A new procedure is described for the derivatization by silylation of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) present in urine, followed by analysis using gas chromatography–tandem mass spectrometry. A conventional procedure for derivatization of the analyte was evaluated using two types of experimental design. A 23 factorial design considered the parameters temperature, reaction time, and the solvent/derivatization agent ratio. A central composite design (CCD) was applied to optimize the values of the significant variables. The optimum conditions were a reaction temperature of 50 °C, a reaction time of 30 min, and a BSTFA/acetone ratio of 40:20. The use of imidazole as a catalyst, together with ultrasonication, reduced the reaction time to 5 min and increased the efficiency of derivatization of THCCOOH, compared with the conventional method. The operating conditions of the tandem mass spectrometer were also optimized. The method was linear in the concentration range 1–50 ng mL−1 (R2 = 0.9951). Intra- and inter-day precisions were 7.7–12.3% and 11.1–13.9%, respectively, recoveries ranged between 91 ± 8% and 101 ± 12%, accuracy (as % bias) was between –11.7% and +0.7%, and limits of detection and quantification were 0.5 and 1.0 ng mL−1, respectively.
