Isothermal and Dynamic Microcalorimetry for Quantifying the Crystallization of an Amorphous Drug during Interactive Powder Mixing

This study reports the crystallization of amorphous nifedipine during an interactive mixing process quantified by using isothermal and dynamic microcalorimetry. Interactive mixtures of amorphous nifedipine and uniform glass beads were prepared by mixing in a Turbula® mixer. The difference in the extent of crystallization of amorphous nifedipine during mixing was characterized by the time it took for the crystallization of a known amount of amorphous nifedipine in isothermal calorimetry and the change in the height of the crystallization peak at 65°C in dynamic calorimetry. It was found that both isothermal and dynamic microcalorimetry are useful techniques for quantifying the physical transition of amorphous nifedipine during interactive mixing. The rate and extent of crystallization of amorphous nifedipine depended on both mixing time and speed, but mixing time played a more dominant role because the transformation of amorphous to crystalline nifedipine was greater after 3180 revolutions (9.7%) than after 405 revolutions (0.9%) at 27 rpm. The same trend was observed at 109 rpm, but the percentage of crystalline nifedipine after 3180 revolutions was only 5.2%. This meant that an increase in mixing time rather than speed increased the rate of amorphous to crystalline transformation. The greatest cause for crystal transformation during interactive mixing was the presence of crystal seeds of the thermodynamically stable nifedipine Modification I because the amount of amorphous to crystalline transformation increased from 2.6% for a completely amorphous mixture to 6.6% for a 92:8 mixture of amorphous and crystalline nifedipine when mixed for 30 minutes at 106 rpm.