Robert D. Johnson 

Russell J. Lewis 

Mike K. Angier

Civil Aerospace Medical Institute

Federal Aviation Administration

Oklahoma City, OK 73125

February 2010

Final Report

False Carbamazepine Positives Due To

10,11-Dihydro-10-Hydroxycarbamazepine

Breakdown in the GC/MS Injector Port

DOT/FAA/AM-10/4

Office of Aerospace Medicine

Washington, DC 20591

OK-10-0077-JAH

Federal Aviation

Administration
NOTICE

This document is disseminated under the sponsorship 

of the U.S. Department of Transportation in the interest 

of information exchange. The United States Government 

assumes no liability for the contents thereof.

___________

This publication and all Office of Aerospace Medicine 

technical reports are available in full-text from the Civil 

Aerospace Medical Institute’s publications Web site: 

www.faa.gov/library/reports/medical/oamtechreports
i

Technical Report Documentation Page 

1. Report No. 2. Government Accession No. 3. Recipient's Catalog No. 

DOT/FAA/AM-10/4 

4. Title and Subtitle 5. Report Date 

Carbamazepine Positives Due To 10,11-Dihydro-10- February 2010 

Hydroxycarbamazepine Breakdown in the GC/MS Injector Port 6. Performing Organization Code 

 

7. Author(s) 8. Performing Organization Report No. 

Johnson RD, Lewis RJ, Angier MK 

9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) 

FAA Civil Aerospace Medical Institute 

P.O. Box 25082 11. Contract or Grant No. 

Oklahoma City, OK 73125 

12. Sponsoring Agency name and Address 13. Type of Report and Period Covered 

Office of Aerospace Medicine 

Federal Aviation Administration 

800 Independence Ave., S.W. 

Washington, DC 20591 14. Sponsoring Agency Code 

15. Supplemental Notes 

This work was accomplished under the approved task AM-B-05-TOX-204. 

16. Abstract 

During the investigation of aviation accidents, postmortem specimens from accident victims are submitted to the 

Federal Aviation Administration’s Civil Aerospace Medical Institute (CAMI) for toxicological analysis. A case 

recently received by CAMI screened positive for the anticonvulsant medication carbamazepine (Tegretol®

) by gas 

chromatography/mass spectrometry (GC/MS). The carbamazepine found during the routine screening procedure 

was subsequently confirmed using a carbamazepine-specific GC/MS procedure. Concurrently, it was discovered 

that the accident victim had been prescribed oxcarbazepine (Trileptal®

). Oxcarbazepine is nearly structurally 

identical to carbamazepine and is metabolized by cytosolic enzymes in the liver to the active compound 10,11-

dihydro-10-hydroxycarbamazepine. The carbamazepine initially found in this case was present due to the 

breakdown of the active oxcarbazepine metabolite in the GC/MS injector port. In the current study this 

conversion is investigated, the percentage of carbamazepine formed at various injector port temperatures is 

determined, and these three compounds are quantified in nine fluid and tissue specimens from the case in 

question. Lastly, liquid chromatography/mass spectrometry (LC/MS) was used to demonstrate the absence of 

carbamazepine, and its formation, in the same specimens. 

 

17. Key Words 18. Distribution Statement 

 

 

Forensic Toxicology, Oxcarbazepine, Carbamazepine, 

GC/MS, LC/MS, Aircraft Accident Investigation 

Document is available to the public through the 

Defense Technical Information Center, Ft. Belvoir, VA 

22060; and the National Technical Information 

Service, Springfield, VA 22161 

19. Security Classif. (of this report) 20. Security Classif. (of this page) 21. No. of Pages 22. Price 

Unclassified Unclassified 9 

Form DOT F 1700.7 (8-72) Reproduction of completed page authorized 

iii

Co

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Reagents, Standards, and Supplies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Instrumentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

. . Gas Chromatographic/Mass Spectroscopic Conditions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

. . Liquid Chromatographic/Mass Spectroscopic Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Calibrators and Controls. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Sample Extraction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Results and Discussio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Carbamazepine Formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

. . Postmortem Specimen Analysis.

Conclusion                                                                                                                                     .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

1

False Carbamazepine Positives due to 10,11-Dihydro-1

Hydroxycarbamazepine Breakdown in the GC/MS Injec

Intr

TheFederalAviationAdministration’sCivilAerospace

Medical Institute (CAMI) is responsible under U.

Department of Transportation Orders 8020.11B an

1100.2Cto “conducttoxicological analysis on specimen

from ... aircraft accident fatalities” and “investigate ...

general aviation and air carrier accidents and search for

biomedical and clinical causes ofthe accidents, including

evidence of ... chemical [use].” Therefore, following a

aviation accident, samples are collected at autopsy and

sent to CAMI’s Forensic Toxicology Research Laboratory,wheretoxicological analysisis conducted on various

postmortem fluids and tissues

Anticonvulsantmedications are commonlyprescribed

for the treatment of epilepsy

1-3 These medications

also act as mood stabilizers and are prescribed in that

function for the treatment of bipolar disorder

4 Two

of the most common anticonvulsant medications are

carbamazepine (CBZ, (Z)-5H-dibenzo[b,f]azepine-5-

carboxamide, Tegretol®) and oxcarbazepine (OXCBZ,

10,11-dihydro-10-oxo-5 H -dibenz(b,f )azepine-5-

carboxamide, Trileptal®). OXCBZ, currently one of t

top-100 prescribed drugs in America,5 is metabolized in

the liver, via cytosolic enzymes, to the active metabolite

10,11-dihydro-10-hydroxycarbamazepine (DiCBZ)

6

These three compounds are nearly identical structurally,

as can be seen in Figure 1

One aviation accident victim recently received by

CAMIscreenedpositiveforCBZby gas chromatography/

massspectrometry (GC/MS). TheCBZfoundduring t

routinescreening procedurewassubsequently confirmed

and quantified using a CBZ-specific GC/MS procedure

However, during the investigation it was discovered

that the accident victim had been prescribed OXCBZ

Specimens from the victim were reanalyzed by GC/MS

to confirmandquantifybothOXCBZanditsmetabolite,

DiCBZ. While analyzing analytical standards of the

compounds by full-scan GC/MS prior to analysis, it

becameevident that CBZ was present following separate

injections of each individual standard

Numerousliquidchromatography (LC)methodshave

been developed for the analysis of these anticonvulsant

medications. Many of these use mass spectrometry as t

detector (LC/MS),1,7-11 while others employ ultraviolet

(UV) detection

12,13 There are, however, few GC/MS

methods cited for this purpose. The current study w

initiatedwiththe goalofevaluatingCBZproduction(and

subsequent false-CBZ positives) following the GC/MS

injection of OXCBZ and DiCBZ. This work employ

both GC/MS and LC/MS on each specimen analyzed

to compare the two analytical techniques

Materials and 

Reagents, Standards, and Suppl

All aqueous solutions were prepared using double

deionized water (DDW), which was obtained using an

ELGA, PURELAB Ultra water system (ELGA, Lowell,

MA). All chemicals were purchased in the highest possible purity and used without any further purificati

All solvents were of HPLC-grade and were obtained

from Fisher Scientific (Fischer Scientific Co., Fair Lawn

NJ). Formic acid (97%) was purchased from ICN (I

Biomedicals, Inc., Irvine, CA). CBZ was obtained f

Cerilliant (CerilliantCorp., Round Rock,TX), OXCB

N

NH2 O

N

NH2 O

O

OXCBZ CBZ

N

NH2 O

OH

DiCBZ

heat

Figure 1. OXCBZ metabolizes to DiCBZ, which can then form CBZ, through dehydration, when 

exposed to high temperatures.
2

and DiCBZ were obtained from Alltech (Grace Corp.

Deerfield, IL), and dihydrocarbamazepine was obtained

from Sigma (Sigma-Aldrich Corp., St. Louis, 

Stock standard solutions ofOXCBZandDiCBZwere

prepared at a concentration of 1 mg/mL in methanol

The CBZ standard came at a concentration of 1 mg/mL

in a sealed ampoule in methanol. A stock solution of t

internal standard (dihydrocarbamazepine) was prepared

at a concentration of 100 μg/mL in methanol

Instrumentation

Gas Chromatographic/Mass Spectroscopic Conditions

Thebench-topGC/MSsystemconsistedof aHewlett

Packard (HP) 6890 series GC, interfaced with a HP

5973 quadrupole MS (Agilent, Palo Alto, CA). T

GC/MSwas operatedwith a transferlinetemperature of

280°Cand a sourcetemperature of 250°C. The MSw

tunedonadailybasisusingperfluorotributylamine. T

electron multiplier voltage was set at 106 eV above the

tune voltage. Chromatographic separationwas achiev

using a Varian, FactorFour, crosslinked 100% methyl

siloxane capillary column (12 m x 0.2 mm i.d., 

μm film thickness). Helium wasemployed as the carr

gas and used at a flow rate of 1.0 mL/min. A HP 6

autosampler was used to inject 1 μL of extract into t

GC/MS. The GC was equipped with a split/splitle

injection port operated at 250°C in the splitless mode

with a purge time of 0.5 min. The oven temperat

profile wasestablished as follows: 130 - 290°Cat 25°C/

min with a final hold time of 1.00 min, resulting in 

total run time of 7.40 min. Initially, standards of e

compound (1 μL of a 100 ng/μL solution)wereinjec

individually and analyzed using the full-scan mode of

the GC/MS, which scanned from 50 to 600 AMU

Quantification and qualifier ions for each analyte were

then selected based on both abundance and mass-tochargeratio(m/z). Toincreasereproducibility andredu

interference, highmassionswereselectedwhen possible

The ions chosen for each respective analyte and the

retention times observed can be seen in Table 1. Up

selection of uniqueions, the MS was run in selected ion

monitoring (SIM) mode with a dwell time of 30 msec

for each recorded ion

Liquid Chromatographic/Mass Spectroscopic Conditions

Analyteseparation was achieved using a Agilent 1200

seriesHPLC(AgilentCorp.,Wilmington,DE)equippe

withaSecurityGuardC-8guardcolumn(4.0x3.0

i.d., 3 μm particles) from Phenomenex (Torrance, CA

followed immediately by an Atlantis LC-18 (150 x 4.

mmi.d.,3 μmparticles) analytical column(WatersC

Milford, MA). Samples were injected using an Agile

G1329Aautosampler(AgilentCorp.,Wilmington,DE

Identificationandquantificationwere accomplishedusing

a Thermofisher Scientific model LTQ XL atmospheric

pressure chemical ionization (APCI) linear ion trap mass

spectrometer (Thermofisher Scientific Corp., San Jose

CA), which utilized nitrogen as the sheath and auxiliary

gas. Control of the HPLC system, integration of t

chromatographic peaks, and communication with the

massspectrometerwere accomplishedvia apersonal computer using Xcalibur LC/MS software (Thermofisher

Scientific Corp., San Jose, CA

Calibrators and Controls

Calibration curves were prepared by serial dilution

utilizing bovine whole blood as the diluent. Calibrato

were prepared from one original stock standard solution

of each compound. Controls were prepared in a simil

manner as calibrators, using the same bovine whole

blood as diluent but employing a second original stock

solution. Calibration curves wereroutinely prepared at

concentration range of 12.5 – 800 ng/mL. A mini

of 5 calibrators were used to construct each calibration

curve. Controls used for the validation of each calibration curve constructed were prepared at concentratio

of 80, 160, and 320 ng/mL. A dihydrocarbamazepi

working internal standard solution was prepared at a

final concentrationof 400ng/mLby dilutionwithDDW

from the stock solution

Table 1. Ions employed and retention times expected for the 

GC/MS-SIM analysis of CBZ, OXCBZ, DiCBZ, and 

dihydrocarbamazepine. 

Compound Ions (m/z)* Retention Time 

CBZ 193, 236, 165 4.68 

OXCBZ 180, 252, 209 4.95 

DiCBZ 193, 254, 210 5.07 

Dihydrocarbamazepine 194, 238, 180 4.55 

* Ions in bold used for quantitation. 
3

Quantification of OXCBZ, DiCBZ, andCBZ in biological specimens was achieved via an internal standard

calibration procedure. Responsefactorswere determin

for each sample. The response factor was calculated 

dividing the area of the analyte peak by the area of the

internal standard peak. Calibration curves were prepar

by plotting a linear regression of the analyte/internal

standard responsefactor versusthe analyte concentration

for the calibrators and were used to determine the concentrations ofeachcompoundincontrols andspecimens

Sample Extractio

Calibrators, controls, and postmortem specimens

were prepared and extracted in the following manner

Tissue specimens were homogenized using a PRO250

post-mounted homogenizer (PRO Scientific, Oxford,

CT) employing a 30.0 mm saw-toothed generator se

to rotate at 22,000 RPM following a 2:1 dilution with

1.00% sodium fluoride (2 g 1.00% NaF:1 g wet tissu

Three mL aliquots of calibrators, controls, and postmortem fluids and 3 g aliquots of tissue homogenate (1

g tissue) were transferred to individual 15 mL screw-top

vials. To each sample, 400 ng of internal standard w

added (1.00 mL of the 400 ng/mL stock solution). 

samples were vortexed and allowed to stand for 10 min

Six mL of 0.10 M phosphate buffer, pH 6.00 was add

toeachspecimen. Themixturewasthenplacedona rota

mixing wheel and mixed for 15 min by simple rotation

of the wheel at 15 rpm. Centrifugation at 2500×g f

15 min allowed for the removal of cellular debris and

proteins. Following centrifugation, the specimens we

transferred to Styre Screen solid-phase extraction (SPE)

columns (United Chemical Technologies, UCT Inc.

Bristol, PA.), which had been pre-conditioned with 2.

mL methanol, followed by 2.00 mL 0.10 M phospha

buffer, pH 6.00. Care was taken not to dry the SPE column prior to extract addition. Column flow rates of 

mL/min were maintained in each step using a Varian 24

port Cerex SPE processor (Varian Co., Harbor City

CA.) with a nitrogen pressure of 3 psi. Onceeach sam

had passed through its respective column, the columns

were washed with 2 mL 0.10 M phosphate buffer, p

6.00, and then dried completely with 25 psi nitroge

for 1 min. The columns were then washed by adding

mL 1.0 M acetic acid and were then dried completel

with 25 psi nitrogen for 2 min. The columns were th

washed by adding 2 mL of hexane and were again dried

completely with 25 psi nitrogen for 2 min. The analyt

were eluted from the columns with 3 mL of methylene

chloride. Eluents were evaporated to dryness in a wat

bath at 40°C under a stream of dry nitrogen, reconstituted in 50 μL ethyl acetate, and transferred to sample

vialsfor analysis. Allspecimenswere analyzed at oneti

to avoid inter-assay variations. Specimens with analy

concentrations above the associated calibration curves

were diluted by an appropriate factor and re-extracted

When specimen dilution was necessary, a control was

diluted by the same factor to ensure dilution accuracy

Results and 

Carbamazepine Formation

This study evaluated the formation of CBZ during

the analysis of OXCBZ and its metabolite, DiCBZ, at

varying injector port temperatures. During the cour

of the experiment, each standard or specimen analyzed

by GC/MS was subsequently evaluated by LC/MS. Th

additional step was employed to determine whether the

source of CBZ formation was the heated GC injector

port. Finally, 8 fluid and tissue specimens (blood, live

lung, kidney, spleen, muscle, brain, and heart) from a

fatal aviation accident victim that had previously been

found positive for both OXCBZ, DiCBZ, and CBZ

were analyzed

TherewerenodeuteratedanalogsavailableforOXCBZ,

DiCBZ, or CBZ at the time of this analysis so a structurally related internal standard, dihydrocarbamazepine,

was employed. All analytes were extracted using a rap

SPE procedure and assayed by both GC/MS and LC/

MS. Even with such a simple extraction procedure, 

analyte suffered interference from endogenous matrix

components. All analyte peaks were completely resolv

by both GC and LC

OXCBZ and DiCBZ were individually evaluated for

possible conversion to CBZ under theextremetemperatures encountered in the GC injection port. The initi

observation of the possible conversion ofeither OXCBZ

or DiCBZ to CBZ during the screening process was observed at a GC injector port temp of 250°C. Therefor

the possible conversion of OXCBZ and/or DiCBZ to

CBZ in the injector port necessitated the evaluation

of the injector port at various temperatures. The 

injector port temperatures evaluated in this study were

200, 225, 250, and 275°C. This evaluation was accomplished by injecting 1 μL of a 100 ng/μL neat sta

of either OXCBZ or DiCBZ separately and monitoring

the formation of CBZ

The production of CBZ, monitored by collection of

its base peak at m/z 193.1, was found to be 0.8 ± 0

(n=4), 0.7 ± 0.1% (n=4), 0.9 ± 0.3% (n=4), and 

0.2% (n=4) of the peak area of the OXCBZ base pea

at m/z 180.1, at GC injection port temperatures of 200

225, 250, and 275°C, respectively. When analyzed 

LC/MS, CBZ was found to be present in the OXCBZ
4

standard, similar to that found by GC/MS. The lack 

GCtemperaturedependant conversionandthepresenceof

CBZ on LC/MS indicated that there was a trace amount

ofCBZ contamination in the OXCBZ standard and that

no thermal conversion of OXCBZ to CBZ occurred at

the temperatures investigated

The production of CBZ from DiCBZ (base peak at

m/z 193.1)wasfound to be 2.4 ± 0.3% (n=4), 4.8 ±

(n=4), 12.8 ± 0.3% (n=4), and 26.6 ± 1.4% (n=4) a

injectionporttemperaturesof200,225,250, and275°C,

respectively. The same DiCBZ standard was analyz

by LC/MS, and CBZ was not detected. The absence 

CBZ in the standard analyzed by LC/MS, coupled with

the temperature dependant conversion seen on the GC,

indicated that there was significant thermal conversion

of DiCBZ to CBZ in the heated injector port. Thelike

mechanism of artifactualCBZ formation is the dehydration of DiCBZ in the heated injector port to form CBZ

Asis clearly evident,the conversion ofDiCBZtoCBZ

is less of a factor at lower temperatures. However, low

GC inlet temperatures were shown to sacrifice GC/MS

sensitivity. Therefore, to minimize the CBZ formati

and maximize the analyte response, we chose to use an

injector temperature of 225°C for the analysis of all

postmortem specimens

Postmortem Specimen Analysis

In fatal aviation accidents, specimens from accident

victims are sent to the Federal Aviation Administration’s

Forensic Toxicology Research Laboratory for toxicological analysis. During initial drug screening, a rece

case appeared to be positive for CBZ and, in fact, was

confirmed positive by GC/MS for the presence of CBZ

However,informationexistedindicatingthatthepilotwas

taking OXCBZ, not CBZ. This case was subsequent

re-analyzed and found positivefor OXCBZ and DiCBZ,

thus prompting this study

Numerous postmortem fluid and tissuesamples from

the victiminthis casewereexaminedusing this optimized

GC/MS method to determine the presence of OXCBZ,

DiCBZ, and the possibleformation of CBZ. All sampl

found positive for CBZ were also analyzed by LC/MS

to determine if the CBZ present was from artifactual

formation. Each fluid and tissuespecimen availablefr

this victim was analyzed. As previously stated, deuterated analogs of these compounds were not available 

internal standards at the time of this study. Therefor

the interpretation of quantitative data in specimen types

other than blood should be closely scrutinized due to

possible variations in extraction efficiencies between

specimen typeseven though theinternalstandard chosen

was structurally very similar

OXCBZ,DiCBZandCBZwerefoundinallspecimens

examined by GC/MS, despite the lower inlet temperature employed. The results of the GC/MS analysis a

shown in Table 2. OXCBZ was found at concentratio

of 0.743, 0.891, 0.973, 2.539, 0.737, 0.391,

and 0.215 μg/mL (μg/g) in blood, liver, lung, kid

spleen, muscle, brain, and heart specimens, respectively

DiCBZ was found at concentrations of 9.848, 38.74

25.696,15.603,14.676,26.859,19.963, and23

mL (μg/g) in blood, liver, lung, kidney, spleen, muscle

brain, and heart specimens, respectively. CBZ was fou

at concentrations of 0.018, 0.068, 0.054, 0.036, dete

(below LOQ), 0.036, 0.051, and 0.015 μg/mL 

in blood, liver, lung, kidney, spleen, muscle, brain, and

heart specimens, respectively. The CBZ present did n

exceed approximately 4% of the DiCBZ peak area in any

specimen analyzed, which follows from our earlier findings using neat standards at this GC inlet temperature

Table 2. Concentrations of OXCBZ, DiCBZ, and CBZ found in fluid and tissue 

specimens obtained from the victim of a fatal aviation accident. 

Specimen OXCBZ* DiCBZ* CBZ*

Blood 0.743 9.848 0.018 

Liver 0.891 38.741 0.684 

Lung 0.973 25.696 0.536 

Kidney 2.539 15.603 0.357 

Spleen 0.738 14.676 Detected 

Muscle 0.391 26.859 0.036 

Brain 0.484 19.963 0.051 

Heart 0.215 23.569 0.015 

* Concentrations given in the units of μg/mL or μg/g.
5

Concentrations of DiCBZ in the specimens analyzed

ranged from 9.8 to 38.7 μg/mL (μg/g). The arti

formation of CBZ was shown above to be due to the

dehydration of DiCBZ in the heated injector port of the

GC/MS. Therefore,even under optimal conditions, o

would expect to detect CBZ in each of these specimens

when analyzed by GC/MS. Asexpected, thiswas the ca

forthesespecimens. Thesamespecimenswere analyzed

second time utilizing LC/MS to determineifCBZwould

be detected with this technique. Following analysis 

was determined that no CBZ was present in any of the

case specimens tested. This further demonstrates t

artifactual formation of CBZ when high concentrations

of DiCBZ are present in thespecimen and the analytical

tool employed is GC/MS, regardless of the injector port

temperature selected

Conc

The findings from this study clearly demonstrate

the thermal transformation of the OXCBZ metabolite,

DiCBZ, to the structurally related CBZ during analysis

Chemical degradation/transformation is particularly

disconcerting in cases resulting in either a false negative

or a false positive analytical finding. If the compou

formed isreadily available and commonly prescribed,the

analytical result obtained following analysis would most

likely not be questioned. Therefore, it is prudent to 

aware that such transformation/degradation can occur

during or prior to drug analysis and for a laboratory to

maintain a high degree of quality assurance so that such

occurrences can be detected if and when they do occur

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