Enantiomeric Identification of Pregabalin by GC-MS via Methylation and S-TPC Chiral Derivatization

J Forensic Sci. 2019 Mar;64(2):406-412. doi: 10.1111/1556-4029.13888. Epub 2018 Aug 6.


Pregabalin is a Schedule V controlled substance which is defined as the (S) enantiomer of 3-(aminomethyl)-5-methylhexanoic acid. It is used legitimately to treat neuropathy in patients with diabetes as well as for epilepsy and fibromyalgia. Pregabalin is an amino acid and an amphoteric compound, which makes it difficult to analyze using the conventional GC-MS instrumentation found in most forensic drug analysis laboratories. Problems associated with the traditional GC-MS analysis of pregabalin include selective solubility, ring closure to the corresponding lactam in the GC injection port and/or the MS transfer line and difficulty with chiral derivatization due to the presence of a carboxylic acid moiety. Here, we show that these challenges can be overcome by methylating (capping) the carboxylic acid portion of the pregabalin molecule and converting to the corresponding methyl ester. Once the methyl ester is synthesized, chiral derivatization at the amine can be achieved to identify the controlled (S) enantiomer of pregabalin via GC-MS.

Keywords: chiral derivatization; drug analysis; enantiomeric separation; forensic science; gas chromatography-mass spectrometry; methylation; pregabalin.

MeSH terms

  • Anti-Anxiety Agents / chemistry
  • Carboxylic Acids / analysis
  • Gas Chromatography-Mass Spectrometry*
  • Humans
  • Methylation
  • Molecular Structure
  • Pregabalin / chemistry*
  • Stereoisomerism


  • Anti-Anxiety Agents
  • Carboxylic Acids
  • Pregabalin