In Silico Prediction of Pharmaceutical Degradation Pathways: A Benchmarking Study

Abstract

Zeneth is a new software application capable of predicting degradation products derived from small molecule active pharmaceutical ingredients. This study was aimed at understanding the current status of Zeneth's predictive capabilities and assessing gaps in predictivity. Using data from 27 small molecule drug substances from five pharmaceutical companies, the evolution of Zeneth predictions through knowledge base development since 2009 was evaluated. The experimentally observed degradation products from forced degradation, accelerated, and long-term stability studies were compared to Zeneth predictions. Steady progress in predictive performance was observed as the knowledge bases grew and were refined. Over the course of the development covered within this evaluation, the ability of Zeneth to predict experimentally observed degradants increased from 31% to 54%. In particular, gaps in predictivity were noted in the areas of epimerizations, N-dealkylation of N-alkylheteroaromatic compounds, photochemical decarboxylations, and electrocyclic reactions. The results of this study show that knowledge base development efforts have increased the ability of Zeneth to predict relevant degradation products and aid pharmaceutical research. This study has also provided valuable information to help guide further improvements to Zeneth and its knowledge base.

Prediction of Hydrolysis Products of Organic Chemicals under Environmental pH Conditions

“…There are also a few examples of software tools to predict abiotic transformation processes, such as the META expert system, which has been expanded to predict phototransformation products 13 . Additionally, the Zeneth 14 software package predicts degradation of pharmaceuticals under the extreme conditions used in stability tests. Hydrolysis reactions may be included as incidental pathways in these software tools for predicting transformation products; however, to our knowledge, there is no software tool available for predicting hydrolytic transformation products in water, without the catalytic effects of enzymes and/or light.…”

In silico and in vitro degradation studies of isolated phloroglucinols eugenial C and eugenial D from Eugenia umbelliflora fruits

“…The software Zeneth 7 (Lhasa Limited, Leeds, UK) used to predict the degradation of active pharmaceuticals ingredients was applied to both eugenial C and eugenial D chemical structures. The compounds were drawn in the software and submitted to prediction of degradation route and the products generated under photolytic, oxidative, thermal, reaction conditions with metals, acid and alkaline hydrolysis.…”

On the Relationship between Classical Structure Determination and Retrosynthetic Analysis/Total Synthesis†

“…In 2013 Parenty et al. of the nonprofit Lhasa Ltd. published “An Expert System To Predict the Forced Degradation of Organic Molecules.” Force degradation, also called stress testing, “uses physical and chemical stresses in order to screen product stability and rapidly obtain larger quantities of degradants that would have been obtained under standard storage conditions as in long‐term or accelerated stability studies.” Forced degradation differs from accelerated and long‐term stability studies by the severity of the conditions to which the test substance and its degradation products are exposed . Figure is a three‐generation pharmaceutical degradation tree presented by Parenty et al.…”

“…There are other distinctions between Figure A and Figure . For example, the expert systems in Figure predict more potential degradants than are observed in practice, likely even more than the most sensitive analytical tools can detect. On the other hand, structure determinations run today without X‐ray crystallography, taking advantage of all analytical tools available, would be far more efficient than the techniques of the first half of the 20 th century for several reasons.…”

“…In the former, the chemist is working with pure substance and the degradation products must all derive from that substance. The “drug” in Figure may well be combined with other substances formulated alongside the active ingredient for any of several purposes, e. g., stabilization agents, bulking agents, diluents, or substances added for therapeutic enhancement . Hence, degradation products may results from these other substances or from combinations of substances.…”