An example of crystal engineering: the case study of Levofloxacin-Quercetin cocrystals

In the last century crystal engineering gained more attention within the scientific community, due to its many potential applications. Notable among these are the enhancement of the physicochemical properties of drugs, the development of controlled drug release systems, the creation of organic semiconductors, the design of chemical sensors, and the production of controlled-release fertilizers. Engineering crystal structures with tailored properties implies that their design and synthesis is guided by precise control of intermolecular interactions that occur between molecules within crystal lattice. In particular, the pharmaceutical sector finds very promising a specific crystal engineering strategy: the use of cocrystals. Pharmaceutical co-crystals are defined as crystalline structures composed of at least an active pharmaceutical ingredient (API) and one or more partner molecules ,in a stoichiometric ratio, hereinafter referred to as “coformers”. In a previous work, the efficiency of the crystal engineering approach was presented in showing the combination between flavonoids and antibiotics as an advanced approach to fight a pathogen called Helicobacter pylori (Uivarosi et al., 2024). In the aforementioned work, the solid-state combination of Levofloxacin (LEVO), an antibiotic and Quercetin (QUE) a flavonoid gave a new crystal structure, a cocrystal-solvate of Ethanol. In this thesis four different cocrystals solvents of LEVO and QUE were synthetized via slurring at room temperature for 72 hours in the dark, with a stoichiometric ratio 1:1 using four different solvents: methanol (MeOH), ethanol (EtOH), 1-propanol (1PR) and isopropanol (IPA) and their desolvated products were analyzed as well. Powder X-ray diffraction and Raman Spectroscopy were applied for the solid-state characterization of these novel materials. Differential Scanning Calorimetry and Thermogravimetric analysis were useful to determine the thermal behavior and stability of these new crystal structures. Performance characterization such as solubility, dissolution tests and wettability measurements were also performed. The wettability of the cocrystals powder in water and sunflower oil was evaluated by contact angle measurements, which showed that cocrystals have a worse wettability than levofloxacin with water, but a slowly better wettability with sunflower oil. Solubility tests were performed using dynamic experiments with the commercial platform Crystal16. Each cocrystal solubility profile was studied in the respective solvent of crystallization. Dissolution tests were conducted both in milli Q water and in a pH=1 solution, to study the difference in release rate between the different cocrystals, levofloxacin, and the physical mixture. The results provided evidence that cocrystallization can be used to control the release rate of the active ingredient over the time. Also, tentative tablets were produced to observe different dissolution behavior in the presence of two routinely used excipients, mannitol and cellulose nanocrystals.