Study On Preparation And Stability Of Novel Nanoamorphous Drugs

The water solubility of drug is the key factor to determine its dissolution.At present,more and more candidate drugs show low water solubility,which seriously limits their further clinical application.Nanotechnology and coamorphous are the frontier technologies that can effectively improve drug solubility.This subject innovatively combines the them to construct a coamorphous nanosystem,and studies the use of this system to improve the solubility of drugs.In this paper,curcumin-artemisinin coamorphous nanosystem and quercetin-lysine coamorphous nanosystem were prepared,and the properties and mechanisms of coamorphous drugs prepared in different molar ratios in terms of particle structure,intermolecular interaction,crystal form,stability,dissolution and antioxidation were studied.The particle size reduction rule,crystallinity change,solidification and drying process of coamorphous in the process of nanometerization was studied,and build a stable nanometer system.In order to obtain the best preparation technology,the wet grinding technology and high-pressure homogenization technology used in the process of drug nanocrystallization were optimized.The experiment confirmed the existence of interaction force-hydrogen bond in curcumin-artemisinin coamorphous system,and its molar ratio and other parameters affected the crystal transformation,which could be stored stably for 6 months and retain strong oxidation resistance.Curcumin-artemisinin coamorphous porous structure can make its particle size reach below 400 nm in a short time during wet grinding.Response surface Box-Behnken method determined the influence of three main factors on particle size reduction in grinding process: drug concentration>grinding time>stabilizer concentration.Higher drug concentration will increase the resistance of grinding process,and stabilizer concentration will affect the viscosity of solution.The particle size of drug particles tends to the extreme value with the increase of grinding time,and the time will not decrease significantly if the time continues to increase.Freeze-dried coamorphous nanosystem can still remain amorphous and have high dissolution after 3 months of storage.During the wet grinding process,the decrease of particle size maintains the low crystallinity,and the dissolution（at 60 min）of the constructed curcumin-artemisinin coamorphous nanosystem is 9 times higher than raw curcumin,and also significantly higher than that of coamorphous nanosystem.In addition,the study of quercetin-lysine coamorphous system also confirmed the existence of intermolecular interaction in this combination.The optimal molar ratio（1:1）can achieve 3-month stability（amorphous）and show good antioxidant effect.In the process of high-pressure homogenization,it was found that the crushed block structure of quercetinlysine coamorphous was rapidly reduced in particle size in the process of homogenization to realize nanoscale.Response surface model analysis confirems that pressure and cycle times have significant effects on the final ultimate particle size.The increased pressure means higher energy input,which contributes to the collision and crushing of drug particles;the particle size will not continue to decrease after the particle breakage reaches the limit during the circulation process.The cured coamorphous nanosystem remained amorphous and showed high dissolution after 3 months.The combined action of nanoparticle size and amorphous in coamorphous nanosystem makes the dissolution performance of quercetinlysine coamorphous nanosystem greatly improved compared with raw quercetin.Through the study of two groups of model drugs,it was found that the significant change of drug morphology and structure in coamorphous system was related to the choice of preparation methods.In the amorphous system,all the components show the amorphization of drug crystal form,and intermolecular interaction（hydrogen bond）was existed between the components.The coamorphous system constructed by the two drugs with the molar ratio of 1:1 shows high physical and chemical stability.And the optimized nanoprocess and curing process could prepare a stable coamorphous nanosystem with high dissolution performance.The coamorphous nanodrugs were prepared into tablets,and the prescription excipients were optimized by orthogonal experiments,and the differences in dissolution rates before and after tableting were compared.Experiments confirmed that the excipients added to the tablet would affect the dissolution rate of nanodrugs,but not the final dissolution of the drug.The dissolution of curcumin-artemisinin coamorphous nanodrug tablets is equivalent to its nano-suspension,and significantly higher than that of curcumin bulk drug tablets,and also higher than that of coamorphous tablets,which indicates the feasibility of tablet preparation and its high dissolution performance.