Investigation of isomerization of dexibuprofen in a ball mill using chiral capillary electrophoresis

Abstract

Besides the racemate, the S-enantiomer of ibuprofen (Ibu) is used for the treatment of inflammation and pain. Since the configurational stability of S-Ibu in solid state is of interest, it was studied by means of ball milling experiments. For the evaluation of the enantiomeric composition, a chiral CE method was developed and validated according to the ICH guideline Q2(R1). The addition of Mg2+, Ca2+, or Zn2+ ions to the background electrolyte (BGE) was found to improve Ibu enantioresolution. Chiral separation of Ibu enantiomers was achieved on a 60.2 cm (50.0 cm effective length) x 75 μm fused-silica capillary using a background electrolyte (BGE) composed of 50 mM sodium acetate, 10 mM magnesium acetate tetrahydrate, and 35 mM heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD) as chiral selector. The quantification of R-Ibu in the mixture was performed using the normalization procedure. Linearity was evaluated in the range of 0.68–5.49% R-Ibu (R2 = 0.999), recovery was found to range between 97 and 103%, the RSD of intra- and interday precision below 2.5%, and the limit of quantification for R- in S-Ibu was calculated to be 0.21% (extrapolated) and 0.15% (dilution of racemic ibuprofen), respectively. Isomerization of S-Ibu was observed under basic conditions by applying long milling times and high milling frequencies.