Solubility and stability advantage of aceclofenac salts

Abstract

The nonsteroidal anti-inflammatory drug aceclofenac was screened with pharmaceutically acceptable coformers to discover novel solid forms of improved solubility. First, the X-ray crystal structure of aceclofenac (ACF) was analyzed to contain the rare carboxylic acid catemer O-H···O synthon, stabilized by auxiliary C-H···O and Cl···O interactions. Slurry grinding of aceclofenac with different coformers in a fixed stoichiometry resulted in salts with cytosine (1:1), piperazine (1:0.5), l-lysine (1:1), and γ-aminobutyric acid (1:1). The problem of drug cyclization to give the inactive indolinone byproduct is avoided in the mild conditions of salt formation. All the salts were characterized by spectroscopic methods, thermal analysis, and X-ray diffraction. Aceclofenac-l-lysine salt showed 135 times faster intrinsic dissolution rate (IDR) and 127 times higher area under the curve (AUC) compared to aceclofenac. ACF-LYS is a high solubility salt that is stable in the accelerated International Conference on Harmonization (ICH) conditions of 40 C and 75% relative humidity for 8 months. © 2013 American Chemical Society.