Awareness of best safety practices in the industrial sector will allow students in chemistry and chemical engineering programs to apply these approaches to their own safety assessments. Process safety is a critical function within the pharmaceutical industry to ensure safety when performing reactions. An introduction to process safety and a series of case studies illustrating how safety is routinely considered within the pharmaceutical industry is presented. The concepts presented herein are applicable to multiple industries, academic research, and chemical reactions conducted on all scales. The case studies include examples where a synthesis was redesigned to afford a triazole intermediate without forming potentially explosive byproducts, an exothermic reaction was controlled by understanding the heat output with time and developing a portion-wise addition procedure, and a reaction that displayed extremely fast gas evolution was managed by using an alternative solvent and controlling the rate of reagent addition.

The use of sodium triacetoxyborohydride (STAB) as a mild and effective reagent for the reduction of imines is well characterized in the literature. For reduction products that require a nonacidic workup, but cannot tolerate a strongly basic quenching regime, the reaction mixture is typically quenched with bicarbonate solution in excess to neutralize any remaining active reagent. We recently experienced a near-miss incident in our pilot plant operation, where the drummed, aqueous waste stream from a reductive amination process generated unexpected internal pressure, resulting in significant deformation of a mild steel drum during temporary storage. This article details the incident, associated hazard evaluation investigation, and recommendation to prevent future occurrences. The root cause was determined to be the slow reaction (hence slow generation of carbon dioxide) of weekly acidic boric acid, with excess potassium bicarbonate, present in the fully quenched aqueous waste stream.

Sponge or skeletal metal catalysts (such as Raney-type hydrogenation catalysts) are ubiquitous and extensively used in large-scale industrial hydrogenation processes, including petrochemical refining, materials manufacturing, and even food chemistry. Despite the many advantages of these nonprecious metal catalysts, they are underutilized in smaller-batch organic synthesis, including pharmaceutical manufacturing processes, because of safety concerns. Here we describe a heretofore little known deactivation procedure using aqueous sodium nitrate that renders the spent catalyst safe to handle even when dry. During development of a chemoselective nitrile reduction using a sponge cobalt catalyst, we demonstrated that this procedure is much safer than other commonly employed oxidative or acidic quenching methods. This procedure should significantly improve the safety aspects of using these catalysts in myriad settings, from lab-scale synthesis to manufacturing processes for active pharmaceutical ingredients.