Solvatomorphism Of Clonixin And Polymorphism Of Potential 2-Phenylamino-Benzoic Acids NSAIDs

Non-steroidal anti-inflammatory drugs（NSAIDs）,the world’s largest prescription drugs,are widely used in the treatment of acute or chronic pains and inflammation caused by immune diseases.NSAIDs are preferred in clinical because it doesn’t lead to addiction and dependency,but it may cause gastrointestinal problems.Improving bioavailability and reducing side effects is a hot topic for studying NSAIDs currently,and the bioavailability and pharmacodynamics are closely related to the crystal form of drugs.Thus,we aim to search for new NSAIDs and study the polymorphism of the drugs at the same time.Based on the previous research of our lab,we designed and synthesized a series of2-phenylamino-benzoic acid derivatives.We also studied the solvatomorphism of clonixin,a commercial drug,and obtained two new solvates inN,N-dimethylformamide and N,N-dimethylacetamide.Clonixinwassynthesizedbyreacting2-chloronicotinicacidwith3-chloro-2-methyl-phenylamine with p-TsOH as catalyst under a nucleophilic aromatic substitution（SNAr）mechanism,and other compounds were synthesized by reacting 2-chlorobenzoic acids with phenylamines with Cu and Cu₂O as catalyst under the Ullmann reaction according to literature.The compounds were all characterized by ¹H-NMR,¹³C-NMR,and FT-IR.Different crystal forms of some of the compounds were obtained through crystal growth in a variety of solvents by slow evaporation.The structures of the crystals were solved by single-crystal X-ray diffraction,and the molecular conformation,crystal packing and interactions were analyzed.Thermal analyses were performed with differential scanning calorimetry（DSC）,and thermogravimetric analysis（TGA）to study the relative stability of these crystals.Computational calculations such as lattice energy computation and Hirshfeld analysis were applied to further understand the relative stability and various intermolecular interactions.Induetime,wewillfurtherinvestigatethepolymorphismof2-phenylamino-benzoic acid derivatives and solvatomorphism of clonixin.The potential of new solvates of clonixin and the polymorphs of the new compounds as NSAIDs will be tested.