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. 2023 Nov:100:106627.
doi: 10.1016/j.ultsonch.2023.106627. Epub 2023 Sep 30.

Ultrasound-assisted continuous crystallization of metastable polymorphic pharmaceutical in a slug-flow tubular crystallizer

Huadong Liao  1 , Wenfeng Huang  2 , Ling Zhou  1 , Lan Fang  1 , Zhenguo Gao  3 , Qiuxiang Yin  4
Affiliations

Ultrasound-assisted continuous crystallization of metastable polymorphic pharmaceutical in a slug-flow tubular crystallizer

Huadong Liao et al. Ultrason Sonochem. 2023 Nov.

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.

Keywords: Carvedilol; Polymorphic transformation; Sonocrystallization; Tubular crystallizer; Ultrasonic irradiation.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Chemical structure of CVD − 1-(9H-carbozol-4-ryloxy)-3-[[2-(2-methoxy phenoxy)ethyl]amino]-2-propanol.
Fig. 2
Fig. 2
The batch experimental apparatus of the CVD solution crystallization process includes a crystallizer, stirring, feeding, and temperature control systems.
Fig. 3
Fig. 3
The tubular experimental apparatus of the CVD solution crystallization process includes a tubular crystallizer system, ultrasound system, feeding system, and temperature control system.
Fig. 4
Fig. 4
Real-time Raman spectrum during batch crystallization of CVD at 323.15 K.
Fig. 5
Fig. 5
Development of intensity values at peaks of 664 cm−1 and 1722 cm−1 during batch crystallization of CVD at 323.15 K.
Fig. 6
Fig. 6
Real-time Raman spectrum during batch crystallization of CVD at 293.15 K.
Fig. 7
Fig. 7
Development of intensity values for the peak at 1409 cm−1 during batch crystallization of CVD at 293.15 K.
Fig. 8
Fig. 8
Pictures of CVD characterization. (a) Microscope image of CVD tubular crystals; (b) microscope image of CVD batch crystals; (c) SEM image of CVD tubular crystals; (d) SEM image of CVD batch crystals.
Fig. 9
Fig. 9
PXRD patterns of CVD in two crystallization strategies.
Fig. 10
Fig. 10
DSC of CVD in two crystallization strategies.
Fig. 11
Fig. 11
Pictures for CVD continuous slug-flow tubular crystallization. (a) No ultrasound irradiation; (b) ultrasound irradiation.
Fig. 12
Fig. 12
Pictures for CVD tubular flow crystallization. (a) Crystal precipitation in the tubular; (b) the crystal was blocked in the tubular; (c) the air bubble-assisted tubular crystallization process has severe wall adhesion; (d) the ultrasound-assisted continuous slug flow tubular crystallization process has no wall adhesion and blockage.
See this image and copyright information in PMC

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