Continuous synthesis of dolutegravir sodium crystals using liquid-gas heterogeneous microreactor |
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Affiliation: | 1. State Key Laboratory of Chemical Engineering and School of Chemical Engineering, East China University of Science and Technology, Shanghai 200237, China;2. Guangxi Key Laboratory of Petrochemical Resource Processing and Process Intensification Technology and School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China |
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Abstract: | In this work, a liquid-gas heterogeneous microreactor was developed for investigating continuous crystallization of dolutegravir sodium (DTG), as well as revealing reaction kinetics and mixing mechanism with 3-min data acquisition. The reaction kinetics models were established by visually recording the concentration variation of reactants over time in the microchannel via adding pH-sensitive fluorescent dye. The mixing intensification mechanism of liquid-gas flow was quantified through the fluorescent signal to indicate mixing process, demonstrating an outstanding mixing performance with a mixing time less than 0.1 s. Compared with batch crystallization, continuous synthesis of dolutegravir sodium using liquid-gas heterogenous microreactor optimizes crystal distribution size, and successfully modifies the crystal morphology in needle-like habit instead of rod-like habit. The microreactor continuous crystallization can run for 5 h without crystal blockage and achieve D90 of DTG less than 30 µm. This work provides a feasible approach for continuously synthesizing dolutegravir sodium, and can optimize the existing pharmaceutical crystallization. |
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