Representative Structures of Molecular Associates Containing Sulfa Drugs, страница 2

As emphasized recently,⁶ unequivocal distinction between such salts and “genuine” cocrystals depends crucially on accurate H atom location. This is usually achieved by single-crystal X-ray analysis, although complementary techniques such as solid-state NMR (SSNMR) may be employed. A recent example of the latter is the unequivocal location of H atoms by ¹⁵N SSNMR in a compound described as a cocrystal of a monophosphate salt of an active pharmaceutical ingredient (API) and phosphoric acid.¹⁵

The assumption that the molecular association between a given pair of drug molecules invariably belongs to one or the other of these types (salt/cocrystal) must be treated with circumspection, especially in view of the possibility of tautomerism in the component molecules. This is exemplified by the interaction between trimethoprim (TMP) and sulfamethoxypyridazine (SMPD), which was shown to result in a cocrystal when the crystallization medium was methanol but as a hydrated salt when crystallization was from water (Figure 3).¹⁶

In the cocrystal TMP·SMPD (no proton transfer involved), the SMPD molecule occurs in the imido-tautomeric form, and the hydrogen bond acceptor and donor pairs are shared between the aminopyrimidine moiety of TMP and the imidopyridazine unit of SMPD. However, in the salt TMP⁺·SMPD^-, the SMPD molecule is in the amide tautomeric form, with the sulfonamide N atom deprotonated while a pyrimidine N atom of TMP is protonated; both hydrogen bonds are thus donated by the TMP cation. It will also be noted that in proceeding from the cocrystal to the salt, there is an exchange of hydrogen-bonded partners (the TMP units are drawn in a roughly parallel orientation while the SMPD units in Figure 3 are in antiparallel orientation). The physical conditions for interconversion of these species have been described,¹⁶ and the forward and reverse processes clearly involve profound changes in the hydrogen-bonding arrangements. This system has pharmaceutical significance as SMPD and TMP are used in combination (as a physical mixture) in a commercial product (Velaten, Hoechst Pharma, Milan, Italy).

The few examples cited above serve to illustrate some of the variety of molecular associations possible between sulfonamides and other drugs, highlighting also subtle molecular changes that may accompany the formation of specific cocrystals or salts.

A systematic study of the interaction between sulfadimidine (Figure 1) and small, pharmacologically relevant molecules commenced in the early 1990s with a report on the X-ray structures of the cocrystals SD·2-aminobenzoic acid 1 and SD·4-aminobenzoic acid 2 (Figure 4).¹⁷ The partner molecule 2-aminobenzoic acid is active as vitamin L₁, a factor necessary for lactation, while 4-aminobenzoic acid (widely known as PABA, for p-aminobenzoic acid) is of academic interest here given its role as an essential metabolite in dihydrofolic acid synthesis, the process which is competitively inhibited by sulfonamide drugs. In both cocrystals, molecular association was confirmed to be the same as that found in the cocrystal SD·2-hydroxybenzoic acid,¹⁸ namely, complementary hydrogen bonding between the carboxyl group of the acid molecule and the imino N atom and a pyrimidinyl N atom of SD, giving rise to the (8) motif. Owing to the possibilities of tautomerism for the sulfonamide component and internal charge transfer for the partner molecules (e.g., 2-aminobenzoic acid contains zwitterions in one of its polymorphs),¹⁹ care was exercised in the location of all hydrogen atoms in the crystallographic studies.

The report describing cocrystals 1 and 2 was soon followed by a second one featuring the X-ray structures of the analogous sulfadimidine cocrystals 3 and 4 (Figure 4), containing acetylsalicylic acid (aspirin) and 4-aminosalicylic acid (PAS, for p-aminosalicylic acid) as the respective partner molecules.²⁰ The latter were chosen for their important pharmacological properties, namely, the analgesic, anti-inflammatory, and antipyretic effects of aspirin, and the tuberculostatic effect of PAS. In compound 3, the first aspirin-containing cocrystal to be structurally characterized, the aspirin molecule was found to adopt a significantly different conformation from that observed in the crystal of pure aspirin. Compounds 1−4 have recently been cited as examples of binary supramolecular assemblies of pharmaceutical relevance.²¹

In a later study, the 1:1 cocrystal between 5-methoxysulfadiazine and aspirin (Figure 5, 5) was isolated and structurally characterized.²² The conformation of the aspirin molecule in 5 was found to match that found in its cocrystal with sulfadimidine (Figure 4, 3). In this context, it is interesting to note that very recent pharmaceutical cocrystallization strategies have focused on aspirin as a partner molecule. For example, a 1:1 carbamazepine−aspirin cocrystal, in which the partner molecules are associated by a carboxylic acid−amide supramolecular heterosynthon with graph set (8), has recently been described.²³

С начала 1970-х годов, серосодержащие препараты Показано, что у сильная тенденция к кристалла polymorphism.1, 2 молекул в этом препарате класса обычно содержат несколько доноров водородной связи и акцепторной функции (рис. 1), что позволяет для формирования разнообразных стабильной супрамолекулярные мотивы в растворе и, следовательно, возможности кристаллизации данного серосодержащие наркотиков в разных формах. Хотя новых антибактериальных и антимикробных