Theobromine, a xanthine derivative analogous to caffeine and theophylline, is an effective central nervous system stimulant. It has lower aqueous solubility than caffeine and theophylline. Salts of theobromine with hydrochloric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and 𝑝-toluenesulfonic acid were prepared using liquid-assisted grinding (LAG). Proton transfer from the strong acid to the weak base imidazole N resulted in N+-H…O− hydrogen-bonded supramolecular assemblies of theobromine salts. The mesylate salt is polymorphic with amide N-H…O dimer and catemer synthons for the theobromine cations. A variable stoichiometry for phosphate salts (1:3 and 1:2.5) were observed with the latter being more stable. All new salts were characterized by FT-IR, PXRD, DSC and finally single crystal X-ray diffraction. In terms of stability, these salts transformed to theobromine within 1 h of dissolution in water. Remarkably, the besylate and tosylate salts are 88 and 58 times more soluble than theobromine, but they dissociated within 1 h. In contrast, theobromine co-crystals with gallic acid, anthranilic acid and 5-chlorosalicylic acid were found to be stable for more than 24 h in the aqueous slurry conditions, except malonic co-crystal which transformed to theobrominewithin 1 h.Water mediated phase transformation of theobromine salts and co-crystalmay be due to the incongruency (high solubility difference) between the components. These results suggest that even though traditional salts are highly soluble compared to co-crystals, co-crystals can be superior in terms of stability.
Volume 132, 2020
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