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

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 sigma(SL) 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 degrees C, at the early stage of nucleation, NIF first nucleates into the metastable beta'-form and later converts into the stable alpha-form during the isothermal crystallization. We are also able to report the heat of fusion of the gamma'-NIF based on the calorimetric experiments.

Automated summary

Crystallization of nifedipine from the supercooled liquid state was studied using rheological and differential scanning calorimetry measurements. The induction and completion times obtained from both methods were used to construct a time-temperature-transformation diagram for nifedipine, and the solid-liquid interfacial surface tension was estimated. The results from both DSC and rheological methods were consistent, showing the nucleation process of nifedipine and estimating the heat of fusion of gamma'-NIF.