Development, optimisation and validation of chromatographic and qNMR spectroscopic methods for the detection and quantification of controlled drugs, psychoactive substances and prescription-only medications

Dixon, David Ian (2024) Development, optimisation and validation of chromatographic and qNMR spectroscopic methods for the detection and quantification of controlled drugs, psychoactive substances and prescription-only medications. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

The supply chains for the illicit drugs market are unregulated and consistency between tablets and powders are not to be expected, typically varying in shape, colour and active API content. This thesis has an overarching focus on cocaine, which is known to be seen in a wide range of purities and can potentially contain a wide range of adulterants dangerous to health. Three analytical techniques, attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy and ion mobility spectrometry (IMS) have been assessed and outlined, providing an alternative to gas chromatography-electron ionisation-mass spectrometry (GC-EI-MS), which is hailed as the “gold-standard” for forensic analysis within current literature. This aims to showcase alternative techniques to GC-EI-MS and to increase accessibility for on-site harm reduction illicit sample testing. Qualitative comparisons between GC-MS, bench-top NMR (BT-NMR) and FT-IR were made to assess their functionality for off-site harm reduction drug testing. GC-MS maintained the “gold-standard”. FT-IR proved to be a useful tool due to its fast, non-destructive analysis but should be used with the use of spectral subtraction to allow multiple component analysis of binary and tertiary illicit drug samples. BT-NMR provides a useful alternative, fully identifying 53.3% of binary mixtures, consisting of illicit cocaine and ecstasy samples, with complete identification of cocaine binary mixtures achievable between 70 – 40 % (w/w) content, matching simulated sample analysis. A 1H qNMR method for the quantification of cocaine in either its freebase or hydrochloride salt forms, within illicit samples (n = 97) was outlined, in the presence of 7 common adulterants: caffeine, benzocaine, phenacetin, ketamine, aspirin, procaine and levamisole, using a low-field (60 MHz) benchtop instrument. Method uses spectral acquisition of ~4.5 minutes using cheap deuterated solvents D2O and CDCl3, with simple sample preparation. Sample analysis was compared with GC-EI-MS showing good correlation (R2 = 0.9399). Method of analysis has also been adapted for no-D solvents allowing for cheaper and simpler analysis. A commercial IMS instrument (IONSCAN 600, Smiths Detection™) was used for sample analysis, performing qualitative analysis on samples containing a high prevalence of “ecstasy” tablets, cocaine and other powders seized from a festival setting. IMS identified the illicit component in 98.2% of samples analysed. Levamisole was the only active adulterant identified within binary mixtures, producing a full identification in 34.0% of samples (n = 18) and no identifications of tertiary mixtures, due to IMS inactive adulterants and low content % (w/w). Positional isomeric discrimination was assessed, showcasing good separation within typically singularly substituted isomers generally following in the order of ortho > meta/para. The characterisation and quantification for the new psychoactive substance 1-(1,3-benzodioxyl-5-yl)-2-(propylamino)butan-1-one (bk-PBDB, putylone), which has not been previously identified within the UK, was outlined. A reference standard was synthesised and common 1D and 2D NMR assignments are outlined, as well as proposed GC-EI-MS fragmentation patterns. This expands on the previous literature which only showed GC-EI-MS and allows other groups or organisations to identify and quantify as necessary.