Salification and cocrystallization to ameliorate physiochemical properties of drugs. Investigation of their interactions inside liposomal formulation with Small Angle X-ray Scattering.

Abstract

The pharmaceutical industry is in a state of constant evolution, driven by the pursuit of innovative strategies to address persistent challenges in drug delivery. These challenges include, on one side, the burning need for more accessible and cost-effective methods to enhance solubility, dissolution rate, and permeability of drugs and, on the other side, the implementation of characterization methods of lipid nanoparticles that has never been so crucial. In this work, salification of theophylline with squaric acid represents the first step in this direction, addressing the challenges posed by its infamous narrow therapeutic indices. Salification reduces API dissolution by a remarkable 54% within the critical first 10 minutes, simulating a controlled released formulation and therefore better controlling the therapeutic and adverse effects of theophylline. Meanwhile, the cocrystallization technique is revolutionizing the delivery of caffeine, a psychoactive substance known for its adverse effects like nervousness and anxiety due to unstable blood concentration levels. By co-crystallizing caffeine with various small molecules, solubility, dissolution rate, and permeability can be meticulously modulated. The caffeine-xinafoic acid cocrystal, for instance, significantly lowers caffeine solubility, decreases dissolution rate, and increases permeability, promising a more controlled and efficient caffeine delivery system. Similarly, we explored the potential of salts and cocrystals to enhance the pharmacokinetics of benzocaine, a widely used local anesthetic. Nine new salts and one cocrystal have been synthesized, each offering substantial improvements in dissolution rates and permeability. These findings not only open avenues for increased bioavailability but also the prospect of extended duration of action for benzocaine. Diving even deeper into the ability of a counterion to affect the physiochemical properties of a drug, the encapsulation of benzocaine salts into a lipid-base formulation like liposomes has been investigated. Therefore, liposomal formulations are meticulously characterized using noninvasive techniques like Small-Angle X-ray Scattering (SAXS). Unique drug localization between lipid tails and alterations in liposome arrangement are unveiled. Furthermore, to make these advanced methods more accessible, a simplified SAXS data analysis method, the beating wave approach, is introduced. This new data analysis method is compared with two different techniques: Fluorescence lifetime imaging microscopy (FLIM) and NanoDSC, both utilized to study all-trans retinoic acid (ATRA) nanoencapsulated in liposomes, and both suggesting interactions between ATRA and the liposomal membrane in good agreement with SAXS data. In conclusion, these multifaceted innovations in pharmaceutical research promise to revolutionize drug delivery, enhance drug performance, and streamline characterization methods. Our aim is to continuously push boundaries, ushering in a new era of pharmaceutical science that addresses the demands for precision, efficiency, and accessibility in drug development.