Citation: Wei Luo, Fen Liu, Yaohao Guo, Junjie Qiu, Jinrui Yan, Shuangliang Zhao, Bo Bao. Continuous synthesis of dolutegravir sodium crystals using liquid-gas heterogeneous microreactor[J]. Chinese Chemical Letters, ;2023, 34(3): 107636. doi: 10.1016/j.cclet.2022.06.059 shu

Continuous synthesis of dolutegravir sodium crystals using liquid-gas heterogeneous microreactor

Wei Luo ^a ,
Fen Liu ^a ,
Yaohao Guo ^a ,
Junjie Qiu ^a ,
Jinrui Yan ^a ,
Shuangliang Zhao ^{a, b} ,
Bo Bao ^{a, *,}

a.
State Key Laboratory of Chemical Engineering and School of Chemical Engineering, East China University of Science and Technology, Shanghai 200237, China
b.
Guangxi Key Laboratory of Petrochemical Resource Processing and Process Intensification Technology and School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China

bbao@ecust.edu.cn

Received Date: 19 April 2022
Revised Date: 15 June 2022
Accepted Date: 21 June 2022
Available Online: 24 June 2022

Figures(9)

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.
- Microreactor continuous crystallization,
- Dolutegravir sodium,
- Reaction kinetics,
- Mixing mechanism,
- Crystal morphology,
- Process operation
1. [1]
  S.W. Keeshin, J. Feinberg, Expert Opin. Drug Saf. 14 (2015) 141–147. doi: 10.1517/14740338.2015.973845
2. [2]
  W. Albrecht, J. Geier, D. Perez, WO 2016102078 A1, 2016.
3. [3]
  T. Wang, H. Lu, J. Wang, et al., J. Ind. Eng. Chem. 54 (2017) 14–29. doi: 10.1016/j.jiec.2017.06.009
4. [4]
  A.J. Alvarez, A.S. Myerson, Cryst. Growth Des. 10 (2010) 2219–2228. doi: 10.1021/cg901496s
5. [5]
  D. Han, T. Karmakar, Z. Bjelobrk, J. Gong, M. Parrinello, Chem. Eng. Sci. 204 (2019) 320–328. doi: 10.1016/j.ces.2018.10.022
6. [6]
  H.H. Tung, E.L. Paul, M. Midler, J.A. Mccauley, Critical issues in crystallization practice, in: H.H. Tung, E.L. Paul, M. Midler, J.A. Mccauley (Eds. ), Crystallization of Organic Compounds: An Industrial Perspective, WILEY, 2009, pp. 101–116.
7. [7]
  S. Lawton, G. Steele, P. Shering, et al., Org. Process Res. Dev. 13 (2009) 1357–1363. doi: 10.1021/op900237x
8. [8]
  X. Peng, P. Feng, Chinese J. Org. Chem. 41 (2021) 2918–2919. doi: 10.6023/cjoc202100051
9. [9]
  K. Plumb, Chem. Eng. Res. Des. 83 (2005) 730–738. doi: 10.1205/cherd.04359
10. [10]
  S.L. Lee, T.F. O'Connor, X. Yang, et al., J. Pharm. Innov. 10 (2015) 191–199. doi: 10.1007/s12247-015-9215-8
11. [11]
  B. Wood, K.P. Girard, C.S. Polster, D.M. Croker, Org. Process Res. Dev. 23 (2019) 122–144. doi: 10.1021/acs.oprd.8b00319
12. [12]
  K. A. Powell, A.N. Saleemi, C.D. Rielly, Z.K. Nagy, Chem. Eng. Process. Process Intensif. 97(2015) 195–212. doi: 10.1016/j.cep.2015.01.002
13. [13]
  K.R. Vandana, Y. Prasanna Raju, V. Harini Chowdary, M. Sushma, N. Vijay Kumar, Saudi Pharm. J. 22 (2014) 283–289. doi: 10.1016/j.jsps.2013.05.004
14. [14]
  R.M. Tona, T.A.O. McDonald, N. Akhavein, J.D. Larkin, D. Lai, Lab Chip 19 (2019) 2127–2137. doi: 10.1039/c9lc00204a
15. [15]
  N. Blagden, M. de Matas, P.T. Gavan, P. York, Adv. Drug Deliv. Rev. 59 (2007) 617–630. doi: 10.1016/j.addr.2007.05.011
16. [16]
  C. Rougeot, J.E. Hein, Org. Process Res. Dev. 19 (2015) 1809–1819. doi: 10.1021/acs.oprd.5b00141
17. [17]
  M. Fujiwara, Z.K. Nagy, J.W. Chew, R.D. Braatz, J. Process Control. 15 (2005) 493–504. doi: 10.1016/j.jprocont.2004.08.003
18. [18]
  M.D. Johnson, S.A. May, J.R. Calvin, et al., Org. Process Res. Dev. 16 (2012) 1017–1038. doi: 10.1021/op200362h
19. [19]
  X. Yang, D. Acevedo, A. Mohammad, et al., Org. Process Res. Dev. 21 (2017) 1021–1033. doi: 10.1021/acs.oprd.7b00130
20. [20]
  K.A. Powell, A.N. Saleemi, C.D. Rielly, Z.K. Nagy, Org. Process Res. Dev. 20 (2016) 626–636. doi: 10.1021/acs.oprd.5b00373
21. [21]
  R. Lakerveld, J.J.H. Van Krochten, H.J.M. Kramer, Cryst. Growth Des. 14 (2014) 3264–3275. doi: 10.1021/cg500090g
22. [22]
  X. Jiang, D. Lu, W. Xiao, et al., AIChE J. 62 (2015) 829–841. doi: 10.1038/hr.2015.73
23. [23]
  W.J. Liu, C.Y. Ma, X.Z. Wang, Procedia Eng. 102 (2015) 499–507. doi: 10.1016/j.proeng.2015.01.199
24. [24]
  S. Mascia, P.L. Heider, H. Zhang, et al., Angew. Chem. Int. Ed. 52 (2013) 12359–12363. doi: 10.1002/anie.201305429
25. [25]
  A.S. Myerson, M. Krumme, M. Nasr, et al., Science 104 (2015) 832–839. doi: 10.1002/jps.24311
26. [26]
  Y. Ke, Q. Zhang, T. Wang, et al., Nano Energy 73 (2020) 104785. doi: 10.1016/j.nanoen.2020.104785
27. [27]
  W. Li, Y. Li, W. Zhang, et al., Chin. Chem. Lett. 32 (2021) 1131–1134. doi: 10.1016/j.cclet.2020.09.039
28. [28]
  L.Y. Pfund, A.J. Matzger, ACS Comb. Sci. 16 (2014) 309–313. doi: 10.1021/co500043q
29. [29]
  R. Storey, R. Docherty, P. Higginson, et al., Crystallogr. Rev. 10 (2004) 45–56. doi: 10.1080/08893110410001664846
30. [30]
  K.S. Elvira, X.C. I Solvas, R.C.R. Wootton, A.J. Demello, Nat. Chem. 5 (2013) 905–915. doi: 10.1038/nchem.1753
31. [31]
  N. Hao, Z. Xu, Y. Nie, et al., Chem. Eng. J. 378 (2019) 122222. doi: 10.1016/j.cej.2019.122222
32. [32]
  S. Marre, K.F. Jensen, Chem. Soc. Rev. 39 (2010) 1183–1202. doi: 10.1039/b821324k
33. [33]
  N. Hao, Y. Nie, J.X.J. Zhang, Biomater. Sci. 7 (2019) 2218–2240. doi: 10.1039/c9bm00238c
34. [34]
  A. Shimoyama, Y. Fujimoto, K. Fukase, Synlett (2011) 2359–2362.
35. [35]
  T. Asai, A. Takata, Y. Ushiogi, et al., Chem. Lett. 40 (2011) 393–395. doi: 10.1246/cl.2011.393
36. [36]
  P.D.I. Fletcher, S.J. Haswell, E. Pombo-Villar, et al., Tetrahedron 58 (2002) 4735–4757. doi: 10.1016/S0040-4020(02)00432-5
37. [37]
  V. Hessel, H. Löwe, Chem. Eng. Technol. 28 (2005) 267–284. doi: 10.1002/ceat.200407167
38. [38]
  K. Wang, L. Li, P. Xie, G. Luo, React. Chem. Eng. 2 (2017) 611–627. doi: 10.1039/C7RE00082K
39. [39]
  I. Shestopalov, J.D. Tice, R.F. Ismagilov, Lab Chip 4 (2004) 316–321. doi: 10.1039/b403378g
40. [40]
  E.M. Chan, A.P. Alivisatos, R.A. Mathies, J. Am. Chem. Soc. 127 (2005) 13854–13861. doi: 10.1021/ja051381p
41. [41]
  P. Laval, N. Lisai, J.B. Salmon, M. Joanicot, Lab Chip 7 (2007) 829–834. doi: 10.1039/b700799j
42. [42]
  Z. Qiao, Z. Wang, C. Zhang, et al., AIChE J. 59 (2012) 215–228.
43. [43]
  N. Shao, A. Gavriilidis, P. Angeli, Chem. Eng. Sci. 64 (2009) 2749–2761. doi: 10.1016/j.ces.2009.01.067
44. [44]
  L. Zha, M. Shang, M. Qiu, H. Zhang, Y. Su, Chem. Eng. Sci. 195 (2019) 62–73. doi: 10.1016/j.ces.2018.11.043
45. [45]
  J.S. Zhang, K. Wang, Y.C. Lu, G.S. Luo, Chem. Eng. Process. Process Intensif. 49 (2010) 740–747. doi: 10.1016/j.cep.2009.10.009
46. [46]
  A. Gunther, S. Khan, M. Thalmann, F. Trachsel, K.F. Jensen, Lab Chip 4 (2004) 278–286. doi: 10.1039/B403982C
47. [47]
  R. Chen, J. Weng, S.F. Chow, R. Lakerveld, Cryst. Growth Des. 21 (2020) 501–511.
48. [48]
  Y. Duan, R. Rausa, P. Fiaschi, K.D. Papadopoulos, Tribiology Int. 98 (2016) 94–99. doi: 10.1016/j.triboint.2016.01.053
49. [49]
  M.M. Scherer, J.C. Westall, M. Ziomek-moroz, P. Tratnyek, Environ. Sci. Technol. 31 (1997) 2385–2391. doi: 10.1021/es960999j
50. [50]
  L.E. Hatcher, W. Li, P. Payne, et al., Cryst. Growth Des. 20 (2020) 5854–5862. doi: 10.1021/acs.cgd.0c00470
51. [51]
  A.R. Klapwijk, E. Simone, Z.K. Nagy, C.C. Wilson, Cryst. Growth Des. 16 (2016) 4349–4359. doi: 10.1021/acs.cgd.6b00465
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