International Journal of Pharmaceutics 297 (2005) 156–161 Enhanced bioavailability of piroxicam via salt formation with ethanolamines Hye-Sun Gwak a , Jun-Shik Choi b , Hoo-Kyun Choi b,c,∗ a College of Pharmacy, Ewha Women’s University, Seoul 120-750, Republic of Korea b College of Pharmacy, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, Republic of Korea c Research Center for Resistant Cells, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, Republic of Korea Received 31 August 2004; received in revised form 21 March 2005; accepted 25 March 2005 Available online 25 April 2005 Abstract Piroxicam can be ionized as a zwitterion that has two pKa values (pKa 1 = 1.86 and pKa 2 = 5.46). Consequently, piroxicam has a low solubility in both polar and nonpolar media, and a low lipophilicity, which results in a low permeability. Three piroxicam- ethanolamine salts were prepared, which had a higher area under the curve (AUC) than piroxicam. There were minimal differences in the AUC among the salt forms. It was reported that the piroxicam triethanolamine salt had a lower permeability across the skin than piroxicam but it had a higher oral bioavailability. Piroxicam monoethanolamine showed the highest C max followed by piroxicam diethanolamine and piroxicam triethanolamine. The dissolution rates of piroxicam and its salts were similar at pH 1.2. Piroxicam monoethanolamine showed the highest dissolution rate at pH 6.8, which was followed by the piroxicam diethanolamine and piroxicam triethanolamine salts. The order of dissolution rate at pH 6.8 matched the order of C max or the AUC after oral administration. © 2005 Elsevier B.V. All rights reserved. Keywords: Piroxicam; Ethanolamine; Salt; Dissolution; Bioavailability 1. Introduction Piroxicam is one of the most potent non-steroidal anti-inflammatory drugs. It is an ionizable water- insoluble drug at a physiological pH. Specifically, piroxicam can be ionized as a zwitterion with two pKa ∗ Corresponding author. Tel.: +82 62 230 6367; fax: +82 62 228 3742. E-mail address: hgchoi@chosun.ac.kr (H.-K. Choi). values (Fig. 1, pKa 1 = 1.86 and pKa 2 = 5.46) (Jinno et al., 2000). A zwitterionic drug possesses a large in- tramolecular multipole moment due to its multiplicity of oppositely charged groups. Consequently, most of these drugs have a low solubility in polar and non- polar media, as well as a low lipophilicity. Although piroxicam belongs to class 2 with a low solubility and high permeability based on the Biopharmaceutics Clas- sification System (Lipka and Amidon, 1999), a phar- macokinetic study of piroxicam revealed that it takes 0378-5173/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2005.03.016