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Development and exploration of the potential of pharmaceutical nano-cocrystals - synergism between co-crystallization and nanotechnology

Grant number: 23/06756-1
Support Opportunities:Regular Research Grants
Duration: February 01, 2024 - January 31, 2026
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Physical-Chemistry
Principal Investigator:Flávio Junior Caires
Grantee:Flávio Junior Caires
Host Institution: Faculdade de Ciências (FC). Universidade Estadual Paulista (UNESP). Campus de Bauru. Bauru , SP, Brazil
Associated researchers: Éverton Carvalho dos Santos ; Fenelon Martinho Lima Pontes ; Maria Ermelinda da Silva Eusébio ; Natália Valadares de Moraes ; Ricardo António Esteves de Castro


Currently, many drugs marketed or under development have problems with low aqueous solubility and inadequate dissolution rate, leading to bioavailability problems. Nanotechnology has been widely developed and applied to improve the solubility of active pharmaceutical ingredients (APIs). Cocrystals have also been receiving much attention in the design and development of drugs, since cocrystallization improves the biopharmaceutical properties of APIs, such as increased solubility, dissolution rate and, consequently, bioavailability. However, the combination of the two strategies to produce nano-cocrystals is still in an early stage of development. Nano-cocrystals, nanometer-scale crystals, can further improve the properties of APIs due not only to the cocrystal structure, but also due to the large surface-to-volume ratio of nanocrystals. In this sense, protease inhibitors (PIs) were chosen as model compounds for the study because they have proven effectiveness, but suffer from low bioavailability, a fact that results in several side effects for patients. Therefore, this project's main objective is to synthesize cocrystals and nano-cocrystals of IPs with better physicochemical properties and to investigate the synergistic effect of the combination between cocrystallization and nanotechnology. Initially, the design of the cocrystals will be based on the principles of crystal engineering, using the ConQuest and Mercury software integrated into the CSD base, in order to evaluate the hierarchy of supramolecular syntons and to evaluate hydrogen bonding propensities, as well as molecular complementarity, thus enabling rational planning for the choice of coformers. The synthesis of cocrystals will be carried out preferably by the mechanochemical method, a green, reproducible, and scalable synthesis method; other synthesis methods will also be evaluated, such as slurry and solution crystallization, in which the latter will be used to obtain single crystals from cocrystals to determine the crystal structure of new cocrystals. From the determination of the crystalline structures, the supramolecular arrangement of the cocrystals and its influence on the physicochemical properties of these materials will be studied. The optimization of the co-crystal synthesis process and the characterization of the formed products will be done using techniques such as DSC, TG-DTA, FTIR, crystallization system (Crystal 16) and powder and single crystal X-ray diffraction. With the formed cocrystals, it will be possible to study and develop the procedures for the synthesis of nano-cocrystals, which will be carried out through the mechanochemical method (botton-up approach) and via wet milling (top-down approach). For the optimization of the synthesis and characterization of the obtained nano-cocrystals, the previously mentioned techniques will be used, as well as scanning electron microscopy (SEM) and transmission (TEM), dynamic light scattering (DLS) and zeta potential. Finally, the most promising products will undergo solubility tests, comparative dissolution profile and permeability in Caco-2 cells. Translation of in vitro observations to associated clinical outcomes using physiology-based pharmacokinetic modeling and simulation (PBPK) will be performed to predict the oral bioavailability and plasma concentration-time profiles of cocrystals and nano-cocrystals. It is expected, therefore, to develop nano-cocrystals capable of providing a significant improvement in the physicochemical properties and, therefore, offer an innovative approach to improve the solubility and bioavailability of these drugs and, consequently, contribute to advances in the frontier of knowledge of area of nano-cocrystallization, which will allow the application to other classes of APIs. (AU)

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