A Study on Crystallization Process of Hydrocortisone
Hydrocortisone(HC) is an important grucocorticoid. It not only is the effective antiphlogistic and immune- suppressive substance with instant effect, but it also shows with low-dosage long-term treatment, clear antiproliferative effects on the cartilage and bone destroying pannus in rheumatoid arthritis. In order to improve the quality and reduce the production cost of HC, a batch integrated crystallization process of HC was studied systematically. It was found that the Polymorphism is a special behavior for HC crystallization. By indexing the HC’s CCD single crystal diffraction, the crystal Miller indices and crystal system were determined. There are three different crystal systems (orthorhombic, monoclinic and rhombohedral), and different crystal habits (cuboid, prism, needle-like, plate and flake) for HC crystal have been obtained by alteration of the operation conditions of crystallization solvents. The morphology, thermal property and particle size of HC crystals were observed based on the measured data with IR spectra, DSC and powder XRD instruments etc. The crystal space lattice of HC also was calculated by running polymorph in commercial software Cerius2. The crystal habit of HC was predicted by BFDH and AE model respectively. The result of AE model with modifications of the surface attachment energy resembles the observed morphology of HC crystallized from different solvents. Crystal yield is determined by crystallization thermodynamics. A general solubility equation was derived from the concept of phase equilibrium and used in the regression of the solubility data while the activities were calculated based on solubility parameters. The theoretical results were in accordance with the experimental solubility data. Metastable zone of HC crystallization was measured and solid-liquid surface energy was calculated. An artificial neural network was applied to the mathematical simulation of crystallization thermodynamics, and preferable approximation was achieved. Estimation of kinetic parameters of nucleation and crystal growth is of essential importance in analysis, design and operation of industrial crystallization processes. The continuous crystal growth mechanism was determined by calculating the surface entropy factor. Nucleation rate equation and growth rate equation were regressed by experiment data with Malvern and FBRM instruments. The two approaches for particle size measurement, Malvern and FBRM, were compared theoretically and experimentally. Nucleation and crystal growth phenomenon unobservable by conventional instruments could be clearly observed by online PVM and FBRM, providing a more efficient way for the control of crystallization. The effects of 44 adsorbents and 35 solvents on decoloration, solubility and crystallization process were screened respectively. A new integrated crystallization process (evaporation dilution and cooling and cycled solvent) was developed and the effect of operation conditions on production has been studied in detail. There are some advantages, such as environment friendly solvents; increased yield and productivity and lower production costs by reduced operation steps for this integration crystallization process. On the basis of thermodynamics and crystallization kinetics, the mathematical model of crystallization process was established. According the simulated result the theoretical optimal operation strategy was established. Using this integration crystallization process，the high quality product was manufactured under the optimized operation schedule. The toxicity of the solvent used in the new process was only 5%～8% of that of the original one, the consumption of solvent was reduced by ～30%，one or two crystallization steps were eliminated, the yield was increased about 5%～15%.
Hydrocortisone crystallization thermodynamics kinetics integrated crystallization process
Jianxin Chen Junsheng Yuan Jingkang Wang Min Su
Engineering Research Center of Seawater Utilization Technology, Ministry of Education School of Chem School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
国际会议
International Symposium on Crystal Engineering and Drug Delivery System 2009(2009晶体工程与药物传送系统国际会议)
天津
英文
80-81
2009-09-05（万方平台首次上网日期，不代表论文的发表时间）