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Excipient Applications in Formulation Design and Drug Delivery pp 37–65Cite as

Reactive Impurities in Excipients

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Abstract

Reactive impurities in pharmaceutical excipients can affect drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development can ensure robust drug product development. This chapter identifies the type and concentration of potentially reactive impurities in commonly used excipients. The excipient impurities are categorized into six major classes: reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources/generation of these impurities, analytical methods for their detection and quantitation, stability of these impurities upon storage and processing, and their potential reactions with drug candidates are discussed. Specific examples of drug–excipient impurity interaction are presented as illustrative case studies. Mitigation strategies and corrective measures are also discussed.

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Abbreviations

AIBN:

Azobisisobutyronitrile

API:

Active pharmaceutical ingredient

BHA:

Butylated hydroxyanisole

BHT:

Butylated hydroxytoluene

cPVP:

Crospovidone

CTA:

Chromotropic acid

DNPH:

2, 4-dinitrophenylhydrazine

EDTA:

Ethylenediamine tetraacetic acid

EU:

European Pharmacopeia

FOX:

Ferrous oxidation-xylenol orange

GC:

Gas chromatography

HCTZ:

Hydrochlorothiazide

HMF:

5-hydroxymethyl-2-furfuraldehyde

HPLC:

High performance liquid chromatography

ICP-AES:

Inductively coupled plasma: atomic emission spectroscopy

HPO:

Hydroperoxide

MCC:

Microcrystalline cellulose

MS:

Mass spectrometry

NaCMC:

Sodium carboxymethyl cellulose

NFV:

N-formylvarenicline

NMV:

N-methylvarenicline

NOC:

N-nitroso compounds

PFBHA:

O-2,3,4,5,6-(penta fluorobenzyl) hydroxylamine hydrochloride

PEG:

Polyethylene glycol

ppm:

Parts per million

PVA:

Polyvinyl alcohol

PVP:

Poly(vinyl pyrrolidone)

RH:

Relative humidity

TPP:

Triphenylphosphine

TPPO:

Triphenylphosphine oxide

USP:

United States Pharmacopeia

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Acknowledgements

The authors would like to thank Helen Fu, Seema Betigeri, Nancy Lewen and Sandy Lee for their contributions in determining trace reactive impurities in excipient samples. The majority of this chapter and illustrations are reprinted from AAPS PharmSciTech, Vol. 12 (© 2011) pp. 1248–1263, with permission from Springer.

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  1. Drug Product Science and Technology, Bristol-Myers Squibb, Co., One Squibb Dr., 08903-0191, New Brunswick, NJ, USA

    Yongmei Wu, Jaquan K. Levons, Ajit S. Narang, Krishnaswamy Raghavan & Rao V. Mantri Ph.D.

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  1. Yongmei Wu
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  2. Jaquan K. Levons
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Correspondence to Rao V. Mantri Ph.D. .

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Editors and Affiliations

  1. Bristol-Myers Squibb, Co., New Brunswick, New Jersey, USA

    Ajit S Narang

  2. Division of Industrial Pharmacy, Department of Pharmacy Practice, The University of Toledo, TOLEDO, Ohio, USA

    Sai H S. Boddu

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Wu, Y., Levons, J., Narang, A., Raghavan, K., Mantri, R. (2015). Reactive Impurities in Excipients. 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_3

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