【作者】 吴晓红；

【导师】 王永莉；

【作者基本信息】 天津大学 ， 化学工程， 2007， 硕士

【摘要】 地塞米松是一种典型的肾上腺皮质激素类药物,具有抗炎、抗毒素、抗过敏、抗休克等药理作用,在临床方面,具有十分重要的意义。目前,国内对其中间体11β-羟基孕甾-1,4,16-三烯-3,20-二酮的生产存在工艺落后、结晶精致收率低、产品纯度低、颗粒小等问题,本文对11β-羟基孕甾-1,4,16-三烯-3,20-二酮溶析-冷却结晶过程进行了较系统的研究。采用自然冷却方法培养了11β-羟基孕甾-1,4,16-三烯-3,20-二酮单晶,由X-射线单晶衍射确定了晶体结构。应用Cerius2分子设计软件分析了真空中的BFDH模型和AE模型晶形。并考察了温度对晶习的影响。采用动态法测定了不同温度和溶剂配比下的11β-羟基孕甾-1,4,16-三烯-3,20-二酮溶解度。并通过回归得到溶解度λh方程。采用激光法测定了11β-羟基孕甾-1,4,16-三烯-3,20-二酮在混合溶剂中不同温度下的介稳区,为工艺的确定和改进提供基础依据。采用间歇动态法测定了11β-羟基孕甾-1,4,16-三烯-3,20-二酮溶析-冷却结晶动力学。运用矩量变换法对实验数据进行处理,建立了生长粒度无关的无聚破的动力学模型,并考察了温度、搅拌速度对二次成核速率和成长速率的影响。以纯度和收率为目标,系统地研究了结晶条件(结晶温度、晶种、溶析剂流加速率、搅拌速率、养晶时间、结晶最终温度等)对溶析-冷却结晶过程的影响,初步确定出了经验最佳的操作工艺。该工艺提高了产品的收率和纯度,实验产品粒度较大、不聚结、晶形完善。上述研究结果可为11β-羟基孕甾-1,4,16-三烯-3,20-二酮结晶过程的进一步研究和工业生产提供依据。上述研究工作及结果均未见文献报道。更多还原

【Abstract】 Dexamethasone is a typical corticosteroids drug, which has very important clinical use. It possesses many merits, such as anti-agnail, anti-toxicity, anti-irritability and anti-shock. Nowadays’produce process of 11β-Hydroxypregna-1 , 4 ,16-triene-3,20-dione (one of dexamethasone intermediates) exist some serious problems in yield and quality. Also the product’s appearance has obvious shortages. In this thesis the dilution and cooling crystallization process of 11β-Hydroxypregna-1,4,16-triene-3,20-dione was studied systematicly.The 11β-Hydroxypregna-1,4,16-triene-3,20-dione single crystal cultivated by cooling method was analyzed by X-ray single crystal diffraction and its structure was determined.Using the Cerius2 software, the crystal morphology in the vacuum was calculated based on BFDH and AE principle respectively. The influence of temperature on crystal habit was also studied.The solubility of 11β-Hydroxypregna-1,4,16-triene-3,20-dione at different solvent ratio and temperature was determined by dynamic method. The solubility data was regressed in the form ofλh equation. The crystallization metastable zone was also studied by laser method. The thermodynamic data can be used to confirm and improve the crystallization process.Nucleation and growth kinetics were measured by batch-operated methods. The empirical equations for secondary nucleation and crystal growth kinetics were gotten by moment method. A size-independent growth rate model without agglomeration or breakage was established. In adition, the influence of temperature and stir speed on secondary nucleation and crystal growth rate were studied.To obtain high yields and purity, the effects of crystallization conditions (such as the crystallization temperature, seed, addition rate of anti-solvent, stir speed and the final temperature) were investigated in detail, as a result, the relatively better operation technics was found. The method of dilution and cooling crystallization has successfully enhanced the product quality and yield in lab. The product has big size and good crystal habit.The paper supplied the basis for further research and scale up on crystallization of 11β-Hydroxypregna-1,4,16-triene-3,20-dione. There is no similar report to above study result has been published in literature up to date.更多还原