Skip to main content

Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug–Excipient Incompatibility

Abstract

Reactive impurities in pharmaceutical excipients could cause 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 ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug–excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

References

  1. Moreton C. Functionality and performance of excipients in a quality-by-design world: part IV. Am Pharm Rev. 2010; Suppl. p. 18–21.

  2. Narang AS, Rao VM, Raghavan K. Excipient compatibility. In: Qiu Y, Chen Y, Zhang GZ, Liu L, Porter W, editors. Developing solid oral dosage forms: pharmaceutical theory and practice. Burlington: Elsevier; 2009. p. 125–46.

    Chapter  Google Scholar 

  3. Kibbe A. Handbook of pharmaceutical excipients. 3rd ed. Washington: American Pharmaceutical Association; 2000. p. 102–6.

    Google Scholar 

  4. Dubost DC, Kaufman MJ, Zimmerman JA, Bogusky MJ, Coddington AB, Pitzenberger SM. Characterization of a solid state reaction product from a lyophilized formulation of a cyclic heptapeptide. A novel example of an excipient-induced oxidation. Pharm Res. 1996;13(12):1811–4.

    PubMed  CAS  Article  Google Scholar 

  5. Katdare A, Chaubal M, editors. Excipient development for pharmaceutical, biotechnology, and drug delivery systems. New York: Informa Healthcare USA, Inc.; 2006. p. 100.

    Google Scholar 

  6. Wirth DD, Baertschi SW, Johnson RA, Maple SR, Miller MS, Hallenback DK, et al. Maillard reaction of lactose and Fluoxetine Hydrochloride, a secondary amine. J Pharm Sci. 1998;87:31–9.

    PubMed  CAS  Article  Google Scholar 

  7. Huang G, Wu Y, Dali M. Determination of formaldehyde and glucose in pharmaceutical excipients by HPLC with pre-column derivatization. HPLC Conference 2007, San Francisco, CA. Poster presentation.

  8. George RC, Barbuch RJ, Huber EW, Regg BT. Investigation into the yellowing on aging of Sabril tablet cores. Drug Dev Ind Pharm. 1994;20:3023–32.

    CAS  Article  Google Scholar 

  9. Wu Y, Dali M, Gupta A, Raghavan K. Understanding drug–excipient compatibility: oxidation of compound A in a solid dosage form. Pharmaceut Dev Tech. 2009;14(5):556–64.

    CAS  Article  Google Scholar 

  10. Njoroge FG, Monnier VM. The chemistry of the Maillard reaction under physiological conditions: a review. Prog Clin Biol Res. 1989;304:85–107.

    PubMed  CAS  Google Scholar 

  11. Hodge JE. The Amadori rearrangement. Adv Carbohydr Chem. 1966;10:169–205.

    Article  Google Scholar 

  12. Li Z, Jacobus LK, Wuelfing WP, Golden M, Martin GP, Reed RA. Detection and quantification of low-molecular-weight aldehydes in pharmaceutical excipients by headspace gas chromatography. J Chromatography A. 2006;1104:1–10.

    CAS  Article  Google Scholar 

  13. del Barrio MA, Hu J, Zhou P, Cauchon N. Simultaneous determination of formic acid and formaldehyde in pharmaceutical excipients using headspace GC/MS. J Pharm Biomed Anal. 2006;41:738–43.

    PubMed  Article  Google Scholar 

  14. Glastrup J. Degradation of polyethylene glycol. A study of the reaction mechanism in a model molecule: tetraethylene glycol. Polym Degrad Stab. 1996;52:217–22.

    CAS  Article  Google Scholar 

  15. Hamburger R, Azaz E, Donbro M. Autoxidation of polyoxyethylenic nonionic surfactants and polyethylene glycols. Pharm Acta Helv. 1975;50:10–7.

    PubMed  CAS  Google Scholar 

  16. Waterman K, Arikpo WB, Fergione MB, Graul TW, Johnson BA, MacDonald BC, et al. N-methylation and N-formylation of a secondary amine drug (Varenicline) in an osmotic tablet. J Pharm Sci. 2008;97(4):1499–507.

    PubMed  CAS  Article  Google Scholar 

  17. Sakharov AM, Mazaletskaya LI, Skibida IP. Catalytic oxidative deformylation of polyethylene glycols with the participation of molecular oxygen. Kinet Catal. 2001;42:662–8.

    CAS  Article  Google Scholar 

  18. Nassar MN, Nesarikar VN, Lozano R, Parker WL, Huang Y, Palaniswamy V, et al. Influence of formaldehyde impurity in Polysorbate 80 and PEG 300 on the stability of a parenteral formulation of BMS-204352: identification and control of the degradation product. Pharmaceut Dev Tech. 2004;9(2):189–95.

    CAS  Article  Google Scholar 

  19. Wang G, Fiske J, Jennings S, Tomasella F, Palaniswamy V, Ray K. Identification and control of a degradation product in Avapro film-coated tablet: low dose formulation. Pharm Dev Tech. 2008;13:393–9.

    CAS  Article  Google Scholar 

  20. Gannett P, Hailu S. In vitro reaction of formaldehyde with fenfluramine: conversion to N-methyl fenfluramine. J Anal Toxicol. 2001;25:88–92.

    PubMed  CAS  Google Scholar 

  21. Desai DS, Rubitski BA, Bergum JS, Varia SA. Effects of different types of lactose and disintegrant on dissolution stability of hydrochlorothiazide capsule formulations. Int J Pharm. 1994;110:257–65.

    CAS  Article  Google Scholar 

  22. Hoydonckx HE, VanRhijn WM, VanRhijn W, Devos DE, Jacobs PA. Furfural and derivatives. In: Ullmann’s encyclopedia of industrial chemistry. Weinheim: Wiley-VCH; 2007. doi:10.1002/14356007.

  23. Brownley Jr CA, Lachman L. Preliminary report on the comparative stability of certified colorants with lactose in aqueous solutions. J Pharm Sci. 1963;52(1):86–93.

    PubMed  CAS  Article  Google Scholar 

  24. Brownley Jr CA, Lachman L. Browning of spray-processed lactose. J Pharm Sci. 1964;53(4):452–4.

    PubMed  CAS  Article  Google Scholar 

  25. Duvall RN, Koshy KT, Pyles JW. Comparison of reactivity of amphetamine, methamphetamine, and dimethylamphetamine with lactose and related compounds. J Pharm Sci. 1965;54(4):607–11.

    PubMed  CAS  Article  Google Scholar 

  26. Bisug SM, Huang WT. Interaction of dextroamphetamine sulfate with spray-dried lactose. J Pharm Sci. 1972;61:1770–5.

    Article  Google Scholar 

  27. Janicki CA, Almond HR. Reaction of Haloperidol with 5-(hydroxymethyl)-2-furfuraldehyde, an impurity in anhydrous lactose. J Pharm Sci. 1974;63:41–3.

    PubMed  CAS  Article  Google Scholar 

  28. Lessen T, Da-Chuan Z. Interactions between drug substances and excipients. 1. Fluorescence and HPLC studies of triazolophtalazine derivatives from Hydralazine Hydrochloride and starch. J Pharm Sci. 1996;85:326–9.

    PubMed  CAS  Article  Google Scholar 

  29. Al-Nimry SS, Assaf SM, Ibrahim MJ, Najib NM. Adsorption of Ketotifen onto some pharmaceutical excipients. Int J Pharm. 1997;149:115–21.

    CAS  Article  Google Scholar 

  30. Aly SAS, Megwa SA. Drug excipient interaction: effect of adsorption of oxytetracycline hydrochloride by some tablet excipients on the physiological availability of the tablets. STP Pharma. 1987;3:652–7.

    CAS  Google Scholar 

  31. Hovorka S, Schoneich C. Oxidative degradation of pharmaceuticals: theory, mechanisms and inhibition. J Pharm Sci. 2001;90:253–69.

    PubMed  CAS  Article  Google Scholar 

  32. Tallon MA, Malawer EG, Machnicki NI, Brush PJ, Wu CS, Cullen JP. The effect of crosslinker structure upon the rate of hydroperoxide formation in dried, crosslinked poly(vinylpyrrolidone). J Appl Polym Sci. 2008;107:2776–85.

    CAS  Article  Google Scholar 

  33. Wasylaschuk WR, Harmon PA, Wagner G, Harman AB, Templeton AC, Xu H, et al. Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci. 2007;96:106–16.

    PubMed  CAS  Article  Google Scholar 

  34. Huang T, Garceau ME, Gao P. Liquid chromatographic determination of residual hydrogen peroxide in pharmaceutical excipients using platinum and wired enzyme electrodes. J Pharm Biol Anal. 2003;31:1203–10.

    CAS  Article  Google Scholar 

  35. Nakamura T, Maeda H. A simple assay for lipid hydroperoxides based on triphenylphosphine oxidation and high-performance liquid chromatography. Lipids. 1991;26:765–8.

    CAS  Article  Google Scholar 

  36. Hoffmann E, Herrle K. U.S. Patent 3,759,880, 1973.

  37. Hartauer K, Gordon A, Baertschi S, Ross J, Luke W, Pearson N, et al. Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets: identification and control of an oxidative degradation product. Pharm Dev Tech. 2000;5(3):303–10.

    CAS  Article  Google Scholar 

  38. Kothari S, Paruchuri S, Rao VM, Desai D. Peroxide scavenging property of croscarmellose sodium and its potential to reduce N-oxidation of piperazine ring containing compounds. 2006; AAPS Poster, San Antonio, TX.

  39. Freed AL, Strohmeyer HE, Mahjour M, Sadineni V, Reid DL, Kingsmill CA. pH Control of nucleophilic/electrophilic oxidation. Int J Pharm. 2008;357(1–2):180–8.

    PubMed  CAS  Article  Google Scholar 

  40. Bahador K, Montazerozohori M, Habibi MH. Urea-hydrogen peroxide (UHP) oxidation of thiols to the corresponding disulfides promoted by maleic anhydride as mediator. Molecules. 2005;10(10):1358–63.

    Article  Google Scholar 

  41. Sims JL, Carreira JA, Carrier DJ, Crabtree SR, Easton L, Hancock SA, et al. A new approach to accelerated drug–excipient compatibility testing. Pharm Dev Tech. 2003;8(2):119–26.

    CAS  Article  Google Scholar 

  42. Miller DM, Buettner GR, Aust SD. Transition metals as catalysts of “autoxidation” reactions. Free Radical Biol Med. 1990;8(1):95–108.

    CAS  Article  Google Scholar 

  43. Ohyashiki T, Kadoya A, Kushida K. The role of Fe3+ on Fe2+-dependent lipid peroxidation in phospholipid liposomes. Chem Pharm Bull. 2002;50(2):203–7.

    PubMed  CAS  Article  Google Scholar 

  44. Brambilla G, Martelli A. Genotoxic and carcinogenic risk to humans of drug–nitrite interaction products. Mutat Res. 2007;635:17–52.

    PubMed  CAS  Article  Google Scholar 

  45. Wessel W, Schoog M, Winkler E. Polyvinylpyrrolidone (PVP), its diagnostic, therapeutic and technical application and consequences thereof. Drug Research. 1971;10:1469–82.

    Google Scholar 

  46. Bartsch H, Ohshima H, Pignatelli B. Inhibitors of endogenous nitrosation mechanisms and implications in human cancer prevention. Mutat Res. 1988;202:307–24.

    PubMed  CAS  Article  Google Scholar 

  47. Brambilla G, Martelli A. Update on genotoxicity and carcinogenicity testing of 472 marketed pharmaceuticals. Mutat Res. 2009;681(2–3):209–29.

    PubMed  CAS  Google Scholar 

  48. Conrad J, Schlemmer K, Eisenbrand G. Nitrosation of bromohexine. Drug Dev and Evaluation. 1990;16:181–97.

    CAS  Google Scholar 

  49. Lundberg JO, Weitzberg E, Gladwin MT. The nitrate nitriteenitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008;7:156–67.

    PubMed  CAS  Article  Google Scholar 

  50. Bottex B, Dorne JL, Carlander D, Benford D, Przyrembel H, Heppner C, et al. Risk-benefit health assessment of food—food fortification and nitrate in vegetables. Trends Food Sci Tech. 2008;19:S113–9.

    Article  Google Scholar 

  51. Narang AS, Rao VM, Farrell T, Ferrizzi D, Castoro J, Corredor C, Jain N, Varia SA, Desai DD. Stability implications of prolonged storage of PVA and PEG-based coating suspension. AAPS poster presentation, New Orleans, LA; 2010.

  52. Chien YW, Van Nostrand P, Hurwitz AR, Shami EG. Drug–disintegrant interactions: binding of oxymorphone derivatives. J Pharm Sci. 1981;70:709–10.

    PubMed  CAS  Article  Google Scholar 

  53. Cory W, Field K, Wu-Linhares D. Is it the method or the process—separating the causes of low recovery. Drug Dev Ind Pharm. 2004;30:891–9.

    PubMed  CAS  Article  Google Scholar 

  54. Rohrs BR, Thamann TJ, Gao P, Stelzer DJ, Bergren MS, Chao RS. Tablet dissolution affected by a moisture mediated solid-state interaction between drug and disintegrant. Pharm Res. 1999;16:1850–6.

    PubMed  CAS  Article  Google Scholar 

  55. Yu H, Cornett C, Larsen J, Hansen JH. Reaction between drug substances and pharmaceutical excipients: formation of esters between cetirizine and polyols. J Pharm and Biomed Anal. 2010;53(3):745–50.

    CAS  Article  Google Scholar 

  56. Fukuyama S, Kihara N, Naksashima K, Morokoshi N, Koda S, Yasuda T. Mechanism of optical isomerization of (S)-N-[1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepine-3-yl]-1H-indole-2-carboxamide (FK480) in soft capsules containing polyethylene glycol 400 and glycerol. Pharm Res. 1994;11:1704–6.

    PubMed  CAS  Article  Google Scholar 

  57. Nishikawa M, Fuji K. Effect of autoxidation of hydrogenated castor oil containing 60 oxyethylene groups on degradation of miconazole. Chem Pharm Bull. 1991;39:2408–11.

    CAS  Google Scholar 

  58. Zografi G, Byrn SR. The effects of residual water on solid-state stability of drugs and drug products, Water Manage. Des Distrib Qual Foods. 1999. p. 397–410.

  59. Badawy SIF. Effect of salt formation on chemical stability of an ester prodrug of a glycoprotein IIb/IIIa receptor antagonist in solid dosage forms. Int J Pharm. 2001;223:81–7.

    PubMed  CAS  Article  Google Scholar 

  60. Badawy SIF, Williams RC, Gilbert D. Chemical stability of an ester prodrug of a IIb/IIIa antagonist in solid dosage forms. J Pharm Sci. 1999;8:428–33.

    Article  Google Scholar 

  61. Gold TB, Smith SL, Digenis GA. Studies on the influence of pH and pancreatin on 13C-formaldehyde-induced gelatin cross-links using nuclear magnetic resonance. Pharm Dev Tech. 1996;1(1):21–6.

    CAS  Article  Google Scholar 

  62. Qiu Z, Stowell JG, Cao W, Morris KR, Byrn SR, Carvajal MT. Effect of milling and compression on the solid-state Maillard reaction. J Pharm Sci. 2005;94:2568–80.

    PubMed  CAS  Article  Google Scholar 

  63. Chen X, Stowell JG, Morris KR, Byrn SR. Quantitative study of solid-state acid–base reactions between polymorphs of flufenamic acid and magnesium oxide using X-ray powder diffraction. J Pharm Biomed Anal. 2010;51:866–74.

    PubMed  CAS  Article  Google Scholar 

  64. Desai D, Rao VM, Guo H, Li D, Stein D, Hu F, Kiesnowski C. An active film-coating approach to enhance chemical stability of a potent drug molecule. Pharm Dev Tech. 2010;1–9.

  65. Akers M. Antioxidants in pharmaceutical products. J Parenteral Sci and Tech. 1982;36(5):222–8.

    CAS  Google Scholar 

  66. Won CM, Tang SY, Strohbeck CL. Photolytic and oxidative degradation of an antiemetic agent, RG 12915. Int J Pharm. 1995;121:95–105.

    CAS  Article  Google Scholar 

  67. Kaufman MJ. Applications of oxygen polarography to drug stability testing and formulation development: solution-phase oxidation of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Pharm Res. 1990;7:289–92.

    PubMed  CAS  Article  Google Scholar 

  68. Higuchi T, Lachman L. Inhibition of hydrolysis of esters in solution by formation of complexes I. Stabilization of benzocaine with caffeine. J Ame Pharm Asso. 1995;44:521–6.

    Article  Google Scholar 

  69. Lachman L, Ravin LJ, Higuchi T. Inhibition of hydrolysis of esters in solution by formation of complexes II. Stabilization of procaine with caffeine. J Am Pharm Assoc. 1956;45:290–5.

    CAS  Google Scholar 

  70. Lachman L, Higuchi T. Inhibition of hydrolysis of esters in solution by formation of complexes. I. Stabilization of tetracaine with caffeine. J Am Pharm Assoc. 1957;46:32–6.

    CAS  Google Scholar 

  71. Guttman DE. Complex formation influence on reaction rate. I. Effect of caffeine on riboflavin base-catalyzed degradation. J Am Pharm Assoc. 1962;51:1162–6.

    CAS  Article  Google Scholar 

  72. Pirinccioglu N, Williams A. Studies of reactions within molecular complexes: alkaline hydrolysis of substituted phenyl benzoates in the presence of xanthines. J Chem Society, Perkin Transactions 2: Phys Org Chem. 1998;1:37–40.

    Article  Google Scholar 

  73. Hirayama F, Kurihara M, Uekama K. Improvement of chemical instability of prostacyclin in aqueous solution by complexation with methylated cyclodextrins. Int J Pharm. 1987;35:193–9.

    CAS  Article  Google Scholar 

  74. Oh IJ, Song HM, Hyun M, Lee KC. Effect of 2-hydroxypropyl-beta-cyclodextrin on the stability of prostaglandin E2 in solution. Int J Pharm. 1994;106:135–40.

    CAS  Article  Google Scholar 

  75. Yamamoto M, Hirayama F, Uekama K. Improvement of stability and dissolution of prostaglandin E1 by maltosyl-β-cyclodextrin in lyophilized formulation. Chem Pharm Bulletin. 1992;40:747–51.

    CAS  Google Scholar 

  76. Bekers O, Beijnen JH, Vis BJ, Suenaga A, Otagiri M, Bult A, et al. Effect of cyclodextrin complexation on the chemical stability of doxorubicin and daunorubicin in aqueous solutions. Int J Pharm. 1991;72:123–30.

    CAS  Article  Google Scholar 

  77. Bekers O, Beijnen JH, Kempers YAG, Bult A, Underberg WJM. Effects of cyclodextrins on N-trifluoroacetyldoxorubicin-14-valerate (AD-32) stability and solubility in aqueous media. Int J Pharm. 1991;68:271–6.

    CAS  Article  Google Scholar 

  78. Gu L, Strickley RG, Chi LH, Chowhan ZT. Drug–excipient incompatibility studies of the dipeptide angiotensin-converting enzyme inhibitor, moexipril hydrochloride: dry powder vs wet granulation. Pharm Res. 1990;7:379–83.

    PubMed  CAS  Article  Google Scholar 

  79. Delonca H, Joachim J, Joachim G, Cantos A. Wet granulation of acetylsalicylic acid. Effect of pH and stabilization agents. Farmaco Ed Prat. 1975;30:89–97.

    CAS  Google Scholar 

  80. Harmon PA, Wuefling WP, Harman AB, Wasylaschuk WR, Givand J, Shelukar S, Reed RA. Role of organic hydroperoxides on process robustness and finished product quality (presented at AAPS) 2004.

    Google Scholar 

  81. Reed RA, Harmon P, Manas D, Wasylaschuk W, Galli C, Biddell R, et al. The role of excipients and package components in the photostability of liquid formulations. PDA J Pharm Sci Tech. 2003;57:351–68.

    CAS  Google Scholar 

  82. Polizzi MA, Singhal D, Colvin J. Mechanoradical-induced degradation in a pharmaceutical blend during high-shear processing. Pharm Dev Tech. 2008;13:457–62.

    CAS  Article  Google Scholar 

  83. Narang A, Lin J, Varia S, Badawy S. Modeling drug degradation in a tablet. AAPS Annual Meeting, New Orleans; 2010.

  84. Badawy SI, Gawronski AJ, Alvarez FJ. Application of sorption–desorption moisture transfer modeling to the study of chemical stability of a moisture sensitive drug product in different packaging configurations. Int J Pharm. 2001;223:1–13.

    PubMed  CAS  Article  Google Scholar 

  85. Chen Y, Li Y. A new model for predicting moisture uptake by packaged solid pharmaceuticals. Int J Pharm. 2003;255:217–25.

    PubMed  CAS  Article  Google Scholar 

  86. Waterman KC, Roy MC. Use of oxygen scavengers to stabilize solid pharmaceutical dosage forms: a case study. Pharm Dev Tech. 2002;7(2):227–34.

    CAS  Article  Google Scholar 

  87. Hartauer KJ, Arbuthnot GN, Baertschi SW, Johnson RA, Luke WD, Pearson NG, et al. Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets: identification and control of an oxidative degradation product. Pharm Dev Tech. 2000;5:303–10.

    CAS  Article  Google Scholar 

  88. Buhler V, Filges U, Schneider T. Stabilized polyvinylpyrrolidone formulation. BASF A.G., Germany. WO; 2000. p. 17.

  89. Fereira PJ, Desjardin MA, Rohloff CM, Berry SA, Zlatkova-Karaslavova ES. Non-aqueous formulations containing biodegradable polymers and methionine and solvents for removing peroxides and reducing the oxidative degradation of drugs. Durect Corp., USA; 2005. p. 36. Cont-in-part of US Ser No. 814,826.

  90. Ashraf-Khorassani M, Taylor LT, Waterman KC, Narayan P, Brannegan DR, Reid GL. Purification of pharmaceutical excipients with supercritical fluid extraction. Pharm Dev Tech. 2005;10:507–16.

    CAS  Article  Google Scholar 

  91. Kumar V, Kalonia S, et al. Removal of peroxides in polyethylene glycols by vacuum drying: implications in the stability of biotech and pharmaceutical formulations. AAPS PharmSciTech. 2006;7:62.

    PubMed  Article  Google Scholar 

  92. Buhler V. Kollidon: polyvinylpyrrolidone excipients for the pharmaceuticals. Berlin: Springer; 2008.

    Google Scholar 

  93. Taylor N. Control excipient reactivity with packaging and aluminum lakes, in: product news, ingredients, excipients, and raw materials. PharmaTechnologist.com; 2010.

  94. Nieuwmeyer F, van der Voort Maarschalk K, Vromans H. Lactose contaminant as steroid degradation enhancer. Pharm Res. 2008;25(11):2666–72.

    PubMed  CAS  Article  Google Scholar 

  95. Ma D, Wasylaschuk WR, Beasley C, Zhao ZZ, Harmon PA, Ballard JM, et al. Identification and quantitation of extractables from cellulose acetate butyrate (CAB) and estimation of their in vivo exposure levels. J Pharm Biomed Anal. 2004;35:779–88.

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Venkatramana M. Rao.

Additional information

Guest Editors: Otilia Koo, Thomas Farrell, Allison Radwick, and Sameer Late

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wu, Y., Levons, J., Narang, A.S. et al. Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug–Excipient Incompatibility. AAPS PharmSciTech 12, 1248–1263 (2011). https://doi.org/10.1208/s12249-011-9677-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-011-9677-z

Key words

  • excipients
  • impurities
  • interaction
  • mitigation
  • variability