Preparation,Characterization And Properties Of Drug-Drug Cocrystals Of Temozolomide And Flavonoids

Drug-drug cocrystals refer to the crystalline material in which two active pharmaceutical ingredients exist in the same crystal lattice at a fixed stoichiometric ratio through noncovalent interactions.Drug-drug cocrystals can not only improve the physical and chemical properties of the two drugs to achieve better therapeutic effects,but also provide an effective way to achieve combined administration at a molecular level.Temozolomide is the first-line anti-glioma drug.However,temozolomide exhibits short oral biological half-life,poor stability and poor tabletability,which limit its clinical effects.Flavonoids are a class of natural products,and show wide range of pharmacological activities,such as antioxidant,anti-inflammatory,antibacterial and anti-tumor effects.Some of them also show anti-glioma activity.However,flavonoids have poor water solubility and cannot be effectively absorbed from gastrointestinal tract,which limits their clinical application.In order to co-administer temozolomide and flavonoids,which have synergistic anti-glioma effects,to achieve the purpose of increasing efficacy and reducing toxicity,it is necessary to address druggability and compatibility issues,including poor stability,short oral half-life,poor tabletability of temozolomide,low solubility of flavonoids and large solubility difference of these two drugsIn the present study,three drug-drug cocrystals of temozolomide with hesperetin,luteolin and myricetin were successfully prepared by mechanical grinding method and suspension crystallization methods.These drug-drug cocrystals were totally characterized by X-ray diffraction analysis,thermal analyses,infrared spectroscopy,and dynamic vapor sorption experiments,and then the stability,solubility and tabletability were investigated.The stability test results show that pure temozolomide degraded during storage accompanied with significant changes in color,crystal phase and chemical composition residues.In comparison,the three cocrystals show better physical and chemical stability.In vitro dissolution experiments showed that the solubility of temozolomide in aqueous solution was decreased after the formation of cocrystals,and the solubility of hesperetin,luteolin and myricetin were all increased,which reduced the solubility difference between temozolomide and these flavonoids and improved the compatibility when temozolomide is co-administered with these flavonoids.,More importantly,the solubility modulation can help to extend the oral half-life of temozolomide and improve the oral absorption of flavonoids.Tablet compression performance studies show that pure temozolomide has poor tabletability and cannot form an intact tablet,while the three drug-drug cocrystals can be compressed into intact tablets without adding any excipients.Especially,the cocrystals of temozolomide/luteolin hydrate and temozolomide/myricetin hydrate can reach the tensile strength of 2 MPa.In summary,the drug-drug cocrystals herein can address the druggability and compatibility issues existing in the combined administration of temozolomide and flavonoids and provide research basis for the construction of anti-glioma combined preparation of temozolomide and flavonoids at a molecular level.