In Pursuit of Multicomponent Crystals of the Sulfa Drugs Sulfapyridine, Sulfathiazole, and Sulfamethoxazole

Abstract

An attempt to synthesize and characterize a series of multicomponent crystals (molecular salts or cocrystals) containing sulfamethoxazole, sulfapyridine, and sulfathiazole was made. Twenty-five different coformers were selected to synthesize cocrystals or molecular salts, and of those, 15 multicomponent crystals were isolated: five cocrystals and one molecular salt containing sulfathiazole, three cocrystals and one molecular salt of sulfamethoxazole, and four cocrystals and one molecular salt containing sulfapyridine. Synthesis was attempted using solution crystallization, as well as dry and liquid-assisted grinding, experiments. These crystals were characterized by single crystal X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and infrared spectroscopy. Many of the successful crystallizations yielded multicomponent crystals with a diverse range of hydrogen bonding networks. The predominant set of coformers responsible for the most successful synthesis attempts were 2-aminopyridine and its derivatives. These coformers formed a ringbased hydrogen bond motif with the corresponding sulfa drug, in addition to several different hydrogen bonds, which contribute to a larger hydrogen bonded network. The multicomponent crystals containing the sulfa drug and a benzoic acid derivative formed a hydrogen bond either between the carboxylic acid and the sulfonamide group or between the carboxylic acid group and the aniline group, in which a proton transfer occurred depending on the specific case.

Differences in Coformer Interactions of the 2,4-Diaminopyrimidines Pyrimethamine and Trimethoprim

“…We expected that in such ternary mixtures, the carboxylic acid would have the highest affinity for the C2–NH 2 /N1 site of tmp/pyr: cocrystals of sulfa drugs and carboxylic acids are rather scarce. Very recently, it is has been stated in the literature that “the chance to form a successful cocrystal containing the sulfa drug and benzoic acid or one of its derivatives is low” . In the same article, a cocrystal screen of sulfathiazole (stz), sulfamethoxazole, and sulfapyridine with a range of coformers including carboxylic acids was reported.…”

“…This R 2 2 (8) motif was also observed in the crystal structures of salts and cocrystals with benzoic acid, salicylic acid, anthranilic acid, 4-aminobenzoic acid, 4-aminosalicylic acid, acetylsalicylic acid, 2-nitrobenzoic acid, 4-nitrobenzoic acid, 2,4-dinitrobenzoic acid, indole-2-carboxylic acid, 4-chlorobenzoic acid, and 5-nitrosalicyclic acid . By contrast, stz/3,5-dinitrobenzoic acid, sulfamethoxazole/3,5-dinitrobenzoic acid, and sulfapyridine/2-chloro-4-nitrobenzoic acid all have different synthons . In the stz·glutaric acid and stz·4-nitrobenzoic acid cocrystals, stz and the carboxylic acid both form homodimers.…”

“…Very recently, it is has been stated in the literature that "the chance to form a successful cocrystal containing the sulfa drug and benzoic acid or one of its derivatives is low". 70 In the same article, a cocrystal screen of sulfathiazole (stz), sulfamethoxazole, and sulfapyridine with a range of coformers including carboxylic acids was reported. Out of the 30 sulfa drug−carboxylic acid combinations tested, only three were successful.…”

“…80 By contrast, stz/3,5dinitrobenzoic acid, sulfamethoxazole/3,5-dinitrobenzoic acid, and sulfapyridine/2-chloro-4-nitrobenzoic acid all have different synthons. 70 In the stz•glutaric acid 81 and stz•4-nitrobenzoic acid 82 cocrystals, stz and the carboxylic acid both form homodimers. In stz•glutaric acid, the dimers are linked via a bifurcated H bond to the amino group and sulfonyl oxygen of two adjacent stz molecules.…”

Synthesis of Ternary Cocrystals, Salts, and Hydrates of Acefylline with Enhanced Dissolution and High Permeability

“…Perlovich 53 built a database of cocrystals and the individual APIs and coformers based on their melting points and fusion enthalpy along with prediction of solubility based on the solubility of the individual components. Crystal engineering and heterosynthon-based strategies to improve solubility, 54−56 solubility and permeability, 57,58 and stability 59 in multicomponent cocrystals 60 continue to be reported for important API categories. 61 Acefylline (ACF) is one such API having poor aqueous solubility (1 mg/mL) and relatively low membrane permeability (log P −0.8 to −1.1) in the BCS class IV category, and its piperazine salt has a higher solubility of 14.7 mg/mL.…”