Exploring Alkyl Ester Salts of L-Amino Acid Derivatives of Ibuprofen: Physicochemical Characterization and Transdermal Potential

Abstract

This research presents novel ibuprofen derivatives in the form of alkyl ester salts of L-amino acids with potential analgesic, anti-inflammatory, and antipyretic properties for potential use in transdermal therapeutic systems. New derivatives of (RS)-2-[4-(2-methylpropyl)phenyl]propionic acid were synthesized using hydrochlorides of alkyl esters (ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and pentyl) of L-glutamine. These were further transformed into alkyl esters of L-amino acid ibuprofenates through neutralization and protonation reactions. Characterization involved spectroscopic methods, including nuclear magnetic resonance and Fourier-transform infrared spectroscopy. Various physicochemical properties were investigated, such as UV–Vis spectroscopy, polarimetric analysis, thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, water solubility, octanol/water partition coefficient, and permeability through pig skin using Franz diffusion cells. The research confirmed the ionic structure of the obtained hydrochlorides of alkyl esters of L-amino acids and ibuprofenates of alkyl esters of L-glutamic acid. It revealed significant correlations between ester chain length and thermal stability, crystallinity, phase transition temperatures, lipophilicity, water solubility, skin permeability, and skin accumulation of these compounds. Compared to the parent ibuprofen, the synthesized derivatives exhibited higher water solubility, lower lipophilicity, and enhanced skin permeability. This study introduces promising ibuprofen derivatives with improved physicochemical properties, highlighting their potential for transdermal therapeutic applications. The findings shed light on the structure–activity relationships of these derivatives, offering insights into their enhanced solubility and skin permeation, which could lead to more effective topical treatments for pain and inflammation.