A NIR, <sup>1</sup>H-NMR, LC-MS and chemometrics pilot study on the origin of carvedilol drug substances: a tool for discovering falsified active pharmaceutical ingredients

Raimondo, Mariangela; Borioni, Anna; Sestili, Isabella; Gaudiano, Maria Cristina

doi:10.1039/d1ay02035h

Cited by 2 publications

(4 citation statements)

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“…The authors' previous results obtained for ibuprofen and carvedilol drug substances (Raimondo et al, 2020;Raimondo et al, 2022) evidenced a chemometric separation in PCA and cluster analyses based on API origin (EU and non-EU) related to specific signals in 1 H-NMR and in LC or LC-MS Q-TOF. This paper reports the results obtained with more techniques and different data analysis approaches.…”

Section: Discussionmentioning

confidence: 90%

“…Overall, the 1 H-NMR combined with PCA is confirmed as a good approach to identify small differences in pharmaceutically active substances (Krakowska et al, 2016;Raimondo et al, 2020;Deconinck et al, 2022;Raimondo et al, 2022;Rebiere et al, 2022).…”

Section: Discussionmentioning

confidence: 91%

“…In recent years, studies of fingerprinting analysis to discover possible falsifications of medicinal products or APIs have been performed (Anzanello et al, 2014;Custers et al, 2014;Acevska et al, 2015;Custers et al, 2016a;Raimondo et al, 2020;Deconinck et al, 2022). The European Official Medicines Control Laboratories (OMCLs) network performed fingerprinting studies on APIs of different manufacturers/origins to develop a tool to detect falsification of the origin of active ingredients (Raimondo et al, 2020;Rebiere et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…The combination of NMR spectroscopy and multivariate classification approaches has recently been used to identify the fingerprints of pharmaceutical chemical substances (Raimondo et al, 2020;Deconinck et al, 2022;Raimondo et al, 2022) and to detect the origin of biological molecules such as heparin (Colombo et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Investigating metformin-active substances from different manufacturing sources by NIR, NMR, high-resolution LC-MS, and chemometric analysis for the prospective classification of legal medicines

Raimondo

Aureli²,

D’Ettorre³

et al. 2023

Front. Anal. Sci.

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Introduction: The characterisation of active substances is an essential tool to ensure the traceability and authenticity of legal medicines. Metformin is a well-established biguanide derivative recommended in oral formulations as a first-line treatment for type 2 diabetes. With its increasing demand, metformin is likely to be an attractive target for falsification and substandard production, thus posing health risks to consumers. Methods that are able to identify even small differences in active pharmaceutical ingredients (APIs) are deemed necessary. The detection of fraudulent practices in APIs is not straightforward, and a single technique that can provide sufficient information to unambiguously address this issue is still not available.Methods: This study investigated an integrated analytical platform based on NIR, 1H-NMR, 13C-NMR, and high-resolution LC-MS combined with chemometrics to profile 32 metformin hydrochloride samples originating from several global authorised manufacturers. The study's aim was to explore differences in the chemical characteristics of metformin hydrochloride APIs to identify or predict a possible classification for each manufacturer in view of prospective authenticity studies. Different pre-processing methods were applied; bucket tables for 1H- and 13C-NMR were obtained, while mass spectrometry data were processed in targeted and untargeted modes. Datasets were individually analysed and merged by a multivariate unsupervised method and performing principal component analysis (PCA). Results and Discussion: The results evidenced differences in cluster behaviour, depending on manufacturers. Each technique has shown a specific clustering tendency, highlighting how different analytical approaches are able to characterise metformin APIs. Some manufacturers’ samples, however, showed similar behaviour independently of the techniques. NIR and 1H-NMR were confirmed as the more predictive techniques if taken individually; 1H-NMR, in particular, achieved good separation between the samples of the two most representative manufacturers. For LC-MS, the targeted approach resulted in a separation in groups clearer than that of the untargeted approach. Nevertheless, the untargeted LC-MS approaches presented in this paper could be a possible alternative to obtaining different information for drug substances, with several different and complex synthetic pathways leading to several unknown impurities. Further grouping of manufacturers emerged by data fusion, highlighting its potential in the traceability of metformin.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Investigating metformin-active substances from different manufacturing sources by NIR, NMR, high-resolution LC-MS, and chemometric analysis for the prospective classification of legal medicines

Raimondo

Aureli²,

D’Ettorre³

et al. 2023

Front. Anal. Sci.

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Citius, Altius, Fortius—Advanced Mass Spectrometry in Service of Forensic Analysis

et al. 2022

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This review presents numerous studies in which mass spectrometry has been used to assist forensic investigation. Due to its unique capabilities, mainly high-resolution mass data and structural information, high sensitivity, and cooperation with separation techniques, this method provides access to many tools streamlining and accelerating sample analysis. Low analyte consumption, advanced derivatization procedures and availability of isotopically labeled standards offer opportunities to study materials previously not considered viable evidence, opening new avenues in forensic investigations.

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A NIR, ¹H-NMR, LC-MS and chemometrics pilot study on the origin of carvedilol drug substances: a tool for discovering falsified active pharmaceutical ingredients

Abstract: Falsification of drugs, entailing the use of drug substances from unknown unapproved suppliers, is one of the main concerns for the quality of medicines. Therefore, traceability of active ingredients represents...

Cited by 2 publications

References 41 publications

Investigating metformin-active substances from different manufacturing sources by NIR, NMR, high-resolution LC-MS, and chemometric analysis for the prospective classification of legal medicines

Investigating metformin-active substances from different manufacturing sources by NIR, NMR, high-resolution LC-MS, and chemometric analysis for the prospective classification of legal medicines

Citius, Altius, Fortius—Advanced Mass Spectrometry in Service of Forensic Analysis

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A NIR, 1H-NMR, LC-MS and chemometrics pilot study on the origin of carvedilol drug substances: a tool for discovering falsified active pharmaceutical ingredients

Abstract: Falsification of drugs, entailing the use of drug substances from unknown unapproved suppliers, is one of the main concerns for the quality of medicines. Therefore, traceability of active ingredients represents...

Cited by 2 publications

References 41 publications

Investigating metformin-active substances from different manufacturing sources by NIR, NMR, high-resolution LC-MS, and chemometric analysis for the prospective classification of legal medicines

Investigating metformin-active substances from different manufacturing sources by NIR, NMR, high-resolution LC-MS, and chemometric analysis for the prospective classification of legal medicines

Citius, Altius, Fortius—Advanced Mass Spectrometry in Service of Forensic Analysis

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A NIR, ¹H-NMR, LC-MS and chemometrics pilot study on the origin of carvedilol drug substances: a tool for discovering falsified active pharmaceutical ingredients