The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development

Dobo, Krista L.; Greene, Nigel; Cyr, Michelle O.; Caron, Stéphane; Ku, Warren W.

doi:10.1016/j.yrtph.2006.01.004

Cited by 109 publications

(65 citation statements)

References 28 publications

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“…Thus, analysts make attempts to determine a way for analyzing various GIs by using unique robust methods as far as possible. In this way, simple HPLC/UV or GC/FID methods are usually performed at the first stage, while more complicated LC/MS or LC/MS/MS methods are used as alternatives (Dobo et al, 2006;Elder et al, 2008b;Liu et al, 2010). Teasdale et al (2009) studied the formation of sulfonate esters as a mechanistic view, and showed that when a slight excess of base is present, there is no discernible reaction rate to form the sulfonate ester and no mechanistic pathway to their formation.…”

Section: Resultsmentioning

confidence: 99%

Genotoxic Impurities in Pharmaceuticals

Jouyban¹,

Parsa²

2012

Toxicity and Drug Testing

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Section: Resultsmentioning

confidence: 99%

Genotoxic Impurities in Pharmaceuticals

Jouyban¹,

Parsa²

2012

Toxicity and Drug Testing

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“…Monitoring potentially genotoxic impurities is of growing importance in the pharmaceutical industry and RP-LC often is inadequate [43]. Genotoxic impurities can be introduced into pharmaceutical formulations during the synthesis of an API, either as a starting material or a by-product, or they can be formed by degradation of the API or other components of the formulation.…”

Section: 4mentioning

confidence: 99%

High-efficiency hydrophilic interaction chromatography by coupling 25cm×4.6mm ID×5μm silica columns and operation at 80°C

Louw

Lynen

Hanna-Brown

et al. 2010

Journal of Chromatography A

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Recently, hydrophilic interaction chromatography (HILIC) has emerged as a valuable orthogonal tool to reversed-phase liquid chromatography (RP-LC) as it allows for resolution of highly polar ionisable compounds. The relationships between separation efficiency, column length and speed of analysis for 4.6 mm ID x 5 µm silica particle columns in HILIC are demonstrated using kinetic plots. The kinetic plots constructed for conventional pressure systems operating at 350 bar and at 30 o C and 80°C are confirmed using experimental data for different column lengths. Efficiencies of more than 130,000 theoretical plates could be achieved by connecting up to six columns of 25 cm. As expected, a significant gain in analysis speed without loss of efficiency could be obtained by operating at 80°C compared to 30°C. The advantages of using long columns in HILIC in combination with elevated column temperature for the pharmaceutical industry are illustrated using test mixtures comprised of commercially available ionisable compounds (including some containing functional groups with potential genotoxic typical structural alerts) as well as real polar ionisable pharmaceuticals. Keywords:Hydrophilic interaction liquid chromatography, high efficiency, kinetic plots, temperature, speed 3 Correspondence:Professor Pat Sandra, Ghent University, Krijgslaan 281 S4-bis, B-9000, Ghent, Belgium E-mail: pat.sandra@richrom.comTel: +32 56 204031; Fax: +32 56 204858 IntroductionReversed-phase liquid chromatography (RP-LC) is by far the most widely employed analytical tool in drug discovery and development. In recent years, the efficiency of RP-LC has been drastically increased through various approaches including using sub-2µm particles in combination with ultra high pressure LC (UHPLC) [1][2][3], increasing the column length and operation at elevated temperature (ETLC) [4][5][6] or by combining both UHPLC and ETLC [7,8].These developments have certainly facilitated the development of generic methodologies for RP-LC for separations of active pharmaceutical ingredients (API's) and impurities [5].Furthermore, these advances have helped separation scientists to exploit early fundamental theories around the principles of separation optimisation with respect to efficiency and speed by utilisation of kinetic plots. For the pharmaceutical industry, which will certainly still have a plethora of conventional HPLC instrumentation in its good manufacturing practice (GMP) laboratories, kinetic plots can certainly serve a purpose in directing how conventional instrumentation and columns can be used more appropriately in combination with ETLC and long columns. This can help to optimize the use of conventional particle diameters (5 µm) to yield either maximum efficiency and to compared to sub-2µm particles, or to increased the speed of analysis.Since these developments, a chromatographic technique that has been enjoying recent attention in the pharmaceutical industry is hydrophilic interaction chromatography (HILIC).HILIC has become a valuable addition t...

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“…2-Dimethylaminoethyl chloride hydrochloride (DMC HCl) shows presence of structural alert for genotoxic mutagenicity and carcinogenicity. The QSTR models predict the compound positive for genotoxicity, mutagenicity and carcinogenicity the compound is shown the positive for mutagenicity in training set used for Ames mutagenicity model [2][3][4][5].In genetics, Genotoxicity describes as property of chemical compound which may damage the genetic information within a cell leading mutations, which can lead to different types of Cancers in Human body in any forms.…”

Section: Introductionmentioning

confidence: 99%

“…The permanent, heritable changes can affect either somatic cells of the organism or germ cells to be passed on to coming/future generations. Cells prevent expression of the genotoxic mutation by either DNA repair or apoptosis; however, the damage may not always be fixed leading to mutagenesis [4,5] Specifically, there is evidence that genotoxic substances may bind directly to DNA and may also act indirectly by affecting enzymes involved in DNA replication. There are three primary effects that Genotoxins can have on organisms by affecting their genetic information.…”

Section: Introductionmentioning

confidence: 99%