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

  • Sathyanarayana Girigani
  • Harnam SinghEmail author
  • Sankar Rao Kola
  • Vijayalaxmi Dayanand Yelmeli
  • Venu Gopal Regula
  • Sakshi Shah
  • Neelu Jain
  • Pramod KumarEmail author


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.


Darunavir Safe industrial process Reduction Deprotection Coupling Critical process impurities 



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.

Compliance with ethical standards

Conflict of interest

The authors declared that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (PDF 1848 kb)


  1. 1.
    J.E. Arts, J.D. Hazuda, Cold Spring Harb Perspect Med 2, a007161 (2012)CrossRefGoogle Scholar
  2. 2.
    M. Mahdi, Z. Szojka, J.A. Mótyán, J. Tozsér, Viruses 7, 6152 (2015)CrossRefGoogle Scholar
  3. 3.
    N. Kumarasamy, A. Patel, S. Pujari, Indian J. Med. Res. 134, 787 (2011)CrossRefGoogle Scholar
  4. 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. 971–976Google Scholar
  5. 5.
    M.R. Ghante, R.S. Shelar, S.D. Sawant, M.M. Kadam, Int. J. Pharm. Pharm. Sci. 6, 240 (2014)Google Scholar
  6. 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, 2011Google Scholar
  7. 7.
    A.N. Kobe, T.S. Akashi, H.M. Takasago, K.I. Kakogawa, N.Y. Matsubara, U.S. Patent 5,929,284, 1999Google Scholar
  8. 8.
    N.M.F. Goyvaerts, P.T.B.P. Wigerinck, H.B. Zinser, B.M. Ebert, U.S. Patent 7,772,411 B2, 2010Google Scholar
  9. 9.
    A.K. Ghosh; G.M. Bilcer, T. Devasamudram, U.S. Patent 7,897,635 B2, 2011Google Scholar
  10. 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, 2011Google Scholar
  11. 11.
    M. Mizhiritskii, E. Marom, U.S. Patent Appl. 2012/0296101 A1, 2012Google Scholar
  12. 12.
    K.R. Babu, V.K. Rao, C.N. Raju, Der Pharma Chem. 3, 389 (2011)Google Scholar
  13. 13.
    A.K. Ghosh, S. Leshchenko, M. Noetzel, J. Org. Chem. 69, 7822 (2004)CrossRefGoogle Scholar
  14. 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, 2001Google Scholar
  15. 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, 2016Google Scholar
  16. 16.
    H.W.P. Vermeersch, D.J.C.T. Thone, D.V. Marie-Louise, U.S. Patent 7,700,645 B2, 2010Google Scholar
  17. 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, 2016Google Scholar
  18. 18.
    S.M. Kelly, B.H. Lipshutz, Org. Lett. 16, 98 (2014)CrossRefGoogle Scholar
  19. 19.
    D.C. Gowda, B. Mahesh, S. Gowda, Indian J. Chem. 40B, 55 (2001)Google Scholar
  20. 20.
    D.C. Gowda, S. Gowda, Indian J. Chem. 42B, 180 (2003)Google Scholar
  21. 21.
    H. Chen, C.N. Nilsen, A. Choudhury, K.L. Sorgi, Arkivoc 14, 1 (2008)Google Scholar
  22. 22.
    J.A. Mangravite, J. Chem. Educ. 60, 439 (1983)CrossRefGoogle Scholar
  23. 23.
    D.C. Gowda, S. Gowda, Indian J. Chem. 39B, 70 (2000)Google Scholar
  24. 24.
    H.D. Burge, D.J. Collins, Ind. Eng. Chem. Prod. Dev. 19, 389 (1980)CrossRefGoogle Scholar
  25. 25.
    I. Pogorelic, M. Filipan- Litvic, S. Merkas, G. Ljubic, I. Cepanec, M. Litvic, J. Mol. Catal. A: Chem. 274, 202 (2007)CrossRefGoogle Scholar
  26. 26.
    M. Srinivasan, A. Yurek-George, A. Ganesan, Mol. Divers. 9, 291 (2005)CrossRefGoogle Scholar
  27. 27.
    A. Isidro- Llobet, M. Alvarez, F. Albericio, Chem. Rev. 109, 2455 (2009)CrossRefGoogle Scholar
  28. 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)CrossRefGoogle Scholar
  29. 29.
    M. Mizhiritskii, E. Marom, U.S. Patent Appl. 20120296101 A1, 2012Google Scholar
  30. 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, 2012Google Scholar
  31. 31.
    P. Kar, R. Lipowsky, V. Knecht, J. Phys. Chem. B. 117, 5793 (2013)CrossRefGoogle Scholar
  32. 32.
    E. Marom, U.S. Patent Appl. 20120035142 A1, 2012Google Scholar
  33. 33.
    M. Chen, Family Health International Biostatistics Workshop (New Delhi, India, 2007)Google Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Sathyanarayana Girigani
    • 1
    • 2
  • Harnam Singh
    • 1
    Email author
  • Sankar Rao Kola
    • 1
  • Vijayalaxmi Dayanand Yelmeli
    • 1
  • Venu Gopal Regula
    • 1
  • Sakshi Shah
    • 1
  • Neelu Jain
    • 2
  • Pramod Kumar
    • 1
    Email author
  1. 1.Chemical Research and Development, API R&D CentreMicro Labs Ltd.BangaloreIndia
  2. 2.Sri Satya Sai University of Technology and Medical SciencesSehoreIndia

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