Design,Synthesis,Characterization And Properties Of Cocrystals Of Several Drugs

The endogenous small molecules of pharmaceutical active ingredients extracted from natural plants have the characteristics of small molecular weight and relatively simple structure.Common natural drugs(such as flavonoids,coumarins,terpenes,phenolic acids,ferns,quinones,polysaccharides,polysaccharides,etc.)have certain therapeutic effects on many diseases,but these natural medicines are often limited in the practical use due to their poor solubility,low bioavailability,low stability,moisture absorption,poor mechanical properties and skin permeability.Therefore,improving the physical and chemical properties of small molecules of natural drugs has received widespread attention,and drug cocrystals can improve their physical and chemical properties without changing the active ingredients and the structures of drug molecules.Therefore,cocrystals are considered to be an effective natural drug modification method.This thesis screens poorly soluble flavonoids(daidzein,apigenin and chrysin),coumarins(coumarin,osthole),testosterone,ferulic acid and some pharmacologically acceptable cocrystal forming agent to prepare corresponding drug cocrystals mainly by solvent volatilization,and 6 new drug cocrystals(1-6)and 3 drug monomers are obtained finally.On this basis,we have also tried other cocrystal preparation methods to compare with the results we have obtained.As our results show,the drug cocrystals1-3 their structures were tested and analyzed by single crystal X-ray diffraction.Furthermore,the physical and chemical properties were analyzed.For cocrystals of4-6,powder X-ray diffraction,differential scanning calorimetry,infrared spectroscopy and other techniques were utilized to characterize and analyze the formation of the cocrystal phase.And the physical and chemical properties have also been studied systematically.As for the three drug monomers,only their structures are described in detail in order to lay the corresponding theoretical foundation for the subsequent cocrystal synthesis.The research content of this paper mainly includes the following three parts:1.This chapter mainly screens two flavonoids(daidzein(D)and chrysin(C))as active pharmaceutical ingredients(API),with 4,4-bipyridine(4,4-BPY)and undecylamino acid(11-Adma)and p-phenylenediamine(PPD)as cocrystal forming agents(CCF),to prepare daidzein-4,4-bipyridine(cocrystal 1),daidzein-undecylamino acid(cocrystal 2)and chrysin-p-phenylenediamine(cocrystal3).After using single crystal X-ray diffraction(SXRD),Fourier infrared spectroscopy(FT-IR),powder X-ray diffraction(PXRD)and Differential Scanning Calorimetry(DSC),their corresponding properties were systematically analyzed.On this basis,the modification experiments of physical and chemical properties were carried out for the corresponding cocrystals.As the results show,the water solubility and acid solubility test results show that the solubilities of cocrystals of 1-3 are improved;the dissolution rate results display that 1-3 have higher dissolution rates than the corresponding active pharmaceutical ingredients;and the tableting results of cocrystals 1-3 show that the cocrystals have better tableting properties than the related active pharmaceutical ingredients.2.In this chapter,ferulic acid(F),chrysin(C)and testosterone(T)are selected as APIs,and 4,4-bipyridine and L-arginine(L-arg)are selected as cocrystal formers,to separately obtain ferulic acid-4,4-bipyridine(cocrystal 4),chrysin-ferulic acid(cocrystal 5)and testosterone-L-arginine(cocrystal 6).And the cocrystal powder of these three compounds were prepared and analyzed by FT-IR,PXRD,DSC and other characterization methods.Obviously,the cocrystal phases can be proved by the experimendts mentioned above.On this basis,the modification experiments of the physical and chemical properties of the corresponding powder cocrystal were also carried out.It can be seen that,compared with APIs,water solubility and acid solubility are improved,the dissolution rates are significantly increased and the cocrystals are easy to form the better tablets.3.In this chapter,coumarin drugs(Esculetin and Osthole)and flavonoid drugs(Apigenin)are selected as APIs,and saccharin,citric acid,thiophene-dicarboxylic acid and aspartic acid are used as CCFs.In the course of the experiments,three drug monomers were prepared,including two isomorphic crystals of cylindroitin monomer and one osthol monomer.In addition,a thiophene-dicarboxylic acid monomer was also unexpectedly obtained.The above crystal structures are all new crystal structures.