A Stability Indicating U-HPLC Method for Milnacipran in Bulk Drugs and Pharmaceutical Dosage Forms
Naresh Tondepu, Shakil S. Sait, K.V. Surendranath, Ravi Kiran Kaja, Suresh Kumar
DOI: 10.4236/ajac.2012.31007   PDF    HTML     7,195 Downloads   13,780 Views   Citations


The objective of the current study was to develop a validated, specific and stability-indicating reverse phase UHPLC method for the quantitative determination of Milnacipran and its related substances. The determination was done for active pharmaceutical ingredient and its pharmaceutical dosage forms in the presence of degradation products, and its process-related impurities. The drug was subjected to stress conditions of hydrolysis (acid and base), oxidation, pho- tolysis and thermal degradation per International Conference on Harmonization (ICH) prescribed stress conditions to show the stability-indicating power of the method. Significant degradation was observed during acid, base, oxidative and neutral stress hydrolysis. The chromatographic conditions were optimized using an impurity-spiked solution and the samples generated from forced degradation studies. In the developed UHPLC method, the resolution between Milnacipran and its process-related impurities was found to be greater than 2.0. Regression analysis shows an r value (correlation coefficient) of greater than 0.999 for Milnacipran and it’s all the five impurities. The chromatographic separation was achieved on a C18 stationary phase. The method employed a linear gradient elution and the detection wavelength was set at 220 nm. The mobile phase consists of buffer and acetonitrile delivered at a flow rate of 0.2 mL?min–1. Buffer consists a mixture of 10 mM Sodium dihydrogen phosphate monohydrate and 10 mM hexane sulfonate sodium salt, pH adjusted to 2.5 using ortho phosphoric acid. The mobile phase A consists of buffer and acetonitrile (950:50, v/v) and mobile phase B consists of acetonitrile. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 99.5%. The developed RP-LC method was validated with respect to linearity, accuracy, precision and robustness.

Share and Cite:

Tondepu, N. , Sait, S. , Surendranath, K. , Kaja, R. and Kumar, S. (2012) A Stability Indicating U-HPLC Method for Milnacipran in Bulk Drugs and Pharmaceutical Dosage Forms. American Journal of Analytical Chemistry, 3, 40-49. doi: 10.4236/ajac.2012.31007.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] R. T. Owen, “Milnacipran Hydrochloride: Its Efficacy, Safety and Tolerability Profile in Fibromyalgia Syndro- me,” Drugs Today, Vol. 44, No. 9, 2008, pp. 653-660. http://dx.doi.org/10.1358/dot.2008.44.9.1256003
[2] R. M. Gendreau, M. D. Thorn, J. F. Gendreau, et al., “Efficacy of Milnacipran in Patients with Fibromyalgia,” Journal of Rheu-matology, Vol. 32, No. 10, 2005, pp. 1975-1985.
[3] C. U. Pae, D. M. Marks, M. Shah, C. Han, B. J. Ham, A. A. Patkar and P. S. Masand, “Milnacipran: Beyond a Role of Antidepres-sant,” Clinical Neuropharmacology, Vol. 32, No. 6, 2009, pp. 355-363. http://dx.doi.org/10.1097/WNF.0b013e3181ac155b
[4] A. Nakagawa, N. Watanabe, I. M. Omori, C. Barbui, A. Cipriani, H. McGuire, R. Churchill and T. A. Furukawa, “Milnacipran versus Other Antidepressive Agents for De- pression,” The Cochrane Library, 2009. doi:10.1002/14651858.CD006529.pub2
[5] R. J. Leo and V. L. Brooks, “Clinical Potential of Milnacipran, a Serotonin and Norepinephrine Reuptake Inhibitor, in Pain,” Current Opinion in Investigational Drugs, Vol. 7, 2006, pp. 637-642.
[6] R. H., Gracely K. Jensen, F. Petzke, et al., “The Effect of Milnacipran on Pain Modulatory Systems in Fibromyalgia: An fMRI Analy-sis,” Annals of the Rheumatic Diseases, Vol. 67, 2008, p. 255.
[7] J. C. Branco, S. Perrot, G. Bragee, et al., “The PTPN22* C1858T Functional Polymorphism Is Associated with Susceptibility to Inflammatory Polyarthritis but Neither This Nor Other Variants Spanning the Gene Is Associated with Disease Outcome,” Annals of the Rheumatic Diseases, 2008, Vol. 67, pp. 251-255.
[8] M. Lecoeur-Lorin, R. Delépée, J. P. Ribet and P. J. Morin, “Chiral Analysis of Milnacipran by a Nonchiral HPLC— Circular Dichroism: Improvement of the Linearity of Dichroic Response by Temperature Control,” Journal of Se- paration Science, Vol. 31, No. 16-17, 2008, pp. 3009- 3014.
[9] A. Patti, S. Pedotti and C. Sanfilippo, “Chiral HPLC Ana- lysis of Milnacipran and Its FMOC-Derivative on Cellu- lose-Based Stationary Phases,” Chirality, Vol. 20, No. 2, 2008, pp. 63-68.
[10] C. Puozzo, C. Filaquier and G. J. Zorza, “Determination of Milnacipran, a Serotonin and Noradrenaline Reuptake Inhibitor, in Human Plasma Using Liquid Chromato-graphy with Spectrofluorimetric Detection,” Journal of Chro- matography B, Vol. 806, No. 2, 2004, pp. 221-228.
[11] Chiba Takeshi, et al., “Determination of Milnacipran in Serum by LC/MS,” Japanese Journal of Pharmaceutical Health Care and Sciences,Vol. 31, No. 6, 2005, pp. 490-495.
[12] C. Puozzo, N. Pozet, D. Deprez, P. Baille, H. L. Ung and P Zech, “Pharmacokinetics of Milnacipran in Renal Impairment,” Eu-ropean Journal of Drug Metabolism and Pharmacokinetics, Vol. 23, No. 2, 1998, pp. 280-286.
[13] J. Caron, et al., “Acute Electrophysiological Effects of Intravenous Milnacipran, a New Antidepressant Agent,” European Neuropsychopharmacology, Vol. 3, No. 4, pp. 493-500.
[14] E. U?aktürk and C. ?afak, “Determination of Milnacipran in Human Plasma Using GC-MS,” Chromatographia, Vol. 72, No. 1-2, 2010, pp. 111-119.
[15] M. Srinivasa Rao, V. Sivaramakrishna, S. V. M. Vardhan and D. Ramachandran “A Validated Rp-Hplc Method for the Estimation of Milnacipran in Tablet Dosage Forms,” International Journal of Chem Tech Research, Vol. 3, No. 3, 2011, pp. 1501-1505.
[16] S. P. Peketi et al., “Validated RP-HPLC Method for Ana- lysis of Milnacipran in Bulk and Formulations,” IRJP, Vol. 1, No. 1, 2010, pp. 138-144.
[17] P. J. Mehta, et al., “Development and validation of RP-HPLC Method for determination of Milnacipran Hydrochloride in pharmaceutical formulations,” International Journal of Phar-macy and Pharmaceutical Sciences, Vol. 2, No. 2, 2010, pp. 137-141.
[18] C. L. Dias, et al., “Comparative Validation Study to Assay Milnacipran Hydrochloride in Capsules by a Stability-Indicating LC and a Second Order Derivative UV Spectroscopic Methods,” Pharmaceutica Analytica Acta, Vol. 1, No. 2, 2010, pp. 1-5.
[19] Stability ICH, “Testing of New Drug Substances and Products Q1A (R2),” International Conference on Harmonization, IFPMA, Geneva, 2003.
[20] USP, United States Pharmacopoeia, “Validation of Com- pendial Methods,” 31st Edition, United States Pharma- copeial Convention, Rock-ville, 2008.
[21] Drug Stability Principles and Practices, 3rd Edition, T. Carstensen and C. T. Rhodes, Eds., Marcel Dekker, New York, 2000.
[22] M. Bakshi and S. Singh, “Development of Validated Stability-Indicating Assay Methods—Critical Re-view,” Jour- nal of Pharmaceutical and Biomedical Analysis, Vol. 28, No. 6, 2002, pp. 1011-1040. doi:10.1016/S0731-7085 (02)00047-X

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.