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Feedback Control of Multicomponent Salt Crystallization
Abstract
A closed-loop strategy is developed for controlling batch cooling multicomponent crystallization. The strategy represents the sequential application of two established feedback control techniques: direct nucleation control followed by supersaturation control. Experimental results show that such a control scheme produces larger crystals (compared to linear cooling crystallization with the same batch time). In using this scheme to control the crystallization of a double salt from a solution containing sodium nitrate and sodium sulfate, we demonstrate the application of supersaturation control to a multicomponent salt crystallization-which requires knowledge of the solubility as a function of temperature, the ability to monitor concentrations in a multicomponent solution, and an appropriate expression for the driving force for crystallization of a salt. In this paper, a methodology for rapidly identifying the solubility of a solute in a multicomponent solution is presented and a new expression for supersaturation-termed the molar supersaturation-is advanced as a measure of the driving force for crystallization of salts.
... This model system came from the original motivating application for our research on crystallization control [Griffin et al., 2015d]. In particular, the relative concentrations of sodium nitrate and sodium sulfate were selected to be representative of nuclear waste compositions at the Hanford site [Nassif et al., 2008]. ...
... The definition of supersaturation is more complicated for multicomponent electrolytic solutions, like that from which darapskite is crystallized. Nevertheless, the molar supersaturation [Griffin et al., 2015d]-a measure analogous to relative supersaturation-can be tracked by monitoring concentration and temperature, provided the more complicated solubility-temperature relationship is known. The molar supersaturation for darapskite is developed in Appendix §A.2. ...
... Solubility trace. For both systems, the solubility-temperature relationship is identified using the solubility trace methodology [Barrett et al., 2010, Kee et al., 2011, which is especially useful for quickly obtaining the solubility-temperature relationship for a multicomponent solution [Griffin et al., 2015d]. The procedure is as follows: the solution is cooled to drive crystallization, allowed to equilibrate at a low temperature, and then slowly heated. ...
... Osim metoda vođenja po konstantnoj prezasićenosti otopine i direktnog vođenja nukleacije razvijene su i metode koje su njihova kombinacija. 18 Iako su te metode vođenja univerzalne i relativno jednostavne za primjenu, nije prikladno uspoređivati ih s metodama temeljenim na modelu procesa. 19 Razvoj modela kristalizacije zahtijeva dosta vremena, ali kao rezultat daje model kojim je moguće simulirati eksperimente umjesto njihova provođenja u laboratoriju. ...
... Promjena iznosa momenata kristala cjepiva s vremenom dana je jedn. (16) - (18). ...
... 33 Cheng and Li calculated the solubility product constant of Mg 5 (CO 3 ) 4 (OH) 2 ·4 H 2 O from solubilities measured at multiple temperatures (with 5°C differences) to analyze the supersaturation profile during the crystallization and its effect on the product morphology. 34 Griffin et al. used this supersaturation formula for supersaturation control in the crystallization of Na 3 SO 4 NO 3 ·H 2 O. 35 They also applied it to create a data-driven empirical model as part of another control strategy. 36 Recently, Albis et al. published a population balance model incorporating K sp -based supersaturation for the crystallization of K 2 SO 4 , 37 but no similar application exists to the best knowledge of the authors for small organic compounds such as diastereomeric salts. ...
... The concept of solubility tracking was applied to indissociable compounds at first, 39,40 but it is more advantageous for dissociable salts. 35 Pregabalin, also known as 3-isobutyl-γ-aminobutyric acid, is a racemate-forming chiral compound with anticonvulsant and anxiolytic effects. 41,42 This top-selling drug was developed and commercialized by Pfizer, but since 2019, it has been available worldwide as a generic medication. ...
... From this initial point, we observed the crystallization of a hydrated double salt, Na 3 SO 4 NO 3 Á H 2 O, on cooling. This choice of model system comes from the motivating application for our research on crystallization control (Griffin et al., 2015). In particular, the relative concentrations of sodium nitrate and sodium sulfate were selected to be representative of nuclear waste compositions at the Hanford site (Nassif et al., 2008). ...
... In this work, the solubility of Na 3 SO 4 NO 3 Á H 2 O in the multicomponent solution was obtained prior to each run with the solubility trace methodology. Furthermore, because Na 3 SO 4 NO 3 Á H 2 O is a multicomponent salt, the molar supersaturation is used (Griffin et al., 2015). ...
We present measurements from batch crystallization as a trajectory in the phase space mapped out by the crystal mass and the total chord count. This new perspective yields a framework for monitoring and controlling crystallization that has two beneficial attributes: first, crystallization is seen as movement—we find that this fosters an intuitive understanding of crystallization kinetics; and, second, the problem of controlling the average crystal size is cast as a trajectory-endpoint control problem—we find that this promotes the development of spatially-oriented control schemes.
The utility of the proposed framework is demonstrated by application. In particular, we apply the framework to: 1) elucidate the effects of simple temperature manipulations on the crystallization kinetics; 2) interpret the actions applied by supersaturation control (SSC) and direct nucleation control (DNC) to produce large crystals; and 3) develop a control scheme—termed spatially-guided action trajectory endpoint control (sGATEC)—that can be applied to produce crystals of pre-selected average size.
... It can be concluded that recirculation to the first stage results in more complex dynamic response. This raises process operation and control related issues: more complex dynamics require more advanced monitoring and control systems (Griffin et al., 2015;Nagy and Braatz, 2012). ...
The batch-production dominated pharmaceutical industries started to evaluate various continuous production platforms recently. With this wave, transitions from batch to continuous crystallization and continuous crystallization design became research topics of interest in the pharma industry. Mixed suspension mixed product removal (MSMPR) crystallizers are intensively investigated due to their relatively simple operation procedure and available experience from other industries. This paper aims to provide a comprehensive population balance model based evaluation of MSMPR cascades with slurry recirculation. Beyond secondary nucleation and crystal growth, a multi-level agglomeration mechanism governing the agglomeration of particles at different turbulence length scales is employed. The dynamic model-equations are transformed and solved using the quadrature method of moments, which paves the way for numerical experimentation and optimal design. An important aim of this paper is to analyze the effects of slurry recycling on system start-up, attainable particle property domains as well as the robustness of the system with respect to kinetic parameter uncertainties and operating condition disturbances. It is shown that the mean product size is generally inversely proportional with the agglomeration degree in a broad operating condition domain for 2,3 and 4-stage MSMPR cascades. The boundaries of the attainable property space are determined numerically by solving appropriate optimization problems. The results suggest that recirculation shrinks the attainable particle size region. The quantification of effects of kinetic parameter uncertainties is approached probabilistically, indicating that the recirculation strategy has weak effects on the robustness in steady-state and transient, too. Finally, simple start-up strategies are compared with the optimal start-up, which revealed that optimization may bring over two-fold start-up time improvement in recirculation enabled systems. However, recirculation results in more complex dynamics, requiring more sophisticated control strategies.
... Supersaturation control (SSC) is another model free control strategy, which is based on the principle that the crystallization process should be conducted in the metastable zone to suppress nucleation (Nagy and Braatz, 2012). These two well established control strategies have found numerous applications, both as solo control strategies (Barrett et al., 2010;Kacker et al., 2016) as well as combined control approach (Griffin et al., 2015) Model based control techniques use real time simulation based on a process model to predict the effects of inputs and disturbances on the systemic output. In essence this translates to real time optimization of the control signal, which in the case of cooling crystallization translates into the prediction of the future temperature profile (Moldoványi et al., 2005;Qin and Badgwell, 2000). ...
Crystallization is a separation and purification process relevant to industrial sectors, such as pharmaceuticals. The maximum possible recovery of solute amount is one of its goals, and the temperature profile is crucial to achieve this. In this work, neural networks-based models were developed to predict the solute concentration of a batch crystallization process and used as internal model in a nonlinear model predictive controller. Three different neural network architectures were considered: the multilayer perceptron (MLP) network, the echo state network (ESN), and the long short-term memory (LSTM). The dataset used for training and testing applied a co-teaching learning algorithm, which uses simulated and experimental data from the batch crystallization of the potassium sulfate (K2SO4). The three network structures were trained to predict the solute concentration one step ahead, using the current temperature and concentration values as feed, and the predictive performances were evaluated for larger prediction horizons. A nonlinear model predictive controller (NMPC) based on the ESN, the most efficient neural network design, was successfully applied to the batch crystallization process to maintain the solute concentration on its desired trajectories by manipulating the operating temperature. The controller's behavior was studied for three different set-points of concentration and supersaturation, varying the initial concentration. The performance of the proposed NMPC was compared to a controller based on a more traditional approach, using the MLP network as internal model.
The kinetic rate equation (KRE) model, unlike the population balance equation model, can describe growth, nucleation, and even Ostwald ripening simultaneously. However, the KRE model cannot be applied in cooling crystallization systems. In this work, we propose a modified KRE model to describe cooling crystallization. The modified KRE model can successfully describe crystal growth and nucleation in cooling crystallization systems. In addition, the metastable zone width was simulated using the modified KRE model and compared with the experimental data in references. The results revealed that the modified KRE model could express the effect of overheating prior to cooling on the metastable zone width. As the extent of overheating increases, the metastable zone width becomes wider, which phenomenon can be clearly simulated by the modified KRE model. This modeling capability is attributed to the behavior of particle clusters that are sized less than the size of sub-nuclei. Because the population balance equation model cannot describe the metastable zone width, the modified KRE model has certain competitive advantages in its application to various crystallization systems.
The control of batch crystallizers is an intensively investigated topic as suitable crystallizer operation can reduce considerably the downstream operation costs and produce crystals of desired properties (size, shape, purity etc.). Nevertheless, the control of crystallizers is still challenging. In this work the development of a fixed batch time full population balance model based adaptive predictive control system for cooling batch crystallizers is presented. The model equations are solved by the high resolution finite volume algorithm involving fine discretization, which provides a high fidelity, accurate solution. A physically relevant crystal size distribution (CSD) to chord length distribution (CLD) transformation is also developed making possible the direct, real-time application of the focused beam reflectance measurement (FBRM) probe in the control system. The measured CLD and concentration values are processed by the growing horizon estimator (GHE), whose roles are to estimate the un-measurable system states (CSD) and to re-adjust the kinetic parameters providing an adaptive feature for the control system. A repeated sequential optimization algorithm is developed for the nonlinear model predictive control (NMPC) optimization, enabling the reduction of sampling time to the order of minutes for the one-day long batch. According to the simulation results the strategy is highly robust to parametric plant-model mismatch and significant concentration measurement noise, providing very good control of the desired CLD.
Crystallization operations are frequently used in a number of industries, in particular in the production of fine chemicals. However, stochastic and nonlinear crystallization kinetics often makes it difficult to determine appropriate operating procedures for producing the desired products. This has motivated the development of online measurement tools and the pursuit of feedback control strategies that can adapt to the observed kinetics and produce consistent products. One important crystal property that often must be controlled is the crystal size distribution. Although a number of feedback control schemes have been proposed to indirectly control the size of crystals, these strategies suffer from the lack of direct feedback on the crystal size during operations. Here we propose the simultaneous use of focused-beam reflectance measurements (FBRM) and attenuated total-reflectance Fourier-transform infrared absorbance (ATR-FTIR) measurements to obtain an online measure of average crystal size: the mass-per-count. In this paper, we give experimental results that indicate a strong correlation between the proposed mass-per-count measure and the average crystal size. Furthermore, we demonstrate the utility of this online measure for determining the effects of certain operations on the evolution of average crystal size. Finally, we use this measure to understand the effects of prevailing feedback strategies - known as supersaturation control and direct nucleation control - and, in doing so, elucidate a feedback control strategy that combines these techniques to produce large crystals more efficiently.
Closed-loop computer control of solution supersaturation based on in-process measurements of the concentration using ATR-FTIR spectroscopy and adaptive determination of the corresponding temperature profile has been applied to control the crystallization of monosodium glutamate from an aqueous solution. The crystal size and its distribution are varied and optimized by applying different control strategies such as rapid desupersaturation, constant supersaturation, and step-changing supersaturation profiles.
Crystallization is the most important unit operation for the separation and purification of chemicals in the pharmaceutical and fine chemical industries. Crystallization processes in pharmaceutical active ingredient manufacturing have been traditionally a recipe-based operations, offering little scope for dynamic process control and improvement. With the change in regulatory climate from quality-by-testing (QbT) to quality-by-design (QbD) and with the advent of the process analytical technology (PAT) initiative, it is timely to examine the impact of such quality-based emphasis on crystallization control. In this paper, we review the important recent developments in the control of crystallization process, and discuss their feasibility and scope for implementation in industrial processes. The control methods to achieve different aspects of crystal product quality, including particle size distribution (PSD), crystal habit and polymorphic form, are discussed separately.
Nuclear power plays a key role in maintaining current worldwide energy growth while minimizing the greenhouse gas emissions. A disposition path for used nuclear fuel (UNF) must be found for this technology to achieve its promise. One likely option is to recycle UNF and immobilize the high-level waste (HLW) by vitrification. Vitrification is the technology of choice for immobilizing HLW from defense and commercial fuel reprocessing around the world. Recent advances in both recycling technology and vitrification show great promise in closing the U.S. nuclear fuel cycle in an efficient fashion. This article summarizes the recent trends, developments, and future options in waste vitrification for both defense waste cleanup and closing the nuclear fuel cycle in the United States.
The academic literature on and industrial practice of control of solution crystallization processes have seen major advances in the past 15 years that have been enabled by progress in in-situ real-time sensor technologies and driven primarily by needs in the pharmaceutical industry for improved and more consistent quality of drug crystals. These advances include the accurate measurement of solution concentrations and crystal characteristics as well as the first-principles modeling and robust model-based and model-free feedback control of crystal size and polymorphic identity. Research opportunities are described in model-free controller design, new crystallizer designs with enhanced control of crystal size distribution, strategies for the robust control of crystal shape, and interconnected crystallization systems for multicomponent crystallization.
The Lasentec focused beam reflectance measurement (FBRM) probe provides in situ particle characterisation over a wide range of suspension concentrations. This is a significant advantage over conventional instruments that require sampling and dilution. However, FBRM gives a chord distribution, rather than a conventional diameter distribution. Both theoretical and empirical methods for converting from chord to diameter data are available, but the empirical method was found to be more successful.
Knowledge of particle properties is essential for understanding how the particles will impact the process. A particle can be defined as a solid with well-defined boundaries; its linear dimensions can range from nanometers (colloids) to millions of meters. It is extremely rare for the particles to be identical in size and shape, so to get a full, accurate, and statistically representative profile of the size or shape distribution of a sample, a large number of particles, often as many as hundreds of thousands, must be analyzed. Once the data have been collected and grouped into the appropriate size intervals, they are usually tabulated and then transformed into a graphical representation. Surface-area-based measurements should be considered when the surface area of the particulate system plays an important role, such as in catalysis, fluidization, dust explosion hazard assessment, or droplet formation. Ensemble techniques, which include laser diffraction, dynamic light scattering, and ultrasonic spectroscopy, can measure large numbers of particles simultaneously. Dynamic light scattering, ultrasonic spectroscopy, sieving, sedimentation, field-flow fractionation are some of the techniques used to know the particle properties. The shape of a large particle can be physically measured and expressed as linear dimensions on orthogonal axes.
The nucleation of the metastable form of a substance or of a mixture of more forms is very common in polymorphic crystallization. Additionally, in industry seed may contain a variable amount of metastable polymorph as impurity, resulting from previous batches or milling, which may compromise the desired outcome of obtaining product of the stable polymorphic form. The natural polymorphic conversion into the stable form is often too slow compared to the normal batch times. In this work, a control strategy to quickly obtain crystals of pure stable form was developed. An active polymorphic feedback control (APFC) strategy is proposed, based on the use of a combination of Raman and ATR-UV/vis spectroscopy using a hierarchical control implementation. The approach detects the formation of the polymorphic mixture and eliminates the metastable form by triggering a controlled dissolution cycle and allowing the growth of the stable form using supersaturation control. A calibration-based approach is used for the solute concentration measurement for the supersaturation control, while for the Raman measurement a calibration-free technique is applied based on the identification of a specific peak in the spectrum associated with the presence of the metastable form. The approach is evaluated in the case of the cooling crystallization of ortho-aminobenzoic acid, used as a model system. It is shown that the proposed APFC technique can lead to pure polymorphic forms in the case of an unseeded crystallization process where nucleation of polymorph mixtures occurs or for seeded crystallization with contaminated seed with unwanted polymorph impurity.
The paper presents a thorough evaluation of different control strategies used in cooling crystallization, namely, unseeded linear cooling, seeded linear cooling, supersaturation control, and automated direct nucleation control. The sensitivity and robustness of supersaturation and automated direct nucleation control approaches are evaluated by varying different process parameters, such as seed loading and heating and cooling rates for the crystallization of paracetamol in isopropyl alcohol. The supersaturation control approach uses concentration information provided by ATR-UV/vis spectroscopy, while the direct nucleation control approach is based on focused beam reflectance measurements. Various statistics were used to assess the performance of each approach and it has been shown that the automated direct nucleation control approach, which requires no prior information about the system, outperformed the other control strategies. For the paracetamol in isopropyl alcohol system, significant variations were found in the metastable zone width in the presence of crystals, which were responsible for the poor performance of the control strategies other than the automated direct nucleation control approach.
In-situ attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and focused-beam reflectance measurement (FBRM) were used to monitor and control the antisolvent crystallization of paracetamol from an acetone–water mixture, which was conducted in a 150 mL flat bottom crystallizer with a Mettler Toledo Easymax Reactor system. Following the monitoring of a series of unseeded and seeded crystallization experiments using a constant addition rate of antisolvent, a simple calculation method for the set point of antisolvent addition rate, to maintain constant supersaturation via ATR-FTIR, was developed and implemented for feedback control of unseeded and seeded crystallizations. The implemented technique used a single peak in the ATR-FTIR spectral region without any calibration to effectively maintain supersaturation to a prespecified set point. By developing a solubility curve in terms of peak height and knowing key information of the process at any given time, the addition rate of antisolvent could be manipulated to suit the demands of the crystallization. Four set point control experiments, three seeded and one unseeded, were investigated for comparison and were compared using FBRM, particle size distribution (PSD), and offline microscope image analysis. The results of the controlled feeding rate experiments show an increase in the final particle size measured by PSD, a decrease in the total batch time, and a reasonable elimination of agglomeration in the system.
Infrared absorbance measurements can be made in situ and rapidly. Calibrating these measurements to give solution compositions can therefore yield a powerful tool for process monitoring and control. In many applications it is desirable to monitor the concentrations of multiple components in a complex solution under varying process conditions (which may introduce error in the absorbance measurements). Establishing a model that is capable of accurately predicting the concentrations of multiple components from infrared absorbance measurements that may be corrupted by error requires a carefully designed calibration procedure-a key part of which is model regression. In this article, a number of commonly used multivariate regression techniques are examined in the context of developing a model for simultaneously predicting the concentrations of four solutes from noisy infrared absorbance measurements. In addition, a tailored support vector regression algorithm-designed to produce a robust (measurement error-insensitive) calibration model-is developed, tested, and compared against these established regression algorithms.
The empirical model developed in the present work allows estimation of crystal size distributions from focused beam reflectance measurements (FBRM) of chord length distributions. The model is constructed from purposely varied crystal size distributions and the corresponding measured chord length distributions, which allows construction of a transformation matrix relating the two distributions. Experimental results show advantages over more complex phenomenological models, presumably because the transformation matrix implicitly embodies such phenomena. The ability of the model to address varying crystal concentration and selectively added size fractions is demonstrated with experimental results. Finally, the simplicity of the approach allows rapid (of order 0.1 s) estimation of crystal size distributions from FBRM, which is a promising outcome for potentially using the approach in an on-line control scheme.
Currently applied methods for measurement of solubility and supersaturation based on viscometry, refractometry, interferometry and density require the separation of phases prior to measurement. ATR (attenuated total reflection) infrared spectroscopy provides a unique configuration in which the infrared spectrum of a liquid phase can be obtained in a slurry without phase separation. The applicability of the technique was investigated using a micro Circle® open boat cell equipped with a ZnSe (zinc selenide) ATR rod. Experiments conducted with aqueous citric acid proved that ATR infrared spectroscopy can be successfully employed to determine solubility and supersaturation.
Secondary nucleation (e.g. due to attrition) and accidental seeding (e.g. from crust on the wall of vessels) are undesired events that often take place during industrial crystallization processes. The crystal size distribution is greatly affected by these events. The typically used open loop control strategies fail to respond to these dynamic changes resulting in undesired end product properties. Variations in seed quality during seeded operations (e.g. initial breeding) can also result in undesired product quality. The automated direct nucleation control (ADNC) approach presented in this paper automatically detects any changes in the system and removes fines in situ. The approach is tested for external seed additions and accidental seeding scenarios. The results show that the ADNC approach is able to detect any changes in the metastable zone width and drive the system accordingly to dissolve unwanted fines providing an automatic in situ fines removal mechanism.
The Fractional Crystallization Pilot Plant was designed and constructed to demonstrate that fractional crystallization is a viable way to separate the high-level and low-activity radioactive waste streams from retrieved Hanford single-shell tank saltcake. The focus of this report is to review the design, construction, and testing details of the fractional crystallization pilot plant not previously disseminated.
Crystallization is one of the most important unit operations used for the separation and purification of crystalline solid products. Appropriate design and control of the crystallization process is paramount to produce crystalline products with tailor-made-properties. This paper provides an overview of selected recent developments in the modelling, monitoring and control of crystallization processes. We consider the topics discussed in this review to be enabling technologies for the development of the next generation of crystallization processes with significantly improved predictability, robustness and controllability.
The temperature profile applied during batch cooling crystallization affects the supersaturation level, which in turn affects the crystal size distribution. It is possible, in principle, to calculate the optimal cooling profile; however, the nucleation and growth kinetics are rarely known to the degree of accuracy necessary for this calculation. The current study demonstrates an alternative approach to determination of the optimal cooling profile without any prior knowledge of kinetic data or subsequent modeling. An attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectrometer was used to monitor the supersaturation level during batch cooling crystallization. The ATR-FTIR was interfaced to a LABMAX automatic reactor system that was used in a feedback mode to control the cooling rate so that the supersaturation level remained close to the solubility throughout the cooling process. The resulting temperature profile corresponds to the optimal operating conditions for the maximum in the mean crystal size.
One of the primary tasks in the clean up of the Hanford Reservation is the retrieval of waste from single-shell and double-shell storage tanks. The waste will be used as feedstock for the vitrification plant under construction in the Hanford 200 East area. To accomplish this tank waste retrieval, the River Protection Project requires physical and chemical data on the nature of the wastes. For several years, laboratory tests have been conducted at the 222-S Laboratory on the dissolution characteristics of Hanford saltcake waste from single shell tanks (Herting 1998, 1999, 2000,2001). The bulk physical and chemical data determined during these studies has provided valuable input for evaluating the Environmental Simulation Program produced by OLI Systems, Inc. of Moms Plains, New Jersey. This computer program is used by the River Protection Project to predict chemical solubility during dilution and retrieval of tank wastes. The characterization of solid phases found in saltcake undergoing dissolution and evaporative concentration is an important adjunct to the bulk physical and chemical properties of the saltcake waste. The phase analysis of Tank BY-109' saltcake, described in this report, was conducted using polarized light microscopy (PLM), X-Ray diffraction (XRD) and scanning electron microscopy (SEM). The phases Na{sub 7}F(PO{sub 4}){sub 2} {center_dot} 19H{sub 2}O, Na{sub 3}FSO{sub 4}, Na{sub 2}C{sub 2}O{sub 4} and NaF were identified in BY-IO9 saltcake by all three instruments, while Na{sub 3}AlF{sub 6} was observed in XRD and SEM analyses. In addition, the SEM found significant amounts of a fine-grained aluminum-rich phase, frequently associated with lesser amounts of chromium and sodium. PLM noted the presence of a fine-grained agglomerated phase that was probably this aluminum-rich phase, and XRD confirmed the presence of an aluminum hydroxide, bayerite, in one sample. Finally, the SEM located a number of discrete particles of an aluminosilicate phase and a uranium-rich phase, as well as occasional particles of exotic composition, such as chromium-rich, calcium/strontium-rich and bismuth/palladium-rich. These phases were too rare, or too poorly crystalline, to be identified by PLM or XRD analysis. While the emphasis of this report is on phase analysis of Tank BY-IO9 saltcake, examples of phases identified in other tanks are included where appropriate. The hope of the authors is that this document will serve as a visual reference for future phase analysis efforts, both at the 222-S Laboratory and at other Department of Energy sites where similar tank waste samples are characterized. At the same time, the reader is cautioned that this is a work in progress, that is, the methods employed here are still being developed and refined.
The Hanford site has 149 underground single-shell tanks (SST) storing mostly soluble, multi-salt mixed wastes resulting from Cold War era weapons material production. These wastes must be retrieved and the salts immobilized before the tanks can be closed to comply with an overall site-closure consent order entered into by the US Department of Energy, the Environmental Protection Agency, and the State of Washington. Water will be used to retrieve the wastes and the resulting solution will be pumped to a proposed pretreatment process where a high-curie (primarily {sup 137}Cs) waste fraction will be separated from the other waste constituents. The separated waste streams will then be vitrified to allow for safe storage as an immobilized high-level waste, or low-level waste, borosilicate glass. Fractional crystallization, a common unit operation for production of industrial chemicals and pharmaceuticals, was proposed as the method to separate the salt wastes; it works by evaporating excess water until the solubilities of various species in the solution are exceeded (the solubility of a particular species depends on its concentration, temperature of the solution, and the presence of other ionic species in the solution). By establishing the proper conditions, selected pure salts can be crystallized and separated from the radioactive liquid phase. The aforementioned parameters, along with evaporation rate, proper agitation, and residence time, determine nucleation and growth kinetics and the resulting habit and size distribution of the product crystals. These crystals properties are important considerations for designing the crystallizer and solid/liquid separation equipment. A structured program was developed to (a) demonstrate that fractional crystallization could be used to pre-treat Hanford tank wastes and (b) provide data to develop a pilot plant design.
In the cooling crystallization of cyclotrimethylene trinitramine (RDX) from γ-butyrolactone, an internal seeding method combined with temperature cycling, was applied to suppress liquid inclusion and improve particle size and size distribution for RDX at initial saturation temperatures of 60−80 °C. The process parameters including initial cooling rate, the range of the temperature cycle, and recooling rate during crystal growth period were determined based on direct measurements of size and amount of liquid inclusion of RDX crystals. Crystal size was measured by a dynamic light scattering particle size analyzer. Liquid inclusion was characterized in mass and area measurement based content by gas chromatography and matching refractive index method combined with image analysis. In the present work, RDX particles with average crystal sizes of 169.0−322.0 μm and inclusion area contents of 4.4−5.3% were obtained. Those values imply that the crystal quality of RDX is much improved compared with those of commercial RDXs such as Hanwha-RDX (conventional grade; average crystal size of 158.0 μm and inclusion area content of 9.3%) and I-RDX (reduced sensitivity grade; average crystal size of 218.0 μm and inclusion area content of 5.0%). For instance, the average crystal size of RDX obtained from a saturated solution at 70 °C by the present method is 290.3 μm, which was much larger than that of I-RDX, but the inclusion area content was about 4.6%, which was even lower than that of I-RDX.
Automation, in situ monitoring, and process control tools are implemented to understand and control the crystallization of an active pharmaceutical ingredient in development. As a first step in the study, the metastable zone is generated automatically by linking a laser backscattering probe to an automated laboratory reactor. Using the metastable zone as a guide, crystallization experiments with varying cooling rates and seeding protocols are conducted and monitored. The evolution of solution concentration and supersaturation is determined by transmitting data from an in situ total reflectance Fourier transform infrared (ATR-FTIR) spectroscope to the laboratory reactor. Supersaturation profiles coupled with data from the laser backscattering probe demonstrate the prevalence of primary and secondary crystal nucleation in the process. A cascaded proportional-integral controller is tuned and implemented to promote crystal growth over nucleation by maintaining supersaturation at low constant values. Nonlinear temperature profiles that result in crystals of larger size are thereby generated.
The modeling of crystal quality (size, shape, and purity) is discussed. Numerical methods for the model solution are reviewed including collocation and Galerkin's method on finite elements. Measurement technologies for on-line crystal size distribution are presented. The difficulties with laser light scattering methods are discussed in detail. Parameter estimation is reviewed and new methods based on nonlinear optimization are presented. Sample calculations of parameters and their uncertainty from experimental data are included. The research literature covering control of continuous and batch crystallization is reviewed, and sample calculations of optimal cooling profiles for batch crystallizers are presented.
An in-line technique involving focused beam reflectance measurement (FBRM) for control of crystal product quality in unseeded systems is proposed. The method consists of nucleation detection followed by a holding time to internally generate seeds through primary nucleation and then controlled conditioning of these seeds using FBRM measurement of the particle size distribution (PSD). The technique has been successfully implemented for the cooling crystallization of glycine and paracetamol in water. Results showed that the crystal product consistency using our technique was comparable to that of externally seeded crystallizations.
In this paper, we report a process control strategy for the production of metastable α-form glycine crystals of a desired mean mass size by manipulating the alternating temperature profile and the final termination temperature. The seed crystals of the α-form glycine introduced were grown successfully to the size of the product with no fine crystals. Generation of the γ-glycine crystals (stable polymorph) was completely avoided. This crystallization method is flexible and easy to operate, because the alternating temperature profile can be determined on-site according to the transient supersaturation and particle count number data obtained from an in-situ ATR-FTIR spectrometer and an in-situ FBRM particle counter, respectively. The termination time or batch time was also determined on-site to a point that the residual supersaturation became zero. This on-site strategy-determination technique is expected to be applied widely for a variety of polymorphic systems other than the glycine−water system as a practical method for the selective crystallization of metastable polymorphs.
The Lasentec focused beam reflectance measurement (FBRM) probe provides in situ particle characterisation over a wide range of suspension concentrations. This is a significant advantage over conventional instruments that require sampling and dilution. However, FBRM gives a chord distribution, rather than a conventional diameter distribution. Both theoretical and empirical methods for converting from chord to diameter data are available, but the empirical method was found to be more successful. The FBRM response has been compared to conventional particle sizing techniques (laser diffraction and electrical sensing zone) for a range of sieved aluminium or calcite suspensions. The mode average of the square-weighted chord length was found to be comparable to other sizing techniques over the range from 50 to 400 μm. The square-weighted FBRM results were essentially unaffected by changes to the instrument focal position, the suspension fluid flow velocity, or the solid fraction in the range 0.1-20% w/v.
An increased interest has been directed towards the crystallization of pharmaceuticals and proteins in recent years, which have addi-tional complications compared to the extensively studied inorganic batch and continuous crystallizations. Recent advances in process analytical technology have enabled the improved modeling and control of batch crystallization. This paper compares simulations and experiments between the classical temperature control approach developed in the 1970–1990s with the concentration-control approach developed more recently. The latter approach, which uses attenuated total reflection–Fourier transform infrared (ATR–FTIR) spectros-copy and feedback control to follow a setpoint trajectory in the solution concentration as a function of temperature, results in reduced sensitivity of the product quality to certain disturbances. The resulting guidelines from the simulations are applied to the experimental investigation of the crystallization of paracetamol in water.
Recent advances in in situ measurement technology and automation of batch crystallizers have enabled the development of batch crystallization recipes in which the desired supersaturation profile is followed by feedback control. This paper describes a new approach for following supersaturation setpoints for antisolvent crystallizations that is easy to implement for the tried crystallization. Simulations and application to a proprietary drug compound demonstrate how this combination of automation and in process measurements enables the rapid development of batch crystallization processes in the pharmaceutical industry.
A systematic approach is developed for the in situ control of the crystal size distribution, and is applied to the aqueous crystallization of paracetamol (acetaminophen) as a model pharmaceutical system. This involves the determination of the solubility curve and the metastable limit, and the operation of concentration-controlled batch crystallization. The solution concentration and the solubility curve of paracetamol in water are determined using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy coupled with chemometrics. The metastable zone width of paracetamol is determined using laser backscattering and ATR-FTIR spectroscopy. Seeded batch crystallizations of paracetamol following a desired supersaturation profile near the metastable limit are carried out using in situ solution concentration measurements obtained from ATR-FTIR spectroscopy. The in situ chord length distributions of crystals obtained from laser backscattering are related to characteristics of the crystal size distribution. Product crystals where the supersaturation temporarily exceeded the metastable limit during operation contained agglomerates and exhibited large size variation. Larger product crystals of more uniform size and shape are obtained from operation where supersaturation was successfully controlled to stay within the metastable limit.
The presence of sulfur in radioactive waste to be incorporated in borosilicate glasses entails difficulties mainly due to the relatively low solubility of sulfates in the vitreous phase. In this work a study is presented on the effects of the ratio R = [Na2O]/[B2O3], the type of sulfate added and the addition of V2O5 on the incorporation of sulfates in borosilicate glasses. Glass samples were prepared at the laboratory scale (up to 50–100 g) by melting oxide and sulfate powders under air in Pt/Au crucibles. XRF and ICP/AES chemical analysis, SEM/EDS, microprobe WDS and Raman spectroscopy were employed to characterize the fabricated samples. The main experimental results confirm that the incorporation of sulfates in borosilicate glasses is favored by the network depolymerization, which evolves with the ratio R. The addition of V2O5 seems to accelerate the kinetics of sulfur incorporation in the glass and, probably, increase the sulfate solubility by modifying the borate network and fostering the formation of voids of shape and size compatible with the sulfur coordination polyhedron in the glassy network. The kinetics of X2SO4 incorporation in the glass seems to be slower when X = Cs.
A key bottleneck in the production of pharmaceuticals and many other products is the formation of crystals from solution. The control of the crystal size distribution can be critically important for efficient downstream operations such as filtration and drying, and product effectiveness (e.g., bioavailability, tablet stability). This paper provides an overview of recent developments in the control of crystallization processes, including activities in sensor technologies, model identification, experimental design, process simulation, robustness analysis, and optimal control.
Crystallization is the main separation and purification process for the manufacturing of drug substances. Not only does crystallization affect the efficiency of downstream operations such as filtering, drying, and formulating, the efficacy of the drug can be dependent on the final crystal form. Advances in simulation and control algorithms and process sensor technologies have enabled the development of systematic first-principles and direct design approaches for the batch control of crystallization processes. These approaches address different challenges associated with pharmaceutical crystallization control. This paper provides an overview of recent technological advances in the in situ control of pharmaceutical crystallization processes. Implementation of the first-principles and direct design approaches are compared, and their relative merits are explained. Areas of future opportunities for application of advanced control strategies in pharmaceutical crystallization are presented.
This article is Restricted Access. It was published in the journal, Crystal Growth and Design [© American Chemical Society] and is available from: http://pubs.acs.org/doi/abs/10.1021/cg800131r The paper presents a thorough simulation and experimental evaluation of the concentration control approach for batch and semibatch crystallization. The sensitivity of concentration feedback control is assessed in the case of various disturbances that result in excessive nucleation events. The enhanced robustness of the concentration control is demonstrated against the widely used direct operation approach, which directly implements the temperature or anti-solvent addition rate versus time. Two adaptive supersaturation control approaches are proposed that employ measurement of the number of particle counts per unit time provided by in-situ laser backscattering, to detect the onset of nucleation and adapt the operating curve accordingly, further enhancing the robustness of the approach. Simulation and experimental results indicate that adaptive concentration control is robust to variations in the nucleation, growth, or dissolution rates due to scale-up or other changes in the process conditions. Restricted access
This article is restricted access. It was published in the journal, Crystal Design and Growth [© American Chemical Society]. The definitive version is available at: http://pubs.acs.org/doi/abs/10.1021/cg800595v The control of crystal size distribution (CSD) in pharmaceutical crystallization is of primary importance, as downstream processes such as filtration or drying are greatly affected by the properties of the CSD. It is recognized that the variability in the final CSD is mainly caused by the significant uncertainties in the nucleation rates, and therefore, a good control of nucleation events is necessary to achieve the desired CSD. In this paper, a new direct nucleation control (DNC) approach is introduced that directly controls the apparent onset of nucleation defined as the formation of new particles with detectable size using in situ instruments. The approach uses information on nucleation and dissolution, provided by focused beam reflectance measurement (FBRM), in a feedback control strategy that adapts the process variables, so that the desired quality of product is achieved, for example large crystals with a narrow CSD. In addition, DNC provides in situ fines removal through the operating protocol, rather than having additional equipment and external recycle loops. DNC does not require concentration measurement and has the advantage of being a model-free approach, requiring no information on nucleation or growth kinetics in order to design an operating curve. The DNC approach automatically and adaptively detects the boundary of the operating zone; hence it is more robust to the presence of impurities or residual solvent than the supersaturation control approach. The approach has been applied for the crystallization of glycine and experimental results demonstrate the benefits of DNC of producing larger crystals with narrower CSD compared to classical operations. Restricted access
Acceleration of the schedule for decontamination of the Hanford site using bulk vitrification requires implementation of a pretreatment operation. Medium-curie waste must be separated into two fractions: one is to go to a waste treatment and immobilization plant and a second, which is low-activity waste, is to be processed by bulk vitrification. The work described here reports research on using fractional crystallization for that pretreatment. Sodium salts are crystallized by evaporation of water from solutions simulating those removed from single-shell tanks, while leaving cesium in solution. The crystalline products are then recovered and qualified as low-activity waste, which is suitable upon redissolution for processing by bulk vitrification. The experimental program used semibatch operation in which a feed solution was continuously added to maintain a constant level in the crystallizer while evaporating water. The slurry recovered at the end of a run was filtered to recover product crystals, which were then analyzed to determine their composition. The results demonstrated that targets on cesium separation from the solids, fractional recovery of sodium salts, and sulfate content of the recovered salts can be achieved by the process tested.
The objective of every industrial crystallization process is to create crystals that meet specifications on size, shape, composition, and internal structure. This objective is achieved using a variety of methods and equipment configurations depending on the properties of the chemical system, the end-product specifications, and the production scale. This paper explain how crystallization is controlled in industrial processes and what challenges must be overcome to achieve better control
Clean Salt Process -Final Report: Environmental Management
- D L Herting
Herting, D. L. Clean Salt Process -Final Report: Environmental Management, 1996.
Advances and New Directions in Crystallization Control Recent Advances in the Monitoring, Modelling and Control of Crystallization Systems Model Identification and Control of Solution Crystallization Processes -a Review
- Z K Nagy
- R D Braatz
- Z K Nagy
- G Fevotte
- H Kramer
- L L Simon
- J B Rawlings
- S M Miller
- W R Witkowski
Nagy, Z. K.; Braatz, R. D. Advances and New Directions in Crystallization Control. Annu. Rev. Chem. Biomol. Eng. 2012, 3. (10) Nagy, Z. K.; Fevotte, G.; Kramer, H.; Simon, L. L. Recent Advances in the Monitoring, Modelling and Control of Crystallization Systems. Chem. Eng. Res. Des. 2013, 91, 1903−1922. (11) Rawlings, J. B.; Miller, S. M.; Witkowski, W. R. Model Identification and Control of Solution Crystallization Processes -a Review. Ind. Eng. Chem. Res. 1993, 32.
Automated in-Line Technique Using Fbrm to Achieve Consistent Product Quality in Cooling Crystallization. Cryst. Growth Des Application of Internal Seeding and Temperature Cycling for Reduction of Liquid Inclusion in the Crystallization of Rdx
- R B H Tan
Tan, R. B. H. Automated in-Line Technique Using Fbrm to Achieve Consistent Product Quality in Cooling Crystallization. Cryst. Growth Des. 2007, 7, 1416−1422. (20) Kim, J.-W.; Kim, J.-K.; Kim, H.-S.; Koo, K.-K. Application of Internal Seeding and Temperature Cycling for Reduction of Liquid Inclusion in the Crystallization of Rdx. Org. Process Res. Dev. 2011, 15, 602−609.
Seeding and Constant-Supersaturation Control by Atr-Ftir in Anti-Solvent Crystallization Novel, Calibration-Free Strategies for Supersaturation Control in Antisolvent Crystallization Processes Active Polymorphic Feedback Control of Crystallization Processes Using a Combined Raman and Atr-Uv
- R B H Tan
- D Duffy
- M Barrett
- B Glennon
- D L Herting
- G A Cooke
Tan, R. B. H. Seeding and Constant-Supersaturation Control by Atr-Ftir in Anti-Solvent Crystallization. Org. Process Res. Dev. 2006, 10, 717−722. (28) Duffy, D.; Barrett, M.; Glennon, B. Novel, Calibration-Free Strategies for Supersaturation Control in Antisolvent Crystallization Processes. Cryst. Growth Des. 2013, 13, 3321−3332. (29) Simone, E.; Saleemi, A. N.; Tonnon, N.; Nagy, Z. K. Active Polymorphic Feedback Control of Crystallization Processes Using a Combined Raman and Atr-Uv/Vis Spectroscopy Approach. Cryst. Growth Des. 2014, 14, 1839−1850. (30) Herting, D. L.; Cooke, G. A.;
Adaptive Concentration Control of Cooling and Antisolvent Crystallization with Laser Backscattering Measurement Development of an Empirical Method Relating Crystal Size Distributions and Fbrm Measurements
- Z K Nagy
- R B H Tan
- R D Braatz
- R W Rousseau
(33)
Woo, X. Y.; Nagy, Z. K.; Tan, R. B. H.; Braatz, R. D. Adaptive Concentration Control of Cooling and
Antisolvent Crystallization with Laser Backscattering Measurement. Cryst. Growth Des. 2008, 9, 182-191.
(34)
Li, H.; Grover, M. A.; Kawajiri, Y.; Rousseau, R. W. Development of an Empirical Method Relating
Crystal Size Distributions and Fbrm Measurements. Chem. Eng. Sci. 2013, 89, 142-151.
- Anti-Solvent Crystallization
Anti-Solvent Crystallization. Org. Process Res. Dev. 2006, 10, 717-722.
- M Fujiwara
- P S Chow
- D L Ma
- R D Braatz
Fujiwara, M.; Chow, P. S.; Ma, D. L.; Braatz, R. D. Paracetamol Crystallization Using Laser
Backscattering and Atr-Ftir Apectroscopy: Metastability, Agglomeration, and Control. Cryst. Growth Des.
2002, 2, 363-370.
- G X Zhou
- M Fujiwara
- X Y Woo
- E Rusli
- H H Tung
- C Starbuck
- O Davidson
- Z H Ge
- R D Braatz
Zhou, G. X.; Fujiwara, M.; Woo, X. Y.; Rusli, E.; Tung, H. H.; Starbuck, C.; Davidson, O.; Ge, Z. H.;
Braatz, R. D. Direct Design of Pharmaceutical Antisolvent Crystallization through Concentration Control.
Cryst. Growth Des. 2006, 6, 892-898.