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Tramadol Hydrochloride
Robert Smyj, Xiao-Ping Wang, Feixue Han
Apotex Inc., Toronto, Ontario, Canada
Contents
1. General Information
1.1 Nomenclature
1.2 Formulae
1.3 Elemental analysis
1.4 Appearance
2. Physical Characteristics
2.1 Ionization constant
2.2 Solubility characteristics
2.3 Partition coefficient
2.4 Optical activity
2.5 Crystallographic properties
2.6 Hygroscopicity
2.7 Thermal methods of analysis
2.8 Spectroscopy
2.9 Mass spectrometry
3. Stability
3.1 Solid-state stability
3.2 Solution-phase stability
4. Methods of Analysis
4.1 Known impurities of tramadol
4.2 Compendial methods of analysis
4.3 Thin-layer chromatography
4.4 High-performance liquid chromatography with UV detection
4.5 High-performance liquid chromatography with fluorescence detection
4.6 High-performance liquid chromatographymass spectrometry
4.7 Electrochemical analysis
4.8 Spectrophotometric analysis
4.9 Gas chromatography with flame ionization or mass spectrometry detection
4.10 Capillary electrophoresis analysis
4.11 Potentiometric titration
5. Pharmacokinetics and Metabolism
5.1 Absorption and bioavailability
5.2 Distribution
464
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465
465
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466
466
466
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468
469
471
475
475
475
477
477
479
481
482
482
483
484
484
485
485
485
486
486
487
463
464
5.3 Metabolism
5.4 Elimination
5.5 Pharmacokinetics in special population
6. Pharmacological Effects
6.1 Mechanism of action
6.2 Adverse reactions
6.3 Drug interactions
7. Method of Chemical Synthesis
Acknowledgments
References
487
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490
490
1. GENERAL INFORMATION
1.1. Nomenclature
1.1.1 Systematic chemical names
(1RS,2RS)-2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)
cyclohexanol hydrochloride [1].
()-cis-2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)
cyclohexanol hydrochloride [24].
()-cis-2-[(Dimethylamino)methyl]-1-(m-methoxyphenyl)
cyclohexanol hydrochloride [2,3].
1.1.2 Nonproprietary names
Tramadol hydrochloride (USAN, JAN) [3].
Tramadol (INN, BAN) [3].
465
Tramadol Hydrochloride
1.2. Formulae
1.2.1 Empirical formula, molecular weight, CAS number
Tramadol
Tramadol hydrochloride
C16H25NO2
C16H25NO2 HCl
263.38
299.84
27203-92-5
36282-47-0
H3C
O
CH3
1.4. Appearance
White or almost white, crystalline powder [1].
White crystals [5].
White, crystalline powder [9].
2. PHYSICAL CHARACTERISTICS
2.1. Ionization constant
Tramadol is known to have a pKa of 9.41 [4].
466
0.1N HCl
1.2
>20
SGF
1.3
>20
0.01N HCl
2.0
>20
2.5
>20
3.5
>20
4.5
>20
5.5
>20
6.0
>20
6.8
>20
7.2
>20
7.5
>20
467
Tramadol Hydrochloride
8000
(Counts)
7000
6000
5000
4000
3000
2000
1000
0
0
10
20
30
(2q)
40
The X-ray powder diffraction pattern of crystalline tramadol hydrochloride was obtained in our laboratory with a Phillips PW3710 X-ray diffractometer using Cu Ka irradiation and is displayed in Figure 11.1. The most
intense peaks observed in the X-ray powder diffraction pattern (Figure 11.1)
have 2y angles of 10.3 , 13.0 , 15.3 , 16.7 , 18.5 , 20.5 , 20.8 , 21.5 ,
24.4 , 26.1 , and 30.7 .
2.6. Hygroscopicity
In our laboratory, tramadol hydrochloride was analyzed using dynamic
vapor sorption. For the analysis, a VTI SGA 100 Symmetric Vapor Sorption
Analyzer was used. The drug substance was first dried to a constant weight at
40 C, then the adsorption/desorption experiment was performed at 25 C.
Adsorption analysis occurred from 5% RH to 95% RH in 10% increments,
while desorption was monitored from 95% RH back to 5% RH, also in 10%
increments. The resulting adsorption/desorption isotherm that was obtained
is displayed in Figure 11.2. The experimental results indicate that tramadol
hydrochloride is nonhygroscopic below 75% RH. Above 85% RH, the drug
substance absorbs water readily resulting in an approximate 16% increase in
weight at the end of the absorption phase. During the desorption phase of
the experiment, some water is lost during the 8575% RH interval; however, a water content of about 10% is retained throughout the 755% RH
desorption phase.
468
20,000
Adsorption
Desorption
18,000
Weight (% change)
16,000
14,000
12,000
10,000
8,000
6,000
4,000
2,000
0,000
0
10
20
30
40
50
60
70
80
90
100
% RH
469
Tramadol Hydrochloride
0
180.53 C
115.6 J/g
182.38 C
8
20
40
60
80
100
120
140
Temperature (C)
Exo up
160
180
200
10
120
0.3435%
(0.03862 mg)
100
Weight (%)
80
60
4
40
2
150.07 C
20
0
0
20
0
50
100
150
Temperature (C)
200
2
250
150 C. Rapid weight loss of the drug substance starts to occur near its melting
point (ca. 180185 C), followed by complete decomposition by 205 C.
2.8. Spectroscopy
2.8.1 UVvis spectroscopy
The UV spectrum of tramadol hydrochloride was obtained on a PerkinElmer Lambda 2 UV/vis spectrometer. The drug substance was dissolved
470
1.0
0.8
0.6
0.4
0.2
0.00
200
220
240
260
280
300
320
340
360
380
400
nm
471
Tramadol Hydrochloride
80
75
70
65
%T
60
55
50
45
40
35
30
24.1
4400 4000
3000
2000
1500
1000
600
cm-1
3307
3018
2930, 2861
1289, 1243
1045
777, 703
2.8.3.2
13
C NMR spectrum
13
The C NMR and DEPT-135 13C NMR spectra of Tramadol hydrochloride are shown in Figures 11.9 and 11.10, respectively. The resonance signal
assignments are provided in Table 11.4.
ppm
10
0.0228
6.6748
6.9282
1.0000
0.9514
0.9435
2.8112
2.2723
0.0832
10
0.9508
1.8721
0.9278
0.0586
Integral
ppm
2
0
0.0221
6.8134
2.0000
7.1585
0.9441
0.5206
2.8805
0.9414
0.9786
1.9111
0.9657
0.9143
Integral
473
Tramadol Hydrochloride
H3C
16
N
H3C
14
15
13
19
12
and enantiomer . Cl
OH
11
10
O
17
CH3
18
Chemical shift
(ppm)
Multiplicitya; coupling
constant (Hz)
Integration
Assignmentb
10.33c
br
1H
H15
7.287.24
app t
1H
H12
7.097.07
2H
6.806.78
1H
5.12c
1H
H7
3.76
3H
H18
1H
H14A
Each br
7H
2.272.22
app t
2H
2.152.12
app d
1.801.38
2.81
e
2.55 , 2.41
7H
app, apparent; br, broad; d, doublet; dd, doublet of doublets; m, multiplet; s, singlet; t, triplet.
Assignments containing the letters A and B denote geminal chemical shift nonequivalent protons.
c
These signals nearly disappear in the D2O exchange spectrum.
d
Signal originating from H9 can be assigned to the 7.097.07 ppm region.
e
This signal partially overlaps with the solvent residual peak originating from DMSO-d6.
f
This signal consists of an overlap with the signal originating from either H16 or H19 and H14B.
b
mass spectrometer. The sample was dissolved in methanol and injected into a
5-mL sample loop of the mass spectrometer and carried into the ionization
source by the mobile phase (1:1 mixture of methanol and 0.1% aqueous
acetic acid) at a flow rate of 100 mL/min. The electrospray ionization mass
spectrum of tramadol hydrochloride is shown in Figure 11.11. The spectrum
displays the protonated tramadol molecular ion peak [M H] at m/z 264.
The MS/MS spectrum of this ion is shown in Figure 11.12. One major fragment ion having an m/z of 58 is observed and is proposed to originate from
the protonated molecular ion of tramadol as shown in Scheme 11.1.
474
ppm
180
Figure 11.9
ppm
160
160
13
140
120
100
80
60
40
20
140
120
13
100
80
60
40
20
475
Tramadol Hydrochloride
Table 11.4
13
H3C
16
N
H3C
14
15
13
19
and enantiomer
Cl
12
OH
9
11
10
O
17
CH3
18
DEPT
Assignment
159.12
C10
150.00
C8
129.06
CH
C12
117.22
CH
C13
111.52, 111.12
Each CH
C9, C11
73.87
C1
59.33
CH2
C14
54.96
CH3
C18
44.77, 40.60
Each CH3
C16, C19
40.39
CH2
C6
40.21
CH
C2
Each CH2
C3, C4, C5
3. STABILITY
3.1. Solid-state stability
From solid-state stress studies, tramadol hydrochloride has been observed to
be a stable compound. Subjecting the drug substance to thermal stress
(60 C, 14 days), heat/high humidity stress (40 C/75% RH, 14 days) and
light stress (380770 nm, 1.9 106 lux-h) did not result in any degradation.
476
264.2
6.9e6
6.5e6
6.0e6
5.5e6
5.0e6
Intensity (cps)
4.5e6
4.0e6
3.5e6
3.0e6
2.5e6
2.0e6
1.5e6
563.4
1.0e6
97.7
527.7
5.0e5
125.4
208.7 246.2
114.1
50
100
150
200
250
312.1
302.2
300
664.0
400.0
286.1
58.3
65.3
350
777.3
641.5
416.4
400
816.2
678.3 713.4
450
500
550
600
650
700
750
800
876.0
850
900
950 1000
m/z, a.m.u.
8.4e6
8.0e6
7.5e6
7.0e6
6.5e6
6.0e6
Intensity (cps)
5.5e6
5.0e6
4.5e6
4.0e6
3.5e6
3.0e6
2.5e6
2.0e6
1.5e6
1.0e6
5.0e5
30
40
50
60
70
80
90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280
m/z, a.m.u.
Figure 11.12 MS/MS spectrum of the protonated tramadol ion peak [M H] at m/z 264.
NaOH, 100 C, 4 h), thermal (water, 100 C, 4 h), and light (380770 nm,
1.2 106 lux-h) stress. The drug substance was observed to degrade slightly
from acidic (0.1N HCl, 100 C, 4 h) and oxidative (3% H2O2, room temperature, 24 h) stress. A degradation pathway for tramadol occurring from
acidic and oxidative solution stress involves conversion into the (1RS,2SR)
stereoisomer (Scheme 11.2). Demethylation of the aryl ether methyl group
of tramadol was also observed to occur from oxidative solution stress
477
Tramadol Hydrochloride
H3C
N
H3C
H3C
N
H3C
OH
CH2
m/z 58
and enantiomer
O
CH3
Scheme 11.1 Proposed fragmentation observed in the MS/MS spectrum of the protonated tramadol ion peak.
H3C
N
H 3C
N
HCl or H2O2
H3C
OH
H3C
H 2O
OH
and enantiomer
O
and enantiomer
O
CH3
CH3
(1RS,2SR)-2-[(dimethylamino)methyl]1-(3-methoxyphenyl)cyclohexanol
Tramadol
Scheme 11.2 Epimerization of tramadol from acidic and oxidative solution stress
conditions.
H3C
N
H3C
N
H2O2
H3C
OH
H2O
OH
and enantiomer
and enantiomer
OH
CH3
Tramadol
H3C
(1RS,2RS)-2-[(dimethylamino)methyl]1-(3-hydroxyphenyl)cyclohexanol
4. METHODS OF ANALYSIS
4.1. Known impurities of tramadol
A number of impurities have been identified as related compounds of tramadol
[1,2,16,17]. The structures, chemical names, and classification of the impurities
are shown in the table below. Impurities A and E are specified impurities listed
in both USP and EP monographs of tramadol drug substance. Impurities BD
are listed in the EP monograph as other detectable impurities. All of the
compendial listed impurities are potential manufacturing process-related
impurities and degradation products. Impurity D is also a human metabolite.
478
Impurities of tramadol
Structure
Chemical name
Classification
H3C
(1RS,2SR)-2[(dimethylamino)methyl]-1(3-methoxyphenyl)
cyclohexanol
EP impurity A
USP RCA
Synthetic impurity/
degradation product
[2-(3-methoxyphenyl)cyclohex-1-enyl]-N,Ndimethylmethanamine
EP impurity B
Synthetic impurity/
degradation product
(1RS)-[2-(3-methoxyphenyl)
cyclohex-2-enyl]-N,Ndimethylmethanamine
EP impurity C
Synthetic impurity/
degradation product
(1RS,2RS)-2[(dimethylamino)methyl]-1(3-hydroxyphenyl)
cyclohexanol (Odesmethyltramadol)
EP impurity D
Synthetic impurity/
degradation product
Metabolite
(2RS)-2-[(dimethylamino)
methyl]cyclohexanone
EP impurity E
USP RCB
Synthetic impurity/
degradation product
N
H3C
OH
O
CH3
and enantiomer
Impurity A
H3C
N
H3C
OCH3
Impurity B
H3C
N
H3C
O
CH3
and enantiomer
Impurity C
H3C
N
H 3C
OH
and enantiomer
OH
Impurity D
H3C
N
H3C
O
and enantiomer
Impurity E
Tramadol Hydrochloride
479
480
Tramadol Hydrochloride
481
482
Tramadol Hydrochloride
483
484
Tramadol Hydrochloride
485
486
titration method for the determination of tramadol. The titration is performed in nonaqueous media with perchloric acid as titrant. The titration
with perchloric acid resulted in potentiometric and conductometric curves with a clear defined peak thus suitable for the determination of the
titration endpoint providing accurate and reproducible results. Each milliliter of 0.1 mol/L HClO4 is equivalent to 29.98 mg of tramadol hydrochloride. The method is fast, accurate, reproducible, and convenient for
the quality control of tramadol hydrochloride in pure state and its dosage
forms.
487
Tramadol Hydrochloride
5.2. Distribution
Tramadol is rapidly distributed in the body after intravenous administration,
with a distribution half-life in the initial phase of 6 min, followed by a slower
distribution phase with a half-life of 1.7 h [53,54]. Volumes of distribution
following oral and intravenous administration to young healthy subjects
were 306 and 203 L, respectively, indicating that tramadol has a high tissue
affinity. Plasma protein binding is low (20%) [54,55].
Tramadol passes placental barrier with umbilical venous plasma concentrations being 80% of maternal concentration. Very small amount of
tramadol and its active metabolite are excreted in breast milk [53].
5.3. Metabolism
Tramadol is extensively metabolized in the liver by cytochrome P450 2D6
(CYP2D6) [5961]. Tramadol undergoes biotransformation to form the Nand O-demethylated compounds (phase 1 reactions) displayed in
Figure 11.13 [60]. The O-demethylated metabolites (M1, M4, and M5)
are further conjugated to glucuronides and sulfates (phase 2 reactions).
The main metabolites are O-demethyl tramadol (M1) and its conjugates,
di-N,O-demethyl tramadol (M5) and its conjugates and N-demethyl
tramadol (M2). N,N-Didemethyl tramadol (M3) and O-demethyl-N,Ndidemethyl tramodal (M4) and its conjugates are only formed in minor
quantities. Among them, M1 is pharmacologically active and is mainly
responsible for the analgesic efficacy of tramadol [62].
H 3C
N
H3C
H3C
N
H3C
O-d
em
N-d
n
latio
em
eth
yla
tion
NH
em
and enantiomer
eth
H3C
M5
and enantiomer
OH
OH
eth
N-d
M1
OH
yla
tion
NH
H 3C
CH3
e
O-d
M2
OH
Tramadol
N-d
OH
t
me
N-d
em
tio
hyla
eth
em
eth
yla
and enantiomer
tion
yla
tion
H2N
H
O-d
em
eth
yla
tion
and enantiomer
O
H2N
OH
OH
OH
CH3
and enantiomer
O
CH3
OH
and enantiomer
M3
M4
488
5.4. Elimination
Tramadol is mainly excreted via the kidneys. Following oral administration
of 14C-labeled tramadol to humans, approximately 90% is excreted in urines
and 10% in feces [59]. 2532% of an oral dose is excreted as unchanged
tramadol. The mean elimination half-life is about 56 h. The mean total
clearance of tramadol was 467 and 742 mL/min following intravenous
and oral administration.
6. PHARMACOLOGICAL EFFECTS
6.1. Mechanism of action
Tramadol produces its analgesia in humans by a multimodal mechanism
[53].
(a) ()-M1 enantiomer acts as a m opioid agonist. Its affinity for the m opioid receptor is about 700-fold more than that of parent drug ()tramadol [65]. ()-M5 also has higher affinity than ()-tramadol
[65]. However, since M5 does not penetrate the bloodbrain barrier
due to its high polarity, its responsibility for the m opioid derived analgesic effect is very limited [53].
(b) Tramadol inhibits serotonin reuptake of serotonin (5-HT). ()Enantiomer is about fourfold more potent than the () Enantiomer [66].
(c) Tramadol inhibits norepinephrine reuptake. ()Tramadol is a more
potent blocker than its () counterpart or M1 [67].
489
Tramadol Hydrochloride
H 3C
NaOH
H 3C
+ (CH2O)n + (CH3)2NHHCI
HCI
H 3C
4
X
X = Li or MgBr
O
H3C HCI
N
H 3C
H3C
CH3
N
and enantiomer
HCI
and enantiomer
OH
CH3
Tramadol hydrochloride
H 3C
OH
CH3
Tramadol
490
ACKNOWLEDGMENTS
The authors are indebted to Dr. Yan Alsmeyer for encouragement and management support.
We also wish to express our appreciation to Dr. Yuri Goldberg for his guidance and to
Ms. Janet Mensah for her assistance in retrieving the cited literature and lastly many
thanks go to our colleagues in the laboratories who contributed material needed for the
preparation of this chapter.
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