Efficient production of uniform nanometer‐sized polymer vesicles in stirred‐tank reactors

Polymer vesicles, so‐called polymersomes, gain more and more attention as potential carriers for medical and biotechnological applications. To put the production of these nanocompartments into action at an industrial scale, an efficient and scalable process has to be established. Moreover, being able to control the resulting particle size distribution (PSD) is vital. In this work, the amphiphilic triblock copolymer poly(2‐methyloxazoline)₁₅–poly(dimethylsiloxane)₆₈–poly(2‐methyloxazoline)₁₅ is formed into polymersomes in miniaturized stirred‐tank reactors. Varying flow conditions have a huge impact on the resulting PSD. Dynamic light scattering measurements show that driving a S‐shaped stirrer at 4000 rpm in unbaffled reactors leads to a monomodal PSD with a low polydispersity index (PDI<0.2). Vesicles with a mean diameter of 200 nm are achieved within less than 1 h in a single production step. The robustness of the established process is shown by producing uniform polymersomes at different temperatures and varying pH and buffer molarities. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43274.     

A novel dynamic membrane reactor concept with radial‐flow pattern for reacting material and axial‐flow pattern for sweeping gas in catalytic naphtha reformers

Naphtha reforming units are of high interest for hydrogen production in refineries. In this regard, the application of membrane concept in radial‐flow tubular naphtha reactors for hydrogen production is proposed. Because of the importance of the pressure drop problem in catalytic naphtha reforming units, the radial‐flow reactors are proposed. A radial‐flow tubular membrane reactor (RF‐TMR) with the radial‐flow pattern of the naphtha feed and the axial‐flow pattern of the sweeping gas is proposed as an alternative configuration for conventional axial‐flow tubular reactors (AF‐TR). The cross‐sectional area of the tubular reactor is divided into some subsections in which walls of the gaps between subsections are coated with the Pd‐Ag membrane layer. A dynamic mathematical model considering radial and axial coordinates ((r, z)‐coordinates) has been developed to investigate the performance of the new configuration. Results show ～300 and 11 kg/h increase in aromatic and hydrogen production rates in RF‐TMR compared with AF‐TR, respectively. Furthermore, smaller catalyst particles with higher efficiency can be used in RF‐TMR due to a slight pressure drop. The enhancement in aromatics (octane number) and hydrogen productions owing to applying simultaneously the membrane concept and radial‐flow pattern in naphtha reactors motivates the application of RF‐TMR in refineries. © 2011 American Institute of Chemical Engineers AIChE J, 2012     

Polymersome formation mechanism and formation rate in stirred‐tank reactors

Uniform polymersomes (polymer vesicles) made of poly(2‐methyloxazoline)₁₅‐b‐poly(dimethylsiloxane)₆₈‐b‐poly(2‐methyloxazoline)₁₅ (PMOXA15–PDMS68–PMOXA15) can be formed in miniaturized‐stirred tank reactors by the aid of a recently published process. In this study, the occurring self‐assembly mechanism was elucidated by using transmission electron microscopy. Subsequent to the initial formation of small spherical micelles and the following fusion to worm‐like micelles, two simultaneously occurring pathways, describing the transformation of further intermediate structures to the desired vesicles, were found. The resulting particle increase was followed by dynamic light scattering. Thus, the vesicle formation rate was judged by the linear increase of the particle diameter over time. While temperature showed no influence, higher initial polymer concentrations and lower final solvent concentrations accelerated the polymersome formation. Besides, the process was crucially dependent on the agitation speed. While spherical micelles did not transform into polymersomes when no stirring or too slow stirring is applied, the self‐assembly process was accelerated by increasing the agitation speed. Uniform polymeric vesicles can be formed under vigorous stirring in stirred‐tank reactors in short process times. In this study, the underlying mechanisms of vesicle formation were elucidated, showing that the polymer forms small micellar structures before undergoing two separate pathways to form the desired vesicular structures. The formation rate of the polymer vesicles was mainly dependent on the agitation speed but also on the polymer and solvent concentrations, highlighting the need for controlled formation conditions. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46077.     

A Continuous‐Flow Cascade Reactor System for Subtilisin A‐ Catalyzed Dynamic Kinetic Resolution of N‐tert‐Butyloxycarbonylphenylalanine Ethyl Thioester with Benzylamine

Alcalase® (Subtilisin A) was immobilized by simple hydrophobic adsorption onto various surface‐grafted macroporous silica gels resulting in easy‐to‐prepare and stable biocatalysts enabling the efficient kinetic resolution (KR) and dynamic kinetic resolution (DKR) of racemic N‐Boc‐phenylalanine ethyl thioester with benzylamine. The immobilized Alcalase biocatalysts, which retained their activity and selectivity when stored at 4 °C for more than a year, were tested in enzymatic aminolysis in batch and continuous‐flow KRs resulting in (S)‐N‐Boc‐phenylalanine benzylamide in high enantiomeric purity. In KR of the racemic thioester by Alcalase‐catalyzed aminolysis in a continuous‐flow reactor, the productivity (specific reaction rate, r_flow) and enantiomeric ratio (E) were studied in the 0–100 °C range. The effect of the temperature on base‐catalyzed racemization of the non‐transformed (R)‐thioester in a continuous‐flow reactor was also investigated in the 0–150 °C range. The continuous‐mode DKR of the racemic thioester in a serial cascade system of six biocatalyst‐filled columns at 50 °C for KR and five grafted silica gel‐filled columns at 150 °C for racemization resulted in the formation of the (S)‐benzylamide in 79% conversion, 8.17 g L ⁻¹ h⁻¹ volumetric productivity and 98% ee. This is the first example of a dynamic kinetic resolution of an amino acid derivative in continuous‐flow mode using an alternating cascade of packed‐bed enzyme reactors and racemization reactors kept at different temperatures.

     

3‐D Simulations of an Internal Airlift Loop Reactor using a Steady Two‐Fluid Model

Three‐dimensional (3‐D) simulations of an internal airlift loop reactor in a cylindrical reference frame are presented, which are based on a two‐fluid model with a revised k‐? turbulence model for two‐phase bubbly flow. A steady state formulation is used with the purpose of time saving for cases with superficial gas velocity values as high as 0.12 m/s. Special 3‐D treatment of the boundary conditions at the axis is undertaken to allow asymmetric gas‐liquid flow. The simulation results are compared to the experimental data on average gas holdup, average liquid velocity in the riser and the downcomer, and good agreement is observed. The turbulent dispersion in the present two‐fluid model has a strong effect on the gas holdup distribution and wall‐peaking behavior is predicted. The CFD code developed has the potential to be applied as a tool for scaling up loop reactors.     

Mixing performance comparison of milliscale continuous high‐shear mixers

Mixing performance of two continuous flow millilitre‐scale reactors (volumes 9.5 mL and 2.5 mL) equipped with rotor‐stator mixers was studied. Cumulative residence time distributions (RTD) were determined experimentally using a step response method. Distributions were measured for both reactors by varying impeller speed and feed flow rate. The mixing effect was determined by measured RTDs. Computational fluid dynamics (CFD) were used to verify that the residence time distribution in the measurement outlet agreed with the outlet flow. The mixing power of both reactors was determined using a calorimetric method. The reactor inlet flow rate was found to affect mixing performance at 1–13 s residence times but the effect of impeller speed could not be noted. Both milliscale reactors are close to an ideal continuous stirred‐tank reactor (CSTR) at the studied impeller speed and flow rate ranges. The specific interfacial area was found to depend on the reactor inlet flow rate at constant impeller speed for the case of copper solvent extraction.

     

Process kinetics of UASB reactors treating non‐inhibitory substrate

The degradation of a non‐inhibitory substrate (sucrose) in upflow anaerobic sludge bed (UASB) reactors with different superficial flow velocites (u_s) was performed to generate experimental data. Additionally, a kinetic model accounting for the mass fraction of methanogens (f) and granule size distribution in UASB reactors is also proposed. At the volumetric loadings of 2.65–21.16 g COD dm^?3 day^?1, both the COD removal efficiency and granule size of the UASB reactors increase with increasing u_s. The f values determined experimentally increase from 0.13–0.24 to 0.27–0.43 if the volumetric loading is increased from 2.65 to 5.29 g COD dm^?3 day^?1. With a further increase in volumetric loading, the f values decline because of the accumulation of volatile fatty acids (VFAs). The predicted residual concentrations of VFAs and COD are in fairly good agreement with the experimental data. From the calculated effectiveness‐factor values, the influence of mass transfer resistance of the substrate sucrose on the overall substrate removal rate should not be neglected. From parametric sensitivity analyses together with the simulated concentration profiles, methanogenesis is the rate‐limiting step. Copyright © 2003 Society of Chemical Industry     

Bioprocess scale‐up: quest for the parameters to be used as criterion to move from microreactors to lab‐scale

Advances in high‐throughput process development and optimization involve the rational use of miniaturized stirred bioreactors, instrumented shaken flasks and microtiter plates. As expected, each one provides different levels of control and monitoring, requiring a compromise between data quantity and quality. Despite recent advances, traditional shaken flasks with nominal volumes below 250 mL and microtiter plates are still widely used to assemble wide arrays of biotransformation/bioconversion data, because of their simplicity and low cost. These tools are key assets for faster process development and optimization, provided data are representative. Nonetheless, the design, development and implementation of bioprocesses can present variations depending on intrinsic characteristics of the overall process. For each particular process, an adequate and comprehensive approach has to be established, which includes pinpointing key issues required to ensure proper scale‐up. Recently, focus has been given to engineering characterization of systems in terms of mass transfer and hydrodynamics (through gaining insight into parameters such as k_La and P/V at shaken and microreactor scale), due to the widespread use of small‐scale reactors in the early developmental stages of bioconversion/biotransfomation processes. Within this review, engineering parameters used as criteria for scaling‐up fermentation/bioconversion processes are discussed. Particular focus is on the feasibility of the application of such parameters to small‐scale devices and concomitant use for scale‐up. Illustrative case studies are presented. Copyright © 2010 Society of Chemical Industry     

Liquid‐phase axial dispersion of turbulent gas–liquid co‐current flow through screen‐type static mixers

This article discusses the characteristics of turbulent gas–liquid flow through tubular reactors/contactors equipped with screen‐type static mixers from a macromixing perspective. The effect of changing the reactor configuration, and the operating conditions, were investigated by using four different screen geometries of varying mesh numbers. Residence time distribution experiments were conducted in the turbulent regime (4500 < Re < 29,000). Using a deconvolution technique, the RTD function was extracted to quantify the axial/longitudinal liquid‐phase dispersion coefficient. The findings highlight that axial dispersion increases with an increasing flow rate and/or gas‐phase volume fraction. However, regardless of the number and geometry of the mixing elements, reactor configuration, and/or operating conditions, the recorded liquid‐phase axial dispersion coefficients in the presence of screens was lower than that for an empty pipe. Furthermore, the geometry of the screen was found to directly affect the axial dispersion coefficient in the reactor. © 2016 American Institute of Chemical Engineers AIChE J, 63: 1390–1403, 2017     

Recognition and Excision Properties of 8‐Halogenated‐7‐Deaza‐2′‐Deoxyguanosine as 8‐Oxo‐2′‐Deoxyguanosine Analogues and Fpg and hOGG1 Inhibitors

Cellular DNA continuously suffers various types of damage, and unrepaired damage increases disease progression risk. 8‐Oxo‐2′‐deoxyguanine (8‐oxo‐dG) is excised by repair enzymes, and their analogues are of interest as inhibitors and as bioprobes for study of these enzymes. We have developed 8‐halogenated‐7‐deaza‐2′‐deoxyguanosine derivatives that resemble 8‐oxo‐dG in that they adopt the syn conformation. In this study, we investigated their effects on Fpg (formamidopyrimidine DNA glycosylase) and hOGG1 (human 8‐oxoguanine DNA N‐glycosylase 1). Relative to 8‐oxo‐dG, Cl‐ and Br‐deaza‐dG were good substrates for Fpg, whereas they were less efficient substrates for hOGG1. Kinetics and binding experiments indicated that, although hOGG1 effectively binds Cl‐ and Br‐deaza‐dG analogues with low K_m values, their lower k_cat values result in low glycosylase activities. The benefits of the high binding affinities and low reactivities of 8‐oxo‐dG analogues with hOGG1 have been successfully applied to the competitive inhibition of the excision of 8‐oxoguanine from duplex DNA by hOGG1.     

Mass Transfer Characteristics in a Rotor‐Stator Reactor

Mass transfer characteristics in a rotor‐stator reactor in terms of the overall volumetric mass‐transfer coefficient (K_xa) using the N₂‐H₂O‐O₂ system were investigated. The effects of various operating parameters including rotation speed, liquid volumetric flow rate, and gas volumetric flow rate on K_xa were systematically examined, and a gas‐liquid mass transfer model was established to predict K_xa. Results reveal that K_xa increased with higher rotation speed, liquid volumetric flow rate, and gas volumetric flow rate. The results also confirm that the predicted values of K_xa were in agreement with the experimental values with deviation within 15 %. The results contribute to a better understanding of mass transfer characteristics in rotor‐stator reactors.     

Computer Simulation of the Performance of a Downer‐Regenerator CFB for the Partial Oxidation of n‐Butane to Maleic Anhydride

A reactor model for a downer‐regenerator circulating fluidized‐bed (CFB) during the partial oxidation of n‐butane to maleic anhydride is presented. Upflow reactors (risers) suffer from severe solids back mixing and gas‐solids‐separation, in comparison down flow reactors exhibit a more uniform gas‐solids flow and reduced backmixing, resulting in narrower residence time distributions. Due to the sensitivity of the VPO catalyst to over‐reduction, downer reactors present an interesting alternative to riser reactors. The reactor models for the downer and the regenerator fluidized‐bed are coupled with reduction and oxidation kinetics for the catalyst, respectively. The influence of the solids residence time distributions for the combined system of both reactors on the oxidation state of the catalyst is explored by a novel newly developed oxygen loading distribution. Simulation results suggest the limited solids‐flux in downers restrict the maximum butane concentrations, while the scale‐up is predicted to be uncritical.     

Radiotracer and particle tracking methods,modeling and scale‐up

Radiotracer techniques are widely used for troubleshooting and detection of pathological flows in industrial reactors. In recent decades, there has been a trend towards using radiotracer techniques for assessing flow field in industrial vessels, likening them to residence time distribution (RTD) measurements. On the other hand, radiation‐based particle tracking techniques such as Radioactive Particle Tracking (RPT) methods have become popular for laboratory investigations flow fields in multiphase reactors. Both the methods have been used to validate respective‐scale phenomenological and CFD models to some success, but in a rather independent and ad hoc fashion and not attempting to link the two techniques as flow interrogators in their respective domains. This communication tries to bridge these two techniques and proposes a way to link the two, and makes a case for using them as complementary techniques for measurements at the two scales, and for validating models at the two scales. © 2016 American Institute of Chemical Engineers AIChE J, 63: 314–326, 2017     

Behavior of Pressure Gradient and Transient Pressure Signals during Liquid‐Liquid Two‐Phase Flow

Liquid‐liquid two‐phase flows are encountered in several process industries, multiphase reactors and oil industries. In each of these applications, identification of flow patterns poses a challenging problem and many efforts are directed towards developing suitable devices for this purpose. In the present work, attempts have been made to use pressure gradient and transient pressure signals to study flow patterns during the simultaneous flow of two liquids through a horizontal pipe. It is observed that the slope of the pressure gradient curves as a function of fluid superficial velocities is a weak function of the flow pattern. However, the variation of the slope with the pattern transition is much more significant when the pressure gradient is normalized with respect to only kerosene flow through the pipe (Δp_TP/Δp_KO). Further attempts have been made to identify flow patterns from transient pressure signals and the statistical analysis of these random signals has been undertaken. The PDF analysis and the wavelet multiresolution technique have been adapted to explain the signals in detail. The flow regimes identified are smooth stratified, wavy stratified, plug flow, ‘three‐layer' flow, ‘oil dispersed in water and water' and ‘oil and water in oil' flow patterns. The signal characteristics are depicted for each flow pattern.     

Onset of flow recirculation in vertical rotating‐disc chemical vapor deposition reactors

Preventing flow recirculation during the epitaxial deposition of thin films of compound semiconductors is essential for growing multilayer films with atomically abrupt interfaces that form a basis for modern optoelectronic devices. A mathematical model describing mass continuity, flow and heat transfer in a vertical rotating‐disc chemical vapor deposition reactor is used to investigate the onset of buoyancy‐ and inertia‐driven flow recirculation. Numerical simulations of axisymmetric flow patterns are performed and different regimes of operation are identified in the parameter space defined by the Reynolds number, the rotational Reynolds number, and the Grashof number. Design criteria for establishing recirculation‐free flows in reactors used for metalorganic vapor‐phase epitaxy (MOVPE) of compound semiconductors are presented. © 2013 American Institute of Chemical Engineers AIChE J, 59: 3530–3538, 2013     

Nitrification by immobilized cells in a micro‐ecological life support system using packed‐bed bioreactors: an engineering study

The nitrifying component of a micro‐ecological life support system alternative (MELISSA) based on microorganisms and higher plants was studied. The MELISSA system consists of an interconnected loop of bioreactors to allow the recycling of the organic wastes generated in a closed environment. Conversion of ammonia into nitrates in such a system was improved by selection of microorganisms, immobilization techniques, reactor type and operation conditions. An axenic mixed culture of Nitrosomonas europaea and Nitrobacter winogradskyi, immobilized by surface attachment on polystyrene beads, was used for nitrification in packed‐bed reactors at both bench and pilot scale. Hydrodynamics, mass transfer and nitrification capacity of the reactors were analysed. Mixing and mass transfer rate were enhanced by recirculation of the liquid phase and aeration flow‐rate, achieving a liquid flow distribution close to a well‐mixed tank and without oxygen limitation for standard operational conditions of the nitrifying unit. Ammonium conversion ranged from 95 to 100% when the oxygen concentration was maintained above 80% of saturation. The maximum surface removal rates were measured as 1.91 gN‐NH₄⁺ m^?2 day^?1 at pilot scale and 1.77 gN‐NH₄⁺ m^?2 day^?1 at bench scale. Successful scale‐up of a packed‐bed bioreactor has been carried out. Good stability and reproducibility were observed for more than 400 days. Copyright © 2004 Society of Chemical Industry     

A CFD‐PBM‐PMLM integrated model for the gas–solid flow fields in fluidized bed polymerization reactors

Although the use of computational fluid dynamics (CFD) model coupled with population balance (CFD‐PBM) is becoming a common approach for simulating gas–solid flows in polydisperse fluidized bed polymerization reactors, a number of issues still remain. One major issue is the absence of modeling the growth of a single polymeric particle. In this work a polymeric multilayer model (PMLM) was applied to describe the growth of a single particle under the intraparticle transfer limitations. The PMLM was solved together with a PBM (i.e. PBM‐PMLM) to predict the dynamic evolution of particle size distribution (PSD). In addition, a CFD model based on the Eulerian‐Eulerian two‐fluid model, coupled with PBM‐PMLM (CFD‐PBM‐PMLM), has been implemented to describe the gas–solid flow field in fluidized bed polymerization reactors. The CFD‐PBM‐PMLM model has been validated by comparing simulation results with some classical experimental data. Five cases including fluid dynamics coupled purely continuous PSD, pure particle growth, pure particle aggregation, pure particle breakage, and flow dynamics coupled with all the above factors were carried out to examine the model. The results showed that the CFD‐PBM‐PMLM model describes well the behavior of the gas–solid flow fields in polydisperse fluidized bed polymerization reactors. The results also showed that the intraparticle mass transfer limitation is an important factor in affecting the reactor flow fields. © 2011 American Institute of Chemical Engineers AIChE J, 58: 1717–1732, 2012     

Operating Characteristics and Performance of a Monolithic Downflow Bubble Column Reactor in Selective Hydrogenation of Butyne‐1,4‐diol

The effects of flow condition, bubble dispersion level, and liquid flow rate on the behavior of a novel monolithic downflow bubble column (M‐DBC) were investigated using a reaction model, the palladium‐catalyzed hydrogenation of butyne‐1,4‐diol. The stable and closely packed homogeneous bubble dispersion present in the bulk region of the M‐DBC allowed effective introduction of the gas‐liquid phase for formation of Taylor flow inside the monolith channels. The condition defined as the minimum level dispersion was required in order to obtain high selectivity towards the intermediate product, cis‐2‐butene‐1,4‐diol. Enhanced reaction rates were obtained at increasing the dispersion level and lowering the liquid flow rate. Comparison with the DBC employing 5 % Pd/C powder catalyst and 1 % Pd‐on‐Raschig‐ring revealed a better performance of the M‐DBC (1 % Pd loading) with the advantage of smaller reaction volume and intensified reaction rate. As an alternative to conventional three‐phase reactors, the M‐DBC was so simple due to its inherent characteristic operation and no specially designed device is required.     

Application of chitosan‐entrapped β‐galactosidase in a packed‐bed reactor system

The model enzyme β‐galactosidase was entrapped in chitosan gel beads and tested for hydrolytic activity and its potential for application in a packed‐bed reactor. The chitosan beads had an enzyme entrapment efficiency of 59% and retained 56% of the enzyme activity of the free enzyme. The Michaelis constant (K_m) was 0.0086 and 0.011 μmol/mL for the free and immobilized enzymes, respectively. The maximum velocity of the reaction (V_max) was 285.7 and 55.25 μmol mL^?1 min^?1 for the free and immobilized enzymes, respectively. In pH stability tests, the immobilized enzyme exhibited a greater range of pH stability and shifted to include a more acidic pH optimum, compared to that of the free enzyme. A 2.54 × 16.51‐cm tubular reactor was constructed to hold 300 mL of chitosan‐immobilized enzyme. A full‐factorial test design was implemented to test the effect of substrate flow (20 and 100 mL/min), concentration (0.0015 and 0.003M), and repeated use of the test bed on efficiency of the system. Parameters were analyzed using repeated‐measures analysis of variance. Flow (p < 0.05) and concentration (p < 0.05) significantly affected substrate conversion, as did the interaction progressing from Run 1 to Run 2 on a bed (p < 0.05). Reactor stability tests indicated that the packed‐bed reactor continued to convert substrate for more than 12 h with a minimal reduction in conversion efficiency. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 1294–1299, 2004     

Fullerene‐Promoted Singlet‐Oxygen Photochemical Oxygenations in Glass‐Polymer Microstructured Reactors

In this paper we report the fabrication of thiolene‐based microstructured reactors (MRs) that have been specifically designed to include solid‐supported reagents within the microchannels network. We propose a convenient solution to realize reversible press‐fit, leak‐proof interconnects that greatly simplify the MR coupling to the external environment such as capillary tubing, sample reservoirs and pumps. The MRs have been used to carry out the oxidation of α‐terpinene and methionine using [60]fullerene, covalently linked to Tentagel^® and silica gel matrices, as a singlet oxygen sensitizer. High conversions have been observed for both substrates although, in the case of α‐terpinene, a partial photodegradation of the endo‐peroxide product was detected. Interestingly, in the case of methionine, a quantitative conversion to the corresponding sulfoxides was achieved in about 40 seconds, using low‐power, white LED illumination. The reaction time is considerably shorter when compared to the batch procedure that requires, for the same process, about one hour illumination and the use of a 300‐W tungsten halogen lamp.