Detection, identification and quantification of a new de-fluorinated impurity in casopitant mesylate drug substance during late phase development: An analytical challenge involving a multidisciplinary approach

Turco, Lucilla; Provera, Stefano; Curcuruto, Ornella; Bernabe, Elena; Nicoletti, Anna; Martini, Luca; Castoldi, Damiano; Cimarosti, Zadeo; Papini, Damiano; Marchioro, Carla; Dams, R.

doi:10.1016/j.jpba.2010.08.010

Cited by 8 publications

(3 citation statements)

References 9 publications

(14 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years, the use of halogen-containing molecules has proliferated in the pharmaceutical industry, where the incorporation of halogens, especially fluorine, has become vitally important for blocking metabolism and enhancing the biological activity of pharmaceuticals. − As a case in point, four of the five top selling small molecule drugs in 2011 contained halogens: Lipitor (atorvastatin, F), Plavix (clopidogrel bisulfate, Cl), Abilify (aripiprazole, Cl), and Advair (fluticasone/salmeterol, F) . The increased use of fluorine in pharmaceuticals has been accompanied by an evolution of tools and technologies for enabling synthetic chemistry, − spectroscopy , and chromatographic separation − of fluorine-containing pharmaceutical candidates.…”

mentioning

confidence: 99%

Chromatographic Resolution of Closely Related Species in Pharmaceutical Chemistry: Dehalogenation Impurities and Mixtures of Halogen Isomers

et al. 2013

View full text Add to dashboard Cite

In recent years, the use of halogen-containing molecules has proliferated in the pharmaceutical industry, where the incorporation of halogens, especially fluorine, has become vitally important for blocking metabolism and enhancing the biological activity of pharmaceuticals. The chromatographic separation of halogen-containing pharmaceuticals from associated isomers or dehalogenation impurities can sometimes be quite difficult. In an attempt to identify the best current tools available for addressing this important problem, a survey of the suitability of four chromatographic method development platforms (ultra high-performance liquid chromatography (UHPLC), core shell HPLC, achiral supercritical fluid chromatography (SFC) and chiral SFC) for separating closely related mixtures of halogen-containing pharmaceuticals and their dehalogenated isosteres is described. Of the 132 column and mobile phase combinations examined for each mixture, a small subset of conditions were found to afford the best overall performance, with a single UHPLC method (2.1 × 50 mm, 1.9 μm Hypersil Gold PFP, acetonitrile/methanol based aqueous eluents containing either phosphoric or perchloric acid with 150 mM sodium perchlorate) affording excellent separation for all samples. Similarly, a survey of several families of closely related halogen-containing small molecules representing the diversity of impurities that can sometimes be found in purchased starting materials for synthesis revealed chiral SFC (Chiralcel OJ-3 and Chiralpak IB, isopropanol or ethanol with 25 mM isobutylamine/carbon dioxide) as well as the UHPLC (2.1 × 50 mm, 1.8 μm ZORBAX RRHD Eclipse Plus C18 and the Gold PFP, acetonitrile/methanol based aqueous eluents containing phosphoric acid) as preferred methods.

show abstract

mentioning

confidence: 99%

Chromatographic Resolution of Closely Related Species in Pharmaceutical Chemistry: Dehalogenation Impurities and Mixtures of Halogen Isomers

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Fluorine incorporation helps to block the metabolism and increase the bioavailability and efficacy of pharmaceuticals [2][3][4][5]. The chromatographic separation of closely related species coming from the synthesis of organofluorine compounds enables research in this area, but the separation of mixtures of closely related fluorination isomers and the separation of fluorine-containing drugs from their desfluoro analogs can be challenging [6][7][8][9][10][11], owing to the close structural similarities and small differences in physical properties between desired and undesired components.…”

Section: Introductionmentioning

confidence: 99%

Search for improved fluorinated stationary phases for separation of fluorine-containing pharmaceuticals from their desfluoro analogs

Regalado

Makarov

McClain

et al. 2015

Journal of Chromatography A

View full text Add to dashboard Cite

“…Several examples have been published in the literature that highlight the application of QbD principles for new chemical entities (NCE). − By exploiting techniques such as design of experiments, process analytical technology (PAT) using sophisticated probes (FT-IR, Raman, etc.) and state-of-the-art scaled lab reactors, a thorough understanding of the manufacturing process is gained.…”

Section: Introductionmentioning

confidence: 99%

Applying QbD Principles To Develop a Generic UHPLC Method Which Facilitates Continual Improvement and Innovation Throughout the Product Lifecycle for a Commercial API

Musters¹,

Bos²,

Kellenbach³

2013

Org. Process Res. Dev.

View full text Add to dashboard Cite

The application of quality-by-design (QbD) principles for new chemical entities (NCEs) is highlighted in several publications. QbD, however, is rarely applied to marketed APIs. Lifecycles of existing APIs are extending. With this extension the focus on drug safety and compliance requires up-to-date knowledge of the product and its production process as over the years expectations in this respect have shifted. We applied QbD principles in order to set up an improved control strategy for the final five steps in the production route of a steroidal contraceptive, which has been produced for over 20 years within our facilities. A generic UHPLC method was developed for the quantitative analysis of the available intermediate batches which have all resulted in compliant API at full commercial scale. On the basis of the batch results, (statistically supported) specifications are proposed to create a range of proven acceptance criteria. This approach allows the application of the historical knowledge of the drug substance and its manufacturing process gained over the years to future production by exploiting the process capability of eliminating impurities and dealing with variability in the quality of the intermediates. Furthermore, it improves the process of specification setting. Generic UHPLC methods enable rapid quantitative monitoring of quality. The use of a generic UHPLC method in combination with the setup of a side-product flow scheme improves process understanding and supports chemical entity design space development. Furthermore, the use of a generic UHPLC method for multiple intermediates also offers the possibility to perform side-product tracing on the basis of retention times. A generic UHPLC method was developed according to QbD principles to create a range of proven acceptance criteria for the assay and side-product determination for the final five steps in the production route of a contraceptive API.

show abstract

Detection, identification and quantification of a new de-fluorinated impurity in casopitant mesylate drug substance during late phase development: An analytical challenge involving a multidisciplinary approach

Cited by 8 publications

References 9 publications

Chromatographic Resolution of Closely Related Species in Pharmaceutical Chemistry: Dehalogenation Impurities and Mixtures of Halogen Isomers

Chromatographic Resolution of Closely Related Species in Pharmaceutical Chemistry: Dehalogenation Impurities and Mixtures of Halogen Isomers

Search for improved fluorinated stationary phases for separation of fluorine-containing pharmaceuticals from their desfluoro analogs

Applying QbD Principles To Develop a Generic UHPLC Method Which Facilitates Continual Improvement and Innovation Throughout the Product Lifecycle for a Commercial API

Contact Info

Product

Resources

About