Stability of doripenem in reconstituted solution – thermal and oxidative decomposition kinetics and degradation products by LC–MS

Abstract

A ultra-fast liquid chromatography method applied to quantitation of doripenem in powder for injection was validated. Validation parameters were assayed and a rapid analysis was established by a reversed-phase system comprising a C column endcapped (50 × 4.0 mm, 2.0 μm), mobile phase consisting of phosphoric acid 0.01% (pH 3.8) and acetonitrile (98:02, v/v) and a flow rate of 0.4 mL min . Drug stability was studied through submission to forced conditions, allowing the major degradation products to be detected and the kinetics parameters to be established. Thermal and oxidative degradation were determined, and indicated a kinetic decomposition following first and second order, respectively. The main degradation products were identified by LC-MS analysis, and the results were evaluated in order to suggest the chemical structures corresponding to respective masses and fragmentations. Six compounds were identified, with m/z 411, 427, 437, 634, 650 and 664. All of them resulted from cleavage of β-lactam ring and alcoholic chain and/or dimerization. These experimental results provide valuable information about the stability of doripenem reconstituted solution and procedures for its handling and storage.

An Integrated Dialysis Pharmacometric (IDP) Model to Evaluate the Pharmacokinetics in Patients Undergoing Renal Replacement Therapy

“…The RRT clearance determined with the IDP model was more in line with the RRT clearance determined with the post-filter approach while effluent based approaches would lead to smaller RRT clearances not capturing adsorption processes. The estimated degradation rate constant for doripenem (half-life of 13.5 h) was in line with degradation observed in destabilizing conditions in the literature such as elevated temperature, oxidative stress or exposure to UV radiation (half-life of 12 h and 27 h vs. >100 h in destabilizing vs. stabilizing conditions, respectively) [12,25,26]. Hence, the estimated degradation was in the range of previously determined half-lives and suggested destabilizing conditions in the effluent.…”

Highly sensitive cadmium sulphide quantum dots as a fluorescent probe for estimation of doripenem in real human plasma: application to pharmacokinetic study

“…The presented approach provides an ultra-sensitive uorescence nano-probe for the estimation of DOR in real human plasma with LOD value reaching 2.0 ng mL À1 compared to the other reported methods. [2][3][4][5][7][8][9]…”

“…From the literature survey, different analytical methods have been reported for the analysis of DOR such as spectrophotometry, 2-5 spectrouorimetry, 6 high-performance liquid chromatography (HPLC), [7][8][9] high-performance thin layer chromatography (HPTLC) 10 and electrochemical 11 methods. From this survey, only one spectrouorimetric method was reported for the determination of DOR.…”

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“…Various reported methods are concerned with the stability of doripenem [14][15][16][17][18][19] . The literature also reveals some of the LC-MS studies 20,21 and NMR studies 22,23 . As per the ICH guidelines entitled "Stability Testing of New Drug Substances and Products" the active substance's inherent stability characteristics can be elucidated through stress testing 24 .…”