Preparation Of Indometacin Solubilization System By Mechanical Ball Milling

Indomethacin?IMC?is a non-steroidal anti-inflammatory drug,which is widely used to relieve the pain caused by various diseases such as joint inflammation and cancer.However,as a drug belongs to class II in the biopharmaceutical classification system?BCS?,IMC has the properties of high permeability and low solubility,which limits its clinical application.Mechanochemical ball milling technology is gaining huge popularity owing to its superior meritsowing to its superior merits,such as no solvent involved in the preparation process,simple and efficient operation.From the technology of ball milling,the solubility and dissolution of drugs are improved by reducing the particle size and crystallinity of drug,along with new phase formation.In view of the poor solubility and dissolution of IMC in clinic,the IMC solubilization system was prepared by mechanicalchemical ball milling technology combined with the solid dispersion,drug cocrystals,the novel solid dispersion and inclusion complex.The main research is as follows:?1?The solid dispersion systems of IMC with disodium glycyrrhizinate?Na₂GA?,hypromellose?HPMC?,mannitol?Man?and hydroxypropylmethylcellulose acetate succinate?HPMCAS?were prepared by mechanical ball milling.The influence of ball milling conditions on solid dispersion of different excipient was explored.The results of DSC,XRD,FTIR,and SEM characterization experiment indicated that the crystal state of drug in the system was transformed into amorphous,the drug was fully dispersed in the auxiliary material system,and solid dispersion of IMC was successfully prepared.The results of solubility and dissolution showed that solid dispersion can effectively improve the solubility and dissolution of IMC,and the solubilization effect was different due to different excipient,Among them,Na₂GA>HPMCAS>Man>HPMC.The results of drug content experiment indicated that the system prepared by ball milling was uniform and IMC had not been destroyed.Besides,the results of stability experiments showed that stability and storage conditions of SD were obviously different due to different excipient,among them,Man>HPMC>HPMCAS>Na₂GA.HPMCAS SD was brtter choice investigated the solubility,dissolution and stability of IMC.?2?The cocrystals of IMC with Saccharin?Sac?and Nicotinamide?NAD?were prepared by mechanical ball milling.The effect of ball milling conditions on the drug cocrystals system prepared by different excipient were investigated by XRD.The results of characterization experiment showed that the system formed a new crystal form,and the cocrystals system was successfully prepared.The results of solubility and dissolution showed that the cocrystals could effectively improve solubility and dissolution of IMC,and the effect of solubilization was different due to different cocrystals co-former,among them,NAD>Sac.The stability experiment showed that the stability of drug cocrystals system was improved compared with that of solid dispersion system.?3?The novel solid dispersion systems of IMC with meglumine?MG?and calcium carbonate?Ca CO₃?were prepared by mechanical ball milling.The influence of ball milling conditions on novel solid dispersion of different excipient was explored.The results of characterization experiment showed that novel solid dispersion of IMC was successfully prepared.The results of solubility and dissolution showed the solubility and dissolution of IMC were affected by the excipient with p H regulation of microenvironment,among them,MG>Ca CO₃.Novel SD with p H regulation of microenvironment can be applied to other solubilization field.?4?The inclusion complex of IMC with hydroxypropyl-?-cyclodextrin?HP-?-CD?and arabinogalactan?AG?were prepared by mechanical ball milling.The influence of ball milling conditions on the inclusion complex of different excipient was explored.The results of phase solubility experiments indicated that IMC inclusion complexes with HP-?-CD and AG were formed respectively in the form of 1:1.The characterization results showed that IMC in the system was in an amorphous state and was encapsulated in the excipient cavity,the inclusion complex of IMC was successfully prepared.The results of solubility and dissolution showed that solubility and dissolution of inclusion complex were improved effectively,among them,HP-?-CD>AG.The stability test showed that the inclusion compound should avoid high temperature and high humidity environment.