Chemical reactivity screening

Use reactor calorimetry testing to determine thermodynamics and kinetics of process. See Appendix 2A (Chemical reactivity hazards screening). 

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

In general, a theoretical evaluation of the hazardous chemical reactivity suggested in Box 2 is not sufficient by itself. The standard practice is to perform screening tests (Boxes 3 and 5). 

Based on the level of knowledge of chemical reactivity hazards, determine if additional screening of reactivity hazards is necessary. Having reactive functional groups might indicate the need to perform literature searches, access databases, or run differential scanning calorimetry. 

FIG. 23 18 CCPS preliminary screening for chemical reactivity hazards. [From Johnson et al. (2003) copyright AIChE reproduced with permission. ]... 

Chapter 3 provides a screening tool to help determine whether chemical reactivity hazards are present that need to be managed and controlled. 

Chapter 3 is a Preliminary Screening Method designed to help identify whether chemical reactivity hazards are present at a facility. It can be used to determine whether the information in this publication is sufficient, or whether additional resources are going to be required, for managing identified chemical reactivity hazards. 

Table 3.1, Example Form to Document Screening of Chemical Reactivity Hazards, with the accompanying flowchart of Figure 3.1, for use with the preliminary screening method of Chapter 3. 

Table 2.3 gives one way for an existing facility to get started toward successfully managing chemical reactivity hazards. This assumes you already have an idea as to what chemical reactivity hazards must be addressed by the management system, such as by answering the questions in the Preliminary Screening Method of Chapter 3. 

Preliminary Screening Method for Chemical Reactivity Hazards... 

A form such as Table 3.1 can be used to document answers to the screening questions and the conclusions that are drawn. The flowchart in Figure 3.1 is an overview of how these questions are connected to determine whether a chemical reactivity hazard can be expected at your facility. 

This screening method may be used by either a single person or a group of persons. A team approach, involving several persons with different knowledge and functional perspectives, has the possibility of better identifying and assessing the potential for chemical reactivity hazards. 

Figure 3.1. Preliminary screening for chemical reactivity hazards summary flowchart.

Up to this point, the chemical reactivity hazards of individual substances, either by themselves or in contact with common environmental materials, have been considered. This last question in the chemical reactivity hazards screening will address the potential for an unintended chemical reaction due to incompatible materials contacting each other. Compatibility, in this context, means the ability of materials to exist in contact without specified (usually hazardous) consequences under a defined scenario. A scenario, in this context, is a detailed physical description of the process whereby a potential inadvertent combination of materials may occur (ASTM E 2012-00). 

If you are certain that NO incompatible materials have a reasonable likelihood of contacting each other and causing undesired consequences, then stop here. If the decision flow of Figure 3.1 has been followed, the Preliminary Screening Method indicates that no significant chemical reactivity hazards are expected at your facility. 

This chapter assumes chemical reactivity hazards exist at your facility. If you are uncertain whether or not you have any chemical reactivity hazards, the Preliminary Screening Method in Chapter 3 can be used to help identify whether chemical reactivity hazards may be present. 

The list in Table 4.2 indicates the basic chemical reactivity hazard information that needs to be known for each substance. This is an extension of the information needed for the Preliminary Screening Method of Chapter 3. The Glossary at the end of of this publication gives definitions for most of the terms used in the table. 

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