Experimental Limiting Oxygen Concentrations for Nine Organic Solvents at Temperatures and Pressures Relevant to Aerobic Oxidations in the Pharmaceutical Industry

Abstract

Applications of aerobic oxidation methods in pharmaceutical manufacturing are limited, in part, because mixtures of oxygen gas and organic solvents often create the potential for a flammable atmosphere. To address this issue, limiting oxygen concentration (LOC) values, which define the minimum partial pressure of oxygen that supports a combustible mixture, have been measured for nine commonly used organic solvents at elevated temperature and pressure. The solvents include acetic acid, N-methyl pyrrolidone, dimethyl sulfoxide, t-amyl alcohol, ethyl acetate, 2-methyltetrahydrofuran, methanol, acetonitrile, and toluene. The data obtained from these studies help define safe operating conditions for the use of oxygen with organic solvents.

Liquid phase oxidation chemistry in continuous-flow microreactors

“…For example, it is necessary to continuously refresh the gas mixture in bubble columns to reach full conversion. 120 The power of an explosion is proportional to the mass of the explosive mixture with the power of 1/3. 121, 122 This relation immediately explains why microreactors are safe to use when employing hazardous reaction conditions.…”

Organic oxidations promoted in vortex driven thin films under continuous flow

“…11,12 Because the terminal product of aerobic oxidations is typically innocuous water, oxygen is commonly considered to be a desirable and benign reagent. 30 Its green chemistry credentials notwithstanding, oxygen (as a gas) is often difficult to handle and can present risks for fire when used with organic substrates and flammable solvents. 31,32 These risks are exacerbated at elevated temperatures and pressuresconditions that also introduce an energy penalty to the process.…”

Scalable thin-layer membrane reactor for heterogeneous and homogeneous catalytic gas–liquid reactions

“…5 However, concerns of process efficiency, scalability, and safety of gas-liquid systems create barriers for pharmaceutical applications and this becomes even more challenging when heterogeneous catalysts are present in gas-liquid systems. 1,6 Over the past decade, continuous flow technology has emerged as a powerful technique to produce active pharmaceutical ingredients (APIs) driven by advantages of continuous technology over conventional batch or semi-batch processes, including steady state operation, enhanced heat and mass transfer rates, reproducibility, and improved safety and process reliability. [7][8][9][10][11][12] These benefits are especially true for gas-liquid reaction systems, where the absence of high-pressure headspace gas and reduced reactor volume of continuous flow reactors significantly improve the safety profiles compared to highpressure reaction vessels.…”

“…Additionally, direct contact of gas and liquid is unfavorable for aerobic oxidations due to the formation of flammable oxidant and organic solvent mixtures. 6 The low cross-tube heat transfer of packed-bed reactors can also lead to a non-uniform temperature profile for highly exothermic reactions, leaving APIs with temperature-sensitive functional groups at risk for degradation.…”