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Study On The Co-crystallization Process Of Sacubitril Valsartan Sodium Supramolecular Complex

Posted on:2021-10-31Degree:DoctorType:Dissertation
Country:ChinaCandidate:X J LiuFull Text:PDF
GTID:1481306569458444Subject:Chemical Engineering
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In the pharmaceutical industry,selection and development of the solid form of an active pharmaceutical ingredient(API)is of great importance.This is because different solid forms of varied crystal polymorph and morphology as well as crystal size distribution could have a major impact on the down-stream processing and on the quality of the crystalline product,leading to compromise in the drug's clinical efficacy.Supramolecular complex as a novel solid form of API has shown great potential and is considered as an indispensible method for solid form drug formulation in the future.The study on the crystallization of supramolecular complexes,in particular on supramolecular drug-drug complexes,is still in its infancy.In this research project,by reference to the sacubitril valsartan sodium,the crystallization of a supramolecular drugdrug complex is investigated.Sacubitril valsartan sodium(LCZ696),a supramolecular complex of valsartan and sacubitril,has a special dual mechanism for targeting one of the largest chronic diseases in humans,namely chronic heart failure.Despite having been on the market for only a relatively short period of time,there is large demand on it on the market.There are reports that in it's industrial production,there have been problems of low filtration efficiency due to crystal size and shape,but the literature on the study of the crystallization process of the supramolecular drug-drug complex LCZ696 is scarce.Based on the LCZ696 system,combining experiments and simulation,the crystallization thermodynamics,crystal characterization,crystal morphology,crystallization kinetics,chiral drug self-assembly mechanism and other aspects were investigated.The thermodynamic properties of S-valsartan were studied.Its solubility in methyl acetate,ethyl acetate,isopropyl acetate,n-butyl acetate,acetone,butanone,chloroform,and acetonitrile were determined and correlated by the van't Hoff equation,Apelblat equation and quadratic polynomial equation.The dissolving enthalpy and entropy of the solution was calculated by van't Hoff equation.Material Studio was used to analyze the the dissolution behavior of the solute in solvent.The thermodynamic properties of S-valsartan provided guidance for the research of LCZ696.Sacubitril calcium salt was used to prepare sacubitril firstly,then LCZ696 crystal was prepared together with valsartan.LCZ696 crystal was characterized by combination with XRPD,SEM,DSC-TGA,IR,Raman and HPLC.The solubility of LCZ696 was measured by turbidity,from which LCZ696 seed crystal was prepared and used in the subsequent experiment.In addition,the results of co-crystallization by valsartan with different chiral configurations were analyzed.Based on the cell structure parameters of LCZ696,Materials Studio was used to optimize cell parameters of LCZ696 by different combinations of six kinds force fields and three kinds of charge distribution.Optimized cell parameters with the smallest change were chosen as the basis of the subsequent simulation.The connection mode of the intramolecular hydrogen bond was investigated.Based on the hydrogen bond,the chiral self-assembly mechanism of Svalsartan and R-valsartan was analyzed to explain the experimental results about different valsartan configurations.The theoretical crystal habits of LCZ696 were obtained by BFDH model,AE model and EM model using Materials Studio software.The effect of acetone and isopropanol the morphology of LCZ696 crystal was studied.MAE model was established to simulate the modified crystal morphology of LCZ696 crystal under the mixed solvent with different mass ratio of acetone-isopropanol,and the influence of solvent on the crystal morphology of LCZ696 was also explained from the molecular level.The crystal morphology prepared by experiment verified the simulated crystal morphology.In situ ATR-FTIR spectroscopy and imaging and image analysis were applied to the study of the multicomponent co-crystallization process involving S-valsartan and sacubitril in which LCZ696 crystals were formed.ATR-FTIR and imaging and image analysis were used to monitor solution concentration and investigate the co-crystallization mechanism.It revealed that the nucleation process was very slow compared with the transformation process,which is indicated that the co-crystallization was controlled by nucleation.LCZ696 crystals are composed of very thin hexagonal plates,which seems indicating that LCZ696 crystals grow mainly in two size dimensions.Stirrer speed and crystal seeds were found to have noticeable effect on the induction time,transformation time and crystal size distribution.The JohnsonMehl-Avrami equation was found to be able to describe the co-crystallization process.
Keywords/Search Tags:LCZ696, co-crystalloization, crystal morphology, crystal simulation, crystallization kinetics
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