Novel Synthons in Sulfamethizole Cocrystals: Structure–Property Relations and Solubility

Abstract

The sulfamethizole antibiotic drug has rich hydrogen bond functionalities (donors: amine NH 2 and imine NH; acceptors: sulfonyl O, thiazolidine N and S, and imidine N) which makes it a functionally diverse molecule to form cocrystals. A cocrystal screen of sulfamethizole (SMT) with COOH, NH 2 , pyridine and CONH 2 functional group containing coformers, e.g.paminobenzoic acid (PABA), vanillic acid (VLA), p-aminobenzamide (ABA), 4,4-bipyridine (BIP), suberic acid (SBA), oxalic acid (OA), and adipic acid (ADP), resulted in six cocrystals and one salt namely, SMT-ADP (1:0.5), SMT-PABA (1:1), SMT-VLA (1:1), SMT-ABA (1:1), SMT-BIP (1:1), SMT-SBA (1:0.5), and SMT-OA (1:1). The novel crystalline adducts were synthesized by liquid-assisted cogrinding and isothermal solvent crystallization. In addition to single-crystal X-ray diffraction, the phase composition of the powder samples was confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Hydrogen bonding interactions between the coformers and SMT are analyzed as six different synthons. In addition to strong N-H···O and O-H···N H-bonds, the cocrystal structures are sustained by weak C-H···O hydrogen bonds. The not so common chalcogen-chalcogen (S···O) type II intermolecular interaction in SMT-ADP cocrystal and chalcogen-nicogen (S···N) type II interaction in SMT-BIP cocrystal were observed. The products were characterized by vibrational spectroscopy to obtain information on the strengths of the intermolecular interactions. Solubility and dissolution experiments on SMT-ADP, SMT-SBA and SMT-OA showed lower intrinsic dissolution rate (IDR) and equilibrium solubility compared to SMT in 0.1N HCl medium, which is ascribed to stronger N-H···O, N-H···N, and O-H···O hydrogen bonds and better crystal packing. The decreased IDR could be useful in controlled/extended release of SMT to improve therapeutic activity of the drug by minimizing its fast systemic elimination in vivo. Furthermore, we observed that SMT-OA salt is formed spontaneously when the components were mixed in acidic medium (0.1N HCl), whereas in neutral medium (phosphate buffer) no SMT-OA salt formation was observed.

Sulfamethizole–2-amino-4,6-dimethoxypyrimidine (1/1)

“…Sulfamethizole is a conformationally flexible drug and has rich hydrogen-bond groups (donors: amine NH 2 and imine NH; acceptors: sulfonyl O atoms, thiazolidine N and S, and imidine N). Therefore, sulfamethizole can easily form a cocrystal and this is reported extensively in the literature (Suresh et al, 2015;Thomas et al, 2015).…”

“…The crystal structure of SMT shows that the molecule exists as the imidine tautomer (Fuglp & Kalman, 1987). SMT displays good solubility in water, but it has a short biological halflife due to fast elimination and therefore bioavailability is limited (Suresh et al, 2015). The drug dose should be increased to overcome this problem.…”

“…The S2-C7-N1-S1 torsion angle is 5.0 (2) , which is comparable with the sulfa (2.8 ) and selanate (5.7 ) salts of sulfamethizole, but lower than in sulfamethizole-4-aminopyridine (7.16 ) and much lower than in cocrystals of suılfamethizole-4-amino benzoic acid (30.8 ) (Thomas et al, 2015). These variations in the dihedral angle were attributed to the strength of the hydrogen bonding involved, since this affects the orientation, conformation and tautomeric form of sulfamethizole due to flexible rotation of the sulfonamide group (Suresh et al, 2015).…”

Hydrogen-bonding chain and dimer motifs in pyridinium and morpholinium hydrogen oxalate salts

“…In compound 3, the hydrogen oxalate is the trans conformer and produces a chain along the a-axis direction and is comparable to compounds reported in the Cambridge Structural Database (CSD version 5.39, updated August 2018, Groom et al, 2016, such as ACOQER (Mora et al, 2017) and FOMBIU (Traut-Johnstone et al, 2014). The hydrogen oxalates in compound 2 are in the cis conformation and form a hydrogen-bonded pair, as seen in a small handful of structures: the combination of this pair-wise interaction with a birfurcated hydrogen bond to a pyridinium cation is also seen in EZECOC (Androš et al, 2011;Chen et al 2012,), GULQOV (Thomas et al, 2015;Suresh et al, 2015), LOFMAW (Hu et al, 2014), YEPBAX (Said et al, 2006), YINVUO (Martin et al, 2013) and XEJRIQ (Edwards & Schafer, 2017). The chain type in 1 is not seen in any hydrogen oxalate compounds in the CSD.…”

Predicting the Effect of pH on Stability and Solubility of Polymorphs, Hydrates, and Cocrystals

“…Pharmaceutical cocrystals (CCs) represent a promising class of solid forms as they can potentially improve the physicochemical properties of the solid active pharmaceutical ingredients (APIs) compared to their pure state [1][2][3][4][5][6][7][8] . These…”