Crystalline Complexes Of Three Tautomeric Drugs:Preparation And Improved Physicochemical Properties

80%⁹0%of chemical drugs exist in solid state,and solid chemical drugs are the main material basis for clinical treatment of diseases.Common solid drug forms include,but not limited to polymorphs,hydrates,solvates,salts,cocorystals,and amorphous.Different forms of solid drugs not only affect the physical and chemical properties of the drug itself,such as hydration stability,solubility and bioavailability,it also greatly affects the efficacy and production technique of pharmaceutical preparations.Therefore,research on the solid form of drugs has become an indispensable link in the drug development process.With the development of supramolecular chemistry and crystal engineering,different drug crystal complexes have become a research hotspot.In this paper,three drugs with different tautomerisms in chemical structure were selected.Stanozolol,glibenclamide and irbesartan were the main drugs,which were introduced into the drug by crystallization/salt coformer.Different tautomers of the drug were stabilized and the novel drug crystal complexes were formed.Powder X-ray diffraction,single Crystal X-ray diffraction,thermal analysis and nuclear magnetic resonance analysis methods were used to characterized the formed drug crystalline complexes.And the physical and chemical properties of the drugs were studied by stability test and dissolution experiment.The details are as follows:1)The crystalline complexes of stanozolol（STAN）and four aromatic carboxylic acid molecules:2,6-dihydroxybenzoic acid（DBA）,2,5-dihydroxybenzoic acid（DHA）,phthalic acid（PHA）and gallic acid（GA）were successfully prepared by mechanical grinding.The novel supramolecular synthons of these crystal complexes are interpreted by single crystal X-ray diffraction and solid state ¹³C nuclear magnetic resonance.In addition,thermal analysis and physical stability against hydration experiments show that all new amorphous phases exhibit good thermal stability and stability against hydration.The results of dissolution experiments showed that all the crystalline complexes except STAN-DBA had excellent dissolution performance..2)PPZ was selected as co-crystal/salt former through solution method and the calculation of molecular electrostatic potential surfaces（MEPS）.Four crystalline complexes of glibenclamide（GLB）and PPZ were prepared by suspension.Powder X-ray diffraction and solid-state nuclear magnetic resonance were used,which determined a new crystalline phase formed.Single crystals of two crystalline complexes were successfully obtained by solution method.The results of crystal analysis showed that GLB-1 and GLB-2 have similar crystal packing structure,and the thermal stability of the four salts was investigated by thermal analysis and stability experiments.The results show that GLB-4has good thermal stability and excellent hydrationstability.3)Two kinds of crystallization/salt coformers were successfully screened,DBA and PPZ,respectively,which co-crystallized with irbesartan（IBS）.The formation of two new salts was confirmed by powder X-ray and solid-state nuclear magnetic resonance techniques.The liquid nuclear magnetic resonance technique has shown that the stoichiometric ratio of IBS and two guest molecules was 1:1,and the thermal analysis and hydration stability experiments showed that all crystalline complexes have good stability.