Solid-state stability of human insulin. II. Effect of water on reactive intermediate partitioning in lyophiles from pH 2-5 solutions: stabilization against covalent dimer formation

Journal of Pharmaceutical Sciences
R G Strickley, B D Anderson

Abstract

Previous studies have established that at low pH human insulin decomposition proceeds through a two-step mechanism involving rate-limiting intramolecular formation of a cyclic anhydride intermediate at the C-terminal AsnA21 followed by intermediate partitioning to various products, most notably desamido insulin and covalent dimers, in both aqueous solution and in the amorphous (lyophilized) solid state. This study examines the product distribution resulting from insulin degradation in lyophilized powders as a function of water content and the phase behavior of the solid (glassy versus rubbery) between pH 3 and 5. In amorphous solids at low water content (glassy state), the cyclic anhydride intermediate of insulin reacts predominantly with water to form deamidated insulin, whereas the intermolecular reaction with another insulin molecule to form a covalent dimer accounts for < or = 15% of the total degradation. Increasing water content reduces the glass transition temperature of insulin to < 35 degrees C, and covalent dimer formation becomes increasingly favored relative to deamidation. An increase in solid-state pH also favors dimerization as deprotonation of the terminal amino groups of insulin renders them more nucleophilic. ...Continue Reading

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Citations

Mar 21, 2007·Pharmaceutical Research·Kenneth C WatermanSheri L Shamblin
Mar 17, 2004·Biochemical and Biophysical Research Communications·Samer SinghRakesh Bhatnagar
Sep 5, 2002·Biochemical and Biophysical Research Communications·Samer SinghRakesh Bhatnagar
Sep 1, 2000·International Journal of Pharmaceutics·W Wang
Aug 26, 1999·International Journal of Pharmaceutics·W Wang
Jan 3, 2006·Diabetes Technology & Therapeutics·Steven WhiteNancy J Harper
Jun 11, 2005·The Journal of Chemical Physics·Sau Lawrence LeeJeffrey R Errington
Feb 12, 2000·Pharmaceutical Development and Technology·P G Shao, L C Bailey
Mar 3, 1999·Journal of Pharmaceutical Sciences·R C BeavisM R DeFelippis
Mar 3, 1999·Journal of Pharmaceutical Sciences·S T Tzannis, S J Prestrelski
Sep 9, 2006·Journal of Pharmaceutical Sciences·Aditya A Wakankar, Ronald T Borchardt
Jul 22, 2014·Journal of Pharmaceutical Sciences·Joshua J KlaeneZhaohui Sunny Zhou
Jul 2, 2009·Journal of Pharmaceutical Sciences·Liuquan Lucy Chang, Michael J Pikal
Mar 23, 2012·Journal of Pharmaceutical Sciences·Michael P DeHart, Bradley D Anderson
Jun 6, 2009·Journal of Pharmaceutical Sciences·Sisir Bhattacharya, Raj Suryanarayanan
Mar 5, 2004·Journal of Pharmaceutical Sciences·Tian-Xiang Xiang, Bradley D Anderson
May 24, 2007·Journal of Pharmaceutical Sciences·Michael P Dehart, Bradley D Anderson
Feb 6, 2004·Journal of Pharmaceutical Sciences·Jinjiang LiGeorge Zografi
Jan 6, 2009·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Alessandra MaroniMaria Edvige Sangalli
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Mar 19, 2013·International Journal of Pharmaceutics·Flore DepreterKarim Amighi
Oct 31, 2006·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Angelika MaschkeAchim Göpferich
Apr 25, 2007·Journal of Pharmaceutical Sciences·Sumie Yoshioka, Yukio Aso
May 7, 1999·Journal of Pharmaceutical Sciences·M C Lai, E M Topp

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