American Journal of Analytical Chemistry, 2011, 2, 126-134
doi:10.4236/ajac.2011.22014 Published Online May 2011 (http://www. SciRP.org/journal/ajac)
Development and Validation of Stability Indicating
RP-HPLC-PDA Method for Tenatoprazole and Its
Application for Formulation Analysis and
Dissolution Study
Sunil R. Dhaneshwar, Vaijanath N. Jagtap
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth University, Poona College of Pharmacy,
Maharashtra, India
Received November 17, 2010; revised January 21, 2011; accepted January 24, 2011
Abstract
In the present study, comprehensive stress testing of tenatoprazole was carried out according to ICH guide-
line Q1A (R2). Tenatoprazole was subjected to stress conditions of hydrolysis, oxidation, photolysis and
neutral decomposition. Extensive degradation was found to occur in acidic, neutral and oxidative conditions.
Mild degradation was observed in basic conditions. The drug is relatively stable in the solid-state. Successful
separation of drug from degradation products formed under stress conditions was achieved on a Kromasil C18
column (250 mm × 4.6 mm, 5.0 μ particle size) using methanol: THF: acetate buffer (68:12:20 v/v) pH ad-
justed to 6.0 with acetic acid as mobile phase, flow rate was 1.0 mL·min–1 and column was maintained at
45˚C. Quantification and linearity was achieved at 307 nm over the concentration range of 0.5 - 160 μg·mL–1
for tenatoprazole. The method was validated for specificity, linearity, accuracy, precision, LOD, LOQ and
robustness.
Keywords: Stability Indicating RP-HPLC-PDA, Method Validation, Column Liquid Chromatography
1. Introduction
Tenatoprazole is a novel proton pump inhibitor which
has imidazopyridine ring connected to a pyridine ring by
sulfinylmethylchain. Tenatoprazole (Figure 1), 5-meth -
oxy-2-(3,5-dimethyl-4-methoxy)-2-pyridyl]methylthio]-i
midazole[4,5-b]pyridine is a prodrug of the proton pump
inhibitor (PPI) class, which is converted to the active
sulfenamide or sulfenic acid by acid in the secretory ca-
naliculus of the stimulated parietal cell of the stomach
[1]. This active species binds to luminally accessible
cysteines of the gastric H+, K+ ATPase resulting in dis-
ulfide formation and acid secretion inhibition [2,3].
However, the anti-secretory and anti-ulcer effects of te-
natoprazole were reported to be 2 - 4 times more potent
than those of omeprazole with long-lasting effects on
gastric acid secretion [4]. All proton pump inhibitors are
unstable when exposed to an acidic milieu, such as the
stomach. Therefore, they are formulated with an enteric
coating that shields the active drug from the acidic gas-
tric environment [5,6]. Tenatoprazole has a greatly ex-
tended plasma half-life in comparison with other proton
pump inhibitors [7]. HPLC method for the quantitative
determination of tenatoprazole in rat plasma [8], phar-
macokinetic study in dog plasma [3-9] and pharmacoki-
netic study in healthy male Caucasian volunteers [10]
have been reported. These methods were developed for
the purpose of determining low level of drug substance
in the biological samples, thus they are not suitable for
routine analysis of formulated product where the content
of API is high in the formulation. Recently one stability
indicating LC-MS/MS method was reported [11] using
C18 column and runtime of 15 min. Large number of
samples are generated during stability study therefore
Figure 1. Structure of tenatoprazole.

S. R. DHANESHWAR ET AL.
127
stability indicating method with short analysis time is
always preferred in order to increase efficiency and for
economics of operations. It also requires that analytical
test procedures for stability samples should be stabili-
ty-indicating and should be fully validated [12].
Therefore the aim of the present study was to develop
a sensitive, precise, accurate and stability indicating RP-
HPLC-PDA method with short runtime for the determi-
nation of tenatoprazole and further application of the
method f or di ssoluti o n study.
2. Experimental
2.1. Materials and Reagents
Laboratory formulated tablets from two lo ts (B. No. SAP
1101, SAP 1102) containing 20 mg of tenatoprazole were
used for analysis. Pure drug sample of tenatoprazole
(98.5%) were obtained as a gift sample from New Health
Care Ltd. Indore (MP). HPLC grade methanol and tetra-
hydrofuran (THF) were procured from Merck and Qua-
ligens Fine Chemicals, respectively (Mumbai, India).
Analytical grade ammonium acetate and acetic acid were
procured from Research Lab Fine Chem. (Mumbai, In-
dia). Double distilled water and tablet placebo were
made at lab scale only.
2.2. Instrumentation and Chromatographic
Conditions
The HPLC system consisted of a binary pump (model
Waters 515), auto sampler (model 717 plus), column
heater, and PDA detector (Waters 2998). Data collection
and analysis were performed using Empower-version 2
software. Separation was achieved on Kromasil C18 column
(250 mm × 4.6 mm, 5.0 µ) maintained at 45˚C using col-
umn oven. Isocratic elution with methanol: tetrahydrofuran:
25mM acetate buffer (68:12:20 v/v) mobile phase adjusted
to pH 6.0 with acetic acid at the flow rate of 1.0 mL·min–1
were carried out. The detection was monitored at 307 nm
and injection volume was 20 µL. The peak purity was
checked with the ph ot odiode ar ra y detector.
2.3. Preparation of Standard Solutions and
Calibration Curve
Standard stock solution of tenatoprazole containing 1000
μg·mL–1 were prepared in methanol. To study the linear-
ity range, serial dilutions were made from 0.50 to 160
µg· mL –1 in mobile phase and injected in to column. Ca-
libration curves were plotted as concentration of drug
versus peak area response. From the standard stock solu-
tions, solution containing 80 µg·mL–1 of tenatoprazole was
injected in to c olumn. The system sui tability test was pe r-
formed from six re pli cat e injecti ons of s ta ndard s olution.
2.4. Analysis of Tablet Formulations
Twenty tablets were weighed accurately and a quantity
of tablet powder equivalent to 100 mg of tenatoprazole
was weighed and dissolved in 80 mL of methanol with
the aid of ultrasonication for 10 min and solution was
filtered through Whatman paper No. 41 into a 100 mL
volumetric flask. Filter paper was washed with the sol-
vent, adding washings to the volumetric flask and vo-
lume was made up to mark. The solution was suitably di-
luted with mobile phase to get a concentration of 80 μg·mL–1
of tenatoprazole.
2.5. Method Validation
The HPLC method was validated in terms of precision,
accuracy and linearity according to ICH guidelines [11].
Assay method precision was determined using nine in-
dependent test solutions. The intermediate precision of
the assay method was also evaluated as inter-day and
intra-day precision. The accuracy of the assay method
was evaluated with the recovery of the standards from
excipients. Three different quantities (low, medium and
high) of the authentic standards were added to the pla-
cebo. The mixtures were extracted and analyzed using
the developed HPLC method. Linearity test solutions
were prepared as described in Section 2.3. The Limit of
Detection (LOD) and Limit of Quantification (LOQ) for
analytes were estimated by injecting a series of dilute
solutions with known concentration. Values of LOD and
LOQ were calculated by using σ (standard Deviation of
response) and b (Slope of the calibration curve) and by
using equations, LOD =
( )
3.3 b σ × and LOQ =
( )
10 b σ ×
. To determine the robustness of the method,
final experimental conditions were purposely altered and
results were examined. The parameters considered
(±values) for the study were, flow rate (±5%), column
temp . (± 2˚C), measurement wavelength (±1 nm), injec-
tion volume (±2 µl), % organic (±5%), buffer strength
(±5 mM) and effect of column from different lots were
studied. The drug solution stability were carried out for
short-term stability by keeping at room temperature for
12 hrs, long-term stability by storing at 4˚C for 30 days
and auto-sampler stability by storing the samples for 24
hrs in the auto-sampler and then analyzing against
freshly prepared solutions. For method development
and optimization, retention factor ( k) were calculated
by using parameters tR (retention time) and tM (elu-
tion time of the solvent front) and by using the equ-
ation k = (tR − tM)/tM.

S. R. DHANESHWAR ET AL.
128
2.6. Dissolution Study
A calibrated dissolution apparatus (USP II) were used
with paddles at 50 rpm and bath temperature maintained
at (37 ± 1)˚C, 450 ml 0.1 N HCl were used as dissolution
medium. During dissolution study 5 ml of sample (with
replacement) were removed from each vessel. Samples
were removed after every 5 min for 45 min. Sample w ere
filtered through a nylon membrane filter (0.45 μm, 25 mm),
2.5 ml of filtrate were diluted to 5 ml with mobile phase
and analyzed by the proposed method. The amount of
tenatoprazole in the test samples were calculated as per-
centage dissolved, from the measured peak area for the
test samples by using Equation (1). Alternatively area of
sample were calculated and compared it with the peak
area for the standard (std.) solution using Equation (2).
Dissolved (%) = (Conc. calculated by using linear
equation × 900/DL) (1)
Dissolved (%) = (900/DL) × (Peak Area (sample)/Peak
Area (std.)) × Conc. (std.) × 100 (2)
where DL = drug load, which is 20 mg of tenatoprazole.
2.7. Method Specificity (Forced Degradation
Study)
Forced degradation of the drug and drug product were
carried out under thermolytic, photolytic, acid/base hy-
drolytic and oxidative stress conditions. For photolytic
stress, drug product in the solid state were irradiated with
UV radiation at 254 and 366 nm. The UV dose from the
lamp at 366 nm were measured by use of a quinine mo-
nohydrochloride (2% solution in water) chemical acti-
nometer as mentioned in the ICH guidelines [10]. Mini-
mum desired exposure (200 Wh/m2) were observed after
irradiation for 26 h. A second photolytic stres s test expe-
riment with greater irradiation time, 52 h, were per-
formed to establish the specificity of the method. Sample
solution containing 2000 mg·mL−1 were subjected to
selected stressed conditions, appropriately diluted and
injected into column. Samples except for photo oxidation
were protected from light. For acid, base and water-in-
duced degradation solutions containing 2000 mg·mL−1 of
the drug were prepared in 0.1N HCl, 0.1N NaOH and
water, heated on constant water bath at 80˚C and ana-
lyzed after 1, 2 and 12 h exposure, respectively. For
oxidative degradation solution were prepared in water
containing 30% v/v of H2O2, heated on constant water
bath at 80˚C and analysed after 1 h.
2.8. Photochemical Degradation an d D r y Heat
Degradation
Photochemical stability of the drug were studied by ex-
posing stock solution (2000 µg·mL−1) as well as solid
drug to short UV and long UV radiations for 26 h and
were used. For dry heat degradation drug in solid form
were placed in oven at 60˚C for 8 hours and used to pre-
pare solution. The solutions were diluted with mobile
phase to have 80 µg·mL−1 and 20 µL of the solution were
injected into the system.
3. Results and Discussion
3.1. Optimization of the Chromatographic
Conditions (Method Development)
The HPLC procedure were optimized with a view to de-
velop stability-indicating assay method. Pure drug along
with its degraded products were injected and run in dif-
ferent solvent systems. Initially methanol and water in
different ratios were tried. It were found that when me-
thanol concentration were increased in the mobile phase,
the degradation product started to elute in dead volume.
Hence concentration of methanol was decreased and
there was improvement in resolution. It was found that
mobile phase consisting of methanol: THF: acetate buf-
fer (68:12:20 v/v) pH adjusted to 6.0 with acetic acid,
flow rate were 1.0 mL·min−1 gives acceptable retention
time of 3 min. (tR), theoretical plates and good resolution
of drug and degradation products (Figure 2).
AU
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00
Minutes
0.70
TEN-3.756
0.60
0.50
0.40
0.30
0.20
0.10
0.00
Figure 2. Tenatoprazole 100 μg·mL−1 standard chromatogram.

S. R. DHANESHWAR ET AL.
129
Well defined symmetrical peaks were obtained upon
measuring the response of eluent under the optimized
conditions after thorough experimental trials. Two col-
umns were used for performance investigations, includ-
ing Kromasil C18 (4.6 × 250 mm, 5 micron) and Symme-
try C18 (4.6 × 250 mm, 5 micron), Symmetry C18 showed
broad, unsymmetrical peak therefore it were replaced
with Kromasil C18 column which produced symmetrical
peaks with good resolution. The UV detector response of
tenatoprazole was studied and the best wavelength was
found to be 3 07 nm showing highe s t sensiti vi ty.
3.2. Method Validation
The method was validated, in accordance with ICH
guidelines, for linearity, range, accur acy, precision, LOD
and LOQ, specificity, ruggedness and robustness [11].
3.2.1. Linearity and Range
For the construction of calibration curves, seven calibra-
tion standard solutions were prepared over the concen-
tration range. Linearity was determined for tenatoprazole
in the range of 0.5 - 160 µg· mL−1. The correlation coeffi-
cient (‘r2’) values were >0.999 (n = 6). Typically, the
regression equations for the calibration curve was found
to be y = 68800 × (−77500) (Figure 2).
3.2.2. For mulati on Analysis an d Ac c u racy
System suitability test were perfo rmed every time before
formulations analysis (Table 1). Formulations were ana-
lysed as described in experimental section. Assay values
were (100 ± 0.8)% for both the formulations accuracy of
the method were calculated by recovery studies at three
levels by standard addition method. Results of formula-
tion analysis and accuracy studies are presented in Table 2.
3.2.3. Precision
The precision of repeatability were studied by replicate
(n = 6) analysis of tablet solutions. The precision was
also studied in terms of intr a-day changes in peak area of
drug solution on the same day and on three diff er ent days
over a period of one week. The intra-day and inter-day
variation were calculated in terms of percentage relative
standard deviation and the results are summarized in
Table 3.
3.2.4. Limit of Detection (LOD) and Limit of
Quantitation (LOQ)
The LOD and LOQ values were found to be 0.49 and
1.50 μg·mL−1, respectively. Low values of these parame-
ter indicates sensitivity of the method.
3.2.5. R obu stness
Robustness was studied as described in Section 2.5, %
R.S.D. of assay was calculated for each condition. The
degree of reproducibility of the results obtained as a re-
sult of small deliberate variations in the method parame-
ters has proven that the method is robust and the results
are summarized in Table 4.
Table 1. System suitability parameters.
Parameter Values ± SD
No of theoretical plates (SD ) 2670 ± 30
USP Tailing Factor (SD ) 1.38 ± 0.02
Capacity factor 2.8 ± 0.02
Typical Peak Purity angle 0.121
Typical Purity threshold 0.245
Table 2. Results of tablet analysis and accuracy studies.
Tablet Label
Claim
Formulation
Study (n = 6) Recovery (accuracy) Study (n = 3)
Tablet
Batch % Assay Found, % RSD Recovery Level % Recovery, % RSD
Tenatoprazole
20mg
SAP 1101, 99.74, 1.05 50 99.68, 0.67
SAP 1102 100.61, 1.23 100 10 0 .10, 0.24
150 101.83, 0.56
Table 3. Result of pre cision study.
Precision Study Parameter Estimated amount, % RSD at selected concentration level
10 µg·mL−1 80 µg·mL−1 150 µg·mL−1
Repeatability, n = 6 100.2, 0.38 101.4, 0.33 99.5, 0.25
Intra-day, n = 3 100.8, 0.55 99.6, 0.51 101.2, 0. 29
Inter-day, n = 3 98.9, 1.13 101.3, 0.76 99.5, 0. 85
Analyst, n = 3 99.5, 0.38 100. 4, 1.06 100.6, 0. 45

S. R. DHANESHWAR ET AL.
130
Table 4. Result of robust ness study.
Parameter (Limit) Level System Suitability Parameters (±SD) n = 3 % Assay, % RSD, n = 3
tR N K
Flow rate, mL−1⋅min
(±0.1 mL)
(–) 0.90 3.87 ± 0.022 2650 ± 22 2.79 ± 0.024 98.54, 1.07
(+) 1.1 3.77 ± 0.021 2660 ± 24 2.82 ± 0.026 99.67, 0.54
% of Organic
(±5%)
(–) 63 3.79 ± 0.026 2670 ± 32 2.79 ± 0. 0 3 2 100.43, 1.0 3
(+) 73 3.82 ± 0.023 2680 ± 36 2.80 ± 0.028 101.43, 1.04
pH of Mobile Phase
(±0.1)
(–) 5.9 3.79 ± 0.019 2690 ± 3 8 2.79 ± 0.029 100.76, 0.75
(+) 6.1 3.81 ± 0.024 2658 ± 36 2.78 ± 0.033 100.54, 0.95
Column form
different suppliers
CIa 3.76 ± 0.022 2660 ± 34 2.80 ± 0.025 100.45, 1.08
CIIb 3.79 ± 0.024 2680 ± 32 2.82 ± 0.026 101.76, 1. 1 6
Wavelength
(±1 nm)
(–) 306 3.84 ± 0.022 2670 ± 28 2.79 ± 0.022 98.87, 1.32
(+) 308 3.81 ± 0.026 2680 ± 3 0 2.81 ± 0.032 98.91, 1.22
Buffer strength
(±5 mM)
(–) 20 3.81 ± 0.019 2670 ± 26 2.80 ± 0.028 101.45, 0.34
(+) 30 3.82 ± 0.024 2690 ± 32 2.82 ± 0.029 101.55, 0.44
Column Tem p.
(±2˚C)
(–) 43 3.77 ± 0.022 2670 ± 28 2.80 ± 0.021 99.45, 0.98
(+) 47 3.78 ± 0.026 2690 ± 33 2.79 ± 0.027 98.55, 1.02
a & b Kromasil C 18 col umns from different l ot s; tR = retention time, N = no of theoretica l pl ates, K = Capacity factor.
TEN-3 .80
1.60
AU
1.40
1.20
1.00
0.80
0.60
0.40
0.20
0.00
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00
Minutes
A
B
C
D
E
F
G
H
I
Figure 3. Specificity Chromatogram consists of A) Mobile Phase, B) Placebo, C) Formulation, D) Standard tenatoprazole, E-I)
system suitability sample.
3.2.6. Specificity
The specificity of the HPLC method is illustrated in
Figure 3, where complete separation of tenatoprazole
was noticed in presence of placebo. In addition, there
was no any interference at the retention time of tenato-
prazole in the chromatogram of tablet solution. There
was complete separation of all the degraded products
under all the stress conditions studied (Figures 4-9) as
presented in Table 5. In peak purity analysis with photo
diode array detector, purity angle was always less than
purity threshold for all the stress conditions. This shows
that the peak of analytes was pure and excipients in the
formulati on and st re ss de graded prod uct s di d not i nterfere.
3.2.7. Di s solution
Dissolution was carried out as described in Section 2.6.4,
dissolution profile was found to be according to the
guidelines and there was a steady and stable release rate
with 85% - 90% amount released within 40 min (Tabl e 6 ,
Figure 10).

S. R. DHANESHWAR ET AL.
131
3.2.8. Sol ution Stability Studies
Solution stability as described in Section 2.5 were per-
formed. Result of short-term, long-term and the auto
sampler stability of tenatoprazole solutions were calcu-
lated from nominal concentrations and found concentra-
tion. All the time results of the stability studies were
within the acceptable limit (98% - 102%).
4. Conclusions
Linear, precise, and accurate RP-HPLC-PDA method has
been developed and validated for quantitative determina-
tion of tenatoprazole from tablet formulations. All the
parameters met the criteria of ICH guidelines for method
validation. The method is very simple, specific, reliable,
Figure 4. Degradation chromatogram of tenatoprazole in 0.1N HCL.
Figure 5. Degradation chromatogram of tenatoprazole in 0.1N NaOH.
Figure 6. Degradation chromatogram of tenatoprazole in 30% H2O2.

S. R. DHANESHWAR ET AL.
132
AU
0.00 0. 50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00
Minutes
TEN-3 .80
0.60
0.50
0.40
0.30
0.20
0.10
0.00
4.202
Figure 7. Degradation chromatogram of tenatoprazole at short UV range (254 nm).
AU
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00
Minutes
TEN-3 .80
0.60
0.50
0.40
0.30
0.20
0.10
0.00
Figure 8. Degradation chromatogram of tenatoprazole at long UV range (366 nm).
AU
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00
Minutes
TEN-3 .80
0.60
0.50
0.40
0.30
0.20
0.10
0.00
Figure 9. Degradation chromategram of tenatoprazole at dry heat degradation 50˚C for 4 hrs.

S. R. DHANESHWAR ET AL.
133
Table 5. Result of stress degradation study.
Stress condition Degraded products reported at tR % Recovery
Peak purity
purity angle purity threshold
2 ml of 0.1 N HCl, 1 h 3.005, 3.346, 4.260 75.67 0.247 0.415
2 ml of 0.1 N NaOH, 2 h 2.307, 2.728, 2.888, 3.516, 4.288 93.2 0.278 0.389
2 ml of 30% H2O2, 1 h 2.986, 3.315, 4.246 78.5 0.403 0.638
Short UV - 254 nm, 26 h 4.202 96.45 0.189 0.278
Long UV - 366 nm, 26 h No degradation peak observed -- 0.289 0.356
Wet heat - 12 h No degradation peak observed -- 0.137 0.267
Dry heat - 60˚C, 8 h No degradation peak observed -- 0.265 0.315
Table 6. Dissolution study data (n = 6).
Time in min. % Tenatoprazole Dissolved
5 10
10 25
15 38
20 55
25 79
30 86
35 90
40 95
45 97
50 99
Time (min)
5 10 15 20 25 30 35 40 45 50 55
% dissolved
100.00
90.00
80.00
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00
Figure 10. Dissolution pr ofile of tenatoprazole in 0.1 N HCl
by propose d m et hod .
rapid and economic as all peaks are well separated and
there is no interference by excipients peaks with total
runtime of 5 min, which makes it especially suitable for
routine quality control an alysis work. Stability indicating
method with short runtime, simple mobile and MS com-
patible mobile phase and application of the method for
dissolution study is an added advantage. The method
were validated according to ICH guidelines and was
found to be reproducible.
5. Acknowledgements
The authors are grateful to New Health Care Ltd. Indore
(MP) for p rovidin g gift sam pl e o f te na toprazole.
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