Study On Rifampin Polymorphism And Crystal Morphology Simulation

Rifampicin is a kind of semi-synthetic broad-spectrum antibacterial drug,mainly used for the prevention and treatment of tuberculosis and other diseases.At present,domestic manufacturers mostly use oxazine process to produce rifampin,and the products have some problems such as mixed crystal form,crystal impurity,small particle size,broken morphology and so on.In this paper,combining experiment with simulation is the main method.The change of product crystal form in 1-butanol-acetone,water-1-butanol and water-acetone mixed solvents were studied and calculated the crystal morphology by molecular simulation.The main contents and conclusions are as follows:Firstly,the stability of two kinds of rifampin pharmaceutical crystal form Ⅰ and Ⅱ in solubility measurement was studied.In the mixed solvents of 1-butanol-acetone and wateracetone,the crystal form Ⅰ change to crystal form Ⅱ after stirring for a long time,thus the crystal form Ⅰ is unstable while the crystal form Ⅱ is stable in the solvent above.At the temperature range of 288.15k～323.15k,equilibrium method was used to determine the solubility data of crystal form Ⅱ in the two mixed solvents.The Apelblat equation,ideal state equation and(CNIBS)/Redlich-Kister equation were used to correlate the solubility data,and the thermodynamic parameters of the dissolution process of crystal form Ⅱ were calculated according to van’t Hoff model.Secondly,the product crystal form of rifampicin in three mixed solvents of 1-butanolacetone,water-1-butanol and water-acetone was studied.In the 1-butanol-acetone system,the initial concentration of the crystal solution and the ratio of 1-butanol to the solvent were changed to determine the optimal formation conditions of product crystal form.The control interval of crystal form Ⅱ are as follows:the ratio of 1-butanol to solvent is less than 30wt%,and the initial solution concentration is 7.5wt%.The control interval of solvate are:the ratio of 1-butanol to solvent is more than 60wt%,and the initial solution concentration is 8.5wt%.The control interval of crystal form Ⅰ are:40wt%1-butanol ratio,and the initial solution concentration is greater than 8.5wt%.The crystal form I obtained from the mixed solvent have a larger particle size and a concentrated particle size distribution,the product quality is better.In the water-1-butanol and water-acetone system,the influence of water content of the system on product crystal form was concerned.The increase of water content in the solvent to 5wt%make the product change from crystal form I to solvate,and the crystallinity decrease from 100%to 58.34%,the crystal morphology change from plate shape to long bar shape.In the wateracetone system,the increase of solvent water content to 7%will cause the crystal degree of the product to drop from 100%to 40.31%,and the amorphous content increase,when the water content of 9%,product will completely change to amorphous.The increase of water is not conducive to the improvement of product quality.Thirdly,the dissolution of the product and raw materials in water,phosphate buffer solution of pH7.0 and HCl solution of 0.1mol/L were compared.The crystal form Ⅱ has the best solubility and the highest dissolution rate in all three systems.Due to the smaller particle size,the dissolution and dissolution rate of the crystal form Ⅰ of the raw material are better than the crystal form Ⅰ obtained in the experiment.The solvate dissolves worst.Finally,the crystal morphology simulation of solvate was carried out.Crystal cell structure of new solvate obtained by cultivation of the single crystal and X-ray single crystal diffraction.The interface model was built by Materials Studio software to analyze the differences in roughness,chemical structure and electrostatic potential of each crystal surface.According to the modified AE model,the influence of mixed solvent on crystal morphology is calculated,and the simulation results are consistent with the experimental results.The results of this study can provide theoretical guidance and basic data for establishing crystal control technology in rifampin industrial production.