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

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.