Liquid purification or separation – Processes – Chromatography
Reexamination Certificate
2001-06-28
2003-03-18
Therkorn, Ernest G. (Department: 1723)
Liquid purification or separation
Processes
Chromatography
C210S198200
Reexamination Certificate
active
06533940
ABSTRACT:
The invention relates to a process for separation in a simulated moving bed of at least one component of a mixture that contains it.
It applies in particular to the preparative chromatography and especially to the separation of optical isomers, used in the pharmaceutical industry.
The technological background is illustrated by Patents EP-A-0769316 and U.S. Pat, No. 5,114,590.
By discontinuous (batch) chromatography, the tendencies are as follows:
To obtain a good resolution, it is necessary to use a large number of theoretical plates (N). Whereas this number of plates in a chromatographic column increases with the ratio L/d
p
2
, whereby L is the length of the column and d
p
is the mean diameter of the particles that it contains, this means that for a given particle size, the longest columns will be preferable to carry out or to improve a chromatographic separation of a mixture of organic components.
The diameter of a column is calculated by taking into account the pressure drop in the latter. It is common practice to operate with the maximum pressure drop that is acceptable. This means that for a given column length, a smaller column diameter D and thus a large L/D ratio will be preferred.
Practical limitations also conflict with the use of large-diameter columns.
The larger the diameter of the column, the higher the ratio between the diameter of the column and the diameter of the tube that feeds the latter. As shown by Etienne et al., 2
ème
Congrès de Génie des Procédés [Second Conference of Process Engineering], Toulouse, France, 417-422, 1989, this leads to a non-piston flow distribution at the intake of the column. By increasing the length of the column, the importance of this phenomenon is discounted.
Some authors (C. Dewaele, M. De Coninck, M. Verzele, Separation Science and Technology, 22 (8-10), 1919-1931, 1987) described a loss of effectiveness by using large column diameters, larger than 44 mm, which is reflected by a broadening of chromatographic peaks, and even a splitting of the peaks into two.
The literature describes the L/D ratios between 2 and 11.5 in the range of chiral separations (J. Dingenen and J. N. Kinkel, J. Chromatogr. A, 666, 627-650, 1994).
The limitations that are described in discontinuous (batch) mode are also encountered in the systems with simulated moving bed adsorption (more columns means more edge effects). For example, in U.S. Pat. No. 4,599,115, it is specified that in a simulated moving bed, the use of large-diameter adsorbent beds leads to non-uniform fluid flows and to high costs of installation and putting into service. The authors therefore proposed a simulated moving bed system characterized by a significant reduction of the operating pressure and energy needs as well as by chromatographic columns that have a high L/D ratio.
BRIEF SUMMARY OF THE INVENTION
This tendency has been emphasized during the last decade. By increasing the L/D ratio, however, the authors maximized the number of plates available in the system at the expense of the productivity expressed in grams of product per kilogram of stationary phase and per day. By the same token, pressure constraints led to high costs.
Contrary to what is taught, it has been noted that by using a system of several chromatographic columns in a simulated moving bed for separating organic components from a mixture that has a low ratio of length of each column to diameter, these above-mentioned drawbacks were eliminated.
More specifically, the invention relates to a process for separating at least one component from a mixture that contains it, in a device that comprises a group of chromatographic columns containing an adsorbent (or stationary phase), mounted in series and in a loop, whereby the loop comprises at least one point for an injection of the mixture, at least one point for draw-off of a raffinate, at least one point for an injection of desorbent and at least one point for draw-off of an extract, in which all of the injection points and draw-off points are offset periodically and simultaneously by the same number of columns in a given direction that is defined relative to that of the flow of a main fluid that circulates through the loop, whereby the process is characterized in that the main fluid is circulated in said chromatographic columns, whereby each of them has a length to diameter L/D ratio of between 0.01 and 0.34 and in that the L
TOT
/D ratio of the total length of the columns to their diameter is between 0.06 and 2.3.
The simulated moving bed system was described in particular in U.S. Pat. No. 2,985,589. It can be operated in simulated counter-current according to this patent or in simulated co-current according to U.S. Pat. No. 4,498,991.
According to a characteristic of the invention, it is advantageous to apply an axial dynamic pressure to each of said columns that is higher than the pressure drop of all of the columns. This dynamic axial compression is generally exerted at the top of the column, by means of, for example, a hydraulic cylinder coupled to a piston, and it prevents the appearance of large dead volumes caused by any movement of the adsorbent phase.
Each column can be kept at a dynamic axial pressure of usually between 3 and 100 bar (1 bar=10
5
Pa) and preferably between 25 and 50 bar.
In general, a distribution system that usually comprises a distributor plate, a frit and optionally a grid between the two is inserted in the piston that constitutes the top of the column and in the lower portion or footing of the column. This system is constructed so as to correct the flow distribution defects produced by the changes of sections at the inlet and the outlet of the column.
According to a characteristic of the process, it has been noted that in addition, when the ratio of the total length of the columns (L
TOT
=nL) to the diameter of the column was between 0.06 and 2.3, the daily production of separated product and the productivity of the separation by substantially reducing, moreover, the stationary phase was improved.
It is possible to work with at most 12 columns. It is nevertheless preferred to use a group of 4 to 8 columns.
The main advantage of the invention lies in chiral separations because of the very high price of chiral stationary phases.
It may be advantageous to reduce the dead volumes that are introduced by, for example, the pump for recycling the fluid from the last column into the first, in the chromatographic loop, by adopting the solutions that are recommended in U.S. Pat. No. 5,578,216 of the applicant, namely the suitable reduction of the length of a column that is immediately upstream from the dead volume when the latter is located downstream from said column and upstream from the draw-off flows of said column, or else the suitable reduction of the length of the column that is immediately downstream from said dead volume when this dead volume is located downstream from the injection flows in said column and upstream from said column.
It is also possible to recommend the solution that consists in desynchronizing the alternation periods of the inputs and outputs of fluids according to U.S. Pat. No. 5,578,215.
The invention also relates to a device for implementing the process. It is a device for separation into a simulated moving bed of at least one component of a mixture that contains it, comprising a group of chromatographic columns containing an adsorbent, mounted in series and in a loop, whereby the loop comprises at least one point for an injection of the mixture, at least one point for draw-off of a raffinate, at least one point for an injection of desorbent and at least one point for draw-off of an extract, whereby the device comprises means for offsetting periodically and simultaneously the set of injection points and draw-off points, of the same number of columns in a given direction that is defined relative to that of the flow of the main fluid that circulates through the loop, and means for circulation of the main fluid that are connected to the first column and the last column, whereby the device is ch
Cavoy Emile
Hamende Michel
Lehoucq Sylvie
Ludemann-Hombourger Olivier
Nicoud Roger-Marc
Novasep
Therkorn Ernest G.
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