Implications of Drug–Polymer Interactions on Time–Temperature–Transformation: A Tool to Assess the Crystallization Propensity in Amorphous Solid Dispersions

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.

Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time–Temperature Transformation

“…In the PVP dispersions, as the polymer concentration was increased, there was a pronounced increase in the T g of dispersions, while the change was modest in HPMCAS. The effect of PVP on T g can be attributed to the strong drug–polymer interactions …”

“…(a) TTT diagram (blue curve) for the crystallization onset time of the ASD with 15% PVP. The data was presented earlier and has been replotted . The t nose cryst was determined to be 90 °C.…”

“…However, the T nose nucl was unaffected by the small change in polymer concentration. Interestingly, the T nose nucl is in the vicinity of the T g of the ASDs . The corresponding time for detecting crystallization is referred to as t nose nucl .…”

“…The corresponding time for detecting crystallization is referred to as t nose cryst (Figure a). The t nose cryst for the NIF–PVP ASD (15% w/w polymer concentration) was ∼8 h . The behavior of the system in the “growth-dominated” region was the focus of our earlier publication.…”

“…An increase in the strength of drug–polymer interactions led to a decrease in CR crit . Interestingly, after cooling at rates >CR crit , when the samples were stored under conditions favoring growth, the crystallization onset time depended on the cooling rate . This suggested that though crystallization was avoided, there was nucleation during cooling.…”