, and Braun–Kovacs equations, fail to describe the behavior of coamorphous pharmaceuticals using parameters consistent with experimental ΔC P and Δα. Here, we develop a robust thermodynamic approach extending the Couchman and Karasz method through the use of activity coefficient models, including the two-parameter Margules, non-random-two-liquid (NRTL), and three-suffix Redlich–Kister models. We find that the models, using experimental values of ΔC P and fitting parameters related to the binary interactions, successfully describe observed synergistic elevations and inflections in the T g versus composition response of coamorphous pharmaceuticals. Moreover, the predictions from the NRTL model are improved when the association-NRTL version of that model is used. Results are reported and discussed for four different coamorphous systems: indomethacin–glibenclamide, indomethacin–arginine, acetaminophen–indomethacin, and fenretinide–cholic acid.