Pharmaceutical Development and Technology, 11:443–451, 2006 Copyright © Informa Healthcare ISSN: 1083-7450 print / 1097-9867 online DOI: 10.1080/10837450600770577 443 LPDT Bioavailability Enhancement of Poorly Water Soluble and Weakly Acidic New Chemical Entity with 2-Hydroxy Propyl-b-Cyclodextrin: Selection of Meglumine, a Polyhydroxy Base, as a Novel Ternary Component Effect of Meglumine on DRF-4367 S. Basavaraj, Vaibhav Sihorkar, T.R. Shantha Kumar, Prakash Sundaramurthi, and Nuggehally R. Srinivas Formulation Research Department, Discovery Research, Dr. Reddy’s Laboratories Ltd., Hyderabad, India P. Venkatesh, Mullangi Ramesh, and Nuggehally R. Srinivas Drug Metabolism and Pharmacokinetic Department, Discovery Research, Dr. Reddy’s Laboratories Ltd., Hyderabad, India Sunil Kumar Singh Medicinal Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Hyderabad, India Nuggehally R. Srinivas Drug Development, Discovery Research, Dr. Reddy’s Laboratories Ltd., Hyderabad, India The purpose of the present study was to investigate the influence of a polyhydroxy base, N-acetyl glucamine (also know as Meglumine), as a ternary component on the complexation of DRF-4367, a poorly water-soluble and weakly acidic anti- inflammatory molecule, with 2-hydroxypropyl-β-cyclodextrin (HPβCD). The molecular inclusion of DRF-4367 with HPβCD alone and in combination with ternary component was aimed at improvement in solubility and, subsequently, dissolution rate- limited oral bioavailability. The solid complexes of DRF-4367 and HPβCD with or without meglumine (binary and ternary sys- tems, respectively) were prepared as coevaporated product in dif- ferent stoichiometric ratios and compared against physical mixture. The formation of inclusion complexes was confirmed by using classical instrumental techniques. Phase solubility stud- ies suggested that meglumine was responsible for solubility improvement via multiple factors rather than just providing a favorable pH. Mechanisms and factors governing solubility enhancement were investigated by using phase solubility and thermodynamic parameters. The complexation of DRF-4367 with HPβCD is thermodynamically favored because the Gibbs free energies of transfer of the drug to the cyclodextrin cavity are negative. The solubilization efficiency and stability were further improved while retaining the favorable Gibbs free energies of transfer with the addition of meglumine. Inclusion ternary com- plex of DRF-4367 with HPβCD and meglumine showed signifi- cant improvement in dissolution compared with uncomplexed drug and binary system. Moreover, the phenomena of reprecipi- tation observed with binary system during dissolution could be avoided with meglumine as an enabling ternary component. This improved physicochemical behavior of ternary complex with the novel inclusion of a polyhydroxy base translated into an enhanced oral bioavailability of DRF-4367 compared with either uncomplexed drug or nanosuspension. Keywords DRF-4367, 2-hydroxypropyl-β-cyclodextrin, ternary component, polyhydroxy base, meglumine, solubilization, new chemical entity INTRODUCTION The advent of combinatorial and high-throughput screening technologies has contributed to influx of lead molecules into discovery pipeline phenomenally. It is esti- mated that about 40% of molecules entering the discovery pipeline fail because of poor solubility or permeability, [1,2] the two important parameters that influence the viability of lead molecules in drug development. Many of the pipeline molecules are highly lipophilic and possess poor aqueous Received 3 October 2005, Accepted 7 January 2006. Address correspondence to Dr. Nuggehally R. Srinivas, Executive Vice President, Drug Development, Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad, India 500 049; Tel: +91 40 2304 5439 ext. 414; Fax: +91 40 2304 5438; E-mail: nrsrinivas@drreddys.com