Improving the solubility of pseudo-hydrophobic chemicals through co-crystal formulation

Natural products are ligands and in vitro inhibitors of Alzheimer's disease (AD) tau. Dihydromyricetin (DHM) bears chemical similarity to known natural product tau inhibitors. Despite having signature polyphenolic character, DHM is ostensibly hydrophobic owing to intermolecular hydrogen bonds that shield hydrophilic phenols. Our research shows DHM becomes ionized at near-neutral pH, allowing the formulation of salts with transformed solubility. The MicroED co-crystal structure with trolamine reveals DHM salts as metastable co-crystalline solids with unlocked hydrogen bonding and a thermodynamic bent to solubilize in water. All co-crystal formulations show better inhibitory activity against AD tau than the nonsalt form, with efficacies correlating to enhanced solubilities. In vitro and in vivo pharmacokinetic measures demonstrate that DHM co-crystals display enhanced absorption and distribution with altered rates of elimination, suggesting that co-crystal formulations could be strategically used to fine-tune delivery properties. These results underscore the role of structural chemistry in guiding the selection of solubilizing agents for chemical formulation. We propose DHM co-crystals are appropriate formulations for research as dietary supplements to promote healthy aging by combating protein misfolding, although central nervous system (CNS) delivery remains a major limitation. DHM may be a suitable backbone for medicinal chemistry and possible development of pharmaceuticals with enhanced CNS exposure.