Project

Back to overview

Chiral resolution in systems exhibiting liquid-liquid phase separations

English title Chiral resolution in systems exhibiting liquid-liquid phase separations
Applicant Mazzotti Marco
Number 143270
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 01.08.2013 - 31.07.2016
Approved amount 212'139.00
Show all

Keywords (4)

Process design; Chirality; Liquid-liquid phase separations; Crystallization

Lay Summary (Italian)

Lead
Chiral resolution
Lay summary

I principi attivi costituiti da molecole chirali caratterizzano oggi la maggior parte dei prodotti farmaceutici commercializzati. Tuttavia, enantiomeri diversi esibiscono interazioni differenti con i sistemi biologici, con effetti sia terapeutici sia tossici, a causa della loro differente chiralità. È pertanto indispensabile isolare la forma chirale di interesse ad un elevato grado di purezza: a tale scopo, una delle tecniche più utilizzate è la cristallizzazione. Un possibile limite nell’impiego di questa tecnica è costituito dalla formazione di una seconda fase liquida oleosa, precedente lo sviluppo della fase solida. Questo fenomeno, nella letteratura noto come “oiling out”, produce dei cristalli contaminati da impurità, in luogo dell’enantiomero solido puro. Generalmente, un processo contraddistinto da oiling out viene abbandonato senza ulteriori ricerche.

Questo progetto si propone di individuare le condizioni operative per ottenere enantiomeri puri, evitando l’ oiling out e consentendo, perciò, una più rapida commercializzazione dei farmaci che li contengono, a beneficio sia dei malati sia della comunità medica.

La comprensione e la sviluppo di un processo di risoluzione enantiomerica, mediante cristallizzazione, richiede numerosi strumenti teorici. Innanzitutto, si deve disporre di un accurato ed attendibile modello termodinamico che indichi a quali condizioni (temperatura, pressione,…) si possano ottenere elevate purezze, evitando al contempo l’oiling out. In secondo luogo, è  necessario caratterizzare la cinetica del processo, così da poter selezionare le condizioni operative migliori, come ad esempio le temperature iniziali e finali, le velocità di alimentazione dei componenti, la velocità di raffreddamento, le concentrazioni. La combinazione delle informazioni termodinamiche e cinetiche permette conseguentemente di sviluppare un processo robusto che ottimizzi la purezza e la produzione dell’enantiomero desiderato.

Lavorando nel progetto INTENANT, finanziato nell’ambito di EU/FP7 (2010-2012), il nostro gruppo ha acquisito esperienza nella caratterizzazione termodinamica dei diagrammi di fase di miscele chirali, incluso il fenomeno di oiling out. Grazie ai risultati di questi progetti, è stata sviluppata una solida base per lo studio delle cinetiche e la stima dei parametri di processo. Combinando tali ricerche e risultati, l’obiettivo, ora, è l’elaborazione dei modelli atti a consentire e facilitare la produzione, tramite cristallizzazione ,di sostanze chirali caratterizzate da oiling out.

Direct link to Lay Summary Last update: 26.07.2013

Lay Summary (English)

Lead
Chiral resolution in systems exhibiting liquid-liquid phase separations
Lay summary

Currently drugs containing a chiral center represent a large fraction of marketed pharmaceuticals. However, it is of prime importance to isolate the target enantiomer due to therapeutic effect or toxicity differences with respect to its other enantiomers. Crystallization is a widely used technique to obtain the desired enantiomer with high purity.  In crystallization processes a challenge is the possible emergence of “oiling out”. Oiling out refers to the formation of an oily phase instead of a pure solid enantiomer, and the process is normally discarded without an in depth investigation. This project aims at designing operating conditions for pharmaceuticals production of pure enantiomeric drugs by avoiding oiling out, and therefore possibly allowing timely marketability of important medicines for patient and overall community care.

Several tools need to be developed in order to understand and design crystallization purification processes for chiral resolution. An accurate thermodynamic model indicates which operating regions yield pure solids, and how to avoid oiling out. Kinetic knowledge guides the selection of operating conditions such as cooling rates, antisolvent addition rates, initial and final temperatures and concentrations. The combination of thermodynamic and kinetic understanding then allows optimal and robust design for maximal recovery and purity of the target enantiomer.

By working in the INTENANT project funded in the frame of EU/FP7 (2010-2012) our group has gathered expertise in the thermodynamic characterization of chiral mixture’s phase diagram, including oiling out. Previous projects developed a strong basis for kinetic measurements and parametric estimation.  Combining previous research the objective is now to develop tools that will enable and facilitate the production by crystallization of chiral substances exhibiting oiling out. 

 

Direct link to Lay Summary Last update: 26.07.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Influence of Liquid-Liquid Phase Separation on the Crystallization of L -Menthol from Water
de Albuquerque Ian, Mazzotti Marco (2017), Influence of Liquid-Liquid Phase Separation on the Crystallization of L -Menthol from Water, in Chemical Engineering & Technology, 40(7), 1339-1346.
Effect of needle-like crystal shape on measured particle size distributions
de Albuquerque I., Ochsenbein D.R., Morari M., Mazzotti M. (2016), Effect of needle-like crystal shape on measured particle size distributions, in AIChE J, 62(9), 2974-2985.
Crystallization process design using thermodynamics to avoid oiling out in a mixture of vanillin and water
de Albuquerque I., Mazzotti M. (2014), Crystallization process design using thermodynamics to avoid oiling out in a mixture of vanillin and water, in Crystal Growth and Design, 14(11), 5617-5625.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Internation Workshop on Industrial Crystallization (BIWIC) Talk given at a conference Influence of oiling out on the crystallization of L-menthol in water 06.09.2016 Magdeburg, Germany Varela de Albuquerque Ian;
European Congress of Chemical Engineering (ECCE) Talk given at a conference Effect of Crystal Shape on Measured Particle Size Distributions 27.09.2015 Nice, France Mazzotti Marco; Varela de Albuquerque Ian;
Summer School on Crystal Shape Engineering Individual talk Characterization and Modelling of Crystallization Processes 06.07.2015 Zurich, Switzerland Mazzotti Marco; Varela de Albuquerque Ian;
International Symposium on Industrial Crystallization (ISIC) Talk given at a conference Applying Thermodynamics for Crystallization Process Design in a Mixture where Oiling Out occurs 16.09.2014 Toulouse, France Mazzotti Marco; Varela de Albuquerque Ian;
International School of Crystallization (ISC) Poster Design of a crystallization process using thermodynamics to avoid oiling out 25.05.2014 Granada, Spain Varela de Albuquerque Ian;
Design of a Crystallization Process Using Thermodynamics to Avoid Oiling Out Individual talk Design of a Crystallization Process Using Thermodynamics to Avoid Oiling Out 15.05.2014 Basel, Switzerland Varela de Albuquerque Ian;


Abstract

A high number of active pharmaceutical ingredients and their intermediates have a chiral center.The two enantiomers often do not have the same therapeutic effect or differ in potency and toxicity.Hence, driven by the strict purity requirements of the regulatory agencies, the interest in thedevelopment of cost-efficient chiral separation techniques has rapidly increased in the recent years.Crystallization is a widely used technique for chiral resolution and guarantees a product of highchiral purity. As the selective crystallization of the target-enantiomer from racemic solutions is notpossible, crystallization can be applied in hybrid chiral resolution processes, where it is precededby a pre-enrichment step accomplished by either by asymmetric synthesis or by an alternativeseparation technique.Designing the crystallization process, the aim is to maximize the recovery of the target-enantiomerfrom the feed solution in as short a time as possible. A thorough understanding of the thermodynamicbehavior of the ternary system involving the two enantiomers and the solvent enablesfinding possible crystallization temperatures yielding equilibria enabling the full recovery of thetarget-enantiomer. A precise characterization of the crystallization kinetics allows for the determinationof operating conditions, so as to increase growth rates and concomitantly keep undesiredphenomena such as agglomeration at a manageable level. Only few studies have dealt with thecharacterization of crystallization kinetics in chiral systems, and, the available design methodologiesare based only on the thermodynamic properties of the system and do not consider kineticaspects. As a consequence, the choice of operating conditions for crystallization is chosen in arather empirical manner.This project aims at exploring, explaining and modeling the thermodynamic behavior and the crystallizationkinetics of chiral systems. By doing this, we will make a step forward in the developmentof design and optimization strategies of hybrid processes for chiral resolution involving crystallization.In this context, the project will involve theoretical, modeling and experimental work. It willhave a three-year duration, will be carried out by one Ph.D. student and will be structured in threesynergistic parts. In the first part, the ternary phase diagram of at least two chiral systems exhibitingthermodynamically stable oiling out will be characterized and modeled. Oiling out refers to theexistence of liquid-liquid phase equilibria and interferes in a disadvantageous manner with the solidliquidequilibria that are exploited for chiral resolution. In the second part, experimental protocolswill be developed for the determination of growth and nucleation kinetics from batch experimentsand applied to the two systems considered in the first part. Developing an understanding of therole of the wrong-enantiomer on the crystallization kinetics of the target-enantiomer is crucial. Inthe third part, we will develop and extend a methodology for the determination of operating temperaturesthat allow for chiral resolution through a cooling crystallization from enantiomericallyenriched solutions. Including the knowledge on the kinetics of crystallization, the methodologywill allow for a rigorous optimization of the crystallization process. The quality of the developedmethodology will be verified by applying it to the systems considered in this project.
-