TY - JOUR

T1 - Novel Synthons in Sulfamethizole Cocrystals

T2 - Structure-Property Relations and Solubility

AU - Suresh, Kuthuru

AU - Minkov, Vasily S.

AU - Namila, Kranthi Kumar

AU - Derevyannikova, Elizaveta

AU - Losev, Evgeniy

AU - Nangia, Ashwini

AU - Boldyreva, Elena V.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - The sulfamethizole antibiotic drug has rich hydrogen bond functionalities (donors: amine NH2 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, NH2, pyridine, and CONH2 functional group containing coformers, e.g., p-aminobenzoic 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 hydrogen 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 a lower intrinsic dissolution rate (IDR) and equilibrium solubility compared to SMT in 0.1 N 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 (0.1 N HCl), whereas in neutral medium (phosphate buffer) no SMT-OA salt formation was observed. (Figure Presented).

AB - The sulfamethizole antibiotic drug has rich hydrogen bond functionalities (donors: amine NH2 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, NH2, pyridine, and CONH2 functional group containing coformers, e.g., p-aminobenzoic 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 hydrogen 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 a lower intrinsic dissolution rate (IDR) and equilibrium solubility compared to SMT in 0.1 N 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 (0.1 N HCl), whereas in neutral medium (phosphate buffer) no SMT-OA salt formation was observed. (Figure Presented).

UR - http://www.scopus.com/inward/record.url?scp=84934779574&partnerID=8YFLogxK

U2 - 10.1021/acs.cgd.5b00587

DO - 10.1021/acs.cgd.5b00587

M3 - Article

AN - SCOPUS:84934779574

VL - 15

SP - 3498

EP - 3510

JO - Crystal Growth and Design

JF - Crystal Growth and Design

SN - 1528-7483

IS - 7

ER -