Metoprolol lactose adduct

. Mass spectrometry was performed for this isolated impurity by ESI technique in positive mode. The positive DI-MS spectrum  of isolated impurity exhibited molecular ion peak as [M + H]⁺ at m/z 592.29 and as sodium adduct [M + Na]⁺ at m/z 614.28. The MS/MS data displayed a dominant fragment at m/z 574.28 which is 17 amu less than the molecular ion peak indicating a removal of the hydroxyl group.
This indicates that the impurity is Metoprolol-lactose adduct as proposed. The high resolution mass proposed
the probable molecular formula C₂₇H₄₅NO_13.


The ¹H NMR spectrum of this impurity displayed signals at δ = 1.27–1.30(6H), δ = 2.73–2.76 (2H), δ = 2.95–2.98 (1H), δ = 3.12–3.18(1H), δ = 3.23 (3H), δ = 3.44–3.68(11H), δ = 3.73–3.77(2H), δ = 3.83–3.84(2H), δ = 4.15–4.17(3H), δ = 4.41–4.43(1H), δ = 4.64–4.67 (1H), δ = 6.68–6.90 (2H), δ = 7.15–7.17(2H)
corresponding to 37 protons, indicating the Metoprolol adduct impurity possibility as it contains total 45 protons out of which 8 protons are of hydroxyl groups of lactose.
The ¹H and ¹³C NMR spectra of Metoprolol adduct impurity and Metoprolol tartrate  was compared and significant changes were observed. In ¹H NMR spectrum of impurity additional 13 protons in aliphatic region were observed. While in ¹³C NMR, additional 12 carbon signals can be seen. Methylene carbons C21 and C16 were observed at 60.5 and 61.8 ppm respectively and 10 carbon signals were observed between 68.5 ppm to 103 ppm. These signals
confirmed the presence of both lactose as well as Metoprolol moieties in the impurity.
Further to confirm the exact structure of Metoprolol adduct impurity, the 2D NMR HSQC has also been reviewed (see
Supplementary Fig. S-5). It was observed that the proton in aliphatic region showing doublet at (4.41–4.43) ppm corresponds to C22 which appeared at 103 ppm. This confirms the presence of anomeric carbon of pyranose ring. Also C17 appeared at 95.4 ppm found to be quaternary carbon which confirms the presence of furanose anomeric carbon. Proton corresponding to C20 found to shown multiplet in the region of (4.15–4.17) ppm which confirms that C20 is from furanose ring. Apart from these interactions, carbon signals appeared at 70.7, 72.2, 74.5, 61.8 ppm confirming the arabinosyl moiety.
Based on the above observations it has been confirmed that the impurity is Metoprolol lactose adduct and the ‘glucose moiety’ of lactose present in adduct exists in furanose form

The ¹H  Metoprolol tartrate

The  ¹³C NMR spectra Metoprolol tartrate

.

The ¹H spectra of Metoprolol adduct impurity

The¹³C NMR spectra of Metoprolol adduct impurity

 
HSQC spectra of Metoprolol adduct impurity

 

 

 

Identification, synthesis, isolation and characterization of new impurity in metoprolol tartrate tablets

Journal of Pharmaceutical and Biomedical Analysis

Volume 117, 5 January 2016, Pages 104–108

• R. Buchi Reddy,
• Kishor R. More^, ,
• Leena Gupta,
• Mukesh S. Jha,
• Laki Magar

• Ipca Laboratories Ltd., Chemical Research Division, Kandivali Industrial Estate, Kandivali (W). Mumbai 400067, India

 http://www.sciencedirect.com/science/article/pii/S0731708515301357

Buchireddy Reguri

Executive Vice President, IPCA Laboratories

R. Buchi Reddy

Executive Vice President

Ipca laboratories Ltd

 

 

 

Dr. Leena Gupta

Senior Research Executive at IPCA

https://in.linkedin.com/in/dr-leena-gupta-86b69518

 

 

Dr.Kishor More

Dy.General Manager at Ipca Laboratories Limited

https://in.linkedin.com/in/dr-kishor-more-3bb6a0109

 

.

Mukesh Jha

Ph.D.

Research Executive

Ipca Laboratories, Mumbai · CRD

 

Laki Magar
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