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Zoltan K Nagy - One of the best experts on this subject based on the ideXlab platform.

  • chapter 2 fundamentals of population balance based crystallization process modeling
    2020
    Co-Authors: Botond Szilagyi, Aniruddha Majumder, Zoltan K Nagy
    Abstract:

    Crystallization is ubiquitous in pharmaceutical manufacturing as a means of separation and purification. The pharmaceutical industry is currently going through a paradigm shift from batch to continuous manufacturing due to its various benefits such as improved Product consistency, improved Productivity, ease of scale up, efficient use of physical space and reduction in energy consumption. Crystallization is a key unit operation in a continuous manufacturing process since in addition to being a critical purification step it also defines the critical properties of the particulate Products. In silico evaluation and design of crystallization systems can significantly reduce process development time and allow the understanding and defining of the optimal operating space. While significant progress has been made to date, this chapter is primarily focused on presenting the basic concepts of modeling and simulation of the two continuous crystallizer platforms – Mixed suspension Mixed Product Removal (MSMPR) crystallizer and plug flow crystallizer (PFC). Starting from the fundamental concepts of the crystallization process, modeling of the various sub processes such as nucleation, growth, aggregation and breakage are discussed. Then, the population balance model for the continuous crystallizer platforms are discussed along with the numerical techniques that can be used to solve the model equations. Finally, a few case studies are presented including cooling and antisolvent crystallizations, as well as crystallization of polymorphic and enantiomeric systems.

  • application of wet milling based automated direct nucleation control in continuous cooling crystallization processes
    Industrial & Engineering Chemistry Research, 2016
    Co-Authors: Yang Yang, Liangcheng Song, Yuqi Zhang, Zoltan K Nagy
    Abstract:

    A novel wet milling-based automated direct nucleation control (WMADNC) concept is proposed and implemented in two continuous cooling crystallization processes in this work. In process 1, WMADNC is implemented upstream to provide closed-loop controlled primary nucleation kinetics and produce seed crystals in situ for continuous Mixed suspension Mixed Product Removal crystallizer (MSMPRC). In process 2, WMADNC is applied downstream to achieve closed-loop controlled secondary nucleation kinetics and reduce particle size for crystals in the MSMPRC through recycling. For both processes, a focused beam reflectance measurement (FBRM)-based closed-loop control approach is successfully implemented to control the nucleation kinetics inside the wet mill therefore to control the final chord length distribution (CLD). In the proposed WMADNC approach, the process critical quality attributes (CQA) (e.g., particle number or size) can be directly controlled by the automated closed-loop control framework, which on one hand...

  • automated direct nucleation control in continuous Mixed suspension Mixed Product Removal cooling crystallization
    Crystal Growth & Design, 2015
    Co-Authors: Yang Yang, Liangcheng Song, Zoltan K Nagy
    Abstract:

    Automated direct nucleation control (ADNC) is a focused beam reflectance measurement-based feedback control approach that is used to produce large and uniform crystals in batch cooling crystallization. In this work, this feedback control approach is modified to work for continuous cooling crystallization processes, including single-stage and multistage Mixed suspension Mixed Product Removal crystallizers. The proposed continuous ADNC approach is observed to provide quick startup, high quality control of crystal size distribution, as well as automated and effective disturbance suppression.

  • toward continuous crystallization of urea barbituric acid a polymorphic co crystal system
    Crystal Growth & Design, 2015
    Co-Authors: Keddon A Powell, Zoltan K Nagy, Chris D Rielly, Giulia Bartolini, Kate Wittering, Ali N Saleemi, Chick C Wilson
    Abstract:

    Pharmaceutical co-crystals are multicomponent molecular systems typically formed through hydrogen bonding of a co-former molecule with the active pharmaceutical ingredient (API). Just as many single component molecular structures can exhibit polymorphism due to the geometry of hydrogen bond donors and acceptors, the same is true for pharmaceutical co-crystals. In this study, the selective co-crystallization of the desired polymorphic form of urea-barbituric acid (UBA) co-crystals (forms I and III) is demonstrated, applying a novel periodic Mixed suspension Mixed Product Removal (PMSMPR) crystallizer cascade. The process was monitored using an integrated process analytical technology (PAT) array consisting of Raman spectroscopy, attenuated total reflectance ultraviolet/visible (ATR-UV/vis) spectroscopy, focused beam reflectance measurement (FBRM), particle vision microscopy (PVM), and an in-house developed commercial crystallization process informatics system (CryPRINS) software tool to determine when a “s...

  • combined cooling and antisolvent crystallization in continuous Mixed suspension Mixed Product Removal cascade crystallizers steady state and startup optimization
    Industrial & Engineering Chemistry Research, 2015
    Co-Authors: Yang Yang, Zoltan K Nagy
    Abstract:

    A continuous multistage Mixed suspension, Mixed Product Removal (MSMPR) cascade crystallization system has been modeled and optimized for both the steady-state and the startup behaviors when both cooling and antisolvent addition are applied as the crystallization driving forces. The optimal steady-state operating profiles of MSMPR cascade crystallizers have been obtained and found to be similar to the optimal batch trajectory. In addition, the minimum startup duration time is used as the objective function to optimize the startup behavior. Methods, including changing the initial solution compositions, applying dynamic antisolvent profiles, applying dynamic temperature profiles, and applying dynamic combined antisolvent and temperature profiles, are discussed and used to formulate the optimization problems. The optimal results indicate that for a cascade of two MSMPR crystallizers, it is possible to achieve a reduction of approximately 50% of the startup duration time and amount of waste. A model-free or d...

Allan S Myerson - One of the best experts on this subject based on the ideXlab platform.

  • Methods for estimating supersaturation in antisolvent crystallization systems
    CrystEngComm, 2019
    Co-Authors: Jennifer M Schall, Gerard Capellades, Allan S Myerson
    Abstract:

    The mole fraction and activity coefficient-dependent (MFAD) supersaturation expression is the least-assumptive, practical choice for calculating supersaturation in solvent mixtures. This paper reviews the basic thermodynamic derivation of the supersaturation expression, revisits common simplifying assumptions, and discusses the shortcomings of those assumptions for the design of industrial crystallization processes. A step-by-step methodology for estimating the activity-dependent supersaturation is provided with focus on ternary systems. This method requires only solubility data and thermal property data from a single differential scanning calorimetry (DSC) experiment. Two case studies are presented, where common simplifications to the MFAD supersaturation expression are evaluated: (1) for various levels of supersaturation of L-asparagine monohydrate in water–isopropanol mixtures and (2) for the dynamic and steady-state Mixed-suspension, Mixed-Product Removal (MSMPR) crystallization of a proprietary API in water–ethanol–tetrahydrofuran solvent mixtures. When compared to the MFAD supersaturation estimation, it becomes clear that errors in excess of 190% may be introduced in the estimation of the crystallization driving force by making unnecessary simplifications to the supersaturation expression. These errors can result in additional parameter regression errors – sometimes by nearly an order of magnitude – for nucleation and growth kinetic parameters, limiting the accurate simulation of dynamic and steady-state crystallization systems.

  • Mixed suspension Mixed Product Removal studies of ciprofloxacin from pure and crude active pharmaceutical ingredients the role of impurities on solubility and kinetics
    Crystal Growth & Design, 2019
    Co-Authors: Gerard Capellades, Helena Wiemeyer, Allan S Myerson
    Abstract:

    Despite the known effects of foreign species on crystallization and the frequently large number of impurities present in multistep pharmaceutical syntheses, the early characterization of continuous crystallization operations may be limited by the availability of representative crude material. As part of the development of an end-to-end process for ciprofloxacin HCl monohydrate, this work evaluates the impact of upstream impurities on Mixed-suspension, Mixed-Product Removal (MSMPR) crystallization kinetics. The kinetic parameters for nucleation and crystal growth in MSMPR crystallization have been estimated for the commercial, purified active pharmaceutical ingredient (API), as well as crude API containing approximately 60 unknown impurities. Results show that, while the upstream impurities did not have a significant impact on the nucleation rate, both the temperature-dependent growth rate coefficient and the growth activation energy decreased in crude API crystallization. This behavior implies that the ef...

  • polymorph control in msmpr crystallizers a case study with paracetamol
    Organic Process Research & Development, 2019
    Co-Authors: Lucrece Nicoud, Filippo Licordari, Allan S Myerson
    Abstract:

    Mixed-suspension Mixed-Product Removal (MSMPR) crystallizers can potentially allow the Production of metastable polymorphs. A necessary (but not sufficient) condition is to select operating conditions such that the steady-state concentration remains above the solubility of the metastable form. In this paper, we provide a framework that helps controlling polymorphism in MSMPR. We consider paracetamol as a model system and target the Production of form II, which is metastable and rapidly converts to form I in batch. We combine experimental characterization (inline infrared spectroscopy, Raman spectroscopy, and imaging) with population balance modeling to investigate the possibility to produce the metastable form in a continuous manner. We identify a design space allowing the visualization of the regions where each form is obtained at steady state as a function of the kinetic parameters of both forms. We show that form II cannot be obtained at steady state in pure ethanol. However, the addition of a small am...

  • Polymorph Control in MSMPR Crystallizers. A Case Study with Paracetamol
    2019
    Co-Authors: Lucrèce Nicoud, Filippo Licordari, Allan S Myerson
    Abstract:

    Mixed-suspension Mixed-Product Removal (MSMPR) crystallizers can potentially allow the Production of metastable polymorphs. A necessary (but not sufficient) condition is to select operating conditions such that the steady-state concentration remains above the solubility of the metastable form. In this paper, we provide a framework that helps controlling polymorphism in MSMPR. We consider paracetamol as a model system and target the Production of form II, which is metastable and rapidly converts to form I in batch. We combine experimental characterization (inline infrared spectroscopy, Raman spectroscopy, and imaging) with population balance modeling to investigate the possibility to produce the metastable form in a continuous manner. We identify a design space allowing the visualization of the regions where each form is obtained at steady state as a function of the kinetic parameters of both forms. We show that form II cannot be obtained at steady state in pure ethanol. However, the addition of a small amount of metacetamol (1% in mass with respect to paracetamol) in the feed is sufficient to obtain form II at steady state. We interpret the effect of metacetamol in light of a kinetic model and quantify its incorporation in the crystals with high-performance liquid chromatography

  • nucleation and growth kinetics for combined cooling and antisolvent crystallization in a Mixed suspension Mixed Product Removal system estimating solvent dependency
    Crystal Growth & Design, 2018
    Co-Authors: Jennifer M Schall, Jasdeep S Mandur, Richard D Braatz, Allan S Myerson
    Abstract:

    Combined cooling and antisolvent crystallization is a critical unit operation in pharmaceutical manufacturing, especially for heat-sensitive or poorly soluble active pharmaceutical ingredients. The model-based design of these systems relies on the accuracy of the underlying growth and nucleation kinetic parameters. Unlike temperature where these kinetic parameters are well-known to follow an Arrhenius relation, their dependency on solvent composition still remains unclear, especially in continuous Mixed-suspension, Mixed-Product Removal (MSMPR) systems. In this paper, we use population balance modeling coupled with nonlinear regression to estimate growth and nucleation parameters as a function of both temperature and solvent composition. As solvent composition increases from 44 vol % to 66 vol % solvent, both growth and nucleation rates were observed to decrease monotonically with their values reduced by almost one-third. It was also shown that, if the solvent dependency is ignored, the yield can be overp...

Yang Yang - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of Mixed suspension Mixed Product Removal crystallization processes coupled with a continuous filtration system
    Chemical Engineering and Processing, 2016
    Co-Authors: David Acevedo, Ramon Pena, Alastair Barton, Yang Yang, Paul Firth
    Abstract:

    Abstract As the pharmaceutical industry evolves and goes through the paradigm shift from batch to continuous manufacturing, innovative processes need to be developed to replace unit operations that have historically been batch operations. This requires innovation in the continuous crystallization field of study as well as innovation in downstream processes ( e.g. filtration, drying, milling, and granulation). Herein a novel and commercially available continuous filter carousel (CFC) system was assessed for its feasibility of continuous filtration while coupled with a continuous Mixed suspension Mixed Product Removal (MSMPR) crystallizer. The filtration system was assessed using two different crystallization systems ( i.e. cooling and antisolvent) with significantly different kinetics and morphologies to assess the robustness of the integrated platform. With proper optimization of the various filtration parameters for the different crystallization systems a controlled state of operation was achieved in each case. The crystal Product from the CFC system shows good consistency with the crystals in the slurry in the MSMPR. Moisture content and Productivity of the filtration system were reported and show dependency on crystal properties. The CFC system was equipped with solvent vessels that aided the continuous filtration by acting as a wash or a clean-in-place solvent, preventing or removing filter clogging, respectively.

  • application of wet milling based automated direct nucleation control in continuous cooling crystallization processes
    Industrial & Engineering Chemistry Research, 2016
    Co-Authors: Yang Yang, Liangcheng Song, Yuqi Zhang, Zoltan K Nagy
    Abstract:

    A novel wet milling-based automated direct nucleation control (WMADNC) concept is proposed and implemented in two continuous cooling crystallization processes in this work. In process 1, WMADNC is implemented upstream to provide closed-loop controlled primary nucleation kinetics and produce seed crystals in situ for continuous Mixed suspension Mixed Product Removal crystallizer (MSMPRC). In process 2, WMADNC is applied downstream to achieve closed-loop controlled secondary nucleation kinetics and reduce particle size for crystals in the MSMPRC through recycling. For both processes, a focused beam reflectance measurement (FBRM)-based closed-loop control approach is successfully implemented to control the nucleation kinetics inside the wet mill therefore to control the final chord length distribution (CLD). In the proposed WMADNC approach, the process critical quality attributes (CQA) (e.g., particle number or size) can be directly controlled by the automated closed-loop control framework, which on one hand...

  • automated direct nucleation control in continuous Mixed suspension Mixed Product Removal cooling crystallization
    Crystal Growth & Design, 2015
    Co-Authors: Yang Yang, Liangcheng Song, Zoltan K Nagy
    Abstract:

    Automated direct nucleation control (ADNC) is a focused beam reflectance measurement-based feedback control approach that is used to produce large and uniform crystals in batch cooling crystallization. In this work, this feedback control approach is modified to work for continuous cooling crystallization processes, including single-stage and multistage Mixed suspension Mixed Product Removal crystallizers. The proposed continuous ADNC approach is observed to provide quick startup, high quality control of crystal size distribution, as well as automated and effective disturbance suppression.

  • combined cooling and antisolvent crystallization in continuous Mixed suspension Mixed Product Removal cascade crystallizers steady state and startup optimization
    Industrial & Engineering Chemistry Research, 2015
    Co-Authors: Yang Yang, Zoltan K Nagy
    Abstract:

    A continuous multistage Mixed suspension, Mixed Product Removal (MSMPR) cascade crystallization system has been modeled and optimized for both the steady-state and the startup behaviors when both cooling and antisolvent addition are applied as the crystallization driving forces. The optimal steady-state operating profiles of MSMPR cascade crystallizers have been obtained and found to be similar to the optimal batch trajectory. In addition, the minimum startup duration time is used as the objective function to optimize the startup behavior. Methods, including changing the initial solution compositions, applying dynamic antisolvent profiles, applying dynamic temperature profiles, and applying dynamic combined antisolvent and temperature profiles, are discussed and used to formulate the optimization problems. The optimal results indicate that for a cascade of two MSMPR crystallizers, it is possible to achieve a reduction of approximately 50% of the startup duration time and amount of waste. A model-free or d...

  • advanced control approaches for combined cooling antisolvent crystallization in continuous Mixed suspension Mixed Product Removal cascade crystallizers
    Chemical Engineering Science, 2015
    Co-Authors: Yang Yang, Zoltan K Nagy
    Abstract:

    Abstract The control approaches for a continuous two stage Mixed suspension Mixed Product Removal (MSMPR) cascade crystallizer are studied in this work. Both cooling and antisolvent addition are applied at both stages to manipulate the process. Considering both crystal size and yield as controlled variables, the attainable region of crystal size and yield is obtained. Two advanced control schemes are discussed: (1) decentralized proportional-integral-derivative (PID) control; and (2) nonlinear model predictive control (NMPC). While decentralized PID control framework is proved to require change of control structure when a relatively large operating region is essential, nonlinear model predictive control scheme shows superior performance for fast target Product property change-over and disturbance rejection.

Liangcheng Song - One of the best experts on this subject based on the ideXlab platform.

  • application of wet milling based automated direct nucleation control in continuous cooling crystallization processes
    Industrial & Engineering Chemistry Research, 2016
    Co-Authors: Yang Yang, Liangcheng Song, Yuqi Zhang, Zoltan K Nagy
    Abstract:

    A novel wet milling-based automated direct nucleation control (WMADNC) concept is proposed and implemented in two continuous cooling crystallization processes in this work. In process 1, WMADNC is implemented upstream to provide closed-loop controlled primary nucleation kinetics and produce seed crystals in situ for continuous Mixed suspension Mixed Product Removal crystallizer (MSMPRC). In process 2, WMADNC is applied downstream to achieve closed-loop controlled secondary nucleation kinetics and reduce particle size for crystals in the MSMPRC through recycling. For both processes, a focused beam reflectance measurement (FBRM)-based closed-loop control approach is successfully implemented to control the nucleation kinetics inside the wet mill therefore to control the final chord length distribution (CLD). In the proposed WMADNC approach, the process critical quality attributes (CQA) (e.g., particle number or size) can be directly controlled by the automated closed-loop control framework, which on one hand...

  • automated direct nucleation control in continuous Mixed suspension Mixed Product Removal cooling crystallization
    Crystal Growth & Design, 2015
    Co-Authors: Yang Yang, Liangcheng Song, Zoltan K Nagy
    Abstract:

    Automated direct nucleation control (ADNC) is a focused beam reflectance measurement-based feedback control approach that is used to produce large and uniform crystals in batch cooling crystallization. In this work, this feedback control approach is modified to work for continuous cooling crystallization processes, including single-stage and multistage Mixed suspension Mixed Product Removal crystallizers. The proposed continuous ADNC approach is observed to provide quick startup, high quality control of crystal size distribution, as well as automated and effective disturbance suppression.

Ewan J Mcadam - One of the best experts on this subject based on the ideXlab platform.

  • is chemically reactive membrane crystallisation faciliated by heterogeneous primary nucleation comparison with conventional gas liquid crystallisation for ammonium bicarbonate precipitation in a co2 nh3 h2o system
    Crystal Growth & Design, 2020
    Co-Authors: Salvatore Bavarella, Mehrez Hermassi, A Brookes, A Moore, P Vale, G Di Profio, Efrem Curcio, Phil Hart, Marc Pidou, Ewan J Mcadam
    Abstract:

    In this study, membrane crystallisation is compared to conventional gas-liquid crystallisation for the precipitation of ammonium bicarbonate, to demonstrate the distinction in kinetic trajectory and illustrate the inherent advantage of phase separation introduced by the membrane to crystallising in gas-liquid systems. Through complete mixing of gas and liquid phases in conventional crystallisation, high particle numbers were confirmed at low levels of supersaturation. This was best described by secondary nucleation effects in analogy to Mixed suspension Mixed Product Removal (MSMPR) crystallisation, for which a decline in population density was observed with an increase in crystal size. In contrast, for membrane crystallisation, fewer nuclei were produced at an equivalent level of supersaturation. This supported growth of fewer, larger crystals which is preferred to simplify Product recovery and limit occlusions. Whilst continued crystal growth was identified with the membrane, this was accompanied by an ...