The Effect Of Chain Length Between Aromatic Rings On The Polymorphism Of N-Arylbenzoic Acid/Nicotinic Acid And Their Homologs

Polymorphs are essentially different crystalline forms of a solid resulting from different crystal packing of the same molecules,or of the same ionic compounds.It was demonstrated that the molecules with conformational flexibility or multiple functional groups have a great tendency for polymorphism.The crystal packing and intermolecular interaction are important in determining the physicochemical properties of the polymorphs.And the solid forms of the active pharmaceutical ingredients（APIs）are critical to its physicochemical properties,such as solubility and dissolution rate,which have an effect on the uptake rate of the drug,and consequently affect its bioavailability and efficacy.Therefore,it is significant to explore polymorphism of compounds,especially new drugs,and then achieve crystal structure prediction and controlled cultivation of crystal forms.In this study,based on the structures of fenamic adcid（FA）and2-（phenylamino）nicotinic acid（2-PNA）,we designed eight homologs of N-arylbenzoic/nicotinic acids,in order to explore the effect of homologation and conformational flexiblility on the polymorphism of these compounds.First of all,we synthesized FA/2-PNA and its homologs through Ullmann/S_NAr reaction between 2-chlorobenzoic acid/2-chloronicotinic acid and amines.All compounds were characterized by ¹H NMR,¹³C NMR,MS and IR.Crystallization by slow evaporation in different solvents was used in polymorph screening.The structures of obtained crystals were determined by single-crystal X-ray diffraction（SCXRD）,and the structural properties were studied by exploring the conformation,subsequent packing and intermolecular interactions of molecules.Powder X-ray diffraction（PXRD）was used to investigate crystal identity and phase purity.Moreover,the thermal properties of each system were investigated by differential scanning calorimetry（DSC）.Finally,the effect of homologation on the polymorphism of the ten compounds were explored based on the intermolecular interactions,crystal packing and conformational analysis.The results indicate that the additional flexibility due to homologation leads to polymorphism.However,the increase of carbon chain length does not lead to more polymorphs because it limits the interactions between molecules and thus packing patterns.Besides,most of the molecules in the crystals are in anti conformation,which are more stable than other conformations.Occasionally,theπ-πinteractions seem to stabilize the crystal packing while the molecules are in the relatively unstable guache conformation.In summary,we confirmed the importance of conformational flexibility as well as molecular interactions on polymorphism.It also has been demonstrated that in addition to the hydrogen bonding,which plays a significant role in stabilizing the crystal,π-πstacking is as important a contributor to the overall stability of the crystals.