Study On Crystallization Process Of Spironolactone

Spironolactone is an inefficient diuretic, which is mainly used in treatment of edema disease. Spironolactone form II is a stable polymorph, and it is widely used in clinical. For the domestic enterprises, there exist the problems in the refining process of spironolactone, such as low purity, small particle size and poor reproducibility. In order to solve these problems, crystallization process of spironolactone was studied systematically from the following aspects.Firstly, the thermodynamic properties of spironolactone were studied. Dynamic method was applied to determine the solubility of spironolactone form II in methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, ethyl acetate and binary ethyl acetate-methanol solvent. The solubility in pure solvent and binary solvents were fitted with Apelblet equation and(CNIBS)/R-K model, respectively. And the dissolution thermodynamic functions of spironolactone in pure solvents and binary solvents were calculated, which can provide the theoretical basis for process optimization and scale-up of industrial crystallization.Then, spironolactone polymorphism and polymorphic transformation were studied to determine the solvent for the crystallization process, A series of spironolactone polymorphs were prepared from cooling crystallization, and crystal structure of polymorphs were analyzed. On the basis of single crystal structure, BFDH model and AE model were applied to predict crystal habbit of spironolactone form II. Meanwhile, the thermodynamically stable polymorph in alcohol solvents was determined by comparing solid-liquid equilibrium relationship of alcohol solvates and form II in corresponding alcohols. Furthermore, there existed the polymorphic transformation phenomenon of spironolactone 1-propanol solvate and 2-propanol solvate in corresponding solvents. Offline monitoring instruments and in-situ monitoring tools were applied to study the polymorphic transformation process from the solvates to unsolvated form II.Lastly, the process optimization of spironolactone evaporative crystallization was based on the above study, combined with the requirements of the manufacturer. The effects of the concentration, evaporation temperature, evaporation rate, the amount of the activated carbon and the decoloring time on intermittent evaporative crystallization process were investigated, and the main factors of affecting the product purity were determined. The semi-continuous evaporative crystallization process was studied to finalize its optimal operation condition. Under these conditions, the crystal products with perfect habbit and CSD,high purity(more than 99.95 %) and high yield(more than 95 %) can be obtained, fully meet the contractual requirements of manufacturer.There is no similar report pubilished in literatures on above study up to date.