A Road Map of Transferring Batch to Continuous Pharmaceutical/fine Chemical Manufacturing: A Case Study on 3-methylpyridine N-oxide Synthesis
Abstract
Many batch-wise pharmaceutical intermediate synthesis reactions, for example, alkylpyridine N-oxide synthesis reaction, are highly exothermic with significant risk of thermal runaway leading to multiple incidents in the past. Employment of continuous reactor for exothermic pharmaceutical synthesis has the advantages of enhanced heat and mass transfer efficiency and becomes a promising alternative in lieu of traditional batch practices in recent years. However, implementation of continuous reactor is still rare in pharmaceutical industry due to challenges of selection of proper reaction conditions, development of novel reactor porotypes for different chemistry, cost effectiveness and safety assessment. A systematic roadmap approach is proposed to provide technical guidelines for transformation of batch to continuous pharmaceutical synthesis employing experimental and computational methodology. The roadmap consists of three parts, (i) identification of inherently safer and more efficient reaction conditions via reaction intensification; (ii) kinetics and thermodynamic modelling; (iii) parallel design and comparison of pressurized semi-batch reactor and tube-in-tube multi-orifice jet mixing plug flow reactor.
Identification of inherently safer and more efficient reaction conditions for semi-batch N-oxidation reaction is experimentally studied using isothermal reaction calorimetry RC1e via response surface methodology. Optimal range of catalyst amount, H₂O₂ dosing rate and reaction temperature for low reactor pressure and high N-oxide yield is found using RSM model and verified with experimental observations. It is found that N-oxidation favor intensified reaction conditions, i.e. high temperature and catalyst concentration. Under those conditions, safety and efficiency is achieved simultaneously.
Wide range of kinetics and thermodynamic data was measured using RC1e under various reaction temperatures and reaction mixture conditions for modeling complex reaction system. Reactor pressure, reaction heat generation rate and in-situ FTIR spectra of liquid phase species were recorded in real‐time during experiments, and final product was quantified using HPLC and GC– MS analytical tools. An integrated thermodynamic and kinetics model of homogeneous N‐ oxidation reaction is developed based on experimental results and past literature findings. For thermodynamic model, activity coefficient of highly non-ideal organic/aqueous system is computed using Wilson excess Gibbs model. Ideal gas law is found satisfactory to calculate incondensable oxygen pressure. For reaction kinetics model, first principle reaction mechanism and kinetics parameters of (a) catalytic N‐oxidation reaction; (b) catalytic hydrogen peroxide decomposition reaction; (c) noncatalytic N‐oxidation reaction; (d) noncatalytic hydrogen peroxide decomposition reaction was derived. Reactor pressure, species concentration and reaction enthalpy are successfully predicted using integrated kinetics and thermodynamic model. The obtained model can be used for inherently safer reactor design and applied to other homogeneous tungstic acid catalytic hydrogen peroxide oxidation processes.
Process intensification inherent safety design principle is applied for designing a novel continuous tube-in-tube jet mixing reactor in place of traditional batch and semi-batch reactors to perform the 3-methylpyridine N-oxidation reaction via hydrogen peroxide. Five most widely used turbulence models are used to predict jet mixing phenomena in the reactor. Among them, realizable k- ε with enhancement wall treatment shows good agreement with the experiments in literature. Different hydrogen peroxide feed conditions are modeled; the results show that the risk of runaway reaction is strongly affected by hydrogen peroxide dosing rate.
Citation
Wang, Jingyao (2020). A Road Map of Transferring Batch to Continuous Pharmaceutical/fine Chemical Manufacturing: A Case Study on 3-methylpyridine N-oxide Synthesis. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /191909.