Application of a Salt Coformer in a Co-Amorphous Drug System Dramatically Enhances the Glass Transition Temperature: A Case Study of the Ternary System Carbamazepine, Citric Acid, and L-Arginine

The use of co-amorphous systems containing a combination of low molecular weight drugs and excipients is a relatively new technology in the pharmaceutical field to improve the solubility of poorly water-soluble drugs. However, some co-amorphous systems show a lower glass transition temperature(T-g) than many of their polymeric solid dispersion counterparts. In this study, we aimed at designing a stable co-amorphous system with an elevated T-g. Carbamazepine (CBM) and citric acid (CA) were employed as the model drug and the coformer, respectively. coamorphous CBM CA at a 1:1 molar ratio was formed by ball milling, but a transition from the glassy to the supercooled melt state was observed under ambient conditions, due to the relatively low T-g of 38.8 degrees C of the co-amorphous system and moisture absorption. To improve the T-g of the coformer, salt formation of a combination of L-arginine (ARG) with CA was studied. First, ball milling of CA ARG at molar ratios of 1:1, 1:2, and 1:3 forming co-amorphous systems was performed and led to a dramatic enhancement of the T-g, depending on the CA ARG ratio. Salt formation between CA and ARG was observed by infrared spectroscopy. Next, ball milling of CBM CA ARG at molar ratios of 1:1:1, 1:1:2, and 1:1:3 resulted in co-amorphous blends, which had a single T-g at 77.8, 105.3, and 127.8 degrees C, respectively. These ternary co-amorphous samples remained in a solid amorphous form for 2 months at 40 degrees C. From these results, it can be concluded that blending of the salt coformer with a drug is a promising strategy to design stable co-amorphous formulations.