Natural Antimicrobials Meet a Synthetic Antibiotic: Carvacrol/Thymol and Ciprofloxacin Cocrystals as a Promising Solid-State Route to Activity Enhancement

The antibiotic ciprofloxacin (CIP) zwitterion has been cocrystallized via slurry and/or ball-milling with carvacrol (CAR) and thymol (THY), also known to exert antimicrobial activity, with the aim of improving the antibacterial activity of ciprofloxacin. In the case of CAR, the 1:4 cocrystal CIP·CAR4 appears to be the most stable phase, where the intermediate phases CIP·CAR3 and CIP·CAR2 have been isolated by stepwise loss of CAR. In the case of THY, the 1:2 cocrystal CIP·THY2 is the most stable, while the 1:4 cocrystal CIP·THY4 easily loses THY to yield the bisadduct. All cocrystals were structurally characterized by single crystal or powder diffraction: in both cocrystals sheets of CIP molecules are intercalated with layers of CAR and THY, respectively, that can be released stepwise upon heating as followed by DSC, TGA and variable temperature XRPD. Preliminary antimicrobial experiments provide encouraging evidence of the enhanced activity of the cocrystals CIP·CAR4 and CIP·THY2 against Escherichia coli (ATCC 25922) with respect to pure ciprofloxacin as well as to physical mixtures of ciprofloxacin with carvacrol or thymol.