Quantum Mechanical Methods for Thermal Hazard Risk Assessment in Early Phase Pharmaceutical Development

Abstract

Quantum mechanical (QM) applications to predict heat of reaction (ΔH r ) and thermal stability of strained aminocarbocylic salts, diazo compounds, and nitroalkanes for early phase thermal hazard risk assessment is presented. We provide examples on the use of explicit solvation to predict accurate ΔH r . Based on the QM calculations, the criticality class of a coppercatalyzed C−N coupling reaction is determined according to Stoessel's reaction criticality class and the predictions are consistent with RC1 calorimetric experiment. We emphasize that to predict accurate ΔH r , it is important to consider the roles of reagents and solvents in QM calculations rather than simply considering the bond formation and bond breaking steps involved with reactants and products. Further, the use of predicted ΔH r for salt formation is applied to predict the thermal stability of bromoacetylene azetidine compounds to establish structure−stability relationship which would be useful to identify stable salt intermediates for safe reaction design. A strong correlation between ΔH r and the left limit of the DSC onset temperature (T init , °C) of the of exothermic peak is identified (T init = −2.85 ΔH r − 99.5). We propose that this model can be used as a prediction tool for novel azetidine salts to provide an estimate of thermal stability before synthesis. In this paper, for the first time we report molecular electrostatic potential (MESP) descriptor for the prediction of T init of diazo compounds. The deepest MESP minimum (V min ) on the diazo group is considered as a probe to quantify the variation in structural effects. A strong correlation between V min and T init is found which would provide a new way of interpreting the thermal stability of novel diazo molecules just based on chemical structure. Further, the applicability of V min is verified on another set of compounds (nitroalkanes) and a good correlation is obtained. The structure− stability relationships that involves V min can be a useful QM descriptor for thermal stability prediction of a variety of molecules.

A Physical Organic Approach towards Statistical Modeling of Tetrazole and Azide Decomposition**

“…In this context, the in silico study of molecular decomposition has been a common practice in the field of high energy materials and in process hazard risk assessments [13, 14] . While considerable computational work has been devoted to the prediction of HEMs performance properties (detonation velocity, detonation pressure, etc.…”

A Physical Organic Approach towards Statistical Modeling of Tetrazole and Azide Decomposition**

“…The dataset contains a diverse range of structures and substitution patterns that are also frequently found in medicinal chemistry. This workflow carries both predictive power and mechanistic interpretability, which could be generalized to the study of other types of high energy compounds and synthetic intermediates across various sectors of chemical synthesis [13–15] …”

“…[13][14][15][16][17] In this context, the in silico study of molecular decomposition has been a common practice in the field of high energy materials and in process hazard risk assessments. [13,14] While considerable computational work has been devoted to the prediction of HEMs performance properties (detonation velocity, detonation pressure, etc. ), [16,[18][19][20][21] methods for the prediction of sensitivity properties [18] (impact sensitivity (IS), [23][24][25][26] friction sensitivity, electric spark sensitivity [27,28] ) and decomposition temperature (T dec ) [29,30] are less established in comparison.…”

“…This workflow carries both predictive power and mechanistic interpretability, which could be generalized to the study of other types of high energy compounds and synthetic intermediates across various sectors of chemical synthesis. [13][14][15]…”

“…Tetrazoles and azides have also emerged as high energy materials (HEMs) that rival traditional nitro‐ and lead‐based explosives owing to their energetic properties, relatively mild syntheses, and reduced toxicity [6, 7, 12] . Nevertheless, the energetic nature of these N‐rich compounds can pose hazards during their preparation, storage, and handling; predicting their sensitivity properties and understanding decomposition mechanisms is thus integral to these applications [13–17] …”