A Research On Co-crystal Of Nucleoside Antiviral Pharmaceuticals

Nucleoside analogues are an important source of antiviral drugs,and with the recent epidemic of viral diseases such as Covid-19 and influenza,there is a growing interest in antiviral drugs.The solid form of a drug affects the solubility,dissolution rate,stability and hygroscopicity of the drug,so the selection of a suitable solid form is a critical step in drug development.Cocrystal as a means to improve the physicochemical properties of a drug without changing its own chemical structure has attracted great interest in recent decades.However,the design,screening and crystallization of cocrystal has been very challenging,and there are many potential cocrystal coformers,and it is crucial to find suitable cocrystal coformers and develop a crystallization process that can achieve GMP production.In this study,the general rules of design,screening and crystallization of nucleoside antiviral cocrystals were investigated using Favipiravir and Remdesivir as model compounds,in an attempt to find a universal and efficient method to find nucleoside cocrystals.Firstly,virtual screening was performed: more than ten potential cocrystal coformers were screened by estimating the binding energy magnitude of drug molecules and ligand molecules through functional group matching method,electrostatic potential surface maxima method and supramolecular synthon method.Then these potential cocrystal coformers were verified and further screened by grinding method,melting method with hot-stage microscope,suspension method and solution crystallization method,and it was found that cocrystal could be obtained only with p-aminobenzoic acid and nicotinamide.Among them,there is a significant fluorescence change before and after the cocrystal formation of p-aminobenzoic acid and favipiravir.Considering that most nucleosides bear fluorescent groups,fluorescence microscopy combined with a hot-loading stage is expected to be a new method for cocrystal screening of this class of drugs.After identifying the cocrystal coformers,two cocrystals were successfully prepared by solution crystallization method by screening the crystallization solvent and reactant ratios.The drug,coformers and cocrystals were analyzed and compared using XRD,DSC,IR and Raman spectra.Single crystals of the two cocrystals were grown and the crystal structures were determined by single crystal X-ray diffraction.Analysis of the crystal structures of the single components and cocrystal revealed that the predicted cocrystal structures differed significantly from the actual structures.The strongest intermolecular interactions still formed between the homologous molecules and the drug dimers bind to coformer dimers through additional hydrogen bonds to form cocrystal.This indicates that the formation of hetero-molecular dimers is not necessary in cocrystal formation,and the virtual screening method of cocrystals still needs to be improved.