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Development of a GC-MS Method for Determination of Benzodiazepine Series Drugs Mass Spectrometry Data Center Kirill Tretyakov1, Aviv Amirav2, Anzor Mikaia1

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Development of a GC-MS Method for Determination of Benzodiazepine Series Drugs Mass Spectrometry Data Center Kirill Tretyakov1, Aviv Amirav2, Anzor Mikaia1 Development of a GC-MS method for determination of Benzodiazepine Series Drugs Mass Spectrometry Data Center Kirill Tretyakov1, Aviv Amirav2, Anzor Mikaia1 1National Institute of Standards and Technology, USA; 2Tel Aviv University, Tel Aviv, Israel. NOVELTY RESULTS and DISCUSSION 4 4 A GC-MS method for determination of drugs of Oxazepam (R =H) and Lorazepam (R =Cl) under EI do not show peaks of molecular ions while in the spectra of their N(1)-methyl analogs Substituents at 5-phenyl are the major donors of eliminating radicals under EI: benzodiazepine series is developed. Thermal and EI these peaks are present. Peaks of ions due to loss of water can be used for determination of M+· of Oxazepam and Lorazepam. induced decompositions of these compounds are studied However, one can suggest that these molecules are converted to quinazolines in a GC injection port, and GC retention indices and the [1] 2 spectra recorded correspond to dehydration products. It also has been established earlier that toluene or xylene solutions of 2 2 2 R R + by varying sample inlet configurations and ion source R + R + Oxazepam and Lorazepam at 110°C decompose with the formation of corresponding quinazoline aldehydes; they are the products of O O O O N N N N systems. Reliable GC retention index (GCRI) values and 4 water elimination. 3 - R mass spectral data are acquired. R 1 3 1 GC retention index values and mass spectra indicate degradation most of Oxazepam and Lorazepam molecules in a GC injection port R N 1 N R 1 R N R R N 3 CH R 3 and further water elimination in a GC column, and probably in EI source (Figure 1). Additional experiments on “Open Probe Fast GC-MS” 4 CH CH R INTRODUCTION R 4 have confirmed degradation of Oxazepam and Lorazepam in a GC system (injection port and column), and experiments conducted on R 4 R Benzodiazepines are widely prescribed drugs. They are “Fast GC-MS with Cold EI” demonstrated sample degradations in the ion source as well. sensitive to elevated temperature. Detection of R1 = Cl, NO ; R2 = H, SiMe ; R3 = H,OSiMe ; R4 = Cl, D, F, H benzodiazepines by various mass spectrometry methods, Injection technique for 100% a a) Inlet temperature 200ºC, standard injection of the 2 3 3 On-column derivatization Sandwich “Oxazepam” Oxazepam including GC-MS, involves preliminary chemical bis TMS derivative Oxazepam solution. injection modification of these compounds yielding stable 0 H O N 280 derivatives; often the spectra of derivatives exhibit 100% b) Inlet temperature 200ºC, standard injection of the 100 a b 314 Oxazepam bisTMS derivative synthesized prior fragmentation pathways useful for structure O +· N N 315 M determination. In this study synthesis, measurements GC-MS experiment. 0 O 286 Cl 234 and examination of GCRI and EI mass spectra of 100% c) Inlet temperature 150ºC, sequential injection of the c 50 trimethylsilyl derivatives of these drugs of abuse are Oxazepam sample and silylating reagent (MSTFA) - 75 Pause between 89 151 177 63 102 205 conducted. Acquired data will be included in the 2017 sample and On-column derivatization. 51 125 268 reagent injection 0 138 39 111 252 release of the NIST/EPA/NIH library. 100% % RelativeIntensity, 28 164 190 213 d d) Inlet temperature 200ºC, sequential injection of the 15 298 Reaction Oxazepam sample and silylating reagent (MSTFA) - 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 EXPERIMENTAL zone at On-column derivatization. m/z Sandwich 0 (imsc-2014) Clonazepam injection 100% 298 Chemicals: Lorazepam (1), Lormetazepam (2), e e) Inlet temperature 200ºC, Sandwich injection of the 100 H O b N N-Desmethylflunitrazepam (3), Clonazepam (4), Oxazepam (5), Oxazepam sample (1mg/mL in acetonitrile) and Reaction silylating reagent (MSTFA). 0 O +· Temazepam (6) are commercially available. zone at N N 272 299 M 100% On-column f ) Inlet temperature 200ºC, standard injection of the O 224 derivatization f 50 F 2 Oxazepam sample preheated at 200ºC followed by R 252 O silylation with the MSTFA reagent. 280 0 75 197 51 102 170 63 134 144 234 N % RelativeIntensity, 28 39 85 122 157 205 Time, min 18 185 0 3 Figure 1. Total ion currents (TIC) obtained for Oxazepam (a), products of its silylation carried out prior (b) and online GC-MS analysis(c, d, e), 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 R m/z and for dehydration product of Oxazepam at 200ºC (f). (imsc-2014) N-Desmethylflunitrazepam 1 N 73 R 100 c Si EI mass spectral data for the standard GC experiment, Open Probe and Cold EI O 4 N 429 R Mass spectral data acquired for Lorazepam on the traditional GC-MS (Figure 2a), on Open Probe Fast GC-MS (Figure 2b) and on Fast O Cl N Si GC-MS with Cold EI (Figure 2c) demonstrate that we actually observe a spectrum of Quinazoline aldehyde (not Lorazepam) when 50 430 M+· spectrum is obtained on a traditional GC-MS instrument. A replacement of a regular GC with an Open Probe Fast GC-MS produces a 147 spectrum that contains spectra of Quinazoline aldehyde and Lorazepam; a spectrum of an unseparated mixture of compounds is 45 313 340 401 415 Relative Intensity, % RelativeIntensity, 179 324 (1) R1,R4= Cl; R2= H; R3= OH. (2) R1,R4= Cl; R2= CH ; R3= OH. acquired. A spectrum of individual Lorazepam is obtained only on Fast GC-MS with Cold EI instrument. However, this spectrum cannot 15 27 59 87 100 113 133 163 205 239 253 267 281 353 371 384 3 0 1 2 3 4 1 2 3 4 be considered as a traditional EI spectrum since low mass peaks are discriminated and intensities of molecular ions are elevated in Cold 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 (3) R = NO2; R ,R = H; R = F. (4) R = NO2; R ,R = H; R = Cl. EI ion source spectra. The results presented in Figures 2 a-c establish that thermal decomposition of Lorazepam occurs in the inlet (imsc-2014) Oxazepam, bis(trimethylsilyl) derivative m/z (5) R1= Cl; R2= H; R3= OH; R4= H. system and in the ion source. 73 100 Si (6) R1= Cl; R2= CH ; R3= OH; R4= H. O 3 d N N CHO O Trimethylsilylation was carried out at 60°C with the use of (Q) 239 a Cl N Si 100 N N,O-Bis(trimethylsilyl) trifluoroacetamide (BSTFA) with 1% Cl 274 D M+· D trimethylchlorosilane (TMCS) or N-Methyl-N-(trime Cl 75 50 302 D +· thylsilyl)trifluoroacetamide (MSTFA) as silylating reagents. On- 433433435 M 111 138 D 50 45 147 D column derivatization of Lorazepam and Oxazepam was 318 177 406 102 % RelativeIntensity, 345 420 performed to identify any thermal decomposition products 163 59 82 100 131 155 184 210 29 50 119 150 203 15 27 243 256 269 282 358 376 389 (Figure 1). 39 62 85 186 0 Relative Intensity, % RelativeIntensity, 0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 m/z Instrumentation and measurements 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 (imsc-2014) Oxazepam-D5, bis(trimethylsilyl) derivative (imsc-2014) Lorazepam Figure 3. EI spectra of Clonazepam (a), N-Desmethylflunitrazepam (b) and TMS ethers of Oxazepam (c) and D5-Oxazepam (d). Standard GC-MS method: EI mass spectra were measured (Q)+(L) 291 on GC-MS systems with quadrupole analyzers (ionization 100 b energy 70 eV; ion source temperature 230oC), with GC conditions: VF-5ms capillary column (30 m, 0.25 mm, 0.25 µm, 75 50 138 239 CONCLUSIONS 1 mL/min helium (He) flow); oven temperature program – from 111 177 274 +· 151 302 M 60°C to 270°C at 10°C/min; inlet and transfer line at 270°C. 51 63 163 263 88 126 202 213 229 320 Open Probe Fast GC-MS: MS conditions were used as in the % RelativeIntensity, 0 • Lorazepam and Oxazepam molecules undergo dehydrating processes in a GC system and in the ion source; 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 standard method, GC conditions: Rx1-5HT capillary column +· (Spec. Edit) Component at scan 2167 (4.338 min) [Model = +111u] in F:\_GCMS_KIRILL\OPEN PROBE\2016-08\2016-08-30\LORAZEPAM_B.D\DATA.MSM • Information on stability of Lorazepam and Oxazepam molecules and their transformation at different stages of (2.0 m, 0.25 mm, 0.1 µm, 2.0 mL/min He flow); oven 320 100 H O GC-MS analysis is obtained and optimal trimethylsilylation conditions for their GC-MS analysis are established; temperature program – from 60°C to 320°C at 200°C/min; inlet c N (L) and transfer line 220°C. OH • An aromatic ring at C-5 is a major source for the elimination of hydrogen and halogen radicals; Cl N Fast GC-MS with Cold EI: GC-MS with Cold EI is based on a 181 • The Influence of a nature of N on dissociative ionization of benzodiazepines is evaluated. 50 214 (1) GC and MS interface with a supersonic molecular beam (SMB) Cl 242 and on the EI of sample compounds while they are vibrationally 89 107 63 75 125 138 152 163 257 277 292 REFERENCES cold in the SMB (hence the name Cold EI) in a fly-through ion % RelativeIntensity, 0 source. GC conditions: Rxi-1HT capillary column (15 m, 0.32 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 [1] M.S.
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