Nucleophilic Group Transfer Reactivity for Fibric Acid Derived Drug Molecules LI LI, ERIC D. NELSON, RANDAL A. SEBURG, ROBERT A. REED Pharmaceutical Research and Development, Merck Research Laboratories, West Point, Pennsylvania 19486 Received 17 November 2005; revised 24 February 2006; accepted 5 April 2006 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20659 ABSTRACT: A novel group transfer reaction is reported in which a drug molecule undergoes a thermally induced 2-methyl-2-yl-propionic acid group transfer from one drug molecule to the carboxylic acid functional group of another. The resulting product, the 2-carboxy isopropyl ester of the parent compound, can itself participate in further reactions to yield a series of homologous products. The structural requirements and solvent dependence of this reactivity were investigated, and the resulting implications for the reaction mechanism were discussed. The experimental data is consistent with solvent-assisted nucleophilic substitution reaction mechanism, where the solvent is a small molecule or a second drug molecule. Hydrogen bonding appears to play an important role in both intramolecular activation of the leaving group, as well as intermolecular interaction with the attacking nucleophile. The reactivity is found to be intrinsic to the 2-arenoxy-2-methylpropionic acid structure, which is common to the extended class of fibrate PPAR drug molecules, suggesting that the potential for this reactivity exists for many of these drug molecules as well. ß 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:1954–1966, 2006 Keywords: nucleophilic reactivity; fibric acid; degradation; HPLC; NMR; PPAR INTRODUCTION Compound A (structure shown in Scheme 1) is a peroxisome proliferator activated receptor (PPAR) agonist for the treatment of noninsulin dependent/type II diabetes, dyslipidemia, and other PPAR mediated diseases and disorders. 1 From the structural point of view, Compound A is a member of an extended class of PPAR drugs, the fibric acid (2-phenoxy-2-methylpropionic acid) derivatives, which have a very important place in the treatment of diabetes. Other members of this structural class include fenofibrate, gemfi- brozil, clofibrate, bezafibrate, and ciprofibrate, as well as a large number of current and past drug candidates. 2,3 Drug stability is a key quality attribute to be considered during the product development pro- cess. Forced degradation studies are widely used to evaluate the intrinsic chemical stability of the drug molecules under various stress conditions, and well-designed degradation model systems can serve as predictive tools to probe the long-term drug stability in the actual formulations. Within the pharmaceutical industry, the general prac- tices for conducting forced degradation studies include stressing the bulk drug under accelerated temperature/humidity conditions alone and in the presence of excipients, as well as exposing drug solutions to acid/base, heat, light, hydrogen per- oxide, and radical initiators to probe the intrinsic sensitivity of the drug molecule to hydrolytic, thermal, photolytic, and oxidative degradation reactions. 4,5 For Compound A, a stable polymorph of the crystalline free acid was selected for formulation development. Forced degradation studies showed that Compound A exhibited significant degra- dation when subjected to thermal stress near its melting point (828C). Degradates I and II 1954 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 9, SEPTEMBER 2006 Correspondence to: Li Li (Telephone: 215-652-8124; Fax: 215-993-5932; E-mail: Li_Li3@Merck.com) Journal of Pharmaceutical Sciences, Vol. 95, 1954–1966 (2006) ß 2006 Wiley-Liss, Inc. and the American Pharmacists Association