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

Acyclovir (ACV) cocrystallization experiments using 2,6-dihydroxybenzoic acid (26DHBA) as a coformer were performed, and two novel forms of acyclovirium 2,6-dihydroxybenzoate (ACV·26DHBA) were prepared. These molecular salts were obtained by different techniques. In addition to the most commonly used methods, such as solution cocrystallization, slurry cocrystallization, and neat or liquid-assisted grinding, microwave-assisted slurry cocrystallization was applied. The use of different solvents allowed for the selective preparation of I and II forms of the ACV·26DHBA salt. Novel adducts were characterized using single-crystal and powder X-ray diffraction. Moreover, the purity of the resulting phases was defined by profile fitting using Rietveld refinement. Fourier transform IR spectroscopy and theoretical studies confirmed the results obtained with X-ray methods. Solubility tests in water and phosphate buffer were performed using UV–vis spectroscopy. Moreover, the thermal stability of ionic complexes was examined using simultaneous thermal analysis (STA). Powder diffraction studies revealed two new salt phases. Forms I and II of ACV·26DHBA salts can be obtained selectively by cocrystallization using appropriate solvents. The use of microwave radiation led to the formation of II, regardless of the liquid medium used. The salt of ACV with 26DHBA showed better solubility than that of pure ACV. In addition, the ionic complexes were found to be stable up to 176 °C for form II and 183 °C for form I, respectively. Two stable forms of ACV salts with 26DHBA, which are more soluble than the pure drug, were described. In addition, not only the possibility of selective cocrystallization using several techniques was shown but also the potential of microwave-assisted cocrystallization as a fast technique that does not require the use of a large amount of solvent was emphasized