Soluble Thiabendazolium Salts with Anthelminthic Properties

Thiabendazole is an anthelmintic drug used to treat strongyloidiasis (threadworm), cutaneous and visceral larva migrans, trichinosis, and other parasites. The active pharmaceutical ingredient is typically administered orally as tablets that should be chewed before swallowing. Current formulations combine the active ingredient with excipients, including sodium saccharinate as a sweetener. Thiabendazole’s low aqueous solubility hinders fast dissolution and absorption through the mucous membranes. We sought to reformulate this medicine to improve both solubility and palatability. We utilized the possibility of protonation of the azole nitrogen atom and selected four different hydrogen donors: saccharin, fumaric, maleic, and oxalic acids. Solvothermal syn-thesis resulted in salts with each co-former, whereas neat and liquid-assisted grinding enabled the synthesis of additional formulations. Product formation was observed by powder X-ray diffraction. To better understand the structural basis of the proton transfer, we solved the crystal structures of the salts with saccharin, maleic acid, and oxalic acid using single-crystal X-ray diffraction. The structure of the salt with fumaric acid was solved by powder X-ray diffraction. We further characterized the salts with vibrational spectroscopic and thermoanalytical methods. We report a broad tunability of the aqueous solubility of thiabendazole by salt formation. Reformulation with maleic acid provided a 60-fold increase in solubility, while saccharin and oxalic acid gave a modest improvement. Fumaric acid resulted in a solid with only slightly higher solubility. Fur-thermore, saccharin is a sweetener, while the acids taste sour. Therefore, the salts formed also result in an in-trinsic improvement of palatability. These results can inform new strategies for oral and chewable tablet for-mulations for treating helminthic infections

Handling Fluorinated Gases as Solid Reagents Using Metal–Organic Frameworks

Fluorine is ubiquitous in the pharmaceutical and agrochemical industries because it improves the bioavailability and metabolic stability of molecules. However, most modern fluoroalkylation and fluorovinylation protocols rely on reagents that are expensive, explosive, or otherwise challenging to use. Fluorinated gaseous reagents are promising alternatives that are overlooked for late-stage functionalization because they require specialized equipment. Herein, we report a general strategy for safely handling inexpensive fluorinated gaseous building blocks as benchtop-stable solid reagents using porous metal–organic frameworks (MOFs). Gas–MOF reagents are employed to facilitate novel fluorovinylation and fluoroalkylation reactions, which represent safe, efficient, and atom-economical alternatives to current methods. Our approach enables high-throughput reaction development with any gaseous reagent, opening the door for the development of myriad new synthetic transformations