Separation process

Details Separation process Separation process

1999-01-19

2002-05-07

Griffin, Steven P. (Department: 1754)

Chemistry: physical processes

Physical processes

Crystallization

C023S301000, C585S812000, C585S816000

Reexamination Certificate

active

06383233

ABSTRACT:

The invention described herein is in the field of separation processes and relates particularly to a crystallisation process for separating a desired substance from an aggregate mixture of substances.
BACKGROUND OF THE INVENTION
Conventional crystallisation involves the saturation of a solvent with a solid material, followed by the induction of supersaturation by lowering the temperature or by evaporation of solvent. The crystallisation velocity can be influenced by the rate of cooling or evaporation, i. e. by the degree of distortion of the thermodynamic equilibrium.
The crystallisation rate—or in equilibrium stage the rate of exchange of molecules at the crystal surface—is very high in a conventional crystallisation process and the probability that a “wrong” molecule gets trapped by other molecules is considerable. Therefore, the conventional crystallisation process reflects only to a very limited extent the maximum possible differences in adsorption energies of different molecules on a certain crystal surface, as is sometimes the case with optimised chromatographic processes, and to a certain extent a highly dynamic situation of “trapping molecules” by the layers of the crystal that successively form.
The purification of mixtures of compounds by emulsion crystallisation is known. In emulsion crystallisation processes, mixtures are purified by forming emulsified droplets of the mixtures and then adding seed crystals of one component of the mixture to thereby selectively crystallise that component, or by cooling the emulsion to induce crystallisation (c.f. EP 0 548 028 Al; Davey et al.,
Nature,
Vol. 375, pp. 664-666 (Jun. 22, 1995); I. Holéci,
Chemicky prûmysi
14/39, pp. 638-641 (1964)).
Though these emulsion crystallisation processes are effective, they possess certain disadvantages. First, the formation of the emulsions requires high-shear equipment, which can be undesirable from a processing standpoint. Second, as the emulsions tend to be thermodynamically unstable, the emulsion droplets tend to coalesce or “oil out”. In addition, the droplet size contemplated (typically 0.5-50 &mgr;m) is large enough to allow undesirable spontaneous crystallization within the droplet with certain types of mixtures.
DETAILED DESCRIPTION OF THE INVENTION
The crystallisation process described herein is directed to a process for separating a desired substance from an aggregate mixture in which process a three phase dispersion is formed, the first phase comprising droplets containing the aggregate mixture, the second phase comprising a liquid transport phase, and the third phase comprising a surface upon which the desired substance can crystallise, whereby a chemical potential exists for crystal growth of the desired substance in the third phase thereby creating a flow of the desired substance from the first phase through the second phase to the third phase where the desired substance crystallises, characterised in that the Gibb's free enthalpy of formation (&Dgr;G) of the droplets is <0. Such droplets form spontaneously, are thermodynamically stable and are small enough to prevent spontaneous crystallisation within them.
The first and second phases of the process according to the present invention together form what is known in the art as a microemulsion. Microemulsions provide the significant advantage that their droplets are typically transparent which facilitates observing and monitoring each specific crystallization process.
In addition, the droplets of a microemulsion provide an interface between the first and second phases having a significantly increased surface in comparison to macroemulsions. Larger surface areas enable higher flow rates of substance from the first to the second phase, and thereby, higher rates of crystallization. Higher crystallization rates are advantageous from the standpoint of the scale-up and commercialization of a process.
The process according to the present invention may be carried out in batch or continuous operation.
“Desired substance” as used herein, refers to inorganic and organic substances having a melting point above −130° C., preferably above −78° C., more preferably above −20° C. The process of this invention is especially indicated for those substances that have been traditionally difficult to purify, e.g. constitution isomers, stereo isomers i.e. cis/trans isomers, diastereomers, enantiomers etc. and homologues. The desired substance can be a pharmaceutical, an agrochemical, a fragrance, a food additive, a chemical intermediate or the like.
“Aggregate mixture” as used herein refers to a mixture containing the desired substance and one or more impurities. The aggregate mixture may be a liquid or a solid, or a liquid and a solid. The aggregate mixture may be optionally dissolved or dispersed in one or more solvents. Droplets of the aggregate mixture are typically formed with the aid of one or more alcohols, whereby the alcohol may be added externally to the dispersion, or may be contributed by the aggregate mixture itself.
In addition, formation of droplets may also be aided by one or more surface active agents, hereinafter described. The surface active agents may be added externally to the dispersion, or may be contributed by the aggregate mixture itself.
The droplets will have a diameter of less than 500 nm, and preferably less than 200 nm, e.g. 5-200 nm. Droplets of this dimension create in a dispersion what is commonly referred to in the art as a microemulsion.
Due to the Gibb's free enthalpy of formation (&Dgr;G) being <0, the droplets will form spontaneously in the second phase, hereinafter described. Formation of these droplets may, however, be accelerated through the use of agitation, e.g. gentle stirring, shaking, pumping or ultrasound.
It is to be understood that the aggregate mixture nay contain one or more desired substances. The desired substances may, according to choice, be separated from the aggregate mixture either individually or simultaneously.
The second phase of the system, which functions as a transport phase through which the desired substance flows before crystallising onto the third phase, is liquid and will be selected based upon the solubility characteristics, nucleation characteristics and the selectivity of the crystallisation process for the desired substance. Preferably the desired substance will be less soluble in the second phase than in the first phase.
In such cases where the desired substance is water insoluble or substantially water insoluble, the second phase is conveniently polar and hydrophilic.
The second phase may further contain an-agent for adjusting the solubility of the desired substance in the second phase and/or the freezing point of the second phase. In such cases where the second phase is water, such agent is conveniently a water soluble inorganic salt such as CaCl
2
, NaCl, KCl, MgCl
2
AlCl
3
, or a water-miscible organic liquid such as an alcohol, ether, ketone, ester, lactone, dimethylsulfoxide (DMSO) and acetonitrile. Water-miscible organic liquids are preferred.
Below is set forth a list of suitable solvents and solvent additives to be used in the first phase or the second phase.
I. Non-polar, lipophilic solvents and additives having a water solubility of ≦5% v/v at room temperature (hereinafter “r.t.”) include:
1. Alkanes such as n-, i- or branched of the general formula —(C
n
H
2n+2
)— including polyethylenes, polypropylenes, cycloalkanes (e.g. cyclopentane, cyclohexane);
2. Alkenes such as n-, i- or branched of the general formula —(C
2
H
2n
)— including cycloalkenes (cyclohexene, terpene), di- or polyalkenes;
3. Alkines such as n-, i- or branched of the general formula —(C
n
H
2n−2
)—, cycloalkines, di- or polyalkines;
4. Aromatics such as unsubstituted aromatics (e.g. benzene, naphthalene), substituted aromatics such as alkylated aromatics (e.g. toluene, xylene, higher alkylated benzenes, alkylated naphthalenes), heterosubstituted aromatics such as halogenated (e.g. chlorobenzene, hexafluorobenzene) and/or nitrated (e.g. nitrobenzene),

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