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RP-HPLC PDA Analysis of Tranexamic Acid in Bulk and Tablet Dosage Form

Article in Analytical Chemistry Letters · November 2017

DOI: 10.1080/22297928.2017.1422438

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 Analytical Chemistry Letters

ISSN: 2229-7928 (Print) 2230-7532 (Online) Journal homepage: http://www.tandfonline.com/loi/tacl20

RP-HPLC PDA Analysis of Tranexamic Acid in Bulk

and Tablet Dosage Form

Ravindra Patil, Ambreen Kauser L. Ahmed, Sandip Firke & Dipali Pawar

To cite this article: Ravindra Patil, Ambreen Kauser L. Ahmed, Sandip Firke & Dipali Pawar (2017)
RP-HPLC PDA Analysis of Tranexamic Acid in Bulk and Tablet Dosage Form, Analytical Chemistry
Letters, 7:6, 813-821

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 TACL 7 (6) 2017 pp 813 - 821 813
ISSN Print: 2229-7928
ISSN Online: 2230-7532

RP-HPLC PDA Analysis of Tranexamic Acid in Bulk and Tablet Dosage Form

Ravindra Patil *, Ambreen Kauser L. Ahmed, Sandip Firke, Dipali Pawar

Department of Pharmaceutical Chemistry, R.C.Patel Institute of Pharmaceutical
Education and Research, Karwand Naka, Shirpur, Maharashtra 425405, India
Received 25 October 2017; accepted in revised form 12 December 2017

Abstract: A simple economic approach of RP HPLC-PDA has been used to separate and estimate the
tranexamic acid in pharmaceutical formulation. Tranexamic acid being non chromophoric, pre-column derivatization
was performed with 2, 4-dinitroflourobenzene solution in aqueous alkaline medium at 60°C. The derivatized
Downloaded by [220.227.57.45] at 20:30 09 January 2018

drug was then determined using C-18 column (250 × 4.6mm, 5 μ) and acetonitrile 65 % v/v in water as the mobile
phase with flow rate of 1 mL/min. The tranexamic acid derivative was detected at a wavelength of 355 nm using
PDA detector. Retention time of tranexamic acid was 9.44 min. The method followed Lambert-beers law in the
concentration range of 6-16 μg/mL with correlation co-efficient equal to 0.9999. The limit of detection and limit
of quantitation were 0.002124 and 0.006434 μg/mL, respectively. The developed method is very sensitive and
can be used for determination of tranexamic acid in pharmaceutical formulations.

Key words: Tranexamic acid, sanger’s reagent, derivatization, RP HPLC.

Introduction derivatization with naphthalene-2-3-dicarbo-

Tranexamic acid, trans- 4- aminomethylcyclo xaldehyde and cyanide 11, an electrochemical
hexacarboxylic acid (Fig. 1) is the most potent method 12, a LC-MS method 13 and UPLC-MS/
antifibrinolytic and hemostatic drug 1. It has been MS 14 have been reported for the analysis of
used for the treatment of heavy menstrual bleed- tranexamic acid. An RP-HPLC method for the
ing and to control bleeding in surgeries 1-4. determination of tranexamic acid and mefenamic
Tranexamic acid acts by competitively inhibiting acid 6 and a GC method are also reported in the
the activation of plasminogen, thereby reducing literature 15. All methods reported so far involve
conversion of plasminogen to plasmin an enzyme complex reactions for the completion of
that degrades fibrin clot 4. Since tranexamic acid derivatization and its quantification.
lacks chromophore, it cannot be detected by UV
spectroscopy. It is therefore essential to derivatize
tranexamic acid to introduce chromophore and de-
termine derivative by HPLC-PDA.
A review of the literature reveals derivatization
of this drug with different reagents followed by
their HPLC determinations. Some of the meth-
ods utilized benzene sulfonyl chloride 5, ninhydrin
6
, phenylisothiocynate 7, 8, 2-hydroxynaphth-alde-
hyde 9 and sodium picrylsulfonate 10. In addition
to these a HPLC-fluorescence method involving Fig. 1. Structure of tranexamic acid

*Corresponding author (Ravindra Patil)

E-mail: < rrp2003@hotmail.com > © 2017, Har Krishan Bhalla & Sons
 Ravindra Patil et al., / TACL 7 (6) 2017 813 - 821
In our method, 2, 4-dinitrofluorobenzne
(Sanger’s reagent) has been used as derivatizing
reagent and the reaction has been accomplished
in process in aqueous borate buffer at alkaline
pH. Also the method does not involve precipita-
tion, filtration and drying process. The derivatized
product was determined by using HPLC with
PDA detector. The developed method can be suc-
cessfully used for tranexamic acid determination
in pharmaceutical formulations.
Experimental
Chemicals and reagents
Tranexamic acid was obtained as gift sample
from Wockhardt Pvt.Ltd., Aurangabad. Sanger’s
reagent (2, 4-dinitroflourobenzene) was purchased
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from HiMedia Laboratories Pvt. Ltd. HPLC
grade acetonitrile was used. All the chemicals used
were of analytical grade and double distilled wa-
ter was used throughout the work. Borate buffer
solution (0.2 M) was prepared as per Indian Phar-
macopeia 2014 procedure. For mobile phase fil-
tration, 0.45 micron nylon filters were used
(Millipore, USA).
Equipment and Chromatographic conditions
For the development of HPLC procedure,
Shimadzu UFLC (LC 20 AD) HPLC system,
equipped with SPD-M20 (Tungsten diode array)
detector and loop injector was used. 20 μl of
analyte was injected in all experiments. Chromato-
graphic conditions were optimized on a Qualisil
BDS C-18 column (250 × 4.6mm, 5μ) and the
mobile phase was prepared by mixing acetonitrile
and water in the ratio (65:35, v/v). The mobile
phase flow rate was set as 1.0 mL/min and all the
chromatographic work were performed at ambi-
ent temperature. Pre-column derivatization tech-
nique was used.
Preparation of stock solution
Accurately weighed 10.0 mg of Tranexamic acid
Table 1. Assay of tranexamic acid tablets
Label claim (mg) Found (mg)
650 642.46
814
was transferred to 100 ml of ambered colored
volumetric flask; volume was adjusted to mark
with mobile phase to obtain the concentration 100
μg/ml.
Derivatization followed by preparation of
standard solutions
From above stock solution to a set of 10.0 ml
ambered colored volumetric flask aliquot volumes
containing the drug over the working concentra-
tion range of 6-16 μg/ml were quantitatively trans-
ferred. A volume of 1.0ml of 0.2 M borate buffer
(pH 10.5) followed by 1.2 ml of 2, 4-dinitro-
flourobenzene solution (0.3 % v/v in methanol)
were added and mixed well. The solutions were
heated in thermostatically controlled water bath
at 60°C for 15 min. The reaction was stopped by
cooling under tap water followed by addition of
0.2 ml of concentrated hydrochloric acid. Finally,
the volume was made up to the mark with mobile
phase (Acetonitrile and water 65:35). The blank
sample was prepared by similar method, except
drug sample was not added. The spectrum of
blank sample is shown in Fig. 2.
Preparation of sample solution
Twenty tablets were accurately weighed and
finely powdered with mortar and pestle. A por-
tion of the powder 12.24 mg equivalent to 10.0
mg of Tranexamic acid was transferred into 100
ml of ambered colored volumetric flask. To it
added 30 ml of methanol, followed by sonication
for 20 minutes and diluted to 100 ml with mobile
phase. The solution was filtered with 0.45 micron
nylon filter; with first 10 ml aliquot was discarded
and then used the filtrate for further preparation
of dilution through derivatization process. The re-
sults of assay are given in Table 1.
Linearity
Five different aliquots of the stock solution were
diluted post derivatization with mobile phase, to
n Recovery (%) RSD (%)
10 98.84 1.87
 Ravindra Patil et al., / TACL 7 (6) 2017 813 - 821 815
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Figure 2. Whole Chromatogram of Blank

obtain the final concentration in the range 6-16
μg/ml. Each HPLC run was repeated three times
for all the concentrations considered. The cali-
bration curve was generated by plotting area un-
der curve against the concentration. The obser-
vation and calibration curve is shown in Table 2.
Accuracy 16
The accuracy of method was checked by re-
covery study. The standard addition method was
employed at 80, 100 and 120 % level; known
Table 2. Linearity study of tranexamic acid
amount of standard Tranexamic acid was added
to pre-analyzed sample (6.0 μg/ml of Tranexamic
acid) and subjected them to the developed RP-
HPLC method. Results are shown in Table 3.
Precision
Precision alludes to how close results from vari-
ous samples are to each other. Intra - day preci-
sions were controlled by examining, the three con-
centrations 6, 8, and 10 μg/ml of tranexamic acid,
for three times on the same day. Everyday

μg/ml)
Concentration (μ Mean peak area ± S.D % R.S.D

6 18098 ± 185.23 1.0234

8 22843 ± 265.32 1.1614
10 28209 ± 310.45 1.1005
12 33234 ± 390.56 1.1517
14 38328 ± 456.78 1.1917
16 42838 ± 484.7 1.1314
Table 3. Results of recovery studies of tranexamic acid

Amount added Found concentration n % Recovery % R.S.D

μg/ml)
(μ μg/ml)
(μ

4.8 4.67 3 97.29 1.165

6 6.16 3 102.66 1.661
7.2 7.37 3 102.36 1.842
 Ravindra Patil et al., / TACL 7 (6) 2017 813 - 821
changeability was evaluated utilizing previously
mentioned three concentrations examined on three
different days. These results show reproducibil-
ity of the assay (Table 4). The % R.S.D. value of
less than 2 and low standard deviation indicates
that the method is precise for the determination
of tranexamic acid.
Repeatability
Repeatability was measured by six HPLC runs
of 10 μg/ml solution of derivatized tranexamic acid.
It is a measure of how the HPLC instrument per-
formed under the given chromatographic condi-
tions. Results are shown in Table 5.
Sensitivity
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816
bration curve. Results are given in Table 6.
Ruggedness
For carrying out robustness, intentional minor
changes were made in the experimental condi-
tions like change in proportion of acetonitrile in
mobile phase and flow rate from 0.9 mL to 1.1
mL. From stock solution, sample solution of
tranexamic acid 10 μg/ml was prepared and ana-
lyzed. Peak area was measured for same con-
centration solution. The result is given in Table 7.
System suitability test 16
System suitability testing is fundamental in find-
ing whether the performance of the chromato-
graphic system is upto the mark. The above pre-

Sensitivity of the proposed method was esti-
mated in terms of Limit of Detection (LOD) and
Limit of Quantitation (LOQ). In order to deter-
mine detection and quantification limit, concen-
trations in the lower part of the linear range of the
calibration curve were used. Tranexamic acid
solutions of 6, 6.4, 6.8,7 and 7.8 μg/ml were pre-
pared. The LOQ and LOD were calculated us-
ing equation LOD=3.3x N/B and LOQ=10x N/B,
where, N is standard deviation of the peak areas
of the drugs (n=3) and B is the slope of the cali-
Table 4. Result of Precision studies
pared solutions for validation were used for sys-
tem suitability test. Results are shown in Table 8.
As shown in table, no. of high theoretical plate,
peak symmetry and proper retention time indicates
that proposed method is suitable for determina-
tion of tranexamic acid in pharmaceutical formu-
lations.
Results and discussions
Derivatization of tranexamic acid
Derivatization is the conversion of analyte by a

Concentration n Intra-day Inter-day

μg/ml)
(μ Amount found % R.S.D Amount found % R.S.D
μg/ml)
(μ μg/ml)
(μ

6 3 6.13 1.156 5.93 1.567

8 3 7.91 1.286 8.09 1.665
10 3 10.09 1.857 9.75 2.0035
Table 5. Result of repeatability studies of tranexamic acid

μg/ml)
Concentration (μ Amount found mean ± S.D % R.S.D

10 10.14 ± 0.11 1.877

Table 6. Sensitivity (LOD and LOQ studies of tranexamic acid

Drug Limit of detection Limit of quantification

μg/mL)
(μ μg/mL)
(μ

Tranexamic acid 0.002124 0.006434

 Ravindra Patil et al., / TACL 7 (6) 2017 813 - 821
Table 7. Result of ruggedness studies
Chromatographic Assay (%) tR (min)±SD Theoretical Tailing
conditions
Acetonitrile:water (65:35) 98.82
Acetonitrile:water (67:33) 98.63
Acetonitrile:water (63:37) 100.25
Flow rate (1.1 mL/min) 100.65
Flow rate (0.9 mL/min) 99.86
Table 8. System Suitability Test
System Suitability test
Retention time
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Theoretical plate (N)
Tailing factor
Capacity factor (k’)
chemical reagent to a derivative that has differ-
ent spectral properties.
Tranexamic acid does not contain π electrons
in its structure. Chemical derivatization procedure
was adopted because tranexamic acid absorbs
weakly in ultraviolet region, a more sensitive
method of assay was obtained by converting the
tranexamic acid to a derivative with a more in-
tensely absorbing chromophore. In the present
work we have derivatise tranexamic acid with 2,
4-dinitrofluorobenzene in an alkaline method so
that it can be determined by HPLC-UV (Fig. 3).
Sanger’s reagent reacts through a nucleophilic
aromatic substitution reaction, in which the pri-
mary aliphatic amino group of tranexamic acid
substitutes the fluoro group on aromatic ring of 2,
4-dinitrofluorobenzene to yield the derivative. The
reaction between Sanger ’s reagent and
tranexamic acid is very slow at room tempera-
ture and required the heating to speed up. In this
reaction hydrochloric acid is used to remove the
interference caused by the excess coloured re-
agent. The λmax of the produced derivative was
found at 355 nm, which was used in HPLC.
Method development and its optimization
In the present work our aim was to develop a
sensitive, simple, accurate and reproducible RP-
HPLC method to determine tranexamic acid. Ini-
817
plates factor
9.44±0.02 29279 1.25
9.51±0.02 29689 1.22
9.39±0.02 29456 1.30
9.01±0.02 28997 1.32
9.76±0.02 29599 1.34
Proposed method
9.44
29279
1.25
3.76
tially different combinations of methanol: water
in mobile phase were tried to get best resolution
of tranexamic acid derivative. The mobile phase
containing water and acetonitrile having ratio 35:65
(v/v) and C-18 column as a stationary phase
proved to be most suitable for resolution with a
flow rate of 1 mL/min. By applying the optimized
chromatographic conditions, symmetrical peak of
tranexamic acid derivative was obtained with a
retention time of 9.44 ± 0.03 min. A chromato-
gram of tranexamic acid derivative is shown in
Fig. 4 and 5. The method development was initi-
ated by using mobile phase 50 % v/v methanol in
water, merged peak was obtained with a reten-
tion time of 14.0 min. Then we changed the mo-
bile phase composition to acetonitrile 60 % v/v in
water, we found that peak of tranexamic acid de-
rivative had good shape but very close to the peak
of Sanger’s reagent. To get complete resolution
the proportion of water was decreased to get com-
position of acetonitrile 65 % v/v in water. This
gave resolved, excellent shape peak of tranexamic
acid derivative with a retention time of 9.44 min.
The mobile phase composition of acetonitrile 65
% v/v in water was considered as optimized con-
dition and used further in all experiments.
Method validation
The RP-HPLC method developed to determine
 Ravindra Patil et al., / TACL 7 (6) 2017 813 - 821 818
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Figure 3. Derivatization reaction of tranexamic acid

with 2, 4-dinitrofluorobenzene (Sanger’s reagent)

Figure 4. Whole Chromatogram of derivatize tranexamic acid

tranexamic acid was validated by ICH guidelines
17
. The parameters of ICH guidelines applied dur-
ing this work were linearity, accuracy, precision,
sensitivity, reproducibility and ruggedness.
Linearity was found with five concentrations in
the range of 6-16 μg/mL. The 6, 8, 10, 12, and 16
μg/mL solutions were prepared and analyzed. The
calibration curve was obtained by plotting con-
centrations on x-axis and their mean areas on y-
axis. Linear regression equation for tranexamic
 Ravindra Patil et al., / TACL 7 (6) 2017 813 - 821
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Figure 5. Zoom Chromatogram of tranexamic acid
acid was Y= 5005x +13074 with the value of cor-
relation co-efficient R2 = 0.9999. This shows that
there is a linear relationship between drug con-
centrations and their peak areas.
Accuracy was found by recovery study using
standard addition method at 80, 100 and 120 %
level; known amount of standard Tranexamic acid
was added to pre-analyzed sample (6.0 μg/ml of
Tranexamic acid) and analyzed by the developed
RP-HPLC method. The percentage relative stan-
dard deviation <2.0 % confirms that the method
is accurate. The results of recovery for
tranexamic acid are given in Table 3.
Precision is the measure of how close the data
values are to each other for a number of mea-
surements under the same analytical conditions.
Intra - day precision was determined by analyz-
ing, the three different concentrations 6, 8, and 10
μg/ml of tranexamic acid, for three times on the
same day. Inter - day precision was assessed us-
ing above mentioned three concentrations ana-
lyzed on three different days. These results show
reproducibility of the assay (Table 4). The %
R.S.D. value of less than 2 indicates that the
method is precise for the determination of
tranexamic acid.
For carrying out robustness, intentional minor
changes were made in the experimental condi-
tions and then response against those changed
parameters was measured. Results are given in
Table 7, which reflect minor variation in chromato-
819
graphic parameters i.e, theoretical plates and tail-
ing factor <2.0 against minor chromatographic
changes.
Repeatability was measured by multiple injec-
tions of a homogenous sample of 10 μg/ml of
tranexamic acid, which gives the performance of
the HPLC instrument under chromatographic
conditions. The percentage relative standard de-
viation of 1.87 % confirms that the method is re-
peatable. Results are shown in Table 5.
Sensitivity of the proposed method was esti-
mated in terms of Limit of Detection (LOD) and
Limit of Quantitation (LOQ). In order to deter-
mine detection and quantification limit, concen-
trations in the lower part of the linear range of the
calibration curve were used. For tranexamic acid,
the value of LOQ was 0.006434 μg/mL and the
value of LOD 0.002124 μg/mL.
System suitability testing is essential for the as-
surance of the quality performance of the chro-
matographic system. Earlier prepared solutions for
chromatographic condition were tested for sys-
tem suitability testing. Results are shown in Table
8. The theoretical plate number depends on elu-
tion time but in general should be > 2000 18. The
number of high theoretical plates (29279), peak
symmetry and proper retention time indicates that
proposed method is suitable for determination
tranexamic acid in pharmaceutical formulations.
Compared to other methods 5, 7-11, 13, 14, this RP
HPLC method is simple as well as economic for
 Ravindra Patil et al., / TACL 7 (6) 2017 813 - 821
the detection of tranexamic acid. This method is
most suitable and appropriate because it does not
involve any precipitation and filtration step in
derivatization, which may lead to losses during
these processes. The derivatization process gets
completed at given conditions; does not require
any special attention for the completion of reac-
tion as reported earlier by Natesan et al 6. There
is neither use of buffer nor any pH condition. The
derivatized mixture is directly diluted with mobile
phase, thus making the method robust due to no
change mobile phase composition during run in
column.
Conclusion
In the present work a simple, accurate, sensi-
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820
in process derivatization was carried out to de-
tect it by UV detector of HPLC. The method was
validated according to ICH guidelines. Method
validation was done by testing its linearity, accu-
racy, precision, values of LOD and LOQ. Com-
pared to other methods, this RP HPLC method is
simple as well as economic for the detection of
tranexamic acid. This method involves in process
pre-column derivatization, with the retention time
9.4 min and total run time of 11.0 min. Also, this
method can determine selectively tranexamic acid
in the pharmaceutical formulation.
Acknowledgement
Authors are thankful to Principal, R. C. Patel
Institute of Pharmaceutical Education and Re-

tive, selective and precise method was developed search, Shirpur for providing necessary facilities
by using RP HPLC-PDA to determine tranexamic to carry out the present work.
acid. Tranexamic acid being non chromophoric,

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