Skip to main content

Advertisement

SpringerLink
Log in

Concomitant Polymorphism in Confined Environment

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The aim of this paper is to demonstrate that multiple crystal forms can be generated on patterned self-assembled monolayers (SAMs) substrates in single experiments in a given solvent system.

Methods

Functionalized metallic islands are fabricated and utilized as individual templates for crystal formation. Taking advantage of the different wetting properties that patterned surfaces offered, arrays of small solution droplets on the nano- and pico- liter scale were produced on the substrates. Different droplet dimensions were deposited on the substrate. As the solvent evaporates from the droplets, crystals were formed within the constrained volume. Crystal habits were examined with optical microscopy while the solid form was identified with Raman microscopy.

Results

With mefenamic acid (MA) and sulfathiazole as model pharmaceutical compounds, two and four different polymorphs, respectively, were observed under identical conditions. Moreover, it is established that the polymorphic distribution is highly dependent on the solvent evaporation rate and the solution concentration. These results imply that multiple crystal forms competitively nucleate in solution, and the probability of each form nucleating is strongly dependent on the supersaturation of the solution. Additionally, solvent was observed to play a role in controlling the solid state outcome.

Conclusions

Multiple crystal forms can concomitantly nucleate on patterned substrates. This technique can particularly be attractive to screen for polymorphs as elusive, metastable solid forms are favored with the creation of high supersaturation and can be stabilized due to the minimal volumes generated.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. H. G. Brittain. Polymorphism in Pharmaceutical Solids. Marcel Dekker, New York, 1999

    Google Scholar 

  2. J. Bernstein. Polymorphism in Molecular Crystals. Oxford University Press, New York, 2002

    Google Scholar 

  3. A. Y. Lee, and A. S. Myerson. Particle engineering: Fundamentals of particle formation and crystal growth. MRS Bull. 31: 881–886 (2006)

    CAS  Google Scholar 

  4. D. Singhal, and W. Curatolo. Drug polymorphism and dosage form design: a practical perspective. Adv. Drug. Deliv. Rev. 56:335–347 (2004)

    Article  PubMed  CAS  Google Scholar 

  5. R. Hilfiker. Polymorphism in the Pharmaceutical Industry. John Wiley & Sons Inc., New York, 2006

    Google Scholar 

  6. (a) Org. Process Res. Des. 7(6):957–1027 (2003); (b) Cryst. Growth Des. 3(6):867–1042 (2003); (c) Cryst. Growth Des. 4(6):1085–1444 (2004); (d) Adv. Drug. Deliv. Rev. 56(3): 235–418 (2004)

  7. H. G. Brittain. Polymorphism and solvatomorphism 2004. In H. G. Brittain (ed.), Profiles of drug substances, excipients, and related methodology, Vol. 32, Elsevier Academic Press, Amsterdam, 2005, pp. 263–283

    Google Scholar 

  8. H. G. Brittain. Polymorphism and solvatomorphism 2005. J. Pharm. Sci. 96:705–728 (2007)

    Article  PubMed  CAS  Google Scholar 

  9. J. D. Dunitz, and J. Bernstein. Disappearing polymorphs. Acc. Chem. Res. 28:193–200 (1995)

    Article  CAS  Google Scholar 

  10. J. Bauer, S. Spanton, R. Henry, J. Quick, W. Dziki, W. Porter, and J. Morris. Ritonavir: an extraordinary example of conformational polymorphism. Pharm. Res. 18:859–866 (2001)

    Article  PubMed  CAS  Google Scholar 

  11. A. S. Raw, M. S. Funess, D. S. Gill, R. C. Adams, F. O. Jr. Holcombe, and L. X. Yu. Regulatory considerations of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs). Adv. Drug. Deliv. Rev. 56:397–414 (2004)

    Article  PubMed  CAS  Google Scholar 

  12. W. Cabri, P. Ghett, G. Pozzi, and M. Alpegiani. Polymorphisms and patent, market, and legal battles: Cefdinir case study. Org. Process. Res. Dev. 11:64–72 (2007)

    Article  CAS  Google Scholar 

  13. G. J. Quallich. Selection of the drug form in exploratory development. In A. F. Abdel-Magid and S. Caron (eds.), Fundamentals of Early Clinical Drug Development: From Synthesis Design to Formulation, John Wiley & Sons, Inc., New York, 2006, pp. 215–246

    Chapter  Google Scholar 

  14. T. Mukuta, A. Y. Lee, T. Kawakami, and A. S. Myerson. Influence of impurities on the solution-mediated phase transformation of an active pharmaceutical ingredient. Cryst. Growth Des. 5:1429–1436 (2005)

    Article  CAS  Google Scholar 

  15. J. Bernstein, R. J. Davey, and J. O. Henck. Concomitant polymorphs. Angew. Chem. Int. Ed. 38:3440–3461 (1999)

    Article  Google Scholar 

  16. A. Y. Lee, I. S. Lee, S. S. Dette, J. Boerner, and A. S. Myerson. Crystallization on confined engineered surfaces: A method to control crystal size and generate different polymorphs. J. Am. Chem. Soc. 127:14982–14983 (2005)

    Article  PubMed  CAS  Google Scholar 

  17. A. Y. Lee, I. S. Lee, and A. S. Myerson. Factors affecting the polymorphic outcome of glycine crystals constrained on patterned substrates. Chem. Eng. Technol. 29:281–285 (2006)

    Article  CAS  Google Scholar 

  18. C. S. Towler, R. J. Davey, R. W. Lancaster, and C. J. Price. Impact of molecular speciation on crystal nucleation in polymorphic systems: The conundrum of γ glycine and molecular ‘self poisoning.’ J. Am. Chem. Soc. 126:13347–13353 (2004)

    Article  PubMed  CAS  Google Scholar 

  19. A. Adam, L. Schrimpl, and P. C. Schmidt. Some physicochemical properties of mefenamic acid. Drug. Dev. Ind. Pharm. 26:477–487 (2000)

    Article  PubMed  CAS  Google Scholar 

  20. R. Panchagnula, R. Sundaramurthy, O. Pillai, and S. Agrawal. Solid-state characterization of mefenamic acid. J. Pharm. Sci. 93:1019–1029 (2004)

    Article  PubMed  CAS  Google Scholar 

  21. A. J. Aguair, and J. E. Zelmer. Dissolution behavior of polymorphs of chloramphenicol palmitate and mefenamic acid. J. Pharm. Sci. 58:983–987 (1969)

    Article  Google Scholar 

  22. T. Umeda, N. Ohnishi, T. Yokoyama, T. Kuroda, Y. Kita, K. Kuroda, E. Tatsumi, and Y. Matsuda. Studies on the drug non-equivalence. XIV. A kinetic study on the isothermal transition of polymorphic forms of tolbutamide and mefenamic acid in the solid state at high temperatures. Chem. Pharm. Bull. 33:2073–2078 (1985)

    PubMed  CAS  Google Scholar 

  23. E. H. Lee, S. R. Byrn, and T. M. Carvajal. Additive-induced metastable single crystal of mefenamic acid. Pharm. Res. 23:2375–2380 (2006)

    Article  PubMed  CAS  Google Scholar 

  24. J. F. McConnell, and F. Z. Company. N-(2,3-Xylyl)anthranilic acid, C15H15NO2. Mefenamic acid. Cryst. Struct. Commun. 5:861–864 (1976)

    CAS  Google Scholar 

  25. S. Romero, B. Escalera, and P. Bustamante. Solubility behavior of polymorph I and II of mefenamic acid in solvent mixtures. Int. J. Pharm. 178:193–202 (1999)

    Article  PubMed  CAS  Google Scholar 

  26. K. H. Park, J. M. B. Evans, and A. S. Myerson. Determination of solubility of polymorphs using differential scanning calorimetry. Cryst. Growth Des. 3:991–995 (2003)

    Article  CAS  Google Scholar 

  27. M. Otsuka, F. Kato, and Y. Matsuda. Effect of temperature and kneading solution on polymorphic transformation of mefenamic acid during granulation. Solid State Ionics 172:451–453 (2004)

    Article  CAS  Google Scholar 

  28. S. Hamad, C. Moon, C. R. A. Catlow, A. T. Hulme, and S. L. Price. Kinetic insights into the role of the solvent in the polymorphism of 5-fluorouracil from molecular dynamics simulations. J. Phys. Chem. B. 110:3323–3329 (2006)

    Article  PubMed  CAS  Google Scholar 

  29. J. Anwar, S. E. Tarling, and P. Barnes. Polymorphism of sulfathiazole. J. Pharm. Sci. 78:337–342 (1989)

    Article  PubMed  CAS  Google Scholar 

  30. D. C. Apperley, R. A. Fletton, R. K. Harris, R. W. Lancaster, S. Tavener, and T. L. Threlfall. Sulfathiazole polymorphism studied by magic-angle spinning NMR. J. Pharm. Sci. 88:1275–1280 (1999)

    Article  PubMed  CAS  Google Scholar 

  31. F. C. Chan, J. Anwar, R. Cernik, P. Barnes, and R. M. Wilson. Ab initio structure determination of sulfathiazole polymorph V from synchrotron X-ray powder diffraction data. J. Appl. Crystallogr. 32:436–441 (1999)

    Article  CAS  Google Scholar 

  32. A. L. Binghan, D. S. Hughes, M. B. Hursthouse, R. W. Lancaster, S. Tavener, and T. L. Threlfall. Over one hundred solvates of sulfathiazole. Chem. Commun. 603–604 (2001)

  33. N. Blagden, R. J. Davey, H. F. Lieberman, L. Williamsn, R. Payne, R. Roberts, R. Rowe, and R. Docherty. J. Chem. Soc., Faraday Trans. 94:1035–1044 (1998)

    Article  CAS  Google Scholar 

  34. S. Khoshkhoo, and J. Anwar. Crystallization of polymorphs: the effect of solvent. J. Phys. D: Appl. Phys. 26:B90–B93 (1993)

    Article  CAS  Google Scholar 

  35. N. Blagden. Crystal engineering of polymorph appearance: the case of sulphathiazole. Powder Technol. 121:46–52 (2001)

    Article  CAS  Google Scholar 

  36. R. Hiremath, J. A. Basile, S. W. Varnety, and J. A. Swift. Controlling molecular crystal polymorphism with self-assembled monolayer templates. J. Am. Chem. Soc. 127:18321–18327 (2005)

    Article  PubMed  CAS  Google Scholar 

  37. T. Threfall. Crystallization of polymorphs: Thermodynamic insight into the role of solvent. Org. Process Res. Dev. 4:384–390 (2000)

    Article  Google Scholar 

  38. B. Sjoestroem, B. Bergenstaahl, M. Lindberg, and A. C. Rasmuson. The formation of submicron organic particles by precipitation in an emulsion. J. Disp. Sci. Tech. 15:89–117 (1994)

    Article  CAS  Google Scholar 

  39. J. L. Hilden, C. E. Reyes, M. J. Kelm, J. S. Tan, J. G. Stowell, and K. R. Morris. Capillary precipitation of a highly polymorphic organic compound. Cryst. Growth Des. 3:921–926 (2003)

    Article  CAS  Google Scholar 

  40. J. M. Ha, J. H. Wolf, M. A.. Hillmyer, and M. D. Ward. Polymorph selectivity under nanoscopic confinement. J. Am. Chem. Soc. 126:3382–3383 (2004)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Financial support from the U.S. Army Medical Research and Material Command (W81XWH0410864) is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Chemical & Biological Engineering, Illinois Institute of Technology, Chicago, Illinois, 60616, USA

    In Sung Lee & Allan S. Myerson

  2. Strategic Technologies, Chemical Development, GlaxoSmithKline plc., P.O. Box 1539, King of Prussia, Pennsylvania, 19406, USA

    Alfred Y. Lee

Authors
  1. In Sung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alfred Y. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Allan S. Myerson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Allan S. Myerson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, I.S., Lee, A.Y. & Myerson, A.S. Concomitant Polymorphism in Confined Environment. Pharm Res 25, 960–968 (2008). https://doi.org/10.1007/s11095-007-9424-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-007-9424-z

Key words

Search

Navigation