Co-Crystals of Sulfamethazine with Some Carboxylic Acids and Amides: Co-Former Assisted Tautomerism in an Active Pharmaceutical Ingredient and Hydrogen Bond Competition Study

Ten new co-crystals of an antibacterial drug sulfamethazine (SFZ) with various carboxylic acid and amide co-formers have been synthesized. These new forms are characterized by single crystal X-ray diffraction, infrared spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Crystal structures with 4-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DHB), 3,4-dichlorobenzoic acid (DCB), sorbic acid (SOR), fumaric acid (FUM), 1-hydroxy-2-naphthoic acid (1HNA), benzamide (BEN), picolinamide (PIC), 4-hydroxybenzamide (HBEN), and 3-hydroxy-2-naphthoic acid (3HNA) are determined. The SFZ molecule displays co-former assisted amidine to imidine tautomerism in the co-crystals in that the sulfonamide NH proton moves to one of the pyrimidine N atoms. In all the cases, the SFZ forms a robust hydrogen bonded synthon with a carboxylic acid (amidine(SFZ)···acid/imidine(SFZ)···acid) or amide (imidine(SFZ)···amide) group from the co-former. The SFZ molecule, in all the carboxylic amide and carboxylic acids, HBA and 3HNA co-crystals, exists in the imidine tautomeric form while it exists in amidine tautomeric form in the rest of the acid co-crystals. Density functional theory (DFT) calculations revealed that the amidine tautomer in free SFZ is much more stable than its imidine tautomeric form, while when it is hydrogen bonded to the co-formers via acid or amide groups, the difference is greatly minimized. But the synthon formation between the stable amidine(SFZ) and amide co-former is sterically hindered; hence the SFZ tautomerizes itself to the imidine(SFZ) form to facilitate the formation of a robust imidine(SFZ)···amide synthon in all the amide based co-crystals in this study. Solubility properties of some of the new co-crystal forms are also studied. The crystal structures are analyzed in the context of hydrogen bond competition between various acceptors and donors, in the presence of other competing functional groups, in the active pharmaceutical ingredient (API) co-crystals.本研究合成了抗菌药物磺胺二甲嘧啶（sulfamethazine, SFZ）与多种羧酸及酰胺类共晶形成物所形成的10种新型共晶。上述新型共晶采用单晶X射线衍射、红外光谱、差示扫描量热法（differential scanning calorimetry, DSC）以及热重分析（thermogravimetric analysis, TGA）进行了表征。本研究确定了以下共晶的晶体结构：对羟基苯甲酸（4-hydroxybenzoic acid, HBA）、2,4-二羟基苯甲酸（2,4-dihydroxybenzoic acid, DHB）、3,4-二氯苯甲酸（3,4-dichlorobenzoic acid, DCB）、山梨酸（sorbic acid, SOR）、富马酸（fumaric acid, FUM）、1-羟基-2-萘甲酸（1-hydroxy-2-naphthoic acid, 1HNA）、苯甲酰胺（benzamide, BEN）、皮考林酰胺（picolinamide, PIC）、对羟基苯甲酰胺（4-hydroxybenzamide, HBEN）以及3-羟基-2-萘甲酸（3-hydroxy-2-naphthoic acid, 3HNA）。 共晶中的SFZ分子呈现出由共晶形成物介导的脒式至亚胺脒式互变异构现象，即磺酰胺NH上的质子转移至嘧啶环的其中一个氮原子。在所有共晶体系中，SFZ均与共晶形成物上的羧酸基团（脒式SFZ···羧酸/亚胺脒式SFZ···羧酸）或酰胺基团（亚胺脒式SFZ···酰胺）形成稳定的氢键合成子。 在酰胺类共晶形成物所参与的共晶以及羧酸类共晶（包括对羟基苯甲酸HBA、3-羟基-2-萘甲酸3HNA共晶）中，SFZ分子均以亚胺脒式互变异构体形式存在；而在其余羧酸类共晶中，SFZ则以脒式互变异构体形式存在。密度泛函理论（density functional theory, DFT）计算结果表明，游离状态下的SFZ脒式互变异构体比亚胺脒式互变异构体更为稳定；但当SFZ通过羧酸或酰胺基团与共晶形成物形成氢键时，二者的稳定性差异会大幅缩小。但游离态稳定的脒式SFZ与酰胺类共晶形成物之间难以形成氢键合成子（存在空间位阻），因此本研究中所有酰胺类共晶体系内的SFZ均会发生互变异构，转化为亚胺脒式结构，以促进稳定的亚胺脒式SFZ···酰胺氢键合成子的形成。 本研究还对部分新型共晶的溶解性能进行了考察。本文结合活性药物成分（active pharmaceutical ingredient, API）共晶体系中存在多种竞争性官能团的背景，分析了各类氢键供体与受体之间的氢键竞争行为，并以此为依据对晶体结构进行了剖析。