Pharmaceutical Research

, Volume 29, Issue 10, pp 2660–2683 | Cite as

Impact of Excipient Interactions on Solid Dosage Form Stability

Expert Review


Drug-excipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug degradation. Recent research has allowed the distinction in chemical instability resulting from direct drug-excipient interactions and from drug interactions with excipient impurities. A review of chemical instability in solid dosage forms highlights common mechanistic themes applicable to multiple degradation pathways. These common themes include the role of water and microenvironmental pH. In addition, special aspects of solid-state reactions with excipients and/or excipient impurities add to the complexity in understanding and modeling reaction pathways. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes. Recent developments in the understanding of degradation pathways further impact methodologies used in the pharmaceutical industry for prospective stability assessment. This paper discusses these emerging aspects in terms of limitations of drug-excipient compatibility studies, emerging paradigms in accelerated stability testing, and application of mathematical modeling for prediction of drug product stability.


capsules compatibility degradation dissolution excipients granules impurities mechanism reaction stability tablets 





active pharmaceutical ingredient


Amadori rearrangement product


butylated hydroxyanisole


butylated hydroxytoluene


gas chromatography






high density polyethylene


high performance liquid chromatography


hydroxypropyl methylcellulose




international conference on harmonization


liquid chromatography tandem with mass spectroscopy


moisture vapor transmission rate


National Formulary


nuclear magnetic resonance (spectroscopy)


polyethylene glycol


pH of maximum solubility


polyvinyl alcohol


polyvinyl pyrrolidone (povidone)


European Pharmacopeia


polyvinylpyrrolidone-vinyl acetate copolymer


powder X-ray diffraction


sorption desorption moisture transfer


solid state NMR


United States Pharmacopeia


  1. 1.
    Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility. AAPS PharmSciTech. 2011;12:1248–63.PubMedCrossRefGoogle Scholar
  2. 2.
    Narang AS, Rao VM, Raghavan K. Excipient Compatibility. In: Qiu Y, Chen Y, Zhang GGZ, Liu L, Porter W, editors. Developing solid oral dosage forms: pharmaceutical theory and practice. Burlington: Elsevier; 2009. p. 125–46.CrossRefGoogle Scholar
  3. 3.
    Mahato RI, Narang AS. Pharmaceutical dosage forms and drug delivery. Boca Raton: CRC; 2012.Google Scholar
  4. 4.
    Antipas AS, Landis MS. Solid-state excipient compatibility testing. Drugs and the Pharmaceutical Sciences, Vol. 153, Taylor and Francis Group, LLC. 2005. pp. 419–458.Google Scholar
  5. 5.
    Carstensen JT, Osadca M, Rubin SH. Degradation mechanisms for water-soluble drugs in solid dosage forms. J Pharm Sci. 1969;58:549–53.PubMedCrossRefGoogle Scholar
  6. 6.
    Tardif R. Reliability of accelerated storage tests to predict stability of vitamins (A, B-1, C) in tablets. J Pharm Sci. 1965;54:281–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Blaug SM, Wesolowski JW. The stability of acetylsalicylic acid in suspension. J Am Pharm Assoc. 1959;48:691–4.Google Scholar
  8. 8.
    Konishi M, Hirai K, Mori Y. Kinetics and mechanism of the equilibrium reaction of triazolam in aqueous solution. J Pharm Sci. 1982;71:1328–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Devani MB, Shishoo CJ, Doshi KJ, Patel HB. Kinetic studies of the interaction between isoniazid and reducing sugars. J Pharm Sci. 1985;74:427–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Mauger JW, Paruta AN, Gerraughty RJ. Consecutive first-order kinetic consideration of hydrocortisone hemisuccinate. J Pharm Sci. 1969;58:574–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Yoshioka S, Aso Y, Shibazaki T, Uchiyama M. Stability of pilocarpine ophthalmic formulations. Chem Pharm Bull. 1986;34:4280–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Khawam A, Flanagan DR. Basics and applications of solid-state kinetics: a pharmaceutical perspective. J Pharm Sci. 2006;95:472–98.PubMedCrossRefGoogle Scholar
  13. 13.
    Dickinson CF, Heal GR. Solid–liquid diffusion controlled rate equations. Thermochimica Acta. 1999;340–341:89–103.CrossRefGoogle Scholar
  14. 14.
    Jander W. Reaction in the solid state at high temperature. I. Rate of reaction for an endothermic change. Zeitschrift fuer Anorganische und Allgemeine Chemie. 1927;163:1–30.CrossRefGoogle Scholar
  15. 15.
    Yoshioka S, Stella VJ. Stability of drugs and dosage forms. New York: Kluwer; 2000.Google Scholar
  16. 16.
    Yoshioka S, Shibazaki T, Eijima A. Stability of solid dosage forms. II. Hydrolysis of meclofenoxate hydrochloride in commercial tablets. Chem Pharm Bull. 1983;31:2513–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Yoshioka S, Uchiyama M. Kinetics and mechanism of the solid-state decomposition of propantheline bromide. J Pharm Sci. 1986;75:92–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Hasegawa J, Hanano M, Awazu S. Decomposition of acetylsalicylic acid and its derivatives in solid state. Chem Pharm Bull. 1975;23:86–97.CrossRefGoogle Scholar
  19. 19.
    Carstensen JT, Kothari RC. Decarboxylation kinetics of 5-(tetradecyloxy)-2-furoic acid. J Pharm Sci. 1980;69:123–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Carstensen JT, Musa MN. Decomposition of benzoic acid derivatives in solid state. J Pharm Sci. 1972;61:1112–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Carstensen JT, Attarchi F. Decomposition of aspirin in the solid state in the presence of limited amounts of moisture II: Kinetics and salting-in of aspirin in aqueous acetic acid solutions. J Pharm Sci. 1988;77:314–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Yoshioka S, Ogata H, Shibazaki T, Ejima A. Stability of sulpyrine. V. Oxidation with molecular oxygen in the solid state. Chem Pharm Bull. 1979;27:2363–71.CrossRefGoogle Scholar
  23. 23.
    Kornblum SS, Sciarrone BJ. Decarboxylation of P-aminosalicylic acid in the solid state. J Pharm Sci. 1964;53:935–41.PubMedCrossRefGoogle Scholar
  24. 24.
    Vyazovkin S, Wight CA. Kinetics in solids. Annu Rev Phys Chem. 1997;48:125–49.PubMedCrossRefGoogle Scholar
  25. 25.
    Zhou D, Schmitt EA, Zhang GG, Law D, Wight CA, Vyazovkin S, Grant DJ. Model-free treatment of the dehydration kinetics of nedocromil sodium trihydrate. J Pharm Sci. 2003;92:1367–76.PubMedCrossRefGoogle Scholar
  26. 26.
    Khawam A, Flanagan DR. Complementary use of model-free and modelistic methods in the analysis of solid-state kinetics. J Phys Chem B. 2005;109:10073–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Hickey MB, Peterson ML, Manas ES, Alvarez J, Haeffner F, Almarsson O. Hydrates and solid-state reactivity: a survey of b-lactam antibiotics. J Pharm Sci. 2007;96:1090–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Snider B, Liang P, Pearson N. Implementation of water-activity testing to replace Karl Fischer water testing for solid oral-dosage forms. Pharm Technol. 31:56, 58, 60, 62, 64–66, 68, 70–71. 2007.Google Scholar
  29. 29.
    Heidemann DR, Jarosz PJ. Preformulation studies involving moisture uptake in solid dosage forms. Pharm Res. 1991;8:292–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Burghart W, Burghart K, Raneburger J. Solid formulation of levothyroxine and/or liothyronine salts containing controlled amount of water for stability. (Globopharm Pharmazeutische Produktions- und Handelsgesellschaft m.b.H., Austria). Patent Application. 2004.Google Scholar
  31. 31.
    Fitzpatrick S, McCabe JF, Petts CR, Booth SW. Effect of moisture on polyvinylpyrrolidone in accelerated stability testing. Int J Pharm. 2002;246:143–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Rowe RC, Sheskey PJ, Weller PJ, Rowe R, Sheskey P, Weller P. Handbook of Pharmaceutical Excipients, APhA Publications. 2003.Google Scholar
  33. 33.
    Kontny MJ. Distribution of water in solid pharmaceutical systems. Drug Dev Ind Pharm. 1988;14:1991–2027.CrossRefGoogle Scholar
  34. 34.
    Patel NK, Patel IJ, Cutie AJ, Wadke DA, Monkhouse DC, Reier GE. The effect of selected direct compression excipients on the stability of aspirin as a model hydrolyzable drug. Drug Dev Ind Pharm. 1988;14:77–98.CrossRefGoogle Scholar
  35. 35.
    Gore AY, Banker GS. Surface chemistry of colloidal silica and a possible application to stabilize aspirin in solid matrixes. J Pharm Sci. 1979;68:197–202.PubMedCrossRefGoogle Scholar
  36. 36.
    De Ritter E, Magid L, Osadca M, Rubin SH. Effect of silica gel on stability and biological availability of ascorbic acid. J Pharm Sci. 1970;59:229–32.PubMedCrossRefGoogle Scholar
  37. 37.
    Perrier PR, Kesselring UW. Quantitative assessment of the effect of some excipients on nitrazepam stability in binary powder mixtures. J Pharm Sci. 1983;72:1072–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Fielden KE, Newton JM, O'Brien P, Rowe RC. Thermal studies on the interaction of water and microcrystalline cellulose. J Pharm Pharmacol. 1988;40:674–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Ahlneck C, Alderborn G. Solid state stability of acetylsalicylic acid in binary mixtures with microcrystalline and microfine cellulose. Acta Pharm Suec. 1988;25:41–52.PubMedGoogle Scholar
  40. 40.
    Yoshioka S, Aso Y, Terao T. Effect of water mobility on drug hydrolysis rates in gelatin gels. Pharm Res. 1992;9:607–12.PubMedCrossRefGoogle Scholar
  41. 41.
    Aso Y, Sufang T, Yoshioka S, Kojima S. Amount of mobile water estimated from 2 H spin–lattice relaxation time, and its effects on the stability of cephalothin in mixtures with pharmaceutical excipients. Drug Stab. 1997;1:237–42.Google Scholar
  42. 42.
    Ahlneck C, Zografi G. The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int J Pharm. 1990;62:87–95.CrossRefGoogle Scholar
  43. 43.
    Shalaev EY, Zografi G. How does residual water affect the solid-state degradation of drugs in the amorphous state? J Pharm Sci. 1996;85:1137–41.PubMedCrossRefGoogle Scholar
  44. 44.
    Hancock BC, Zografi G. The relationship between the glass transition temperature and the water content of amorphous pharmaceutical solids. Pharm Res. 1994;11:471–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Tong P, Zografi G. Effects of water vapor absorption on the physical and chemical stability of amorphous sodium indomethacin. AAPS PharmSciTech. 5: No pp given. 2004.Google Scholar
  46. 46.
    Waterman KC, Gerst P, Macdonald BC. Relative humidity hysteresis in solid-state chemical reactivity: A pharmaceutical case study. Journal of pharmaceutical sciences. 2011.Google Scholar
  47. 47.
    Waterman KC, MacDonald BC. Package selection for moisture protection for solid, oral drug products. J Pharm Sci. 2010;99:4437–52.PubMedCrossRefGoogle Scholar
  48. 48.
    Khan S, Giradkar P, Yeole P. Formulation design of ranitidine hydrochloride to reduce its moisture absorption characteristics. PDA J Pharm Sci Technol. 2009;63:226–33.PubMedGoogle Scholar
  49. 49.
    Glombitza BW, Oelkrug D, Schmidt PC. Surface acidity of solid pharmaceutical excipients. Part 1. Determination of the surface acidity. Eur J Pharm Biopharm. 1994;40:289–93.Google Scholar
  50. 50.
    Stanisz B. The influence of pharmaceutical excipients on quinapril hydrochloride stability. Acta Pol Pharm. 2005;62:189–93.PubMedGoogle Scholar
  51. 51.
    Crowley P, Martini L. Drug-excipient interactions. Pharmaceutical Technology Europe. 13:26–28, 30–32, 34. 2001.Google Scholar
  52. 52.
    Zannou EA, Ji Q, Joshi YM, Serajuddin AT. Stabilization of the maleate salt of a basic drug by adjustment of microenvironmental pH in solid dosage form. Int J Pharm. 2007;337:210–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Wirth DD, Baertschi SW, Johnson RA, Maple SR, Miller MS, Hallenbeck DK, Gregg SM. Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine. J Pharm Sci. 1998;87:31–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Murugesan R, Kaimulankara G, Pillai SRS. A novel pharmaceutical composition. (Fourrts (India) Laboratories Private Limited, India). Patent Application: IN 2005-CH990. 2007.Google Scholar
  55. 55.
    Murthy KS, Ghebre-Sellassie I. Current perspectives on the dissolution stability of solid oral dosage forms. J Pharm Sci. 1993;82:113–26.PubMedCrossRefGoogle Scholar
  56. 56.
    Gordon MS, Rudraraju VS, Rhie JK, Chowhan ZT. The effect of aging on the dissolution of wet granulated tablets containing super disintegrants. Int J Pharm. 1993;97:119–31.CrossRefGoogle Scholar
  57. 57.
    Digenis GA, Gold TB, Shah VP. Cross-linking of gelatin capsules and its relevance to their in vitro-in vivo performance. J Pharm Sci. 1994;83:915–21.PubMedCrossRefGoogle Scholar
  58. 58.
    Digenis GA, Sandefer EP, Page RC, Doll WJ, Gold TB, Darwazeh NB. Bioequivalence study of stressed and nonstressed hard gelatin capsules using amoxicillin as a drug marker and gamma scintigraphy to confirm time and GI location of in vivo capsule rupture. Pharm Res. 2000;17:572–82.PubMedCrossRefGoogle Scholar
  59. 59.
    Meyer MC, Straughn AB, Mhatre RM, Hussain A, Shah VP, Bottom CB, Cole ET, Lesko LL, Mallinowski H, Williams RL. The effect of gelatin cross-linking on the bioequivalence of hard and soft gelatin acetaminophen capsules. Pharm Res. 2000;17:962–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Dey M, Enever R, Kraml M, Prue DG, Smith D, Weierstall R. The dissolution and bioavailability of etodolac from capsules exposed to conditions of high relative humidity and temperatures. Pharm Res. 1993;10:1295–300.PubMedCrossRefGoogle Scholar
  61. 61.
    Bonfilio R, Pires SA, Ferreira LMB, de Almeida AE, Doriguetto AC, de Araujo MB, Salgado HRN. A discriminating dissolution method for glimepiride polymorphs. J Pharm Sci:794–804. 2012.Google Scholar
  62. 62.
    Phadnis NV, Suryanarayanan R. Polymorphism in anhydrous theophylline–implications on the dissolution rate of theophylline tablets. J Pharm Sci. 1997;86:1256–63.PubMedCrossRefGoogle Scholar
  63. 63.
    Forni F, Coppi G, Iannuccelli V, Vandelli MA, Cameroni R. The grinding of the polymorphic forms of chloramphenicol stearic ester in the presence of colloidal silica. Acta Pharm Suec. 1988;25:173–80.Google Scholar
  64. 64.
    Hemenway J, Kirby S, Narang A, Rao V, Paruchuri S, Derbin G, Stamato H. Effect of water activity and water absorption properties on the stability of film-coated tablet formulations of a moisture sensitive active pharmaceutical ingredient, American Association of Pharmaceutical Scientists Annual Meeting, New Orleans, LA, 2010.Google Scholar
  65. 65.
    Airaksinen S, Karjalainen M, Kivikero N, Westermarck S, Shevchenko A, Rantanen J, Yliruusi J. Excipient selection can significantly affect solid-state phase transformation in formulation during wet granulation. AAPS PharmSciTech. 2005;6:E311–322.PubMedCrossRefGoogle Scholar
  66. 66.
    Tantry JS, Tank J, Suryanarayanan R. Processing-induced phase transitions of theophylline–implications on the dissolution of theophylline tablets. J Pharm Sci. 2007;96:1434–44.PubMedCrossRefGoogle Scholar
  67. 67.
    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.PubMedCrossRefGoogle Scholar
  68. 68.
    Guerrieri P, Taylor LS. Role of salt and excipient properties on disproportionation in the solid-state. Pharm Res. 2009;26:2015–26.PubMedCrossRefGoogle Scholar
  69. 69.
    Stephenson GA, Aburub A, Woods TA. Physical stability of salts of weak bases in the solid-state. J Pharm Sci. 2011;100:1607–17.PubMedCrossRefGoogle Scholar
  70. 70.
    Bharate SS, Bharate SB, Bajaj AN. Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review. Journal of Excipients and Food Chemicals. 2010;1:3–26.Google Scholar
  71. 71.
    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.PubMedCrossRefGoogle Scholar
  72. 72.
    Abdoh A, Al-Omari MM, Badwan AA, Jaber AM. Amlodipine besylate-excipients interaction in solid dosage form. Pharm Dev Technol. 2004;9:15–24.PubMedCrossRefGoogle Scholar
  73. 73.
    Santos AFO, Basilio Jr ID, Souza FS, Medeiros AFD, Ferraz Pinto M, Santana DP, Macedo RO. Application of thermal analysis in study of binary mixtures with metformin. J Therm Anal Calorim. 2008;93:361–4.CrossRefGoogle Scholar
  74. 74.
    Monajjemzadeh F, Hassanzadeh D, Valizadeh H, Siahi-Shadbad MR, Mojarrad JS, Robertson TA, Roberts MS. Compatibility studies of acyclovir and lactose in physical mixtures and commercial tablets. Eur J Pharm Biopharm. 2009;73:404–13.PubMedCrossRefGoogle Scholar
  75. 75.
    Monajjemzadeh F, Hassanzadeh D, Valizadeh H, Siahi-Shadbad MR, Mojarrad JS, Robertson T, Roberts MS. Assessment of feasibility of Maillard reaction between baclofen and lactose by liquid chromatography and tandem mass spectrometry, application to pre formulation studies. AAPS PharmSciTech. 2009;10:649–59.PubMedCrossRefGoogle Scholar
  76. 76.
    Desai SR, Shaikh MM, Dharwadkar SR. Preformulation compatibility studies of etamsylate and fluconazole drugs with lactose by DSC. J Therm Anal Calorim. 2003;71:651–8.CrossRefGoogle Scholar
  77. 77.
    Sarisuta N, Lawanprasert P, Puttipipatkhachorn S, Srikummoon K. The influence of drug-excipient and drug-polymer interactions on butt adhesive strength of ranitidine hydrochloride film-coated tablets. Drug Dev Ind Pharm. 2006;32:463–71.PubMedCrossRefGoogle Scholar
  78. 78.
    Mutalik S, Naha A, Usha AN, Ranjith AK, Musmade P, Manoj K, Anju P, Prasanna S. Preparation, in vitro, preclinical and clinical evaluations of once daily sustained release tablets of aceclofenac. Arch Pharm Res. 2007;30:222–34.PubMedCrossRefGoogle Scholar
  79. 79.
    Li S, Patapoff TW, Overcashier D, Hsu C, Nguyen TH, Borchardt RT. Effects of reducing sugars on the chemical stability of human relaxin in the lyophilized state. J Pharm Sci. 1996;85:873–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Larsen J, Cornett C, Jaroszewski JW, Hansen SH. Reaction between drug substances and pharmaceutical excipients: Formation of citric acid esters and amides of carvedilol in the solid state. J Pharm Biomed Anal. 2009;49:11–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Bruce LD, Shah NH, Waseem Malick A, Infeld MH, McGinity JW. Properties of hot-melt extruded tablet formulations for the colonic delivery of 5-aminosalicylic acid. Eur J Pharm Biopharm. 2005;59:85–97.PubMedCrossRefGoogle Scholar
  82. 82.
    Ballard JM, Zhu L, Nelson ED, Seburg RA. Degradation of vitamin D3 in a stressed formulation: the identification of esters of vitamin D3 formed by a transesterification with triglycerides. J Pharm Biomed Anal. 2007;43:142–50.PubMedCrossRefGoogle Scholar
  83. 83.
    March J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fourth Edition. 1992.Google Scholar
  84. 84.
    Huffman RW, Donzel A, Bruice TC. Aminolysis of esters. VII. The reaction of lysine with phenyl acetate and triacetin. J Org Chem. 1967;32:1973–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Yu H, Cornett C, Larsen J, Hansen SH. Reaction between drug substances and pharmaceutical excipients: formation of esters between cetirizine and polyols. J Pharm Biomed Anal. 2010;53:745–50.PubMedCrossRefGoogle Scholar
  86. 86.
    Wong J, Wiseman L, Al-Mamoon S, Cooper T, Zhang LK, Chan TM. Major degradation product identified in several pharmaceutical formulations against the common cold. Anal Chem. 2006;78:7891–5.PubMedCrossRefGoogle Scholar
  87. 87.
    Schildcrout SA, Risley DS, Kleemann RL. Drug-excipient interactions of seproxetine maleate hemihydrate: Isothermal stress methods. Drug Dev Ind Pharm. 1993;19:1113–30.CrossRefGoogle Scholar
  88. 88.
    Killion Jr RB, Stella VJ. The nucleophilicity of dextrose, sucrose, sorbitol, and mannitol with p-nitrophenyl esters in aqueous solution. Int J Pharm. 1990;66:149–55.CrossRefGoogle Scholar
  89. 89.
    Bundgaard H, Larsen C. Piperazinedione formation from reaction of ampicillin with carbohydrates and alcohols in aqueous solution. Int J Pharm. 1979;3:1–11.CrossRefGoogle Scholar
  90. 90.
    Bundgaard H, Larsen C. Kinetics and mechanism of the sucrose-accelerated degradation of penicillins in aqueous solution. Int J Pharm. 1978;1:95–104.CrossRefGoogle Scholar
  91. 91.
    Bundgaard H, Larsen C. The influence of carbohydrates and polyhydric alcohols on the stability of cephalosporins in aqueous solution. Int J Pharm. 1983;16:319–25.CrossRefGoogle Scholar
  92. 92.
    Badawy SI, Williams RC, Gilbert DL. Effect of different acids on solid-state stability of an ester prodrug of a IIb/IIIa glycoprotein receptor antagonist. Pharm Dev Technol. 1999;4:325–31.PubMedCrossRefGoogle Scholar
  93. 93.
    Hartley RF, Huang Y, Cassidy M, Razler TM, Qian F, Hussain MA. The Degradation Kinetics and Mechanism of an Oxadiazole Derivative, a g-Secretase Inhibitor Drug Candidate. Journal of pharmaceutical sciences. Submitted. 2011.Google Scholar
  94. 94.
    Badawy SI, Hussain MA. Microenvironmental pH modulation in solid dosage forms. J Pharm Sci. 2007;96:948–59.PubMedCrossRefGoogle Scholar
  95. 95.
    Akiyama Y, Yoshioka M, Horibe H, Hirai S, Kitamori N, Toguchi H. pH-independent controlled-release microspheres using polyglycerol esters of fatty acids. J Pharm Sci. 1994;83:1600–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Tatavarti AS, Mehta KA, Augsburger LL, Hoag SW. Influence of methacrylic and acrylic acid polymers on the release performance of weakly basic drugs from sustained release hydrophilic matrices. J Pharm Sci. 2004;93:2319–31.PubMedCrossRefGoogle Scholar
  97. 97.
    Doherty C, York P. The in-vitro pH-dissolution dependence and in-vivo bioavailability of frusemide-PVP solid dispersions. J Pharm Pharmacol. 1989;41:73–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Badawy SI, Gray DB, Zhao F, Sun D, Schuster AE, Hussain MA. Formulation of solid dosage forms to overcome gastric pH interaction of the factor Xa inhibitor, BMS-561389. Pharm Res. 2006;23:989–96.PubMedCrossRefGoogle Scholar
  99. 99.
    Streubel A, Siepmann J, Dashevsky A, Bodmeier R. pH-independent release of a weakly basic drug from water-insoluble and -soluble matrix tablets. J Control Release. 2000;67:101–10.PubMedCrossRefGoogle Scholar
  100. 100.
    Gabr KE. Effect of organic acids on the release patterns of weakly basic drugs from inert sustained-release matrix tablets. Eur J Pharm Biopharm. 1992;38:199–202.Google Scholar
  101. 101.
    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.PubMedCrossRefGoogle Scholar
  102. 102.
    Badawy SI. Effect of salt form 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.PubMedCrossRefGoogle Scholar
  103. 103.
    Waterman KC, Adami RC, Alsante KM, Antipas AS, Arenson DR, Carrier R, Hong J, Landis MS, Lombardo F, Shah JC, Shalaev E, Smith SW, Wang H. Hydrolysis in pharmaceutical formulations. Pharm Dev Technol. 2002;7:113–46.PubMedCrossRefGoogle Scholar
  104. 104.
    Irwin WJ, Iqbal M. Solid-state stability: the effect of grinding solvated excipients. Int J Pharm. 1991;75:211–8.CrossRefGoogle Scholar
  105. 105.
    Kitamura S, Miyamae A, Koda S, Morimoto Y. Effect of grinding on the solid-state stability of cefixime trihydrate. Int J Pharm. 1989;56:125–34.CrossRefGoogle Scholar
  106. 106.
    Badawy S, Vickery R, Shah K, Hussain M. Effect of processing and formulation variables on the stability of a salt of a weakly basic drug candidate. Pharm Dev Technol. 2004;9:239–45.PubMedCrossRefGoogle Scholar
  107. 107.
    Mahato RI, Narang AS. Pharmaceutical dosage forms and drug delivery, CRC Press. 2011.Google Scholar
  108. 108.
    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.CrossRefGoogle Scholar
  109. 109.
    Wasylaschuk WR, Harmon PA, Wagner G, Harman AB, Tempelton AC, Xu H, Reed RA. Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci. 2007;96:106–16.PubMedCrossRefGoogle Scholar
  110. 110.
    Hartauer KJ, Arbuthnot GN, Baertschi SW, Johnson RA, Luke WD, Pearson NG, Rickard EC, Tingle CA, Tsang PKS, Influence REW. 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 Technol. 2000;5:303–10.PubMedCrossRefGoogle Scholar
  111. 111.
    Kothari S, Paruchuri S, Rao V, Desai D. Peroxide scavenging property of croscarmellose sodium and its potential to reduce N-oxidation of piperazine ring containing compounds. San Antonio: American Association of Pharmaceutical Scientists; 2006.Google Scholar
  112. 112.
    Wu Y, Dali M, Gupta A, Raghavan K. Understanding drug-excipient compatibility: oxidation of compound A in a solid dosage form. Pharm Dev Technol. 2009;14:556–64.PubMedCrossRefGoogle Scholar
  113. 113.
    Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive impurities in excipients: profiling, identification and mitigation of drug–excipient incompatibility. AAPS PharmSciTech. 2011.Google Scholar
  114. 114.
    Hartauer KJ, Arbuthnot GN, Baertschi SW, Johnson RA, Luke WD, Pearson NG, Rickard EC, Tingle CA, Tsang PK, Wiens RE. 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 Technol. 2000;5:303–10.PubMedCrossRefGoogle Scholar
  115. 115.
    Yarkala S, Amaravadi S, Rao VU, Vijaykumar V, Navalgund SG, Jagdish B. Role of excipients on N-oxide raloxifene generation from raloxifene-excipients binary mixtures. Chem Pharm Bull. 2009;57:1174–7.PubMedCrossRefGoogle Scholar
  116. 116.
    Wasylaschuk WR, Harmon PA, Wagner G, Harman AB, Templeton AC, Xu H, Reed RA. Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci. 2007;96:106–16.PubMedCrossRefGoogle Scholar
  117. 117.
    Buhler V. Kollidon: Polyvinylpyrrolidone excipients for the pharmaceuticals, Springer-Verlag berlin Heidelberg, Germany. 2008.Google Scholar
  118. 118.
    Narang AS, Rao VM, Desai DS. Effect of antioxidants and silicates on peroxides in povidone. J Pharm Sci. 2012;101:127–39.PubMedCrossRefGoogle Scholar
  119. 119.
    Carvalho T, Rao V, Levons J, Wu J, Narang A, Paruchuri S, Stamato H, Varia S, Hemenway J. Formation of reactive impurities in PEG 400 and effects of antioxidants and oxidation inducers on the reaction rates. Washington: American Association of Pharmaceutical Sciences Annual Meeting; 2011.Google Scholar
  120. 120.
    Buhler V, Filges U, Schneider T. Stabilized polyvinylpyrrolidone formulation. (BASF A.-G., Germany). Patent Application: WO 2000059478. 2000.Google Scholar
  121. 121.
    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). Patent Application: US 2005276856. 2005.Google Scholar
  122. 122.
    Ashraf-Khorassani M, Taylor LT, Waterman KC, Narayan P, Brannegan DR, Reid GL. Purification of pharmaceutical excipients with supercritical fluid extraction. Pharm Dev Technol. 2005;10:507–16.PubMedCrossRefGoogle Scholar
  123. 123.
    Kumar V, Kalonia Devendra S. Removal of peroxides in polyethylene glycols by vacuum drying: implications in the stability of biotech and pharmaceutical formulations. AAPS PharmSciTech. 2006;7:62.PubMedCrossRefGoogle Scholar
  124. 124.
    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.PubMedCrossRefGoogle Scholar
  125. 125.
    Yuan LC, Dahl TC, Oliyai R. Effect of carbonate salts on the kinetics of acid-catalyzed dimerization of adefovir dipivoxil. Pharm Res. 2000;17:1098–103.PubMedCrossRefGoogle Scholar
  126. 126.
    Nassar MN, Nesarikar VN, Lozano R, Parker WL, Huang Y, Palaniswamy V, Xu W, Khaselev N. 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. Pharm Dev Technol. 2004;9:189–95.PubMedCrossRefGoogle Scholar
  127. 127.
    Janicki CA, Almond Jr HR. Reaction of haloperidol with 5-(hydroxymethyl)-2-furfuraldehyde, an impurity in anhydrous lactose. J Pharm Sci. 1974;63:41–3.PubMedCrossRefGoogle Scholar
  128. 128.
    Mollica J, Rehm C, Smith J. Hydrolysis of hydrochlorotiazide. J Pharm Sci. 1969;58:1380–4.CrossRefGoogle Scholar
  129. 129.
    Desai DS, Rubitski BA, Varia SA, Huang MH. Effect of formaldehyde formation on dissolution stability of hydrochlorothiazide bead formulations. Int J Pharm. 1994;107:141–7.CrossRefGoogle Scholar
  130. 130.
    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.CrossRefGoogle Scholar
  131. 131.
    Desai DS, Ranadive SA, Lozano R, Varia SA. Dissolution instability of encapsulated marketed tablets. Int J Pharm. 1996;144:153–8.CrossRefGoogle Scholar
  132. 132.
    Waterman KC, Arikpo WB, Fergione MB, Graul TW, Johnson BA, Macdonald BC, Roy MC, Timpano RJ. N-methylation and N-formylation of a secondary amine drug (Varenicline) in an osmotic tablet. J Pharm Sci. 2008;97:1499–507.PubMedCrossRefGoogle Scholar
  133. 133.
    Wang G, Fiske JD, Jennings SP, Tomasella FP, Palaniswamy VA, Ray KL. Identification and control of a degradation product in Avapro film-coated tablet: low dose formulation. Pharm Dev Technol. 2008;13:393–9.PubMedCrossRefGoogle Scholar
  134. 134.
    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;13:1811–4.PubMedCrossRefGoogle Scholar
  135. 135.
    Lessen T, Zhao DC. Interactions between drug substances and excipients. 1. Fluorescence and HPLC studies of triazolophthalazine derivatives from hydralazine hydrochloride and starch. J Pharm Sci. 1996;85:326–9.PubMedCrossRefGoogle Scholar
  136. 136.
    Desai D, Rao V, Guo H, Li D, Bolgar M. Stability of low concentrations of guanine-based antivirals in sucrose or maltitol solutions. Int J Pharm. 2007;342:87–94.PubMedCrossRefGoogle Scholar
  137. 137.
    Narang AS, Rao V, Farrell T, Ferrizzi D, Castoro J, Corredor C, Jain N, Varia S, Desai D. Stability implications of prolonged storage of PVA and PEG-based coating suspension. New Orleans: American Association of Pharmaceutical Sciences Annual Meeting; 2010.Google Scholar
  138. 138.
    Sakharov AM, Mazaletskaya LI, Skibida IP. Catalytic oxidative deformylation of polyethylene glycols with the participation of molecular oxygen. Kinet Catal. 2001;42:662–8.CrossRefGoogle Scholar
  139. 139.
    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.CrossRefGoogle Scholar
  140. 140.
    Fukuyama S, Kihara N, Nakashima K, Morokoshi N, Koda S, Yasuda T. Mechanism and suppression of optical isomerization of FK 480 in soft capsules containing polyethylene glycol 400 and glycerol. Drug Stab. 1996;1:128–31.Google Scholar
  141. 141.
    Waterman KC, Adami RC, Alsante KM, Hong J, Landis MS, Lombardo F, Roberts CJ. Stabilization of pharmaceuticals to oxidative degradation. Pharm Dev Technol. 2002;7:1–32.PubMedCrossRefGoogle Scholar
  142. 142.
    Bindra DS, Williams TD, Stella VJ. Degradation of O6-benzylguanine in aqueous polyethylene glycol 400 (PEG 400) solutions: concerns with formaldehyde in PEG 400. Pharm Res. 1994;11:1060–4.PubMedCrossRefGoogle Scholar
  143. 143.
    Narang A, Kanthasamy M, Castoro J, Varia S, Desai D. Effect of pro- and anti-oxidants on the formation of formyl species in PVA- and PEG-based tablet coating material. Washington: American Association of Pharmaceutical Sciences Annual Meeting; 2011.Google Scholar
  144. 144.
    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]-1 H-indole-2-carboxamide (FK480) in soft capsules containing polyethylene glycol 400 and glycerol. Pharm Res. 1994;11:1704–6.PubMedCrossRefGoogle Scholar
  145. 145.
    Nishikawa M, Fujii K. Effect of autoxidation of hydrogenated castor oil containing 60 oxyethylene groups on degradation of miconazole. Chem Pharm Bull. 1991;39:2408–11.CrossRefGoogle Scholar
  146. 146.
    Ku MS, Lu Q, Li W, Chen Y. Performance qualification of a new hypromellose capsule: Part II. Disintegration and dissolution comparison between two types of hypromellose capsules. Int J Pharm. 2011;416:16–24.PubMedCrossRefGoogle Scholar
  147. 147.
    Sherry Ku M, Li W, Dulin W, Donahue F, Cade D, Benameur H, Hutchison K. Performance qualification of a new hypromellose capsule: part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps Plus, Quali-V and gelatin capsules. Int J Pharm. 2010;386:30–41.PubMedCrossRefGoogle Scholar
  148. 148.
    Podczeck F, Jones BE. The in vitro dissolution of theophylline from different types of hard shell capsules. Drug Dev Ind Pharm. 2002;28:1163–9.PubMedCrossRefGoogle Scholar
  149. 149.
    Tuleu C, Khela MK, Evans DF, Jones BE, Nagata S, Basit AW. A scintigraphic investigation of the disintegration behaviour of capsules in fasting subjects: a comparison of hypromellose capsules containing carrageenan as a gelling agent and standard gelatin capsules. Eur J Pharm Sci. 2007;30:251–5.PubMedCrossRefGoogle Scholar
  150. 150.
    International Conference on Harmonization. Draft Revised Guidance on Impurities in New Drug Substances. Q3A(R). In F. Register (ed.), 65(140):45085–45090. 2000.Google Scholar
  151. 151.
    International Conference on Harmonization. Draft Revised Guidance on Impurities in New Drug Products. Q3B(R). In F. Register (ed.), Vol. 65. 2000. pp. 44791–44797.Google Scholar
  152. 152.
    International Conferences on Harmonization. Impurities-- Guidelines for Residual Solvents. Q3C. In F. Register (ed.), Vol. 62. 1997. p 67377.Google Scholar
  153. 153.
    EMEA guidance. EMEA Guide line on the specification limits for residues of metal catalysts or metal reagents In EMEA (ed.), Doc Ref EMEA/CHMP/SWP/4446/2000, London. 2008.Google Scholar
  154. 154.
    Roy J. Pharmaceutical impurities - a mini review. AAPS PharmSciTech. 2002;3:1–8.CrossRefGoogle Scholar
  155. 155.
    Hong J, Lee E, Carter JC, Masse JA, Oksanen DA. Antioxidant-accelerated oxidative degradation: a case study of transition metal ion catalyzed oxidation in formulation. Pharm Dev Technol. 2004;9:171–9.PubMedCrossRefGoogle Scholar
  156. 156.
    Reed RA, Harmon P, Manas D, Wasylaschuk W, Galli C, Biddell R, Bergquist PA, Hunke W, Templeton AC, Ip D. The role of excipients and package components in the photostability of liquid formulations. PDA J Pharm Sci Technol. 2003;57:351–68.PubMedGoogle Scholar
  157. 157.
    Wang J, Wen H, Desai D. Lubrications in tablet formulations. Eur J Pharm Biopharm. 2010;75:1–15.PubMedCrossRefGoogle Scholar
  158. 158.
    Wyttenbach N, Birringer C, Alsenz J, Kuentz M. Drug-excipient compatibility testing using a high-throughput approach and statistical design. Pharm Dev Technol. 2005;10:499–505.PubMedCrossRefGoogle Scholar
  159. 159.
    Plackett RL, Burman JP. The design of optimum multifactorial experiments. Biometrika. 1946;33:305–25.CrossRefGoogle Scholar
  160. 160.
    Durig T, Fassihi AR. Identification of stabilizing and destabilizing effects of excipient-drug interactions in solid-dosage form design. Int J Pharm. 1993;97:161–70.CrossRefGoogle Scholar
  161. 161.
    International Council for Harmonization. Guidance for Industry: Q1E Evaluation of Stability Data. 2004.Google Scholar
  162. 162.
    Waterman KC, Adami RC. Accelerated aging: prediction of chemical stability of pharmaceuticals. Int J Pharm. 2005;293:101–25.PubMedCrossRefGoogle Scholar
  163. 163.
    Sinclair W, Leane M, Clarke G, Dennis A, Tobyn M, Timmins P. Physical stability and recrystallization kinetics of amorphous ibipinabant drug product by fourier transform raman spectroscopy. J Pharm Sci. 2011;100:4687–99.PubMedCrossRefGoogle Scholar
  164. 164.
    Kontny MJ, Koppenol S, Graham ET. Use of the sorption–desorption moisture transfer model to assess the utility of a desiccant in a solid product. Int J Pharm. 1992;84:261–71.CrossRefGoogle Scholar
  165. 165.
    Chen Y, Li Y. A new model for predicting moisture uptake by packaged solid pharmaceuticals. Int J Pharm. 2003;255:217–25.PubMedCrossRefGoogle Scholar
  166. 166.
    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.PubMedCrossRefGoogle Scholar
  167. 167.
    Narang AS, Lin J, Varia SA, Badawy S. Modeling drug degradation in a tablet. New Orleans: American Association of Pharmaceutical Sciences Annual Meeting; 2010.Google Scholar
  168. 168.
    Naversnik K, Bohanec S. Predicting drug hydrolysis based on moisture uptake in various packaging designs. Eur J Pharm Sci. 2008;35:447–56.PubMedCrossRefGoogle Scholar
  169. 169.
    George RC. Investigation into the yellowing on aging of Sabril tablet cores. Drug Dev Ind Pharm. 1994;20:3023–32.CrossRefGoogle Scholar
  170. 170.
    Rivera SL, Ghodbane S. In vitro adsorption-desorption of famotidine on microcrystalline cellulose. Int J Pharm. 1994;108:31–8.CrossRefGoogle Scholar
  171. 171.
    Siepmann JI, Martin MG, Chen B, Stubbs JM, Potoff JJ. Monte Carlo simulations of supercritical fluid extraction systems. Abstracts of Papers, 220th ACS National Meeting, Washington, DC, United States, August 20–24, 2000 FIELD Full Journal Title: Abstracts of Papers, 220th ACS National Meeting, Washington, DC, United States, August 20–24, 2000:COMP-143. 2000.Google Scholar
  172. 172.
    D'Souza AJ, Schowen RL, Borchardt RT, Salsbury JS, Munson EJ, Topp EM. Reaction of a peptide with polyvinylpyrrolidone in the solid state. J Pharm Sci. 2003;92:585–93.PubMedCrossRefGoogle Scholar
  173. 173.
    Chien YW, Van Nostrand P, Hurwitz AR, Shami EG. Drug–disintegrant interactions: binding of oxymorphone derivatives. J Pharm Sci. 1981;70:709–10.PubMedCrossRefGoogle Scholar
  174. 174.
    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.PubMedCrossRefGoogle Scholar
  175. 175.
    Claudius JS, Neau SH. The solution stability of vancomycin in the presence and absence of sodium carboxymethyl starch. Int J Pharm. 1998;168:41–8.CrossRefGoogle Scholar
  176. 176.
    Senderoff RI, Mahjour M, Radebaugh GW. Characterization of adsorption behavior by solid dosage form excipients in formulation development. Int J Pharm. 1982;83:65–72.CrossRefGoogle Scholar
  177. 177.
    Al-Nimry SS, Assaf SM, Jalal IM, Najib NM. Adsorption of ketotifen onto some pharmaceutical excipients. Int J Pharm. 1997;149:115–21.CrossRefGoogle Scholar
  178. 178.
    Botha SA, Lotter AP. Compatibility study between naproxen and tablet excipients using differential scanning calorimetry. Drug Dev Ind Pharm. 1990;16:673–83.CrossRefGoogle Scholar
  179. 179.
    Rowe RC, Forse SF. Pitting: a defect on film coated tablets. Int J Pharm. 1983;17:347–9.CrossRefGoogle Scholar
  180. 180.
    Swaminathan V, Kildsig DO. An examination of the moisture sorption characteristics of commercial magnesium stearate. AAPS PharmSciTech. 2001;2:28.PubMedCrossRefGoogle Scholar
  181. 181.
    Kararli TT, Needham TE, Seul CJ, Finnegan PM. Solid-state interaction of magnesium oxide and ibuprofen to form a salt. Pharm Res. 1989;6:804–8.PubMedCrossRefGoogle Scholar
  182. 182.
    Ahlneck C, Waltersson J-O, Lundgren P. Difference in effect of powdered and granular magnesium stearate on the solid state stability of acetylsalicylic acid. Acta Pharmaceutica Technologica. 33:21–26. 1987.Google Scholar
  183. 183.
    Thakur AB, Morris K, Grosso JA, Himes K, Thottathil JK, Jerzewski RL, Wadke DA, Carstensen JT. Mechanism and kinetics of metal ion-mediated degradation of fosinopril sodium. Pharm Res. 1993;10:800–9.PubMedCrossRefGoogle Scholar
  184. 184.
    Johansen H, Moller N. Solvent deposition of drugs on excipients II: interpretation of dissolution, adsorption, and absorption charcteristics of drugs. Arch Pharm Chem (Sci). 1977;5:33–42.Google Scholar
  185. 185.
    Tischinger-Wagner H, Endres W, Rupprecht H, Weingart A. [Oxidative degradation of linoleic acid methyl ester in suspensions of inorganic excipients. 1. Auto-oxidation in the presence of silicic acid products and aluminum oxide]. Pharmazie. 42:320–324. 1987.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Ajit S. Narang
    • 1
  • Divyakant Desai
    • 1
  • Sherif Badawy
    • 1
  1. 1.Drug Product Science and TechnologyBristol-Myers Squibb, Co.New BrunswickUSA

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