Designing Anti-bacterial Supramolecular Gels from Primary Ammonium Dicarboxylate (PAD) salts for Self-Delivery Applications

Abstract

Primary ammonium dicarboxylate (PAD) salts often display 2D columnar hydrogen bonded networks known as PAD supramolecular synthon in the context of crystal engineering. PAD synthon is known to play an effective role in supramolecular gelation. Vehicle free drug delivery (VFDD) vis-à-vis conventional drug delivery (CDD) is advantageous as it does not require any vehicle to deliver the drug. In here, we disclose the development anti-bacterial VFDD system based on PAD salts. Synthesis, structures and supramolecular gelation behaviour of 20 PAD salts derived from 5 dicarboxylic acids – (CH2)n-(COOH)2 (n = 4, 7, 10, 12 and 14) and 4 therapeutic amines – amantadine (AMN), tyramine (TRM), tryptamine (TRP) and mafenide (MAF) are reported. Interestingly, 40% of the PAD salts were able to gel methyl salicylate (MS) – an important ingredient in many commercially available topical ointments. The gels were characterized by rheology and TEM. Underlying supramolecular interactions were analysed by single crystal X-ray diffraction (SXRD) studies carried out on as many as 9 salts. The gelator salt, C14•2MAF, containing anti-bacterial drug mafenide as the amine part, showed excellent anti-bacterial behaviour against E. coli. Detailed biological studies suggested C14•2MAF to exhibit its anti-bacterial property by bacterial cell membrane disruption and ROS generation. Gradual release of C14•2MAF from a MS-gel bed and sheer thinning of the gel phase clearly indicated C14•2MAF MS gel to have its potential use as a supramolecular topical gel for anti-bacterial treatment.