Journal of Chromatographic Science 2015;53:226– 232
doi:10.1093/chromsci/bmu044 Advance Access publication June 5, 2014
The Ultra-Performance Liquid Chromatography Determination of Domperidone
and Its Process-Related Impurities
Laura Curtin Whelan1*, Michael Geary2, Mary Wharton2 and Paul Sweetman3
1
Department of Applied Science, Shannon ABC, Limerick Institute of Technology, Moylish Park, Limerick, Ireland, 2Department of
Applied Science, Limerick Institute of Technology, Moylish Park, Limerick, Ireland, and 3Janssen Pharmaceutical Ltd, Cork, Ireland
*Author to whom correspondence should be addressed. Email: laura130382@yahoo.co.uk
Received 21 August 2013; revised 9 April 2014
A rapid ultra-performance liquid chromatography (UPLC) method for the
determination of domperidone in the presence of its process impurities
and droperidol was developed and validated. The rapid chromatograph-
ic separation was achieved using a sub 2 mm Hypersil Zorbax eXtra
Densely Bonded C18 column (30 3 4.6 mm, i.d., 1.8 mm). A gradient
mobile phase consisting of Solvent A: 0.06 M ammonium acetate and
Solvent B: methanol, with a flow rate of 1 mL/min was employed. The
column temperature was set at 4088 C, and the diode-array detector
was set at 280 nm. An injection volume of 3 mL was used. The current-
ly utilized European Pharmacopeia (Eur. Pharm.) method employed by
Janssen Pharmaceuticals Ltd was run on a Hypersil Base-Deactivated
Silica C18 column (100 3 4.6 mm, i.d., 3 mm) with a run time of
12.5 min. The developed UPLC method, with a run time of 7.5 min
was determined to be accurate, precise, specific, robust and highly
sensitive according to the International Conference on Harmonization
guidelines. The method herein demonstrated a reduction in analysis
time of 40%, allowing for a much higher sample throughput. A solvent
consumption decrease of over 58% was also observed, which results in
a dramatic reduction in running costs for Janssen Pharmaceuticals Ltd.
Introduction
Domperidone, 5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimi-
dazol-1-yl)propyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-
2-one, is an antidopaminergic agent. It acts by preventing dopa-
mine binding to the receptors at the chemoreceptor trigger
zone. Domperidone is commonly employed as an antiemetic
drug used to prevent nausea and vomiting (1) and is the active
ingredient in motilium tablets and suppositories. It also acts as
a prokinetic agent and enhances the strength of the esophageal
sphincter and is used in the treatment of gastroparesis (delayed
gastric emptying) (2, 3). Lately, domperidone has taken preva-
lence as a galactagogue ( promotes lactation) and has been
used to increase breast milk production in women who have a
low milk count (4, 5). Droperidol, 2H-benzimidazol-2-one,1-[1-
[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydro-4-pyridinyl]-1,
3-dihydro-1-1-[3-( p-fluorobenzoyl)propyl]-1,2,[3,6-tetrahydro-4-
pyridyl]-2-benzimidazolinone, is also an antidopaminergic agent.
It is utilized within this study as a resolution check for
domperidone.
The HPLC method employed by Janssen Pharmaceuticals to
determine domperidone in its active pharmaceutical ingredient
(API) form and in the presence of its six impurities and droper-
idol is found in the Eur. Pharm (Figure 1). As well as being a
worldwide prokinetic and antiemetic drug, domperidone is cur-
rently being investigated in extensive studies as a galactagogue.
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Downloaded from https://academic.oup.com/chromsci/article-abstract/53/2/226/306713/The-Ultra-Performance-Liquid-Chromatography
by Universitatea de Medicina si Farmacie ''Carol Davila user
on 06 October 2017
Article
Women who give birth preterm commonly suffer with inade-
quate production of breast milk. Asztalos et al. (4) is currently
investigating the use of domperidone in the enhancement of
breast milk in women who have given birth to preterm babies.
Women who have given birth by cesarean section also often
fail to produce a sufficient amount of breast milk.
Jantarasaengaram et al. (5) found that treating these women
with domperidone tablets increased their milk production con-
siderably. Knoppert et al. (6) studied the optimal dosage of dom-
peridone given to this particular demographic and discovered
over a 4-week period, a 20 mg dose of domperidone, three
times daily steadily increased their milk flow. Zavitsanos et al.
(7) developed a sensitive HPLC – mass spectrometry method to
determine domperidone in human blood plasma and in human
breast milk. No previous study had been undertaken to deter-
mine domperidone in breast milk, and it was discovered that
domperidone does cross the blood barrier into breast milk but
to a lesser extent than other galactagogue agents and therefore
reduces the risk of toxicity to the mother and baby (8).
Domperidone has been examined by several authors within
the literature, in numerous different matrices and using many dif-
ferent liquid chromatography (LC) methods; Michaud et al. (9)
developed a sensitive LC method to determine domperidone
and its major metabolites formed in vitro by human liver micro-
somes. Ali et al. (10) employed HPLC to concurrently analyze
methyl- and propyl-paraben and domperidone in oral suspension.
Ali et al. (11) employed HPLC to detect domperidone in the
wastewater runoff of certain pharmaceutical companies.
Several authors including Wang et al. and Xu et al. have devel-
oped ultra-performance liquid chromatography – tandem mass
spectrometric (UPLC – MS-MS) methods to determine domperi-
done in blood plasma (12, 13). However, very little work has
been done on the development and validation of a method for
the examination of impurities in the bulk product. One such
paper similar to the present study by Seshadri et al. (14) devel-
oped a method for the estimation of impurities in the pharma-
ceutical dosage form of omeprazole and domperidone
capsules. The newly developed method offers a much reduced
analysis time; between 2 and 7 times faster, when compared
with these published works. It also has the advantage of employ-
ing a sub 2 mm column as opposed to traditional columns used in
these articles.
The primary target of this work was to develop and validate a
rapid method to determine domperidone in the presence of its pro-
cess impurities and make it suitable for immediate use by Janssen
Pharmaceuticals Ltd. The new rapid method cuts time, which in-
creases sample throughput and decreases solvent consumption.

Figure 1. Chemical structure of domperidone, its six impurities and droperidol.
The laboratory stability studies indicate that domperidone and its
impurities remain stable for up to 48 h; therefore, allowing for lon-
ger sequences to be run than previously undertaken.
Experimental
Chemicals and reagents
Samples of domperidone standard (API), its six impurities and dro-
peridol standard were received from Janssen Pharmaceutical Ltd,
Downloaded from https://academic.oup.com/chromsci/article-abstract/53/2/226/306713/The-Ultra-Performance-Liquid-Chromatography
by Universitatea de Medicina si Farmacie ''Carol Davila user
on 06 October 2017
Table I
Gradient Elution for (A) the Original Method and (B) the Optimized Method
(A) Gradient elution for original method (B) Gradient elution for optimized
method
Time %B (MEOH) Time %B (MEOH)
0 30 0 30
10 100 5.5 100
12 100 6.5 100
12.5 30 7.0 30
7.5 30
Cork, Ireland. All standards are certified reference material (CRM).
HPLC-grade methanol was purchased from Van Waters and Rogers
International (VWR). HPLC-grade ammonium acetate was also
purchased from VWR. Ultrapure water was obtained using a
TKA-Water Purification System.
Chemical names
All standards are CRM.
(i) Domperidone: 5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1
H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imi-
dazol-2(3H)-one; (ii) droperidol: 1-f1-[4-(4-fluorophenyl)-4-
oxobutyl]-1,2,5,6-tetrahydropyridin-4-yl]-1,3-dihydro-2H-benzi-
midazol-2-one; (iii) impurity A: 5-chloro-1-( piperidin-4-yl)-1,
3-dihydro-2H-benzimidazol) 2-one; (iv) impurity B: 4-(5-chloro-
2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-formylpiperidin; (v)
impurity C: cis-4-(5-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-
1-yl)-1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1yl)propyl]pi-
peridine 1-oxide; (vi) impurity D: 5-chloro-3-[3-(2-oxo-2,
3-dihydro-1H-benzimidazol-1-yl)propyl]-1-[1-[3-(2-oxo-2,3-dihydro-
1H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1,3-dihydro-2H-
benzimidazol-2-one; (vii) impurity E: 1-[3-[4-(5-chloro-2-oxo-2,
3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]propyl]-3-[3-(2-
oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]-1,3-dihydro-2H-
benzimidazol-2-one and (viii) impurity F: 1,3-bis[3-[4-(5-chloro-
2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]propyl]-
1,3-dihydro-2H-benzimidazol-2-one.
Instrumentation
An Agilent 1200 Rapid Resolution Liquid Chromatography sys-
tem was used for this analysis. It contains a 1200 series binary
pump SL, a vacuum degasser, a 1200 series high-performance
auto sampler, a 1200 series thermostatted column compartment
SL and a 1200 series diode-array detector (DAD) SL for up to
80 Hz operation that were controlled by ChemStation B.02.01
SR1 data acquisition and evaluation software.
Chromatographic conditions
Table I(A) illustrates the gradient elution program for the elution
of domperidone and its impurities. A 3 mm Hypersil Base-
Deactivated Silica (BDS) C18 column (100  4.6 mm, i.d., 3 mm)
was employed in the current European Pharmacopeia method
employed by Janssen. Table I(B) illustrates the developed gradi-
ent elution program for the elution of domperidone and its
impurities utilizing the sub 2 mm Hypersil eXtra Densely
Bonded (XDB) C18 column (30  4.6 mm, i.d., 1.8 mm). An
UPLC Method for the Determination of Domperidone 227
 extra equilibration step is added from 7.0 to 7.5 min, to equili-
brate the column for the next injection; giving a total run time
of 7.5 min. A flow rate of 1 mL/min and UV detection at
280 nm were used. The column temperature was maintained at
408C, and an injection volume of 3 mL was employed. Solvent A
was filtered through 0.20 mm nylon filters.
Standard preparation
A stock solution of 100 mg/mL was prepared by weighing 2.5 mg
of domperidone standard, its six impurities and droperidol stan-
dard into a 25-mL amber volumetric flask. Five concentrations
ranging from 15 to 55 mg/mL were made from the stock solution
in intervals of 10 mg/mL. These concentrations were used to
determine the linearity, precision and accuracy. Limit of detec-
tion (LOD) and limit of quantification (LOQ) dilutions were pre-
pared experimentally.
Method Validation
Linearity
Linearity test solutions ranging from 15 to 55 mg/mL in incre-
ments of 10 mg/mL were prepared from a 100 mg/mL multicom-
ponent stock solution (as per standard preparation). Triplicate
injections at each concentration were carried out. The mean av-
erage of the areas for domperidone, its six impurities and droper-
idol were determined and plotted against concentration. The
equation of the line, along with correlation coefficient was
then determined by means of least squares linear regression for
each compound.
Accuracy
The accuracy values for domperidone, its process impurities and
droperidol were derived from the linearity data at concentrations
of 15 – 55 mg/mL. Triplicate injections at each concentration
were undertaken. Accuracy is measured as percent recovery,
which is calculated using the corresponding regression
equations.
Limit of detection and limit of quantification
The LOD and LOQ for all impurities such as domperidone and
droperidol were determined according to the International
Conference on Harmonization (ICH) guidelines. Signal-to-noise
ratio of 3 : 1 for LOD and 10 : 1 for LOQ was determined experi-
mentally. The diluted concentrations were then injected in
triplicate.
Precision
The precision of the method was assessed according to Janssen’s
guidelines. Analysis repeatability, injection repeatability and in-
termediate precision were determined at 15 and 35 mg/mL, 25
and 45 mg/mL and 25 and 55 mg/mL concentrations, respective-
ly. Six replicate injections of each concentration were deter-
mined. Following the ICH guidelines, all relative standard
deviation (RSD) must be ,2%. Analysis and injection repeatabil-
ity were carried out under identical conditions on the same day,
228 Curtin Whelan et al.
Downloaded from https://academic.oup.com/chromsci/article-abstract/53/2/226/306713/The-Ultra-Performance-Liquid-Chromatography
by Universitatea de Medicina si Farmacie ''Carol Davila user
on 06 October 2017
and intermediate precision was carried out by a different analyst
on a different day.
Selectivity
Selectivity was confirmed by successfully separating the com-
pound of interest (the API, domperidone) from other compo-
nents, i.e., impurities. A 15 mg/mL solution containing the API,
domperidone, its six impurities and droperidol were injected
in triplicate along with triplicate separate injections of each indi-
vidual impurity, the API and droperidol.
Robustness
Robustness testing was carried out according to the ICH guide-
lines, wherein a parameter of the analytical procedure can be al-
tered slightly without affecting the resulting chromatograph. If
the results of a method are affected then those parameters
should be controlled and a statement added to the method doc-
umentation. Mobile phase velocity, wavelength and initial and
final percent organic in the mobile phase were altered, and the
resolution between the critical pairs was observed. Standard sam-
ples of 25 and 55 mg/mL containing domperidone, its process
impurities and droperidol were used to determine robustness.
Each concentration was injected in triplicate.
Sample stability
Stability studies were carried out at Janssen’s request to deter-
mine the time frame in which the sample remained stable for
analysis. The stability of the standard solutions was determined
by storing four identical 55 mg/mL standard samples in clear
and amber vials in the 48C fridge and at ambient temperatures
for 8 weeks after preparation. All four vials were injected after
24 h, 48 h, 1 week and every week up to Week 8, and the results
were compared with fresh sample.
Results
Method development and optimization
The original injection volume of 10 mL was too large for the new
shorter column. A new injection volume was determined utiliz-
ing the following formula:
VolCol2
InjVolCol1  ¼ InjVolCol2 :
VolCol1
where InjVolCol1, injection volume on original BDS column;
InjVolCol2, injection volume on Zorbax sub 2 mm column;
VolCol1, column volume of original BDS column; VolCol2, column
volume of Zorbax sub 2 mm column.
Column volume is calculated as P  R 2  L. where, P ¼ 3.14,
2
R is radius and L is the length of the column.
1; 994
10 mL  ¼ 3 mL.
6; 647
From the above equation, an injection volume of 3 mL was calcu-
lated. Impurities D and E coelute in the original method. The gra-
dient steps, column temperature and flow rate were altered, to
 Figure 2. The resulting chromatogram for the analysis of domperidone, its process impurities and droperidol utilizing the optimized method with the sub 2 mm XDB column [55 mg/
mL, chromatographic conditions as in Table I(B)].

try and separate these two impurities but to not avail. The orig- Table II
inal flow rate of 1.5 mL/min was reduced to 1 mL/min. This was Linearity Data for Domperidone, Its Process-Related Impurities and Droperidol
to improve resolution, peak shape and also to reduce pressure. Compound Slope Y-intercept Correlation coefficient
The gradient steps were adjusted in increments to try and
Imp A 2.43 0.37 0.9998
achieve optimum separation in the shortest time possible. Imp B 2.88 0.71 0.9999
Increasing the temperature to 408C that lowered the back pres- Imp C 2.92 1.10 0.9999
Imp D&E 6.37 3.43 0.9995
sure and reduced the retention time of the API. The optimal gra- Imp F 2.74 1.04 0.9998
dient conditions for the new rapid method were as per Domperidone 3.80 0.98 0.9999
Table I(B), with a flow rate of 1 mL/min. The DAD was set to Droperidol 2.80 0.45 0.9999
280 nm, and the column temperature was set to 408C. An injec-
tion volume of 3 mL was used. The retention times of domperi-
done, its six impurities and droperidol were as follows:
impurity A: 1.29 min, impurity B: 2.57 min, domperidone: Table III
Recovery Data for Domperidone
3.93 min, droperidol: 4.11 min, impurity C: 5.01 min, impurities
D&E: 4.43 min and impurity F: 4.85 min (Figure 2). Concentration (mg/mL) %Recovery
15 101
25 101
35 98.9
Method Validation 45 99.6
Linearity 55 98.0

Table II

Table IV
Accuracy LOD and LOQ Values for Domperidone, Its Related Impurities and Droperidol

Table III Compound LOD (mg/mL) LOQ (mg/mL)

Imp A 0.11 0.30
Imp B 0.04 0.11
Limit of detection and limit of quantification Imp C 0.04 0.12
Imp D 0.05 0.14
Table IV Imp E 0.08 0.22
Imp F 0.08 0.24
Domperidone 0.04 0.12
Droperidol 0.05 0.15
Precision
Table V
Robustness
This method was deemed robust to slight changes of mobile phase
Selectivity velocity by þ0.1 mL/min, wavelength by +2 nm and initial and
Figure 3 final percent organic in mobile phase composition by +5%.

UPLC Method for the Determination of Domperidone 229

Downloaded from https://academic.oup.com/chromsci/article-abstract/53/2/226/306713/The-Ultra-Performance-Liquid-Chromatography

by Universitatea de Medicina si Farmacie ''Carol Davila user
on 06 October 2017
 Table V
%RSD for Precision Studies of Domperidone, Its Impurities and Droperidol

Compound Analysis repeatability Injection repeatability Intermediate repeatability

15 mg/mL 35 mg/mL 25 mg/mL 45 mg/mL 25 mg/mL 55 mg/mL
Imp A 0.25 0.40 0.46 0.21 0.51 0.29
Imp B 0.30 0.48 0.48 0.21 0.47 0.30
Imp C 0.31 0.52 0.52 0.17 0.42 0.24
Imp D&E 0.29 0.24 0.24 0.28 0.25 0.26
Imp F 0.35 0.57 0.57 0.50 0.51 0.32
Domperidone 0.63 0.43 0.43 0.23 0.43 0.28
Droperidol 0.65 0.39 0.39 0.24 0.27 0.28

Figure 3. The resulting chromatogram for selectivity under optimum conditions using the sub 2 mm XDB column [15 mg/mL, chromatographic conditions as in Table I(B)].

Table VI
ambient temperature. According to the pharmacopeia mono-
% Difference for Laboratory Stability Studies after 48 h graph domperidone elutes at 6.5 min.
Following some initial experimental work and an extensive
Compound Clear vial Brown vial Clear vial ambient Brown vial ambient
48C 48C temperature temperature
survey of available columns, an XDB sub 2 mm column was cho-
sen. This column had similar specification, i.e., % carbon and sur-
Imp A 0.09 0.04 1.15 1.50
Imp B 0.33 0.31 1.83 1.92
face area to the BDS column. As discussed in Results section, the
Imp C 0.18 0.17 1.75 1.99 method was optimized by altering mobile phase, flow rate, col-
Imp D&E 0.16 0.15 1.50 1.68 umn temperature and gradient steepness on separate occasions
Imp F 0.28 0.20 1.63 1.70
Domperidone 0.21 0.19 1.48 1.56 and in small increments. After rigorous testing, with the aim of
Droperidol 0.12 0.07 1.35 1.49 achieving the fastest conceivable time and best possible resolu-
tion a gradient as per Table I(B) was established. The 7.5 min
run time included a 1 min wash stop and 0.5 min reequilibration
Sample stability
step. A flow rate of 1 mL/min, injection volume of 3 mL, column
Table VI
temperature of 408C and wavelength set at 280 nm were em-
ployed. Resolution between the critical pair’s domperidone
and droperidol and impurities F and C were 2.32 and 2.16, re-
Discussion spectively, .2.0 set out by Eur. Pharm. (Figure 2).
The purpose of this study was to develop and optimize a rapid The new rapid UPLC method demonstrates far superior anal-
method with significant reduction in analysis time while main- ysis times to the pharmacopeia method and also the articles re-
taining efficiency and to validate this rapid UPLC method accord- ported within this study, see Table VII. As mentioned in
ing to the ICH guidelines. Introduction section, several authors have developed LC meth-
The original domperidone method utilized by Janssen em- ods for domperidone analysis in many different matrices;
ployed a Hypersil BDS C18 column (100  4.6 mm, i.d., 3 mm) however, limited literature is available on the separation of dom-
with a run time of 12.5 min and a flow rate of 1.5 mL/min. The peridone and its impurities in the bulk formation. One compara-
original injection volume was 10 mL, and the column was at ble study by Seshadri et al. (14) developed and validated a

230 Curtin Whelan et al.

Downloaded from https://academic.oup.com/chromsci/article-abstract/53/2/226/306713/The-Ultra-Performance-Liquid-Chromatography

by Universitatea de Medicina si Farmacie ''Carol Davila user
on 06 October 2017
 Table VII
Comparison of the Herein Described and Previously Reported Articles for Domperidone
Authors Curtin et al. Eur. Phar.
Analysis time (min) 7.5 12.5
Domperidone retention time (min) 3.9 6.5
Column Sub 2 mm XDB C18 BDS C18 3 mm
Injection volume (mL) 2 10
method to determine domperidone and its impurities in the
pharmaceutical dosage form. With an analysis time of 55 min
and domperidone eluting at 31.6 min, this method was seven
times slower than the new rapid method developed herein.
Michaud et al. (9) developed a sensitive HPLC method with fluo-
rescence detection and an analysis time of 13 min. Domperidone
eluted at 12.1 min nearly three times slower than the present
study. The same is true for other published works within this
study, all of the run times were much longer than the run time
herein. This method employed a reduced particle-size column,
and according to the van Deemter equation smaller particle-
size columns offer more efficient chromatography. The injection
volumes herein were much smaller in comparison to the pub-
lished methods; which prevent peak broadening and offer better
peak shape (15).
Method Validation
The new UPLC method was validated under the following param-
eters according to the ICH guidelines: linearity, accuracy, preci-
sion, LOD and LOQ, selectivity, robustness and some stability
studies were undertaken.
Linearity
Calibration curves for domperidone, its impurities and droperi-
dol all gave a linear response over the range of 15 – 55 mg/mL.
The mean values of the slopes, intercepts and correlation coeffi-
cients are given in Table II.
Accuracy
Accuracy values were determined as percent recovery from the
linearity samples in the range of 15– 55 mg/mL. Percent recover-
ies for the API ranged from 98.02 to 100.87% and are illustrated in
Table III.
Limit of detection and limit of quantification
The LOD and LOQ were determined experimentally according to
the ICH guidelines, following 3 : 1 and 10 : 1 ratios, respectively.
The diluted concentrations determined can be seen in Table IV.
Precision
Precision results were determined as %RSD, which according to
the ICH guidelines should be ,2%. All three precision studies
met the acceptance criteria. The results can be seen in Table V.
Downloaded from https://academic.oup.com/chromsci/article-abstract/53/2/226/306713/The-Ultra-Performance-Liquid-Chromatography
by Universitatea de Medicina si Farmacie ''Carol Davila user
on 06 October 2017
Michaud et al. Ali et al. Ali et al. Seshadri et al.
13 12 20 55
12.2 8.4 8.29 31.6
ODS, C18 5 mm 5 mm, OP, C8 Waters symmetry 5 mm, C18 ODS 5 mm C18
10 –30 10 5 Not given
Selectivity
Domperidone, each impurity and droperidol were each injected
separately and in triplicate. A 20 mg/mL multicomponent stan-
dard solution was also injected in triplicate. All peaks were
well resolved, and domperidone was successfully eluted without
interference from the impurities.
Robustness
The parameters altered were mobile phase velocity (þ0.1 mL/
min), wavelength (+2 nm) and initial and final percent organic
in mobile phase composition (+5%). All changes brought about
minor decrease in resolution between the critical pairs, but res-
olution remained at an acceptable level proving this new rapid
UPLC method to be robust.
Sample stability
As can be seen from Table VI, all compounds remained stable for
48 h in all conditions proving that domperidone and its impuri-
ties can now be analyzed in long sequences without sample deg-
radation taking place. Marginal differences in degradation were
detected between clear and amber vials at both temperatures,
and significant differences, however, were detected between
the 48C and ambient temperatures. After 48 h under ambient
temperatures, degradation was only just below Janssen’s recom-
mended 2%, consequently, sequence run times should be no lon-
ger than 48 h when analyzing domperidone in the presence of its
process impurities.
Conclusion
A new rapid UPLC method for the analysis of domperidone, its
impurities and droperidol was successfully developed and vali-
dated on an XDB sub 2 mm column. The analysis time was re-
duced by 40% from the currently utilized Eur. Pharm. method,
allowing for a much higher sample throughput. Solvent con-
sumption was reduced by 58%, thus greatly reducing solvent
waste costs and proving the new method to be both economical-
ly and environmentally friendly. Excellent resolution was demon-
strated throughout the analysis.
The developed method was validated according to the ICH
guidelines, and the method proved to be accurate, precise, robust
and sensitive. Some stability studies were also carried out; dom-
peridone and its impurities demonstrated no photosensitive re-
actions but were temperature dependent. However, all samples
remained stable for up to 48 h in ambient temperatures; there-
fore, sequence runs of up to 48 h can now be carried out by
Janssen Pharmaceuticals Ltd without degradation taking place.
UPLC Method for the Determination of Domperidone 231
 When compared with other published articles, the current
study demonstrated much shorter analysis time, allowing for
higher sample throughput and also offered minimal sample prep-
aration. This rapid method is suitable for analysis of domperidone
in the presence of its process impurities and droperidol.
Acknowledgments
The authors thank the management of Shannon Applied
Biotechnology Centre and Janssen Pharmaceutical Ltd, Cork
for supporting this work.
References
1. Marchetti, F., Maestro, A., Rovere, A., Zanon, D., Arrighini, A., Bertolani,
P., et al.; Oral ondansetron versus domperidone for symptomatic
treatment of vomiting during acute gastroenteritis in children:
multicentre randomized controlled trial; BMC Pediatrics, (2011);
11: 15.
2. British Medical Association; British National Formulary (BNF)
Pharmacopeia Forum 58; Vol. 389. BMJ Group and RPS Publishing,
London, England, (2009), pp. 225–228.
3. Sahyoun, H.A., Costall, B., Naylor, R.J.; Catecholamine-induced relaxa-
tion and contraction of the lower oesophageal and pyloric sphincters
of guinea-pig stomach: modification by domperidone; Journal of
Pharmacy and Pharmacology, (1982); 34: 318–324.
4. Asztalos, E.V., Campbell-Yeo, M., daSilva, O.P., Kiss, A., Knoppert, D.C.,
Ito, S.; Enhancing breast milk production with domperidone in
mothers of preterm neonates; BMC Pregnancy and Childbirth,
(2012); 12: 87.
5. Jantarasaengaram, S., Sreewapa, P.; Effects of domperidone on aug-
mentation of lactation following caesarean delivery at full term;
International Journal of Genecology and Obstetrics, (2012); 116:
240–243.
232 Curtin Whelan et al.
Downloaded from https://academic.oup.com/chromsci/article-abstract/53/2/226/306713/The-Ultra-Performance-Liquid-Chromatography
by Universitatea de Medicina si Farmacie ''Carol Davila user
on 06 October 2017
6. Knoppert, D.C., Page, A., Warren, J., Seabrook, J.A., Carr, M., Angelini,
M., et al.; The effect of two different domperidone doses on maternal
milk production; Journal of Human Lactation, (2013); 29: 38 –44.
7. Zavitsanos, A.P., MacDonald, C., Bassoo, E., Gopaul, D.; Determination
of domperidone in human serum and human breast milk by high-per-
formance liquid chromatography-electrospray mass spectrometry;
Journal of Chromatography B, (1999); 730: 9– 24.
8. Gabay, M.P.; Galactogogues: medications that induce lactation;
Journal of Human Lactation, (2002); 18: 274– 279.
9. Michaud, V., Simard, C., Turgeon, J.; An improved HPLC assay with
fluorescence detection for the determination of domperidone and
three major metabolites for application to in vitro drug metabolism
studies; Journal of Chromatography B, (2007); 852: 611– 616.
10. Ali, M.S., Ghori, M., Khatri, A.R.; Stability indicating simultaneous de-
termination of domperidone (DP), methylparaben (MP) and propyl-
paraben by high performance liquid chromatography (HPLC);
Journal of Pharmaceutical and Biomedical Analysis, (2006); 41:
358– 365.
11. Ali, I., Gupta, V.K., Singh, P., Punt, H.V.; Screening of domperidone in
waste water by high performance liquid chromatography and liquid
extraction methods; Talanta, (2006); 68: 928– 931.
12. Wang, X., Qin, F., Jing, L., Zhu, Q., Li, F., Xiong, Z.; Development and
validation of UPLC-MS/MS method for determination of domperi-
done in human plasma and its pharmacokinetic application;
Journal of Biomedical Chromatography, (2013); 27: 371– 376.
13. Xu, D.H., Lou, H.G., Yuan, H., Jiang, B., Zhou, Q., Zhang, Z.M., et al.;
Quantitative determination of domperidone in human plasma by
ultraperformance liquid chromatography with electrospray ioniza-
tion tandem mass spectrometry; Biomedical Chromatography,
(2008); 22: 433–440.
14. Seshadri, R.K., Raghavaraju, T.V., Chakravarthy, I.E.; A single gradient
stability-indicating reversed-phase LC method for the estimation of
impurities in omeprazole and domperidone capsules; Scientia
Pharmaceutica, (2013); 81: 437–438.
15. Kazakevich, Y.V., LoBrutto, R.; HPLC for pharmaceutical scientists.
1st ed. John Wiley & Sons Inc., Hoboken, New Jersey, (2007). ISBN
978-0-471-68162-5.