Multicomponent crystals of sulfapyridine and sulfadiazine

Abstract

Crystal engineering principles were used to cocrystallize sulfa drugs, sulfapyridine (SFP) and sulfadiazine (SFD) with aromatic acids and an amine via solution crystallization. Sulfapyridine formed cocrystals with 3-nitrobenzoic acid (SFP∙3NBA), 5-bromosalicylic acid (SFP∙5BSA), 4-dimethylaminopyridine (SFP∙4DMAP) and salts with 4-nitrobenzoic acid [SFP+][4NBA-], 3,5-dinitrosalicylic acid [SFP+][DNSA-] and 3,5-dibromosalicylic acid [SFP+][DBSA-], while sulfadiazine formed a salt with 3,5-dinitrosalicylic acid [SFD+][DNSA-]. The newly formed complexes were analyzed by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), fourier transform infrared spectroscopy (FTIR), single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD) and nuclear magnetic resonance spectroscopy (1H and 13C NMR). The hydrogen bonding and crystal packing of the new solid forms were analyzed with the aid of Mercury and CrystalExplorer. The SFP and SFD compounds exhibit tautomerism. In this work it was investigated how the introduction of coformers with varying acidity provides the possibility to form a variety of synthons, and therefore disrupt the common preferred interactions within the sulfonamides. Using selected acids as coformers, the effect on crystal packing of the coformer’s substituent position was examined by using the isomers 3NBA and 4NBA. 5BSA and DBSA were employed to analyse the effect of the number of substituents on hydrogen bond formation and crystal packing. In addition, it was investigated how small structural changes in the pharmaceutical compound influences the crystal packing by cocrystallising structurally similar SFP and SFD with the same coformer. Evaluation of the change in coformer acidity was studied by using a pyridine coformer, 4DMAP, and its crystal packing was analyzed and compared to structures formed with carboxylic acid coformers. Finally, we examined how inter-conversion of tautomers promotes crystal formation by conforming to the geometric demands of the different coformers.