Theobromine cocrystals with monohydroxybenzoic acids – synthesis, X-ray structural analysis, solubility and thermal properties

Abstract

Theobromine, a compound from the purine alkaloid group, is much less soluble in polar solvents than its analogues, i.e. caffeine and theophylline, that is why it was used as an active pharmaceutical ingredient (API) model in cocrystal preparation.

Synthon hierarchy in theobromine cocrystals with hydroxybenzoic acids as coformers

“…The ortho-hydroxyl groups in 2HBA, 23DHBA, 24DHBA, 25DHBA and 26DHBA in theobromine, 42 theophylline 43,85,86 and caffeine 44,87 cocrystals form intramolecular hydrogen Table 10 The comparison of systems composed of strong hydrogen bonds in theobromine, theophylline and caffeine complexes with mono-and dihydroxybenzoic acids [42][43][44][85][86][87] 84 c Cocrystal was obtained, which was confirmed by powder XRD patterns, but cocrystallization of these substances did not give good quality monocrystals. 44 bonds O-H hydroxyl ⋯OC carboxyl .…”

“…In CSATBR, where acid-amide heterosynthons are formed through the exo-oxygen atom, the endo-oxygen atom does not take part in strong hydrogen bond formation. There are also Table 8 Supramolecular synthons in theophylline cocrystals with mono- 42 and dihydroxybenzoic acids 43,85,86 three structures with amide-acid heterosynthons with exo-carbonyl group participation. In HIJYEF, the exo-oxygen atom is not hydrogen bonded, in MUPPET, this oxygen atom is a double proton acceptor from two water molecules, and in ZOYBOG, the endo-oxygen atom accepts a proton from the hydroxyl group, and, additionally, water molecules are proton donors to the exo-oxygen atom.…”

“…In earlier work, we report theobromine with monohydroxybenzoic acid cocrystals. 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.…”

“…Particular theobromine synthons identified in its cocrystals with mono-42 and dihydroxybenzoic acids.…”

A Review on Co-crystals of Herbal Bioactives for Solubility Enhancement: Preparation Methods and Characterization Techniques

“…136 Goldyn et al developed co-crystals of theobromine with 3-hydroxybenzoic acid (3-HBA), 2-hydroxybenzoic acid (2HBA), and 2,4dihydroxybenzoic (2,4-HBA) acid by solvent evaporation and reported an increase in solubility of the herbal bioactive by 3 to 6 times. 137 Bergenin is a trihydroxybenzoic glycoside with a potent immunomodulatory action. It also exerts immunosuppressive and anti-inflammatory action.…”