Solubility and Stability Advantage of Aceclofenac Salts

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.