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Crystallization: Optimal control and advanced monitoring 2.0 (CrystOCAM 2.0)

English title Crystallization: Optimal control and advanced monitoring 2.0 (CrystOCAM 2.0)
Applicant Mazzotti Marco
Number 155971
Funding scheme Project funding (Div. I-III)
Research institution Institut für Verfahrenstechnik ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Chemical Engineering
Start/End 01.06.2015 - 31.08.2018
Approved amount 395'100.00
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Keywords (5)

crystallization; monitoring; morphology; control; particle size distribution

Lay Summary (German)

Lead
Kristallisation ist ein kritischer Prozessschritt während der Produktion von vielen Feinchemikalien und den meisten pharmazeutischen Erzeugnissen. Zum einen erlaubt Kristallisation die Trennung von Produkt und unerwünschten (da mitunter giftigen) Nebenprodukten, zum anderen beeinflusst dieser Schritt wichtige physikalische Eigenschaften, wie zum Beispiel die Grösse und Form der entstehenden Kristalle. Beide Faktoren haben Auswirkungen auf die Verarbeitbarkeit sowie die Aufnahmegeschwindigkeit im menschlichen Körper.Im Vorgängerprojekt ist es mittels innovativer Messtechnik und Modellen gelungen, neue Erkenntnisse über die Mechanismen zu gewinnen, welche die Kristallform beeinflussen. Das Ziel dieses Projekts ist es nun, sich dieses neue Verständnis zu Nutze zu machen und die Rahmenbedingungen von realen Prozessen gezielt so zu wählen, dass Kristalle die gewünschten Eigenschaften aufweisen. Die Resultate dieser Versuche werden helfen, bessere und robustere Prozesse zu gestalten.
Lay summary

Sowohl unsere Fähigkeit Prozesse zu optimieren als auch das Potential Probleme zu erkennen und anschliessend zu lösen sind abhängig von der Tiefe des Verständnis, welches bzgl. der zu Grunde liegenden Mechanismen besteht. Es liegt im Sinne der Gesellschaft, die Suche nach diesem exakteren Verständnis zu fördern. Dies ist besonders der Fall in Gebieten wie der Chemiewirtschaft, die in der Schweiz oftmals hochaktive Wirkstoffe produziert. Es gilt hier, die Qualität dieser Produkte zu sichern und allfällige Fehler strikt zu vermeiden.

Das vorausgegangene Projekt (CrystOCAM) erlaubte es, die Veränderung von Grösse und Form von Kristallen während realer Prozesse detailliert und mit statistischer Signifikanz mit zu verfolgen und mittels physikalischen Modellen zu erklären. Kernstück der Arbeit ist dabei ein neuentwickeltes Kamerasetup, welches es ermöglicht, Kristalle in grosser Anzahl kurzzeitig dem Prozess zu entnehmen, von zwei Perspektiven zu fotografieren und anschliessend wieder zurückzuführen.

In dem neuen Projekt sollen die Lehren aus dem ersten Teil genutzt werden, um die Form und Grösse der geformten Kristalle in eine gewünschte Richtung zu lenken. Insbesondere sollen a) die geprüften mathematischen Modelle genutzt werden, um Voraussagen über das Verhalten des Systems unter verschiedenen Prozessbedingungen treffen zu können, was es wiederum erlaubt, ‚optimale‘ Strategien zu entwerfen und b) der Erfolg dieser Strategien direkt via Messung des tatsächlichen Systemzustands geprüft werden, um bei Bedarf eine Kurskorrektur zu ermöglichen (Feedback-Regelung).

Direct link to Lay Summary Last update: 17.06.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
From needle-like toward equant particles: A controlled crystal shape engineering pathway
Bötschi Stefan, Rajagopalan Ashwin Kumar, Rombaut Igor, Morari Manfred, Mazzotti Marco (2019), From needle-like toward equant particles: A controlled crystal shape engineering pathway, in Computers & Chemical Engineering, 131, 106581-106581.
Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. IV. Modeling and Control of Dissolution
Bötschi Stefan, Rajagopalan Ashwin Kumar, Morari Manfred, Mazzotti Marco (2019), Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. IV. Modeling and Control of Dissolution, in Crystal Growth & Design, 19(7), 4029-4043.
Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. III. Wet Milling
Rajagopalan Ashwin Kumar, Bötschi Stefan, Morari Manfred, Mazzotti Marco (2019), Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. III. Wet Milling, in Crystal Growth & Design, 19(5), 2845-2861.
Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. II. Cooling Crystallization Experiments
Rajagopalan Ashwin Kumar, Bötschi Stefan, Morari Manfred, Mazzotti Marco (2018), Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. II. Cooling Crystallization Experiments, in Crystal Growth & Design, 18(10), 6185-6196.
An Alternative Approach to Estimate Solute Concentration: Exploiting the Information Embedded in the Solid Phase
Bötschi Stefan, Rajagopalan Ashwin Kumar, Morari Manfred, Mazzotti Marco (2018), An Alternative Approach to Estimate Solute Concentration: Exploiting the Information Embedded in the Solid Phase, in The Journal of Physical Chemistry Letters, 9, 4210-4214.
Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. I. Concepts and Simulation Studies
Bötschi Stefan, Rajagopalan Ashwin Kumar, Morari Manfred, Mazzotti Marco (2018), Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. I. Concepts and Simulation Studies, in Crystal Growth & Design, 18(8), 4470-4483.
A comprehensive shape analysis pipeline for stereoscopic measurements of particulate populations in suspension
Rajagopalan Ashwin Kumar, Schneeberger Janik, Salvatori Fabio, Bötschi Stefan, Ochsenbein David R., Oswald Martin R., Pollefeys Marc, Mazzotti Marco (2017), A comprehensive shape analysis pipeline for stereoscopic measurements of particulate populations in suspension, in Powder Technology, 321, 479-493.
Multi-Objective Path Planning for Single Crystal Size and Shape Modification
Bötschi Stefan, Ochsenbein David R., Morari Manfred, Mazzotti Marco (2017), Multi-Objective Path Planning for Single Crystal Size and Shape Modification, in Crystal Growth & Design, 17(9), 4873-4886.
Agglomeration of Needle-like Crystals in Suspension. II. Modeling
Ochsenbein David R., Vetter Thomas, Morari Manfred, Mazzotti Marco (2015), Agglomeration of Needle-like Crystals in Suspension. II. Modeling, in Crystal Growth & Design, 15(9), 4296-4310.

Collaboration

Group / person Country
Types of collaboration
Computer Vision and Geometry lab (CVG), Institute of Visual Computing, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
2019 American Institute of Chemical Engineers (AIChE) Annual Meeting Talk given at a conference Controlled Manipulation of the Size and Shape of Needle-like Compounds in a Cyclic Process 10.11.2019 Orlando, United States of America Bötschi Stefan; Rajagopalan Ashwin Kumar; Morari Manfred; Mazzotti Marco;
12th European Congress of Chemical Engineering Talk given at a conference Controlled Manipulation of Size and Shape of Needle-like Compounds Using Wet-Milling 15.09.2019 Florence, Italy Bötschi Stefan; Mazzotti Marco; Morari Manfred; Rajagopalan Ashwin Kumar;
50th Annual Conference of the British Association of Crystal Growth Talk given at a conference On the Manipulation of the Size and Shape of Needle-like Crystals 09.07.2019 London, Great Britain and Northern Ireland Bötschi Stefan; Morari Manfred; Rajagopalan Ashwin Kumar; Mazzotti Marco;
2018 American Institute of Chemical Engineers (AIChE) Annual Meeting Talk given at a conference Two Feedback Control Schemes for the Size and Shape of Needle-like Crystals Growing in Suspension. 28.10.2018 Pittsburgh, United States of America Rajagopalan Ashwin Kumar; Mazzotti Marco; Morari Manfred; Bötschi Stefan;
2018 American Institute of Chemical Engineers (AIChE) Annual Meeting Talk given at a conference Experimental Implementation of a Model-Free Feedback Controller for the Size and Shape of Needle-like Crystals Growing in Suspension 28.10.2018 Pittsburgh, United States of America Bötschi Stefan; Morari Manfred; Rajagopalan Ashwin Kumar; Mazzotti Marco;
25th International Workshop on Industrial Crystallization Talk given at a conference Size and shape feedback control for growth-dominated batch crystallization processes 05.09.2018 Rouen, France Mazzotti Marco; Rajagopalan Ashwin Kumar; Bötschi Stefan; Morari Manfred;
20th International Symposium on Industrial Crystallization Talk given at a conference The Potential of Size and Shape Feedback Control for Crystal Populations 03.09.2017 Dublin, Ireland Bötschi Stefan; Mazzotti Marco; Morari Manfred;
20th International Symposium on Industrial Crystallization Poster 3D reconstruction and shape classification of crystals for measuring multi-dimensional particle size and shape distribution 03.09.2017 Dublin, Ireland Mazzotti Marco; Rajagopalan Ashwin Kumar; Bötschi Stefan;
23rd International Workshop on Industrial Crystallization Poster A Path Planning Methodology for the Size and Shape Modification of Single Crystals via Temperature Cycling 06.09.2016 Magdeburg, Germany Mazzotti Marco; Morari Manfred; Bötschi Stefan;
30th Meeting of the European Crystallographic Association Talk given at a conference Toward the mitigation of growth rate dispersion through pretreatment of seed crystals 28.08.2016 Basel, Switzerland Rajagopalan Ashwin Kumar; Mazzotti Marco; Bötschi Stefan;
12th International Workshop of the Crystal Growth of Organic Materials Poster Characterizing and mitigating growth rate dispersion effects 26.06.2016 Leeds, United Kingdom, Great Britain and Northern Ireland Bötschi Stefan; Mazzotti Marco; Rajagopalan Ashwin Kumar; Morari Manfred;


Associated projects

Number Title Start Funding scheme
191875 ERASE: Emission Reduction by Array of Sensor Electronics 01.10.2020 Early Postdoc.Mobility
135218 Crystallization: Optimal control and advanced monitoring (CrystOCAM) 01.09.2011 Project funding (Div. I-III)

Abstract

CrystOCAM 2.0 is a proposed follow-up project for a currently ongoing undertaking of the same name (SNF project number 200021-135218). CrystOCAM 2.0 aims at the design and further refinement of a new generation of process analytical technology (PAT) tools and software that allow for an unprecedented capability to measure, model and control the size and shape of crystals during crystallization from solution. The importance of crystallization in the pharmaceutical, food and fine chemical industries stems from its ability to yield highly pure solid products. Beside the final chemical purity, however, the solid state form, the size and the shape of the resulting particles are of paramount importance for the product quality, because they determine characteristics such as filterability, tabletability, flowability and even bioavailability. Practitioners in these industries are well aware of the fact that crystals can take on a variety of shapes, even for the same chemical substance. Any form of control over particle size and especially shape should allow for the design of improved processes. Until recently, however, the optimization of crystallization processes in terms of particle morphology has been hindered by a major obstacle: The lack of reliable, fast and quantitative measurement devices, which prohibited the online monitoring and hence modeling and optimization. The measurement setup and the analysis protocols developed in CrystOCAM are reliable, sensitive as well as accurate and therefore recognized by the scientific community as valuable contributions. Using these newly developed techniques, concepts and phenomena have been uncovered that could not have been monitored in a quantitative fashion prior to the CrystOCAM project. Given these developments, additional opportunities to ask and answer more complex questions have emerged, which are not only of interest from a purely scientific point of view, but also possess the potential to impact industrial applications. These considerations can be categorized into two major research directions which we would like to pursue within the scope of a follow-up project (CrystOCAM 2.0), namely: the study of single crystals and the evaluation of advanced shape manipulation concepts by unconventional processing techniques. The first point, initially motivated by an unexpected discovery during the monitoring of crystal growth of particle ensembles (a significant broadening of the shape distribution; see below), will permit a focused, separate investigation of crystal growth under idealized and highly controlled conditions. The resulting information in turn may be used to shed light on the mechanistic details affecting entire distributions. The second subject aims at expanding the list of decision variables that allow tuning particle shape, e.g., through the introduction of inline milling or temperature cycling.Both subjects would profit from the knowledge and tools that have been developed during the fruitful cooperation of the previous venture and would further advance the field of particle shape measurement, modeling, and control. With the tackling of more complex processes and an additional, heightened focus on the behavior of single crystals, CrystOCAM 2.0 will continue to improve the understanding of fundamental aspects of crystal shape evolution in crystallization processes as a whole.The work is to be carried out by two doctoral students at two groups at ETH Zurich, the Separation Processes Laboratory (SPL) headed by Prof. Marco Mazzotti and the Automatic Control Laboratory (IfA) headed by Prof. Manfred Morari.The following deliverables are expected:- Design of a novel apparatus capable of measuring the exact morphology of single crystals in suspension in real time, allowing the determination of growth and dissolution kinetics of individual facets and helping to acquire data useful for determining the influence of surface defects in seed particles.- A set of verified dynamic models for additional, more complex dynamic processes, such as growth and dissolution cycles, agglomeration and needle breakage.- Development of novel controller structures that are based on the knowledge obtained from both simulations and experiments of the above mentioned complex processes. - Experimental investigations into the practical feasibility and efficacy of the proposed schemes.
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