Chiral separation of terbutaline by supercritical fluid chromatography with peak purity determination by UPLC–MS and modeling for chiral recognition mechanism

Abstract

BACKGROUND

Terbutaline is the drug of choice for asthma patients but it exists in racemic mixture. (R)-(−)-terbutaline is 200 times more active than (S)-(+)-terbutaline yet it is not advisable to prescribe racemic mixture due to certain adverse effects of (S)-(+)-terbutaline. Therefore, a fast, effective and reproducible separation method is necessary.

RESULTS

Chiral separation was achieved on Chiralpak-IE and Chiralpak-IG columns (250 × 4.6 mm, 5 μm) using carbon dioxide-methanol (CO₂-MeOH, 60:40) with a 0.2% triethylamine mobile phase. The flow was 1.0 mL min⁻¹ with detection at 223 nm using a photodiode array (PDA) detector. The values of retention, separation and resolution factors were in the ranges 1.88–2.38, 1.14–1.26 and 0.91–1.17, respectively; with best separation with Chiralpak-IE. The tailing factors and number of theoretical plates were in the range of 1.0–1.23 and 487–3699. The purity of the separated peaks was determined by ultra-performance liquid chromatography–mass spectrometry (UPLC–MS); indicating 100% purity of the peaks. The chiral recognition was determined by modeling with binding affinities −5.0 and −6.0 for S- and R-enantiomers, respectively; indicating S-enantiomer elution first followed by R-enantiomers. The major forces responsible for the chiral resolution were hydrogen bonding and π-π interactions.

CONCLUSION

Owing to the great demand for optically active pure drugs and high economic pressure on analytical techniques, the chiral separation of terbutaline was achieved via inexpensive supercritical fluid chromatography. The reported method may be used to prepare optically active pure terbutaline drugs (R-enantiomers) at a pilot scale. © 2024 Society of Chemical Industry (SCI).