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Predicting Drug Substances Autoxidation

Drug development aims to bring to market active pharmaceutical ingredients (APIs) identified during the drug discovery process. During this phase, the drugs undergo many tests to fully characterize their physical and chemical properties. Risk assessment is really what this is all about! It is less risky for pharmaceutical companies to assess potential development issues earlier rather than later (e.g., polymorphism, solubility, stability) in order to assess the manufacturability of the actives.Researchers typically don't have a large quantity of material to work with early in development. For this reason, in-silico methods such as those deployed within the BIOVIA Materials Studio?? modelling and simulation environment are very valuable. Materials Studio enables researchers to predict and understand the relationship between a material's molecular structure and its properties and/or behaviour.Amongst all stability stress tests performed, degradation is certainly one of the top issues pharmaceutical research scientists need to assess early by focusing on a number of possible API degradation mechanisms, including autoxidation (or hydrogen abstraction). The reaction between the pharmaceutical compounds and molecular oxygen can initiate an oxidative chain reaction that can lead to the reduction of the therapeutic agent, formation of toxic products, decreased bioavailability and other degradation processes. A research paper published this summer describes an in silico method for estimating bond dissociation energies based on the Density Functional Theory (DFT), a well-known computational chemistry tool for performing electronic structure calculations. The results can be used to assess the propensity of a drug substance with respect to autoxidation.The method was built using the BIOVIA Pipeline Pilot?? scientific workflow authoring application (and in particular the Pipeline Pilot Materials Studio Collection) to automate all the required quantum mechanical calculations. All steps of the workflow including jobs submission, execution on a remote cluster and analysis were fully automated using Pipeline Pilot. The calculations were conducted via a secure web interface allowing for efficient analysis, reporting and sharing of results.Initially, the method was validated against a set of 45 molecules and subsequently applied to APIs with known degradation history. Eventually, the risk assessment shown in the following figure was obtained.In conclusion, such Bond Dissociation Energy (BDE) calculations may be taken as a complementary source of information with experimental stress testing for early compound stability profiling. In addition, the authors reported that 'there is no need to be a highly skilled computational expert to use the Pipeline Pilot protocol.'Predicting Drug Substances AutoxidationLienard P, Gavartin J, Boccardi G, Meunier M.Pharm Res. 2014 Aug 13
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