Design,Synthesis And Structure-Property Relationship Of Diabetic Drug-Drug Multicomponent Crystals

Multicomponent crystals have important academic significance and application value in pharmaceutical science since they show excellent designability and can modulate the physicochemical property of drugs.However,the introduction of co-formers or salt-formers for traditional multicomponent crystals（TMC）will lead to a decrease of drug content in prescription.Simultaneously,the lack of understanding on molecular assembly in crystals and structure-property relationships further becomes the main obstacle for rational design and synthesis.Therefore,this study is improvement of physicochemical property oriented based on the advantages of multicomponent crystals and combined with the strategy of drug combination.Specifically,oral antidiabetic drugs are chosen as models to synthesis drug-drug multicomponent crystals（DDMC）and explore their molecular assembly features,and further establish the structure-property relationship from molecular level.Firstly,the lack of deep understanding of molecular assembly in crystals restrictes the solid-state development of drugs.Aiming at this problem,gliquidone（GQD）is taken for an example and its crystal structure is analyzed in this research.Results indicate that the S（6）stacking mode formed by the sulfonylurea group is the key factor causing that only one polymorph of GQD is reported.Further,crystal engineering strategy is used to modify the original stacking mode of GQD and fortunately,eight multicomponent crystals are obtained.And subsequently,solubility and powder property are improved.Secondly,seeing that the structure-property relationship in multicomponent crystals is not clear and hinders the rational design and synthesis,DDMC is designed combined with the previous study on molecular assembly and the concept of drug combination.Concretely,tolbutamide（TOL）and metformin（MET）are selected since they both have physicochemical defects and their simple chemical structures are easy to obtain single crystals.Finally,TOL-MET is obtained,and water solubility and hygroscopicity are improved concurrently.Detailed analysis on structure-property relationship indicates that the beneficial effect is attributed to the“sandwich”stacking mode with shielding effect and the free hydrogen-bonding sites in crystal structures.Subsequently,for the problem of low solubility of sulfonylureas and high hygroscopicity of biguanides,this study combined the established structure-property relationship and the drug combination in clinical,two DDMCs including GQD-MET and glibenclamide（GBA）-MET are synthesized.To certify the effect of products,physicochemical properties are tested,in vitro and in vivo evaluations are carried out.Results show that DDMCs can modulate solubility and hygroscopicity of the parent drugs concurrently.Moreover,pharmacokinetics study shows DDMC increases AUC_0-t of GQD by 2.2 times and increases AUC_0-t of GBA by 3.0 times.Finally,as for thiazolidinediones which also show dissolution defect,improvement measurement for pioglitazone（PGT）is proposed in light of the benefits of DDMC.And simultaneously,PGT-MET is synthesized and the corresponding structure-property relationship is established.Results show that the solubility of PGT is enhanced by 2.0 times and 28.7 times in p H 1.2 and p H 6.8 buffer solutions respectively.Meanwhile,water absorption decreases from 80%to 21%at 95%relative humidity and the relative bioavailability shows 2.4 times higher than PGT.Study on structure-property relationship suggests that besides"sandwich"crystal packing mode and free hydrogen-bonding sites,the strength of hydrogen bonds can also affect the properties.In summary,aiming at the problem of low solubility and high hygroscopicity of oral antidiabetic drugs as well as the lack understanding of structure-property relationship in multicomponent crystals,a series of DDMCs are synthesized based on the strategy of crystal engineering and drug combination.Results show that the corresponding physicochemical property of antidiabetic drug is improved and the bioavailability in vivo is increased.Moreover,the structure-property relationship of DDMC is further studied and successfully established.