Viscoleo, Ph. Eur Grade medium chain triglyceride, C8/C10 (MCT) was purchased from Delios V (Illertissen, Germany), lecithin (E80) for the intravenous emulsion was obtained from Lipoid AG (Ludwigshafen, Germany) and glycerol from Sigma Aldrich (St. Louis, MO, USA). Hypergrade acetonitrile from Merck (Darmstadt, Germany) was used for the HPLC–MS/MS analysis, ethanol was from De Danske Spritfabrikker
(Aalborg, Denmark) and deuterated aripiprazole used as the internal standard in the bioanalysis was purchased from Toronto Research Chemicals Linsitinib molecular weight Inc. (Toronto, ON, Canada). Purified water was obtained from a Millipore Milli-Q Ultrapure Water purification system (Billerica, MA, USA). All other chemicals were of analytical grade or higher. Aripiprazole lauroxil was obtained by an alkylation of aripiprazole using sodium hydride and chloromethyl laurate [33] in a mixture of N,N-dimethylformamide and tetrahydrofuran. After an aqueous work-up followed by column chromatography, aripiprazole lauroxil was isolated in 60% yield (LC purity: 96%) with data corresponding to that reported in literature [24]. To obtain N-hydroxymethyl
aripiprazole, aripiprazole was alkylated using sodium hydride and benzyl chloromethyl ether in a mixture of N,N-dimethylformamide and tetrahydrofuran [ 34]. After an aqueous work-up followed by column chromatography, the BOM-protected aripiprazole was isolated in 41% yield as confirmed by analytical data (data not shown). The BOM-protected aripiprazole was then stirred in methanol containing one equivalent HCl and Pearlman’s catalyst under an atmosphere of hydrogen to remove the benzyl group. The FER mixture was filtered ABT-263 cost and concentrated to give N-hydroxymethyl aripiprazole HCl in >95% yield (LC purity: 89%)
with data corresponding to that reported in the literature [ 24]. To follow the spontaneous conversion from N-hydroxymethyl aripiprazole to aripiprazole, a stock solution in DMSO-d6 was made so the reaction could be started by adding the stock solution into a phosphate buffer, pH 7.4, which thereby contained 0.5% v/v DMSO-d6. The final concentration of N-hydroxymethyl aripiprazole in the buffer was 9 µM equal to the solubility of aripiprazole in water [ 35]. The degradation was followed at both 25 °C and 37 °C by continuous measurements. 1H NMR spectra were measured at 600.163 MHz on a Bruker AV-III-600 equipped with a 5 mm TCI CryoProbe. Referencing was done to DMSO-d6 (2.51 ppm). Solvent suppression with excitation sculpting [ 36] using a square 180 pulse of 4 ms was applied on aqueous solutions. Acquisition time was 1.7 s and repetition delay was 3 s A Lorentzian Line broadening of 1.0 Hz was applied before FT, and the aromatic region was baseline corrected manually using a 4th degree polynomial fit before integration. An in vitro experiment was conducted in triplicate by adding 30 µL 1 µM aripiprazole lauroxil dissolved in ethanol to 1.47 mL rat plasma from female Sprague Dawley rats at 37 °C.
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