Metoclopramida Degradacion
Metoclopramida Degradacion
Metoclopramida Degradacion
Original Article
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.
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
chromatographic stationary and mobile phases due to differ- 3. NaH2PO4$H2O (3.4 g/L) and octane-1-sulphonic acid sodium
ences in their molecular structures. To obtain a good resolu- salt (0.4 g/L) as a buffer (pH 2.5, 3, 3.5, 4) in combination with
tion among the impurities and main drug substance different acetonitrile.
stationary phases were tested considering; 4. (NH4)H2PO4 (2.5 g/L) and pentane-1-sulphonic acid sodium
salt (0.4 g/L) as a buffer (pH 2.5, 3, 3.5, 4) in combination with
a. The feature of stationary phase. acetonitrile.
b. The particle size of the column.
Considering the Metoclopramide and their related com- 3.1.1. Selection of stationary phase
pounds, buffer of acidic nature was preferred for optimization; It is clear from the molecular structure (Fig. 1), that all com-
the following mobile phases with gradient elution were tested, pounds do not possess a functional group which can readily
ionize indicating polar in nature. Hence we started the devel-
1. NaH2PO4$H2O (3.4 g/L) and pentane-1-sulphonic acid so- opment activity with C8 stationary phase of various manu-
dium salt (0.4 g/L) as a buffer (pH 2.5, 3, 3.5, 4) in combina- facturers using different mobile phases. The poor resolution
tion with acetonitrile. between Metoclopramide and ACETYLMETO and broad peak
2. NaH2PO4$H2O (3.4 g/L) and pentane-1-sulphonic acid so- shape for Metoclopramide implies that C8 stationary phase is
dium salt (0.4 g/L) as a buffer (pH 2.5, 3, 3.5, 4) in combina- not suitable for this application. Hence C18 stationary phase
tion with methanol. was chosen to improve resolution among the peaks and peak
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.
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).
shape for Metoclopramide. The peak shape for Metoclopra- and response, acetonitrile was tried as an organic modifier.
mide and resolution among all components improved with The baseline was found to be good and response for all com-
Waters X-terra RP18, 150 mm 4.6 mm, 3.5 m columns. ponents was improved. The peak shape for all components
was also improved and hence acetonitrile was selected as the
3.1.2. Influence of mobile phase buffer salt and surfactants organic modifier.
The resolution among related impurities and Metoclopramide
was found poor using mobile phase with octane-1-sulfonic 3.1.4. Influence of pH of the mobile phase buffer
acid sodium salt. Mobile phase containing pentane-1-sulfonic The mobile phase was buffered because of the existence of
acid sodium salt with ammonium phosphate instead of ionizable groups in the chemical structure of the drug, which
octane-1-sulfonic acid sodium salt gives the better resolution. could ionize at different pH values. The pH values tested were
However, one unknown impurity is merging with 2.5, 3.0 and 3.5. Finally, the best results were obtained at pH
ACETYLMETO. Ammonium phosphate is replaced with 3.0 0.1 by adjusting with orthophosphoric acid solution. The
sodium phosphate buffer keeping pentane-1-sulfonic acid so- choice of this mobile phase is justified by the excellent sym-
dium salt as such, gives the better separation among the metry of the peaks and adequate retention times of Metoclo-
impurities. pramide and its degradents.
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 3 773
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Pharmacokinetics of metoclopramide intravenously and
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5. Vergin H, Bishop-Freudling GB, Strobel K, Reeves DS. RP-
The simple UPLC method developed for the quantitative
HPLC method with electrochemical detection for the
determination of related compounds of Metoclopramide and determination of metoclopramide in serum and its use in
its possible degradation products is precise, accurate and pharmacokinetic studies. Biomed Chromatogr.
specific for the analysis of bulk material and formulation 2001;8:513e517.
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tory results for all the parameters tested. The developed of stability indicating HPLC method for estimation of
metoclopramide Hydrochloride from a novel formulation. J
method is stability indicating and can be used for the routine
Pharm Res. 2009;2(2):290e295.
analysis of production samples.
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Identification and full characterization of a new
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Conflicts of interest 8. Maquille A, Habib Jiwan JL. LCeMS characterization of
metoclopramide photolysis products. J Photochem Photobiol A.
2009;205:197e202.
All authors have none to declare.
9. (a)FDA, Food and Drug Administration. Guidance for Industry:
Analytical Procedures and Methods Validation, (Draft Guidance);
1994;
(b)FDA, Food and Drug Administration, Center of drug
Evolution and Research. Reviewer Guidance, Validation of
Acknowledgment
Chromatographic Methods; 1994.
10. (a)ICH. International Conference on Harmonization, October
The authors thank Hospira Health Care India Pvt Ltd Man- 1994, Text on Validation of Analytical Procedures Q2A; 1994;
agement for encouragement and support. Cooperation (b)ICH. International Conference on Harmonization November
extended by all colleagues of Analytical Research Division is 1996, Validation of Analytical Procedures Methodology (Q2B);
gratefully acknowledged. 1996.