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An improved and robust scale-up process aided with identification and control of critical process impurities in darunavir ethanolate

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Abstract

A robust and safe industrial process, including five isolations and drying steps for widely prescribed anti-HIV (protease inhibitor) drug darunavir ethanolate 2, has been developed. A salient feature of this process is the development of procedures enabling the efficient synthesis of multi-kilogram quantity of darunavir ethanolate, and process demonstrations through plant scale preparation are offered where darunavir molecule has been prepared with overall > 70% chemical yield and > 99.8% purity without involving any purification procedure(s), with all possible process impurities below than the desired limit (not more than 0.08%) were isolated, synthesized and characterized. The developed process is entirely robust, very efficient and demonstrated up to kilograms scale.

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Notes

  1. http://www.cancer.org/acs/groups/cid/documents/webcontent/002295-pdf.pdf.

  2. https://aidsinfo.nih.gov/education-materials/fact-sheets/21/58/fda-approved-hiv-medicines.

  3. http://emedicine.medscape.com/article/1533218-overview#a2.

  4. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htm.

References

  1. J.E. Arts, J.D. Hazuda, Cold Spring Harb Perspect Med 2, a007161 (2012)

    Article  Google Scholar 

  2. M. Mahdi, Z. Szojka, J.A. Mótyán, J. Tozsér, Viruses 7, 6152 (2015)

    Article  CAS  Google Scholar 

  3. N. Kumarasamy, A. Patel, S. Pujari, Indian J. Med. Res. 134, 787 (2011)

    Article  CAS  Google Scholar 

  4. Centers for Disease Control and Prevention (2012, November 30). Vital signs: HIV infection, testing, and risk behaviors among youths - United States. Morbidity and Mortality Weekly Report (MMWR) 61(47), pp. 971–976

  5. M.R. Ghante, R.S. Shelar, S.D. Sawant, M.M. Kadam, Int. J. Pharm. Pharm. Sci. 6, 240 (2014)

    CAS  Google Scholar 

  6. M.L. Vazluez, R.A. Mueller, J.J. Talley, D.P. Getman, G.A. DeCrescenzo, J.N. Freskos, R.M. Heintz, D.E. Berternshaw, U.S. Patent RE 42,889 E, 2011

  7. A.N. Kobe, T.S. Akashi, H.M. Takasago, K.I. Kakogawa, N.Y. Matsubara, U.S. Patent 5,929,284, 1999

  8. N.M.F. Goyvaerts, P.T.B.P. Wigerinck, H.B. Zinser, B.M. Ebert, U.S. Patent 7,772,411 B2, 2010

  9. A.K. Ghosh; G.M. Bilcer, T. Devasamudram, U.S. Patent 7,897,635 B2, 2011

  10. P.T.B.P. Wigerinck, D.L.N.G. Surleraux, W.G. Verschueren, H.A. DeKock, W.A.A. Aelterman, U.S. Patent Appl. 2011/0160468 A1, 2011

  11. M. Mizhiritskii, E. Marom, U.S. Patent Appl. 2012/0296101 A1, 2012

  12. K.R. Babu, V.K. Rao, C.N. Raju, Der Pharma Chem. 3, 389 (2011)

    CAS  Google Scholar 

  13. A.K. Ghosh, S. Leshchenko, M. Noetzel, J. Org. Chem. 69, 7822 (2004)

    Article  CAS  Google Scholar 

  14. M.L. Vazluez, R.A. Mueller, J.J. Talley, D.P. Getman, G.A. DeCrescenzo, J.N. Freskos, R.M. Heintz, D.E. Berternshaw, U.S. Patent 6,248,775 B1, 2001

  15. Q.P.J.L. Mario, K.B.R. Romanie, V.R. Jan, L.C.S. Maria, K.J.H.M. Hero, L.F.A. Marie, Patent EP 1732931 B1, 2016

  16. H.W.P. Vermeersch, D.J.C.T. Thone, D.V. Marie-Louise, U.S. Patent 7,700,645 B2, 2010

  17. H. Singh, T.G. Varadaraju, S. Shah, S.R. Kola, P.K. Sahu, V.G. Regula, V.R. Rayavarpu, P. Kumar, S.K. Dubey, Indian Patent 2451/CHE/2014 A, 2016

  18. S.M. Kelly, B.H. Lipshutz, Org. Lett. 16, 98 (2014)

    Article  CAS  Google Scholar 

  19. D.C. Gowda, B. Mahesh, S. Gowda, Indian J. Chem. 40B, 55 (2001)

    Google Scholar 

  20. D.C. Gowda, S. Gowda, Indian J. Chem. 42B, 180 (2003)

    CAS  Google Scholar 

  21. H. Chen, C.N. Nilsen, A. Choudhury, K.L. Sorgi, Arkivoc 14, 1 (2008)

    Google Scholar 

  22. J.A. Mangravite, J. Chem. Educ. 60, 439 (1983)

    Article  CAS  Google Scholar 

  23. D.C. Gowda, S. Gowda, Indian J. Chem. 39B, 70 (2000)

    Google Scholar 

  24. H.D. Burge, D.J. Collins, Ind. Eng. Chem. Prod. Dev. 19, 389 (1980)

    Article  CAS  Google Scholar 

  25. I. Pogorelic, M. Filipan- Litvic, S. Merkas, G. Ljubic, I. Cepanec, M. Litvic, J. Mol. Catal. A: Chem. 274, 202 (2007)

    Article  CAS  Google Scholar 

  26. M. Srinivasan, A. Yurek-George, A. Ganesan, Mol. Divers. 9, 291 (2005)

    Article  CAS  Google Scholar 

  27. A. Isidro- Llobet, M. Alvarez, F. Albericio, Chem. Rev. 109, 2455 (2009)

    Article  CAS  Google Scholar 

  28. D.S. Coffey, M.N. Hawk, S.W. Pedersen, S.J. Ghera, P.G. Marler, P.N. Dodson, M.L. Lytle, Org. Process Res. Dev. 8, 945 (2004)

    Article  CAS  Google Scholar 

  29. M. Mizhiritskii, E. Marom, U.S. Patent Appl. 20120296101 A1, 2012

  30. V. Ahire, S. Sasne, A. Deshmukh, K. Kumbhar, A. Bhatnagar, D. Verma, R. Vyas, G. Singh, N. Bhise, U.S. Patent Appl. 20120237770 A1, 2012

  31. P. Kar, R. Lipowsky, V. Knecht, J. Phys. Chem. B. 117, 5793 (2013)

    Article  CAS  Google Scholar 

  32. E. Marom, U.S. Patent Appl. 20120035142 A1, 2012

  33. M. Chen, Family Health International Biostatistics Workshop (New Delhi, India, 2007)

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Acknowledgements

The authors greatly appreciate financial support for this work from Micro Labs Ltd., API Division Centre, ML-27, Bangalore. We thank our group colleagues for their appreciated contribution. The Analytical Department of Micro Labs Limited acknowledged for providing support for analytical and spectral data.

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Authors and Affiliations

  1. Chemical Research and Development, API R&D Centre, Micro Labs Ltd., Bommasandra-Jigani Link Road, KIADB Industrial Area, Bangalore, Karnataka, 560105, India

    Sathyanarayana Girigani, Harnam Singh, Sankar Rao Kola, Vijayalaxmi Dayanand Yelmeli, Venu Gopal Regula, Sakshi Shah & Pramod Kumar

  2. Sri Satya Sai University of Technology and Medical Sciences, Sehore, Madhya Pradesh, 466001, India

    Sathyanarayana Girigani & Neelu Jain

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  1. Sathyanarayana Girigani
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  2. Harnam Singh
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  3. Sankar Rao Kola
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  5. Venu Gopal Regula
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Correspondence to Harnam Singh or Pramod Kumar.

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Girigani, S., Singh, H., Kola, S.R. et al. An improved and robust scale-up process aided with identification and control of critical process impurities in darunavir ethanolate. Res Chem Intermed 46, 267–281 (2020). https://doi.org/10.1007/s11164-019-03948-4

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