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Structural identification and characterization of impurities in moxifloxacin

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Abstract

In the synthesis of Moxifloxacin four prominent impurities were detected in HPLC analysis. These impurities were detected in gradient HPLC method. They were isolated from enriched mother liquors and were characterized as 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(S,S)-N-methyl-2,8-diazabicyclo (4,3,0) non-8yl]-4-oxo-3-quinoline carboxylic acid (Impurity-1), methyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(S,S)-2,8-diazabicyclo(4,3,0)non-8-yl]-4-oxo-3-quinoline carboxylate (impurity-2), and 1-cyclopropyl-6-fluoro-1,4 dihydro-8-hydroxy-7-[(S,S)-2,8-diazobicyclo(4,3,0)non-8-yl]-4-oxo-3-quinoline carboxylicacid (impurity-3), 1-cyclopropyl-6,7-difluoro-8-hydroxy-4-oxo-1,4 dihydro-3-quinoline carboxylicacid (impurity-4) by means of 1H, 13C NMR, DEPT, IR and mass spectral data. Structural elucidation by spectral data was discussed.

Introduction

Moxifloxacin is a new 8-methoxy quinolone with enhanced anti-gram positive activity in vitro compared with ciprofloxacin and ofloxacin [1], [2], [3]. Moxifloxacin differs from other quinolones in that it has a methoxy function at the 8-position and a diazabicyclononyl moiety with S,S-configuration at the 7-position. The results of well-designed, prospective and comparative clinical trials proved moxifloxacin to be safe and efficacious in treating community-acquired respiratory tract infection, sinusitis, acute exacerbation’s of chronic bronchitis and pneumonia.

The analysis of moxifloxacin bulk drug revealed the presence of four impurities which were up to 0.1%. As per the stringent regulatory requirements the impurity profile study has to be carryout for any final product to identify and characterize all the unknown impurities that are present at a level of >0.1%. This paper describes the isolation and characterization of impurities present in the bulk drug of moxifloxacin. Though chiral separation of moxifloxacin intermediate diazabicyclo compound was cited in the literature [4], the impurity profile study of moxifloxacin was not reported to the best of our knowledge.

Section snippets

Samples

The investigated samples were obtained from synthetic R&D laboratory of Dr. Reddy’s Laboratories Ltd., Bulk Actives, Unit-III, Hyderabad, India. The impurities were synthesized from the same laboratory.

High performance liquid chromatography (analytical)

A Waters Model Alliance 2690-separation module equipped with a waters 996-photo diode array UV detector was used. The analysis was carried out on ACE 5 C18 column, 250mm×4.0 mm i.d., 5 μm particle size (advanced chromatography technologies ACT, Scotland) with a mobile phase consisting of A: 10 ml H3

Synthesis of moxifloxacin

The scheme for the synthesis of moxifloxacin [5] was shown in the Fig. 1

Detection of impurities 1, 2, 3 and 4

A typical LC-chromatogram of moxifloxacin bulk drug was recorded using the LC- method as described in Section 2.2.The target impurities under study were marked as impurity-1, impurity-2, impurity-3, and impurity-4. Retention times and structures of these impurities and moxifloxacin are shown in Table 1.

Isolation of impurities by preparative HPLC

An isocratic reverse phased solvent system discussed under Section 2.3 was used for the isolation of these impurities. All the fractions of impurities isolated were concentrated and extracted

Acknowledgements

The authors wish to thank the management of Dr. Reddy’s Laboratories Ltd., Bulk Actives Unit-III for supporting this work. Co-operation from colleagues of Dr. Reddy’s Laboratories Ltd., Bulk Actives III especially Dr. P. Pratap Reddy, Mr. D.V. Subba Rao and Analytical research development of Discovery Research division is appreciated.

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    Citation Excerpt :

    The proposed formulae of the [M+H]+ ions, observed and calculated masses, measurement errors and product ions for the MOX and its impurities are summarized in Table 1. Among these ten impurities, four (impurities 3–6) have been collected in European Pharmacopoeia [2] while one (impurity 8) has been reported by Kumar [5], so that they can be easily identified by comparison with reference data. In addition, three impurities (impurities 1, 2, and 7) were identified by using the high accurate molecular mass combined with multiple-stage mass spectrometric data and fragmentation rules.

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