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Effects of Moisture and Residual Solvent on the Phase Stability of Orthorhombic Paracetamol

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Abstract

Purpose

At high relative humidity (RH), orthorhombic paracetamol (form II) crystallized from ethanol transforms to monoclinic (form I) faster than such crystallized from the melt. The present study attempts to elucidate the reasons for this difference in stability.

Methods

The transformation of form II was investigated by powder X-ray diffraction, optical microscopy, gravimetric moisture sorption, thermogravimetry, and vibrational spectroscopy.

Results

Solution-grown form II was found to be always contaminated with form I nuclei but still transforms much faster than corresponding physical mixtures of the pure forms in high RH, at a rate that is depending on the RH and the size of the crystals. A 0.1–0.6% w/w mass loss, inversely related to the initial monoclinic content, was observed during transformation of solution-grown form II, and was found to be due to residual ethanol that could not be removed by grinding, indicating incorporation by a solid solution mechanism.

Conclusions

Moisture triggers the growth of existing form I nuclei but it exerts a weaker effect on nucleation, and the presence of residual ethanol greatly accelerates the transformation.

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References

  1. M. Haisa, S. Kashino, R. Kawai, and H. Maeda. The monoclinic form of p-hydroxyacetanilide. Acta Cryst. B32:1283–1285 (1976).

    CAS  Google Scholar 

  2. M. Haisa, S. Kashino, and H. Maeda. The orthorhombic form of p-hydroxyacetanilide. Acta Cryst. B30:2510–2512 (1974).

    Google Scholar 

  3. M. Peterson, Sh. Morissette, C. McNulty, A. Goldsweig, P. Shaw, M. LeQuesne, J. Monagle, N. Encina, J. Marchionna, A. Johnson, J. Gonzalez-Zugasti, A. Lemmo, S. Ellis, M. Cima, and Ö. Almarsson. Iterative high-throughput polymorphism studies on acetaminophen and an experimentally derived structure for form III. J. Am. Chem. Soc. 124:10958–10959 (2002).

    Article  PubMed  CAS  Google Scholar 

  4. I. Oswald, D. Allan, P. McGregor, S. Motherwell, S. Parsons, and C. Pulham. The formation of paracetamol (acetaminophen) adducts with hydrogen-bond acceptors. Acta Cryst. B58:1057–1066 (2002).

    CAS  Google Scholar 

  5. P. McGregor, D. Allan, S. Parsons, and C. Pulham. Preparation and crystal structure of a trihydrate of paracetamol. J. Pharm. Sci. 91:1308–1311 (2002).

    Article  PubMed  CAS  Google Scholar 

  6. A. Parkin, S. Parsons, and C. Pulham. Paracetamol monohydrate at 150 K. Acta Cryst. B58:o1345–o1347 (2002).

    Google Scholar 

  7. P. Di Martino, A. M. Guyot Hermann, P. Conflant, M. Drache, and J. C. Guyot. A new pure paracetamol for direct compression: the orthorhombic form. Int. J. Pharm. 128:1–8 (1996).

    Article  Google Scholar 

  8. A. Burger, and R. Ramberger. On the polymorphism of pharmaceuticals and other molecular crystals. II. Mikrochim. Acta II:273–316 (1979).

    Google Scholar 

  9. L. Yu. Inferring thermodynamic stability relationship of polymorphs from melting data. J. Pharm. Sci. 84:966–974 (1995).

    Article  PubMed  CAS  Google Scholar 

  10. M. Sacchetti. Thermodynamic analysis of DSC data for acetaminophen polymorphs. J. Thermal Anal. 63:345–350 (2001).

    Article  CAS  Google Scholar 

  11. E. Boldyreva, V. Drebushchak, I. Paukov, Y. Kovalevskaya, and T. Drebushchak. DSC and adiabatic calorimetry study of the polymorphs of paracetamol. An old problem revisited. J. Thermal. Anal. 77:607–623 (2004).

    Article  CAS  Google Scholar 

  12. J. Ledru, C. Imrie, C. Pulham, R. Céolin, and J. Hutchinson. High pressure differential scanning calorimetry investigations on the pressure dependence of the melting of paracetamol polymorphs I and II. J. Pharm. Sci. 96:2784–2794 (2007).

    Article  PubMed  CAS  Google Scholar 

  13. G. Perlovich, T. Volkova, and A. Bauer-Brandl. Polymorphism of paracetamol. Relative stability of the monoclinic and orthorhombic phase revisited by sublimation and solution calorimetry. J. Thermal. Anal. 89:767–774 (2007).

    Article  CAS  Google Scholar 

  14. G. Nichols, and C.S. Frampton. Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution. J. Pharm. Sci. 87:684–693 (1998).

    Article  PubMed  CAS  Google Scholar 

  15. M. Lang, A. Grzesiak, and J. Matzger. The use of polymer heteronuclei for crystalline polymorph selection. J. Am. Chem. Soc. 124:14834–14835 (2002).

    Article  PubMed  CAS  Google Scholar 

  16. F. Fabbiani, D. Allan, W. David, S. Moggach, S. Parsons, and C. Pulham. High-pressure recrystallisation—a route to new polymorphs and solvates. Cryst. Eng. Comm. 6:504–511 (2004).

    CAS  Google Scholar 

  17. M. Mikhailenko. Growth of large single crystals of the orthorhombic paracetamol. J. Cryst. Growth. 265:616–618 (2004).

    Article  CAS  Google Scholar 

  18. N. Al Zoubi, I. Nikolakakis, and S. Malamataris. Crystallisation conditions and formation of orthorhombic paracetamol from ethanolic solution. J. Pharm. Pharmacol. 54:325–333 (2002).

    Article  PubMed  CAS  Google Scholar 

  19. N. Al Zoubi, K. Kachrimanis, and S. Malamataris. Effects of harvesting and cooling on crystallisation and transformation of orthorhombic paracetamol in ethanolic solution. Eur. J. Pharm. Sci. 17:13–21 (2002).

    Article  PubMed  CAS  Google Scholar 

  20. N. Al Zoubi, and S. Malamataris. Effects of initial concentration and seeding procedure on crystallisation of orthorhombic paracetamol from ethanolic solution. Int. J. Pharm. 260:123–135 (2003).

    Article  PubMed  CAS  Google Scholar 

  21. K. Kachrimanis, D. Braun, and U. J. Griesser. Quantitative analysis of paracetamol polymorphs in powder mixtures by FT-Raman spectroscopy and PLS regression. J. Pharm. Biomed. Anal. 43:407–412 (2006).

    Article  PubMed  CAS  Google Scholar 

  22. A. Calka, and A. Radlinski. The local value of the Avrami exponent: a new approach to devitrification of glassy metallic ribbons. Mater. Sci. Eng. 97:241–246 (1988).

    Article  CAS  Google Scholar 

  23. J. W. Christian. The theory of transformations in metals and alloys, Part I. 2Pergamon Press, Oxford, 1975.

    Google Scholar 

  24. W. Ostwald. Studien über die Bildung und Umwandlung fester Körper. Z. Phys. Chem. 22:289–330 (1897).

    CAS  Google Scholar 

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

    Article  Google Scholar 

  26. G. Zhang, and D. Grant. Incorporation mechanism of guest molecules in crystals: solid solution or inclusion? Int. J. Pharm. 181:61–70 (1999).

    Article  PubMed  CAS  Google Scholar 

  27. G. Zhang, and D. Grant. Formation of liquid inclusions in adipic acid crystals during recrystallization from aqueous solutions. Cryst. Growth Des. 5:319–324 (2005).

    Article  CAS  Google Scholar 

  28. F. Herbstein. On the mechanism of some first-order enantiotropic solid-state phase transitions: from Simon through Ubbelohde to Mnyukh. Acta Cryst. B62:341–383 (2006).

    CAS  Google Scholar 

  29. Y. Mnyukh. Polymorphic transitions in crystals: nucleation. J. Cryst. Growth 32:371–377 (1976).

    Article  CAS  Google Scholar 

  30. Y. Mnyukh, N. Paflinova, N. Petropavlov, and N. Uchvatova. Polymorphic transitions in molecular crystals—III. Transitions exhibiting unusual behaviour. J. Phys. Chem. Solids 36:127–144 (1975).

    Article  CAS  Google Scholar 

  31. ICH Q3C (R3) Impurities: Guideline for residual solvents. International Conference on Harmonization (2005).

  32. C. Witschi, and E. Dolker. Residual solvent in pharmaceutical products: acceptable limits, influences in physicochemical properties, analytical methods and documented values. Eur. J. Pharm. Biopharm. 43:215–242 (1997).

    Article  CAS  Google Scholar 

  33. A. Cruz Cabeza, G. Day, W. Motherwell, and W. Jones. Solvent inclusion in form II carbamazepine. Chem. Comm. 16:1600–1602 (2007).

    Article  PubMed  CAS  Google Scholar 

  34. F. Fabbiani, L. Byrne, J. McKinnon, and M. Spackman. Solvent inclusion in the structural voids of form II carbamazepine: single-crystal X-ray diffraction, NMR spectroscopy and Hirshfeld surface analysis. Cryst. Eng. Comm. 9:728–731 (2007).

    CAS  Google Scholar 

  35. U. J. Griesser. The importance of solvates. In R. Hilfiker (ed.), Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim, Germany, 2006, pp. 211–234.

    Google Scholar 

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Acknowledgements

The authors thank Dr. M. Szelagiewicz of Solvias AG, for the assistance in the TG-FTIR measurements, Katharina Winkler for preliminary studies on the moisture induced phase transitions in a diploma thesis at the University of Innsbruck and Prof. Bill David (ISIS Facility, Rutherford Appleton Laboratory, Chilton, UK) for helpful discussions.

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, School of Pharmacy, University of Thessaloniki, Thessaloniki, 54124, Greece

    Kyriakos Kachrimanis

  2. Institute of Pharmacy, University of Innsbruck, Innrain 52, 6020, Innsbruck, Austria

    Katharina Fucke, Michael Noisternig & Ulrich J. Griesser

  3. Solvias AG, Klybeckstrasse 191, 4002, Basel, Switzerland

    Bernd Siebenhaar

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  1. Kyriakos Kachrimanis
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  2. Katharina Fucke
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  3. Michael Noisternig
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  4. Bernd Siebenhaar
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  5. Ulrich J. Griesser
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Correspondence to Kyriakos Kachrimanis.

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Kachrimanis, K., Fucke, K., Noisternig, M. et al. Effects of Moisture and Residual Solvent on the Phase Stability of Orthorhombic Paracetamol. Pharm Res 25, 1440–1449 (2008). https://doi.org/10.1007/s11095-007-9529-4

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  • DOI: https://doi.org/10.1007/s11095-007-9529-4

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