Abstract
Metastable polymorphic pharmaceuticals have garnered significant attention in recent years due to their enhanced physicochemical properties, including solubility, bioavailability, and intellectual property considerations. However, the manufacturing of metastable form pharmaceuticals remains a formidable challenge. The stable preparation of metastable carvedilol (CVD) form Ⅱ crystals during CVD production is elusive, leading to substantial inconsistencies in product quality and regulatory compliance. In this study, we successfully prepared metastable CVD Form Ⅱ crystals using a continuous tubular crystallizer. Our findings demonstrate that the tubular crystallizer exhibits high efficiency and robustness for generating metastable crystal Form Ⅱ. We optimized the crystallization process by incorporating air bubble segments and employing ultrasonic irradiation strategies to overcome blockages and wall sticking issues encountered during operation. Ultimately, we developed an ultrasound-assisted continuous slug-flow tubular crystallization method and evaluated its performance. The results indicate that the CVD crystals produced through this process are resilient, sustainable, and uninterrupted products with promising potential for producing metastable polymorphic pharmaceuticals while effectively addressing encrustation problems associated with continuous tubular crystallization.