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.
Similar content being viewed by others
References
Gardner CR, Walsh TC, Almarsson O. Drugs as materials: valuing physical form in drug discovery. Nat Rev Drug Discov. 2004;3:926–34.
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.
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, 545–570
Florence AT, Attwood D. Physicochemical principles of pharmacy. 5th ed. London: Pharmaceutical Press; 2011.
Bundgaard H, Larsen C. Piperazinedione formation from reaction of ampicillin with carbohydrates and alcohols in aqueous solutions. Int J Pharm. 1979;3:1–11.
Baertschi SW, Pharmaceutical stress testing: predicting drug degradation. Taylor and Françis informa vol 153 Healthcare; 2005
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 2003
Kieffer J, Bremond E, Lienard L, Boccardi G. In silico assessment of drug substances chemical stability. J Mol Struct THEOCHEM. 2010;954:75–9.
Parr RG, Yang W. Density-functional theory of atoms and molecules. New York: Oxford University Press; 1989.
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.
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.
Blanksby SJ, Ellison GB. Bond dissociation energies of organic molecules. Acc Chem Res. 2002;36:255–63.
Sharp TR. Calculated carbon–hydrogen bond dissociation enthalpies for predicting oxidative susceptibility of drug substance molecules. Int J Pharm. 2011;418:304–17.
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.
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, 3902-3909
Gryn’ova G, Hodgson JL, Coote M. Revising the mechanism of polymer autooxidation. Org Biomol Chem. 2011;9:480–90.
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.
Bolland JL, Gee G. Trans Faraday Soc. 1946;42:244.
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.
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.
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.
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.
Hohenberg P, Kohn W. Inhomogeneous electron gas. Phys Rev B. 1964;136:864–71.
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.
Delley B. From molecules to solids with the DMol3 approach. J Chem Phys. 2000;113:7756.
Delley B. Time dependent density functional theory with DMol3. J Phys Condens Matter. 2010;22:384208.
Accelrys Software, Inc. Accelrys 2013
Delley B. An all-electron numerical method for solving the local density functional for polyatomic molecules. J Chem Phys. 1990;92:508.
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.
Perdew JP, Burke K, Ernzerhof MG. Generalized gradient approximation made simple. Phys Rev Lett. 1996;77:3865.
Becke AD. Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys. 1993;98:5648–52.
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.
Blanksby SJ, Ellison GB. Bond dissociation of organic molecules. Acc Chem Res. 2003;36:255–63.
Florey ed, Analytical profiles of drug substances Vol 14, New York Academic Press 1985, 59
Florey ed, Analytical profiles of drug substances Vol 20, New York Academic Press 1991, 405
Baertschi SW. Pharmaceutical stress testing: predicting drug degradation. Taylor and Françis informa. Healthc. 2005;153:100.
Florey ed, Analytical profiles of drug substances Vol 18, New York Academic Press 1989; 245
Albini A, Fasani E. Drugs: photochemistry and photostability. An overview and practical problems. Cambridge: The royal Society of Chemistry; 1998. p. 21.
Sanofi private communication
Florey ed, Analytical profiles of drug substances Vol 1, New York Academic Press 1972:93
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lienard, P., Gavartin, J., Boccardi, G. et al. Predicting Drug Substances Autoxidation. Pharm Res 32, 300–310 (2015). https://doi.org/10.1007/s11095-014-1463-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-014-1463-7