| Hydrocortisone (HC) , 11β,17α,21-trihydroxypregn-4-ene-3,20-dione, is an important grucocorticoid. It is not only 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 integration crystallization process of HC was studied systematically both in experiment and theory. It was found that the Polymorphism is a special behavior for HC crystallization. By indexing the HC's CCD single crystal diffraction data, 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 operation condition of crystallization process. The Characteristics of HC crystals including its morphology, thermal property, particle size, etc. 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 decided 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 through 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. 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 explored 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 detailed. There are many 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 was decreased about 30%,one or two crystallization steps were eliminated, the yield was increased about 5%～15%. This paper supplied the basic data and foundation operation schedule for engineering scale up and further search on crystallization process of HC. There is no similar report to above study result has been published in literature up to date.
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