Implications of Drug–Polymer Interactions on Time–Temperature–Transformation: A Tool to Assess the Crystallization Propensity in Amorphous Solid Dispersions
Rahul Lalge, N. S. Krishna Kumar, Raj Suryanarayanan
Abstract
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.