Study On Cocrystals Of Lenvatinib,Olaparib And Drug-Drug Cocrystal Of 5-Fluorouracil And Kaempferol

The improvement of solubility of insoluble drugs is always a major challenge in drug research and development.Drug cocrystals refer to crystals in which active pharmaceutical ingredients and cocrystal formers are combined in the same crystal lattice by hydrogen bonds,π···· π stacking and van der Waals force at a fixed stoichiometric ratio.When two active pharmaceutical ingredients are combined in the same lattice,a drug-drug cocrystal is formed.In this dissertaion,the solubility of lenvatinib and olaparib was improved by cocrystal technology,and the solubility of 5-fluorouracil and kaempferol was optimized by the formation of drug-drug cocrystal.1.Lenvatinib can be used for targeted treatment of thyroid cancer and renal cell carcinoma in clinic.Its medicinal form is a mesylate,but its clinical application is affected by its low solubility.Three cocrystals of lenvatinib with benzoic acid,4-hydroxybenzoic acid and fumaric acid was obtained by solvent assisted grinding and suspension methods.X-ray diffraction,thermal analysis,infrared spectroscopy and dynamic water adsorption experiments were used to characterize the three cocrystals.The results of powder dissolution experiments showed that the solubility of the cocrystals with benzoic acid and 4-hydroxybenzoic acid was 2.2 times and 3.1 times that of lenvatinib mesylate,respectively.The results of intrinsic dissolution experiments showed that the dissolution rate of benzoic acid cocrystal was comparable to that of lenvatinib mesylate,while the dissolution rate of 4-hydroxybenzoic acid cocrystal was2.1 times that of lenvatinib mesylate.These results indicate that lenvatinib-4-hydroxybenzoic acid cocrystal has good potential for development.2.Olaparib is mainly used for the treatment of ovarian cancer.The present marketed form is form A,and its water solubility was less than 0.25 mg/ml,which affects the clinical application of olaparib.Four cocrystals of olaparib with fumaric acid,maleic acid,malonic acid and oxalic acid was obtained by solvent assisted grinding and suspension methods.X-ray diffraction,thermal analysis,infrared spectroscopy and dynamic water adsorption experiments were used to characterize the cocrystals.Their solubility,tableability and stability was then evaluated.The formation of cocrystal improved the apparent solubility of olaparib to a great extent.The apparent solubility of fumaric acid,maleic acid,malonic acid and oxalic acid cocrystals were 8.3,4.6,5.1and 4.8 times that of olaparib.The tableting performance have also been improved.However,only the fumaric acid cocrystal can maintain the original phase in the threemonth accelerated stability experiment,and the other three cocrystals have undergone phase transformation.It is indicated that olaparib fumaric acid cocrystal has good potential for development.3.5-fluorouracil is a chemotherapeutic drug,which is used in the treatment of gastric cancer,liver cancer,skin cancer and other cancers.It has the characteristics of good solubility,poor permeability,short half-life,severe side effects and large individual absorption difference.Recently,it has been reported that natural product kaempferol and 5-fluorouracil can be used synergistically to treat colorectal cancer.But kaempferol has poor water solubility and cannot be absorbed in the gastrointestinal tract.5-Fluorouracil-kaempferol drug-drug cocrystal with stoichiometric ratio of 1:1 were successfully prepared by solvent assisted grinding,suspension and evaporative crystallization methods.The ternary phase diagrams under different temperatures were established to understand the thermodynamic behavior of the cocrystals.Single crystal and powder X-ray diffraction,thermal analysis,infrared spectroscopy and dynamic water adsorption experiments were used to characterize the cocrystals.It was found that the stability and solubility of kaempferol were improved,and the solubility of 5-fluorouracil was decreased.Therefore,5-fluorouracil-kaempferol cocrystal is expected to improve the oral bioavailability of kaempferol,prolong the oral absorption of 5-fluorouracil,reduce the side effects and individual differences,and has the potential to be developed as an effective drug combination.