Investigation On Polymorphs Of Lansoprazole And Its Crystallization Process

Lansoprazole is an irreversible proton pump inhibitor,clinically used for gastric ulcer,reflux esophagitis,duodenal ulcer,Zollinger-Ellison syndrome(gastrinoma),especially for the effect of inhibitory on helicobacter pylori.Lansoprazole has been developed into a variety of crystal porlymorphs,however,the crystal size of them is generally low.It still has problems like low stability,small bulk density,poor fluidity,and safe hidden trouble.The fluidity and stability of drugs are of great significance to the post-treatment of drugs and the prevention of adverse drug reactions.Therefore,this work systematically studies the polymorphism of lansoprazole and the transformation between different crystal forms and their crystallization process.First of all,the crystallization thermodynamics of lansoprazole is studied.Solubility of lansoprazole in 12 kinds of pure solvent(methanol,ethanol,propanol,isopropanol,n-butyl alcohol,isobutyl alcohol,acetone,acetonitrile,methyl acetate,ethyl acetate,propyl acetate,butyl acetate)was measured by static gravimetric method.The modified Apelblat equation,the ?h model and the NRTL model were used to correlate the solubility data.The dissolution thermodynamic properties,which provided basic data for the design of crystallization process,were evaluated by NRTL model.This work successfully developed three kinds of new porlymorphs of lansoprazole:ethanol solvate,form ? and monohydrate.The new porlymorphs were fully characterized by powder X-ray diffraction,microscope analysis,thermal analysis,Raman spectrum analysis,water analysis and infrared spectrum analysis methods to characterize the microstructure and morphology.The solubility and fluidity of the three new porlymorphs were investigated,and the results showed that the solubility and fluidity were better than that of the raw materials.The solvent-mediated phase transformation between ethanol solvate and monohydrate was studied by combining in-situ and offline methods.The population balance model was used to fit the experimental data,determining the rate control steps,the change profiles of crystal size distribution and relative content of both polymorphs.The solid-solid phase between ethanol solvate and form II was also investigated.The desolvation kinetics of the ethanol solvate and the adsorption kinetics of form ?were analyzed.Finally,the crystallization process of lansoprazole monohydrate is optimized on the basis of the above research.The effects of the crystallization methods,crystal seed,initial concentration,cooling rate,addition rate of antisolvent,the stirring speed and other conditions on product quality and particle size distribution were investigated.The lansoprazole with better crystal shape,higher puity,bigger particle size and narrower partical size distribution were produced by the optimized crystallization process.