Pharmaceutical co-crystals are multicomponent molecular crystals formed by the co-crystallization of active pharmaceutical ingredients (APIs) with small organic molecules, called coformers. They constitute a novel class of crystalline forms ideally with improved physico-chemical properties, when compared to the parent API.1–4 In recent times, the study of pharmaceutical co-crystals has become an integral part of crystal engineering.5–7 Due to the availability of several potential organic coformers, there exists tremendous scope for identifying a large number of possible co-crystal forms for a particular API. The literature provides several examples of co-crystals with a proven track record in achieving better stability, solubility, dissolution rates, and improved mechanical properties when compared with the parent APIs.8–12 The formation of a co-crystal is generally achieved as a result of recognition established between the complementary functional groups present on the two molecular species. Of the several interactions present in any crystal structure, combinations of a few significant ones actually determine the stable crystal structure; these combinations are referred to as supramolecular synthons.13–15 Because the constituents of a pharmaceutical co-crystal are distinct molecules (API and coformer), the synthons formed are typically unsymmetrical and have been termed as heterosynthons.16, 17 An understanding of the possible heterosynthons and their consistency in appearance is important for the effective design of co-crystals. In this context, carboxylic acid–amide, carboxylic acid–pyridine, and phenol–pyridine are among the best studied of heterosynthons.18–20
Triazoles constitute a major building block in the crystal structures of several drug molecules but their intermolecular interactions are not well studied. The pKa of 1,2,4-triazole is 2.2, making it a weaker base than pyridine (5.14). It is interesting to note that the N-rich pyridazine ring with a similar pKa value (2.10) is also not well studied in crystal engineering. This may be due to the weaker hydrogen bonds formed by less basic heterocyclics. For the 1421 hits for 1,2,4-triazoles in the Cambridge Structural Database (CSD), only a very few neutral co-crystals are reported.21 A detailed analysis of the supramolecular synthons present in the crystal structures of triazoles (with the number of chemical units >1) was carried out. The molecular complexation of 1,2,4-triazoles with carboxylic acids and phenols is infrequent. However, hydrated forms of triazole with various hydrogen bond patterns are numerous.a One of the best examples of a pharmaceutical co-crystal involving a 1,2,4-triazole and a carboxylic acid is the 2:1 molecular complex of the antifungal drug itraconazole with succinic acid (SA); this complex reportedly achieves a higher solubility when compared to the crystalline drug.22 Thus, a systematic evaluation of heterosynthons present in the co-crystals of 1,2,4-triazoles is interesting from both academic and commercial viewpoints. This is the aim of the present work.
The present study focuses on synthon preferences of the 1,2,4-triazole ring by examining the hydrogen bonds in co-crystals of a 1,2,4-triazole containing drug, alprazolam (ALP). This drug belongs to the benzodiazepine class and is used to treat moderate to severe anxiety disorders, panic attacks, and depression.23, 24 ALP works by slowing down the movement of chemicals in the brain that may become unbalanced, which in turn results in a reduction in nervous tension (anxiety). Alprazolam is marketed under the trade names Xanax, Xanor, Alprax, and Niravam and these are among the most marketed drugs in the United States and Europe. To develop a better understanding of the supramolecular synthons involving the triazole fragment, we carried out several co-crystallization experiments of ALP with carboxylic acids, boric acid, boronic acids, sulfonic acids, and phenols. Of the several combinations tried we were successful in obtaining single crystals of molecular complexes in 20% of the cases. These complexes have been analyzed to identify novel and robust heterosynthons between the 1,2,4-triazole moiety and various complementary functional groups. In this article, we report the recognition patterns in co-crystals of alprazolam with the following coformers: benzoic acid (BA), 4-aminobenzoic acid (ABA), 2,6-dihydroxybenzoic acid (26DHB), 3,5-dihydroxybenzoic acid (35DHB), 2,6-difluorobenzoic acid (26DFB), 3,5-difluorobenzoic acid (35DFB), oxalic acid (OA), fumaric acid (FA), succinic acid (SA), boric acid (BORA), 1,4-benzenediboronic acid (BDBA), 4-hydroxyphenylboronic acid (HPBA), hydroquinone (HQ), and 2,4,6-trichlorophenol (TCP). Some of the binary compounds isolated crystallized as neutral molecules. These are referred to here as “co-crystals.” In some cases, proton transfer occurs across a hydrogen bond. These compounds are referred to as “salts.” Taken together, the co-crystals and salts are referred to as “molecular complexes.”