Novel Purine Alkaloid Cocrystals with Trimesic and Hemimellitic Acids as Coformers: Synthetic Approach and Supramolecular Analysis

Abstract

In this work, benzene-1,3,5-tricarboxylic (trimesic acid, TMSA) and benzene-1,2,3-tricarboxylic acid (hemimellitic acid, HMLA) were used as coformers for cocrystal synthesis with chosen purine alkaloids. Theobromine (TBR) forms cocrystals TBR• TMSA and TBR•HMLA with these acids. Theophylline (TPH) forms cocrystals TPH•TMSA and TPH•HMLA, the cocrystal hydrate TPH•TMSA•2H 2 O and the salt hydrate (TPH) + •(HMLA) − •2H 2 O. Caffeine (CAF) forms the cocrystal CAF•TMSA and the cocrystal hydrate CAF•HMLA•H 2 O. The purine alkaloid derivatives were obtained by solution crystallization and by neat or liquid-assisted grinding. The powder X-ray diffraction method was used to confirm the synthesis of the novel substances. All of these solids were structurally characterized, and all synthons formed by purine alkaloids and carboxylic acids were recognized using a single-crystal X-ray diffraction method. The Cambridge Structural Database was used to determine the frequency of occurrence of analyzed supramolecular synthons, which is essential at the crystal structure design stage. Determining the influence of structural causes on the various synthon formations and molecular arrangements in the crystal lattice was possible using structurally similar purine alkaloids and two isomers of benzenetricarboxylic acid. Additionally, UV− vis measurements were made to determine the effect of cocrystallization on purine alkaloid solubility.

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

“…For the Changes in the values of the valence angles in the alkaloid imidazole ring as a result of proton transfer from the acid molecule to the imidazole N atom. It has been shown that the values of the and valence angles are greater in the protonated forms ( 1 < 2 and 1 < 2 ), while the value of the valence angle decreases ( 1 > 2 ) (Gołdyn et al, 2021). salts, in both cases, there are hydrogen bonds of medium strength, and in the experimental IR spectra, broad absorption with three ABC bands was observed.…”

Improving Crystal Morphology through Cocrystallization: A Case Study of Rufinamide-Trimesic Acid Cocrystal

“…While TMA is not currently listed as Generally Recognized as Safe (GRAS) and may not be among the first choices for pharmaceutical coformers, its historical success in cocrystallization with various APIs provides evidence of its potential utility in this context. Noteworthy examples include successful cocrystallization of TMA with carbamazepine, etravirine, nevirapine, curcumin, pyrazinamide, caffeine, , theophylline, , theobromine, cytosine, and phloroglucinol . It is also crucial to note that regulatory statuses to include TMA in the FDA GRAS list may change with ongoing research and appropriate toxicity studies, shaping perspectives on the use of TMA in pharmaceuticals.…”

Six novel multicomponent systems of theobromine with carboxylic acids: crystallographic structures, solubility determination and DFT calculations

“…It can also be used as a phosphodiesterase inhibitor, weak adenosine receptor antagonist, smooth muscle relaxor, etc. 16 Cocrystals or cocrystal hydrates or salts of TBR with 5-chlorosalicylic acid, 17 malonic acid, 18 acetic acid, 19 melamine, 20 trifluoroacetic acid, 18 1,3,5-benzenetricarboxylic acid, 21 methanesulfonic acid, 22 oxalic acid, 23 2,3-dihydroxybenzoic acid, 24 2,4-dihydroxybenzoic acid, 24 3,4-dihydroxybenzoic acid, 24 3,5-dihydroxybenzoic acid, 24 gallic acid, 25 3-hydroxybenzoic acid, 26 salicylic acid, 27 benzene-1,2,3-tricarboxylic acid, 21 vanillic acid, 28 vanillin acid, 29 quercetin, 10 and 4-hydroxybenzoic acid 26 were reported. At present, there are no data about the cocrystals and hydrates of TBR with p -COA, 2,4,6-TRM, 1-H-2-NA and CAM.…”