Specific intermolecular interaction with sodium glycocholate generates the co-amorphous system showing higher physical stability and aqueous solubility of Y5 receptor antagonist of neuropeptide Y, a brick dust molecule

Drugs with poor water and lipid solubility are termed “brick dust.” We previously successfully developed a co-amorphous system of a novel neuropeptide Y₅ receptor antagonist (AntiY₅R), a brick dust molecule, using sodium taurocholate (NaTC) as a co-former. However, the maximum improvement in AntiY₅R dissolution by the co-amorphous system was only approximately 10 times greater than that of the crystals. Therefore, in the current study, other bile salts, including sodium cholate (NaC), sodium chenodeoxycholate (NaCC), and sodium glycocholate (NaGC), were examined as co-formers to further improve AntiY₅R dissolution. NaC, NaCC, and NaGC have glass transition temperatures above 150°C. All three co-amorphous systems prepared successfully retained the amorphous form of AntiY₅R for 3 months at 40°C, but the co-amorphous system with NaGC (AntiY₅R-NaGC; 1:9 molar ratio) provided the highest improvement in AntiY₅R dissolution, which was approximately 50 times greater than that of the crystals. Possible intermolecular interactions via the glycine moiety of NaGC more than the other bile salts would contribute to the highest dissolution enhancement with AntiY₅R-NaGC. Thus, NaGC would be a promising co-former for formulating stable co-amorphous systems to enhance the dissolution behavior of brick dust molecules.