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Spectroscopic Methods for Determination of Dexketoprofen Trometamol and

Tramadol HCl

Article · January 2014

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 RESEARCH ARTICLE

Spectroscopic Methods for Determination of Dexketoprofen

Trometamol and Tramadol HCl
Mokhtar M Mabrouk1, Sherin F Hammad1, Hamed M El-Fatatry1, Samah F El-Malla1*
Abstract: Two sensitive spectrophotometric methods; using first derivative 1D spectrophotometry (method I) and dual
wavelength spectrophotometry (method II), were developed and validated for the simultaneous determination of
dexketoprofen trometamol and tramadol HCl in binary mixtures and synthetic mixture. Method I was based on measuring 1D at
242 nm for determination of dexketoprofen trometamol and 1D at 232 nm for determination of tramadol HCl. Method II was
based on measuring the absorbance difference between 259 nm and 281.6 nm for determination of dexketoprofen trometamol
and between 225 nm and 281 nm for determination of tramadol HCl. Linearity range for dexketoprofen trometamol using
methods I and II was found to be 4.00–30.00 μg.ml-1. For tramadol HCl the linearity range was found to be 20.00–100.00 μg.ml-1
for both methods. The developed methods were successfully applied for the determination of dexketoprofen trometamol and
tramadol HCl in synthetic mixture containing all possible excipients present in tablet dosage form. The mean percentage
recovery values were found to be 98.68±0.34 and 99.34±0.48 for method I and 101.05±0.41, 101.13±0.54 for method II for
dexketoprofen trometamol and tramadol HCl, respectively.

INTRODUCTION acute pain of moderate to severe intensity. Each tablet

Dexketoprofen trometamol is (S)-(+)-2-(3-Benzoylphenyl)
propionic acid, with 2-amino-2-(hydroxymethyl)-1,3-
propanediol (1:1) (Mol. wt. 375.42, pKa 4.5). It is a cyclo-
oxygenase inhibitor and used as analgesic and anti-
inflammatory drug. [1, 2]
Non-steroidal anti-inflammatory drugs (NSAIDs) are
contains 25.00 mg dexketoprofen trometamol and 75.00
mg tramadol hydrochloride. This fixed dose combination
was in phase III clinical trial. [8, 9]
Dexketoprofen was determined by several methods
including; UV spectro-photometry, [10] HPLC [10] and TLC.
[11] Dexketoprofen was also determined simultaneously

often utilized in postoperative analgesia because they
have analgesic effects comparable to opioids but lack their
adverse effects. Dexketoprofen is the S(+) enantiomer of
ketoprofen. Recently there is a trend to synthesize the
enantiomers of various drugs which give these agents a
with different drugs such as thiocolchicoside. [12]
Tramadol was determined by several methods
including; spectrophotometry, [13-16] spectrofluoremetry, [15]
electrochemical method, [17] HPLC, [14, 18-20] GC [21, 22] and CE.
[23] Tramadol was also determined simultaneously with

more controlled profile and minimize their adverse
effects. [3]
Tramadol HCl is (1RS, 2RS)-2-[(Dimethylamino)
methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride
(Mol. Wt 299.84, pKa 9.41). It is an opioid receptor agonist
and nor-adrenaline reuptake inhibitor and used as
analgesic drug. [4-6] The chemical structures of
dexketoprofen trometamol and tramadol HCl are shown in
Figure 1.
Dexketoprofen trometamol is added to intravenous
tramadol to control severe pain after laparoscopic
cholecystectomy in hospitalized patients. Compared to
administration of opioids alone for pain relief; combination
of NSAIDs with opioids decrease the incidence of
respiratory depression and over sedation while increasing
mobility and recovery of intestinal function faster. [3]
A randomized, double-blind, placebo and active-
controlled, parallel-group study was developed to evaluate
the analgesic efficacy and safety of dexketoprofen
trometamol and tramadol hydrochloride oral fixed
combination on moderate to severe acute post-operative
pain. [7] Recently, Menarini (Italian pharmaceutical
company) has started the development of a fixed
combination of dexketoprofen trometamol and tramadol
hydrochloride as tablet formulation for the treatment of
1Department of Pharmaceutical Analytical Chemistry, Faculty of
Pharmacy, Tanta University, Egypt.
E-mail: elmallasfarouq@gmail.com
*Corresponding author
different drugs such as; ibuprofen, [24] acetaminophen, [25, 26]
acetaminophen and aceclofenac, [27] acetaminophen and
domperidone, [28] ketamine and methaone. [29] The only
method reported in literature for determination of
dexketoprofen trometamol and tramadol HCl with
haloperidol was LC–DAD method. [30]
The aim of this work was to develop simple, sensitive
and validated spectroscopic methods; First derivative 1D
spectrophotometry (method I) and dual wavelength
spectrophotometry (method II) for the determination of
dexketoprofen trometamol and tramadol HCl in their
binary and synthetic mixtures.
Application of derivative spectrophotometry offers a
powerful tool for quantitative analysis of multi-component
mixtures. It offers greater selectivity than normal
spectrophotometry as it decreases spectral overlap and
allows better resolution. [31, 32]
Despite of the presence of severe spectral overlap of
dexketoprofen trometamol and tramadol HCl, their
simultaneous determination is possible by direct UV
spectrophotometry using dual wavelength method. “The
absorbance difference between two points on the mixture
spectra is directly proportional to the concentration of the
component of interest independent of interfering
component”. The most striking features of dual
wavelengths method are its simplicity, sensitivity and
rapidity. It is also an easier and economical method than
HPLC separation technique and does not require the use of
any expensive or toxic HPLC solvents. These advantages
make it especially suitable for routine quality control. [33, 34]

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 RESEARCH ARTICLE
O OH
OH .
O CH3
Dexketoprofen trometamol
Figure 1: Structure of dexketoprofen trometamol and tramadol HCl
MATERIALS AND METHODS
Apparatus and Software
Jasco (V-530) UV-Vis double beam spectrophotometer
equipped with 1 cm quartz cells and connected to a
personal computer loaded with [Jasco]-[spectra manager]
software. Absorption spectra were recorded on wavelength
range of 220-340 nm at scan rate 400 nm.min−1; and
spectral band 0.2 nm.
Pure Drugs
Dexketoprofen trometamol and tramadol HCl were kindly
supplied by Sigma Company for Pharmaceutical Industries
Quesna, Menofia, Egypt. Their purity was found to be
99.17% and 100.47%, respectively, according to the
specific absorbance (A1%, 1cm) values reported. [2]
Chemicals and Reagents
Methanol was analytical grade (Sigma Aldrich 99.8%), HCl
was of analytical grade (37%, Merck, Germany). Excipients
of tablet; crosscarmelose sodium, hydroxyl propyl methyl
cellulose (HPMC), lactose monohydrate, magnesium
stearate, microcrystalline cellulose (avicel), polyethylene
glycol 6000, polysorbate, pregelatinized starch and
titanium oxide were kindly donated by Sigma Company for
Pharmaceutical Industries.
Standard Solutions and Calibration
1. Dexketoprofen Trometamol
Dexketoprofen trometamol stock standard solution (1.00
mg.ml-1) was prepared in methanol. Working standard
solution (100.00 Pg ml-1) was prepared by diluting 10.00
ml of dexketoprofen trometamol stock solution to 100.00
ml with 0.1N HCl.
2. Tramadol Hydrochloride
Tramadol HCl stock standard solution (1.00 mg.ml-1) was
prepared in methanol. Working standard solution (100.00
Pg.ml-1) was prepared by diluting 10.00 ml of tramadol HCl
stock solution to 100.00 ml with 0.1N HCl.
Laboratory Prepared Mixtures for Method Validation
A set of laboratory prepared mixtures of dexketoprofen
trometamol and tramadol HCl in the ratio (1:3) were
prepared by transferring different aliquots of each of
dexketoprofen trometamol and tramadol HCl working
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H3C
H
N
H3C
NH2 OH . HCl
OH
O
CH3
OH
Tramadol hydrochloride
standard solutions into 10.00 ml volumetric flask and
diluting to volume with 0.1N HCl. These mixtures were
used for accuracy and precision calculations.
Construction of Calibration Curve
1. Derivative Spectrophotometric Method
Different aliquots were taken from dexketoprofen
trometamol and tramadol HCl working solutions (100.00
Pg.ml-1) and diluted with 0.1N HCl to obtain solutions of
dexketoprofen trometamol ranging from 4.00 to 30.00
Pg.ml-1 and solutions of tramadol HCl ranging from 20.00 to
100.00 Pg. ml-1.
UV spectra were scanned for these solutions using 0.1N
HCl as blank. Then first order derivative spectra 1D were
calculated at ΔO= 9. The zero-crossing points of 1D spectra
of dexketoprofen trometamol and tramadol HCl were
assigned. Dexketoprofen trometamol was determined by
measuring 1D amplitudes at 242 nm; which is the zero
crossing for tramadol HCl. Similarly, tramadol HCl was
determined by measuring 1D amplitudes at 232 nm; which
is the zero crossing for dexketoprofen trometamol.
Calibration curves were constructed by plotting 1D
amplitudes at 242 and 232 nm against corresponding
concentrations for dexketoprofen trometamol and
tramadol HCl, respectively.
2. Dual Wavelength Spectrophotometric Method
Different aliquots were taken from dexketoprofen
trometamol and tramadol HCl working solutions (100.00
Pg.ml-1) and diluted with 0.1 N HCl to obtain solutions of
dexketoprofen trometamol ranging from 4.00 to 30.00
Pg.ml-1 and solutions of tramadol HCl ranging from from
20.00 to 100.00 Pg.ml-1.
UV spectra were scanned for these solutions using 0.1N
HCl as blank. Then two wavelengths were selected for each
drug that the absorbance difference (dA) at these
wavelengths equals zero for the other. Dexketoprofen
trometamol was determined by measuring the dA between
259 nm and 281.6 nm; at which dA for tramadol HCl equals
zero. And similarly tramadol HCl was determined by
measuring the dA between 225 nm and 281 nm; at which
dA for dexketoprofen trometamol equals zero. Calibration
curves were obtained by plotting dA (259-281.6) and dA
(225-281) against corresponding concentrations for
dexketoprofen trometamol and tramadol HCl, respectively.
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 RESEARCH ARTICLE
Figure 2: Zero-order UV spectra of 20.00 Pg.ml-1 dexketoprofen
trometamol ( …… ) and 60.00 Pg.ml-1 tramadol HCl (____) in 0.1N
HCl
0.060
0.050
0.040
242 nm
0.030
0.020
1D
0.010
0.000
0 5
Concentration μg.ml-1
Figure 4: Calibration curve of dexketoprofen trometamol by the proposed first derivative spectrophotometric method at 242 nm
Preparation of Synthetic Mixture
Synthetic mixture equivalent to one tablet was prepared by
mixing 25.00 mg dexketoprofen trometamol, 75.00 mg
tramadol HCl and the following expected inactive
ingredients; 9.00 mg crosscarmelose sodium, 3.00 mg
hydroxyl propyl methyl cellulose (HPMC), 80.00 mg lactose
monohydrate, 6.00 mg magnesium stearate, 100.00 mg
microcrystalline cellulose (avicel), 3.00 mg polyethylene
glycol 6000, 2.00 mg polysorbate, 18.00 mg pregelatinized
starch and 3.00 mg titanium oxide.
The synthetic mixture was transferred to a 100.00 ml
volumetric flask, dissolved in 50.00 ml methanol and
sonicated for 15 minutes. Then the solution was made up to
the required volume using methanol. The solution was
filtered and the first 10.00 ml of the filtrate was discarded.
1.00 ml of the filtrate was transferred to a 10.00 ml
volumetric flask and made up to final volume with 0.1N HCl
to obtain a solution containing; 25.00 andPg.ml-1 of
dexketoprofen trometamol and tramadol HCl, respectively.
The procedures were carried out as mentioned and then
concentrations of both drugs were calculated from the
corresponding regression equations.
RESULTS AND DISCUSSION
Analytical methods for the determination of binary mixture
without previous separation are of interest to quality
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Figure 3: First-order derivative spectra of 20.00 Pg.ml-1
dexketoprofen trometamol ( …… ) and 60.00 Pg.ml-1 tramadol HCl
(____ ) in 0.1N HCl
y = 0.0016x - 0.0004
R² = 0.9993
10 15 20 25 30 35
control (QC) labs and national regulatory authorities (NRA)
around the world. [32]
Literature review revealed that only LC-DAD method
was employed for simultaneous determination of
dexketoprofen trometamol and tramadol HCl with
haloperidol, which requires sophisticated instrument and
HPLC grade solvents. [30]
In the present research work an attempt has been made
to develop simple, sensitive and accurate
spectrophotometric methods (1D and dual wavelength
spectrophotometry) for the analysis of combination of
dexketoprofen trometamol and tramadol HCl.
Spectrophotometric methods are the most commonly
used techniques and continue to enjoy wide popularity. The
common availability of the instrumentation, the simplicity
of procedures, speed, precision and accuracy of the
technique still make spectrophotometric methods attractive.
Method Development
It is quite clear that there is extensive spectral overlap in
the zero-order UV absorption spectra of dexketoprofen
trometamol and tramadol HCl (Figure 2). The study of their
derivative spectra may overcome this difficulty; thus their
first derivative spectra were obtained.
The first derivative spectrum of dexketoprofen
trometamol exhibits absorption minima at 242 nm while
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 RESEARCH ARTICLE

0.160
0.140
0.120
0.100

232 nm
0.080
y = 0.0014x + 0.0027
0.060 R² = 0.9996
1D
0.040
0.020
0.000
0 20 40 60 80 100 120
Concentration μg.ml-1

Figure 5: Calibration curve of tramadol HCl by the proposed first derivative spectrophotometric method at 232 nm

0.90
0.80
0.70
dA( 259 - 281.6)

0.60
0.50
0.40 y = 0.0259x + 0.0007
0.30 R² = 0.9997

0.20
0.10
0.00
0 10 20 30 40
Concentration μg.ml-1
Figure 6: Calibration curve of dexketoprofen trometamol by the proposed dual wavelength spectrophotometric method

1.4

1.2
y = 0.0135x + 0.0394
1 R² = 0.9992
dA (225-281)

0.8

0.6

0.4

0.2

0
0 20 40 60 80 100
Concentration μg. ml-1

Figure 7: Calibration curve of tramadol HCl by the proposed dual wavelength spectrophotometric method

tramadol HCl reads zero. Tramadol HCl exhibits absorption
maxima at 232 nm while dexketoprofen trometamol reads
zero, as shown in Figure 3. The proposed method was
found to be valid for the simultaneous determination of
dexketoprofen trometamol and tramadol HCl in different
laboratory prepared mixtures.
Dual wavelength spectroscopy offers an efficient
method for analyzing a component in presence of an
interfering component. In the normal course of analysis by
this method; one of the drugs was considered as a
component of interest and the other drug was considered
as an interfering component and vice-versa. For
elimination of interferences, dual wavelength method had
been developed; in which two wavelengths were selected
for each drug in a way so that the difference in absorbance
was zero for another drug. [33] Dexketoprofen trometamol
exhibits equal absorbance at 225 nm and 281 nm, where
absorbance differences dA225-281 were measured for the
determination of tramadol HCl; similarly tramadol HCl has
equal absorbance at 259 nm and 281.6 nm; where
absorbance differences dA259-281.6 were measured for the
determination of dexketoprofen trometamol as shown in
Table 1.
Method Validation
The developed methods were validated according to the
ICH guidelines. [35, 36] The following validation parameters
were addressed:

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 RESEARCH ARTICLE

Table 1: The Wavelengths (O

O1, O2) Selected for Estimation of Dexketoprofen Trometamol and Tramadol HCl by Dual Wavelength Method

Component O1 O2
Dexketoprofen trometamol 259 281.6
Tramadol HCl 225 281

Table 2: Quantitative Parameters for the Determination of Dexketoprofen Trometamol and Tramadol HCl with the Proposed Methods

Method Compound Linearity (P

Pg.ml-1) O(nm) r a (10-4) b (10-3) Sy/x (10-4) Sa (10-4) Sb (10-5) DL (P
Pg.ml-1) QL (P
Pg.ml-1)
Dexketoprofen
1D
4-30 242 0.9996 -4.42 1.60 4.04 2.64 1.59 0.54 1.65
trometamol
Tramadol HCl 20-100 232 0.9997 27.8 1.38 8.64 8.20 1.19 1.93 5.86
Dexketoprofen
Dual 4-30 259-281.6 0.9998 70 25.9 42 27 20 0.34 1.04
trometamol
wavelength
Tramadol HCl 20-100 225-281 0.9995 393 13.5 114 97 16 2.38 7.21
r: correltion coefficient, a: intercept, b: slope, Sy/x: residual standard deviation of the regression line, Sa: standard error of intercept, Sb: standard error of slope, DL: detection limit, QL: quantitation limit

Table 3: Evaluation of the Accuracy for the Determination of Dexketoprofen Trometamol and Tramadol HCl by the Proposed Methods According to ICH Guidelines

1D Dual Wavelength
Concentration Taken Mean Mean Mean Mean
Concentration Found Recovery Concentration Found Recovery
Pg.ml-1) Concentration Recovery -1
Concentration Recovery
Pg.ml-1) % Pg.ml ) %
FoundP
Pg.ml-1) %±S.D. Found (PPg.ml-1) %±S.D.
Dexketoprofe 10 9.81 9.81 10.13 9.91 99.13 9.96 10.19 10.12 10.09 100.92
99.83 100.95
n trometamol 20 19.70 19.85 19.78 19.78 98.88 19.98 19.87 20.37 20.07 100.37
±1.43 ±0.59
30 30.15 30.48 30.70 30.44 101.47 30.23 30.37 30.80 30.46 101.55
Tramadol HCl 30 31.05 30.45 30.19 30.57 101.88 30.30 30.85 30.58 30.58 101.93
100.38 99.88
60 60.86 59.68 60.15 60.23 100.38 59.52 58.27 58.61 58.80 98.00
±1.51 ±1.97
90 88.35 88.95 89.64 88.98 98.87 88.87 90.61 89.73 89.74 99.71

Table 4: Evaluation of the Intra-day and Inter-day Precision for the Determination of Dexketoprofen Trometamol and Tramadol HCl According to ICH Guidelines

1D Dual wavelength
Intra-day Inter-day Intra-day Inter-day
Concentration Taken
Mean Mean Mean Mean
Pg.ml-1) R.S.D. R.S.D. R.S.D. R.S.D.
Concentration S.D. Concentration S.D. Concentration S.D. Concentration S.D.
% % % %
Found Pg.ml-1) Found Pg.ml-1) Found (P
Pg.ml-1) Found Pg.ml-1)
Dexketoprofen 10 9.91 0.18 1.85 10.01 0.17 1.67 10.09 0.12 1.17 10.10 0.04 0.38
trometamol 20 19.78 0.08 0.39 19.95 0.11 0.55 20.07 0.26 1.31 20.34 0.33 1.64
30 30.44 0.28 0.92 30.31 0.29 0.97 30.46 0.30 0.97 30.11 0.19 0.62
Tramadol HCl 30 30.57 0.44 1.45 29.55 0.22 0.74 30.58 0.27 0.89 30.15 0.63 2.08
60 60.23 0.60 0.99 60.83 0.53 0.86 58.80 0.65 1.10 59.33 0.62 1.05
90 88.98 0.65 0.73 91.61 0.24 0.27 89.74 0.87 0.97 90.02 1.37 1.52

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 RESEARCH ARTICLE
Table 5: Recovery Data of Dexketoprofen Trometamol and Tramadol HCl from Synthetic Mixture by the Proposed Methods
Concentration
Method Drug
TakenPg.ml-1)
Dexketoprofen
1D
25
trometamol
Tramadol HCl 75
Dexketoprofen
Dual 25
trometamol
wavelength
Tramadol HCl 75
1. Linearity
Calibration curves were obtained for dexketoprofen
trometamol and tramadol HCl in the linearity range
mentioned. Figure 4-7 illustrates the linear relationship
between concentrations of dexketoprofen trometamol or
tramadol HCl by Method I and II. The quantitative
statistical parameters for the determination of
dexketoprofen trometamol and tramadol HCl were
summarized in Table 2. The high values of correlation
coefficients (r) with negligible intercepts indicate good
linearity of the calibration curves.
2. Detection and Quantitation Limits
Detection (DL) and quantitation (QL) limits can be
calculated depending on standard deviation of the response
and the slope. They may be expressed as: DL = 3.3V/ S
and QL = 10V/ S where; "V" is the standard deviation of y-
intercept of regression line and "S" is the slope of the
calibration curve. [35, 36] Calculated DL and QL of the
proposed methods are shown in Table 2.
3. Accuracy
The accuracy of the proposed methods was evaluated by
analyzing three different laboratory prepared mixtures of
dexketoprofen trometamol and tramadol HCl in the ratio
(1:3) within the linearity range three times. Accuracy was
expressed as the recovery % ±S.D, (Table 3).
4. Precision
The precision of an analytical method gives information on
the random errors. It expresses the closeness of agreement
between a series of measurements obtained from multiple
sampling of the same homogenous sample under
prescribed condition. [35] It includes repeatability (intra-
day) and intermediate (inter-day) precision. Precision was
carried out for both methods by analyzing three different
laboratory prepared mixture "three replicates" of
dexketoprofen trometamol and tramadol HCl within the
linearity range. Standard deviation (S.D.) and relative
standard deviation (R.S.D. %) values of the results obtained
were calculated (Table 4).
5. Specificity
According to ICH [35, 36] specificity is the ability to assess
unequivocally the analyte in the presence of components
which may be expected to be present. Typically these might
include impurities, degradants, matrix, etc. For testing
specificity of the proposed method; the % recovery of
dexketoprofen trometamol and tramadol HCl was
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Concentration Found Mean Concentration Mean Recovery
Pg.ml-1) Pg.ml-1)
Found (P %±S.D.
24.57 24.69 24.74 24.67 98.68±0.34
74.47 74.89 74.17 74.51 99.34±0.48
25.30 25.15 25.34 25.26 101.05±0.41
76.30 75.72 75.52 75.85 101.13±0.54
determined in mixtures containing both drugs with the
possible excipients present in dosage form by the two
proposed methods as shown in Table 5.
CONCLUSION
Two new spectrophotometric methods for the
simultaneous determination of dexketoprofen trometamol
and tramadol HCl were developed. The first derivative 1D
and dual wavelength spectrophotometric methods were
applied for the simultaneous determination of
dexketoprofen trometamol and tramadol HCl either in their
bulk powder form or in their laboratory prepared synthetic
mixtures. Results demonstrated the lack of interference
from dosage form excipients and the usefulness of the
methods. Both methods are simple, sensitive, precise,
accurate, inexpensive and non-polluting to environment.
They are suitable for routine quality control analysis of
dexketoprofen trometamol and tramadol HCl in
pharmaceutical preparations.
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Cite this article as: Mokhtar M Mabrouk, Sherin F
Hammad, Hamed M El-Fatatry et al. Spectroscopic
Methods for Determination of Dexketoprofen
Trometamol and Tramadol HCl. Inventi Impact: Pharm
Analysis & Quality Assurance, 2014(4):276-282, 2014.
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