Phase Equilibrium Studies on N-Oxidation Systems to Determine Homogeneous Mixture Conditions
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Date
2018-10-24
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Abstract
The N-oxidation of alkylpyridines is used in the pharmaceutical industries to synthesize alkylpyridine N-oxides that are involved in the production of analgesic and anti-inflammatory drugs. The synthesis process involves continuous addition of aqueous hydrogen peroxide (35% w/w) solution to a mixture of alkylpyridine and phosphotungstic acid catalyst. The oxidation is accompanied by undesired decomposition of hydrogen peroxide, which produces large amounts of oxygen and water vapor. This reaction introduces a series of hazards during the operation including the potential to over pressurize an improperly vented reactor and generation of an oxygen-rich atmosphere in an alkyl pyridine flammable environment. The decomposition is accelerated during the N-oxidation of higher order alkylpyridines (lutidines, collidines) due to mass transfer limitations caused by the separation of the liquid into organic and aqueous phase. Also, the presence of phosphotungstic acid (catalyst) in the aqueous phase further intensifies the peroxide decomposition reducing the safety and efficiency of the process. It is thus essential to identify homogeneous reaction conditions and operate the reactor in a regime where phase separation is prevented.
The immiscibility between the alkylpyridine and water is primarily responsible for the liquid phase heterogeneity during the N-oxidation. The current work addresses this research gap by investigating the influence of the alkylpyridine N-oxide on the phase separation since the N-oxide is known for its increased reactivity. Experimental and theoretical studies were conducted on 2,6-lutidine/2,6-lutidineN-oxide/water mixtures at different temperatures. The phase equilibrium experiments were conducted at 110 °C in lab-scale calorimeters wherein the ternary mixtures were analyzed with the help of in-situ FTIR spectroscopy. It was found that the extent of heterogeneity between 2,6-lutidine and water is reduced dramatically by the presence of 2,6-lutidine-N-oxide as indicated by the phase diagram.
In order to support the experimental work, the UNIQUAC thermodynamic model was used to estimate the biphasic compositions and predict the LLE curve for the ternary mixture. The energy parameters used in the equations, which describe the intermolecular interactions were calculated based on molecular dynamics simulations. Apart from this, the molecular parameters for N-oxide were obtained by following a quantum mechanical approach, which utilized a surface building algorithm for constructing the molecular surface. The results predicted by the model provide a satisfactory representation of the experimental data at T = 110 °C. In addition to this, the influence of temperature on the phase behavior was studied by generating phase equilibrium data at T = 100 and 125 °C.
The findings from this research study can be used to implement the inherent safety concept – “Hybridization” to the N-oxidation system wherein the concentration of product N-oxide can be controlled to maintain a less hazardous environment.
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Ab initio methods, Molecular Simulations, Phase diagrams, Monte Carlo, Inherent safety, Hybridization