Research On Polycrystalline Form Of Ticagrelor And Its Cocrystal Properties

Ticagrelor（TG）is a treatment for acute coronary syndromes（ACS）,which can reduce the incidence of cardiovascular death,myocardial infarction and stroke in patients with ACS or a history of myocardial infarction.However,as a BCS class IV drug,it has low solubility and poor permeability.In order to improve the solubility of TG,according to the synthesis principle of hydrogen bond supramolecular synthons in crystal engineering,new TG crystal from and TG cocrystals were screened and characterized by X-ray single crystal diffraction（SXRD）,X-ray powder diffraction（PXRD）,fourier transform infrared spectroscopy（FT-IR）,differential scanning calorimetry（DSC）and nuclear magnetic resonance hydrogen spectroscopy（¹H-NMR）.The in vitro solubility was studied by pharmaceutical dissolution tester,high performance liquid chromatography（HPLC）and ultraviolet-visible spectrophotometer（UV-Vis）.The specific contents are as follows:Preparation and characterization of new TG crystal form.Using n-hexane as the phase transformation solvent,new TG crystal form was obtained by the solvent-mediated method in an insoluble state.The new TG crystal from was characterized by PXRD,FT-IR,DSC and SEM,and the solubility was determined.In the simulated gastric fluid with p H=1.2 and the simulated intestinal fluid with p H=6.8,the solubility of new TG crystal form decreased to 0.89 times that of TG crystal form II.In a volume fraction of 30%ethanol/water solution,the solubility of new TG crystal form was about 1.75 times that of TG crystal form II.It provides reference for the further study of TG crystal application.Screening and characterization of TG cocrystal.TG·3,4-DHA·H₂O cocrystal was prepared by liquid-assisted grinding method,antisolvent method and solvent evaporation method,using 3,4-dihydroxybenzoic acid（3,4-DHA）as the cocrystal former.The cocrystal was characterized by PXRD,FT-IR,DSC and SXRD.In the simulated gastric fluid with p H=1.2,the solubility of TG·3,4-DHA·H₂O cocrystal was 1.38 times that of TG crystal form II,which is valuable for further development.TG·2,4-DHA（1:1）,TG·2,5-DHA（1:1）,and TG·2,6-DHA（1:1）cocrystals were prepared by liquid-assisted grinding method and solvent evaporation method,using 2,4-dihydroxybenzoic acid（2,4-DHA）,2,5-dihydroxybenzoic acid（2,5-DHA）and 2,6-dihydroxybenzoic acid（2,6-DHA）as cocrystal formers.The three kinds of cocrystals were characterized by PXRD,FT-IR,DSC and¹H-NMR.In the simulated gastric fluid with p H=1.2,the order of solubility was TG·2,4-DHA>TG·2,6-DHA>TG·2,5-DHA>TG,which increased by 3.14,1.33 and 2.45 times,respectively.The single crystal structures of the three cocrystal structures need to be further studied.In addition,TG·OA（1:1）cocrystal was prepared by liquid-assisted grinding,slurry conversion method,ultrasound-assisted method and solvent evaporation method,using malonic acid（OA）as the cocrystal former.The cocrystal was characterized by PXRD,FT-IR,DSC and ¹H-NMR.The solubility of TG·OA decreased to 0.70 times of TG crystal form II in the simulated gastric fluid with p H=1.2.In the simulated duodenal solution with p H=4.0 and the simulated intestinal solution with p H=6.8,the solubility of TG·OA both decreased to 0.37 times of TG crystal form Ⅱ.