Effect of Crystal Packing on H-Bond Parameters: X-Ray Structure of the Sulfadimidine p-Chlorobenzoic Acid Co-crystal

Abstract

Co-crystal formation is of significant current interest, especially in the context of pharmaceutical development. 1 The reaction between the antibacterial sulfadimidine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide] and a series of benzoic acid derivatives, both in the solid-state and in solution, yielded 1:1 co-crystals whose properties and solid-state reactions have recently been reviewed. 2 The title structure 1 (Fig. 1) is a representative member of this series, typified by the formation of the R(8) hydrogen bonded motif between the cocrystallizing partners. An earlier attempt to correlate the N-H·O and O-H·N distances comprising this specific R 2 2 (8) system with pKa differences between the co-crystal partners was partially successful, but was based on the X-ray structures of a series of analogs that contained only one co-crystal molecule in the asymmetric unit. 3 An examination of the title structure, however, with two molecules of the co-crystal in the asymmetric unit, allows possible effects of the crystal packing on the variability of the hydrogen bonded parameters to be distinguished.Colorless crystals of 1 were grown by the slow evaporation of an acetonitrile solution containing an equimolar mixture of sulfadimidine and p-chlorobenzoic acid. As proven by PXRD analysis, the identical phase could also be obtained by solidstate co-grinding of the components in a ball-mill for 10 min. Although sulfadimidine and p-chlorobenzoic acid yielded DSC fusion endotherms peaking at 197 and 243˚C, respectively, 1 melted at 207˚C. Co-crystal formation was also confirmed by shifts of the N-H infrared stretching bands of pure sulfadimidine (3436, 3337, 3236 cm -1 ) to significantly higher frequencies in the product (3469, 3376, 3256 cm -1 ). Intensity data were measured from a crystal of size 0.38 ¥ 0.38 ¥ 0.40 mm at room temperature (294 ± 2 K), and were corrected for Lp and absorption effects. With Z = 8, the space group P21/c requires the asymmetric unit to comprise two cocrystal units. The structure was solved by direct methods and refined by full-matrix least-squares on F 2 using SHELXL 97. All hydrogen atoms were located unequivocally in difference

Differences in Coformer Interactions of the 2,4-Diaminopyrimidines Pyrimethamine and Trimethoprim

“…In all cases, the carboxylic acid formed a pair of H bonds with the sulfonamide/N(heterocycle) site of either the amidine or the imidine tautomer of smz. 71 This R 2 2 (8) motif was observed in the crystal structures of salts and cocrystals with benzoic acid, 72 salicylic acid, 73 anthranilic acid, 4-aminobenzoic acid, 74 4-aminosalicylic acid, acetylsalicylic acid, 75 2-nitrobenzoic acid, 76 4-nitrobenzoic acid, 77 2,4dinitrobenzoic acid, indole-2-carboxylic acid, 78 4-chlorobenzoic acid, 79 and 5-nitrosalicyclic acid. 80 By contrast, stz/3,5dinitrobenzoic acid, sulfamethoxazole/3,5-dinitrobenzoic acid, and sulfapyridine/2-chloro-4-nitrobenzoic acid all have different synthons.…”

Proton-transfer compounds with 4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (sulfamethazine): the structures and hydrogen bonding in the salts with 5-nitrosalicylic acid and picric acid

“…The structures of a significant number of these have been reported, e.g. with benzoic acid (Arman et al, 2010), salicylic acid (Patel et al, 1988), anthranilic and 4-aminobenzoic acids (Caira, 1991), 4-aminosalicylic and acetylsalicylic acids (Caira, 1992), 2-nitrobenzoic acid (Smith & Wermuth, 2013a), 4-nitrobenzoic acid (Smith & Wermuth, 2012), 2,4-dinitrobenzoic and indole-2-carboxylic acids (Lynch et al, 2000), 4-chlorobenzoic acid (Lucaciu et al, 2008), and 4-hydroxybenzoic, 2,4-dihydroxybenzoic, 3,4-dichlorobenzoic, 1-hydroxy-2-naphthoic and 3-hydroxy-2-naphthoic acids (Ghosh et al, 2011). Only two aliphatic examples are known, viz.…”

Sweet Sulfamethazine Acesulfamate Crystals with Improved Compaction Property

“…Sulfamethazine (SMT, Figure a) is a sulfonamide antibacterial drug which is used to treat or prevent infections in both humans and animals, with a broad spectrum of activity against Gram-positive bacteria, Gram-negative bacteria, and some protozoa. , SMT can exist in two neutral tautomers, i.e., amidine − and imidine, ,, cation (protonation of the −NH 2 group, p K a,1 = 2.65), − and anion (deprotonation of the sulfonamide −NH– group, p K a,2 = 7.65) . Correspondingly, various organic salts and pharmaceutical cocrystals of SMT were prepared and characterized with a focus on crystal structures and solid–state properties. − Taste masking and compaction property enhancement of SMT are desired for developing high-quality oral tablet products because of its bitter taste . Additionally, our preliminary data suggest that SMT exhibit poor compaction properties.…”