Abstract
Unintended physicochemical interaction of an excipient with a drug substance in a dosage form can result in the complexation or binding of the drug, resulting in slow and/or incomplete drug release in a dissolution medium. It is important to assess the risk whether such interactions would reduce oral bioavailability of a drug from its dosage form. This chapter describes the development of a methodology to assess the biorelevance of the drug release impact of drug-excipient binding interactions using a model compound, brivanib alaninate. This methodology was developed using a combination of modeling and simulation tools as well as experimental data generated in vitro and in vivo. In addition, general application of this principle and methodology to other drug substances and binding affinities of drugs with excipients as a function of dose is described.
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Abbreviations
- AUC0−t :
-
Area under the plasma concentration-time curve from dosing till time of last sampling (72 h)
- BA:
-
Brivanib alaninate
- CCS:
-
Croscarmellose sodium
- Cmax :
-
Maximum concentration reached in plasma
- HPLC:
-
High performance liquid chromatography
- HPMC:
-
Hydroxypropyl methyl cellulose
- ITC:
-
Isothermal titration calorimetry
- NMR:
-
Nuclear magnetic resonance
- SSG:
-
Sodium starch glycollate
- t½ :
-
Plasma half life
- Tmax :
-
The time of maximum plasma concentration
- USNF:
-
United States National Formulary
- Vd:
-
Volume of distribution
- xPVP:
-
Crospovidone
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Acknowledgements
We thank our biostatistics colleague, James Bergum, for help with statistical analyses of data. The majority of this chapter and illustrations are reprinted from Journal of Pharmacy and Pharmacology, Vol 64 (© 2012) pp 553–565, with permission from John Wiley and Sons.
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Narang, A. et al. (2015). Drug Excipient Interactions. In: Narang, A., Boddu, S. (eds) Excipient Applications in Formulation Design and Drug Delivery. Springer, Cham. https://doi.org/10.1007/978-3-319-20206-8_2
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DOI: https://doi.org/10.1007/978-3-319-20206-8_2
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