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 Hi High-pe -performa rmance liquid chromatograp raphy with UV detection 4.5 High-p High-perf erform ormanc ance e liquid liquid chroma chromatog tograp raphy hy with with fluor fluoresc escenc ence e detect detection ion 4.6 High-performance liquid chromatography – mass spectrometry 4.7 Electrochemical analysis 4.8 Spectrophotometric analysis 4.9 Gas chromatogr chromatography aphy with flame flame ioniza ionization tion or mass spectrome spectrometry try detection 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
487 488 488 488 488 488 489 489 490 490
1. GENERAL GENERAL INFORM INFORMATION ATION
1.1. Nomenclatur Nomenclature e 1.1.1 Systemat Systematic ic chemical chemical names (1RS ,2 ,2RS )-2-[(Dimethylamino)meth )-2-[(Dimethylamino)methyl]-1-(3-meth yl]-1-(3-methoxyphenyl) oxyphenyl) cyclohexanol hydrochloride [1] [1].. ()-cis-2-[(Dimethylamino)methy -2-[(Dimethylamino)methyl]-1-(3-meth l]-1-(3-methoxyphenyl) oxyphenyl) cyclohexanol hydrochloride [2 – 4]. 4]. ()-cis-2-[(Dimethylamino)methyl]-1-( m-methoxyphenyl) cyclohexanol hydrochloride [2,3] hydrochloride [2,3]..
1.1.2 Nonpropriet Nonproprietary ary names names Tramadol hydrochloride (USAN, JAN) [3] [3].. Tramadol (INN, BAN) [3] [3]..
1.1.3 Proprietary Proprietary names names Amadol [5,6] [5,6],, Contramal [5] [5],, Contramol [6] [6],, Conzip [7] [7],, Dromadol [8] [8],, Crispin [5,6], [5,6], Fortra Fortrado doll [6] [6],, Rybi Rybix x ODT ODT [7] [7],, Ryzo Ryzolt lt [7] [7],, TRADO TRADOLLPUREN [6] Tradonal [5] [5],, Trama [6] [6],, Trama AbZ [6] [6],, Trama beta [6] [6],, Tramadol [6] [6],, Tramad Tramadura ura [6] [6],, Trama Tramaget getic ic [6] [6],, Tramag Tramagit it [6] [6],, Tramak Tramakee [6,8],, Tramal [5,6,8] [6,8] Tramal [5,6,8],, Trama-Sanorania [6] [6],, Tramdolar [6] [6],, Tramedphano [6],, Tramundin [6] [6] [6],, Topalgic [6] [6],, Ultram [3 – 8], 8], Ultram ER [7] [7],, Zamadol [5,8],, Zamadol SR [6] [5,8] [6],, Zydol [5,8] Zydol [5,8],, Zyndol SR [6] [6]..
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1.2. 1.2. Formul Formulae ae 1.2.1 Empirical Empirical formula, formula, molecular molecular weight, CAS number Tramadol Tramado adol hyd hydrochlorid ride
C16H25NO2 C16H25NO2 HCl
263.38 299.84
27203-92-5 36282-47-0
1.2.2 Structural Structural formula formula H3C N
H
H3C
and enantiomer . HCl OH
O
CH3
1.3. Elemental Elemental analys analysis is 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 Appearance White or almost white, crystalline powder [1] [1].. White crystals [5] [5].. White, crystalline powder [9] [9].. 2. PHYSIC PHYSICAL AL CHARAC CHARACTERI TERISTIC STICS S
2.1. Ionization Ionization constan constantt Tramadol is known to have a p K a of 9.41 [4] [4]..
2.2. Solubility Solubility characte characteristics ristics The EP [1] EP [1] and and USP [9] USP [9] both 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 [4] the 1.2–7.5 pH range has been found to be >20 mg/mL (see Table (see Table 11.1). 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 1 R ,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 (c ¼ 1.00; methanol) with a melting point of 171–172 C D ¼ þ 29.6 [11]. While the (1S ,2S ) hydrochloride salt is reported to have a specific rotation: [a]RT (c ¼ 1.00; methanol) and a melting point of D ¼ 29.6 172–173 C [11].
2.5. Crystallographic properties Tramadol hydrochloride is known to exist in crystalline and amorphous forms [12 – 14]. 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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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 85–75% RH interval; however, a water content of about 10% is retained throughout the 75–5% RH desorption phase.
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20,000 Adsorption Desorption
18,000 16,000 14,000 ) e g n 12,000 a h c % ( 10,000 t h g 8,000 i e W 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 180–184 C [1] and 180–181 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
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0 180.53 °C 115.6J/g
−2 ) g / W ( w −4 o l f t a e H
−6
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
8
150.07 C
80
6
) % ( 60 t h g i e 40 W
4
2 20
) C / % ( t h g i e w . v i r e D
0
0
−2
−20 0
50
100
150
Temperature ( C)
200
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 UV – vis 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
A
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 ¼ 7.2 103) and 272 nm (e ¼ 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-d 6. 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 60
T 55 % 50 45 40 35 30 24.1 4400
4000
3000
2000
1500
1000
600
-1 cm
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 (NþdH) stretch
1607, 1579, 1481
Aromatic ring skeleton stretch
1289, 1243
Alcohol (CdO) stretch, ether asymmetric (C dOdC) stretch
1045
Ether symmetric (CdOdC) stretch
777, 703
Aromatic (CdH) out of plane bend
2.8.3.2
13
C NMR spectrum
The 13C 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
l a r g e t n I
ppm
3 4 1 9 . 0
6 1 7 8 1 5 7 1 6 9 . 9 . 9 . 0 1 0
10
8
4 1 4 9 . 0
6
5 0 8 8 . 2
6 0 2 5 . 0
4
1 4 4 9 . 0
5 0 8 0 5 0 1 . 0 . 7 2
4 3 1 8 . 6
1 2 2 0 . 0
2
0
Figure 11.7 1H NMR spectrum of tramadol hydrochloride.
l a r g e t n I
ppm
6 8 5 0 . 0
10
8 1 8 0 2 7 5 7 2 9 . 8 . 9 . 0 1 0
8
2 3 8 0 . 0
6
2 3 1 2 1 7 8 . 2 . 2 2
4
5 2 0 4 3 8 0 1 4 2 0 5 9 . 9 . 0 . 9 . 0 6 1 0
8 4 7 6 . 6
8 2 2 0 . 0
2
Figure 11.8 1H NMR (D2O exchange) spectrum of tramadol hydrochloride.
0
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Table 11.3 1H NMR spectral data for tramadol hydrochloride H
H3C
16
N H3C
H
+
14
3
15
2
4
19 13
1
12
8
11
9
and enantiomer . Cl−
5 6
OH 7
10
O
17 CH 3 18
Chemical shift (ppm)
Multiplicitya; coupling constant (Hz) Integration
Assignmentb
10.33c
br
1H
H15
7.28–7.24
app t
1H
H12
7.09–7.07
m
2H
H9d, H11, H13
6.80–6.78
m
1H
5.12c
s
1H
H7
3.76
s
3H
H18
2.81
dd; J ¼ 10.5, 12.8
1H
H14A
2.55e, 2.41f
Each br
7H
H14B, H16, H19
2.27–2.22
app t
2H
H2, H3, H4, H5, H6
2.15–2.12
app d
1.80–1.38
m
7H
a
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 D 2O exchange spectrum. d Signal originating from H9 can be assigned to the 7.09–7.07 ppm region. e This signal partially overlaps with the solvent residual peak originating from DMSO- d 6. 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 þ H]þ 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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180
Figure 11.9
ppm
160
160
140
120
100
80
60
40
20
13
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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Tramadol Hydrochloride
Table 11.4
13
C NMR spectral data for tramadol hydrochloride H
H3C
16
N H3C
H
+
14
3
15
2
4
19
and enantiomer 13
1
12
8
11
9
.
−
Cl
5 6
OH 7
10
O
17 CH 3 18
Chemical shift (ppm)
DEPT
Assignment
159.12
C
C10
150.00
C
C8
129.06
CH
C12
117.22
CH
C13
111.52, 111.12
Each CH
C9, C11
73.87
C
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 (380–770 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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264.2
6.9e6 6.5e6 6.0e6 5.5e6 5.0e6 4.5e6
) s 4.0e6 p c ( y t i 3.5e6 s n e 3.0e6 t n I 2.5e6 2.0e6 1.5e6
563.4
1.0e6
97.7 527.7
5.0e5
58.3 65.3
50
125.4 208.7 246.2
114.1
100
150
200
250
312.1 302.2
300
664.0
400.0
286.1
350
641.5 416.4
678.3 713.4
400 45 0
5 00
550
6 00
6 50 7 00
777.3 816.2
7 50 80 0
876.0
8 50
900
950 1000
/ , a.m.u.
m z
Figure 11.11 Electrospray ionization mass spectrum of tramadol hydrochloride. 58.1
8.4e6 8.0e6 7.5e6 7.0e6 6.5e6 6.0e6
) s p c ( y t i s n e t n I
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
/ , a.m.u.
m z
Figure 11.12 MS/MS spectrum of the protonated tramadol ion peak [Mþ H]þ at m / z 264.
NaOH, 100 C, 4 h), thermal (water, 100 C, 4 h), and light (380–770 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 (1 RS ,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
H
H
+
H3C
H3C
+
N H3C
OH
CH2
/ 58
m z
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
H3C
H
N HCl or H 2O2
H3C OH
H3C
H2O
OH
and enantiomer O
H
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
H
N H2O2
H3C
OH
H3C
H2O OH
and enantiomer
and enantiomer
O
OH
CH3
Tramadol
H
(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 B–D 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 ,N dimethylmethanamine
EP impurity B Synthetic impurity/ degradation product
(1RS )-[2-(3-methoxyphenyl) cyclohex-2-enyl]-N ,N dimethylmethanamine
EP impurity C Synthetic impurity/ degradation product
(1RS ,2RS )-2[(dimethylamino)methyl]-1(3-hydroxyphenyl) cyclohexanol (O desmethyltramadol)
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
OCH 3
Impurity B H3C N H3C
O CH3
and enantiomer
Impurity C H3C N H3C
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: 11.6–12.1% 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: 98.0–102.0% 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: 90.0–110.0% 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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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: 90.0–110.0% 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: 10–40%; 8 h: 50–85%; 10 h: 65–95%; 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) 180–184 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 þ0.10 (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 ): 99.0–101.0% (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) chloroform–methanol–glacial acetic acid (9:2:0.1, v/v/v) and (ii) chloroform–toluene–ethanol (9:8:1, v/v/v). The UV densitometry was carried out at l ¼ 270 nm. The developed method is of high sensitivity and low detection and determination limits ranging from 0.044 to 0.35 m g. 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
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method can be used for impurity control of medicines containing tramadol hydrochloride. Meyyanathan et al. [19] reported a simple, precise, rapid, andselective highperformance thin-layer chromatography methodfor 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 acetate–methanol–ammoniasolution (7:1:0.5, v/v/v) was used as mobile phase. Detection and quantitation were performed densitometrically at l ¼ 275 nm. The linear range of the analysis was 1.0–2.5 mg and percentage recovery was 100.8–108.4%. 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 researchgroups 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) [20 – 25]. 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 C 18 XTerra™ (150 4.6 mm, 5 m) column using acetonitrile–0.015 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 0.15–2.4 mg/mL. The low RSDvalues 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 buffer–methanol–acetonitrile (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
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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) [26 – 36]. 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 2.5–250 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 1.0–1280 ng/mL of the parent drug and its metabolites and limit of quantitation of 1.0 ng/mL was obtained for analytes using 10 m L injection.
4.6. High-performance liquid chromatography – mass spectrometry Several high-performance liquid chromatography–mass spectrometry (LC–MS) methods for the analysis of tramadol, its degradation products, and metabolites have been published in the literature [37 – 40]. Godoy et al. [37] recently reported a simultaneous analysis of tramadol and major degradation products and metabolites using an HPLC–tandem mass spectrometry method (LC–MS–MS). Tramadol is available as a racemic mixture of (þ)-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 hexane–ethanol (95.5:4.5, v/v) plus 0.1% diethylamine as mobile phase. Under these conditions, recovery of 80–90% 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.
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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 15–75 m M with a detection limit of 2.2 m M. Tramadol could be determined concentrations between 9 and 50 m M at a sampling rate of 90 samples/h with a detection limit of 1.7 m M 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 97–102%.
4.8. Spectrophotometric analysis Several spectrophotometric analysis methods for tramadol and its related impurities were reported in literature [43 – 45]. Rajasekhar et al. [43] developed a spectrophotometric assay determination method of tramadol in bulk as well as capsule dosage forms. Tramadol obeyed Beer’s law in a concentration of 10–150 m g/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 5–25 and 50–250 m g/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
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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, 1–15 and 1–16 m g/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 [46 – 48]. 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 12.5–10,000 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 GC–MS enantiomeric assay determination method of tramadol and O -desmethyltramadol by GC–MS. 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 anal ysis by gas chromatography–electron 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) [49 – 51]. 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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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 ( T max) 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 (C max) and area under the curve (AUC) increase linearly over the dose range of 50–400 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, C max 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 C max 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. C max 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].
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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) [59 – 61]. Tramadol undergoes biotransformation to form the N and 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,N didemethyl 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].
H3C N
H
H3C
H3C N
H
H3C
M1
N -
d e m e t h y l a t i o n
OH
o n l a t i t h y e d e m O -
OH
and enantiomer O
H
H3C
M5
and enantiomer
NH
OH
o n l a t i t h y e m - d e
H
O
H3C
M2
CH3
OH
Tramadol
N -
d e m e t h y l a t i o n and enantiomer
OH
N -
de m e t h y l a t i o n
NH
H2N
H
o n l a t i t h y e d e m O -
and enantiomer O
H
OH
N -
de m e t h y l a t i o n
H2N
and enantiomer O
CH3
and enantiomer OH
OH CH3
OH
M3
Figure 11.13 Metabolic pathways of tramadol in phase 1 reactions.
M4
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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]. 25–32% of an oral dose is excreted as unchanged tramadol. The mean elimination half-life is about 5–6 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) (þ)-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 blood–brain 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). (þ)Enantiomer is about fourfold more potent than the ( ) Enantiomer [66]. (c) Tramadol inhibits norepinephrine reuptake. ( )Tramadol is a more potent blocker than its ( þ) 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
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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 C max, 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) [15,74 – 77]. 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 O
H3C
H3C
N
N H3C
+ (CH2O)n + (CH3)2NH·HCI
2
NaOH
3
· HCI
H3C
5
O
1
O
4 X X = Li or MgBr
O
H3C · HCI N
H3C
H
H3C
CH3
N and enantiomer
HCI
H3C
and enantiomer
OH
O
CH3
Tramadol hydrochloride
Scheme 11.4 Synthesis of tramadol.
H
OH
O
CH3
Tramadol
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[6,10,15,75 – 84], 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 [10,74,75,77 – 84]. There are several strategies given in the literature for the removal of the 1RS ,2SR isomer from tramadol [15,74,75,77,80 – 82,86] 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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Tramadol Hydrochloride
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