Process intensification (PI) is a design framework which aims to create smaller, safer and more efficient processes. There have been many reviews on process intensification and attempts to define it since its inception over 20 years ago. Process intensification approaches often involve the reduction in the size of the process units to increase heat and mass transfer rates and, in multiphase processes, to manipulate and control the flow patterns and increase the interfacial areas.

The benefits of operating in small scale units stem from the thin fluidic films and the decreased diffusion distances, which increase the heat and mass transfer rates resulting in homogeneous concentration and temperature fields. Residence times can be shortened, thus avoiding side reactions, increasing selectivity and reducing waste. The decrease in length scales also increases the importance of surface or interfacial forces over inertial, viscous and gravitational ones; as a result, flow patterns in two-phase systems tend to be regular. Channel walls with different wettabilities can be fabricated to separate two-phase mixtures or impose certain patterns in the channels. The large interfacial area-to-volume ratios benefit mass transfer, while the large channel surface-to-volume ratios improve heat transfer. Flows are laminar in many cases and, combined with the regular flow patterns, can be modelled more easily. The small volumes reduce the risks of handling hazardous materials, while accidents are better contained. Intensification is often linked to continuous flow processing. The homogeneous conditions in channels facilitate monitoring and allow modularity where the process steps are separated by controlling, for example, the temperature or the addition of reactants along the channel.

Processes involving two immiscible liquids are widespread industrially and intensification has already been shown to benefit emulsifications (1–3) and reactions including hydrogen peroxide oxidations and (trans-)esterifications (4, 5). Among two-phase liquid processes, extractions are commonly used for the separation of materials in, among others, the pharmaceutical (proteins, antibiotics in aqueous two-phase systems), energy (uranium in nuclear spent fuel reprocessing; carbon dioxide or hydrogen sulfide removal) and mining (copper and precious metals) sectors (6, 7). Industrially, extractions are carried out in mixer settler units or pulsed columns which suffer from inhomogeneous and not well-characterised flow fields and large inventories. Intensified approaches have already been applied in the extraction of bio-based chemical precursors (8, 9), transition metals (10) including platinum group metals (11), lanthanides (12, 13) and actinides (14, 15), acetone in toluene-water systems (16–18). Because of the improved efficiency and reduced volumes of the small units, the amount of solvent required is reduced; this paves the way for the use of novel, efficient but sometimes expensive solvents (such as ionic liquids). In addition, external fields such as centrifugal, magnetic and ultrasonic can easily be applied to improve mixing, separation or reaction rates. The majority of the intensified demonstrations are in single channels. For industrial applications it is necessary to increase throughput by increasing the number of channels, which is presently a major challenge.

In what follows, liquid-liquid extractions in intensified small-scale contactors are reviewed. These include extractions in single channels and in confined impinging jets cells as well as approaches to increase throughput via scale out, where many parallel channels are combined with appropriate manifolds. Developments on the use of centrifugal forces to enhance separations in small channels in CCC systems are discussed. The combination of intensified technologies with novel ionic liquid solvents is also considered.

When two immiscible liquids flow together in small channels, many flow patterns can form, ranging from segmented to annular and dispersed flows, as can be seen in the example in Figure 1. Parallel flows, where the two liquids flow in continuous layers next to each other, can also occur, usually by modifying either the wetting properties or the geometry of the channel walls.

Fig. 1.

The segmented, plug or slug flow pattern has been extensively studied because it appears for a wide range of phase flow rates and has been linked to high mass transfer rates. In this pattern, the dispersed phase moves as drops with size larger than the channel diameter (plugs) separated by slugs of the continuous phase (see Figure 1). Usually, there is a thin film of the continuous phase between the plugs and the channel wall. As the film is usually very thin, axial dispersion is limited. In addition, within each phase, circulation patterns are established which improve radial mixing (see Figure 2). As a result, a plug-flow reactor configuration establishes with improved radial and decreased axial mixing that ensures uniform residence times for the reactants.

Fig. 2.

In the small channel contactors, the flow characteristics and the mass transfer performance are closely related. The plug and slug lengths determine not only the interfacial area but also the mixing characteristics within the two phases. Apart from the flow rate ratio and the properties of the two phases, the plug and slug lengths depend significantly on the geometry of the inlet. Plug lengths have been reported by many investigators (19, 20) but there is no single model to predict them a priori.

Interfacial areas can be calculated from the measured plug and slug lengths and shapes of the front and back ends of the plugs. It has been found that the specific interfacial area (interfacial area per unit volume of the contactor) depends on the channel diameter, the flow rate ratio, the total velocity and the inlet geometry. Interfacial areas ranging from 2760 m² m^–3 to 4800 m² m^–3 in 0.5 mm, 0.75 mm and 1 mm internal diameter (ID) channels have been reported by Kashid et al. (21), whilst Li and Angeli (13) measured specific interfacial areas up to 8500 m² m^–3 for smaller channels of 0.2 mm ID, using high-speed imaging. In larger channels, with a diameter of 4 mm, the specific interfacial area decreased to values up to 880 m² m^–3. The circulation times within the plugs or slugs can be calculated when the velocity fields in the phases are known. Velocity field measurements have been carried out with particle image velocimetry (PIV) (22) or predicted from computational fluid dynamics (CFD) simulations (23). The results have shown that mixing is improved as the velocity increases and the plug and slug lengths decrease.

Segmented flow contactors have been used for many liquid-liquid mass transfer and reaction operations. In the case of fast reactions, the overall rate of the process is primarily controlled by the rate of mass transfer and microreactors have been shown to intensify processes. A typical example is the transesterification reaction of vegetable oils to produce biodiesel, where yields over 90% can be achieved under 30 s residence time in 240 μm hydraulic diameter channels (24). Regarding liquid-liquid metal extractions, combined with ionic liquids as the solvent phase, microchannels have been applied to the separation of uranium (25) and europium (13) for spent nuclear fuel reprocessing and for analysis in nuclear waste management. Channel sizes between 0.2 mm and 2 mm were used and extraction efficiencies >80% were achieved in <30 s. Pedersen et al. (26) achieved separation >90% of titanium-45 for use in positron imaging in less than 15 s in 0.75 mm perfluoroalkoxy (PFA) tubing.

The overall volumetric mass transfer coefficient for a solute being transferred from the aqueous to the organic phase is given by Equation (i) (15):

(i)

where ɛ_aq is the volume fraction of the aqueous phase, C_aq,eq is the concentration of the solute in the aqueous phase at equilibrium, C_aq,init is the concentration of the solute in the aqueous phase at residence time T₁ and C_aq,fin is the concentration of the solute in the aqueous phase at residence time T₂.

High-value precious metals such as platinum and palladium have also been extracted using intensified contactors. Yin et al. (11) and Kriel et al. (27, 28) extracted high-value metals (Pt, Pd) using parallel flow contactors. These metals are often found in mixtures at low concentrations (for example, from spent automotive catalysts) and their extraction may not be economic using conventional devices. In particular, Kriel et al. (27) demonstrated the extraction, scrub and stripping processes in flow channels with overall recovery rates over 95%. By modelling the flowsheet of spent nuclear fuel reprocessing using intensified extractors for the first time, Bascone et al. (29) showed important reductions in solvent use and in radiolytic degradation.

To increase throughput, large channel sizes should be considered that still preserve the benefits of small-scale operations, such as thin fluid films and enhanced heat and mass transfer rates. The extraction efficiencies and the volumetric mass transfer coefficients for channels between 0.5 mm and 4 mm ID were measured by Tsaoulidis and Angeli (25) and k_Lα as high as 0.06 s^–1 were found, even at the largest channels. The k_Lα increased as the channel diameter decreased. In smaller channels, however, the pressure drop increased and the throughput decreased. There is, therefore, a trade-off between mass transfer performance, throughput and energy requirements which needs to be carefully considered when designing plug flow separators.

To integrate the small channel extractors with the rest of the process, the separation of the two phases at the end of the channel should be considered. In small channels, wettability and interfacial effects are important and have been successfully implemented for the separation of the organic and aqueous phases. Separators with side channels or membranes that are preferentially wetted by the organic or aqueous phases have been tested. Currently, however, there are few commercially available options (for example, Zaiput Flow Technologies, USA); for parallel processing with many channels (see Section 4 below) the separator capital costs would scale linearly with the number of channels. Alternatively, gravity separators can still be used for systems with high throughput and sufficient density difference (>0.1 g cm^–3, (30)). In gravity settlers, however, the mass transfer between the phases can continue and diminishes the benefits of well-controlled conditions of the small channel.

An alternative option for increasing throughput in small channels is to increase the velocities of the two fluidic streams in an impinging jets inlet configuration. In recent years, there has been a renewed interest in using confined impinging jets reactors (CIJR) for many applications, such as crystallisation (31), nanoparticle synthesis using liquid precipitation (32), micromixing (33), extraction (15) and bioreactions (34). The high energy dissipation rates due to collision and redirection of the fluidic jets in the impingement zone make the contactor particularly suited for applications where rapid mixing of the fluids is necessary. When the two jets are immiscible liquids, then the large energy dissipation rates result in the formation of dispersions. A typical configuration of a cylindrical CIJR at 180° nozzle angle is shown in Figure 3(a).

Fig. 3.

The mixing and dispersed phase size are affected by a number of geometric characteristics, such as main channel (D) and nozzle (d_j ) size, main channel to nozzle size ratio, inter-nozzle distance (Id), nozzle height and impingement angle. The main challenge in developing confined impinging jets contactors for a particular application is the quantification of the effects of the parameters on the resulting drop sizes. There are many studies on impinging jets with miscible liquids, which demonstrate that for improved mixing the two opposing jets should have similar momentum so that they collide in the middle plane (35). Studies of impinging jets in confined spaces with immiscible liquids are very limited. The drop size has been related to the energy dissipation rate, while the uniformity of the dispersions depends on the geometric design of the contactor, the phase ratio and the intensity of mixing in the impingement zone (36). The energy dissipation rate (ɛ) can be described as the ratio of the power available due to kinetic energy change (K) at collision over the mixing volume of the impingement zone (V_iz ), according to Equation (ii):

(ii)

where

(iii)

and and are the mass flow rates (kg s^–1) of Phase 1 and Phase 2 respectively, u₁ and u₂ are the average velocities of Phase 1 and Phase 2, respectively, and ρ is the density of the mixture.

The Sauter mean diameter, given by Equation (iv):

(iv)

(where n is the number of drops and d_i is the diameter of the drop i in the distribution) has been related to the specific energy dissipation rate as follows (37), Equation (v):

(v)

The dependence of the average drop size on the energy dissipation in the impingement zone is presented in Figure 4 for two different aqueous/organic phase systems (15). As can be seen, at low energy dissipation values, the drop size depends on the geometry of the system and the fluid properties, while at larger ɛ, above 600 W kg^–1, the drop sizes converge. Similar results were also found by Siddiqui (2) for aqueous/organic systems in impinging jets contactors with the addition of emulsifiers, while in less viscous systems a stronger dependence of drop size on energy dissipation rate was observed.

Fig. 4.

It has been found that the dispersions formed in impinging jets have low polydispersity. Tsaoulidis and Angeli (36) reported polydispersity indices (PdI) as low as 0.05, for an oil/water system, for a wide range of jet velocities from 0.17 m s^–1 to 6.2 m s^–1. Interfacial area-to-volume ratios were significantly affected by the velocities of the jets and the values varied between 2000 m² m^–3 and 12,000 m² m^–3. Siddiqui (2, 3) also reported very narrow drop size distributions in a sunflower oil/water emulsification process with surfactants, for dispersed phase fractions up to 10% and drop sizes less than 10 μm.

The few mass transfer studies available have also revealed high mass transfer coefficients compared to other contactors as can be seen in Table I. k_Lα can be one to two orders of magnitude higher than in conventional contactors and two to three times higher than in microchannels. Values are similar to those of centrifugal contactors, however, the specific power input for centrifugal contactors can be two to three orders of magnitude higher when compared to a confined impinging jets cell (16).

The studies revealed that high mass transfer coefficients were obtained at short residence times (<4 s), with values up to 1 s^–1. Several parameters were found to affect mass transfer, including geometric characteristics and flow rate ratio. In Figure 5(a), mass transfer rates were calculated for two different main channel sizes i.e. 2 mm and 3.2 mm. It is shown that k_Lα depend on channel size at short residence times but are independent of the channel sizes at long times. The 3.2 mm channel should then be preferred because it has higher throughput and reduced pressure drop compared to the 2 mm channel. The mass transfer coefficient also increases with increasing collision velocities of the two jets (shown as the sum of the two velocities, u_tot in Figure 5(b)). The velocity of the liquid jets will define the position of the point of impingement (Figure 6) and will affect the uniformity of the flow pattern in the main channel as well as the drop size distribution.

Fig. 5.

Fig. 6.

Impinging jets systems have been used for more than four decades now but it is still not possible to determine accurately the effects of the dominant variables including aspect ratio of jet inlets, dead volume at the mixing section, fluid properties on the drop size and the mass transfer performance of the contactors.

Harmsen (41) identified four hurdles that any PI innovation must address before it can be implemented industrially. These are: (a) risk of failure by combining novel aspects; (b) scale-up knowledge uncertainty; (c) equipment unreliability; and (d) improved safety, health and environmental risks. The main hurdle faced by single-channel contactors is the scale-up uncertainty. Currently, there are no applications of small-channel extractors at large commercial or pre-commercial scales reported in the literature.

While single small channel flow contactors and reactors are highly efficient, the scale-up of the throughput without losing the small-scale advantages remains a main challenge. Scale-up can be achieved by increasing the number of channels operating in parallel (‘scale out’ or ‘number-up’). It is not trivial, however, to reproduce accurately the flow conditions of a single channel in many parallel ones. The challenge is to design a flow distributor within the process-specific maldistribution tolerance of the total flow rate and of the flow rate ratio of the two phases for each channel.

Scale out for single-phase processes requires a flow distributor that can achieve almost the same flow rate and thus residence time, in all channels. Single-phase flow distributors are commonly encountered in multi-tubular reactors, catalytic converters and other honeycomb catalysts. The distributors usually take one of two forms, bifurcation or consecutive manifolds, as shown in Figure 7. The consecutive manifold has a small footprint compared to the bifurcation one. Approaches based on resistance networks have been used to design manifolds that reduce flow non-uniformities among the channels (42).

Fig. 7.

In the case of multiphase systems, both the residence time and the flow rate ratio of the two phases are critical for the performance of the process and should be constant among the many channels of the manifold. There are two types of two-phase flow distributors: split-combine and combine-split (Figure 8). Combine-split designs first bring the two fluids in contact and then distribute the two-phase mixture into as many channels as necessary. Combine-split distributors do not have dead volumes and have been successfully designed by Hoang et al. (43) at a chip-scale; the design has been tested for up to eight channels but it may be unfeasible to increase further the number of channels.

Fig. 8.

Split-combine distributors (or double manifolds) distribute each of the single-phase fluids independently into as many channels as necessary and then bring them in contact. This type of distributor can, in turn, be either a bifurcation or a consecutive manifold.

Maldistribution of gas-liquid flows in double manifolds and the effects of manufacturing tolerances were studied experimentally by Al-Rawashdeh et al. (44) for square main channels with 1 mm side. The authors achieved deviations in the residence time below 20% by controlling the pressure drop in the distribution sections. Garciadiego Ortega et al. (45) developed a method to analyse the two-phase flow maldistribution and used a resistance network model to simulate the double manifolds. The effect of the number of channels on the maldistribution was also studied and scaling-laws for the design of these distributors were proposed as well as a procedure for an effective and economic double manifold design. The first step is to define the single-channel size and flow rates for a particular process and define the sensitivity of its performance to flow maldistribution. This defines the maldistribution tolerances, which determine the dimensions of the flow distributor. Finally, the pumping requirements are calculated. There is a trade-off between pumping requirements and maldistribution, with low maldistribution tolerances resulting in high pumping costs.

A promising intensified separation technology is high-performance CCC. It is a form of liquid-liquid extraction that achieves separation by repeated partitioning of solutes between two immiscible liquid phases, as they interact in a continuous length of coiled tubing under centrifugal and Archimedean forces. The tubing is wrapped around a cylindrical drum (called a bobbin) to form typically a three-dimensional (3D) helical configuration with one or several layers. Within the CCC column, one of the liquid phases is held stationary by a combination of hydrodynamic and hydrostatic forces generated as a result of rotating the column in planetary motion, while the other mobile phase is continuously pumped through the coil and serves to transport the solutes through the system. The J-type CCC is the most commonly used, where the bobbin is mounted on a planetary axis, driven by a central axis so that the column rotates about its own axis while it revolves around the central axis at the same velocity in the same direction (Figure 9(a)). The double rotation of the column during its planetary motion produces a variable centrifugal force field. This force field creates a unique mixing pattern in which a series of sequential mixing and settling zones are generated simultaneously along the length of the column. These alternating mixing and settling steps are essential to the chromatographic process as they promote solute transfer between the phases and therefore, separation of species with different partition coefficients.

Fig. 9.

In the last decade, the use of ionic liquids either as solvents or additives in liquid-liquid extractions has expanded considerably because of their unique properties. Ionic liquids are organic salts that are liquid at room temperature. The stability, phase behaviour and greater solvating power of ionic liquids, together with the ability to design their structure, can increase both the flexibility and performance of separations and allow separations that were not previously considered possible. The combination of the two technologies, ionic liquids and CCC, therefore represents an exciting approach to intensified liquid-liquid separations. However, the use of ionic liquids in CCC is not a trivial task due to their relatively high viscosities, which can introduce significant problems for the majority of traditional CCC machines that are mostly low pressure. To overcome the pressure limitations previously encountered using the CCC technique, AECS-QuikPrep^TM Ltd, UK in collaboration with the QUILL Research Centre have reported on the design and construction of a modified high backpressure CCC instrument (Figure 9(b)). The high solvating power of ionic liquids allows separations to be run at very high sample loadings which gives rise to high space-time yields for ionic liquid and CCC separations. The ability to custom design ionic liquids allows a greater range of mobile phases to be employed and enables separations with pH neutral water as the mobile phase, where previously toxic organic solvents (such as acetonitrile), concentrated salt solutions (such as aqueous dipotassium phosphate), polymers (such as polyethylene glycol) or acids (such as nitric acid) were used. Scale up can be achieved with the increased capacity CPC instrument (46). Ionic liquids have been applied successfully as a major solvent system component for a wide range of separations (47–49) including:

The combination of ionic liquids with CCC has been successfully used in the separation of the anticancer drug lentinan at a scale 10–100 times the scales of earlier separations (50). Lentinan is found in shiitake mushrooms (Lentinus edodes) and is used as an adjunct to therapy in combination with chemotherapeutic drugs such as fluorouracil to modulate the body’s immune system activity. Lentinan naturally exists in water and salt solutions but is easily denatured by solvents. This means that for the isolation and purification process of lentinan, water based solvent systems are required. The conventional purification of lentinan normally involves up to 10 steps. An ionic liquid-based aqueous biphasic solvent system (ABSS) was developed using 1-n- butyl-3-methylimidazolium salts [C₄mim]Cl / 2.5 M K₂[HPO₄]_(aq) (1:1) mixture (51), which allowed lentinan separations on the 1–3 g scale, without denaturing the lentinan. This CCC process used aqueous [C₄mim]Cl as the mobile phase and the lentinan was separated from the [C₄mim]Cl solution by the addition of ethanol to the [C₄mim]Cl phase. The [C₄mim]Cl can be recovered and reused after the lentinan has been precipitated. The ethanol can also be recovered by evaporation allowing it to be reused. This leads to a separation process that does not consume solvents or reagents.

An improved lentinan process has also been developed with a novel ABSS based on microemulsions. Surface active ionic liquids such as 1-dodecyl-3-methylimidazolium di(iso-octyl)phosphinate ([C₁₂mim][DiIOP]), when mixed with water and hexane produce a water immiscible microemulsion phase, which contains 75 mol% water (Figure 10). The aqueous phase is composed of >99% water, which allows water to be used as the mobile phase in CCC separations, with the microemulsion as the stationary phase. This greatly simplifies product isolation since the product does not end up mixed with large quantities of involatile chromatography solvent constituents. Also, this approach does not produce any solvent waste (other than water) making this a very green and inexpensive separation to run. The full lentinan process takes the freeze dried hot water extract of shiitake mushrooms (Figure 11(a)) and precipitates lentinan from this crude extract dissolved in [C₄mim]Cl, using ethanol. The precipitated 80% lentinan (Figure 11(b)) is then purified with the water-microemulsion solvent system shown in Figure 10 to give the off-white 95% lentinan shown in Figure 11(c) on the 25 g per run scale. Recent industrial uses of CCC and CPC instruments are in the refining of galantamine from daffodils (for example, BioExtractions (Wales) Ltd, UK) or the red spider lily (52), the purification of cannabinoids and metal ion separations associated with the nuclear industry.

Fig. 10.

Fig. 11.

Liquid-liquid extractions are widely used for the separation and purification of many compounds. Small channels (up to 4 mm in diameter) and a combination with external fields, such as centrifugal forces, can significantly intensify the process by reducing residence times, improving extraction and extraction efficiencies and reducing the amount of solvent required. Mass transfer coefficients up to 1 s^–1 have been measured in the impinging jet contactors. These characteristics have made possible the implementation of novel and often expensive solvents such as ionic liquids with significant improvements to the separation. Droplet-based flows (dispersed or plug flow patterns) in particular have been shown to enhance mass transfer and increase interfacial areas. However, the throughputs are small and scale out would be required before they can be applied to industry. On the other hand, the fast mass transfer rates and well-characterised flow patterns render small channels suitable for analysis and for research on new extractants. Impinging jets have increased throughputs and can produce dispersions with narrow size distribution and large interfacial areas. CCC devices with alternating mixing and settling steps allow separation of species with different partition coefficients and have been used to optimise solvent systems and conditions for separations. High throughputs can be achieved with the increased capacity CPC which has simpler rotor design and fewer moving parts compared to CCC (46, 53).

At small scales, the contactor geometry significantly affects the flow and mass transfer characteristics. Possibilities are open for novel contactor designs that exploit interfacial and wettability effects to establish desirable flow patterns and enhance mass transfer. For the commercial application of the technology in production, robust scale-out designs for two-phase systems need to be further developed and the sensitivity of their performance against flow maldistribution needs to be tested.

“Process Systems Engineering for Pharmaceutical Manufacturing” is an ambitious reference comprising 24 chapters covering process systems engineering (PSE) methods and case studies of interest to engineers working in pharmaceutical process development, model development, process simulation, process optimisation and supply-chain or enterprise optimisation. Business model optimisation, including optimisation of clinical trials and supply chain, are topics covered in Chapters 1 and 21–24. Continuous manufacturing of drug product (downstream) is a key theme covered in Chapters 6 and 16–20, while process control, flowsheet modelling and key unit operation modelling are covered in Chapters 5, 7, 8–11 and 13–15. Of particular interest is the topic of small molecule upstream development and workup solvent selection and optimisation discussed in Chapters 3–4, with case studies involving separation solvent selection presented for ibuprofen, artemisinin and diphenhydramine in Chapter 4.

Chapter 2, ‘The Development of a Pharmaceutical Oral Solid Dosage Forms’ submitted by Rahamatullah Shaikh, Dónal P. O’Brien, Denise M. Croker and Gavin M. Walker (University of Limerick, Ireland), provides a summary of solid oral dosage form development, covering solubility and dissolution kinetics, pKa, excipient types and the standard formulation processes of direct compression as well as wet and dry granulation and capsule filling. This chapter is recommended reading for anyone not familiar with formulation of drug tablets as it provides a well-organised summary helpful in understanding the types of processes modelled in the chapters on continuous manufacturing, flowsheet and unit operation modelling as it relates to drug product.

I have organised this review according to general topics covered rather than by sequential order of the chapters.

Chapter 1, ‘New Product Development and Supply Chains in the Pharmaceutical Industry’, contributed by Catherine Azzaro-Pantel (Université de Toulouse, France), introduces the pharmaceutical supply chain and summarises the product life cycle of a drug starting from discovery through clinical trials, registration and commercialisation. This chapter provides a concise summary of clinal trial phases, pre-launch and launch activities and is recommended reading for those not familiar with the pharmaceutical business model and drug development process (Figure 1).

Fig. 1.

Chapter 21, contributed by Brianna Christian and Selen Cremaschi (Auburn University, USA), covers ‘Planning of Pharmaceutical Clinical Trials Under Outcome Uncertainty’. The authors reference an increase in attrition rates in clinical trials and state “the time from discovery to product launch of a drug is around 10–15 years with an average research and development (R&D) cost of about $2.6 billion per drug” as motivating factors driving the need for better clinical trial optimisation. This chapter provides details of a “perfect information” deterministic mixed-integer linear programming model (MILP) problem including constraints. By using an innovative heuristic modification to the stochastic programming model a five order of magnitude improvement is reported.

Chapter 22, ‘Integrated Production Planning and Inventory Management in a Multinational Pharmaceutical Supply Chain’ contributed by Naresh Susarla and Iftekhar A. Karimi (National University of Singapore) presents a MILP model for a complex supply chain and provides a strategy to optimise inventory, resources and production schedules in the supply chain to maximise profit. The intent of the model is as a tool for decision making for “production planning and scenario analysis in a multinational pharmaceutical enterprise”. To mitigate risk associated with the complex, multinational network of supply, drug inventories of 180 days are not atypical. However, high levels of inventory come at a cost. A change introduced in the supply network may have impact on inventories, lead-times and dependencies as impacted by other portions of the supply network. In this chapter the authors describe their approach to this optimisation problem. While looking at the authors’ formulation of their case study problem, the value of working with fewer strategic suppliers in a vertically integrated supply network is evident in that it will minimise the complexity, delay and cost associated with a complex network. A takeaway from this chapter is that pharmaceutical companies can anticipate improved access to software tools to compare the impact of supply chain alternatives as research is translated into commercial software offerings.

Chapter 12, ‘PAT for Pharmaceutical Manufacturing Process Involving Solid Dosages Forms’ contributed by Andrés D. Román-Ospino and Ravendra Singh (Rutgers, The State University of New Jersey, USA), Vanessa Cárdenas and Carlos Ortega-Zuñiga (University of Puerto Rico, USA), presents near-infrared (NIR) calibration models and chemometrics. For those not skilled in process analytical technology (PAT) and analytical determination, this chapter is very informative and provides comparison of various methods for analytical data fitting to determine blend uniformity for real-time control of continuous pharmaceutical processes. Principal component analysis (PCA), partial least squares (PLS) and multivariate curve resolution alternating least squares (MCR-ALS) are presented as suitable techniques for multiple parameter determination where linear regression or classical least squares methods are not suitable. Layering of talc and lactose as a specific case study in non-homogeneity is discussed in this chapter. Finally, a process example utilising Unscrambler^® X Process Pulse II (Camo Analytics AS, Norway) and NIR (Viavi Solutions Inc, USA) is presented where Unscrambler^® X software is utilised to generate and upload a calibration model generated via methods presented in the chapter. In the example the NIR data processing system is interfaced to a DeltaV^TM distributed control system (Emerson Electric Co, USA) to provide real time process control of a tableting process.

Chapter 19, ‘Monitoring and Control of a Continuous Tumble Mixer’ contributed by Carlos Velázquez, Miguel Florían and Leonel Quiñones, (University of Puerto Rico, USA), presents a case study for the mixing of naproxen sodium with excipient using a continuous mixer designed by Velázquez. The PAT technology implemented for this case study employed the use of NIR in conjunction with Unscrambler^® X in a PAT implementation similar to that described in Chapter 12. The closed-loop control dynamics for the experimental mixer are evaluated. A finding from the study is that a different control scheme is required for very low dosage active pharmaceutical ingredient (API) vs. higher dosages. The authors identified flowrate control of API addition at very low dosage as variable due to poor powder flow properties as well as limitations of the NIR methods employed in low dosage applications.

Chapter 9, ‘Crystallization Process Monitoring and Control Using Process Analytical Technology’ contributed by Levente L. Simon (Syngenta Crop Protection AG, Switzerland), Elena Simone (University of Leeds, UK) and Kaoutar Abbou Oucherif (Eli Lilly and Co, USA), introduces quality by design (QbD) and reviews online analytical techniques available for crystallisation monitoring and control which include attenuated total reflectance Fourier-transform infrared (ATR-FTIR), Raman spectroscopy, acoustic spectroscopy, conductivity measurement, refractive index measurement, turbidity measurement, focused beam reflectance measurement (FBRM) and particle vision and measurement (PVM).

Automated direct nucleation control (ADNC) along with polymorph determination and control via Raman and attenuated total reflectance ultraviolet (ATR-UV) spectroscopy are presented for batch and continuous crystallisation processes. The ADNC method involves heating and cooling cycles to control crystal count as measured by FBRM to a specified target. In the batch implementation, after initial nucleation, the system automatically heats to dissolve fines and heating and cooling cycles proceed until the crystallisation endpoint (low solution concentration). An advantage of this method is that from PAT data collected, the metastable zone width (MSZW) and solubility curves may be constructed. Since solubility curves are not required prior to running ADNC experiments, this method is useful for process development. An interesting adaptation of the ADNC method to a two-stage continuous mixed-suspension mixed-product removal (MSMPR) crystalliser system is an innovation by Yang et al. (1) where heating and cooling is performed on the jacket of a wet mill while the MSMPR crystalliser is maintained at constant temperature. The MSMPR with wet mill achieves both form control and FBRM particle count control under continuous flow operation.

Chapter 5, ‘Flowsheet Modeling of a Continuous Direct Compression Process’ contributed by Seongkyu Yoon, Shaun Galbraith, Bumjoon Cha and Huolong Liu (The University of Massachusetts Lowell, USA), summarises the scope of individual unit operation models for continuous powder blending, powder feeding (and potency control), tablet press, feed frame and tablet compaction. The authors highlight both a population balance model (PBM) as well as a stirred-tanks-in-series modelling approach to blending. The value of the modelling is in being able to accurately predict the response of perturbations on key quality attributes of finished tablets. An accurate system-wide process model allows implementation of both feedback and feedforward (predictive) control methodologies which can be developed and tested offline, provided that the underlying unit operation models are accurate. Modelling will facilitate development of continuous direct compression (CDC) processes and control schemes for CDC, where elimination of granulation results in simpler, less expensive processes.

Chapter 6, ‘Applications of a Plant-Wide Dynamic Model of an Integrated Continuous Pharmaceutical Plant: Design of the Recycle in the Case of Multiple Impurities’ submitted by Brahim Benyahia (Loughborough University, UK), takes the continuous methodology described in Chapter 5 a step further by integrating the chemical synthesis steps (upstream) with the formulation and tabletting steps (downstream) into a single continuous flowsheet. Of interest is the impact of wash-factor (i.e. wash volumes) and recycle (purge ratio) on the quantity of in-specification product produced. The recycle of wash streams is not often performed in batch API but in continuous processing this recycle provides potential for optimisation and cost savings. The evaluation of wash factors and their limits as potential critical process parameters (CPP) is performed following a model-driven QbD approach. In the case study presented, plant dynamics are compared for both full purge and full recycle purge ratios.

Chapter 11 ‘Process Dynamics and Control of API Manufacturing and Purification Processes’ submitted by Maitraye Sen, Ravendra Singh and Rohit Ramachandran (Rutgers, The State University of New Jersey, USA) introduces a hybrid model predictive control/proportional-integral-derivative (MPC-PID) controller in which a single model based controller coupled with one PID temperature controller replaced four separate PID controllers in a continuous API/pharmaceutical intermediate process comprised of crystallisation, filtration, drying and excipient blending operations. PBM and discrete element method (DEM) methods were utilised to model the process while PCA was used to generate a reduced-order model for use by the model predictive controller. Various control schemes can be tested and optimised entirely in silico allowing investigations of system or controller response to transient conditions and process upsets to be investigated. The authors used MATLAB^® (MathWorks Inc, USA) to fit data resulting from process simulations to transfer functions useful for model predictive control. gPROMS^® (Process Systems Enterprise Ltd, UK) was utilised for PBM calculations and EDEM^® (DEM Solutions Ltd, UK) was used to simulate the mixer where a PCA method was fit to six components from the DEM model.

Chapter 13, ‘Model-Based Control System Design and Evaluation for Continuous Tablet Manufacturing Processes (via Direct Compaction, via Roller Compaction, via Wet Granulation)’ contributed by one of the editors of the volume, Ravendra Singh (Rutgers, The State University of New Jersey, USA), is a review of model-based control for a formulation process which includes blending, granulation, roller compaction, milling and tableting. For the case study in Chapter 13, a PBM is employed in gPROMS^®, but this time for the roller compactor. Unlike the example in Chapter 11, the API crystallisation, isolation and drying steps are not included as API is taken as the input and blended with excipients prior to granulation.

Chapter 7, ‘Advanced Multiphase Hybrid Model Development of Fluidized Bed Wet Granulation Processes’ submitted by Ashutosh Tamrakar, Dheeraj R. Devarampally and Rohit Ramachandran (Rutgers, The State University of New Jersey, USA), implements a hybrid computational fluid dynamics (CFD)/DEM approach to model the coupled behaviour of fluid flow and collisions. The authors transfer data from their CFD-DEM model to a PBM to provide resulting distributions from the granulation process. The DEM-CFD-PBM approach considers residence time in the spray zone, particle collision frequency, aggregation, attrition, particle temperatures and fluid/particle velocities. Residence time in the two zones (spray zone and drying zone) is impacted by fluid flow within the zones and the passing of particles between zones as modelled via CFD-DEM. Results from the CFD-DEM runs are exported to the PBM to investigate sensitivity to inlet gas temperature and gas flow rate. Excellent fit of experimental data from the fluid bed granulator is achieved.

Chapter 15, ‘Advanced Control for the Continuous Dropwise Additive Manufacturing of Pharmaceutical Products’ was contributed by Elçin Içten (Amgen Inc, USA), Gintaras V. Reklaitis and Zoltan K. Nagy (Purdue University, USA). In this chapter the authors describe a system and control methodology for the generation of solid oral dosage forms via a drop on demand (DoD) additive manufacturing technique involving dropwise deposition of API as solvent solution or as solvent/polymer melt (see Figure 2).

Fig. 2.

The DoD system is particularly useful for generation of personalised medicine for highly potent (low dosage) products. The authors present a control scheme based on image analysis of each drop and investigate various cooling profiles for the substrate (tablets). The authors present a polynomial chaos expansion (PCE) surrogate model for prediction of crystallisation, total dosage and product attributes as a function of drop attributes and cooling profile. The PCE model provides a QbD approach for predictive performance of the tablets’ release profile.

Chapters 16–18 present case studies for automation of continuous pharmaceutical process plants where process control is the focus. Chapters 17 and 18 have a bit of redundancy with Chapter 13 as all three chapters are based on a series of published articles by one of the editors of the volume, Ravendra Singh. Chapter 18 is focused on formulation without granulation but with a control scheme to control tablet hardness by controlling tablet press punch depth and real-time measurement of bulk density is used in a feedforward control scheme. Detailed discussion of the control hardware, sensors and control algorithms for the pilot plant is presented in Chapter 17. Process modelling allows complex system dynamics, interactions and control schemes to be investigated and optimised in silico, as enabling technology in the development of robust continuous drug manufacturing processes.

Chapter 3, ‘Innovative Process Development and Production Concepts for Small-Molecule API Manufacturing’, contributed by John M. Woodley (Technical University of Denmark), summarises innovations in process systems engineering used to facilitate process development and optimisation. After a viable process model is developed, ‘virtual experimentation’ may be used to better focus benchtop experiments. Alternative routes and separation schemes can be evaluated if physical property data is available. The CAPEC-PROCESS Industrial Consortium (now the Process and Systems Engineering Centre (PROSYS)) at the Technical University of Denmark has contributed to the generation of physical property estimation methods to address this need.

The author describes use of template processes in which processes under development are fit to a template scheme based on conditions known to work for similar processes. For instance, a reaction step is evaluated against a process template for which simulation and laboratory models already exist (Figure 3). The sufficiency of the template is tested and then the process is optimised using modelling tools already developed for the template process. The author notes that while the template process approach may only be adaptable to 80% of process candidates, for those processes which are adapted, existing knowledge may be leveraged in the development of the new process. Process templating is a powerful tool in the application of PSE models for process integration and intensification and may be useful in evaluating process scheme alternatives when an API synthetic scheme involves multiple transformations.

Fig. 3.

Chapter 4, ‘Plantwide Technoeconomic Analysis and Separation Solvent Selection for Continuous Pharmaceutical Manufacturing: Ibuprofen, Artemisinin, and Diphenhydramine’ contributed by Samir A. Diab, Hikaru G. Jolliffe and Dimitrios I. Gerogiorgis (University of Edinburgh, UK), provides an evaluation of continuous separation steps vs. their batch separation counterparts. The authors noted that for the three continuous API processes evaluated by others, the evaluations had focused on performing the chemistry steps continuously and had not implemented continuous separation steps. As shown in Figure 4, the authors present a continuous liquid-liquid extraction (LLE) separation scheme as a replacement for the batch scheme found in the literature for ibuprofen (IBU). In addition, the authors evaluated additional solvents including n-heptane, cyclohexane, methylcyclohexane and isooctane and found many of the solvent choices to be suitable when a continuous LLE process is used vs. a continuous process. Using process modelling, the efficiencies of separation, the quantities of solvent and an economic comparison of alternative solvents are presented. For a continuous IBU extraction using heptane, the authors project capital savings of 58% and operating savings greater than 50% vs. the batch process utilising diethylether. The case studies presented in this chapter are based on process simulations performed by the authors and not on actual laboratory data. While it does not validate a final solvent choice, the use and conclusions based on simulation data highlight the value of a modelling-based approach to selecting workup or extraction solvents with environmental, flammability and regulatory suitability.

Fig. 4.

“Process Systems Engineering for Pharmaceutical Manufacturing” is a diverse collection of reviews and case studies, most of which were published previously. While this book provides an excellent summary of process modelling and computing with a view to the increased importance of robust simulation tools in pharmaceutical process development and manufacturing, more recent journal publications may provide additional or more in-depth information on the current state of specific technologies or algorithms described in the book. It is also evident that much of the key work in these areas has yet to be done. One topic missing from discussion in the book is the advent of quantum computing and the potential quantum computing presents in solving optimisation problems in process systems engineering. I would look forward to seeing an additional volume added to the series as the technology develops.

The Oxford Battery Modelling Symposium was held in Oxford, UK, from 18th to 19th March 2019. The conference was specifically designed to gather mathematicians, chemists and engineers within the battery modelling community. It was very well received and brought together 170 participants with worldwide representation from academia, research organisations and industry involved in modelling at different scales (atomic length-scale, continuum and control-oriented modelling). This review will focus on eleven talks presented in the four sessions and organised as follows:

Electrochemical processes can be modelled using a continuum approach (that relies on material specific parameters, sometimes difficult to measure) or from first principles. As electrochemical processes are thermally activated, in ‘Connecting Electronic Structure to Phenomenological Continuum Models of Electrochemical Processes’ by Anton Van der Ven (University of California Santa Barbara, USA) it was shown that temperature and entropy play a key role for understanding the physics and the properties of materials. As such, a statistical mechanics approach is beneficial, although computationally very demanding. Van der Ven introduced the open-source software Cluster Approach to Statistical Mechanics (CASM) developed in his group and available from GitHub (1). In CASM, for a certain material, the thermodynamic and kinetic properties obtained from density functional theory can be fed into continuum models to realise fast and computationally undemanding first-principle multiscale simulations for dynamic processes such as electrochemical processes. This tool can be used to predict thermodynamic and kinetic properties of various classes of materials (such as layered, olivines, spinels and alloys), see Figure 1 (2).

Fig. 1.

In literature both accurate first-principle methods and continuum theories are available to predict the properties of materials and interfaces. However, rigorous ways to connect the two approaches are still lacking. In ‘Mind the Gap – Towards an Atomistic Understanding of Battery Materials Interfaces’, Denis Kramer (University of Southampton, UK) described strategies to build continuum models starting from first principle calculations and their application to crystallisation. The coverage effect in the size-stabilisation of nanocrystals during electrochemical processes and the crystallisation process of manganese(IV) oxide polymorphs have been discussed (3). Finally the effect of Li⁺ ions in the stabilisation of some MnO₂ polymorphs was described in this framework.

In ‘Modeling Porous Intercalation Electrodes with Continuum Thermodynamics and Multi-scale Asymptotics’ by Manuel Landstorfer (Weierstrass Institute for Applied Analysis and Stochastics, Germany), a description of the procedure for modelling porous cathodes was provided. For such electrodes three scales can be identified (the double layer scale, the macroscopic porous media scale and the microstructure scale). Landstorfer started by describing the metal-electrolyte interface and electron transfer in the double layer through a non-equilibrium thermodynamic continuum model (4). The model was scaled up to electrode particle scale and treated with a matched asymptotic expansion method. Finally, Landstorfer discussed a third scale: the macroscopic porous media scale. He introduced homogenisation techniques for the prediction of transport properties at porous scale. This multiscale methodology was applied to model thermodynamic properties, diffusion processes and the open circuit potentials of intercalation cathodes for Li-ion batteries with different chemical composition and porosity.

‘Electrochemical Energy Storage’ by John Newman (University of California Berkley, USA) was a keynote lecture on mathematical modelling approaches for the design of batteries. Newman introduced various methodologies (such as continuum modelling, (kinetic) Monte Carlo and molecular dynamics) and their application to the modelling of intercalation electrodes and electrolytes in Li-ion batteries. He showed how these tools can improve understanding of the electrochemical processes as well as of failure mechanisms taking place in battery materials, helping to design high power and high energy battery materials.

Bob McMeeking (University of California Santa Barbara, USA) presented a model for the redox kinetics at an interface between a solid electrolyte and a Li metal anode in ‘Redox Kinetics, Interface Roughening and Solid Electrolyte Cracking in Solid State Lithium-Ion Batteries’. This model was based on the extension of the Butler-Volmer equation through the inclusion of the effect of the mechanical stress across the anode-electrolyte interface. This method was applied to the investigation of the morphological stability of the interface between the Li anode and the solid electrolyte for various current densities and solid electrolyte resistivities. Moreover, the extended Butler-Volmer equation was used to model the evolution of cracking in ceramic solid electrolytes caused by Li insertion into pre-existing defects on the electrolyte surface. The model showed how the pressure generated by Li insertion into the flaw causes the propagation of cracking in the solid electrolyte and consequent Li dendrite growth. Finally, the extended Butler-Volmer equation was used to identify the maximum Li pressure and critical lengths (a₁) of defects within a series of ceramic electrolytes to avoid the propagation of Li dendrites (a₁ = 2 μm for Li₇La₃Zr₂O₁₂ (LLZO)) (5).

The kinetics and uniformity of Li insertion reactions at the solid-liquid interface govern the rate capability and lifetime of Li-ion batteries. Martin Bazant (Massachusetts Institute of Technology, USA) presented a model for the prediction of phase transformations of intercalation materials in ‘Control of Battery Phase Transformations by Electro-Autocatalysis’. The approach was based on a thermodynamic framework for chemical kinetics applied to charge transfer (namely, the Marcus and extended Butler-Volmer equations) (6).

Reaction-driven phase transformations are common in electrochemistry, when charge transfer is accompanied by ion intercalation or deposition in a solid phase. The model allows rationalisation of phase separation of Li-rich and Li-poor islands for low discharge rates that affect the stability and cyclability of Li-ion batteries. The model also proved that high discharge rates favour the formation of solid-solution phases through an electro-autocatalytic mechanism, later experimentally confirmed for lithium iron phosphate (LFP) (7). The model can be extended to the investigation of electrodeposition, corrosion, chemical intercalation, precipitation and cell biology.

Göran Lindbergh (KTH Royal Institute of Technology, Sweden) presented an extended physics-based porous electrode model accounting for particle surface stress that was used to describe ageing of nickel manganese cobalt oxide cathode (LiNi_x Mn_y Co_z O₂, NMC) with composition x = y = z = 0.33 (namely NMC111). In ‘An Extended Porous Electrode Model for NMC111 in Lithium-Ion Batteries’ the performances of NMC111 were experimentally investigated via a galvanostatic intermittent titration technique and two models were used to fit the experiments: (i) a standard pseudo-two-dimensional (P2D) model; and (ii) an extended surface stress P2D model that included a stress factor depending on the Li concentration gradient in the material. Model (ii) could accurately extract transport, kinetic, thermodynamic and stress properties for the whole spectrum of operative conditions (low and high charge-discharge rates, temperature and external pressure). Although the standard model works well for low potentials (less particle surface stress), the porous electrode stress model predicts the ageing of NMC at high potentials (high surface stress).

‘Physically-Informed Models for Improved Cell Design and Operation of Lithium-Sulphur Cells’ by Monica Marinescu (Imperial College London, UK) was a lecture about the necessity of using physically-informed models to predict the mechanisms and performance of batteries. The accumulated experience on physically-informed models for Li-ion was used as a starting point for engineering Li-S batteries. Modified equivalent circuit network models were used for Li-S batteries modelling in order to take into account phenomena like shuttling, dissolution and precipitation. Moreover, simple physics-derived zero-dimensional (0D) and one-dimensional (1D) continuum models for the prediction of open circuit voltage and of the effects of mass transport on discharge, degradation mechanisms and capacity fade for commercially-sized Li-S batteries were presented (8–10).

Gregory Plett (University of Colorado, Colorado Springs, USA) delivered a keynote lecture titled ‘Physics-Based Reduced-Order Models of Lithium-Ion Cells for Battery Management Systems’ about physically-informed control models. Plett reviewed the standard physics-based model particularly focusing on how this model could be converted to a physics-based reduced-order model (PBROM). Battery-management systems provide a continuous estimate of state-of-charge, state-of-health, available energy and available power of battery packs. Traditional computational methods rely on empirical equivalent circuit models of the batteries. These models are computationally fast and robust. However, although accurate for many tasks, they cannot predict the internal electrochemical state of the cell. On the other hand, physics-based models that provide good predictions of the internal electrochemical state are too complex to apply to battery-management systems, which are heavily parametrised and have robustness and convergence issues. PBROM is a method that, while reducing the computational requirement of physics-based models, retains their prediction accuracy and can be used for battery management systems.

In ‘Decoding the Electron Swelling for Advanced Battery Diagnostics’ Anna Stefanopoulou (University of Michigan, USA) presented a conjugated experimental and computational control model to account for battery degradation. Since standard control models do not account for swelling and ageing, during the talk Stefanopoulou introduced experimental apparatus to probe battery degradation and convert the observables (measured terminal voltage and surface temperatures) into parameters to implement control models to predict swelling and ageing (11). In particular, observations of the cell swelling during charging were used to estimate the loss of active material and loss of Li inventory in the anode, which is useful for avoiding Li-plating during fast charge.

The last talk was delivered by Scott Trimboli (University of Colorado, Colorado Springs, USA). The ‘Model Predictive Control using Physics-Based Models for Advanced Battery Management’ was a lecture on the model predictive control (MPC) developed in collaboration with Plett. Starting from the PBROM, Trimboli showed the mathematical implementation of MPC. MPC is an effective real-time control strategy that employs a ‘look-ahead’ approach to foresee dynamic behaviours in the battery pack before they happen. This approach can be coupled with the ability of PBROM to enforce hard constraints on internal electrochemical variables (precursors to degradation or unsafe operation conditions), making MPC appealing for advanced battery management, where safety, lifetime and improved performance are crucial (12).

The Oxford Battery Modelling Symposium aimed to bring together the battery modelling community. It was well attended and the 12 talks as well as the 25 posters were high quality. The four sessions of talks were successfully organised to provide a full overview of the current state of the art in Li-ion and next generation battery modelling, spanning from first-principle investigations to control-oriented approaches.

This Springer volume focuses on the design, characteristics and development potential of proton exchange membrane fuel cell (PEMFC) and solid oxide fuel cell (SOFC) technologies for both stationary and portable applications. The contents are organised into three themes: (a) energy policy and electrical power (Chapters 1–3); (b) optimisation of fuel cells (FCs) through design and synthesis of novel catalysts (Chapters 4–8); (c) optimisation of FCs through modelling and simulation (Chapters 9–18). The book forms a useful compendium of research activities across the globe that gives the reader a general overview rather than an in-depth treatment of any one area. The layout and presentation are of the usual Springer high standard with clearly visible graphs and illustrations; the book was compiled in 2018.

Chapter 1, ‘Fuel Cell Technology: Policy, Features, and Applications – A Mini-Review’ by S. Bashir (Texas A&M University-Kingsville, USA) et al., starts with a comparative analysis of the energy policies of presidents Eisenhower and Trump with lots of facts and figures regarding historical energy use and energy vector types. The text covering fuel cells is PEM-centric (no SOFC or phosphoric acid fuel cell (PAFC)) and battery vehicles are not included in the discussion.

Chapter 2, ‘Concept of Hydrogen Redox Electric Power and Hydrogen Energy Generators’ by K. Ono (Kyoto University, Japan), argues that particular bipolar electrode configurations and power supply arrangements in coupled electrolyser or FC systems can improve overall efficiencies markedly over existing setups. Ono maintains one can treat the system as a combination of electrostatic energy and electrical to chemical energy conversion. I found the reasoning difficult to follow, perhaps because there are considerable conceptual challenges faced in dealing with electrostatic terms in highly condensed phases (see e.g. (1)). Unfortunately, no experimental data are presented to support the claims by Professor Ono.

Chapter 3, ‘Evaluation of Cell Performance and Durability for Cathode Catalysts (Platinum Supported on Carbon Blacks or Conducting Ceramic Nanoparticles) During Simulated Fuel Cell Vehicle Operation: Start-Up/Shutdown Cycles and Load Cycles’ by M. Uchida (University of Yamanashi, Japan) et al., is a comprehensive work on the mechanistic details of degradation mechanisms and with proposed mitigation protocols. Different supports are looked at, not just carbon. We are reminded of the importance of understanding the practical challenges of stack design and operation in respect of membrane electrode assembly (MEA) degradation mechanisms. Degradation tests are based on voltammetric cycling to mimic start-up and shut-down automotive duty cycles. Perhaps not surprisingly, platinum dissolves and aggregates and carbon corrodes and different accelerated ageing protocols give different results. This is very important in the commercial world – you may not agree with the customers’ tests, but they are the ones your product will be judged by!

Chapter 4, ‘Metal Carbonyl Cluster Complexes as Electrocatalysts for PEM Fuel Cells’ by J. Uribe-Godinez (Centro Nacional de Metrologia, Mexico) offers a general introduction and good summary of work in the field on catalysis preparation for PEMFC systems. Carbonyl complexes can be heat treated to produce metallic-like clusters and here the author looks at rhodium, iridium and osmium species with a heat-treatment regime up to 500°C in either nitrogen or hydrogen or thermolysed by redox in a suitable solvent. Unfortunately, there are no mass or specific surface area activity-based data so although a comparison with a 30 wt% Pt on XC72R catalyst is made, it is difficult to assess specific-area based catalytic activity.

Chapter 5, ‘Non-Carbon Support Materials Used in Low-Temperature Fuel Cells’ is written by X. Cao (Soochow University, China) et al. Traditional carbon supports used in FCs are prone to degradation through oxidation and many attempts have been made to find substitutes that can offer competitive performance, durability and cost. The authors give us a survey of the state-of-the-art. However, it is clear that carbon is favoured as a support (for good reason) and is unlikely to be substituted in the near term for low-temperature FCs.

Chapter 6, ‘Noble Metal Electrocatalysts for Anode and Cathode in Polymer Electrolyte Fuel Cells’ by S. Sharma and C. M. Branco (University of Birmingham, UK) is potentially a vast subject to tackle and the chapter covers the basics of what is understood about the performance-morphology related aspects of precious metal catalysts for PEMFC electrocatalysis. There is a particular emphasis on the oxygen reduction reaction (ORR).

Chapter 7, ‘Nanomaterials in Proton Exchange Membrane Fuel Cells’ is written by Y. Zhang (Harbin Institute of Technology, China) et al. In this chapter the PEM emphasis is a little more on direct methanol oxidation than the previous chapter and there is a shift of emphasis towards zero-dimensional, one-dimensional and two-dimensional materials. Carbon features explicitly in the form of nanotubes and graphene.

Chapter 8, ‘Nanostructured Electrodes for High-Performing Solid Oxide Fuel Cells’ by H. Ding (Colorado School of Mines, USA), reviews solution-based, ion infiltration methods of catalysing surfaces in electrode structures. Solution impregnation is well-known in the catalysis industries in general and it is no surprise that it has been adopted with enthusiasm by the SOFC research and development community. Much of the know how has been developed through traditional empirical methods and this chapter reviews progress in the field for a wide variety of catalysts from base and precious metals to complex oxides.

Chapter 9, ‘Modelling Analysis for Species, Pressure, and Temperature Regulation in Proton Exchange Membrane Fuel Cells’ is written by Z. Wang (Texas A&M University-Kingsville, USA). The model emphasis is on understanding the controlling factors in flooding of the MEA under steady-state conditions. The construction of the conservation equations for momentum, mass, species, charge and energy are given in some detail.

In Chapter 10, ‘The Application of Computational Thermodynamics to the Cathode-Electrolyte in Solid Oxide Fuel Cells’ by S. Darvish and M. Asadikiya (Florida International University, USA), the authors use the calculation of phase diagrams (CALPHAD) modelling approach with an emphasis on perovskite and fluorite structural motifs. A comprehensive summary of the materials challenge for SOFC materials when used as electrolytes and cathodes is presented. Complexity is added wherein multiple phases can form due to reaction of the components with gaseous impurities either in the air supply or through, for example, carbon dioxide cross-over from the anode. The CALPHAD approach allows for a workable description of the important defect chemistry of the complex oxides to be predicted together with ionic and electronic conductivities.

In Chapter 11, ‘Application of DFT Methods to Investigate Activity and Stability of Oxygen Reduction Reaction Electrocatalysts’ by X. Chen (Southwest Petroleum University, China) et al., the authors describe the use of density functional theory (DFT) to model and understand the behaviour of PEMFCs at the catalyst level with a focus on the ORR. Not surprisingly, the oxygen binding energy to (pure) metal surfaces is an activity descriptor of choice and its simplest exposition is in the well-known volcano plot which has platinum and palladium close to the apex. More sophisticated approaches consider the energetics of binding of the key intermediates and a mapping of the associated potential energy surface. As well as metallic-type catalysts, some metal-centred, macrocyclic moieties are also investigated for activity. Finally, the stabilities of these various types of ORR catalysts are considered.

Chapter 12, ‘Hydrogen Fuel Cell as Range Extender in Electric Vehicle Powertrains: Fuel Optimization Strategies’ is written by R. Álvarez and S. Corbera (Universidad Nebrija, Spain). As the title suggests, the purpose described in this chapter is to optimise strategies for combining battery and FC power units for range extension. There is a useful summary of the current ‘competitive posturing’ between the various proponents of battery and FC-powered vehicles. A MATLAB^®/Simulink^® vehicle model, coupled with the use of genetic algorithm routines, has been developed to examine the interplay of the electrical and mechanical components of the system over selected drive cycles. Importantly, the FC in this case study is used to maintain the charge of the lithium ion battery rather than as an alternative power source for coupling to the drivetrain directly.

Chapter 13, ‘Totalized Hydrogen Energy Utilization System’ by H. Ito and A. Nakano (National Institute of Advanced Industrial Science and Technology (AIST), Japan) describes a hydrogen-based energy storage system utilising a reversible FC/electrolyser coupled with a metal hydride tank with fluctuating renewable electrical power inputs and heat and electrical power outputs (combined heat and power (CHP)). The heat flow from the system can be both positive and negative i.e. used for cooling or heating. The prototype demonstrator is a ten cell PEM-type stack with <1 kW output. The totalised hydrogen energy utilisation system (THEUS) was run continuously for three days on a fixed duty cycle and data collected and analysed.

Chapter 14, ‘Influence of Air Impurities on the Performance of Nanostructured PEMFC Catalysts’ by O. A. Baturina (Naval Research Laboratory, USA) et al., discusses the practical issues associated with using PEMFC units in the real world with different environments where air-borne pollutants or atmospheric conditions can pose a risk to the proper functioning and longevity of the PEMFC. An example shown is the dramatic and irreversible drop in cathode performance when exposed to low levels of compounds such as hydrogen chloride and bromomethane vapour. The various poisoning mechanisms are discussed together with possible mitigation strategies.

Chapter 15, ‘Solid-State Materials for Hydrogen Storage’ by R. Pedicini (Institute for Advanced Energy Technologies, Italy) et al., gives a general introductory review covering physisorption and chemisorption-based materials. The authors describe the often conflicting requirements that need to be met for a successful hydrogen storage material, such as the storage capacity, the kinetics of release and uptake and the resilience to mechanical degradation after many duty cycles. More novel, polymeric or inorganic hybrid materials are considered including polyether ether ketone-manganese dioxide (PEEK-MnO₂) composites and the use of more esoteric materials such as mixed metal oxides from volcanic ash.

In Chapter 16, ‘Stress Distribution in PEM Fuel Cells: Traditional Materials and New Trends’ by J. de la Cruz (CONACYT-INEEL, Mexico) et al., the authors remind us that as PEMFC stack technology advances, more attention needs to be focused on the mechanical and electrical engineering aspects of cell components such as the bipolar plates and membranes to optimise performance, manufacturability, durability and cost.

Chapter 17, ‘Recent Progress on the Utilization of Nanomaterials in Microtubular Solid Oxide Fuel Cell’ is written by M. H. Mohamed (Universiti Teknologi Malaysia) et al. Effective extension of the electrode-electrolyte-reactant interface in FCs presents material and electrode processing challenges. Micro-tubular SOFCs (MT-SOFCs) are a recent development for engineering porosity in the ceramic anode and cathode where the more traditional pore formers are substituted and supplemented using tailored hollow fibres. Inevitably, there is a compromise to be had in terms of ensuring good densification of materials to minimise ohmic drops while enabling reactant and product transport to function adequately at higher current densities. The authors present a brief review of progress in both medium and higher temperature SOFC systems.

Chapter 18, ‘Nanostructured Materials for Advanced Energy Conversion and Storage Devices: Safety Implications at End-of-Life Disposal’ is written by S. Bashir (Texas A&M University-Kingsville, USA) et al. It is increasingly important for manufacturers to demonstrate that they have considered and mitigated against environmental damage that may arise from the disposal of products at end of life. The conclusion from this work using iron oxide nanoparticles as a test probe of materials entering the environment is that best practice should use a combination of life cycle assessment (LCA) and risk assessment (RA) methodologies.

In summary then, this volume brings together an interesting collection of articles covering mainly hydrogen PEM and SOFC technologies that will help build a more balanced understanding of the commercialisation and technical challenges arising from catalyst behaviour through to stack design.