Towards the discovery of unrevealed flufenamic acid cocrystals via structural resemblance for enhanced topical drug delivery

Si Li; Bianfei Xuan; Si Nga Wong; Hok Wai Lee; Kam-Hung Low; Shing Fung Chow

doi:10.1016/j.ijpharm.2024.124959

Towards the discovery of unrevealed flufenamic acid cocrystals via structural resemblance for enhanced topical drug delivery

Int J Pharm. 2024 Nov 15:668:124959. doi: 10.1016/j.ijpharm.2024.124959. Online ahead of print.

Authors

Si Li¹, Bianfei Xuan², Si Nga Wong¹, Hok Wai Lee², Kam-Hung Low³, Shing Fung Chow⁴

Affiliations

¹ Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China; Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, New Territories, Hong Kong.
² Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
³ Department of Chemistry, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
⁴ Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China; Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, New Territories, Hong Kong. Electronic address: asfchow@hku.hk.

PMID: 39550015
DOI: 10.1016/j.ijpharm.2024.124959

Abstract

Cocrystallization has emerged as a promising formulation strategy for modulating transdermal drug absorption by enhancing solubility and permeability. However, challenges related to cocrystal dissociation in the semi-solid state need to be addressed to mitigate regulatory concerns before the widespread implementation of topical cocrystal products in clinical practice. This study aimed to develop oil-based topical formulations incorporating cocrystals with distinct thermodynamic stabilities, followed by investigating the roles of different structurally similar coformers and oily vehicles on their physicochemical properties. Three pharmaceutical cocrystals of poorly water-soluble flufenamic acid (FFA) were synthesized with isomeric pyridine carboxamides in a 1:1 stoichiometry via rapid solvent removal. These included the reported flufenamic acid-nicotinamide cocrystal (FFA-NIC), the long-elusive flufenamic acid-isonicotinamide cocrystal (FFA-IST) and flufenamic acid-picolinamide cocrystal (FFA-PIC). The resulting cocrystals, which exhibited different hydrogen bonding patterns, were characterized using powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, and structural analysis through single crystal X-ray diffraction. The cocrystals were further formulated in a series of oleaginous and absorption bases, including liquid paraffin, Vaseline, lanolin, and theobroma oil, for topical delivery. The cocrystal dissociation, content uniformity, and in vitro membrane diffusion were assessed. Notably, although all FFA cocrystals exhibited thermodynamic instability in aqueous solution, a significantly reduced propensity for cocrystal dissociation was observed in the ointment bases. Integrated computational analyses of packing efficiency and interaction energy revealed that the thermodynamic stability of cocrystals followed a descending order of FFA-NIC > FFA-PIC > FFA-IST. Compared with raw FFA, FFA-IST and FFA-PIC, which had larger positive ΔV_non-H and ΔE_cocryst, achieved superior cumulative diffusion of FFA from Vaseline, with a 4.3-fold (p = 0.0003) and 3.3-fold (p = 0.0029) increase at 6 h in a Franz diffusion cell model, respectively. The diffusion of all FFA cocrystals mainly followed the Higuchi kinetic model and was positively correlated with the intrinsic dissolution rate.

Keywords: Cocrystal; Diffusion; Dissociation; Flufenamic acid; Topical formulation.