A sensitive, precise, specific, linear, and stability-indicating gradient HPLC method was developed for the estimation of doripenem in active pharmaceutical ingredient (API) and in injectable preparations. Chromatographic separation was achieved on C18 stationary phase with a mobile phase gradient consisting of acetonitrile, methanol, and pH 5.2 phosphate buffer. The mobile phase flow rate was 0.8？mL/min, and the eluted compounds were monitored at 210？nm. The method is linear over the range of 0.335 to 76.129？μg/mL. The correlation coefficient was found to be 0.999. The numbers of theoretical plates and tailing factor for doripenem were 53021 and 0.9, respectively. Doripenem was subjected to the International Conference on Harmonization (ICH) prescribed hydrolytic (acid, base, and neutral), oxidative, photolytic, and thermal stress conditions. Among all the above-mentioned conditions, the drug was found to be stable under photolytic degradation. Peak homogeneity data for doripenem in the chromatograms from the stressed samples obtained by use of the photodiode array detector demonstrated the specificity of the method for analysis of doripenem in presence of the degradation products. The performance of the method was validated according to the present ICH guidelines for specificity, limit of detection, limit of quantification, linearity, accuracy, precision, and robustness. 1. Introduction Doripenem (S-4661) (Figure 1) is a recently developed member of the carbapenem class of beta-lactam antibiotics. Similarly to meropenem and ertapenem, but unlike imipenem, doripenem has a 1-β-methyl side chain that provides resistance to the renal enzyme I-dehydropeptidase. Doripenem has been shown to have broad-spectrum activity against Gram-negative and Gram-positive pathogens including strains of Pseudomonas aeruginosa [1, 2]. Doripenem, like other carbapenems, was developed for the treatment of hospitalized patients with moderate or severe bacterial infections [3]. Figure 1: Structure of doripenem. An extensive literature survey revealed that there are certain methods reported on the stability of doripenem both in solid state and solutions [4–13]. In our knowledge and after an exhaustive revision of the literature, there is no evidence about the stability indicating gradient HPLC assay method of this drug in bulk and its formulation. Moreover, an official method for its determination has not been yet described in any Pharmacopoeia. Consequently, the implementation of an analytical methodology to determine doripenem in API and its formulation is a pending challenge
References
[1]
R. N. Jones, H. S. Sader, and T. R. Fritsche, “Comparative activity of doripenem and three other carbapenems tested against Gram-negative bacilli with various β-lactamase resistance mechanisms,” Diagnostic Microbiology and Infectious Disease, vol. 52, no. 1, pp. 71–74, 2005.
[2]
H. M. Wexler, A. E. Engel, D. Glass, and C. Li, “In vitro activities of doripenem and comparator agents against 364 anaerobic clinical isolates,” Antimicrobial Agents and Chemotherapy, vol. 49, no. 10, pp. 4413–4417, 2005.
[3]
R. N. Jones, H. K. Huynh, and D. J. Biedenbach, “Activities of doripenem (S-4661) against drug-resistant clinical pathogens,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 8, pp. 3136–3140, 2004.
[4]
P. A. Psathas, A. Kuzmission, K. Ikeda, and S. Yasuo, “Stability of doripenem in vitro in representative infusion solutions and infusion bags,” Clinical Therapeutics, vol. 30, no. 11, pp. 2075–2087, 2008.
[5]
C. Sutherland and D. P. Nicolau, “Development of an HPLC method for the determination of doripenem in human and mouse serum,” Journal of Chromatography B, vol. 853, no. 1-2, pp. 123–126, 2007.
[6]
J. Cielecka-Piontek, A. Jelińska, A. Do？hań, and P. Zalewski, “Kinetic and thermodynamic analysis of degradation of doripenem in the solid state,” International Journal of Chemical Kinetics, vol. 44, pp. 722–728, 2012.
[7]
L. Mantovani, C. T. M. Sayago, V. B. Camargo et al., “Stability-indicating RP-HPLC method for analysis of the antibiotic doripenem in pharmaceutical formulation-comparison to UV spectrophotometry and microbiological assay,” Acta Chromatographica, vol. 24, pp. 367–382, 2012.
[8]
J. Cielecka-Piontek and A. Jelinska, “The UV-Derivative spectrophotometry for the determination of doripenem in the presence of its degradation products,” Spectrochimica Acta A, vol. 77, pp. 554–557, 2010.
[9]
J. Cielecka-Piontek, K. Michalska, P. Zalewski, and A. Jelińska, “Recent advances in stability studies of carbapenems,” Current Pharmaceutical Analysis, vol. 7, pp. 213–227, 2011.
[10]
E. Dailly, R. Bouquié, G. Deslandes, P. Jolliet, and R. le Floch, “A liquid chromatography assay for a quantification of doripenem, ertapenem, imipenem, meropenem concentrations in human plasma: application to a clinical pharmacokinetic study,” Journal of Chromatography B, vol. 879, no. 15-16, pp. 1137–1142, 2011.
[11]
K. Michalska, G. Pajchel, and S. Tyski, “Determination of doripenem and related substances in medicinal product using capillary electrophoresis,” Journal of Separation Science, vol. 34, no. 4, pp. 475–482, 2011.
[12]
J. L. Crandon, C. Sutherland, and D. P. Nicolau, “Stability of doripenem in polyvinyl chloride bags and elastomeric pumps,” American Journal of Health-System Pharmacy, vol. 67, no. 18, pp. 1539–1544, 2010.
[13]
K. Berthoin, C. S. le Duff, J. Marchand-Brynaert, S. Carryn, and P. M. Tulkens, “Stability of meropenem and doripenem solutions for administration by continuous infusion,” Journal of Antimicrobial Chemotherapy, vol. 65, no. 5, pp. 1073–1075, 2010.
[14]
ICH Q1A (R2), “Stability Testing of New Drug Substances and Products,” 2003.
[15]
ICH Q2 (R1), “Validation of Analytical Procedures: Text and Methodology,” 2005.
[16]
“Stability testing of new drug substance and products Q1A (R2),” in Proceedings of the International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use, pp. 1–18, February 2003.
