Abstract
Fine crystals of active pharmaceutical ingredient (API) with sizes of 0.1–10 μm are undesirable as they may cause difficulty in downstream operations, including filtration, washing, and drying, as well as issues in storage, formulation, and transportation. Dicumarol, synthesized via the condensation reaction of 4-hydroxycoumarin with formaldehyde, was used as a model drug in the present study. Due to the extreme insolubility in water, dicumarol crystals would rapidly precipitate, resulting in sizes less than 5 μm during the course of reactive crystallization. Therefore, our aims are to increase the crystal size of dicumarol in reactive crystallization, and to improve powder properties. Dimethylacetamide (DMAc) was identified as a suitable solvent for substituting water due to the higher dicumarol solubility, allowing a wider operating window to lower nucleation rates, and thereby, produce large-sized dicumarol crystals. The crystal size of dicumarol was enlarged by adjusting the addition mode of formaldehyde during semibatch reactive crystallization. Fast nucleation could thus be avoided. The reaction solution was sampled for the evolution of crystal habit observed by optical microscopy, and its kinetic process was thoroughly studied. Dicumarol crystals were enlarged to about 200 μm with an 85.2 % yield, with the improved powder properties: Carr’s index at 16.4±1.6 % and angle of repose at 37.0±0.5°. Fourier-transform infrared spectroscopy and powder X-ray diffraction confirmed the chemical and crystal properties of the final dicumarol products.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call