Optimization Of Solid Forms Of Ethinyl Estradiol,Vortioxetine And Mifepristone To Improve The Physicochemical Properties

In solid oral pharmaceutics,the solid form of the active pharmaceutical ingredient?API?is of great significance to the physicochemical properties,the pharmaceutics formulation,clinical therapeutic efficacy,industrial processing characteristics,logistic process and protection of intellectual property rights of the drug.In this thesis,three poorly soluble oral drugs ethinyl estradiol?EE?,vortioxetine?VOT?and mifepristone?MIF?are used as research objects.Based on the different structural characteristics and physicochemical properties of different drug molecules,three drugs were optimized to improve the physicochemical properties successfully with cocrystal,salt,amorphous and co-amorphous drug solid forms.This thesis mainly includes the following research contents:?1?Five drug cocrystal forms of ethinyl estradiol were prepared using nicotinamide?NA?,piperazine?PZ?,tetramethylpyrazine?TET?,4,4'-bipyridine?BIP?and imidazole?IZ?.Their chemical composition,structural features and physicochemical properties were characterized.All five ethinyl estradiol cocrystals are assembled by chain structures of hydrogen bonding,of which EE-NA and EE-TET?H₂O have unique spiral chain structures and assembly methods.The EE-PZ structure has a unique disordered structure which plays an important role in the formation and stabilization of the crystal structure.Obvious"spring-parachute effect"was observed in the dissolution behavior of EE-NA and EE-PZ:The maximum API concentration of EE-NA can reach 123.9?g/m L?1.65 times over saturated concentration of ethinyl estradiol?,EE-PZ has a longer fall time?120 min?at supersaturated solubility while maintaining high dose levels for longer periods.In addition,the cocrystal forms successfully improved the anti-hygroscopicity of ethinyl estradiol.This is the first attempt to optimize the solid form of ethinyl estradiol by a drug cocrystal strategy and successfully improve its physicochemical properties.?2?Three medicated salt forms of vortioxetine were prepared using sulfonic compounds such as sulfanilic acid?SA?,p-toluenesulfonic acid?TA?and 5-sulfosalicylic acid?SSA?.Their chemical composition,structural features and physicochemical properties were characterized.The three vortioxetine salt forms are assembled by charge-assisted hydrogen bonding recognition.The thermal behavior patterns and structural characteristics of water molecules in VOT-TA?H₂O and VOT-SSA?H₂O structures are significantly different.water molecules doesn't participate in the formation of the structural skeleton of VOT-TA?H₂O,but plays an important role in the formation of the VOT-SSA?H₂O structural skeleton.The solubility of all three salt forms were improved.VOT-TA?H₂O and VOT-SSA?H₂O have an API solubility of 3-4 fold over the free vortioxetine in water.VOT-SA has an API concentration of 1.28 mg/m L?approximately 12 times over the saturation concentration of vortioxetine?,which has significant dissolution advantages.VOT-SA also shows excellent physical stability and anti-hygroscopicity performance.?3?The anti-solvent and freeze-drying method were used to prepare amorphous mifepristone,and three kinds of co-amorphous systems of mifepristone were prepared by using small molecule multiple organic acid carriers such as oxalic acid?OA?,malonic acid?MA?and citric acid?CA?.Their chemical composition,structural features and physicochemical properties were characterized.XPS showed that mifepristone and small molecule organic acid carriers did not undergo proton transfer and salt formation process in the co-amorphous system.The solubility of the three mifepristone co-amorphous systems in water was significantly improved.Among them,MIF-OA?1:1?has an API equilibrium concentration of 0.92 mg/m L?130 times over the saturated concentration of amorphous mifepristone?,which has a significant dissolution advantage.In terms of stability,MIF-OA?1:1?has high thermal stability and anti-hygroscopicity performance.This is the first attempt to optimize the solid form of mifepristone with small molecule organic acid carriers and successfully improve its physicochemical properties.