Representative Structures of Molecular Associates Containing Sulfa Drugs

From the early 1970s, sulfa drugs were shown to have a strong tendency toward crystal polymorphism.^1,2 Molecules in this drug class typically contain multiple hydrogen bond donor and acceptor functions (Figure 1), allowing for the formation of a diverse range of stable supramolecular motifs in solution and hence the possible crystallization of a given sulfa drug in multiple forms. Though newer antibacterial and antimicrobial drugs have supplanted many sulfonamides, the latter still enjoy widespread use because of their low cost and relatively efficient action against common bacterial diseases. Studies probing the mechanism of sulfa drug resistance by the target dihydropteroate synthase continue,³ indicating that certain questions regarding the action of these drugs still remain unanswered.

The focus of this brief review is the interaction of sulfa drugs with drug molecules in other classes to form cocrystals, a natural extension of the solid-state chemistry of the sulfonamides. While a compound between sulfathiazole and proflavin containing equimolar proportions of the two had been employed to treat bacterial infections as early as the 1940s,⁴ more systematic investigation of cocrystallization phenomena involving sulfonamides was resumed somewhat later, numerous studies in this area having been reported during the last three decades, some of them serving as models for more recent work in pharmaceutical cocrystallization in general. Factors contributing to the ongoing interest in the investigation of interactions between sulfonamides and drugs in other classes included commercial interest in exploiting synergistic antibacterial effects (e.g., co-trimoxazole, containing sulfamethoxazole and trimethoprim in a 1:5 molar ratio),⁵ continued use of sulfonamides in third-world countries, and the ready availability and relatively low cost of these drugs.

Several relevant studies are described here to highlight insights into cocrystallization afforded by sulfonamides as model partners. Specific phenomena and processes exemplified by these studies include cocrystal formation in solution, the kinetics of solid-state cocrystallization, and “exchange” reactions that take place in the solid state (e.g., cocrystal A·B(s) + C(s) → cocrystal A·C(s) + B(s)) or, in the case of solvated cocrystals, their conversion to other solvates by exposure to different solvent vapors.

Single-crystal X-ray diffraction and powder X-ray diffraction (PXRD) were the major techniques employed in the investigation of these phenomena because of their respective abilities to establish the molecular structures of cocrystals unequivocally and quantify them in mixtures. While the current definition of a cocrystal excludes salts,⁶ some of the compounds described in this review contain identical hydrogen-bonded motifs to those found in “genuine” cocrystals, their formation, however, being mediated by proton transfer from one partner molecule to the other. These compounds nevertheless merit inclusion in the discussion, as this subtle structural feature should not preclude their exploitation as potential medicinal agents. Furthermore, the possibility of such a salt transforming into a cocrystal cannot be ruled out and an example of such behavior is cited below.

Representative Structures of Molecular Associates Containing Sulfa Drugs. As a class, cocrystals between sulfa drugs and antibacterials such as trimethoprim [2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine, TMP] embody a well-established synergy between the component drugs (a desirable property of pharmaceutical cocrystals) that results, in this case, from sequential blocking of bacterial dihydropteroate synthetase and dihydrofolate reductase.⁵ This feature favors their use in genuine pharmaceutical applications. An early physicochemical study of the 1:1 molecular compound between sulfamethoxazole (SMX) and TMP (Figure 2) was carried out by Giordano et al.⁷ who used DSC, PXRD, and FTIR to characterize this material. The precise nature of the molecular association, namely, hydrogen bonding between the partners, was established in later studies.^8,9 In this case, owing to the relatively strong acidic character of SMX (pK_a = 5.7), proton transfer from the sulfonamide to a pyrimidine nitrogen atom of TMP accompanies their reaction, leading to formation of an eight-membered hydrogen-bonded ring with graph set (8) (Figure 2). This compound, TMP⁺·SMX^-, is technically a salt and therefore does not satisfy the current definition of a cocrystal.⁶ On the other hand, reaction between TMP and the less acidic sulfa drug sulfadimidine (pK_a = 7.4) in methanolic solution does not involve proton transfer and a cocrystal TMP·SD results instead (Figure 2), also characterized by a hydrogen-bonding motif (8), which in this case is “symmetrical”, each component acting as both H-bond donor and H-bond acceptor.¹⁰ Sardone at al. had earlier noted that acid strength is a key parameter in determining the outcome of such interactions.¹¹

Other earlier examples of 1:1 salts containing sulfonamides include complexes between the antiseptic 9-aminoacridine and sulfamethoxypyridazine,¹² 9-aminoacridine and sulfadimidine,¹³ (both associates containing an acridinium−sulfanilamidate ion pair), and the complex between trimethoprim and sulfametrole,¹⁴ discussed in detail in a later section.