A Calix[4]arene Supramolecular Gel for Pharmaceutical Crystal Growth Enabled by Anion-Induced Conformational Modulation

Two novel calix[4]arene derivatives (compounds 1 and 2), incorporating 1,2,3-triazole and d/l-phenylalanine moieties within the linker, have been prepared. Upon the addition of tetrabutylammonium dihydrogen phosphate (TBAHP) followed by sonication at 42−48 °C for 15 min, compound 1 formed a supramolecular gel in n-butanol, whereas 2 did not undergo gelation under identical conditions. Variable-temperature 1H NMR studies suggest that dihydrogen phosphate induces a conformational change in 1, consistent with modulation of the calix[4]arene framework, thereby exposing additional intermolecular interaction sites that promote supramolecular gel assembly. Rheological measurements demonstrated that both the mechanical stability and the storage modulus of the resulting gel increased with increasing concentrations of the Compound 1/TBAHP system in n-butanol. Although the gel exhibited thixotropic behavior, recovery of the gel structure following shear was relatively slow. Notably, a pharmaceutical salt cocrystal comprising furosemide and its tetrabutylammonium salt was successfully grown within the Compound 1/TBAHP/n-butanol supramolecular gel. Although the same salt cocrystal could also be obtained from a TBAHP/n-butanol solution, crystallization required a higher concentration of furosemide than in the gel system.