The Potential of Microwave Radiation and Mechanochemistry in the Formation of Purine Alkaloids Cocrystals Using Pyromellitic Acid as a Coformer: Synthesis, Structural, Spectroscopic, Thermal Analysis, and Biological Properties

Cocrystallization provides an efficient approach to modifying a wide range of physicochemical properties of active pharmaceutical ingredients (APIs), including solubility, dissolution rate, melting point, and hygroscopicity. Therefore, the development of effective and fast cocrystallization techniques is crucial for selectively obtaining a specific crystalline form. This study explores the potential of green chemical methods for synthesizing multicomponent cocrystals of theobromine (TBR) and theophylline (TPH) using pyromellitic acid (PMLA) as a coformer. Solution-based screening experiments with TBR resulted in the identification of a new TBR·PMLA 2:1 cocrystal. In the case of TPH, four new multicomponent forms were discovered, including two polymorphic TPH·PMLA 2:1 cocrystals (forms I and II) and two cocrystal solvates: TPH·PMLA·MeOH 2:1:2 and TPH·PMLA·H2O 1:1:2. Cocrystallization via grinding enabled the formation of cocrystals within 30 min to 2 h, while microwave-assisted cocrystallization significantly reduced the process time to just 5 min. Powder X-ray diffraction (PXRD) confirmed the formation of the obtained cocrystals, and single-crystal X-ray diffraction (SXRD) facilitated X-ray structural analysis for the characteristic supramolecular synthons formation in the crystal. Simultaneous thermal analysis (STA) demonstrated the high thermal stability of the studied systems. Additionally, a variable-temperature SXRD experiment, performed for the TPH·PMLA·MeOH 2:1:2 single crystal in the 300–415 K range, revealed negative volumetric thermal expansion of this cocrystal solvate and a gradual solvent release, ultimately leading to a phase transition into the TPH·PMLA 2:1 II cocrystal. UV–vis spectroscopy confirmed an enhancement in TBR solubility and a decrease in TPH solubility in water following cocrystallization using PMLA. Furthermore, biological studies demonstrated the influence of the cocrystallization on the inhibition of specific bacterial and fungal strains.