Explosive Hazard Identification in Pharmaceutical Process Development: A Novel Screening Method and Workflow for Shipping Potentially Explosive Materials

Abstract

When a material is identified as potentially capable of explosive propagation by the Yoshida correlation, process safety scientists have few options for semiquantitatively assessing the hazards associated with the use of that material. Oxygen balance calculations, the Rule of 6, and the United Nations (U.N.) explosive functional group list are commonly employed qualitative/semiquantitative methods to assess explosivity without requiring additional experimental data. In contrast, a full United Nations Transportation of Dangerous Goods testing regimen requires, at a minimum, 2 kg of material for Test Series 1 alone, an excessive amount that is rarely available in early pharmaceutical development. A new assessment, called the O.R.E.O.S. method, has been developed that combines the three traditional methods for screening of explosive properties (Oxygen balance calculations, the Rule of 6, and the Explosive functional group list) with the Onset of decomposition determined by differential scanning calorimetry and the proposed Scale. This new assessment has been applied to known energetic materials that are flagged as potentially capable of explosive propagation by the Yoshida correlation and has been shown to be effective at classifying materials in a scale-dependent manner. The tool is customizable to fit any organization’s internal guidance on handling energetic materials. This assessment should find wide utility in both pharmaceutical development groups and contract research organizations as a means to classify compounds that may require further testing before scale-up or to steer project teams to discover safer alternatives. A brief description of the challenges associated with transporting materials for U.N. Series Testing is also presented with the aim of demystifying the process for obtaining such valuable data.

Multidecagram Scale Synthesis of an Endoperoxide, Precursor of Anti-malarial and Anti-leishmanial Agents, via Free-Radical [2 + 2 + 2] Annulation with Molecular Oxygen

“…It was originally proposed for azides 36,37 and it is an empirical guideline used to anticipate if a molecule can be considered relatively safe to handle. 38 The condition is that the molecule presents at least six carbon atoms per energetic functionality, in our case the peroxy bond. In compound 7, the ratio between the number of carbon atoms and number of energetic functionalities is 16, much higher than the safety limit of 6.…”

“…The belief that the unknown hazardous properties of endoperoxides such as 7 do not require extraordinary safety standards in the 0.1–0.2 g scale was supported by the “rule of 6”. It was originally proposed for azides , and it is an empirical guideline used to anticipate if a molecule can be considered relatively safe to handle . The condition is that the molecule presents at least six carbon atoms per energetic functionality, in our case the peroxy bond.…”

Importance of Thermal Stability Data to Avoid Dangerous Reagents: Temozolomide Case Study

“…The O.R.E.O.S. methodology (Table 3) developed at Vertex for screening potentially explosive materials 15 examines TMZ's oxygen balance 16 (OB), applies the Rule of 6, 17 identifies explosive functional groups (ExFGs), 18 takes into account the onset temperature of decomposition, and applies a hazard ranking depending on the scale at which a chemist will be operating.…”

Precompetitive Collaborations in the Pharmaceutical Industry: Process Safety Groups Work Together to Reduce Hazards, from R&D Laboratories to Manufacturing Facilities

“…Process safety scientists in the pharmaceutical industry are chemists and engineers who dedicate themselves to identify and minimize potential risks associated with thermally unstable materials, combustible dusts, and runaway reactions from R&D laboratories to manufacturing facilities. Numerous publications illustrate such work accomplished by process safety scientists. − For example, Tian et al evaluated thermal safety on a hydroamination reaction using DMSO as solvent, studied the potential autocatalytic decomposition with DMSO, and successfully launched the process for commercial production safely.…”