Study On The Crystallization Process Of Lovastatin

As the first commercial product of the HMG-CoA reductase inhibitors (statins), Lovastatin is widely used for cholesterol lowering. Meanwhile it is also the key material in the manufacture of simvastatin. In industry, purification of Lovastatin was achieved by several times of recrystallization. The crystallization is one of the most important and costly operation unit in the whole process of lovastatin manufacture, and the domestic products are incapable of competing with overseas products in international market. Hence, the systematic study on the crystallization process of Lovastatin was carried out.The powder diffraction profile for Lovastatin crystal was collected by X-ray diffraction technique. Also the single crystal of lovastatin was cultured and used to determine the CIF data. Using the Cerius2 software, the theoretical crystal habit of lovastatin was predicted by BFDH and AE model respectively. The result of AE model resembles the observed morphology.Crystallization thermodynamics is the key factor in design and optimization of the crystallization process. In this thesis, the solubility and metastable zone of lovastatin in several pure solvents and acetone+water mixtures with varied mole ratios at different temperatures were measured by laser monitoring method. The effects of the cooling rate and the mole fraction of acetone on the metastable zone were studied. The induction period was also measured. At the same time, the melting point was measured by Differential Scanning Calorimetry (DSC).The crystallization kinetics is essential important in design and operation of industrial crystallization process. Nucleation and crystal growth kinetic parameters were determined by batch dynamic method, and a size dependent growth rate model was established. The effects of operational conditions on the crystallization process were analyzed by this model. The character of crystal surface was detected by Atomic Force Microscopy (AFM). Then the continuous growth can be concluded from the harsh crystal surface.On the basis of thermodynamics and kinetics study, the crystallization process of lovastatin was optimized experimentally. The effect of process conditions (such as...