Investigation On Polymorphs And Crystallization Process Of Rifampicin

Rifampicin is a kind of semisynthetic broad-spectrum antimicrobials,which has been widely used in the treatment of disease caused by mycobacterium tuberculosis in the clinical.Due to its high efficacy against tuberculosis,it has been designated as a drug for the treatment of tuberculosis.There are two polymorph forms of rifampicin.Currently,there exist some problems for rifampicin produced by domestic pharmaceutical companies such as small crystal size,low bulk density and poor fluidity.Therefore,in this work,polymorphs and crystallization processes of rifampicin were systematically investigated on the basis of crystal engineering theory.In the thermodynamic study of rifampicin,the solubility of form ? and form ? of rifampicin in acetonitrile or acetone pure solvent and the solubility of form ? in(acetone + water)binary solvent mixture were measured by a dynamical method.Based on the modified Apelblat equation and the Van't Hoff model,the experimental solubility data were correlated respectively.Furthermore,the standard dissolution thermodynamic properties,including the enthalpy,entropy and Gibbs free energy,were also calculated according to the Van't Hoff model.In the dissolution testing study of rifampicin,a direct powder compressing method was used to prepare tablet of rifampicin.Then dissolution rate of form I and form ? of rifampicin was measured at the optimal operation conditions.It was showed that form ? has a higher dissolution rate than form ?.In order to explore dissolution kinetics of rifampicin,the dissolution process was analyzed by Higuchi model and Power Law model.From the results,it was proved that the dissolution process of rifampicin is controlled by the non-Fickian diffusion.In the study of solution-mediated polymorphic transformation of rifampicin,the transformation of rifampicin from form ? to form ? was characterized by a series of tools.To explore the effect of solvent on transformation,the transformation experiments were carried out in three solvents.Furthermore,a mathematical model was built to describe the kinetics of transformation process by using experimental data.It can be seen that the calculation results are basically identical with the experimental results.On the basis of above theoretical research,the effect of evaporation rate,cooling methods,seed,initial liquid concentration,and stirring speed on the quality and size distribution of the product was investigated to optimize the crystallization process.According to above experimental results,the optimal crystallization operation conditions of rifampicin form I and form ? were obtained.