Quality control of medicinal cannabis: implementation of a generic sfc-ms method to address counterfeiting with synthetic cannabinoids

There is a growing interest in using cannabis for medicinal purposes as research shows evidence
of its therapeutic properties. However, to be successfully ported in the pharmaceutical field,
several aspects such as its quality must be evaluated and ensured. In this context, we address
the possibility of counterfeiting of cannabis with synthetic cannabinoids and report the
development of a robust method based on supercritical fluid chromatography coupled with mass
spectrometry (SFC-MS) that could help in detecting such adulterations.
Considering the high number of already available synthetic cannabinoids and the high rate of
development of novel structures, we aimed to develop a generic method suitable for the analysis
of a large panel of substances using seventeen synthetic cannabinoids from multiple classes as
model compounds.
Firstly, a suitable column was chosen after a screening phase. The mobile phase (modifier
composition) was also set after these preliminary tests. Secondly, a method optimization was
carried out using a design of experiments (DoE) and Bayesian design space (DS) methodology
that follows ICH Q8 R2 guideline recommendations. This approach is increasingly recommended
for the robust optimization of analytical methods. The DoE selected was a four-factor central
composite design. Then, according to the goal of adequately analyzing future unknown
compounds, the criterion separation S was set to -0.5 to obtain a method with the highest
separation capacity. This quality by design (QbD) approach shows flexibility as it permits the
testing of various conditions within the DS to tune the separation taking into account that some
adaptations might be needed during routine analysis, since it is impossible to predict which
compound will be found.
Finally, the quantitative performances of the method were demonstrated by means of a validation
step based on total error approach for the quantification of a selected synthetic cannabinoid in
fiber type cannabis plant matrix. Sample preparation was performed with solid-liquid extraction
(SLE) followed by filtration and dilution. The acceptance limits were set at ±15% and the β-
expectation tolerance limits at 90 % probability level. The results show that the method is valid
over the whole dosing range assessed of 2.5 - 7.5% (w/w) and the LOD equal to 14.40 ng/mL.
The implementation of this method should be straightforward considering the ease of sample
preparation, the use of a simple modifier composition and the high specificity and sensitivity
achieved with mass spectrometry. This work adds an innovative tool to address the challenges
of ensuring medicinal cannabis quality and will prove useful in the context of counterfeit drugs
tracking.