supplementary materials

A variety of strategies have been adopted by solid state chemist to tailor the physiochemical properties of an active pharmaceutical ingredient (API). One such strategy is to prepare salt forms of these API's using the concept of crystal engineering (Desiraju, 1989) and supramolecular chemistry (Lehn, 1995). We have reported from our laboratory, the crystal structure of pyrimethamine (PMN), (Sethuraman & Muthiah, 2002) an antifolate drug used in antimalarial chemotherapy and treatment of opportunistic infections in patients with AIDS. Investigations of a fairly large number of crystal structures of pyrimethamine salts involving carboxylates (Sethuraman et al., 2003; Stanley et al., 2002) and a few sulfonates (Hemamalini et al., 2005; Balasubramani et al., 2007) have shown an inclination towards the formation of certain robust motifs and a variety of supramolecular architectures. The CSD survey by Haynes et al. (2004) on the sulfonate salts, revealed various hydrogen bonding patterns and their preferences with specific functional groups.

It is therefore of interest, to investigate the packing preferences and supramolecular architectures of the title compound (Scheme 1). The compound crystallizes in the triclinic space group P1, with two molecules in the asymmetric unit (Figure 1). The crystallographically independent pyrimethamine molecules (A and B) are protonated at N1A and N1B positions as is evident from the increase in respective bond angle at C—N—C, when compared to its neutral form (Sethuraman & Thomas Muthiah, 2002). The bond lengths and angles between the two molecules are in good agreement, with those observed in computer modeling studies on dihydrofolate reductase DHFR–PMN complexes (Sansom et al., 1989) and the crystal structure of metoprine (De et al., 1989).

Each of the protonated pyrimethaminium (N1A and N1B) cations interacts with two oxygen atoms of the respective sulfonate anion through two N—H···O hydrogen bonds, forming an eight membered ring motif R₂²(8) (Etter, 1990; Bernstein et al., 1995). It is well known that sulfonates imitate carboxylates in forming such bidentate motifs (Baskar et al., 2003). Despite this analogy, what makes things interesting is the higher level of supramolecular organization assumed by the two independent molecules. The pyrimethaminium cation A is centrosymmetrically paired through N4—H···N3 hydrogen bonds involving the 4-amino group and the N3 atom of the pyrimidine to form the ring motif R₂²(8). In addition to the base pairing, one of the sulfonate oxygen atoms (O2B) bridges the 2-amino and the 4-amino groups on both sides. The combination of such base-pairing patterns and the further bridging of the oxygen atom, leads to the formation of a linear array of four hydrogen bonds. The corresponding graph-set notations are R₃²(8), R₂²(8) and R₃²(8). Occurrence of such an array is a characteristic feature observed in structures reported earlier (Stanley et al., 2002).

The pyrimethaminium cation B does not form any base pairs across its inversion related molecule, instead it forms hydrogen bonds with the 3-pyridine sulfonate(A) through N2B—H···O3A, C16A—H···N3B, N4B—H···N17A interactions to form motifs with R₂²(9) and R₂²(7) graph set notations (Figure 2). Combination of these motifs leads to the formation of a triplet hydrogen bond array. A previous report from our laboratory on a closely related system, pyrimethaminium benzene sulfonate salt did not yield such an array. This might be due to the absence of acceptor in the benzene ring (Balasubramani et al., 2007).

Other than these strong interactions, the crystal structure is stabilized by C—H···O, C—H···N interactions and π–π stacking interactions between the PMN (B) molecules, with a centroid-to-centroid distance of 3.9465 (13) Å, an interplanar spacing of 3.4332 (8) Å and a centroid offset of 1.946 Å.

From this analysis, it is evident that sulfonates, as usual has a penchant for the formation of bidentate motif and the intermolecular interactions involved in this structure paves way to the formation of two different hydrogen bonded arrays. Identification of such patterns will help in design and construction of preferred hydrogen bonding patterns on drug like molecules.