supplementary materials

Theophylline (1,3-dimethyl-7H-purine-2,6-dione) is a drug used in the treatment of respiratory diseases such as asthma. It has been reported that theophylline forms a monohydrate as a function of relative humidity and poses challenges in the formultion stages (Khankari and Grant, 1995). Using the cocrystallization as an aid to improve the physical stability, several theophylline cocrystals with dicarboxylic acids have been prepared and studied for their physical stability (Trask et al., 2006, Childs et al., 2007). Cocrystals which involve two or more active pharmaceutical ingredients (APIs) are relatively unexplored solid forms of APIs which have potential relevance in the context of combination drugs for pharmaceutical drug development (Aitipamula et al., 2009, Bhatt et al., 2009). We have recently reported trimorphs of a pharmaceutical cocrystal involving two APIs, namely ethenzamide (2-ethoxybenzamide), and gentisic acid and shown that the dissolution rate of the cocrystal polymorphs improved by two times when compared to the parent ethenzamide (Aitipamula et al., 2009). In the present paper, we report a 1:1 cocrystal of theophylline with gentisic acid and analyzed the hydrogen bonding.

The crystal structure of the title cocrystal contains each one molecule of theophylline and gentisic acid in the asymmetric unit (Fig. 1). In the structure, two molecules of theophylline which are related by an inversion centre form a dimer involving N—H···O hydrogen bonds (Table 1). Hydroxy atom O5 of the gentisic acid acts as an intramolecular O—H···O hydrogen bond donor to the carbonyl of carboxyl group and also involves in a bifurcated O—H···O hydrogen bond to atom O3 at (-x, -y + 1, -z) (Fig. 2). Hydroxy atom O4 acts as a hydrogen bond donor to atom N2 of the theophylline at (-x, -y + 2, -z + 1), thus generating chains of alternating dimers of theophylline and gentisic acid running parallel to [21–1]. In addition, there is a C—H···O hydrogen bond between C4 of the theophylline and O5 of the gentisic acid. The 5-hydroxyl group (O6) of the gentisic acid acts as a hydrogen bond donor to atom O2 of the theophylline at (1 + x, -1 + y, 1 + z), thus generating a hydrogen bonded sheet parallel to the (21–1) plane (Fig. 2). The crystal structure is further stabilized by a π-π interaction involving pyrimidine ring of theophylline and phenyl ring of gentisic acid: Cg1···Cg2 (x, y, z) = 3.348 (1) Å, where Cg1 and Cg2 denote the centroids of N3/C2/N4/C1/C5/C3 of the theophylline and C8—C13 of the gentisic acid, respectively (Fig. 3).

Zaworotko and co-workers distinguished between two types of hydrogen bonding possibilities in cocrystal structures depending on whether the interacting complementary functional groups are the same or different (Fleischman et al., 2003). In type I, an API forms hydrogen bonds like in pure structure, e.g. dimers, catemers, etc. (homosynthons) and such units are connected by cocrystal former spacer, and in type II, both the API and cocrystal former involve in heterosynthon formation. The title cocrystal belongs to type I, in which both the theophylline and gentisic acid molecules form dimers involving homosynthons, and such dimers are connected via O—H···O hydrogen bonds (Fig. 2).