Skip to main content
Log in

Solid forms of pharmaceuticals: Polymorphs, salts and cocrystals

  • Invited Review Paper
  • Published:
Korean Journal of Chemical Engineering Aims and scope Submit manuscript

Abstract

Control and selection of the properties of active pharmaceutical ingredients is a crucial part of the drug development process. One major part of this process is the selection of an appropriate solid form. This review will discuss three major types of crystalline solids, polymorphs, salts and cocrystals and processes used to develop and find these forms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. J.W. Mullin, Crystallization, 4th Ed., Butterworth-Heinemann (2001).

  2. L. Yu, G. A. Stephenson, C.A. Mitchell, C.A. Bunnell, S.V. Snorek, J. J. Bowyer, T. B. Borchardt, J.G. Stowell and S. R. Byrn, J. Am. Chem. Soc., 122(4), 585 (2000).

    Article  CAS  Google Scholar 

  3. M. R. Caira, In Design of Organic Solids, 198, 163 (1998).

    Article  CAS  Google Scholar 

  4. J. Bauer, S. Spanton, R. Henry, J. Quick, W. Dziki, W. Porter and J. Morris, Pharm. Res., 18(6), 859 (2001).

    Article  CAS  Google Scholar 

  5. D. J. Kempf, K. C. Marsh, J. F. Denissen, E. Mcdonald, S. Vasavanonda, C.A. Flentge, B. E. Green, L. Fino, C. H. Park, X. P. Kong, N. E. Wideburg, A. Saldivar, L. Ruiz, W. M. Kati, H. L. Sham, T. Robins, K. D. Stewart, A. Hsu, J. J. Plattner, J. M. Leonard and D.W. Norbeck, P. Natl. Acad. Sci., USA, 92(7), 2484 (1995).

    Article  CAS  Google Scholar 

  6. D. Law, S. L. Krill, E. A. Schmitt, J. J. Fort, Y. H. Qiu, W. L. Wang and W. R. Porter, J. Pharm. Sci., 90(8), 1015 (2001).

    Article  CAS  Google Scholar 

  7. J. Bernstein, Polymorphism in molecular crystals, Clarendon, Oxford (2002).

    Google Scholar 

  8. S. R. Byrn, Solid state chemistry of drugs, Academic, New York (1999).

    Google Scholar 

  9. W. Z. Ostwald, Phys. Chem., 22, 289 (1897).

    CAS  Google Scholar 

  10. J. Aaltonen, M. Alleso, S. Mirza, V. Koradia, K. C. Gordon and J. Rantanen, Eur. J. Pharm. Biopharm., 71(1), 23 (2009).

    Article  CAS  Google Scholar 

  11. S. L. Morissette, Ö. Almarsson, M. L. Peterson, J. F. Remenar, M. J. Read, A.V. Lemmo, S. Ellis, M. J. Cima and C. R. Gardner, Adv. Drug. Deliv. Rev., 56(3), 275 (2004).

    Article  CAS  Google Scholar 

  12. S. Mirza, I. Miroshnyk, J. Heinamaki, L. Christiansen, M. Karjalainen and J. Yliruusi, Aaps. Pharm. Sci., 5(2), 39 (2003).

    Article  Google Scholar 

  13. I. Miroshnyk, L. Khriachtchev, S. Mirza, J. Rantanen, J. Heinamaki and J. Yliruusi, Cryst. Growth Des., 6(2), 369 (2006).

    Article  CAS  Google Scholar 

  14. M. D. Hollingsworth, M. L. Peterson, K. L. Pate, B. D. Dinkelmeyer and M. E. Brown, J. Am. Chem. Soc., 124(10), 2094 (2002).

    Article  CAS  Google Scholar 

  15. S. L. Childs, L. J. Chyall, J. T. Dunlap, D. A. Coates, B. C. Stahly and G. P. Stahly, Cryst. Growth Des., 4(3), 441 (2004).

    Article  CAS  Google Scholar 

  16. B. A. Garetz, J. Matic and A. S. Myerson, Phys. Rev. Lett., 89(17), 175501 (2002).

    Article  Google Scholar 

  17. G. Ruecroft, D. Hipkiss, T. Ly, N. Maxted and P.W. Cains, Org. Proc. Res. Dev., 9(6), 923 (2005).

    Article  CAS  Google Scholar 

  18. M. D. Lang, J.W. Kampf and A. J. Matzger, J. Pharm. Sci., 91(4), 1186 (2002).

    Article  CAS  Google Scholar 

  19. A.Y. Lee, I. S. Lee, S. S. Dettet, J. Boerner and A. S. Myerson, J. Am. Chem. Soc., 127(43), 14982 (2005).

    Article  CAS  Google Scholar 

  20. I. S. Lee, A. Y. Lee and A. S. Myerson, Pharm. Res., 25(4), 960 (2008).

    Article  CAS  Google Scholar 

  21. A. Singh, I. S. Lee and A. S. Myerson, Cryst. Growth Des., 9(2), 1182 (2009).

    Article  CAS  Google Scholar 

  22. S. M. Berge, L. M. Bighley and D. C. Monkhouse, J. Pharm. Sci., 66, 1 (1977).

    Article  CAS  Google Scholar 

  23. P. H. Stahl, G. Wermuth, G. (Eds): Handbook of Pharmaceutical Salts; Properties, Selection and Use (International Union of Pure and Applied Chemistry), New York, Wiley-VCH (2002).

    Google Scholar 

  24. C.B. Aakeroy, M. E. Fasulo and J. Desper, Mol. Pharma., 4(3), 317 (2007).

    Article  Google Scholar 

  25. R. J. Bastin, M. J. Bowker and B. J. Slater, Org. Proc. Res. Dev., 4, 427 (2000).

    Article  CAS  Google Scholar 

  26. B. D. Anderson and K. P. Flora, in’The Practice of Medicinal Chemistry’, Ed. C.G. Wermuth, Academic Press Ltd. London, Chapter 34 (1996).

    Google Scholar 

  27. S. F. Kramer and G. L. Flynn, J. Pharm. Sci., 61, 1896 (1972).

    Article  CAS  Google Scholar 

  28. A. T. M. Serajuddin, P. C. Sheen, D. Mufson, D. F. Bernstein and M. A. Augustine, J. Pharm. Sci., 75, 492 (1986).

    Article  CAS  Google Scholar 

  29. S. Li, P. Doyle, S. Metz, A. E. Royce and A. T. M. Serajuddin, J. Pharma. Sci., 94(10), 2224 (2005).

    Article  CAS  Google Scholar 

  30. T. D. Gross, K. Schaab, M. Ouellette, S. Zook, J. P. Reddy, A. Shurtleff, A. I. Sacaan, T. Alebic-Kolbah and H. Bozigian, Org. Proc. Res. Dev., 11, 365 (2007).

    Article  CAS  Google Scholar 

  31. J. B. Dressman, P. Bass, W. A. Ritschel, D. R. Friend, A. Rubinstein and E. Ziv, J. Pharm. Sci., 82, 857 (1993).

    Article  CAS  Google Scholar 

  32. E. Redenti, L. Szente and J. Szejtli, J. Pharm. Sci., 90(8), 979 (2001).

    Article  CAS  Google Scholar 

  33. T. L. Russel, R. R. Berardi, J. L. Barnett, T. L. O’sullivan, J.G. Wagner and J. B. Dressman, Pharm. Res., 11, 136 (1994).

    Article  Google Scholar 

  34. P. L. Gould, Int. J. Pharm., 33, 201 (1986).

    Article  CAS  Google Scholar 

  35. C. C. Sun and D. J. Grant, AAPS, Pharm. Sci. Suppl., 1, S–174 (1999).

    Google Scholar 

  36. M. Gazda, R. J. Dansereau, D. J. Crail, D. H. Sakkab and M. M. Virgin, Pharm. Sci., 1, S403 (1998).

  37. R. B. Hammond, R. S. Hashim, C. Ma and K. J. Roberts, J. Pharm. Sci., 95(11), 2361 (2006).

    Article  CAS  Google Scholar 

  38. S. N. Black, E. A. Collier, R. J. Davey and R. J. Roberts, J. Pharm. Sci., 96(5), 1053 (2007).

    Article  CAS  Google Scholar 

  39. L. R. Madivada, R. R. Anumala, G. Gilla, S. Alla, K. Charagondla, M. Kagga, A. Bhattacharya and R. Bandichhor, Org. Proc. Res. Dev., 13, 1190 (2009).

    Article  CAS  Google Scholar 

  40. A. Sallmann, Bottmingen, R. Pfister and B. Switzerland, US3558690 (1971).

  41. R. Bucci, A. D. Magrì, A. L. Magrì and Fresenius, J. Anal. Chem., 362, 577 (1998).

    CAS  Google Scholar 

  42. J. Bradshaw, B. J. Price and J.W. Clitherow, GB1565966 (1980).

  43. G. J. Durant, J. C. Emmett and C. R. Ganellin, US3950333 (1976).

  44. H. Yasufumi, Y. Isao, I. Yoshio, T. Shinichi, I. Noriki, I. Yasuo and T. Masaaki, US4283408 (1981).

  45. Ö. Almarsson and M. J. Zaworotko, Chem. Commun., 17, 1889 (2004).

    Article  Google Scholar 

  46. I. Miroshnyk, S. Mirza and N. Sandler, Expt. Opin. Drug Deliv., 6, 333 (2009).

    Article  CAS  Google Scholar 

  47. M. C. Etter, J. Phys. Chem., 95, 4601 (1991).

    Article  CAS  Google Scholar 

  48. C.C. Seaton, K. Chadwick, G. Sadiq, K. Guo and R. J. Davey, Cryst. Growth Des., 10, 726 (2010).

    Article  CAS  Google Scholar 

  49. S. L. Morissettea, Ö. Almarsson, M. L. Peterson, J. F. Remenar, M. J. Read, A.V. Lemmo, S. Ellis, M. J. Cima and C. R. Gardner, Adv. Drug Deliv. Rev., 56, 275 (2004).

    Article  Google Scholar 

  50. A. V. Trask and W. Jones, Top. Curr. Chem., 35, 3523 (2005).

    Google Scholar 

  51. K. Chadwick, R. Davey, G. Sadiq, W. Cross and R. Pritchard, Cryst. Eng. Comm., 11, 412 (2009).

    CAS  Google Scholar 

  52. S. J. Nehm, B. Rodríguez-Spong and N. Rodríguez-Hornedo, Cryst. Growth Des., 6, 592 (2006).

    Article  CAS  Google Scholar 

  53. J. F. Remenar, M. L. Peterson, P.W. Stephens, Z. Zhang, Y. Zimenkov and M. B. Hickey, Mol. Pharma., 4(3), 386 (2007).

    Article  CAS  Google Scholar 

  54. A.V. Trask, W. D. S. Motherwell and W. Jones, Cryst. Growth Des., 5(3), 1013 (2005).

    Article  CAS  Google Scholar 

  55. P. Vishweshwar, J. A. McMahon, J. A. Bis and M. J. Zaworotko, J. Pharm. Sci., 95, 499 (2006).

    Article  CAS  Google Scholar 

  56. S. L. Childs, L. J. Chyall, J. T. Dunlap, V. N. Smolenskaya, B. C. Stahly and G. P. Stahly, J. Am. Chem. Soc., 126(41), 13335 (2004).

    Article  CAS  Google Scholar 

  57. A. Bak, A. Gore, E. Yanez, M. Stanton, S. Tufekcic, R. Syed, A. Akrami, M. Rose, S. Surapaneni, T. Bostick, A. King, S. Neervannan, D. Ostovic and A. Koparkar, J. Pharm. Sci., 97(9), 3942 (2008).

    Article  CAS  Google Scholar 

  58. J. F. Remenar, S. L. Morissette, M. L. Peterson, B. Moulton, J. M. MacPhee, H. R. Guzmán and Ö. Almarsson, J. Am. Chem. Soc., 125(28), 8456 (2003).

    Article  CAS  Google Scholar 

  59. J. Galcera and E. Molins, Cryst. Growth Des., 9(1), 327 (2009).

    Article  CAS  Google Scholar 

  60. N. Shan and M. J. Zaworotko, Drug Discov. Today, 13(9–10), 440 (2008).

    Article  CAS  Google Scholar 

  61. N. Schultheiss and A. Newmanwill, Cryst. Growth Des., 9(6), 2950 (2009).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Allan S. Myerson.

Additional information

Allan S. Myerson is Professor of the Practice of Chemical Engineering in the Department of Chemical Engineering at the Massachusetts Institute of Technology. Professor Myerson was educated at Columbia University (BS) the University of Virginia (MS and PhD). Professor Myerson research focuses on separations processes in the chemical and pharmaceutical industry with an emphasis on crystallization from solution. Professor Myerson is a co-PI in the, Novartis-MIT Center for Continuous Manufacturing. He has published 5 books including the “Handbook of Industrial Crystallization” 158 papers and is the inventor on 32 US patents. Professor Myerson has consulted for approximately 100 companies worldwide and was honored in 2008 with the American Chemical Society Award in Separations Science and Technology.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sarma, B., Chen, J., Hsi, HY. et al. Solid forms of pharmaceuticals: Polymorphs, salts and cocrystals. Korean J. Chem. Eng. 28, 315–322 (2011). https://doi.org/10.1007/s11814-010-0520-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11814-010-0520-0

Key words

Navigation