Predicting Drug Substances Autoxidation

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• 作者：P. Lienard (1)
  J. Gavartin (2)
  G. Boccardi (3) (4)
  M. Meunier (2)
  
  1. Pharmaceutical Science Department ; Sanofi R&D ; 13 Quai Jules Guesde ; 94403 ; Vitry-sur-Seine Cedex ; France
  2. Accelrys ; 334 Milton Road Science Park ; Cambridge ; CB4 0WN ; UK
  3. Analytical Sciences ; Sanofi Research Centre of Milan ; Piranesi ; 38 ; 20137 ; Milan ; Italy
  4. Institute for Chemical and Biochemical Research via G. Colombo 81 ; 20133 ; Milan ; Italy
  
• 关键词：Degradation ; Autoxidation ; Computational chemistry ; Pharmaceutical ; DFT
• 刊名：Pharmaceutical Research
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：32
• 期：1
• 页码：300-310
• 全文大小：791 KB
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• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Pharmacy
  Biochemistry
  Medical Law
  Biomedical Engineering
  
• 出版者：Springer Netherlands
• ISSN：1573-904X

文摘

Purpose Chemical degradation and stability in formulation is a recurrent issue in pharmaceutical development of drugs. The objective of the present study was to develop an in silico risk assessment of active pharmaceutical ingredients (APIs) stability with respect to autoxidation. Methods The chemical degradation by autoxidation of a diverse series of APIs has been investigated with molecular modelling tools. A set of 45 organic compounds was used to test and validate the various computational settings. Aiming to devise a methodology that could reliably perform a risk assessment for potential sensibility to autoxidation, different types of APIs, known for their autoxidation history were inspected. To define the level of approximation needed, various density functional theory (DFT) functionals and settings were employed and their accuracy and speed were compared. Results The Local Density Approximation (LDA) gave the fastest results but with a substantial deviation (systematic over-estimation) to known experimental values. The Perdew-Burke-Ernzerhof (PBE) settings appeared to be a good compromise between speed and accuracy. Conclusions The present methodology can now be confidently deployed in pharmaceutical development for systematic risk assessment of drug stability.