Design,Preparation And Performance Evalu-Ation Of Drug Cocrystal Based On Hydroxyl-Carboxylate Supramolecular Synthon

In the pharmaceutical industry,it is well known that drug development is a long,arduous and expensive process,which is often accompanied by high risks and low success rates.According to statistics,only about 1%of active pharmaceutical ingredients are successfully developed and appear on the marketplace.The main challenge for drug development is the deficiencies of the drug in terms of physicochemical properties such as solubility,stability,and permeability.The properties of materials are dependent on their solid-state structures,obviously,the physical and chemical properties of the drug can be improved by changing the solid form of the drug.In recent years,pharmaceutical cocrystals as a new solid form of drug has provided a new strategy for the development of new drug products with excellent physicochemical properties and pharmacological properties,and has received extensive attention of the pharmaceutical industry and researcher.In this paper,four different subclasses of flavonoids were selected as the research object andthe physicochemical properties of flavonoids were improved by the strategy of cocrystal based on the hydroxy-carboxylate supramolecular synthon,whichbetaine as crystal coformers.In addition,¹³C chemical shift of solid 2-picolinic acid was assigned by DFT/crystallography integrated approach?1?The cocrystals of BAI,PHL,QUE with BTN were prepared by solvent evaporation method,and their crystal structures were also obtained.Through structural analysis,it is known that among the three co-crystals prepared,there is a strong hydroxy-carboxylate interaction between flavonoids and betaine.The powder samples can be obtained by grounding or stirring.These cocrystals were characterized by a range of analytical methods,including powder X-ray diffraction,differential scanning calorimetry,solid state nuclear magnetic resonance.Solubility experiments show that the three cocrystals have better solubility properties thantheir parent drugs,the equilibrium solubility of BAI-BTN,PHL-BTN and QUE-BTN increased by 1.73,1.59 and 3.67 times,respectively.Stability experiments show that the three cocrystals have better physical stability under 70%-85%RH conditions.?2?Three kinds of cocrystals about DAID and BTN were prepared by solvent evaporation method,grounding and rotary evaporation method,among them,form A and form B structures were also obtained.Structural analysis showed that there is difference in the stoichiometric ratios and hydrogen bonding sites between them.Dissolution experiments showed that the prepared Form B had an equilibrium solubility increase of about 2.2 times compared to the raw material.?3?PCA is commonly used as crystal coformer in cocrystal design,which contains both the neutralmolecules and zwitterions in the same crystal structure.Chemical shiftassignmentforPCAby experimental approach,e.g.,2D NMR methods,is extremely time consuming because the¹H spin-lattice relaxation time?T1?is too long.In this paper,a virtual structure was constructed.The chemicalshift is in good agreement with the experimental values based on this virtusal structure,the standard deviation??_C=2.1 and the most??_C<5,which provides a basis for determining the presence of 2-picolinic acid in the crystal complex.