Drug-Drug Cocrystals And Co-Amorphous Studies Of DPP-4 Inhibitor-Class Hypoglycemic Drugs

Due to the limitations of monotherapy in the treatment of complex diseases such as diabetes,cardiovascular and cerebrovascular diseases,and cancer,more and more combination drug regimens have been proposed in clinical applications.The preparation of multiple drugs into compound preparations is a method to realize the combination of drugs,but the simple physical mixing of drugs has problems such as poor uniformity,large differences between batches,affecting drug stability,and incompatibility of preparations caused by differences in solubility.Therefore,it is necessary to develop new technologies and methods to promote the development of combination medicines.The construction of the two drugs as drug-drug cocrystals or co-amorphous has the advantages of good uniformity,small difference between batches,and the physical and chemical properties can be designed and regulated,which has become a new method for the development of compound preparations.Dipeptidyl peptidase 4（DPP-4）inhibitors are one of the popular targets for the treatment of type 2diabetes,and can be combined with other hypoglycemic drugs such as metformin and thiazolidinediones Sulfonylureas and insulin can achieve better hypoglycemic effects,and can also be combined with angiotensin inhibitors such as valsartan for the treatment of diabetic nephropathy.In this paper,DPP-4 inhibitory preparations were used as models for sitagliptin phosphate and vildagliptin,and drug-drug cocrystals or co-amorphous studies were carried out:1.Sitagliptin phosphate（SIT）is a potent and highly selective DPP-4 inhibitor approved by the FDA in 2006 for marketing as a hydrate.SIT is a BCS I drug with high water solubility（approximately 120 mg/m L）,rapid oral absorption,and relatively short half-life.Pioglitazone hydrochloride is a thiazolidinedione insulin sensitizer,which has a synergistic effect in the treatment of type 2 diabetes mellitus in combination with sitagliptin phosphate,but the water solubility is poor.In this paper,drug-drug cocrystals screening was carried out for SIT and PGH,and the molar ratio 1:1:2.5 and 1:1:1.5 was obtained by ball milling and suspension method,respectively Drug-drug cocrystal hydrates（SIT-PGH·2.5H₂O and SIT-PGH·1.5H₂O）.It was carried out using PXRD,¹H NMR,TG,DSC,FT-IR,SEM,etc.Comprehensive solid-state characterization with investigation of physicochemical properties such as solubility,stability,and tabletability of cocrystals.The results of powder dissolution experiments showed that both eutectic hydrates could delay the release of SIT and PGH in hydrochloric acid solution at p H 1.2.Accelerated stability experiments showed that SIT-PGH·2.5H₂O could maintain a stable crystal phase within 3 months,while SIT-PGH·1.5H₂O was transformed into a physical mixture of two APIs within 2 months.The tabletability experiment showed that the tensile strength of all cocrystals tablets was much higher than that of the API under the same compaction pressure,indicating that the formation of cocrystals significantly improved the compressibility of SIT and PGH.2.Vildagliptin（VLG）is another orally administered DPP-4 inhibitor after sitagliptin,which was approved for marketing in the European Union in 2008.VLG belongs to BCS I drugs,has high water solubility（about 170 mg/m L）,rapid absorption after oral administration,short half-life,and needs to be administered twice daily at a dose of 100 mg in the morning and evening.Clinically,VLG can be combined with valsartan（VAL）in the treatment of early diabetic nephropathy.However,VAL has poor water solubility,which severely limits its oral bioavailability and clinical efficacy.In this paper,three drug-drug co-amorphous forms（VVBM,VVSE and VVILC）with VLG and VAL with molar ratios of 1:1 were successfully prepared by ball milling,rotary evaporation and ionic liquid conversion,and comprehensive solid-state characterization was carried out by PXRD,¹H NMR,DSC,FT-IR,SEM,etc.,and the stability,equilibrium solubility and characteristic dissolution properties of the co-amorphous were investigated.The results showed that all amorphous forms could remain amorphous for three months.The formation of co-amorphous significantly increased the apparent solubility and dissolution rate of VAL,reduced the apparent solubility and dissolution rate of VLG,and reduced the difference in solubility between VLG and VAL,which was conducive to improving the compatibility of the combination of the two.It can be seen that VLG and VAL co-amorphous have the potential to be further developed into compound preparations.