Influence of solid phase and formulation processing on stability of Abbott-232 tablet formulations - Excipients

Influence of solid phase and formulation processing on stability of Abbott-232 tablet formulations
Received: 29 November 2005; Revised: 13 April 2006; Accepted: 2 May 2006
J. Wardrop 1 *, D. Law 1, Y. Qiu 2, K. Engh 2, L. Faitsch 2, C. Ling 3
Published Online: 4 Aug 2006
Journal of Pharmaceutical Sciences
Wiley InterScience
Copyright ? 2006 Wiley-Liss, Inc.
1Manufacturing Science and Technology, Global Pharmaceutical Operations, Abbott Laboratories, North Chicago, Illinois 60064
2Global Formulation Sciences - Solids, Global Pharmaceutical and Analytical Sciences, Abbott Laboratories, North Chicago, Illinois 60064
3Global Analytical Research and Development, Global Pharmaceutical and Analytical Sciences, Abbott Laboratories, North Chicago, Illinois 60064

email: J. Wardrop (Jacqueline.Wardrop@abbott.com)
*Correspondence to J. Wardrop, Manufacturing Science and Technology, Global Pharmaceutical Operations, Abbott Laboratories, North Chicago, Illinois 60064. Telephone: (847) 935 5619; Fax: (847) 936 0095
Keywords
tablet ? amorphous ? stability ? wet granulation ? direct compression ? polarized light microscopy ? phase transformation
Abstract
Abbott-232 is a chemically stable, highly water soluble non-hygroscopic compound selected for development as a potent uroselective 1A agonist. An anhydrate, a monohydrate, and an amorphous phase were isolated. The anhydrate was chosen for formulation development based on solid-state characterization. Excipients for immediate release (IR) tablet formulations were selected according to compatibility studies. However, the prototype IR tablets designed for clinical trials were found to be chemically unstable. Thus, process-induced phase transformation was investigated as the likely cause of the observed instability. Since the drug loading in the formulations was low (1%), model granulations containing 30% drug were evaluated to test this hypothesis. Investigation using a variety of analytical techniques indicated that the observed degradation was, indeed, a result of a solution-mediated phase transformation from anhydrate to amorphous Abbott-232 during wet granulation. A new direct compression formulation was, therefore, developed to prevent the solution-mediated process induced phase transition. Since the drug loading was low, a polarized light microscope (PLM) method was used to evaluate the solid phase in the new formulation. PLM confirmed that the original anhydrate form remained unchanged in tablets manufactured by the dry process. Stability studies confirmed that both IR and extended release (ER) tablets of Abbott-232 were successfully developed for clinical trials using direct compression. ? 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:2380-2392, 2006
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