Phase diagram and nucleation kinetics of barbituric acid – Urea Co-crystal: Focus on metastable zone width and activation energy.

[Display omitted] • Draw the phase diagram of BAUR-Ⅰ. • Investigate the effects of cooling rates and urea concentrations on MSZWs. • Analyze the nucleation process by the self-consistent Nývlt-like and classical 3D models. • Explore the activation energy of BAUR-Ⅰ. As an intermediate for preparing sedative drugs, barbituric acid (BA) is often used for anesthesia and hypnosis in clinical practice. Due to the poor solubility of BA, barbituric acid – urea co-crystal (BAUR) was prepared to improve the physicochemical properties and bioavailability of BA. Notely, urea is also required in the production process of BA, so selecting urea as the co-crystal former will not bring additional impurities. BAUR has three forms reported. In this paper, the phase diagram of BAUR-Ⅰ was measured to determine the limit concentration of urea. Further, the nucleation metastable zone experiments were conducted to investigate the effects of cooling rates and urea concentrations during the nucleation. The nucleation process was then simulated using two approaches: the self-consistent Nývlt-like approach and the classical 3D model approach. Combined with the calculation of nucleation activation energy E sat , it can conclude that increasing the concentration of urea widens the metastable region to inhibit the nucleation of form Ⅰ in the cooling crystallization. [ABSTRACT FROM AUTHOR]