CHAPTER ELEVEN

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

Profiles of Drug Substances, Excipients, and Related Methodology, Volume 38

ISSN 1871-5125
http://dx.doi.org/10.1016/B978-0-12-407691-4.00011-3

2013 Elsevier Inc.

All rights reserved.

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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

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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].

1.1.3 Proprietary names

Amadol [5,6], Contramal [5], Contramol [6], Conzip [7], Dromadol [8],
Crispin [5,6], Fortradol [6], Rybix ODT [7], Ryzolt [7], TRADOLPUREN [6] Tradonal [5], Trama [6], Trama AbZ [6], Trama beta [6],
Tramadol [6], Tramadura [6], Tramagetic [6], Tramagit [6], Tramake
[6,8], Tramal [5,6,8], Trama-Sanorania [6], Tramdolar [6], Tramedphano
[6], Tramundin [6], Topalgic [6], Ultram [38], Ultram ER [7], Zamadol
[5,8], Zamadol SR [6], Zydol [5,8], Zyndol SR [6].

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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

1.2.2 Structural formula

H3C
N

H3C

and enantiomer . HCl

OH

O
CH3

1.3. Elemental analysis

Free base: %C: 72.96, %H: 9.57, %N: 5.32, %O: 12.15.
Hydrochloride salt: %C: 64.09, %H: 8.74, %Cl: 11.82, %N: 4.67, %O:
10.67.

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].

2.2. Solubility characteristics

The EP [1] and USP [9] both indicate that tramadol hydrochloride is freely
soluble in water and in methanol and very slightly soluble in acetone. The
drug substance is also described as being readily soluble in water and ethanol
[4]. In our laboratory, the aqueous solubility of tramadol hydrochloride in
the 1.27.5 pH range has been found to be >20 mg/mL (see Table 11.1).

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Table 11.1 Aqueous solubility of tramadol hydrochloride at different pH

Solvent
pH
Solubility (mg/mL)

0.1N HCl

1.2

>20

SGF

1.3

>20

0.01N HCl

2.0

>20

0.05 M phosphate buffer

2.5

>20

0.05 M phosphate buffer

3.5

>20

0.05 M phosphate buffer

4.5

>20

0.05 M phosphate buffer

5.5

>20

0.05 M phosphate buffer

6.0

>20

0.05 M phosphate buffer

6.8

>20

0.05 M phosphate buffer

7.2

>20

0.05 M phosphate buffer

7.5

>20

SGF, simulated gastric fluid.

2.3. Partition coefficient

The n-octanol/water log partition coefficient (log P) for tramadol hydrochloride is known to be 1.35 at pH 7 [4].

2.4. Optical activity

Tramadol hydrochloride consists of a racemic mixture of the 1R,2R and
1S,2S isomers, thus lacks any optical activity. Methods for separating the
racemate of tramadol have been reported in Refs. [10,11]. The (1R,2R)
isomer as the hydrochloride salt is described to have a specific rotation:


[a]RT
D 29.6 (c 1.00; methanol) with a melting point of 171172 C
[11]. While the (1S,2S) hydrochloride salt is reported to have a specific

rotation: [a]RT
D 29.6 (c 1.00; methanol) and a melting point of

172173 C [11].

2.5. Crystallographic properties

Tramadol hydrochloride is known to exist in crystalline and amorphous
forms [1214]. Tramadol base has been reported to exist as a crystalline
monohydrate [15]. Tramadol base in anhydrous form at room temperature
is described as an oil [15].

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Tramadol Hydrochloride

8000
(Counts)
7000
6000
5000
4000
3000
2000
1000
0
0

10

20

30

(2q)

40

Figure 11.1 X-ray powder diffraction pattern of crystalline tramadol hydrochloride.

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.

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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

Figure 11.2 Adsorption/desorption isotherm of tramadol hydrochloride.

2.7. Thermal methods of analysis

2.7.1 Melting behavior
Melting points of 180184  C [1] and 180181  C [5,8] have been reported
for tramadol hydrochloride.
2.7.2 Differential scanning calorimetry
DSC analysis of tramadol hydrochloride has been performed in our laboratory on a TA 2920 DSC unit with Universal Thermal Solutions V2.5H
Software. The sample was weighed directly into an aluminum holder with
the lid placed on top (uncrimped). After an initial equilibration at 25  C, the
sample was heated to 200  C at a rate of 10  C/min. All activities were carried out under a N2 purge (50 cc/min). One endothermic event was
observed for the sample with melting onset and peak maximum temperatures of 180.53 and 182.38  C, respectively. The thermogram for tramadol
hydrochloride is presented in Figure 11.3.
2.7.3 Thermogravimetric analysis
TGA analysis was performed in our laboratory on a TA Instruments Q500 Q
Series TGA unit using a dynamic high-resolution mode. The sample was
heated from ambient temperature to 220  C at a rate of 10  C/min. All activities were carried out under a helium purge (balance purge: 10 mL/min, sample purge: 60 mL/min). The thermogravimetric thermogram of tramadol
hydrochloride (Figure 11.4) indicates a weight loss of about 0.34% up to

469

Tramadol Hydrochloride

0
180.53 C
115.6 J/g

Heat flow (W/g)

182.38 C

8
20

40

60

80

100

120

140

Temperature (C)

Exo up

160

180

200

Universal V3.5B TA instruments

Figure 11.3 Differential scanning calorimetry thermogram of tramadol hydrochloride.

10

120
0.3435%
(0.03862 mg)

100

Weight (%)

80

60
4
40
2

Deriv. weight (%/C)

150.07 C

20
0

0
20
0

50

100

150

Temperature (C)

200

2
250

Universal V3.5B TA instruments

Figure 11.4 Thermogravimetric thermogram of tramadol hydrochloride.

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

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1.0

0.8

0.6
0.4
0.2
0.00
200

220

240

260

280

300

320

340

360

380

400

nm

Figure 11.5 Ultraviolet absorption spectrum of tramadol hydrochloride.

in methanol at a concentration of 10.58 mg/L and scanned from 200 to

400 nm. The UV spectrum (Figure 11.5) shows absorption maxima at
217 nm (e 7.2  103) and 272 nm (e 2.0  103).
2.8.2 Vibrational spectroscopy
The FT-IR spectrum of tramadol hydrochloride was obtained using a
Perkin-Elmer Paragon 16PC FT-IR spectrometer. The spectrum was
recorded for a potassium bromide pellet containing 1.7 mg of the drug substance and 178 mg of KBr. The resulting spectrum is displayed in
Figure 11.6. A summary of the functional group assignments for the characteristic absorption bands that were observed is provided in Table 11.2.
2.8.3 Nuclear magnetic resonance spectroscopy
Both the 1H NMR (including a D2O exchange experiment) and 13C
NMR spectra of tramadol hydrochloride were obtained in a Bruker
AV-400 spectrometer, operating at 400.133 MHz (1H NMR) or at
100.623 MHz (13C NMR). Spectra were recorded for a solution of
tramadol hydrochloride in DMSO-d6. Chemical shifts are reported in
ppm relative to TMS.
2.8.3.1 1H NMR spectrum

The 1H NMR spectra of tramadol hydrochloride are shown in Figures 11.7

and 11.8 (D2O exchange spectrum), and the resonance signal assignments
are provided in Table 11.3.

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80
75
70
65

%T

60
55
50
45
40
35
30
24.1
4400 4000

3000

2000

1500

1000

600

cm-1

Figure 11.6 Infrared absorption spectrum of tramadol hydrochloride.

Table 11.2 Band assignments for the infrared absorption spectrum of tramadol
hydrochloride
Band energy (cm1)
Assignment

3307

Alcohol (OdH) stretch

3018

Aromatic (CdH) stretch

2930, 2861

Aliphatic (CdH) stretch

2632, 2514, 2482

Ammonium (NdH) stretch

1607, 1579, 1481

Aromatic ring skeleton stretch

1289, 1243

Alcohol (CdO) stretch, ether asymmetric (CdOdC)

stretch

1045

Ether symmetric (CdOdC) stretch

777, 703

Aromatic (CdH) out of plane bend

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.

2.9. Mass spectrometry

An electrospray ionization mass spectrometry study of tramadol hydrochloride was carried out on a Perkin-Elmer/Sciex API-300 triple quadrupole

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

Figure 11.7 H NMR spectrum of tramadol hydrochloride.

Figure 11.8 1H NMR (D2O exchange) spectrum of tramadol hydrochloride.

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

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Table 11.3 1H NMR spectral data for tramadol hydrochloride

H

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

H9d, H11, H13

6.806.78

1H

5.12c

1H

H7

3.76

3H

H18

dd; J 10.5, 12.8

1H

H14A

Each br

7H

H14B, H16, H19

2.272.22

app t

2H

H2, H3, H4, H5, H6

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.

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Robert Smyj et al.

180

Figure 11.9

ppm

160

160
13

140

120

100

80

60

40

20

C NMR spectrum of tramadol hydrochloride.

140

Figure 11.10 DEPT-135

120
13

100

80

60

40

C NMR spectrum of tramadol hydrochloride.

20

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Table 11.4

13

C NMR spectral data for tramadol hydrochloride

H

H3C

16

N
H3C

14

15

13

19

and enantiomer

Cl

12

OH
9

11

10

O
17

CH3
18

Chemical shift (ppm)

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

26.16, 24.47, 21.16

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.

3.2. Solution-phase stability

The stability of tramadol hydrochloride has also been investigated from solution stress conditions. Tramadol hydrochloride was stable from basic (0.1N

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Robert Smyj et al.

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.

Figure 11.11 Electrospray ionization mass spectrum of tramadol hydrochloride.

58.1

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

m/z 264 [M + H]+

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

Scheme 11.3 Demethylation of tramadol from oxidative solution stress conditions.

(Scheme 11.3). The aryl ether demethylated derivative of tramadol is also

known to be a metabolite (see Section 5.3).

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.

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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

4.2. Compendial methods of analysis

4.2.1 USP methods of analysis
The USP [2] prescribes the following tests for tramadol drug substance:
Identification A: infrared absorption h197 Ki.
Identification B: chloride h191i: an aqueous solution (1 in 100) meets the
requirements.
Residue on ignition h281i: NMT 0.1%.
Heavy metals h231i method I: NMT 20 ppm.
Content of chloride: 11.612.1% of chloride is found.
Water determination h921i method 1a: NMT 0.5%.
Acidity: NMT 0.4 mL of 0.01N sodium hydroxide is required to produce
an yellow color.
Assay by isocratic HPLC: 98.0102.0% calculated on the anhydrous basis.
Organic impurities
1. Procedure 1 by TLC:
Impurity E (USP tramadol related compound B): NMT 0.2%
2. Procedure 2 by HPLC:
Impurity A (USP tramadol related compound A): NMT 0.2%
Any individual impurity: NMT 0.1% each
Total impurities: NMT 0.4%
USP pharmaceutical preparations include immediate release oral solid dosage Tramadol Hydrochloride Tablets and Tramadol Hydrochloride
Extended-Release Tablets. The following tests are prescribed for USP
Tramadol Tablets [16]:
Identification A: infrared absorption h197 Ki.
Identification B: the retention time of the major peak of the sample solution corresponds to that of the standard solution as obtained in the Assay.
Assay by isocratic HPLC: 90.0110.0% of the labeled amount of
tramadol hydrochloride.
Organic Impurities by isocratic HPLC:
Impurities A: NMT 0.2%.
Impurities B and C: NMT 0.2% each.
Any unspecified impurity: NMT 0.2%.
Total impurities: NMT 0.7%.
Dissolution h711i
Medium: 0.1N HCl, 900 mL.
Apparatus 1: 100 rpm.
Time: 30 min.
Quantitation: isocratic HPLC method as directed in the Assay.

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Robert Smyj et al.

Limit: NLT 80% (Q) of the labeled amount of tramadol hydrochloride is

dissolved in 30 min.
Uniformity of dosage units h905i: quantitative method by isocratic
HPLC method as directed for the Assay; meets the requirements of
h905i.
The following tests are prescribed for USP Tramadol Hydrochloride
Extended-Release Tablets [17]:
Identification: the retention time of the major peak in the chromatogram
of the sample solution corresponds to that in the chromatogram of the
standard solution as obtained in the Assay.
Ultraviolet Absorption h197Ui: the UV absorption spectrum of the sample solution exhibits maximum and minima at the same wavelength as
that of a similar solution of the standard solution.
Assay by isocratic HPLC: 90.0110.0% of the labeled amount of
tramadol hydrochloride.
Organic impurities by isocratic HPLC:
Impurities A: NMT 0.2%.
Impurities D: NMT 0.1%.
Impurity B and Impurity C: NMT 0.1% each (as an individual
unspecified impurity).
Any unspecified impurity: NMT 0.1%.
Total impurities: NMT 0.5%.
Dissolution h711i
Medium: 0.1N HCl, 900 mL.
Apparatus 1: 75 rpm.
Sample time: 2, 4, 8, 10, and 16 h.
Quantitative method: UV at 271 nm.
Limit: NLT 80% (Q) of the labeled amount of tramadol hydrochloride is
dissolved in 30 min.
Limits: 2 h: NMT 15%; 4 h: 1040%; 8 h: 5085%; 10 h: 6595%; 16 h:
NLT 80%.
Uniformity of dosage units h905i: meets the requirements.

4.2.2 EP/BP methods of analysis

The EP/BP harmonized monograph prescribes the following tests for
tramadol hydrochloride drug substance [1]:
Identification A: melting point (2.2.14) 180184  C.
Identification B: infrared absorption (2.2.24).

Tramadol Hydrochloride

481

Identification C: TLC (2.2.27); the principal spot in the chromatogram

obtained with test solution for impurity E is similar in position and size to
the principal spot in the chromatogram obtained with reference solution.
Identification D: it gives reaction of chloride (2.3.1).
Appearance of solution: the solution is clear (2.2.1) and colorless (2.2.2,
method II).
Acidity: NMT 0.4 mL of 0.01 M sodium hydroxide is required to
change the color of the indicator to yellow.
Optical rotation (2.2.7): 0.10 to 0.10 (1 g/20 mL, water).
Heavy metals (2.4.8): maximum 20 ppm.
Water (2.5.12): maximum 0.5% determined on 1.000 g.
Sulfated ash (2.4.14): maximum 0.1% determined on 1.0 g.
Assay by potentiometric titration (2.2.20): 99.0101.0% (anhydrous
substance).
Impurity E by thin-layer chromatography (2.2.7): NMT 0.2%
Related substances by HPLC isocratic method:
Impurity A: NMT 0.2%.
Any unspecified impurity: NMT 0.10% each.
Total impurities: NMT 0.4%.
Disregard limit: 0.02%.

4.3. Thin-layer chromatography

Krzek et al. [18] reported a thin-layer chromatography and densitometric
procedure for quantitative determination of tramadol and its major impurities in pharmaceutical preparations. The separation was performed on silica
gel-coated chromatographic plate using two mobile phases: (i)
chloroformmethanolglacial acetic acid (9:2:0.1, v/v/v) and (ii) chloroformtolueneethanol (9:8:1, v/v/v). The UV densitometry was carried
out at l 270 nm. The developed method is of high sensitivity and low
detection and determination limits ranging from 0.044 to 0.35 mg. For individual constituents, the recovery ranges from 93.23% to 99.66%. In addition, the stability of tramadol in solution was investigated, including an
effect of solution pH, temperature, and incubation time. It was found that
tramadol decomposes in various ways in acidic and basic environments producing Impurity C and Impurity A as major degradation products in acidic
conditions and Impurity A as a major degradation product in basic conditions, respectively. The levels of these impurities depend on solution pH
and temperature. The thin-layer chromatography and densitometric

482

Robert Smyj et al.

method can be used for impurity control of medicines containing tramadol

hydrochloride.
Meyyanathan et al. [19] reported a simple, precise, rapid, and selective highperformance thin-layer chromatography method for the analysis of tramadol in
pharmaceutical formulations. The method uses chlorzoxazone as an internal
standard. The stationary phase was silica gel 60 F254 prewashed with methanol.
Ethyl acetatemethanolammonia solution (7:1:0.5, v/v/v) was used as mobile
phase. Detection and quantitation were performed densitometrically at
l 275 nm. The linear range of the analysis was 1.02.5 mg and percentage
recovery was 100.8108.4%. This high-performance thin-layer chromatography and densitometric procedure for determination of tramadol in solid dosage
forms is accurate, precise, rapid, and selective. It can, therefore, be easily and
conveniently adopted for routine quality control analysis.

4.4. High-performance liquid chromatography with

UV detection
Several research groups have reported quantitative determination of tramadol in
drug substance, drug dosage forms, human plasma, serum, and blood samples
using high-performance liquid chromatography with UV detection (HPLCUV) [2025]. For example, Zecevic et al. [20] reported a novel, rapid
HPLC-UV method for the determination of tramadol and its major related
impurities and degradation products. The separation was carried out on a C18
XTerra (150  4.6 mm, 5 m) column using acetonitrile0.015 M Na2HPO4
buffer (2:8, v/v) as mobile phase (pH 3.0) at a flow rate 1.0 mL/min, temperature of the column 20  C, and UV detection at 218 nm. The method was
found to be linear (r > 0.995) in the range of 0.152.4 mg/mL. The low
RSD values indicate good precision. The high recovery values indicate excellent accuracy of the method. Rajendraprasad et al. [21] developed a simple
reverse-phase HPLC method for assay of tramadol in bulk and capsule dosage
form. The assay was carried out on Phenomonex Gemini C-18
(250  4.6 mm, 5 m) column using a mobile phase consisting of potassium
dihydrogen phosphate buffermethanolacetonitrile (40:40:20). The eluent
was monitored at 280 nm. The method was validated and recovery studies
confirmed the accuracy of the assay method.

4.5. High-performance liquid chromatography with

fluorescence detection
Although tramadol molecule contains a benzene ring, UV detection is
unsuitable for its analysis in low concentration and in urine and plasma

Tramadol Hydrochloride

483

samples due to lack of sensitivity and selectivity. Several research groups

have reported quantitative determination of tramadol and its major metabolites using high-performance liquid chromatography with fluorescence
detection (HPLC-fluorescence detection) [2636]. For example, Mehvar
et al. [26] reported a stereospecific HPLC-fluorescence detection method
for simultaneous quantitation of the enantiomers of tramadol and its active
metabolites O-demethyl tramadol and O-demethyl-N-demethyl tramadol
in human plasma. The separation was achieved using a Chiralpak AD column with a mobile phase of hexane:ethanol:diethylamine (94:6:0.2) and a
flow rate of 1 mL/min. The fluorescence of analytes was then detected at
excitation and emission wavelengths of 275 and 300 nm, respectively.
The method was validated in the plasma concentration range of
2.5250 ng/mL with a lower limit of quantitation of 2.5 ng/mL. Bahrami
et al. [27] developed a HPLC method with enhancement of fluorescence
intensity of tramadol and its main metabolites using precolumn derivatization with 9-fluorenylmethyl chloroformate as labeling agent. The analytical
method was linear over the concentration range of 1.01280 ng/mL of the
parent drug and its metabolites and limit of quantitation of 1.0 ng/mL was
obtained for analytes using 10 mL injection.

4.6. High-performance liquid chromatographymass

spectrometry
Several high-performance liquid chromatographymass spectrometry
(LCMS) methods for the analysis of tramadol, its degradation products,
and metabolites have been published in the literature [3740]. Godoy
et al. [37] recently reported a simultaneous analysis of tramadol and major
degradation products and metabolites using an HPLCtandem mass spectrometry method (LCMSMS). Tramadol is available as a racemic mixture
of ()-trans-tramadol and ()-trans-tramadol. This method was claimed to
be the first study using tandem mass spectrometry as a detection system for
the simultaneous analysis of two trans-tramadol enantiomers and their major
metabolites. The best chromatographic resolution was obtained on a
Chiralpak AD column, which was operated under normal-phase conditions
using a mixture of hexaneethanol (95.5:4.5, v/v) plus 0.1% diethylamine as
mobile phase. Under these conditions, recovery of 8090% was obtained.
Quantitation limit of 0.5, 0.5, and 0.1 ng/mL was obtained for each
trans-tramadol, O-desmethyltramadol, and N-desmethyltramadol enantiomers, respectively. The method was validated to be precise and accurate.

484

Robert Smyj et al.

4.7. Electrochemical analysis

There are a few examples of the determination of tramadol hydrochloride in
pharmaceutical dosage forms by an electrochemical analysis method [41,42].
Garrido et al. [41] reported a square-wave voltammetric (SWV) method and
a flow injection analysis system. Amperometric detection was developed for
the determination of tramadol hydrochloride in pharmaceutical dosage
forms. The SWV method enables the determination of tramadol over the
concentration range of 1575 mM with a detection limit of 2.2 mM.
Tramadol could be determined concentrations between 9 and 50 mM at a
sampling rate of 90 samples/h with a detection limit of 1.7 mM using the
flow injections system. The electrochemical methods developed were successfully applied to the determination of tramadol in pharmaceutical dosage
forms without any pretreatment of the samples. Recovery values were
between 97102%.

4.8. Spectrophotometric analysis

Several spectrophotometric analysis methods for tramadol and its related
impurities were reported in literature [4345]. Rajasekhar et al. [43] developed a spectrophotometric assay determination method of tramadol in bulk
as well as capsule dosage forms. Tramadol obeyed Beers law in a concentration of 10150 mg/mL exhibiting maximum absorption at 270 nm. The
results have been validated statistically and recovery studies confirmed that
the accuracy of the assay method. Abdellatef et al. [44] reported two simple
and sensitive kinetic spectrophotometric analysis methods for the determination of tramadol hydrochloride. The first method is based upon a kinetic
investigation of the oxidation reaction of the drug with alkaline potassium
permanganate at room temperature for a fixed time at 20 min. The absorbance of the colored manganate ions was measured at 610 nm. The second
method is based on the reaction of tramadol hydrochloride with 4-chloro-7nitrobenzofurazan (NBD-Cl) in the presence of 0.1 M sodium bicarbonate.
The spectrophotometric measurements were recorded by measuring the
absorbance at 467 nm at fixed time at 25 min on thermostated water bath
at 90
1  C. The absorbance concentration plots in both methods were linear over the range of 525 and 50250 mg/mL, for the first and second
methods, respectively. The two methods have been applied successfully
to commercial capsules and other dosage forms. Vinay et al. [45] used
two sulfonthalein dyes in the extraction-free spectrophotometric assay of
tramadol in dosage forms and in spiked human urine based on the ion-pair

Tramadol Hydrochloride

485

reaction followed by spectrophotometric analysis. The methods are based on

the formation of yellow ion-pairs between tramadol and two sulfonthalein
dyes. Under the optimum conditions, tramadol could be assayed in the concentration ranges, 115 and 116 mg/mL with correlation coefficient
greater than 0.999.

4.9. Gas chromatography with flame ionization or mass

spectrometry detection
Several gas chromatography methods were reported for the determination of
tramadol and its impurities with either flame ionization detection or mass
spectrometry detection [4648]. Ho et al. [46] reported a rapid, sensitive,
precise, and accurate GC method with flame ionization detection. It is comprised of only a one-step extraction procedure with dichloromethane. The
recovery of tramadol was greater than 88%. Calibration graphs were linear
over the concentration range of 12.510,000 ng/mL with a coefficient of
variation, both within-day and between-day, of less than 10% at any level.
The limit of detection was 8 ng/mL based on signal-to-noise ratio of 3.
Chytil et al. [47] developed a GCMS enantiomeric assay determination
method of tramadol and O-desmethyltramadol by GCMS. Chromatography was performed on an Rt-bDEXcst column containing alkylated
b-cyclodextrins as a chiral selector. Nefopam was used as an internal standard. The method involves a simple solid-phase extraction with chiral analysis by gas chromatographyelectron ionization mass spectrometry. This
method was successfully used to determine the concentration of enantiomers
of tramadol and its metabolites.

4.10. Capillary electrophoresis analysis

Several research groups have reported separation of tramadol enantiomers by
capillary electrophoresis (CE) [4951]. For instance, Rudaz et al. [49] successfully applied cyclodextrins to the enantiomeric resolution of racemic
tramadol in drug substance, drug dosage forms. The CE method has been
demonstrated to be selective, linear, accurate, and precise, and the method
was able to detect 0.3% and to quantitate 1% of the minor enantiomer in the
presence of the major one at the target value.

4.11. Potentiometric titration

The EP/BP harmonized monograph prescribes an assay method by potentiometric titration [1]. Bodiroga et al. [52] also reported a potentiometric

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Robert Smyj et al.

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.

5. PHARMACOKINETICS AND METABOLISM

The pharmacokinetics of tramadol has been well documented in several reviews [53,54].

5.1. Absorption and bioavailability

After oral administration, tramadol is rapidly and almost completely absorbed.
The plasma concentrations are detectable within approximately 0.5 h [55].
Times to reach peak plasma concentration (Tmax) are within 1.2 h after oral
administration of drops [56] and within 2 h after oral administration of solid
dose [55]. Peak plasma concentrations (Cmax) and area under the curve (AUC)
increase linearly over the dose range of 50400 mg [53,56]. The extent of oral
absorption of tramadol is almost 100%. Due to the first-pass metabolism, the
absolute bioavailability is 70% [53,56].
Following multiple oral administration of tramadol 100 mg four times
daily, Cmax and AUC are 16% and 36% higher, respectively, than after a single 100-mg dose. The increased bioavailability is likely due to the saturated
first-pass metabolism [53,57].
Oral administration of tramadol 100 mg following a high-fat food results
in a 17% higher Cmax and a 10% higher AUC than the corresponding values
in fasted subjects. This increase of the bioavailability by food is not considered clinically relevant [53].
The absorption of tramadol after rectal administration of 100 mg
suppositories began within a few minutes. Cmax was reached within
3.3 h. The absolute bioavailability is slightly higher than that after oral
administration, probably due to a reduced first-pass metabolism after rectal
administration [58].

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

Figure 11.13 Metabolic pathways of tramadol in phase 1 reactions.

M4

488

Robert Smyj et al.

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.

5.5. Pharmacokinetics in special population

The metabolism and analgesic effect of tramadol was higher in extensive
metabolizers of CYP2D6 than in poor metabolisers. M1 production
in microsomes prepared from the liver of a poor metabolizer was markedly
reduced [63]. Biotransformation of tramadol appears to be significantly
reduced in African subjects. In 10 Nigerian volunteers, about 96% of
tramadol was excreted unchanged in the urine after oral administration [64].
The terminal elimination half-life of tramadol is prolonged in patients
with impaired renal and hepatic function. Doses and intervals may be
adjusted [53,54].

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].

6.2. Adverse reactions

The most frequent adverse events of tramadol are nausea, dizziness, drowsiness, fatigue, sweating, vomiting, and dry mouth [68]. Tramadol has less

489

Tramadol Hydrochloride

respiratory depressant potential than other opioids, such as morphine and

oxycodone [69,70]. Tramadol also has a low abuse potential and does not
precipitate a withdrawal syndrome [71,72]. Overdose of tramadol is associated with neurological toxicity. Cardiovascular toxicity has not been
reported. The most common symptoms of tramadol overdose are lethargy,
nausea, tachycardia, agitation, seizures, coma, hypertension, and respiratory
depression [73].

6.3. Drug interactions

Coadministration of Cimetidine, a typical enzyme inhibitor, results in an
increase of tramadol AUC and elimination half-life. When coadministrated
with carbamazepine, a typical enzyme inducer, tramadol Cmax, AUC, and
elimination half-life is reduced by 51%, 26%, and 54%, respectively [53].

7. METHOD OF CHEMICAL SYNTHESIS

The synthesis of tramadol hydrochloride (Scheme 11.4) is known to
begin with a Mannich reaction between cyclohexanone (1), paraformaldehyde (2) (or formaldehyde [74,75]), and dimethylamine hydrochloride (3)
(or monodimethylamine sulfate [75]) to form 2-dimethylaminomethylcyclohexanone hydrochloride (4) [15,7477]. After converting 4 to the
free base (5), the addition of m-methoxyphenyl magnesium bromide (or
m-methoxyphenyl lithium [76,78]) to 5 occurs to produce tramadol base
H 3C

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

Scheme 11.4 Synthesis of tramadol.

H 3C
OH

CH3

Tramadol

490

Robert Smyj et al.

[6,10,15,7584], which is then converted to the HCl salt

[10,76,79,80,83,85]. In the addition reaction, the 1RS,2SR stereoisomer
of tramadol is produced as a by-product [10,74,75,7784]. There are several
strategies given in the literature for the removal of the 1RS,2SR isomer from
tramadol [15,74,75,77,8082,86] or tramadol hydrochloride [10,79,87].
Modifications to the addition reaction such as the use of additives [85] or
transition metal salts [78] are reported to increase stereoselectivity in the formation of tramadol. Recently, a synthetic route for the asymmetric synthesis
of one enantiomer of tramadol has been described [88]. Continuous flow
conditions have also been used to produce tramadol [83,84].

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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