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2. In Silico Prediction of Pharmaceutical Degradation Pathways: A Benchmarking Study Using the Software Program Zeneth

Author

Hemingway, Rachel, primary, Baertschi, Steven W., additional, Benstead, David, additional, Campbell, John M., additional, Coombs, Maggie, additional, Huang, Zongyun, additional, Khalaf, Ryan, additional, Ott, Martin A., additional, Ponting, David J., additional, Reid, Darren L., additional, Stevenson, Neil G., additional, Webb, Samuel J., additional, White, Angela, additional, and Zelesky, Todd, additional

Published
2024
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3. Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood–Brain Barrier: The Discovery of AZD1390

Author

Pike, Kurt G., primary, Hunt, Thomas A., additional, Barlaam, Bernard, additional, Benstead, David, additional, Cadogan, Elaine, additional, Chen, Kan, additional, Cook, Calum R., additional, Colclough, Nicola, additional, Deng, Chao, additional, Durant, Stephen T., additional, Eatherton, Andrew, additional, Goldberg, Kristin, additional, Johnström, Peter, additional, Liu, Libin, additional, Liu, Zhaoqun, additional, Nissink, J. Willem M., additional, Pang, Chengling, additional, Pass, Martin, additional, Robb, Graeme R., additional, Roberts, Caroline, additional, Schou, Magnus, additional, Steward, Oliver, additional, Sykes, Andy, additional, Yan, Yumei, additional, Zhai, Baochang, additional, and Zheng, Li, additional

Published
2024
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4. Studies towards enhanced fastness of ink jet dyes

Author

Benstead, David John

Subjects
676
Abstract

A series of magenta azo dyes for use in inkjet printers have been synthesised in order to study the effects of substituted arylhydrazide substituents on their light and ozone fastness. Large-scale syntheses were successfully adapted to the laboratory and arylhydrazides were coupled to an existing azo dye via a cyanuric chloride coupling reaction in good yield and purity. Improved methodologies were developed for the synthesis of a series N-methylhydrazides, N,N’-dimethylhydrazides and N’-isopropylhydrazides. N-methylhydrazides were synthesised by reaction of methylhydrazine with an appropriate acid chloride. N.N’-dimethylhydrazides were synthesised from N-methylhydrazides, avoiding the use of the carcinogenic dimethylhydrazine employed in previous syntheses. Synthesis was via a reductive amination strategy employing previously unreported N-methyl, N’-methylidene arylhydrazides, followed by reduction with sodium cyanoborohydride. N’-isopropylhydrazides were also prepared via reductive amination, following condensation of commercially available hydrazides with propanone, again followed by reduction with sodium borohydride. The newly synthesised dyes were tested at Avecia (Blackley) for light and ozone fastness according to standard protocols. The N-methylhydrazides series of dyes showed slightly improved ozone fastness, light fastness was essentially unchanged across the range of dyes. Solution ozonolysis experiments were carried out on simple dye systems, such as 1-phenylazo-2-napthol and 1-phenylazo-4-napthol. In order to study the effects of azo / hydrazone tautomerism, some of the “locked” tautomers of these compounds were synthesised by methylation of the appropriate functional group. The main intermediate formed was napthoquinone. Solution ozonolysis was also performed on some of the more complex hydrazide substituted dyes previously synthesised and the rates of ozonolysis determined.

Published
2005

5. In SilicoPrediction of Pharmaceutical Degradation Pathways: A Benchmarking Study Using the Software Program Zeneth

Author

Hemingway, Rachel, Baertschi, Steven W., Benstead, David, Campbell, John M., Coombs, Maggie, Huang, Zongyun, Khalaf, Ryan, Ott, Martin A., Ponting, David J., Reid, Darren L., Stevenson, Neil G., Webb, Samuel J., White, Angela, and Zelesky, Todd

Abstract

Zeneth, a software application for the prediction of chemical degradation of small organic molecules, incorporates a knowledge base of rules to predict degradation pathways. In addition, the knowledge base contains property predictors that modulate the predicted likelihood of a given degradation product. In this study, a C–H bond dissociation energy (C–H BDE) predictor, which has been integrated into the software, was utilized. To determine this software’s predictive capabilities [using its knowledge base (2020.1.0 KB)], experimentally derived degradation profiles for 25 drug substances were compared to Zeneth predictions. These degradation profiles were derived from forced degradation studies, including accelerated and long-term stability studies, aligned with International Council for Harmonisation (ICH) guidelines. In addition, two case studies highlighting how prediction data can be utilized to confirm experimental data or assist with the identification of unknown degradation products have been presented. The specificity of prediction results was evaluated; transformation types that often predict degradation products not observed experimentally were identified, and an assessment of the causes is presented. The sensitivity for the study group was also evaluated using a historic knowledge base (2012.2.0 KB), enabling an assessment of how the predictive capabilities have improved over this period; the comparison demonstrated a 40% increase in sensitivity. This study has demonstrated that the ongoing expansion and optimization of this in silico tools knowledge base continues to result in improvements in its predictive capability and its ability to impart insight into the drug degradation knowledge space to aid pharmaceutical development.

Published
2024
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7. Strategies for Identity Testing of Therapeutic Oligonucleotide Drug Substances and Drug Products

Author

Capaldi, Daniel, primary, Akhtar, Nadim, additional, Atherton, Tom, additional, Benstead, David, additional, Charaf, Ayman, additional, De Vijlder, Thomas, additional, Heatherington, Carl, additional, Hoernschemeyer, Joerg, additional, Jiang, Hong, additional, Rieder, Ulrike, additional, Ring, Francis, additional, Peter, Robert, additional, Stolee, Jessica A., additional, and Wechselberger, Rainer, additional

Published
2020
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