The Separation of the Enantiomers of Asparagine by Crystallization .The Separation of the Enantiomers

  • View
    212

  • Download
    0

Embed Size (px)

Text of The Separation of the Enantiomers of Asparagine by Crystallization .The Separation of the...

  • The Separation of the Enantiomers of Asparagine by Crystallization

    Karim Elgarhy

    Department of Chemical Engineering

    McGill University, Montreal

    August 2005

    A thesis submitted to Mc Gill University in partial

    fulfillment of the requirements of the degree of Doctor of Philosophy

    Karim Elgarhy, 2005

  • 1+1 Library and Archives Canada Bibliothque et Archives Canada Published Heritage Branch

    Direction du Patrimoine de l'dition

    395 Wellington Street Ottawa ON K1A ON4 Canada

    395, rue Wellington Ottawa ON K1A ON4 Canada

    NOTICE: The author has granted a non-exclusive license allowing Library and Archives Canada to reproduce, publish, archive, preserve, conserve, communicate to the public by telecommunication or on the Internet, loan, distribute and sell theses worldwide, for commercial or non-commercial purposes, in microform, paper, electronic and/or any other formats.

    The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.

    ln compliance with the Canadian Privacy Act some supporting forms may have been removed from this thesis.

    While these forms may be included in the document page cou nt, their removal does not represent any loss of content from the thesis.

    Canada

    AVIS:

    Your file Votre rfrence ISBN: 978-0-494-25138-6 Our file Notre rfrence ISBN: 978-0-494-25138-6

    L'auteur a accord une licence non exclusive permettant la Bibliothque et Archives Canada de reproduire, publier, archiver, sauvegarder, conserver, transmettre au public par tlcommunication ou par l'Internet, prter, distribuer et vendre des thses partout dans le monde, des fins commerciales ou autres, sur support microforme, papier, lectronique et/ou autres formats.

    L'auteur conserve la proprit du droit d'auteur et des droits moraux qui protge cette thse. Ni la thse ni des extraits substantiels de celle-ci ne doivent tre imprims ou autrement reproduits sans son autorisation.

    Conformment la loi canadienne sur la protection de la vie prive, quelques formulaires secondaires ont t enlevs de cette thse.

    Bien que ces formulaires aient inclus dans la pagination, il n'y aura aucun contenu manquant.

  • ABSTRACTS

    Abstracts

  • ASSTRACTS

    Abstract

    Enantiomers are chiral molecules (i.e. they are mirror-images of each other). They

    have identical physical properties except for the rotation of polarized light. However their

    chemical properties are different when reacting with other chiral molecules. The majority

    of biological processes involve the reaction of two or more chiral molecules. There is

    therefore a strong interest coming from the pharmaceutical, food and agricultural industry

    for the separation of enantiomers.

    Separation methods such as chromatography exist but are generally expensive and

    limited in scale. Stereosynthesis often has prohibitive development and operating costs.

    For 10 to 15% of known enantiomeric systems, a conglomerate is formed upon

    crystallization (each individual crystal contains only one type of enantiomer).

    Crystallization is widely used as an inexpensive separation process which takes

    advantage of the difference in solubility of the compounds to be separated and yields very

    high purities in one separation stage. There is no difference in solubility between two

    enantiomers but in the special case of conglomerates, a difference in crystallization rate

    can be used as the driving force for the separation of the enantiomers.

    In this project, the effects of the important parameters governmg the

    crystallization of asparagine (ASN) were studied in order to develop a separation method

    based on crystallization. ASN is an amino acid having two enantiomers (L-ASN and D-

    ASN) and forming a conglomerate. The effects of mixing speed, crystallization

    temperature, initial supersaturation and seeds (amount, type and time of addition) on the

    crystallization rates were studied. The crystallization temperature was shown to have a

    negligible effect over the range studied. Increasing initial supersaturations had a strong

    11

  • ASSTRACTS

    accelerating effect on the crystallization. The addition of L-ASN seeds increased the

    crystallization rate of L-ASN without affecting that of D-ASN. The corresponding

    statement was true for D-ASN. Larger amounts of seeds and faster mixing increased

    crystallization rates. Separation methods were developed and 95.8-97.7% pure

    enantiomers with yields of 73.1 % were obtained in a cyclic process. The growth and

    desupersaturation rates were also modeled.

    111

  • ASSTRACTS

    Rsum

    Les nantiomres sont des molcules chirales (i.e. ils sont l'image l'un de l'autre

    dans un miroir). Leurs proprits physiques sont identiques l'exception de leur rotation

    de la lumire polarise. Cependant, leurs proprits chimiques sont diffrentes lorsqu'ils

    ragissent avec d'autres molcules chirales. La plupart des processus biologiques

    impliquent au moins une raction entre molcules chirales. Il y a donc un intrt

    grandissant de la part des industries pharmaceutique et agroalimentaire en particulier pour

    l'isolation d'nantiomres.

    Des mthodes de sparation, (ex. la chromatographie) existent mais sont souvent

    limites au niveau de la productivit et des cots. La stro synthse a aussi souvent des

    cots de dveloppement et d'opration prohibitifs.

    Dans 10 15% des cas, les systmes d'nantiomres forment un conglomrat lors

    de la cristallisation. Chaque cristal ne contient alors qu'un nantiomre.

    La cristallisation est frquemment utilise comme procd de sparation

    conomique qui utilise la diffrence de solubilit des composants sparer et qui produit

    une puret leve en une tape.

    Il n'y a pas de diffrence de solubilit entre deux nantiomres mais dans le cas

    ou un conglomrats est form, une diffrence du taux de cristallisation peut tre utilise

    pour sparer les nantiomres.

    Dans le prsent projet, les effets de paramtres important dans la cristallisation de

    l'asparagine (ASN) furent tudis pour dvelopper une mthode de sparation fonde sur

    la cristallisation. L'ASN est un acide amin qui a deux nantiomres (L-ASN et D-ASN)

    et qui forme un conglomrat. Les effets de la temprature de cristallisation, de la

    IV

  • ABSTRACTS

    sursaturation initiale, de germes de cristal (quantit, type et temps d'addition) et de la

    vitesse d'agitation sur les taux de cristallisation furent tudis. Il fut dmontr que la

    temprature de cristallisation avait un effet ngligeable dans l'intervalle tudie. Un

    augmentation de la sursaturation acclra la cristallisation. L'addition de germe de L-

    ASN augmenta le taux de cristallisation de la L-ASN mais n'eut pas d'effet sur la D-

    ASN. L'affirmation correspondante fut dmontre pour la D-ASN. Une plus grande

    quantit de germes et une agitation plus rapide augmenta les taux de cristallisation. Des

    mthodes de sparation furent dvelopps et des nantiomres purs a 95.8-97.7% et des

    rendements de 73.1 % furent obtenus lors de procds cycliques. Les taux de croissance et

    de dsursaturation furent aussi modliss.

    v

  • ACKNOWLEDGEMENTS

    Acknowledgements

    1 wish to thank my supervisor Professor Dimitrios Berk for his guidance as weil as

    our research team and the Chemical Engineering departmental staff for their technical

    support. 1 also wish to express my gratitude to my parents, my brothers and my girlfriend

    for their moral support.

    vi

  • TABLE OF CONTENTS

    Table of Contents

    VIl

  • TABLE OF CONTENTS

    1 Introduction.......................... ....................................................... 1

    2 Background Information and Literature Survey. . .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

    2.1 Amino Acids and Asparagine....................................................... 7

    2.2 Enantiomers, Diastereomers and Conglomerates............................. .... 8

    2.2.1 Enantiomers..................................................................... 8

    2.2.2 Diastereomers................................................................... 10

    2.2.3 Conglomerates..................................................... ............. 10

    2.3 Methods for the Separation of Enantiomers.................. ... ... ... ... ...... ... Il

    2.3.1 Chromatography... ......... ...... ...... ... ... ... ... ... ......................... Il

    2.3.2 Stereosynthesis............................................................... ... 12

    2.3.3 Other Separation Methods.................................................. ... 13

    2.4 The Crystallization Process......................................................... 13

    2.4.1 Definitions... ... ......... ...... ......... ..................... ...... ...... ........ 14

    2.4.2 Nucleation.................................................................... ... 14

    2.4.3 Growth........................................................................... 17

    2.4.4 Other Processes ...................................................... '" ........ 19

    2.4.5 Approaches for Modeling.................................................. .... 20

    2.5 Separation of Enantiomers by Crystallization... ... ... ........ ...... .......... ... 21

    2.5.1 Transform