The Stability Of Supersaturated Solutions Of Ritonavir Solid Dispersions

At present,no matter in the market drugs or candidate drugs,insoluble drugs occupy a high proportion,so improving the solubility of insoluble drugs is an urgent problem to be solved in pharmaceutical preparations.There are many ways to improve the solubility of drugs,among which solid dispersion is an effective way,but its stability is poor,before reaching the absorption site,drug molecules tend to crystallize,so that its solubility advantage is lost,and then the bioavailability is reduced.Therefore,it is necessary to pay attention to the stability of amorphous solid dispersion（ASD）.In this study,Ritonavil was used as the model drug,and the ternary solid dispersion was prepared using hydroxypropylcellulose acetate succinate（HPMCAs）and sodium dodecyl sulfate（SDS）as the carrier,which could not only improve the dissolution,but also inhibit the drug crystallization after dissolution,so as to improve the bioavailability.This research firstly characterizes the formation and crystallization process of the second dispersed phase in ritonavir supersaturated solution in order to better understand the supersaturated system.Then,HPMCAS-HF was screened out through the crystal suppression experiment to have a better effect of crystallization suppression.A solid dispersion was prepared with HPMCSA-HF as a carrier,and the relationship between drug loading and dissolution was investigated.The results showed that the lower the drug loading,the higher the dissolution.The solid dispersion was characterized by DSC,XPRD,SEM,and FTIR.The results indicated that RTV existed in an amorphous state,and the interaction between RTV and HPMCAS-HF was dominated by hydrogen bonds.Then on the basis of the RTV-HPMCAS-HF binary system,a ternary solid dispersion was developed by adding a surfactant.Through solubility experiment and crystallization suppression experiment,it was screened out that SDS has good effect,and the influence of the ratio of RTV/HPMCAS-HF/SDS on the crystallization suppression effect was investigated.A ternary solid dispersion prepared by the ratio of RTV:HPMCAS-HF:SDS=1:4:1 was determined via dissolution experiment as the best prescription.DSC,XPRD,SEM,FTIR indicated that RTV existed in an amorphous state,the interaction between RTV and HPMCAS-HF is dominated by hydrogen bonds,and there is no interaction between them and SDS.The relative bioavailability of ritonavir ternary solid dispersion was investigated through rat pharmacokinetic experiments.The results showed that AUC_（0-t）of the ritonavir ternary solid dispersion and the Reference formulation(Norvir^?)were 8952.60±1213.20 ng-hr/m L and 7430.92±545.71 ng-hr/m L,respectively,indicating that the ritonavir ternary solid dispersion has higher bioavailability.This project successfully prepared RTV/HPMCAS-HF/SDS ternary solid dispersion to improve the solubility and bioavailability of RTV.It is expected that the combination of multiple carrier materials can overcome the instability and crystallization of solid dispersion after dissolution.It provides ideas for the development of more solid dispersion-based dosage forms of drugs,and has a certain in-depth and innovative nature.