Study On Process Crystallization Of Chlorpropamide

Chlorpropamide is a kind of oral sulfonylureas,which is a long-term hypoglycemic drug for the treatment of type Ⅱ diabetes.At present,the date of solubility and crystallization process of chlorpropamide are hard to find.In this paper,the solid-liquid phase equilibrium and crystallization process of chlorpropamide were studied.In this paper,we determine the solubility of chlorpropamide in 14 organic pure solvents(8 alcohol solvents:ethanol,n-propanol,isopropanol,n-butanol,isobutanol,2-butanol,n-pentanol and isoamyl alcohol,6 ester solvents:ethyl acetate,propyl acetate,isopropyl acetate,butyl acetate,amyl acetate and methyl propionate)and two mixed solvents(ethanol+water,ethanol+acetic acid)by the laser dynamic method.Apelblat model,van’t Hoff model,Wilson model and NRTL model were used to fit the solubility of chlorpropamide in 14 pure solvents.Apelblat model and J-A model fit the solubility of mixed solvent,and Apelblat model is better than J-A model.According to the model parameters of Wilson’s model,the thermodynamic properties of chlorpropamide,i.e.the values of Δ mixG、Δ mixH and Δ mixS were calculated,The dissolution process of chlorpropamide in 14 selected solvents is spontaneous.The thermodynamic mixing variables of chlorpropamide and the powder X-ray diffraction data of the indicator chlorpropamide were simulated by Materials Studio software to obtain the crystal cell parameters of chlorpropamide,then simulate the crystal morphology of chlorpropamide.The molecular models of chlorpropamide and five solvents were optimized by using Forcite module in the simulation of thermodynamic mixing variables.The changes of thermodynamic mixing variables(binding energy curve,Chi parameter,mixing energy and average binding energy)in different solvents at 20℃ and at different temperatures were simulated by using the Blends module.Comparing the simulation results with the experimental results,it is found that they are the same.In order to obtain the crystal cell structure of chlorpropamide,the powder X-ray diffraction of chlorpropamide is carried out to obtain the diffraction data and the XRD data is indexed.The empty crystal cell of chlorpropamide was obtained by X-cell indexation,the crystal cell was refined,The model molecules were constructed and optimized.The crystal structure was determined by analysis and refined with Rietveld option to obtain the crystal cell structure of chlorpropamide.The BFDH model of Morphogy module was used to predict the crystal morphology of chlorpropamide.The crystallization experiments of chlorpropamide were carried out by comparing the two crystallization methods of cooling crystallization and solution crystallization.The effects of different crystallization conditions such as initial concentration,crystallization temperature,stirring rate,crystallization time,drop acceleration rate of solubilizer and the ratio of solvent and solubilizer on the crystallization of chlorpropamide were investigated.The better crystallization process was determined:the crystallization initial concentration is 0.045g/ml and crystallization temperature is 20℃,the stirring rate is 150rpm,time of crystal culture is 30min,the drop acceleration rate of the solubilizer water is 1ml/min and the ratio of solvent and solubilizer is 1:2.