Combinations of Tautomeric Forms and Neutral-Cationic Forms in the Cocrystals of Sulfamethazine with Carboxylic Acids

Abstract

The cocrystals of sulfamethazine with different acids, namely, 2-mercaptophenylcarboxylic acid, 2,6-pyridinedicarboxylic acid, 4-(4-hydroxyphenylazo)phenylcarboxylic acid, 3-(4-hydroxyphenyl)propanoic acid, and 4-(phenyl)phenylcarboxylic acid, are studied here. Each has distinct notable supramolecular features. The pyrimidin-2-amine unit of the sulfamethazine provided unique examples of cocrystals in which amidine and imidine forms or neutral and protonated forms of sulfamethazine are observed in 2:2 ratios. Hence, this study provides avenues to explore cocrystals with tautomeric forms together in a cocrystal and also neutral and protonated cocrystal partners as apparent multicomponents in cocrystals. Among the cocrystals, three of them have the amidine form of the sulfamethazine in respective self-assembly. The cocrystal of 2-mercapto-phenylcarboxylic acid with sulfamethazine has the amidine form and it has the distinction of having S–H···π interactions. The cocrystal of sulfamethazine with 2,6-pyridinecarboxylic acid is a rare example of a 1:1 cocrystal of sulfmethazine with dicarboxylic acid. It has methanol molecules as a solvent of crystallization. Sulfamethazine forms a hydrated cocrystal with 4-(4-hydroxyphenylazo)-phenylcarboxylic acid that has conventional R 2 2 (8) synthons of amidine hydrogen-bonding with carboxylic acid. The phenolic part of the acid component is anchored to the water molecule and provides a robust self-assembly. The hydrated cocrystal of sulfamethazine with 3-(4-hydroxyphenyl)propanoic acid (2:2 cocrystal) has two independent molecules of sulfamethazine, one in amidine form and the other in imidine form. It has two neutral carboxylic acids anchored through complementary hydrogen bonds and also has two water molecules of crystallization. The cocrystal of sulfamethazine with 4-(phenyl)phenylcarboxylic acid is also a 2:2 cocrystal. It is a di-hydrate, which has a neutral and protonated form of sulfamethazine. The neutral form is hydrogen-bonded to a neutral carboxylic acid, whereas the protonated form is charge-assisted hydrogen-bonded to the corresponding carboxylate anion.

Self-Assemblies of Solvates, Ionic Cocrystals, and a Salt Based on 4-{[(4-Nitrophenyl)carbamoyl]amino}-N-(pyrimidin-2-yl)benzene-1-sulfonamide: Study in the Solid and Solution States

“…Structures of both solvates were determined by single-crystal X-ray diffraction. It may be noted that the solvates of sulfadiazine were observed in the amine or the imine form, which have been well studied in the literature. − In the present example of the two solvates of the urea-derived sulfadiazine the bond distances and bond angles among the constituent atoms of the diazine ring suggested that both solvates were in amine form. The crystal structure of H3Sulfaurea·DMF (triclinic P 1̅ space group, Z = 2) further revealed that it had hydrogen-bonded homodimeric amine–amine synthons (B in Figure ) in the self-assembly.…”

Changes in the proportions of an active pharmaceutical through cocrystals

“…Single crystal X-ray crystallographic study revealed that the unit cell of the crystal of the salt was comprised of HSTZ cation and a Hpdc anion with half a molecule of water. The cation adopted imine form, which is the conventionally observed form in cocrystals of sulfathiazole (Singh & Baruah, 2019;Wang et al, 2018). However, in related cocrystals or salts both the tautomers were also found together (Singh & Baruah, 2019).…”

“…The cation adopted imine form, which is the conventionally observed form in cocrystals of sulfathiazole (Singh & Baruah, 2019;Wang et al, 2018). However, in related cocrystals or salts both the tautomers were also found together (Singh & Baruah, 2019). One N-H bond of the protonated amine group participated in N1-HˑˑˑO7 hydrogen bond with a bridging water molecule, which further linked an oxygen atom of carboxylate anion through O7-HˑˑˑO hydrogen bond.…”

“…Cocrystals and salts of sulfathiazole drugs have been well studied (Caira, 2007;Domingos, Fernandes, Duarte, Piedade, & Piedade, 2016;Pan et al, 2019;Samanta, Kanaujia, & Reddy, 2014;Tailor & Patel, 2015;Zhang et al, 2017). Some sulfa-drugs show amineimine tautomerism (D and E of Figure 2) that influences nature of their cocrystals (Singh & Baruah, 2019;Wang et al, 2018).…”

Collecting the Molecular and Ionization States of Irbesartan in the Solid State

“…The first one is sulfamethazine. The amidine tautomer, imidine tautomer, anion, and cation have been observed in the structures of sulfamethazine and its crystalline complexes. − The other three APIs are piroxicam, meloxicam, and enrofloxacin, all of which showed the existence of neutral and zwitterionic molecular forms, as well as cationic and anionic states in reported structures. − For sulfamethazine, piroxicam, and enrofloxacin, the proton tautomeric sites are consistent with the protonation/deprotonation sites. Meloxicam shows a little difference.…”