Implications of Drug-Polymer Interactions on Time-Temperature-Transformation: A Tool to Assess the Crystallization...

The critical cooling rate (CR_crit) to prevent drug crystallization during the preparation of nifedipine amorphous solid dispersions (ASDs) was determined through the time-temperature-transformation (TTT) diagram. ASDs were prepared with polyvinylpyrrolidone, hydroxypropylmethyl cellulose acetate succinate, and poly(acrylic acid). ASDs were subjected to isothermal crystallization over a wide temperature range, and the time and temperature dependence of nifedipine crystallization onset time (t_C) was determined by differential scanning calorimetry (DSC) and synchrotron X-ray diffractometry. TTT diagrams were generated for ASDs, which provided the CR_crit for the dispersions prepared with each polymer. The observed differences in CR_crit could be explained in terms of differences in the strength of interactions. Stronger drug-polymer interactions led to longer t_C and decreased CR_crit. The effect of polymer concentrations (4-20% w/w) was also influenced by the strength of the interaction. The CR_crit of amorphous NIF was ∼17.5 °C/min. Addition of 20% w/w polymer resulted in a CR_crit of ∼0.05, 0.2, and 11 °C/min for the dispersions prepared with PVP, HPMCAS, and PAA, respectively.