L-Alaninium borneol ester flurbiprofenate: a dual-function ionic carrier for enhanced solubility and transdermal...

Flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), suffers from poor aqueous solubility and limited skin permeability, hindering its bioavailability for both oral and transdermal delivery. In this study, a novel ionic conjugate, L-alaninium borneol ester flurbiprofenate (AlaOBor∙F), was synthesized via two-step routes involving esterification and salt formation. Two synthetic strategies were evaluated and compared: direct acid-catalyzed esterification using thionyl chloride and an alternative coupling approach employing dicyclohexylcarbodiimide and 4-dimethylaminopyridine with Boc-protected amino acids. The resulting compounds were fully characterized by NMR, FT-IR, DSC, TG, and XRD. AlaOBor∙F exhibited significantly improved physicochemical properties compared to flurbiprofen, including enhanced solubility (0.229  g/dm³ in water vs. 0.028  g/dm³ for flurbiprofen), reduced lipophilicity (logarithmic partition coefficient: 2.03), and superior transdermal permeability in ex vivo Franz diffusion cell studies (steady-state flux: 27  µg/cm²·h). Additionally, AlaOBor∙F retained the antioxidant potential of flurbiprofen and demonstrated no significant cytotoxicity in human fibroblasts and THP-1 monocytes up to 100 µg/mL. Furthermore, in lipopolysaccharide-stimulated monocytes, the derivative reduced interleukin-1β, interleukin-6, and cyclooxygenase-2 expression in a dose-dependent manner, surpassing the anti-inflammatory effects of flurbiprofen. These results suggest that ionic pairing with L-alaninium borneol ester is a promising strategy to enhance solubility, permeability, and therapeutic efficacy of NSAIDs for topical administration.