Plantwide design and economic evaluation of two Continuous Pharmaceutical Manufacturing (CPM) cases: Ibuprofen and artemisinin

Increasing Research and Development (R&D) costs, growing competition from generic manufacturers and dwindling market introduction rates for novel drug products bolster the efforts of pharmaceutical firms to secure competitiveness by investigating Continuous Pharmaceutical Manufacturing (CPM). The present paper explores the CPM of two key Active Pharmaceutical Ingredients (APIs), ibuprofen and artemisinin: cost savings and material efficiency benefits are evaluated for CPM vs. batch processing, with two continuous options for each API. Capital Expenditure (CapEx) savings of up to 57.0% and 19.6% and corresponding Operating Expenditure (OpEx) savings of up to 51.6% and 29.3% have been determined for ibuprofen and artemisinin, respectively. Total projected cost savings for a 20-year plant lifetime can reach 54.5% and 20.1%, respectively. Environmental (E)-factors (mass of waste generated per unit mass of product) of 43.4 (for ibuprofen) and 12.2 (for artemisinin) have been computed, indicating environmental and material efficiency advantages for these conceptual continuous pharmaceutical processes.     

Globally optimal reactor network synthesis via the combination of linear programming and stochastic optimization approach

Reactor network synthesis based on superstructure optimization is often a complex non-linear programming problem (NLP), which is very difficult to solve by means of the traditional optimization approaches. To solve this problem, a double-level new optimization method which combines linear programming and stochastic optimization approach is proposed in this paper. In addition, a superstructure network that includes continuous stirred-tank reactor (CSTR) and plug flow reactor (PFR) which is approximated as a series of CSTRs is constructed. By the proposed method and the superstructure network, the NLP is divided into a linear programming in flow rate and reactor volume space, and a stochastic optimization problem in concentration space. We solve two cases to illustrate the feasibility of the proposed method. The results show that this new optimization method can reduce the scales and difficulties of the problem and give more suitable structure of the reactor network, as well as better reactor size than those reported in the literature.     

Microwave assisted flow synthesis: Coupling of electromagnetic and hydrodynamic phenomena

This article describes the results of a modeling study performed to understand the microwave heating process in continuous‐flow reactors. It demonstrates the influence of liquid velocity profiles on temperature and microwave energy dissipation in a microwave integrated milli reactor‐heat exchanger. Horizontal cocurrent flow of a strong microwave absorbing reaction mixture (ethanol + acetic acid, molar ratio 5:1) and a microwave transparent coolant (toluene) was established in a Teflon supported quartz tube (i.d.: 3 × 10^?3 m and o.d.: 4 × 10^?3 m) and shell (i.d.: 7 × 10^?3 m and o.d.: 9 × 10^?3 m), respectively. Modeling showed that the temperature rise of the highly microwave absorbing reaction mixture was up to four times higher in the almost stagnant liquid at the reactor walls than in the bulk liquid. The coolant flow was ineffective in controlling the outlet reaction mixture temperature. However, at high flow rates it limits the overheating of the stagnant liquid film of the reaction mixture at the reactor walls. It was also found that the stagnant layer around a fiber optic temperature probe, when inserted from the direction of the flow, resulted in much higher temperatures than the bulk liquid. This was not the case when the probe was inserted from the opposite direction. The experimental validations of these modeling results proved that the temperature profiles depend more on the reaction mixture velocity profiles than on the microwave energy dissipation/electric field intensity. Thus, in flow synthesis, particularly where a focused microwave field is applied over a small tubular flow reactor, it is very important to understand the large (direct/indirect) influence of reactor internals on the microwave heating process. © 2014 American Institute of Chemical Engineers AIChE J, 60: 3824–3832, 2014     

Continuous lipase‐catalyzed synthesis of hexyl laurate in a packed‐bed reactor: optimization of the reaction conditions in a solvent‐free system

BACKGROUND: Hexyl laurate has been applied widely in cosmetic industries and is synthesized by chemical methods with problems of cost, environmental pollution, and by‐products. In this study, Lipozyme^® IM77 (from Rhizomucor miehei) was used to catalyze the direct‐esterification of hexanol and lauric acid in a solvent‐free system by utilizing a continuous packed‐bed reactor, wherein the aforementioned difficulties could be overcome. Response surface methodology (RSM) and three‐level‐three‐factor Box‐Behnken design were employed to evaluate the effects of synthesis parameters, such as reaction temperature (45–65 °C), mixture flow rate (0.25–0.75 mL min^?1) and concentration of lauric acid (100–300 mmol L^?1) on the production rate (µmol min^?1) of hexyl laurate by direct esterification. RESULTS: The production rate was affected significantly by the mixture flow rate and lauric acid concentration. On the basis of ridge‐max analysis, the optimum synthesis conditions for hexyl laurate were as follows: 81.58 ± 1.76 µmol min^?1 at 55 °C, 0.5 mL min^?1 flow rate and 0.3 mol L^?1 lauric acid. CONCLUSION: The lipase‐catalyzed synthesis of hexyl laurate by Lipozyme^® IM‐77 in a continuous packed‐bed bioreactor and solvent‐free system was successfully developed; optimization of the reaction parameters was obtained by Box–Behnken design and RSM. Copyright © 2008 Society of Chemical Industry     

Whole Cell Biotransformation of 5-(4-(2-(2-Pyridyl)methylamino)ethoxy)benzylidenethiazolidine-2,4-dione to its Benzyl Derivative Using a Yeast Reductase

Whole yeast cell reductive biotransformation of a benzylidene thiazolidinedione to its corresponding benzyl derivative has been scaled up from laboratory to small pilot plant scale. The fermentation conditions for the yeast Rhodotorula rubra were examined and cell titres increased by optimising the medium. Problems encountered in handling substrates of low water solubility are discussed. Various techniques are described for adapting the procedure for process scale operation using the general principles of process scale-up and integration. Liquid–liquid extraction using a dense solvent was performed on whole broth systems using a continuous flow liquid–liquid separator. Fatty acid impurities were removed using selective solvent extraction. © 1997 SCI.     

Hydrodynamics of slurry bubble column during dimethyl ether (DME) synthesis: Gas-liquid recirculation model and radioactive tracer studies

Radioactive tracer measurements, using impulse injections of Ar⁴¹, powdered oxide of Mn⁵⁶ and real catalyst particles doped with an oxide of Mn⁵⁶, conducted at the Advance Fuels Development Unit (AFDU) slurry bubble column (BC) reactor during dimethyl ether (DME) synthesis (reactor pressure of 5.27 MPa, reactor temperature of , inlet superficial gas velocity of 17.1 cm/s, and a catalyst loading of 36 wt%) at LaPorte, Texas, are interpreted. The differences in the responses obtained by the catalyst and fine powdered Mn₂O₃ tracer injections are minimal indicating the validity of the pseudo-homogeneous assumption for the liquid plus solid (catalyst) phase mixtures. The gas-liquid recirculation model [Gupta et al., 2001a. Comparison of single- and two-bubble class gas-liquid recirculation models—application to pilot-plant radioactive tracer studies during methanol synthesis. Chemical Engineering Science 56(3), 1117-1125. 2001b. Hydrodynamics of churn turbulent bubble columns: gas-liquid recirculation and mechanistic modeling. Catalysis Today 64(3-4), 253-269], based on a constant bubble size, describing gas-liquid mass transfer superimposed on turbulent mixing of the gas and liquid phases, is used to simulate the gas, liquid and catalyst tracer responses acquired at the AFDU. The model is able to predict the characteristic features of the experimental responses observed for gas, slurry powder and catalyst tracers at different reactor elevations. The fact, that the same model was previously shown capable of predicting both gas and liquid radioactive tracer responses during methanol and Fischer-Tropsch (FT) synthesis, indicates that this model offers a relatively simple tool for assessing mixing and transport in bubble (BCs) for a variety of gas conversion processes and provides a phenomenologically based framework for BC reactor modeling.     

Synthesis of reactor networks in overall process flowsheets within the multilevel MINLP approach

This paper presents the superstructure-based mixed-integer non-linear programming approach to the synthesis of reactor networks in an equation-oriented environment. The model comprises a general superstructure in which the exact formulation of the recycle reactor (RR) and a continuous stirring tank reactor (CSTR) are embedded so as to enable a different feeding (cross flow, side stream), recycling and bypassing. The reactor arrangement is capable of representing several reactor systems such as a pure CSTR, a pure plug flow reactor, pure RR, their combinations and also a cross flow reactor. The superstructure is suitable either for an isothermal or non-isothermal, simple or complex reactor network. With the multilevel-hierarchical strategy, it is possible to postulate the superstructure at different levels of representation of flowsheet alternatives. Therefore, the superstructure is optimized more effectively and reliably. The approach has been applied to a complex non-isothermal reaction problem — an industrial example of the production of allyl chloride.     

Effect of shear stress on the growth of continuous culture of Synechocystis PCC 6803 in a flat-panel photobioreactor

The effect of hydrodynamic forces generated by air bubbles on cell growth of continuous culture of Synechocystis PCC 6803 was studied in a flat-panel photobioreactor. Keeping all relevant parameters constant enables the optimization of individual parameters, for which a continuous cultivation approach has significant advantages. Continuous culture of Synechocystis PCC 6803 was cultivated under different gas velocities from 0.022 m s^?1 up to 0.128 m s^?1. Based on direct determination of effective growth rate at constant cell densities, cell damage due to shear stress induced by the increasing gas velocity at the sparger was directly observed. A significant decrease of effective growth rate was observed at gas velocity of 0.085 m s^?1 generated at the gas flow rate of 200 ml min^?1, indicating cell damage by shear stress. Optimization of gas volume and the development of an effective aeration system corresponding to a given reactor setup is important to realize a reliable cell growth.     

Inter- and Intra-Community Variability in Continuous Coarse Particulate Matter (PM10-2.5) Concentrations in the Los Angeles Area

Continuous coarse particulate matter (CPM, PM _10?2.5 ) concentrations were measured hourly at three different sites in the Los Angeles area from April 2008 through May 2009 as part of a larger study of the characteristics and toxicology of CPM. Mean hourly concentrations calculated seasonally ranged from less than 5 μg m ^–3 to near 70 μg m ^–3 at the three sites depending upon the CPM source variability and prevailing meteorology. Different diurnal concentration profiles were observed at each site. Correlation analysis indicates that CPM concentrations can generally be explained by wind-induced road dust re-suspension, particularly in drier seasons. CPM concentrations between the sites were not appreciably correlated and metrics used to assess variability between the sites—the coefficients of divergence—indicated that CPM concentrations were heterogeneous. The relative CPM contribution to observed PM ₁₀ concentrations varied by season and between sites. Additional concurrent CPM data available within a few km of the three sites indicate that intra-community variability can be on the same order as that observed for inter-community variability, although a similar analysis using PM ₁₀ data yielded reduced heterogeneity. The results indicate that accurate exposure assessment to CPM in the Los Angeles area requires measurements of CPM concentrations at different sites with higher temporal resolution than a single daily mean value.     

Kinetics of the Syntheses of Mesityl Oxide (MO) and Methyl Isobutyl Ketone (MIBK) in a Fixed-Bed Flow Reactor (FBR)

Nb₂O₅/SiO₂ and Pd/Nb₂O₅/SiO₂ catalysts were studied for the liquid phase syntheses of mesityl oxide (MO) and methyl isobutyl ketone (MIBK) in a fixed bed flow reactor (FBR). Catalyst activities as high as 1.7 g/h g_cat and selectivities ranging from 93.4 to 100% for MO synthesis were observed. The catalyst activity was found to be a strong function of space velocity likely due to product inhibition. A synergistic effect was observed whereby the catalyst activity for all organic products increased by 22% and the MIBK productivity increased by 20% at 160 °C and WHSV = 8.6 h^?1 from the introduction of hydrogen to the reactor. However, the MIBK selectivity was constrained to less than 83.5% due to competing reactions.     

Intensified and safe ozonolysis of fatty acid methyl esters in liquid CO2 in a continuous reactor

We demonstrate a continuous reactor for performing the ozonolysis of fatty acid methyl esters (FAMEs) using liquid CO₂ as solvent. The fast reaction kinetics allows the use of small‐volume reactors to completely convert the FAMEs, forming secondary ozonides as the primary products. The short residence times also help maximize the yields of the secondary ozonides by minimizing over‐oxidation and the formation of oligomeric products. The liquid CO₂ medium promotes safe reactor operation by providing an essential fraction of overall reactor cooling and by diluting the vapor phase organics. We also demonstrate a continuous stirred reactor for the safe thermal decomposition of the secondary ozonides to their corresponding acids and aldehydes. Using a lumped kinetic model for the thermal decomposition of the ozonolysis products, we estimate activation energy values of 108.6 ± 0.6 kJ mol^?1 for the decomposition of secondary ozonides and 122 ± 3 kJ mol^?1 for the decomposition of the undesired oligomeric species. © 2017 American Institute of Chemical Engineers AIChE J, 63: 2819–2826, 2017     

Characterization and optimization of an oscillatory baffled reactor (OBR) for ozone-water mass transfer

Ozone-water mass transfer was investigated using an oscillatory baffled reactor (OBR) operated as a semi-batch and as a co-current up flow continuous reactor. The effects of input ozone concentration, input gas and water flow rates, and oscillation conditions on gas hold up, volumetric mass transfer coefficient and mass transfer efficiency were determined. The same reactor was operated as a baffled column (without oscillation) and as a bubble column to assess the effect of the reactor arrangement on the mass transfer. The results show that the OBR was 5 and 3 times more efficient for ozone-water mass transfer than the baffled and bubble columns, respectively. The enhancement obtained with OBR over the baffled column reactor was found to decrease with gas flow rate due to changes in bubble flow pattern from homogenous to heterogeneous. Under continuous flow conditions, the performance of the baffled reactor and the OBR were found to be twice efficient for ozone-water mass transfer than when operating under semi-batch conditions. The mass transfer effeciency (MTE) was found to increase from 57% using the baffled reactor to 92% with OBR under continuous flow at water and gas superficial velocities of 0.3 and 3.4 cm s⁻¹, respectively.     

Optimal flowsheet configuration of a polymerization process with embedded molecular weight distributions

We consider the optimal reactor network synthesis of a polymerization process with detailed molecular weight distributions (MWDs). Based on an industrial high‐density polyethylene (HDPE) slurry process model including an embedded MWD, a fully connected process superstructure of continuous stirred tank reactors (CSTRs) is established through the introduction of splitters. Using this generalized superstructure as a basis, two nonlinear programming (NLP) problem formulations, which simultaneously maximize the monomer conversion and minimize the deviation between the calculated and target MWDs, are developed by applying multiobjective optimization (MO) methods. Different optimal flowsheet configurations are generated by systematically manipulating a set of continuous decision variables. Several case studies that consider different specifications on MWD are conducted to illustrate the effectiveness and efficiency of the proposed synthesis approach. Numerical results show that the optimal flowsheet configurations overcome the limitations of conventional reactor network structures and help to increase reactor productivity at the desired product quality. © 2015 American Institute of Chemical Engineers AIChE J, 62: 131–145, 2016     

Fischer–Tropsch synthesis in slurry-phase reactors over Mn- and Zr-modified Co/SiO2 catalysts

Fischer–Tropsch (F–T) synthesis was carried out in a gas-flowed slurry-phase reaction system over Mn- and Zr-modified Co/SiO₂ catalysts. A 0.5 L stirred tank slurry reactor (STSR) was used for catalyst screening and a 12.5 L slurry bubble column reactor (SBCR) was used for trial pilot operation. While using the 0.5 L reactor for catalyst screening, Co supported on the SiO₂ with an average pore size of 10 nm showed a high catalytic performance for the F–T synthesis due to the suitable Co particle size in the catalyst. Zr promoter improved the activity and Mn promoter improved the stability of Co/SiO₂ catalyst for the F–T synthesis. H₂-TPR profiles indicated that Zr and Mn promoters improved the reduction degree of Co₃O₄ particles (on SiO₂ surface) to Co⁰ active species in H₂ flow at low temperature. While using the 12.5 L reactor for trial pilot operation over Mn–Zr–Co/SiO₂ catalyst, the space-time yield (STY) of C₅₊ hydrocarbons (liquid fuel) showed almost the same values when various solvents (n-C₁₆H₃₄, n-C₁₄H₃₀, diesel from petrol station, F–T crude oil) were used. Diesel and F–T crude oil are suitable for using in a large-scaled F–T synthesis plant owing to the low prices. Mn–Zr–Co/SiO₂ catalyst achieved a STY of C₅₊ hydrocarbons larger than 1000 g-C₅₊ kg-cat^? 1 h^? 1 in the 12.5 L reactor. The production capacity of liquid fuel from the 12.5 L reactor reached to 15.6 L per day (assumed for 24 h continuous operation). The stirring was very important for the F–T synthesis both reaction in the 0.5 L reactor and reaction in the 12.5 L reactor. The shape of slurry reactor also influenced the CO conversion for the F–T synthesis: reaction in the 12.5 L SBCR gave a higher CO conversion than that of reaction in the 0.5 L STSR (at the same W/F value under the same stirring speed) because the slender column reactor (SBCR) extended the residue time of reaction gas in the slurry-phase containing catalyst.     

Progress in the research and development of p-xylene liquid phase oxidation process

The process of p-xylene liquid phase oxidation to produce purified terephthalic acid (PTA) involves a series of liquid phase radical reactions, chemical absorption, reactive crystallization, and evaporation. A commercial PTA production flow sheet includes a number of unit operations, which construct a complex process system. In this paper, a review of research and development (R&D) works on PTA process carried out in Zhejiang University during recent years is introduced. The works cover the oxidation and crystallization kinetics, gas-liquid mass transfer and evaporation, reactor modeling, database development, novel reactor design, process modeling, simulation, and optimization. The author emphasizes the viewpoint through this case study that chemical reaction engineering should be developed to process system engineering to extend its scope, and particular attention should be paid on reactor and process modeling.     

Superstructure optimization of integrated fast pyrolysis‐gasification for production of liquid fuels and propylene

Motivated by the apparent advantages of fast pyrolysis and gasification, a novel integrated biorefinery plant is systematically synthesized for coproducing premium quality liquid fuels and propylene. The required heat and fluidization promotion of the fast pyrolyzer are provided by hot syngas from the gasifier. Light gas and syngas from the fast pyrolyzer are finally converted to hydrocarbons via Fischer‐Tropsch synthesis. Multiple syngas production technologies, hydrocarbon production and downstream upgrading routes are incorporated within a superstructure optimization based process synthesis framework. This is the first article to investigate the benefits associated with the introduction of conventional catalytic cracking and dewaxing from a systems engineering perspective. Surrogate models describing the gasifiers and rigorous equations for Fischer‐Tropsch effluents validated by our experimental collaborator are introduced. Through investigation of five scenarios the primary parameters affecting overall economic performance are identified through ranking of the relevant candidates. Comparisons of the hybrid conversion route and stand‐alone routes are made. © 2016 American Institute of Chemical Engineers AIChE J, 62: 3155–3176, 2016     

Cultivation of spirulina maxima in an annular photochemical reactor

An 8-L annular photochemical reactor has been designed and built for the cultivation of micro- or semi-microalgae at the laboratory scale. It may be operated in batch or continuous mode and is controlled for pH, temperature, gas mixture ratio (CO₂ and air), flow rate, light intensity and also illumination type (daylight or plant growth light) and mode (continuous or intermittent). It behaves as a perfect mixed reactor for all concentrations of algal cells. The reactor was used for the cultivation of the blue-green alga Spirulina maxima in a synthetic medium in both batch and continuous operations. At the dilution rate of 0.24 day^?1, the optimal productivity was 0.91 g/L-day for biomass or 0.55 g/L-day for protein. This is equivalent to 14.5 g/m²-day for biomass or 8.7 g/m²-day for protein. The optimal productivity as well as the chemical composition of the algal biomass were comparable to results obtained from pilot plant studies and reported in the current literature.     

Toward a Continuous‐Flow Synthesis of Boscalid®

A two‐step continuous‐flow protocol for the synthesis of 2‐amino‐4′‐chlorobiphenyl, a key intermediate for the industrial preparation of the fungicide Boscalid^® is described. Initial tetrakis(triphenylphosphine)palladium‐catalyzed high‐temperature Suzuki–Miyaura cross‐coupling of 1‐chloro‐2‐nitrobenzene with 4‐chlorophenylboronic acid in a microtubular flow reactor at 160 °C using the tert‐butanol/water/potassium tert‐butoxide solvent/base system provides 4′‐chloro‐2‐nitrobiphenyl in high yield. After in‐line scavenging of palladium metal with the aid of a thiourea‐based resin, subsequent heterogeneous catalytic hydrogenation is performed over platinum‐on‐charcoal in a dedicated continuous‐flow hydrogenation device. The overall two‐step homogeneous/heterogeneous catalytic process can be performed in a single operation providing the desired 2‐amino‐4′‐chlorobiphenyl in good overall yield and high selectivity.     

The effects of dilution rate and glucose concentration on continuous acetone–butanol–ethanol fermentation by Clostridium acetobutylicum immobilized on bricks

BACKGROUND: Owing to the rapid depletion of petroleum fuel, the production of butanol through biological routes has attracted increasing attention. However, low butanol productivity severely impedes its potential industrial production. It is known that the immobilization of whole cells can enhance productivity in the acetone‐butanol‐ethanol (ABE) continuous fermentation process. Therefore, the objective of this study was to develop a low‐cost continuous operation for butanol production. RESULTS: Bricks were chosen as cell support because of their low cost and ease of use for immobilization. The solvent productivity for the bricks with immobilized cells was 0.7 g L^?1 h^?1, 1.89 times that of free cells (0.37 g L^?1 h^?1) at a dilution rate of 0.054 h^?1. The productivity improvement can contribute to greater retention of biomass inside the reactor due to immobilization. The increase in glucose feed concentration raised total solvent production. However, it resulted in a decrease in yield (grams of solvents produced per gram of glucose introduced). Continuous operation with immobilized cells at a dilution rate of 0.107 h^?1 resulted in a solvent productivity of 1.21 g L^?1 h^?1, 2.1 times that of the operation at 0.027 h^?1. However, the yield (butanol produced per glucose consumed) was decreased to 0.19 from 0.29 under the same glucose feeding condition of 60 g L^?1. CONCLUSION: The increase in dilution rate and feed glucose concentration enhanced productivity, but decreased the utilization of substrates and the final solvent concentration. Therefore, a balance between productivity and glucose utilization is required to ensure continuous process operation. Copyright © 2011 Society of Chemical Industry     

Study of the Characteristics of Methanol Synthesis in a Recirculation Slurry Reactor – A Novel Three‐Phase Synthesis Reactor

A process feasibility analysis on the liquid phase methanol synthesis (LPMeOH^TM) process was performed in a recirculation slurry reactor (RSR). In the three‐phase RSR system, a fine catalyst is slurried in the paraffin and this catalyst slurry is continuously recirculated through the nozzle from the slurry sector to the entrained sector by a pump. The syngas is fed concurrently with the downward flow of slurry to form the methanol product. A laboratory scale mini‐pilot plant version of a recirculation slurry reactor system was successfully designed and built to carry out process engineering research, and in addition, an identical cold model was built to measure the mass transfer coefficient in the recirculation slurry reactor. The effects of operating conditions, including temperature, pressure, gas flow rate and catalyst slurry recirculation flow rate on the productivity of methanol were studied. This experimental data helps the scale‐up and commercialization of the methanol synthesis process in recirculation slurry reactors.