Influence of particle size and manufacturing conditions on the recrystallization of amorphous Enzalutamide

Abstract

Non-isothermal differential scanning calorimetry was used to study the influences of particle size and mechanically induced defects on the recrystallization kinetics of amorphous Enzalutamide. Enzalutamide prepared by hot melt extrusion and spray-drying was used as a model material. The recrystallization rate was primarily accelerated by the presence of the processing-damaged surface of the powder particles. The actual surface/volume ratio associated with decreasing particle size fulfilled only a secondary role. Interestingly, higher quench rate during the extrusion led to a formation of thermally less stable material (with the worse stability being manifested via lower activation energy of crystal growth in the amorphous matrix). This can be the consequence of the formation of looser structure more prone to rearrangements. The recrystallization kinetics of the prepared Enzalutamide amorphous materials was described by the two-parameter autocatalytic kinetic model. The modified single-curve multivariate kinetic analysis (optimized for the data obtained at heating rate 0.5 °C•min−1) was used to calculate the extrapolated kinetic predictions of long-term isothermal crystal growth. The predictions were made for the temperatures from the range of drug shelf-life and processing for each particle size fraction. By the combination of the mass-weighted predictions for the individual powder fractions it was possible to obtain a very reasonable (temperature-extrapolated) prediction of the crystallization rate for the as-prepared unsieved powdered amorphous Enzalutamide.