Study On Consistency Of Formability And Stability Of Tetrahydropalmatine,Tetrandrine Solid Dispersion

Objective:Solid dispersion（SD）is one of the most effective strategies to improve the solubility of insoluble drugs,in which the active drug components are dispersed in the carrier materials in molecular form,amorphous form or microcrystal.Because the drug molecules in SD are in the amorphous form with high energy,the surface free energy is large,and the particle size decreases,the specific surface area and wettability increase,so as to improve the solubility,dissolution and bioavailability.Only when the properties of SD remain stable can it promote dissolution,improve solubility and bioavailability.In the formulation of SD,carrier materials can increase the glass transition temperature of SD,reduce intermolecular mobility,prevent the accumulation of active drug molecules,etc.,thus play a role in maintaining the stability of SD,so reasonable selection of carrier materials plays a key role in maintaining the stability of SD.In general,the carrier materials are selected based on the formability of SD,but the formability and stability are not taken into account.The previous study of our group found that the SD,with excellent properties at the beginning may harden,agglomerated,recrystallized and lost the SD characteristics during storage.Therefore,in this paper,the spray drying method was used to prepare THP-SD and Tet-SD,to study the effect of carrier materials on the formability and stability of THP-SD and Tet-SD,and the consistency of different carrier materials on the formability and stability of THP-SD and Tet-SD,in order to provide reference for the reasonable selection of carrier materials.Dissolution is one of the most important pharmaceutical properties of SD,and it is the basis to determine whether SD can successfully improve the bioavailability of insoluble drugs.Therefore,the correlation between the stability of physical and chemical properties and dissolution stability of THP-SD and Tet-SD was analyzed,and the influence mechanism of dissolution stability was analyzed,so as to provide some reference for studying the dissolution stability of THP-SD and Tet-SD.Methods:（1）Polyvinylpyrrolidone K30（PVPK30）,hydroxypropyl methylcellulose 55（HPMC55）,polycaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(Soluplus^?)as carriers,tetrahydropalmatine（THP）and Tetrandrine（Tet）as model drugs,THP-SD and Tet-SD with different drug-carrier mass ratios were prepared by spray drying.The effect of drug loading on SD was investigated by the changes of apparent solubility,intermolecular interaction and thermal stability,and the best drug load was selected.（2）THP-SD and Tet-SD with 20%drug loading were characterized from the aspects of intermolecular interaction,drug state,thermal stability,surface morphology,surface free energy and its component,and the effects of different polymers on the formability of SD were discussed.（3）according to the accelerated test method in the Technical guidelines for the study of Chemical Drug Stability,THP-SD and Tet-SD prepared by spray drying were placed under the experimental condition of 40±2℃.The dissolution behavior,relative crystallinity,intermolecular interaction,surface free energy and its components of THP or Tet in SD were measured periodically,and the effect of carrier materials on the stability of SD was discussed.And the effects of different carrier materials on the formability and stability of SD.（4）the physical and chemical stability and dissolution stability of SD were modeled by statistical analysis software SIMCA-P+14.1,the factors affecting the dissolution stability and their effects were determined,and the mechanism of dissolution stability was analyzed.Results:The results showed that after the preparation of SD,the solubility and thermal stability of the drug were improved,and the intermolecular interaction force was enhanced,but with the increase of drug loading,its thermal stability and solubility decreased,and when the drug loading of the two drugs was 20%,the thermal stability and solubility were the best.The intermolecular interaction,thermal stability,drug existence state,dissolution behavior,wettability and surface free energy of THP-SD and Tet-SD were studied.the results show that the formability of THP-SD and Tet-SD prepared by Soluplus^?is the best.The changes of drug content,relative crystallinity and dissolution behavior of THP-SD and Tet-SD were studied.the results showed that the stability of THP-SD prepared by HPMC55 was the best,and that of Tet-SD prepared by PVPK30 was the best.It can be concluded that the effects of carrier materials on the formability and stability of SD are not consistent.For the model of SD physical and chemical property stability and dissolution stability,OPLS analysis can better fit the model,explain variables and more accurately predict the key factors affecting dissolution stability than PLS analysis.The non-polar component is the key factor affecting the dissolution stability,and it shows a strong positive correlation.The larger the non-polar component of SD is,the worse the dissolution stability is.Conclusion:the selection of SD carrier materials should not only be based on the initial physical and chemical properties and dissolution behavior of SD,but also comprehensively consider the stability of SD.The surface properties of the powder have influence on the dissolution stability of SD,so it is suggested that when selecting carrier materials,the carrier with small non-polar components should be selected on the basis of ensuring the formability.