Glycyl-l-histidyl-l-lysine as a novel co-former in co-amorphous systems: Enhanced aqueous solubility and physical stability.

Co-amorphous systems have emerged as a promising strategy to enhance the aqueous solubility of poorly water-soluble drugs. Although amino acids have been widely studied as co-formers, some amino acid-based co-amorphous systems exhibit limited dissolution improvement and inadequate physical stability. In this study, glycyl-l-histidyl-l-lysine (GHK) was selected as a co-former due to its biocompatibility and multiple functional groups, which were expected to enhance the dissolution and the physical stability of pure amorphous drugs. Basic mebendazole, neutral tadalafil and acidic indomethacin were selected as the model drugs. Glycine, histidine and lysine were used as co-formers for comparison. All drug-co-former combinations were prepared by ball milling at a 1:1 molar ratio. GHK achieved complete amorphization with all three model drugs within 15 min of milling, whereas most amino acid-based mixtures remained partially crystalline even after 60 min of milling. The formation of homogeneous amorphous forms was confirmed by differential scanning calorimetry, indicated by a single glass transition temperature in the drug-GHK system. The drug-GHK systems exhibited significantly enhanced dissolution performance, including faster dissolution rates, higher drug concentration and sustained supersaturation (up to 1440 min) compared to both the pure crystalline and amorphous drugs. Furthermore, physical stability studies confirmed that GHK-based systems maintained amorphous forms for at least 6 months, outperforming both amino acid-based counterparts and pure amorphous drugs. Notably, salt formation and hydrogen bonding were associated with the observed improvements in dissolution performance and physical stability. In conclusion, GHK represents a promising co-former, expanding the design space for co-amorphous systems.