Study On Polymorphism And Multicomponent Crystals Of Aripiprazole

Aripiprazole(APZ)is the first-line medication for the treatment of mental disorders.However,APZ has a poor solubility in water,which seriously affects its bioavailability.In response to these two problems,we mainly study on polymorphism transformation,and develop the new solid form of APZ based on crystal engineering,to improve the dissolution rate and solublity of APZ.Firstly,the polymorphism and transformation of APZ were studied.APZ Form III,IV and V were prepared by suspension crystallization method,and a new crystal form(Form X)was discovered,and its melting point(185.23℃)is significantly higher than the existing crystal form(120-148.5℃).The influence of the solvent on the APZ crystal form was explored from the polarity of the solvent and the ability of the hydrogen bond donor and acceptor.The thermodynamic solubility of APZ Form III in six organic solvents was determined by dynamic method,and the result shows that APZ has greater solubility in polar aprotic solvents.According to the results of solvent-mediated transformation experiment and the solubility data,the polymorphism transformation process of APZ was monitored via in-situ FTIR and Raman.The research on polymorphism of APZ provide method guidance for the preparation and regulation of polymorphism.Secondly,the structure and physicochemical properties of APZ binary multicomponent crystals were under study,to improve the solubility of APZ.Based on crystal engineering,six salt forms of APZ with aromatic acids and alkyl acids were prepared by wet grinding and solution crystallization,and four crystal stuctures of them were obtained.The basic solid-state characterization,crystal structure analysis,stability test,and dissolution behavior in p H 4.0 acetic acid buffer solution were studied,and the results show that the maximum balance concertration of APZ is related to the relative solubility of salt formers,crystal packing and lattice energy.And the salt form of APZMalic acid improving the dissolution maximum concertration of APZ about double,which reflect the regulating effect of salt formers on the properties of APZ.Finally,the ternary multicomponent crystals of antischizophrenia drug were designed and prepared.Taking aripiprazole(APZ),risperidone(RPD),and paliperidone(PLPD)as model drugs,three series of eight ternary multicomponent crystals were prepared using suspension crystallization,including APZ-RPDdicarboxylic acid,APZ-PLPD-dicarboxylic acid,RPD-PLPD-dicarboxylic acid.one of the crystals was successfully analyzed by Single crystal X-ray diffraction.In addition,through Molecular Electrostatic Potential calculation and X-ray photoelectron characterization.We found that the N2 atoms of APZ,RPD,PLPD and the carboxyl of acids could form charge assisted hydrogen bond.The above studies,from the monocrystal form of APZ and the binary salt form of APZ,to the ternary multicomponent crystals research.The polymorphism transformation law of APZ was studied,and the multicomponent crystals were designed and prepared by crystal engineering,which tuning the physicochemical properties of APZ,and making a certain sense on pharmaceutical significance and practical value.