Environment, Development and Sustainability

, Volume 15, Issue 1, pp 1–21 | Cite as

A system view of solvent selection in the pharmaceutical industry: towards a sustainable choice

  • S. Perez-Vega
  • E. Ortega-Rivas
  • I. Salmeron-Ochoa
  • P. N. Sharratt


This paper presents a review of approaches that may be useful for the selection of solvents in the early stages of process development for the synthesis of active pharmaceutical ingredients. Characteristics of the methodologies and their applicability in early stages are explored. Early stages of development are recognised as ideal for detecting benefits and issues regarding the use of solvents. The “system” concept is introduced for the evaluation and selection of solvents in pharmaceutical processes; this concept does not yet seem to be widely utilised within the fine chemicals and pharmaceutical industries. System analysis is considered an important tool for viewing solvent selection from a holistic perspective. Hence, approaches suitable for the early stages of development and considering a holistic perspective might deliver more sustainable processes. The evolution of the synthesis of Ibuprofen API is used to illustrate this concept.


API HSE Solvent selection System Early stage Process development Key factors 



Active pharmaceutical ingredient


Best route innovative technology evaluation and selection techniques


Computer-aided molecular design


Environmental fate and risk assessment


Ionic non-random two liquid segment activity coefficient thermodynamic model


Food and drug administration


Finished pharmaceutical product


Good manufacturing practice


Hazardous air pollutants


Anhydrous hydrogen fluoride


Health safety and environment


Lifecycle assessment


Maximum available control technology


Methodology for environmental impact minimisation


Medicine and healthcare products regulation agency


Non-random two liquid thermodynamic model


Non-random two liquid segment activity coefficient thermodynamic model


Regulatory starting materials


Universal Functional Activity coefficient


United States environmental protection agency


Volatile organic compounds


Volatile organic emissions


Waste reduction algorithm


  1. Alexander, B., Barton, G., Petrie, J., & Romagnoli, J. (2000). Process synthesis and optimisation tools for the environmental design: Methodology and structure. Computers & Chemical Engineering, 24(2–7), 1195–1200.CrossRefGoogle Scholar
  2. Anderson, N. G. (2000). Practical process research and development. Oxford, UK: Academic Press.Google Scholar
  3. Basu, P. K. (1998). Pharmaceutical process development is different! Chemical Process Engineering, 94(9), 75.Google Scholar
  4. Basu, P. K., Mack, R. A., & Vinson, J. M. (1999). Consider a new approach to pharmaceutical process development. Chemical Engineering Progress, 95(8), 82.Google Scholar
  5. Bierma, T. J., & Waterstraat, F. (2000). Chemical management: Reducing waste and cost through innovative supply strategies. New York, Chichester: Wiley.Google Scholar
  6. Bouncel, E., Stairs R., & Wilson, H. (2003). The role of the solvent in chemical reactions, Volume 6 Oxford chemistry master, Oxford University Press.Google Scholar
  7. Cann, M. C., & Connelly, M. E. (2000). Real-world cases in green chemistry. Washington, DC: American Chemical Society. Environmental Protection Agency.Google Scholar
  8. Chen, C.-C., & Crafts, P. A. (2006). Correlation and prediction of drug molecule solubility in mixed solvent systems with the non-random two-liquid segment activity coefficient (NRTL-SAC). Industrial & Engineering Chemistry Research, 45(13), 4816–4824.CrossRefGoogle Scholar
  9. Chen, H., & Shonnard, D. R. (2004). Systematic framework for the environmentally conscious chemical process design: Early and detail design stages. Industrial & Engineering Chemistry Research, 43(2), 535–552.CrossRefGoogle Scholar
  10. Chen, C.-C., & Song, Y. (2004a). Solubility modeling with a nonrandom two-liquid segment activity coefficient model. Industrial & Engineering Chemistry Research, 43(26), 8354–8362.CrossRefGoogle Scholar
  11. Chen, C.-C., & Song, Y. (2004b). Generalized electrolyte-NRTL model for mixed-solvent systems. AIChE Journal, 50(8), 1928–1941.CrossRefGoogle Scholar
  12. Chen, H., Wen, Y., Waters, M. D., & Shonnard, D. R. (2002). Design guidance for chemical process using environmental and economic assessments. Industrial & Engineering Chemistry Research, 41(18), 4503–4513.CrossRefGoogle Scholar
  13. Constable, D. J. C., Jimenez-Gonzales, C., & Henderson, R. K. (2007). Perspective on solvent use in the pharmaceutical industry. Organic Process Research & Development, 11(1), 133–137.CrossRefGoogle Scholar
  14. Curzons, A. D., Constable, D., & Cunningham, V. L. (1999). Solvent selection guide: A guide to integration of environmental, health and safety criteria into the selection of solvents. Clean Products and Process, 1(2), 82–90.Google Scholar
  15. Curzons, A. D., Constable, D., Mortimer, D., & Cunningham, V. L. (2001). So you think your process is green, how do you know?—Using principles of sustainability to determine what is green—A corporate perspective. Green Chemistry, 3(1), 1–6.CrossRefGoogle Scholar
  16. DiMasi, J. A., Hansen, R. W., & Grabowski, H. G. (2003). The price of innovation: New estimates of drug development costs. Journal of Health Economics, 22(2), 151–185.CrossRefGoogle Scholar
  17. Eden, M. R., Jorgensen, S. B., Gani, R., & El-Halwagi, M. M. (2004). A novel framework for simultaneous separation process and product design. Chemical Engineering and Processing, 43(5), 595–608.CrossRefGoogle Scholar
  18. Elango, V., Murphy, M. A., Smith, B. L., Davenport, K. G., Mott, G. N., Zey, E. G., et al. (1991). Method for producing ibuprofen. US Patent 4,981,995.Google Scholar
  19. Elgue, S., Prat, L., Cognet, P., Cabassud, M., Lann, J. M., & Cezerac, J. (2004). Influence of solvent choice on optimisation of reaction-separation operation: Application to a Beckmann rearrangement reaction. Separation and Purification Technology, 34(1–3), 273–281.CrossRefGoogle Scholar
  20. Frank, T. C., Downey, J. R., & Gupta, S. K. (1999). Quickly screen solvents for organic solids. Chemical Engineering Progress, 95(12), 41–61.Google Scholar
  21. Gani, R. (2004). Chemical product design: Challenges and opportunities. Computers & Chemical Engineering, 28(12), 2441–2457.CrossRefGoogle Scholar
  22. Gani, R., Jimenez-Gonzalez, C., ten Kate, A., Crafts, P. A., Powell, M. J., Powell, L., et al. (2006). A modern approach to solvent selection. Chemical Engineering, 113(3), 30–43.Google Scholar
  23. Gao, J., & Furlani, T. R. (1995). Simulating solvent effects in organic chemistry. Computational Science and Engineering, 2(3), 24–33.CrossRefGoogle Scholar
  24. Gracin, S., Brinck, T., & Rasmuson, A. C. (2002). Prediction of solubility of solid organic compounds in solvents by UNIFAC. Industrial & Engineering Chemistry Research, 41(20), 5114–5124.CrossRefGoogle Scholar
  25. Grünig, R., & Kühn, R. (2005). Successful decision-making: A systematic approach to complex problems. Berlin, Heidelberg: Springer.Google Scholar
  26. Heinzle, E., Weirich, D., Brogli, F., Hoffmann, V., Koller, G., Verduyn, M., et al. (1998). Ecological and economic objective functions for screening in integrated development of fine chemical processes. 1. Flexible and expandable framework using indices. Industrial & Engineering Chemistry Research, 37(8), 3395–3407.CrossRefGoogle Scholar
  27. Hostrup, M., Harper, P. M., & Gani, R. (1999). Design of environmentally benign processes: Integration of solvent design and separation process synthesis. Computers & Chemical Engineering, 23(10), 1395–1414.CrossRefGoogle Scholar
  28. Humphrey, J. L., & Keller, G. E., I. I. (1997). Separation process technology. London: McGraw-Hill.Google Scholar
  29. Jaksland, C. A., Gani, R., & Lien, K. M. (1995). Separation process design and synthesis based on thermodynamic insights. Chemical Engineering Science, 50(3), 511–530.CrossRefGoogle Scholar
  30. Jimenez-Gonzales, C., Curzons, A. D., Constable, D., & Cunningham, V. L. (2005). Expanding GSK’s solvent selection guide-application of lifecycle assessment to enhance solvent selection. Clean Technology and Environmental Policy, 7(1), 42–50.CrossRefGoogle Scholar
  31. Jimenez-Gonzalez, C., Poechlauer, P., Broxterman, Q. B., Yang, B.-S., Ende, D., Baird, J., et al. (2011). Key green engineering research areas for sustainable manufacturing: A perspective from pharmaceutical and fine chemicals manufacturers. Organic Process Research & Development, 15(4), 900–911.CrossRefGoogle Scholar
  32. Kim, K.-J., & Diwekar, U. M. (2002). Integrated solvent selection and recycling for continuous processes. Industrial Engineering Chemistry Research, 41(18), 4479–4488.CrossRefGoogle Scholar
  33. Kolar, P., Shen, J.-W., Tsuboi, A., & Ishikawa, T. (2002). Solvent selection for pharmaceuticals. Fluid Phase Equilibria, 194–197, 771–782.CrossRefGoogle Scholar
  34. Krewer, U., & Liauw, M. A. (2002). Pollution prevention through solvent selection and waste minimization. Industrial & Engineering Chemistry Research, 41(18), 4534–4552.CrossRefGoogle Scholar
  35. Lee, S., & Robinson, G. (1995). Process development: Fine chemicals from grams kilograms, Oxford chemistry primers; 30 Oxford science publications, Oxford University Press.Google Scholar
  36. Li, M., Harten, P. F., & Cabezas, H. (2002). Experiences in designing solvents for the environment. Industrial & Engineering Chemistry Research, 41(23), 5867–5877.CrossRefGoogle Scholar
  37. Liu, Y., & Watanasiri, S. (1999). Successfully simulate electrolyte systems. Chemical Engineering Progress, 95(10), 25–42.Google Scholar
  38. Lyndley, D. D., Curtis, T. A., Ryan, T. R., De la Garza, E. M., Hilton, C. B., & Kenesson, T. M. (1991). Process for the production of 4’-Isobutylacetophenone. US Patent 5,068,448.Google Scholar
  39. Mirmehrabi, M., Rohani, S., & Perry, L. (2005). Thermodynamic modeling for activity coefficient and prediction of solubility: Part 2. Semipredictive or semiempirical models. Journal of Pharmaceutical Sciences, 95(4), 798–809.CrossRefGoogle Scholar
  40. Modi, A., Aumond, J. P., Mavrovouniotis, M., & Stephanopoulos, G. (1996). Rapid plantwide screening of solvents for batch processes. Computers & Chemical Engineering, 20(1), S375–S380.CrossRefGoogle Scholar
  41. Muller, F. L., & Latimer, J. M. (2009). Anticipation of scale up issues in pharmaceutical development. Computers & Chemical Engineering, 33(5), 1051–1055.CrossRefGoogle Scholar
  42. Nass, K. K. (1994). Rational solvent selection for cooling crystallizations. Industrial & Engineering Chemistry Research, 33(6), 1580–1584.CrossRefGoogle Scholar
  43. Palaniappan, C., Srinivasan, R., & Tan, R. (2004). Selection of inherently safer process routes: A case study. Chemical Engineering and Processing, 43, 647–653.CrossRefGoogle Scholar
  44. Peccei, A. (1977). The human quality. Oxford, UK: Pergamon Press.Google Scholar
  45. Perez-Vega, S., Peter, S., Salmeron-Ochoa, I., Nieva-de la Hidalga, A., & Sharratt, P. N. (2011). Analytical hierarchy processes (AHP) for the selection of solvents in early stages of pharmaceutical process development. Journal of Process Safety and Environmental Protection, 89(4), 261–267.CrossRefGoogle Scholar
  46. Pistikopoulos, E. N., & Stefanis, S. K. (1998). Optimal solvent design for environmental impact minimization. Computers & Chemical Engineering, 22(6), 717–733.CrossRefGoogle Scholar
  47. Sakizlis, V., Perkins, J. D., & Pistikopoulos, E. N. (2004). Recent advances in optimization-based simultaneous process and control design. Computers & Chemical Engineering, 28(10), 2069–2086.CrossRefGoogle Scholar
  48. Sharratt, P. (1997). Batch process design. London, UK: Blackie Academic and Professional.CrossRefGoogle Scholar
  49. Sharratt, P., & Sparshott, M. (1996). Case studies in environmental technology. Institute of Chemical Engineers.Google Scholar
  50. Sheldon, R. A. (2005). Green solvents for sustainable organic synthesis: State of the art. Royal Society of Chemistry, 7(5), 267–278.Google Scholar
  51. Shetgiri, N., Patil, S., & Kelaskar, R. (2005). API scale-up during research and development. Pharmaceutical Technology, electronic edition, 1(3).Google Scholar
  52. Sinha, M., Achiene, L. E. K., & Ostrovsky, G. M. (1999). Environmentally benign solvent design by global optimization. Computers & Chemical Engineering, 23(10), 1381–1394.CrossRefGoogle Scholar
  53. Smallwood, I. (1993). Solvent recovery handbook. London, UK: McGraw-Hill.Google Scholar
  54. Stuart NJ and Sanders AS (1968) Phenyl propionic acids. US 3385886. Patent.Google Scholar
  55. Thomas, B., & Karl Hans, S. (1994). Knowledge integrating system for the selection of solvents for extractive and azeotropic distillation. Computers & Chemical Engineering, 18, S25–S29.CrossRefGoogle Scholar
  56. Tucker, J. L. (2006). Green chemistry, a pharmaceutical perspective. Organic Process Research & Development, 10, 2.CrossRefGoogle Scholar
  57. USEPA. (1997). Profile of the pharmaceutical manufacturing industry. http://www.epa.gov/compliance/resources/publications/assistance/sectors/notebooks/pharma.pdf.
  58. Wang, Y., & Achiene, L. E. K. (2002). A hybrid global optimization approach for solvent design. Chemical Engineering and Processing, 26, 1415–1425.Google Scholar
  59. Whiting, W. B. (1996). Effects of uncertainties in thermodynamic data and models on process calculations. Journal of Chemical Engineering Data, 41(5), 935–941.CrossRefGoogle Scholar
  60. Willis, C., & Willis, M. (1995). Organic synthesis, Volume 31, Oxford Chemistry Primers, Oxford science publications.Google Scholar
  61. Wypych, G. (2006). Important determinants of solvent selection. Chemical Engineering, 113(6), 54–60.Google Scholar
  62. Zgurovsky, M. Z., & Pankratova, N. D. (2007). System analysis: Theory and applications. Berlin: Springer.Google Scholar
  63. Zhang, Y., Bakchi, B., & Sahledemessie, E. (2008). Lifecycle Assessment of an Ionic Liquid versus Molecular Solvents and Their Applications. Environmental Science Technology, 42(5), 1724–1730.CrossRefGoogle Scholar
  64. Zhao, R., & Cabezas, H. (1998). Molecular thermodynamics in the design of substitute solvents. Industrial & Engineering Chemistry Research, 37(8), 3268–3280.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • S. Perez-Vega
    • 1
  • E. Ortega-Rivas
    • 1
  • I. Salmeron-Ochoa
    • 1
  • P. N. Sharratt
    • 2
  1. 1.School of Chemical ScienceAutonomous University of ChihuahuaChihuahuaMexico
  2. 2.Institute of Chemical and Engineering SciencesJurong IslandSingapore

Personalised recommendations