| dc.description.abstract | Fine solid particles are often harvested in reactive crystallization. From the perspective of process engineering, fine crystals with sizes of 0.1 to 10 μm are undesirable, for they can cause problems in downstream unit operations, such as filtration, washing and drying. In addition, other physical properties, such as bulk density, powder flowability, agglomeration, and crystal size distribution (CSD), may cause difficulties in storage, formulation, and transportation. Dicumarol was used as a model drug in this research, and synthesized by condensation reaction of 4-hydroxycoumarin with formaldehyde originally in water. Since dicumarol is extremely insoluble in water, dicumarol crystals would be rapidly precipitated in 1 min during the course of reactive crystallization, and the resulting crystal size was less than 5 μm. Very fine dicumarol crystals led to the formation of hard lumps during filtration and drying. Therefore, the aim of this research is to increase the crystal size of dicumarol in reactive crystallization, and to further improve powder properties. First, through an initial solvent screening among 24 solvents, N,N-dimethylacetamide (DMAc) was identified to be suitable for substituting for water to improve the solubility of dicumarol, which provided a relatively wide operating window to reduce the nucleation rate, and thereby, produced large-sized dicumarol crystals. In this thesis, it was discussed that the crystals were slowly crystallized by cooling after the synthesis of dicumarol, and the result has successfully produced dicumarol crystals near 100 μm. In addition, the degree of supersaturation could be controlled at a lower value by changing the addition mode of the formaldehyde aqueous solution in reactive crystallization. Fast nucleation could be avoided thereby favoring crystal growth. The reaction solution was sampled during the experiment, the evolution of crystal habit was observed by optical microscopy (OM), and its kinetic process was thoroughly studied and compared. The final experimental results have successfully increased the crystal size of dicumarol to about 200 μm, and the yield was up to 85.3%. The HPLC assay was 103.1%. The powder properties, including Carr’s index and angle of repose, were measured, and our best case showed the much improved values of 16.4±1.6% and 37.0±0.5°, respectively. All sample solids were characterized by Fourier transform infrared spectroscopy (FT-IR) and powder X-ray diffraction (PXRD) to identify the chemical and crystal properties of the final products. | en_US |