In a previous study [1], we reported for the first time the spontaneous formation of a cholesteric liquid crystal (CLC) arising from the supramolecular association between clarithromycin (CTY) and ascorbic acid (AA). This system displayed stable helical organization and a notable enhancement in the antimicrobial and antibiofilm activity of CTY. Building on these results, the present study investigates the preparation and characterization of a new supramolecular system composed of CTY (Fig. 1A) and N-acetylcysteine (NAC, Fig. 1B).

CTY is a semisynthetic macrolide antibiotic classified as a Biopharmaceutics Classification System (BCS) class II drug, characterized by high intestinal permeability and limited aqueous solubility [2]. It shows broad activity against Gram-positive pathogens, certain Gram-negative bacteria of respiratory and gastrointestinal importance, and organisms such as Mycoplasma, Chlamydophila, Legionella, and Helicobacter [3]. Nevertheless, its clinical effectiveness is increasingly threatened by the rise of resistant strains [4], [5].

Due to its well-known antimicrobial, antibiofilm, and mucolytic effects, NAC was chosen as a counterion, particularly relevant for chronic respiratory infections [6], [7], [8]. The pKa difference of more than three units between the ionizable groups of NAC and CTY makes it suitable for forming stable supramolecular salts capable of inducing new mesomorphic phases.

The CTY:NAC combination is especially relevant in cystic fibrosis, a disease marked by thick mucus and persistent bacterial infections [9]. Forming supramolecular salts between CTY and NAC could improve their activity against Staphylococcus aureus biofilms, a clinically important pathogen in cystic fibrosis and a major contributor to severe respiratory and systemic infections [10], [11], [12].

Liquid crystals (LCs) are anisotropic materials whose degree of molecular order lies between that of crystalline solids and isotropic liquids. Amphotropic cholesteric LCs combine thermotropic and lyotropic behaviours and display a helical organization driven by the chirality of their molecular components [13], [14], [15], [16], [17]. These structural, optical, and rheological features, together with their inherent ability to self-assemble without excipients, make them promising platforms for the design of functional and adaptive pharmaceutical systems.

Supramolecular gels, like liquid crystals, are based on the reversible self-assembly of small molecules [18], [19]. In aqueous media, they can form hydrogels capable of immobilizing the liquid phase [20], and upon solvent removal, they convert into low-porosity xerogels that preserve part of the original supramolecular network [21]. The coexistence of gel-like and liquid-crystalline phases in a single system underscores the structural versatility of CTY and provides insight into its molecular organization and stabilization.

This study presents the synthesis and characterization of the CTY:NAC system, representing the second CLC reported from CTY. CTY forms self-organized structures with different counterions and yields a stable xerogel when the solvent is removed. This behaviour suggests that CTY-based supramolecular systems could be developed as inhalable formulations for cystic fibrosis, effectively targeting S. aureus biofilms.