Preparation And In Vitro Evaluation Of Aripiprazole Microparticles And Their Orally Disintegrating Tablets

Objective:As a chronic mental disorder,schizophrenia(SZ)poses a serious threat to human health.Aripiprazole(APZ)is a multi receptor atypical antipsychotic drug,often known as dopamine system stabilizer,with high safety,less adverse reactions and wide clinical application.However,as a dihydroquinolinone drug,the solubility of APZ is very poor,coupled with liver metabolism and P-glycoprotein efflux,resulting in its low treatment effect.In this study,to prepare APZ microparticles without carrier excipients by rapid membrane emulsificationsolvent evaporation method.In order to enhance its dispersibility in water,accelerate the dissolution rate in vitro,and improve the bioavailability.It is inconvenient for the administration of microparticle freeze-dried powder,and it is easy for the patients with mental illness to vomit and hide drugs.In order to improve the medication compliance of patients,APZ microparticle freeze-dried powder is used as the intermediate to prepare orally disintegrating tablets by freeze-drying method.The structure of orally disintegrating tablets is loose and porous,which can be rapidly disintegrating in the mouth without water.It is a new rapid release preparation.The combination of microparticle preparation technology and orally disintegrating tablets can effectively improve the drug release process and provide reference for the development of other insoluble drug formulations.Methods:(1)Preparation of aripiprazole microparticles:?The pre-prescription study of APZ API was carried out.The method for determination of APZ by HPLC was established.The equilibrium solubility and oil-water partition coefficient of APZ in different media were determined by shaking flask method;?APZ microparticles without carrier excipients were prepared by rapid membrane emulsification-solvent evaporation method.The particle size,span and apparent morphology of APZ microparticles were used as indexes to investigate the preparation process by single factor,and the optimal preparation conditions were preliminarily determined.(2)Characterization and physicochemical properties of aripiprazole microparticles:?Laser particle size analyzer,scanning electron microscope,differential scanning calorimetry(DSC)and powder X-ray diffraction(PXRD)were used to investigate the appearance,rehydration,morphology,particle size distribution and crystalline state of APZ microparticles and API;?High performance liquid chromatography(HPLC)was used to determine the content uniformity of APZ microparticles;?Ultraviolet and visible spectrophotometry(UV)was used to detect the PVA residue in APZ microparticles;?Gas chromatography(GC)was used to determine the dichloromethane residue in APZ microparticles.(3)In vitro release of aripiprazole microparticles:The release behavior of APZ microparticles and API in phosphate buffer containing surfactant was investigated by direct release method,and the difference of drug release behavior in vitro was evaluated.(4)Preparation of aripiprazole microparticle orally disintegrating tablets:APZ microparticle orally disintegrating tablets were prepared by freeze-drying method with APZ microparticle freeze-dried powder as the preparation intermediate.The types of excipients were screened by single factor with appearance,disintegration time and micro morphology as indexes,and then the dosage of excipients was optimized by central composite design and response surface methodology with disintegration time as indexes.(5)Quality evaluation of aripiprazole microparticle orally disintegrating tablets:The properties,disintegration time limit,weight difference and content uniformity of the selfdeveloped preparation were investigated according to the general principles of Chinese Pharmacopoeia(2020 Edition);According to the guidelines for bioequivalence test of generic drugs(Japan)and IF document for generic drugs of aripiprazole orally disintegrating tablets,the in vitro dissolution behaviors of reference preparation,APZ microparticle orally disintegrating tablets and APZ API orally disintegrating tablets were compared.Results:(1)Preparation of aripiprazole microparticles:?Pre-prescription study:a method for the determination of APZ was established,and all the methodological studies were all qualified;The results of equilibrium solubility and oil-water partition coefficient showed that the solubility of APZ API was very poor;?The optimized preparation process of APZ microparticles was as follows:organic solvent DCM,PVA concentration in water phase 3%,drug concentration in oil phase 0.7%,oil-water phase volume ratio 1:1,curing solution 3%PVA solution(pH8.5),once through the film,and mechanical stirring curing.(2)Characterization and physicochemical properties of aripiprazole microparticles:APZ microparticle lyophilized powder was white powder,which could be dispersed by shaking with water.The rehydration property of APZ microparticle lyophilized powder was better than that of API;Under the scanning electron microscope,the APZ API was different in size,and the APZ microparticles were uniform flakes;APZ microparticles had a more uniform particle size distribution than API;The results of DSC and PXRD showed that the crystalline form of the microparticles did not change,but the degree of crystallization decreased;The average drug content of APZ microparticles was 97.58%,RSD was 0.67%.The particle content within and between batches was similar,and there were almost no PVA and dichloromethane residues.(3)In vitro release of aripiprazole microparticles:Phosphate buffer containing 0.05%sodium dodecyl sulfate(SDS)(release medium I:pH6.8,release medium ?:pH7.4)was selected as the release medium;The average cumulative release rates of APZ microparticles in the two release media were more than 50%at 2 h,and they were completely released at 48 h,while the average cumulative release rates of API were less than 50%at 48 h;The in vitro release of API in release medium I was more in line with the logistic equation,and the release in release medium ? was in line with the first-order equation.The drug release behavior of APZ microparticles in both release media fitted the logistic equation best.(4)Preparation of aripiprazole microparticle orally disintegrating tablets:Through the optimization of the prescription,the composition of APZ microparticle orally disintegrating tablets was determined as follows:the main drug 3 mg,the matrix agent mannitol 12.5 mg,and the adhesive pullulan 9.5 mg.(5)Quality evaluation of aripiprazole microparticle orally disintegrating tablets:The appearance of APZ microparticle orally disintegrating tablets was white and uniform,the shape was complete and full,the surface was bright and clean,and there was no crack edge or crack phenomenon;In the longitudinal section,the channels were arranged in order and uniform in size;The disintegration time limit,weight difference and content uniformity were in accordance with the relevant provisions of the pharmacopoeia;The dissolution behavior of APZ microparticle orally disintegrating tablets was similar to that of APZ API orally disintegrating tablets only in pH5.0 phosphate buffer solution.The dissolution of APZ microparticle orally disintegrating tablets was higher than that of APZ API orally disintegrating tablets in pH1.2 hydrochloric acid solution,pH6.8 phosphate buffer solution(containing 0.02%sodium dodecyl sulfate)and water(containing 0.1%sodium dodecyl sulfate).Conclusion:The rapid membrane emulsification process is stable,which is helpful to improve the dispersion of insoluble drugs in water,improve the content uniformity of hydrophobic drugs in the preparation process,and accelerate the dissolution rate of insoluble drugs.It is expected to improve the absorption process of drugs in vivo to a certain extent.The freeze-drying method is used to prepare the microparticle freeze-dried powder into orally disintegrating tablets,which is beneficial to reduce or avoid the first pass effect of the liver,reduce gastrointestinal irritation,and improve patient compliance with medication.It provides ideas for the development of drug formulations for the elderly,children and some special diseases.