Salts of purine alkaloids caffeine and theobromine with 2,6-dihydroxybenzoic acid as coformer: structural, theoretical, thermal and spectroscopic studies

Abstract

The study of various forms of pharmaceutical substances with specific physicochemical properties suitable for putting them on the market is one of the elements of research in the pharmaceutical industry. A large proportion of active pharmaceutical ingredients (APIs) occur in the salt form. The use of an acidic coformer with a given structure and a suitable pK a value towards purine alkaloids containing a basic imidazole N atom can lead to salt formation. In this work, 2,6-dihydroxybenzoic acid (26DHBA) was used for cocrystallization of theobromine (TBR) and caffeine (CAF). Two novel salts, namely, theobrominium 2,6-dihydroxybenzoate, C7H9N4O2 +·C7H5O4 − (I), and caffeinium 2,6-dihydroxybenzoate, C8H11N4O2 +·C7H5O4 − (II), were synthesized. Both salts were obtained independently by slow evaporation from solution, by neat grinding and also by microwave-assisted slurry cocrystallization. Powder X-ray diffraction measurements proved the formation of the new substances. Single-crystal X-ray diffraction studies confirmed proton transfer between the given alkaloid and 26DHBA, and the formation of N—H...O hydrogen bonds in both I and II. Unlike the caffeine cations in II, the theobromine cations in I are paired by noncovalent N—H...O=C interactions and a cyclic array is observed. As expected, the two hydroxy groups in the 26DHBA anion in both salts are involved in two intramolecular O—H...O hydrogen bonds. C—H...O and π–π interactions further stabilize the crystal structures of both compounds. Steady-state UV–Vis spectroscopy showed changes in the water solubility of xanthines after ionizable complex formation. The obtained salts I and II were also characterized by theoretical calculations, Fourier-transform IR spectroscopy (FT–IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and elemental analysis.

Novel Adducts of Acyclovir with 2,6-Dihydroxybenzoic Acid: Synthesis and Structural, Theoretical, and Spectroscopic Analyses

“…This confirms the proton transfer from the COOH group and formation of the ACV cation. Similar changes were also observed in FT-IR spectra of 26DHBA salts. – …”

Enhancing the Bioavailability of a Novel Enrofloxacin Salt by Inhibiting Precipitation via a Crystallization Inhibitor

“…Utilizing an acidic coformer with a given structure and a suitable p K a value toward purine alkaloids containing a basic imidazole N atom can lead to salt formation. Two novel salts, theobrominium 2,6-dihydroxybenzoate (I) and caffeinium 2,6-dihydroxybenzoate (II), were synthesized . Theobromine is characterized by a relatively low water solubility, and its cocrystallization with 2,6-dihydroxybenzoic acid resulted in the formation of salt I, which was 2.4 times more soluble in water than the pure alkaloid.…”

Synthesis, crystal structures and magnetic properties of Pyrazole-Carboxylic acid complexes

“…Coordination compounds having infinite structures have been intensively studied, with significant progress having been made in the fields of materials science and coordination chemistry. 5–11…”

“…Coordination compounds having infinite structures have been intensively studied, with significant progress having been made in the fields of materials science and coordination chemistry. [5][6][7][8][9][10][11] It is well known that many factors such as synthetic methods, central metals, ligands, and pH can influence the final structures of complexes. 12,13 Heterocyclic carboxylic acids are important intermediates in the synthesis of nitrogen-containing biologically active compounds, pharmaceuticals, and agrochemicals.…”