j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 6 5 e7 7 3

Available online at www.sciencedirect.com

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Original Article

Novel validated stability-indicating UPLC method

for the determination of Metoclopramide and its
degradation impurities in API and pharmaceutical
dosage form

Prathyusha Sowjanya a,*, Palani Shanmugasundaram a, Petla Naidu b,

Sanjeev Kumar Singamsetty b
a
Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Vels University, Chennai 600117, India
b
Analytical Research & Development, Hospira Health Care India Pvt Ltd., Irungattukottai, Chennai 602105, India

article info abstract

Article history: Aim: To develop a stability-indicating reversed phase ultra performance liquid chromato-
Received 9 May 2013 graphic (RP-UPLC) method for the determination of related substances in Metoclopramide
Accepted 5 July 2013 bulk drugs and pharmaceutical dosage form.
Available online 29 July 2013 Method: The chromatographic separation was achieved using a Waters X-terra RP18
(150
4.6 mm), 3.5 mm particle size column using the gradient program with mobile phase
Keywords: consisting of solvent A: 30 mM monobasic sodium phosphate and 2.3 mM of pentane-1-
LCMS sulphonic acid sodium salt (pH 3.0 buffer) and solvent-B (Acetonitrile). A flow rate of 1.2 mL/
Metoclopramide min and UV detector at 273 nm was used. The runtime was 18 min within which Metoclopra-
Stress degradation products mide and its four impurities, ACETYLMETO, ACMA, CLEE and ACME were well separated.
Ultra performance liquid chroma- Results and discussion: The drug was subjected to stress conditions such as oxidative, acid & base
tography (UPLC) hydrolysis, thermal and photolytic degradation. Metoclopramide was found to degrade signif-
Validation icantly in photolytic, oxidative & thermal stress conditions and stable in acid, base, hydrolytic &
humidity stress conditions. The major degradation impurities in oxidation and photolytic
degradation were identified by LCMS. The degradation products were well resolved from the
main peak and its impurities, thus proved the stability-indicating power of the method.
Conclusion: The developed method was validated as per ICH guidelines with respect to
specificity, linearity, limit of detection, limit of quantification, accuracy, precision and
robustness. The calibration curves obtained for the four impurities were linear over the
range 0.062e3.040 mg/mL.
Copyright ª 2013, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights
reserved.

* Corresponding author. Tel.: þ91 4427141358; fax: þ91 4427156816.

E-mail address: prathyusha.pchgs@gmail.com (P. Sowjanya).
0974-6943/$ e see front matter Copyright ª 2013, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jopr.2013.07.004
766 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 6 5 e7 7 3

1. Introduction and acetonitrile were purchased from Ranbaxy Chemicals,

Metoclopramide is chemically 4-amino-5-chloro-N-[2-(dieth-
ylamino)ethyl]-2-methoxybenzamide, an antiemetic and
gastroprokinetic agent. It is commonly used to treat nausea
and vomiting, to facilitate gastric emptying in people with
gastroparesis, and as a treatment for gastric stasis often
associated with migraine headaches. The antiemetic action of
Metoclopramide is due to its antagonist activity at D2 re-
ceptors in the chemoreceptor trigger zone (CTZ) in the central
nervous system (CNS)dthis action prevents nausea and
vomiting triggered by most stimuli.1 At higher doses, 5-HT3
antagonist activity may also contribute to the antiemetic ef-
fect. The gastroprokinetic activity of Metoclopramide is
mediated by muscarinic activity, D2 receptor antagonist ac-
tivity and 5-HT4 receptor agonist activity.2 Metoclopramide is
freely soluble in water and ethanol and practically insoluble in
ether. The molecular formula is C14H22ClN3O2, which corre-
sponds to a molecular weight of 299.80.
Very few analytical methods have been reported for the
quantitative determination of Metoclopramide in formula-
tions as well as biological fluids. These include gas chroma-
tography3,4 and high performance liquid chromatography.5,6
These previously published methods comprise of compli-
cated mobile systems and are not directly applicable for this
novel type of dosage form which is prepared and need more
investigation for method development and validation. How-
ever, no stability indicating UPLC methods were reported to
estimate Metoclopramide and its degradation products
(Fig. 1). The proposed method was stability indicating by
which all the degradation products of Metoclopramide can be
estimated quantitatively at very low levels.
2. Experimental
2.1. Chemicals and reagents
Metoclopramide (purity 99.0%) and standard materials of
degradation products were obtained from Hospira Health Care
India Pvt Ltd, Chennai, India. Monobasic sodium phosphate,
pentane-1-sulfonic acid sodium salt, orthophosphoric acid
New Delhi, India and all are of HPLC grade. Water was purified
by milli-Q-water purification system (Millipore, Bedford, MA,
USA) and used for preparation of all the solutions.
2.2. UPLC instrumentation and condition
The analysis was performed using Waters Acquity system
equipped with a binary solvent delivery pump and PDA de-
tector. Data acquisition and processing were done by using
Empower2 software version FR5 (Waters Corporation, USA).
The chromatographic separation was performed using a Wa-
ters X-terra RP18 column (150
4.6 mm), 3.5 m particle column.
The mobile phase was a mixture of mobile phase A and mobile
phase B. Mobile phase A was mono sodium phosphate (3.4 g/L)
and pentane-1-sulfonic acid sodium salt (0.4 g/L) adjusted to
pH 3.0 with orthophosphoric acid and acetonitrile as mobile
phase B. The gradient program T (min) ¼ % B: 0 ¼ 10, 2 ¼ 15,
5 ¼ 17, 7 ¼ 20, 8 ¼ 25, 9 ¼ 30, 13 ¼ 25, 15 ¼ 10, and 18 ¼ 10, with
flow rate of 1.2 mL/min was employed. The injection volume
was 10 mL while the detector was set at 273 nm. The column
temperature was maintained at 35  C.
2.2.1. Preparation of buffer, diluent, standard and sample
solution
About 3.4 g of monobasic sodium phosphate dissolved in
800 mL of water, adjusted to pH 3.5  0.05 with dilute
orthophosphoric acid solution was used as buffer. The di-
luent used was a mixture of buffer, acetonitrile and water in
the ratio of 80:15:5 (v/v/v).
A stock solution of Metoclopramide Hydrochloride (240 mg/
mL) was prepared by dissolving an appropriate amount in the
diluent. Standard solution containing 6 mg/mL was prepared
from this stock solution. 5 mL of Metoclopramide injection USP
solution containing 5000 mg/mL was dissolved in 25 mL of diluent
to give a solution containing 1000 mg/mL as sample solution.
2.3. Forced degradation sample solution for specificity
study
The study was intended to ensure the separation of Metoclo-
pramide and its degradation impurities. Forced degradation

O O
Cl N Cl N
NH O NH

H2N O NH O

Metoclopramide ACETYLMETO

O O O
Cl Cl Cl
OH O O O

H2N O NH O H2N O

ACMA CLEE ACME

Fig. 1 e Structures of Metoclopramide and its impurities.

 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 6 5 e7 7 3 767

study was performed to evaluate the stability indicating

properties and specificity of the method. Multiple stressed
samples were prepared as indicated below.

2.3.1. Hydrolytic conditions: acid, base, water induced

degradation
Solution containing 1 mg/mL of Metoclopramide was treated
with 1 N HCl, 1 N NaOH and water respectively. These samples
were refluxed at 80  C for 5 h. After cooling the solutions were
neutralized and diluted with diluent.

2.3.2. Oxidative condition: hydrogen peroxide-induced

degradation
Solution containing 1 mg/mL of Metoclopramide was treated
with 6% w/v H2O2 at 40  C for 6 h was cooled and diluted with
diluent.

2.3.3. Thermal degradation study

The drug solution (5 mg/mL) was subjected to heat at 105  C for
24 h. After cooling 5 mL of the above solution was transferred in
a 25 mL volumetric flask, diluted to the volume with diluent.

2.3.4. Photolytic degradation study

The drug solution (5 mg/mL) was exposed to the UV light in the
photolytic chamber providing an overall illumination of
1.2 million lux h and ultraviolet energy of 200 W h/square
meters for 184 h. 5 mL of the above solution was transferred in
25 mL volumetric flask, diluted to the volume with diluent.

2.3.5. Humidity degradation study

Metoclopramide injection USP (5 mg/mL) was subjected to
25  C/90% RH for 7 days. 5 mL of the above solution was
transferred in 25 mL volumetric flask, diluted to the volume
with diluent.

3. Results and discussion

Fig. 2 e UV Spectrum of Metoclopramide and its impurities.
3.1. Method development and optimization

The development of selective method for determination of

Metoclopramide and its related substances is described as an
important issue in method development. Metoclopramide
and its related substances show different affinities for

Fig. 3 e Representative chromatogram of Metoclopramide spiked with impurities.

768 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 6 5 e7 7 3
chromatographic stationary and mobile phases due to differ-
ences in their molecular structures. To obtain a good resolu-
tion among the impurities and main drug substance different
stationary phases were tested considering;
a. The feature of stationary phase.
b. The particle size of the column.
Considering the Metoclopramide and their related com-
pounds, buffer of acidic nature was preferred for optimization;
the following mobile phases with gradient elution were tested,
1. NaH2PO4$H2O (3.4 g/L) and pentane-1-sulphonic acid so-
dium salt (0.4 g/L) as a buffer (pH 2.5, 3, 3.5, 4) in combina-
tion with acetonitrile.
2. NaH2PO4$H2O (3.4 g/L) and pentane-1-sulphonic acid so-
dium salt (0.4 g/L) as a buffer (pH 2.5, 3, 3.5, 4) in combina-
tion with methanol.
Fig. 4 e Representative chromatograms of Metoclopramide on acid stress (a), base stress (b), peroxide stress (c), water stress
(d), photolytic (e), thermal (f) and humidity (g) degradations.
3. NaH2PO4$H2O (3.4 g/L) and octane-1-sulphonic acid sodium
salt (0.4 g/L) as a buffer (pH 2.5, 3, 3.5, 4) in combination with
acetonitrile.
4. (NH4)H2PO4 (2.5 g/L) and pentane-1-sulphonic acid sodium
salt (0.4 g/L) as a buffer (pH 2.5, 3, 3.5, 4) in combination with
acetonitrile.
3.1.1. Selection of stationary phase
It is clear from the molecular structure (Fig. 1), that all com-
pounds do not possess a functional group which can readily
ionize indicating polar in nature. Hence we started the devel-
opment activity with C8 stationary phase of various manu-
facturers using different mobile phases. The poor resolution
between Metoclopramide and ACETYLMETO and broad peak
shape for Metoclopramide implies that C8 stationary phase is
not suitable for this application. Hence C18 stationary phase
was chosen to improve resolution among the peaks and peak
 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 6 5 e7 7 3 769

Fig. 4 e (continued).

Fig. 5 e LCMS data of Metoclopramide peroxide degradation impurity.

770 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 6 5 e7 7 3

Fig. 6 e LCMS data of Metoclopramide photolytic degradation impurity.

shape for Metoclopramide. The peak shape for Metoclopra-
mide and resolution among all components improved with
Waters X-terra RP18, 150 mm
4.6 mm, 3.5 m columns.
3.1.2. Influence of mobile phase buffer salt and surfactants
The resolution among related impurities and Metoclopramide
was found poor using mobile phase with octane-1-sulfonic
acid sodium salt. Mobile phase containing pentane-1-sulfonic
acid sodium salt with ammonium phosphate instead of
octane-1-sulfonic acid sodium salt gives the better resolution.
However, one unknown impurity is merging with
ACETYLMETO. Ammonium phosphate is replaced with
sodium phosphate buffer keeping pentane-1-sulfonic acid so-
dium salt as such, gives the better separation among the
impurities.
and response, acetonitrile was tried as an organic modifier.
The baseline was found to be good and response for all com-
ponents was improved. The peak shape for all components
was also improved and hence acetonitrile was selected as the
organic modifier.
3.1.4. Influence of pH of the mobile phase buffer
The mobile phase was buffered because of the existence of
ionizable groups in the chemical structure of the drug, which
could ionize at different pH values. The pH values tested were
2.5, 3.0 and 3.5. Finally, the best results were obtained at pH
3.0  0.1 by adjusting with orthophosphoric acid solution. The
choice of this mobile phase is justified by the excellent sym-
metry of the peaks and adequate retention times of Metoclo-
pramide and its degradents.

3.1.3. Influence of organic modifier 3.1.5. Selection of wavelength

Initially methanol was used as an organic modifier which Based on the spectra of Metoclopramide and its related sub-
gives the poor baseline with baseline drift. The retention for stances 273 nm was selected as detection wavelength for the
all impurities was increased leading to inadequate resolution method. The UV spectrum of Metoclopramide and its impu-
among the peaks. To improve the resolution among the peaks rities were shown in Fig. 2.

Table 1 e Forced degradation studies of Metoclopramide.

Condition % Degradation Purity angle Purity threshold Purity flag Mass balance

Acid 0.05 1.645 6.927 No 100.85%

Base 0.09 1.596 6.955 No 100.65%
Oxidation 5.60 1.693 5.212 No 97.22%
Water 0.02 1.376 6.790 No 99.05%
Photolytic 8.10 1.794 3.856 No 94.34%
Heat 1.36 1.601 6.741 No 98.82%
Humidity 0.03 2.676 4.570 No 100.30%
 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 6 5 e7 7 3 771

273 nm; hence the typical chromatogram was recorded at this

Table 2 e Intra day e Inter day precision studies of
Metoclopramide related substances. wavelength. The typical UPLC chromatograms (Fig. 3) repre-
sent the satisfactory separation of all components among
Name of impurity Intra day precision Inter day precision
each other.
a a a a
% Of % % Of %
impurity RSD impurity RSD 3.2. Results of forced degradation studies/specificity
ACETYLMETO 0.217 0.3 0.219 0.9
ACMA 0.211 0.0 0.211 0.2 Forced degradation studies were performed on Metoclopra-
CLEE 0.210 0.3 0.210 0.6 mide Injection USP to demonstrate selectivity and stability-
ACME 0.223 0.0 0.222 0.9 indicating capability of the proposed RP-UPLC method.
a Mean of six replicates. Accordingly the degradation stress studies were conducted by
stressing with acid, base, peroxide, water, photolytic, heat and
humidity as mentioned in the Section 2.3.
3.1.6. Flow rate optimization Degradation was not observed in a Metoclopramide sam-
Different mobile phase flow rates (1.0, 1.2 and 1.4 mL/min) ple during acid, base, hydrolytic and humidity stress. About
were investigated. The optimum flow rate for which the col- 1.36%, 5.6% and 8.10% of degradation were observed in
umn plate number was maximum, with the best resolution thermal, oxidative and photolytic stress respectively (Fig. 4).
between all compounds and a short runtime (18 min) observed The major impurity observed in peroxide degradation was
was 1.2 mL/min. found to be N-oxide of Metoclopramide with molecular mass
of 315. LCMS data of the oxidation impurity is shown in Fig. 5.
3.1.7. Column temperature optimization The impurity was reported as a new metabolite earlier.7
Column thermostat temperatures were used at 30  C, 35  C Metoclopramide was highly photo labile in solution. Major
and 40  C for better peak shapes, baseline and resolution. At impurity of molecular mass 562 was observed in photolytic
the column oven temperature of 35  C the finest baseline degradation. LCMS data of photo degradation impurity is
resolution was observed between all the components. shown in Fig. 6. The structures of the photo degradation
After an extensive study, the method has been finalized on impurities were reported earlier based on LC-MS character-
Waters X-terra RP18, 150 mm
4.6 mm, 3.5 m using variable ization.8 Dissociation of chlorine is the major photo degra-
composition of solvent A: NaH2PO4 (3.4 g/L), pentane-1- dation pathway of Metoclopramide and is generally followed
sulfonic acid sodium salt (0.4 g/L), pH adjusted to 3.0 with by coupling of the products to generate high molecular
orthophosphoric acid and solvent B: acetonitrile. The flow rate weight products.
of the mobile phase was 1.2 mL/min. The UPLC gradient pro- Peak purity test results from the PDA detector confirmed that
gram (T/%B) was set as 90/0, 90/1, 85/2, 83/5, 80/7, 75/8, 70/9, the Metoclopramide peak obtained from all of the stress sam-
75/13, 90/15 and 90/18. The column compartment temperature ples analyzed, was homogenous and pure. Peak purity results
was kept at 35  C and the injection volume was 10 mL. The from the PDA detector for the peaks produced by the degrada-
detector response for all the components found maximum at tion of Metoclopramide, confirmed that all these peaks were

Table 3 e Limit of quantification & Limit of detection.

Name of impurity Limit of quantification Limit of detection

Conc. mg/mL % Of impurity % RSD Conc. mg/mL % Of impurity % RSD

ACETYLMETO 0.104 0.010 1.6 0.034 0.003 4.9

ACMA 0.067 0.007 2.8 0.022 0.002 4.8
CLEE 0.112 0.011 1.8 0.037 0.001 2.9
ACME 0.112 0.011 1.4 0.037 0.001 4.1

Table 4 e Linearity study of Metoclopramide Related substances.

% Spike ACETYLMETO ACMA CLEE ACME
level a a a a a a a a
Added Recovered Added Recovered Added Recovered Added Recovered

LOQ 0.107 0.107 0.062 0.069 0.114 0.119 0.109 0.106

50 1.073 1.100 1.041 1.077 1.036 1.102 1.094 1.142
75 1.502 1.543 1.458 1.473 1.450 1.432 1.532 1.532
100 2.146 2.195 2.083 2.105 2.071 2.131 2.188 2.232
150 3.005 3.035 3.040 3.040 3.024 3.049 3.063 3.147
r 0.999924 0.999962 0.999914 0.999942

a mg/mL; r ¼ correlation coefficient.

772 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 6 5 e7 7 3

homogenous and pure for all the stressed samples analyzed.

Table 6 e Robustness study of Metoclopramide Related
The mass balance results were calculated for all of the stressed substances.
samples and were found to be more than 94% (Table 1). The
Parameter RRT of impurity
purity and assay of Metoclopramide were unaffected by the
presence of its impurities and degradation products, which ACETYLMETO ACMA CLEE ACME
confirms the stability-indicating power of the developed Column 30 C 
0.87 1.32 1.65 1.90
method. ACETYLMETO & ACMA are found to be degradation Temperature 35  C 0.88 1.32 1.67 1.89
impurities and CLEE and ACME are process related impurities. 40  C 0.89 1.31 1.72 1.90
pH of buffer 2.8 0.88 1.32 1.67 1.89
3.0 0.88 1.34 1.70 1.91
3.3. Results of method validation study 3.2 0.88 1.31 1.66 1.88
Flow rate 1.0 mL min1 0.88 1.32 1.67 1.89
3.3.1. Method validation 1.2 mL min1 0.88 1.29 1.68 1.89
The described method has been validated for the assay and 1.4 mL min1 0.88 1.33 1.72 1.90
related substances by UPLC determination. According to FDA9
and ICH,10 the key analytical parameters that are required for
validation are accuracy, precision, linearity, recovery, LOD,
LOQ and ruggedness. 3.3.4. Linearity
The linearity of the test method was established from the LOQ
3.3.2. Precision to 150% of the test concentration for Metoclopramide and its
The repeatability of the developed UPLC method was checked related substances. The correlation coefficients obtained were
by a six-fold analysis of the Metoclopramide sample spiked greater than 0.9999. The result showed that an excellent cor-
with the four impurities. The RSD of peak area was calculated relation existed between the peak area and concentration of
for each impurity. Inter and Intra-day variation and analyst the analyte (Table 4).
variation were studied to determine the intermediate preci-
sion of the developed method. The RSD of the area of Meto- 3.3.5. Accuracy
clopramide related compound ACETYLMETO, ACMA, CLEE The accuracy of an analytical procedure expresses the close-
and ACME was within 0.3%. The RSD of results obtained in ness of agreement between the reference value and the value
intermediate precision studies was within 0.9% (Table 2). found. The percentage recovery of ACETYLMETO, ACMA, CLEE
and ACME ranged from 99 to 105% (Table 5). Chromatograms
3.3.3. Limit of detection and limit of quantification of spiked samples at 0.2% level of all four impurities in a
Limit of detection (LOD) and limit of quantification (LOQ) Metoclopramide sample are shown in Fig. 3.
values were determined using the signal to noise ratio
method. The LOD of Metoclopramide and its impurities were 3.3.6. Robustness
found to be in the range of 0.001e0.004 mg/mL (of analyte The robustness of an analytical procedure is a measure of its
concentration 1 mg/mL). The LOQ of Metoclopramide and its capacity to remain unaffected by small but deliberate varia-
impurities were found to be in the range of 0.07e0.1 mg/mL. tions in chromatographic method parameters and provided an
The precision for Metoclopramide and its impurities at LOQ indication of its reliability during normal usage. In all the var-
level was below 3.0% RSD (Table 3). ied chromatographic conditions (flow rate, pH of the mobile

Table 5 e Accuracy eRecovery study of Metoclopramide Related substances.

% Spike ACETYLMETO ACMA
level a a a a
Added Recovered % Recovery Added Recovered % Recovery

LOQ 0.107 0.107 100.0 0.062 0.063 100.5

50 1.073 1.100 102.5 1.041 1.077 103.5
75 1.502 1.543 102.7 1.458 1.473 101.0
100 2.146 2.195 102.3 2.083 2.105 101.1
150 3.005 3.035 101.0 3.040 3.071 101.1

% Spike CLEE ACME

level a a a a
Added Recovered % Recovery Added Recovered % Recovery

LOQ 0.114 0.119 104.4 0.109 0.109 100.0

50 1.036 1.036 100.0 1.094 1.142 104.4
75 1.450 1.450 100.0 1.532 1.570 102.5
100 2.071 2.130 102.9 2.188 2.232 102.0
150 3.024 3.049 100.8 3.063 3.147 102.7

a mg/mL.
 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 6 5 e7 7 3
phase and column temperature), the resolution between im-
purities and analyte was found to be more than 2.0 (Table 6).
3.3.7. Solution stability and mobile phase stability
The %RSD values of the four impurities during solution sta-
bility and mobile phase stability experiments were within
1.0%. No significant change was observed in the content of
impurities during solution stability and mobile phase stability
experiments confirm that sample solutions and mobile phase
used during the study were stable up to 48 h.
4. Conclusion
The simple UPLC method developed for the quantitative
determination of related compounds of Metoclopramide and
its possible degradation products is precise, accurate and
specific for the analysis of bulk material and formulation
samples. The method was fully validated, showing satisfac-
tory results for all the parameters tested. The developed
method is stability indicating and can be used for the routine
analysis of production samples.
Conflicts of interest
All authors have none to declare.
Acknowledgment
The authors thank Hospira Health Care India Pvt Ltd Man-
agement for encouragement and support. Cooperation
extended by all colleagues of Analytical Research Division is
gratefully acknowledged.
773
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