Abstract
Reactive impurities in excipients are often the attributed cause of drug product instability. Development of an excipient and drug product control strategy requires detailed understanding, identification, and quantitation of the rate and extent of formation of reactive impurities in excipients. This chapter highlights some of the methodologies that can be utilized to generate such an understanding using poly(ethylene glycol) as a model excipient. A 2,4-Dinitrophenylhydrazine (DNPH) pre-column derivatization HPLC-UV method was developed to quantify levels of formaldehyde and acetaldehyde in PEG solutions. Formic acid and acetic acid were quantified by HPLC-UV. Effects of excipient source, water content, pH, trace levels of hydrogen peroxide or iron metal, and antioxidants on the formation of reactive impurities was quantitated. Formic acid was the major degradation product in nearly all cases. The presence of water increased the rate of formation of all impurities, as did the presence of hydrogen peroxide and trace metals. Acidic pH increased the formation of acetaldehyde and acetic acid. Antioxidants BHA, BHT, propyl gallate vitamin E TPGS and sodium metabisulfite were effective, while ascorbic acid and acetic acid were not. This work highlights the general methodology that can be used to study reactive impurities in excipients.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- BHA:
-
Butylated hydroxyanisole
- BHT:
-
Butylated hydroxytoluene
- DNPH:
-
2,4-Dinitrophenylhydrazine
- HPLC:
-
High performance liquid chromatography
- PEG:
-
Poly(ethylene glycol)
- Vitamin E-TPGS:
-
d-alpha tocopheryl polyethylene glycol 1000 succinate
- UV:
-
Ultra violet
References
Bergh M, Magnusson K, Nilsson JLG, Karlberg AT (1998) Formation of formaldehyde and peroxides by air oxidation of high purity polyoxyethylene surfactants. Contact Dermat 39(1):14–20
Bindra DS, Williams TD, Stella VJ (1994) Degradation of O6-benzylguanine in aqueous polyethylene glycol 400 (PEG 400) solutions: concerns with formaldehyde in PEG 400. Pharm Res 11(7):1060–1064
del Barrio M-A, Hu J, Zhou P, Cauchon N (2006) Simultaneous determination of formic acid and formaldehyde in pharmaceutical excipients using headspace GC/MS. J Pharm Biomed Anal 41(3):738–743
Fukuyama S, Kihara N, Nakashima K, Morokoshi N, Koda S, Yasuda T (1994) Mechanism of optical isomerization of (S)-N-[1-(2-fluorophenyl)-3, 4, 6, 7-tetrahydro-4-oxopyrrolo [3, 2, 1-jk][l, 4]-benzodiazepine-3-y1]-1H-indole-2-carboxamide (FK480) in soft capsules containing polyethylene glycol 400 and glycerol. Pharm Res 11(12):1704–1706
Huang G, Wu Y, Dali M (2006) Determination of reducing sugar and formaldehyde impurities in pharmaceutical excipients by HPLC with precolumn derivatization. In: HPLC Conference, poster presentation, San Francisco, CA, USA, 2006
Li Z, Kozlowski BM, Chang EP (2007) Analysis of aldehydes in excipients used in liquid/semi-solid formulations by gas chromatography-negative chemical ionization mass spectrometry. J Chromatogr A 1160(1):299–305
McGinity JW, Hill JA, La Via AL (1975) Influence of peroxide impurities in polyethylene glycols on drug stability. J Pharm Sci 64(2):356–357
Sakharov A, Mazaletskaya L, Skibida I (2001) Catalytic oxidative deformylation of polyethylene glycols with the participation of molecular oxygen. Kinet Catal 42(5):662–668
Tallon M, Malawer E, Machnicki N, Brush P, Wu C, Cullen J (2008) The effect of crosslinker structure upon the rate of hydroperoxide formation in dried, crosslinked poly (vinylpyrrolidone). J Appl Polym Sci 107(5):2776–2785
Wasylaschuk WR, Harmon PA, Wagner G, Harman AB, Templeton AC, Xu H, Reed RA (2007) Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci 96(1):106–116
Waterman KC, Adami RC, Alsante KM, Hong J, Landis MS, Lombardo F, Roberts CJ (2002) Stabilization of pharmaceuticals to oxidative degradation. Pharm Dev Technol 7(1):1–32
Waterman KC, Arikpo WB, Fergione MB, Graul TW, Johnson BA, MacDonald BC, Roy MC, Timpano RJ (2008) N‐methylation and N‐formylation of a secondary amine drug (varenicline) in an osmotic tablet. J Pharm Sci 97(4):1499–1507
Wu Y, Dali M, Gupta A, Raghavan K (2009) Understanding drug-excipient compatibility: oxidation of compound A in a solid dosage form. Pharm Dev Technol 14(5):556–564
Wu Y, Levons J, Narang AS, Raghavan K, Rao VM (2011) Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility. AAPS PharmSciTech 12(4):1248–1263
Acknowledgements
The majority of this chapter and illustrations are reprinted from Journal of Pharmaceutical Sciences, Vol. 101 (© 2012) pp. 3305–3318, with permission from John Wiley and Sons.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Hemenway, J. et al. (2015). Reactive Impurities in PEG: A Case Study. 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_4
Download citation
DOI: https://doi.org/10.1007/978-3-319-20206-8_4
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-20205-1
Online ISBN: 978-3-319-20206-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)