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Pharmaceutical Research

, Volume 32, Issue 1, pp 300–310 | Cite as

Predicting Drug Substances Autoxidation

  • P. Lienard
  • J. Gavartin
  • G. Boccardi
  • M. Meunier
Research Paper

Abstract

Purpose

Chemical degradation and stability in formulation is a recurrent issue in pharmaceutical development of drugs. The objective of the present study was to develop an in silico risk assessment of active pharmaceutical ingredients (APIs) stability with respect to autoxidation.

Methods

The chemical degradation by autoxidation of a diverse series of APIs has been investigated with molecular modelling tools. A set of 45 organic compounds was used to test and validate the various computational settings. Aiming to devise a methodology that could reliably perform a risk assessment for potential sensibility to autoxidation, different types of APIs, known for their autoxidation history were inspected. To define the level of approximation needed, various density functional theory (DFT) functionals and settings were employed and their accuracy and speed were compared.

Results

The Local Density Approximation (LDA) gave the fastest results but with a substantial deviation (systematic over-estimation) to known experimental values. The Perdew-Burke-Ernzerhof (PBE) settings appeared to be a good compromise between speed and accuracy.

Conclusions

The present methodology can now be confidently deployed in pharmaceutical development for systematic risk assessment of drug stability.

KEY WORDS

Degradation Autoxidation Computational chemistry Pharmaceutical DFT 

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

We wish to express our deep acknowledgement to several individuals for assistance encouragement and advice: Jean-René Authelin, Antonio Guerreiro, Jérome Kieffer, Nicolas Marchand and Guy Rossey for project initiation and scientific inputs.

References

  1. 1.
    Gardner CR, Walsh TC, Almarsson O. Drugs as materials: valuing physical form in drug discovery. Nat Rev Drug Discov. 2004;3:926–34.PubMedCrossRefGoogle Scholar
  2. 2.
    Palucki M, Higgins JD, Kwong E, Templeton AC. Strategies at the interface of drug discovery and development: early optimization of the solid state phase and preclinical toxicology formulation for potential drug candidates. J Med Chem. 2010;53(16):5897–905.PubMedCrossRefGoogle Scholar
  3. 3.
    Gorman EM, Padden BE, Munson EJ. Stability: Physical and Chemical. 2008; Wiley & Sons Inc. in Gad SC “Preclinical Development handbook: ADME and biopharmaceutical properties” Chapter 16, 545–570Google Scholar
  4. 4.
    Florence AT, Attwood D. Physicochemical principles of pharmacy. 5th ed. London: Pharmaceutical Press; 2011.Google Scholar
  5. 5.
    Bundgaard H, Larsen C. Piperazinedione formation from reaction of ampicillin with carbohydrates and alcohols in aqueous solutions. Int J Pharm. 1979;3:1–11.CrossRefGoogle Scholar
  6. 6.
    Baertschi SW, Pharmaceutical stress testing: predicting drug degradation. Taylor and Françis informa vol 153 Healthcare; 2005Google Scholar
  7. 7.
    Guidance for Industry Q1A(R2) Stability testing of new drug substances and products U.S. Department of health and human services food and drug administration, November 2003Google Scholar
  8. 8.
    Kieffer J, Bremond E, Lienard L, Boccardi G. In silico assessment of drug substances chemical stability. J Mol Struct THEOCHEM. 2010;954:75–9.CrossRefGoogle Scholar
  9. 9.
    Parr RG, Yang W. Density-functional theory of atoms and molecules. New York: Oxford University Press; 1989.Google Scholar
  10. 10.
    Boccardi G, Deleuze C, Gachon M, Palmisano G, Vergnaud JP. Autoxidation of tetrazepam in tablets: prediction of the degradation impurities from the oxidative behaviour in solution. J Pharm Sci. 1992;81:183–5.PubMedCrossRefGoogle Scholar
  11. 11.
    P. Harmon and G. Boccardi, Oxidative susceptibility testing, in: S. W. Baertschi, K. M. Alsante, R.R. Red, ed., Pharmaceutical stress testing - predicting drug degradation, Informa, 2011.Google Scholar
  12. 12.
    Blanksby SJ, Ellison GB. Bond dissociation energies of organic molecules. Acc Chem Res. 2002;36:255–63.CrossRefGoogle Scholar
  13. 13.
    Sharp TR. Calculated carbon–hydrogen bond dissociation enthalpies for predicting oxidative susceptibility of drug substance molecules. Int J Pharm. 2011;418:304–17.PubMedCrossRefGoogle Scholar
  14. 14.
    Rocha GB, Freire RO, Simas AM, Stewart JJP. RM1: A reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br, and I. J Comput Chem. 2006;27:1101–11. doi: 10.1002/jcc.20425.PubMedCrossRefGoogle Scholar
  15. 15.
    Michael J. S. Dewar,* Eve G. Zoebisch, Eamonn F. Healy, and James J. P. Stewart AM1: A new general purpose quantum mechanical molecular model’ J. Am.Chem.Soc 107, 3902-3909Google Scholar
  16. 16.
    Gryn’ova G, Hodgson JL, Coote M. Revising the mechanism of polymer autooxidation. Org Biomol Chem. 2011;9:480–90.PubMedCrossRefGoogle Scholar
  17. 17.
    Benson SW. Effects of resonance and structure on the thermochemistry of organic peroxy radicals and the kinetics of combustion reactions. J Am Chem Soc. 1965;87:972–9.CrossRefGoogle Scholar
  18. 18.
    Bolland JL, Gee G. Trans Faraday Soc. 1946;42:244.CrossRefGoogle Scholar
  19. 19.
    Reid DL, Calvitt JC, Zell MT, Miller KG, Kingsmill CA. Early prediction of pharmaceutical oxidation pathways by computational chemistry and forced degradation. Pharm Res. 2004;21(9):1708–17.PubMedCrossRefGoogle Scholar
  20. 20.
    Jonsson M, Wayner DDM, Armstrong DA, Yu D, Rauk A. On the thermodynamics of peptide oxidation: anhydrides of glycine and alanine. J Chem Soc Perkin Trans. 1998;2:1967–72.CrossRefGoogle Scholar
  21. 21.
    Leopoldini M, Marino T, Russo N, Toscano M. Antioxidant properties of phenolic compounds: H-Atom versus electron transfer mechanism. J Phys Chem A. 2004;108:4916–22.CrossRefGoogle Scholar
  22. 22.
    Alves CN, Borges RS, Da Silva ABF. Density functional theory study of metabolic derivatives of the oxidation of paracetamol. Int J Quantum Chem. 2006;106:2617–23.CrossRefGoogle Scholar
  23. 23.
    Hohenberg P, Kohn W. Inhomogeneous electron gas. Phys Rev B. 1964;136:864–71.CrossRefGoogle Scholar
  24. 24.
    Levy M. Universal variational functionals of electron densities, first-order density matrices, and natural spin-orbitals and solution of the v-representability problem. Proc Natl Acad Sci U S A. 1979;76:6062–5.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Delley B. From molecules to solids with the DMol3 approach. J Chem Phys. 2000;113:7756.CrossRefGoogle Scholar
  26. 26.
    Delley B. Time dependent density functional theory with DMol3. J Phys Condens Matter. 2010;22:384208.PubMedCrossRefGoogle Scholar
  27. 27.
    Accelrys Software, Inc. Accelrys 2013Google Scholar
  28. 28.
    Delley B. An all-electron numerical method for solving the local density functional for polyatomic molecules. J Chem Phys. 1990;92:508.CrossRefGoogle Scholar
  29. 29.
    Vosko SH, Wilk L, Nusair M. Accurate spin-dependent electron liquid correlation energies for local spin density calculations: a critical analysis. Can J Phys. 1980;58:1200–11.CrossRefGoogle Scholar
  30. 30.
    Perdew JP, Burke K, Ernzerhof MG. Generalized gradient approximation made simple. Phys Rev Lett. 1996;77:3865.PubMedCrossRefGoogle Scholar
  31. 31.
    Becke AD. Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys. 1993;98:5648–52.CrossRefGoogle Scholar
  32. 32.
    Lewin JL, Cramer CJ. Rapid quantum mechanical models for the computational estimation of C-H bond dissociation energies as a measure of metabolic stability mol. Pharm. 2004;1:128–35.Google Scholar
  33. 33.
    Blanksby SJ, Ellison GB. Bond dissociation of organic molecules. Acc Chem Res. 2003;36:255–63.PubMedCrossRefGoogle Scholar
  34. 34.
    Florey ed, Analytical profiles of drug substances Vol 14, New York Academic Press 1985, 59Google Scholar
  35. 35.
    Florey ed, Analytical profiles of drug substances Vol 20, New York Academic Press 1991, 405Google Scholar
  36. 36.
    Baertschi SW. Pharmaceutical stress testing: predicting drug degradation. Taylor and Françis informa. Healthc. 2005;153:100.Google Scholar
  37. 37.
    Florey ed, Analytical profiles of drug substances Vol 18, New York Academic Press 1989; 245Google Scholar
  38. 38.
    Albini A, Fasani E. Drugs: photochemistry and photostability. An overview and practical problems. Cambridge: The royal Society of Chemistry; 1998. p. 21.CrossRefGoogle Scholar
  39. 39.
    Sanofi private communicationGoogle Scholar
  40. 40.
    Florey ed, Analytical profiles of drug substances Vol 1, New York Academic Press 1972:93Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • P. Lienard
    • 1
  • J. Gavartin
    • 2
  • G. Boccardi
    • 3
    • 4
  • M. Meunier
    • 2
  1. 1.Pharmaceutical Science DepartmentSanofi R&DVitry-sur-Seine CedexFrance
  2. 2.AccelrysCambridgeUK
  3. 3.Analytical SciencesSanofi Research Centre of MilanMilanItaly
  4. 4.Institute for Chemical and Biochemical Research via G. Colombo 81MilanItaly

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