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Impact of Excipient Interactions on Solid Dosage Form Stability

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ABSTRACT

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.

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Abbreviations

Alu:

aluminum

API:

active pharmaceutical ingredient

ARP:

Amadori rearrangement product

BHA:

butylated hydroxyanisole

BHT:

butylated hydroxytoluene

GC:

gas chromatography

HCl:

hydrochloride

HCTZ:

hydrochlorothiazide

HDPE:

high density polyethylene

HPLC:

high performance liquid chromatography

HPMC:

hydroxypropyl methylcellulose

HPO:

hydroperoxide

ICH:

international conference on harmonization

LC/MS:

liquid chromatography tandem with mass spectroscopy

MVTR:

moisture vapor transmission rate

NF:

National Formulary

NMR:

nuclear magnetic resonance (spectroscopy)

PEG:

polyethylene glycol

pHmax :

pH of maximum solubility

PVA:

polyvinyl alcohol

PVP:

polyvinyl pyrrolidone (povidone)

PhEur:

European Pharmacopeia

PVP-VA:

polyvinylpyrrolidone-vinyl acetate copolymer

PXRD:

powder X-ray diffraction

SDMT:

sorption desorption moisture transfer

ssNMR:

solid state NMR

USP:

United States Pharmacopeia

REFERENCES

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Chapter  Google Scholar 

  3. Mahato RI, Narang AS. Pharmaceutical dosage forms and drug delivery. Boca Raton: CRC; 2012.

    Google Scholar 

  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.

  5. Carstensen JT, Osadca M, Rubin SH. Degradation mechanisms for water-soluble drugs in solid dosage forms. J Pharm Sci. 1969;58:549–53.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  7. Blaug SM, Wesolowski JW. The stability of acetylsalicylic acid in suspension. J Am Pharm Assoc. 1959;48:691–4.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  10. Mauger JW, Paruta AN, Gerraughty RJ. Consecutive first-order kinetic consideration of hydrocortisone hemisuccinate. J Pharm Sci. 1969;58:574–8.

    Article  PubMed  CAS  Google Scholar 

  11. Yoshioka S, Aso Y, Shibazaki T, Uchiyama M. Stability of pilocarpine ophthalmic formulations. Chem Pharm Bull. 1986;34:4280–6.

    Article  PubMed  CAS  Google Scholar 

  12. Khawam A, Flanagan DR. Basics and applications of solid-state kinetics: a pharmaceutical perspective. J Pharm Sci. 2006;95:472–98.

    Article  PubMed  CAS  Google Scholar 

  13. Dickinson CF, Heal GR. Solid–liquid diffusion controlled rate equations. Thermochimica Acta. 1999;340–341:89–103.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  15. Yoshioka S, Stella VJ. Stability of drugs and dosage forms. New York: Kluwer; 2000.

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  17. Yoshioka S, Uchiyama M. Kinetics and mechanism of the solid-state decomposition of propantheline bromide. J Pharm Sci. 1986;75:92–6.

    Article  PubMed  CAS  Google Scholar 

  18. Hasegawa J, Hanano M, Awazu S. Decomposition of acetylsalicylic acid and its derivatives in solid state. Chem Pharm Bull. 1975;23:86–97.

    Article  CAS  Google Scholar 

  19. Carstensen JT, Kothari RC. Decarboxylation kinetics of 5-(tetradecyloxy)-2-furoic acid. J Pharm Sci. 1980;69:123–4.

    Article  PubMed  CAS  Google Scholar 

  20. Carstensen JT, Musa MN. Decomposition of benzoic acid derivatives in solid state. J Pharm Sci. 1972;61:1112–8.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  23. Kornblum SS, Sciarrone BJ. Decarboxylation of P-aminosalicylic acid in the solid state. J Pharm Sci. 1964;53:935–41.

    Article  PubMed  CAS  Google Scholar 

  24. Vyazovkin S, Wight CA. Kinetics in solids. Annu Rev Phys Chem. 1997;48:125–49.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  29. Heidemann DR, Jarosz PJ. Preformulation studies involving moisture uptake in solid dosage forms. Pharm Res. 1991;8:292–7.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

  32. Rowe RC, Sheskey PJ, Weller PJ, Rowe R, Sheskey P, Weller P. Handbook of Pharmaceutical Excipients, APhA Publications. 2003.

  33. Kontny MJ. Distribution of water in solid pharmaceutical systems. Drug Dev Ind Pharm. 1988;14:1991–2027.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  40. Yoshioka S, Aso Y, Terao T. Effect of water mobility on drug hydrolysis rates in gelatin gels. Pharm Res. 1992;9:607–12.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  46. Waterman KC, Gerst P, Macdonald BC. Relative humidity hysteresis in solid-state chemical reactivity: A pharmaceutical case study. Journal of pharmaceutical sciences. 2011.

  47. Waterman KC, MacDonald BC. Package selection for moisture protection for solid, oral drug products. J Pharm Sci. 2010;99:4437–52.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  50. Stanisz B. The influence of pharmaceutical excipients on quinapril hydrochloride stability. Acta Pol Pharm. 2005;62:189–93.

    PubMed  CAS  Google Scholar 

  51. Crowley P, Martini L. Drug-excipient interactions. Pharmaceutical Technology Europe. 13:26–28, 30–32, 34. 2001.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  54. Murugesan R, Kaimulankara G, Pillai SRS. A novel pharmaceutical composition. (Fourrts (India) Laboratories Private Limited, India). Patent Application: IN 2005-CH990. 2007.

  55. Murthy KS, Ghebre-Sellassie I. Current perspectives on the dissolution stability of solid oral dosage forms. J Pharm Sci. 1993;82:113–26.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  62. Phadnis NV, Suryanarayanan R. Polymorphism in anhydrous theophylline–implications on the dissolution rate of theophylline tablets. J Pharm Sci. 1997;86:1256–63.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  68. Guerrieri P, Taylor LS. Role of salt and excipient properties on disproportionation in the solid-state. Pharm Res. 2009;26:2015–26.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  83. March J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fourth Edition. 1992.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  94. Badawy SI, Hussain MA. Microenvironmental pH modulation in solid dosage forms. J Pharm Sci. 2007;96:948–59.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  104. Irwin WJ, Iqbal M. Solid-state stability: the effect of grinding solvated excipients. Int J Pharm. 1991;75:211–8.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  107. Mahato RI, Narang AS. Pharmaceutical dosage forms and drug delivery, CRC Press. 2011.

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  117. Buhler V. Kollidon: Polyvinylpyrrolidone excipients for the pharmaceuticals, Springer-Verlag berlin Heidelberg, Germany. 2008.

  118. Narang AS, Rao VM, Desai DS. Effect of antioxidants and silicates on peroxides in povidone. J Pharm Sci. 2012;101:127–39.

    Article  PubMed  CAS  Google Scholar 

  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. Buhler V, Filges U, Schneider T. Stabilized polyvinylpyrrolidone formulation. (BASF A.-G., Germany). Patent Application: WO 2000059478. 2000.

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  128. Mollica J, Rehm C, Smith J. Hydrolysis of hydrochlorotiazide. J Pharm Sci. 1969;58:1380–4.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  131. Desai DS, Ranadive SA, Lozano R, Varia SA. Dissolution instability of encapsulated marketed tablets. Int J Pharm. 1996;144:153–8.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

  152. International Conferences on Harmonization. Impurities-- Guidelines for Residual Solvents. Q3C. In F. Register (ed.), Vol. 62. 1997. p 67377.

  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.

  154. Roy J. Pharmaceutical impurities - a mini review. AAPS PharmSciTech. 2002;3:1–8.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  157. Wang J, Wen H, Desai D. Lubrications in tablet formulations. Eur J Pharm Biopharm. 2010;75:1–15.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  159. Plackett RL, Burman JP. The design of optimum multifactorial experiments. Biometrika. 1946;33:305–25.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  161. International Council for Harmonization. Guidance for Industry: Q1E Evaluation of Stability Data. 2004.

  162. Waterman KC, Adami RC. Accelerated aging: prediction of chemical stability of pharmaceuticals. Int J Pharm. 2005;293:101–25.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. Naversnik K, Bohanec S. Predicting drug hydrolysis based on moisture uptake in various packaging designs. Eur J Pharm Sci. 2008;35:447–56.

    Article  PubMed  CAS  Google Scholar 

  169. George RC. Investigation into the yellowing on aging of Sabril tablet cores. Drug Dev Ind Pharm. 1994;20:3023–32.

    Article  CAS  Google Scholar 

  170. Rivera SL, Ghodbane S. In vitro adsorption-desorption of famotidine on microcrystalline cellulose. Int J Pharm. 1994;108:31–8.

    Article  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  177. Al-Nimry SS, Assaf SM, Jalal IM, Najib NM. Adsorption of ketotifen onto some pharmaceutical excipients. Int J Pharm. 1997;149:115–21.

    Article  CAS  Google Scholar 

  178. Botha SA, Lotter AP. Compatibility study between naproxen and tablet excipients using differential scanning calorimetry. Drug Dev Ind Pharm. 1990;16:673–83.

    Article  CAS  Google Scholar 

  179. Rowe RC, Forse SF. Pitting: a defect on film coated tablets. Int J Pharm. 1983;17:347–9.

    Article  CAS  Google Scholar 

  180. Swaminathan V, Kildsig DO. An examination of the moisture sorption characteristics of commercial magnesium stearate. AAPS PharmSciTech. 2001;2:28.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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. 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 

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  1. Drug Product Science and Technology, Bristol-Myers Squibb, Co., One Squibb Dr., P.O. Box 191, New Brunswick, New Jersey, 08903-0191,, USA

    Ajit S. Narang, Divyakant Desai & Sherif Badawy

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Narang, A.S., Desai, D. & Badawy, S. Impact of Excipient Interactions on Solid Dosage Form Stability. Pharm Res 29, 2660–2683 (2012). https://doi.org/10.1007/s11095-012-0782-9

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