Salts and Co-crystals of Theobromine and their phase transformations in water

Abstract

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 theobromine within 1 h. Water mediated phase transformation of theobromine salts and co-crystal may 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.

Dissolution Enhancement in Cocoa Extract, Combining Hydrophilic Polymers through Hot-Melt Extrusion

“…This property is a sine qua non condition for the dissolution of solid dosage forms administered orally [ 29 ]. According to a previous report, CE presents a deficient wettability [ 7 ]. Figure 6 A displays the contact angle results calculated for the seven HME extrudates.…”

“…Furthermore, the poor mechanical and physicochemical properties of dried vegetal extracts can result in deficient flow behavior and inadequate compactness, hindering large-scale production [ 5 ]. Indeed, CE has remarkably deficient flow and wettability characteristics [ 6 ], while TB has restricted solubility and a poor dissolution profile [ 7 , 8 ].…”

Synthon hierarchy in theobromine cocrystals with hydroxybenzoic acids as coformers

“…Theobromine is very slightly soluble in water (0.330 g L −1 ). 29 Therefore, to improve its aqueous solubility cocrystals with dihydroxybenzoic acids were prepared. Solubility values were determined using steady-state absorption spectroscopy.…”

“…obtaining polymorphic forms, [5][6][7][8][9][10][11][12][13] solvates and hydrates, 14-21 cocrystals [22][23][24][25][26] or salts. [27][28][29][30] Polymorphs of APIs have different properties, such as hygroscopicity, stability, solubility or processability, but, in many cases, it is not possible to predict or design a specific polymorphic form of an API. Moreover, some of them may be metastable and may undergo phase transformations, 31,32 which may result in undesirable changes in physicochemical properties.…”

“…42 Both of these studies fit into the mainstream of structural studies of purine alkaloid cocrystals. 29,43,44 Their aim is to hierarchize supramolecular synthons responsible for the molecular arrangement in xanthine cocrystals. The design of new pharmaceutical derivatives with the desired physicochemical properties, having two or more components, could be simpler with a greater understanding and knowledge of the synthonic hierarchy in organic cocrystals.…”