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.

抗生素药物磺胺甲噻二唑（sulfamethizole）拥有丰富的氢键官能团：氢键供体包括氨基NH₂与亚胺NH，氢键受体涵盖磺酰基氧、噻唑烷N与S以及脒基N，这使其成为一类功能多样的共晶（cocrystal）制备底物。以磺胺甲噻二唑（简称SMT）为研究对象，针对带有羧基、氨基、吡啶基与酰胺基的共晶配体（coformer）开展共晶筛选，所选用的共晶配体包括对氨基苯甲酸（p-aminobenzoic acid, PABA）、香草酸（vanillic acid, VLA）、对氨基苯甲酰胺（p-aminobenzamide, ABA）、4,4'-联吡啶（4,4-bipyridine, BIP）、辛二酸（suberic acid, SBA）、草酸（oxalic acid, OA）以及己二酸（adipic acid, ADP），最终得到六种共晶与一种盐，分别为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）以及SMT–OA（1:1）。上述新型结晶加合物通过液辅助共磨法与恒温溶剂结晶法合成。除采用单晶X射线衍射（single-crystal X-ray diffraction）表征外，还通过粉末X射线衍射（PXRD，powder X-ray diffraction）与差示扫描量热法（DSC，differential scanning calorimetry）确认了粉末样品的物相组成。对共晶配体与SMT之间的氢键相互作用分析表明，其存在六种不同的超分子合成子（synthon）。除强N–H···O与O–H···N氢键外，共晶结构还由弱C–H···O氢键维系稳定。在SMT–ADP共晶中观察到较为罕见的硫族-硫族（S···O）II型分子间相互作用，在SMT–BIP共晶中则观察到硫族-氮族（S···N）II型分子间相互作用。通过振动光谱法对产物进行表征，可获取分子间相互作用强度的相关信息。对SMT–ADP、SMT–SBA与SMT–OA三种加合物开展溶解度与溶出实验后发现，在0.1 N HCl介质中，三者的固有溶出速率（IDR，intrinsic dissolution rate）与平衡溶解度均低于纯SMT，这归因于更强的N–H···O、N–H···N与O–H···O氢键作用以及更优异的晶体堆积方式。固有溶出速率的降低可用于SMT的控释/缓释给药，通过减少其在体内的全身快速清除，提升该药物的治疗活性。此外，研究发现当组分在酸性介质（0.1 N HCl）中混合时，会自发形成SMT–OA盐；而在中性介质（磷酸盐缓冲液，phosphate buffer）中则未观察到该盐的生成。