WO2007128918A1

WO2007128918A1 - Method for purification of an organic acid by chromatography

Info

Publication number: WO2007128918A1
Application number: PCT/FR2007/000773
Authority: WO
Inventors: Marc-André Theoleyre; Stanislas Baudouin
Original assignee: Applexion
Priority date: 2006-05-05
Filing date: 2007-05-04
Publication date: 2007-11-15
Also published as: FR2900654A1; FR2900654B1

Abstract

The invention therefore provides a method for separating an organic acid by passage of this solution on a chromatographic fixed bed consisting of an anionic resin and consisting of several zones in series characterized in that it consists of several sequences, each sequence consisting of the following steps: (a) maintaining continuous circulation in the closed loop, (b) introducing said aqueous solution and recovering a raffinate; (c) introducing the eluent and recovering a raffinate; (d) introducing the eluent and recovering an extract; in selected points of the zones. Application to the purification of citric acid.

Description

24873PC

PROCESS FOR PURIFYING ORGANIC ACID BY CHROMATOGRAPHY

FIELD OF THE INVENTION

The present invention relates to a process for separating an organic acid, such as citric acid, from an aqueous solution containing such an acid and impurities, by chromatography of this solution on a fixed bed of resin. STATE OF THE ART

The fermentation production of an organic acid, such as citric acid, leads to an aqueous culture broth containing the dissolved organic acid (eg citric acid), microorganisms and impurities essentially consisting of substrate residues and cellular metabolism of said microorganisms.

When the acid is present in said culture broth, in its acid form, the traditional means of purification of this acid is the formation of an insoluble calcium salt by contacting said broth with lime, and then recovering by filtration approximately pure organic acid salt, the main impurities remaining in the filtrate.

By the action of sulfuric acid on this salt, after filtration, an aqueous solution of organic acid and insoluble gypsum (calcium sulfate) are then obtained.

The saturated organic acid solution of calcium salts thus obtained is then purified by the action of ion exchangers, by crystallization or by solvent separation.

The above technique leads to the production of large quantities of gypsum, waste with no market value.

On the other hand, the regeneration of the demineralization resins of a saturated solution of said calcium salts mobilizes significant amounts of acid and base which are found in the effluents.

To overcome these disadvantages, a number of methods have been proposed.

Thus, US Pat. No. 4,855,494 describes a method for purifying citric acid, based on the removal of high molecular weight molecules by ultrafiltration and adsorption on a soda-regenerated adsorbent resin, this primary purification being supplemented by ion exchange purification. However, this process does not eliminate small residual sugars from fermentation.

Furthermore, US-A-4,720,579 proposes a direct purification of citric acid by chromatography, after clarification, without going through the liming and acidification steps. In this patent, it is proposed to use an adsorbent resin, of weak anionic resin type, with elution with water or with dilute sulfuric acid. By keeping the pH of the medium below the first pKa value of the citric acid, the latter is adsorbed and 24873PC

2 can thus be separated from the culture broth. This same patent also suggests to carry out the continuous separation according to the Simulated Moving Bed (SMB) method described in US Patent No. 2,985,589.

Compared to the process of US Pat. No. 4,855,494, the chromatographic process according to US Pat. No. 4,720,579 has the advantage of eliminating residual sugars. The resins that may be used in this document are resins, in particular AMBERLITE IRA-68® from Rohm & Haas. .

A similar method has also been described for the purification of lactic acid in US Pat. No. 5,068,418. Finally, Canadian patent CA-A-2,007,126 describes a continuous chromatography system implementing an SMB system. for the purification of organic acids. He recommends the use of a weak and described anionic resin for the purification of citric acid, a 12-column SMB system filled with anionic resin such as AMBERLITE IRA-67® from Rohm & Haas. The yield obtained by using such an SMB system is greater than 99% and the purity of the citric acid obtained is greater than 98%, the productivity of the system being 520 g of citric acid per liter of resin and day.

Moreover, in this process, the elution of the citric acid is delayed and it is separated from the impurities (dyes, minerals and residual sugars of the fermentation). The implementation of an SMB process for such purification leads to the use of a large volume of resin. The resins conventionally available for this application, for example the acrylic resin of the AMBERLITE IRA-67® type from the company ROHM & HAAS, have an average size d ₅₀ of the order of 650 μm and a low particle size homogeneity, the coefficient of uniformity being only of the order of 1.7 (it will be recalled that a perfectly homogeneous granular mass has a coefficient of uniformity of 1). SUMMARY OF THE INVENTION

It has now been demonstrated that the use of a semicontinuous process, called sequential SMB (or SSMB), made it possible to obtain, in the context of the purification of an organic acid, quite interesting results. Moreover, it has been found that the particle size of the resin strongly influences the separation process.

It is on the basis of these findings that the processes according to the invention have been developed.

Thus, the invention provides a method for separating an organic acid from an aqueous solution containing such an acid and impurities, by passing this solution on a chromatographic fixed bed comprising an anionic resin and comprising several zones in series, liquid flow means being disposed between adjacent areas and between the last and first areas so as to be able to create a looped fluid flow 24873PC

3, said organic acid being selectively more strongly retained by said resin and at least one of the impurities being relatively less strongly retained on this resin than the organic acid, characterized in that it comprises several sequences, each sequence comprising the following steps: (a) maintain a continuous circulation in the closed loop,

(b) introducing a certain volume of said aqueous solution at the head of an area and substantially simultaneously withdrawing the same volume of a liquid rich in the impurity or impurities relatively less strongly retained, at a point downstream of this zone, the loop being open; (c) introducing a certain volume of an eluent capable of displacing the more retained organic acid at the head of an area situated upstream of the zone in which said aqueous solution is introduced and withdrawing substantially the same volume of a substantially a liquid rich in the impurity (s) relatively less strongly retained from the downstream point defined in step (b), the loop being open; and (d) introducing said eluent in the same zone as that in which it is introduced during the preceding step (c) and substantially simultaneously withdrawing the organic acid at a point situated between this zone and that in which the solution is introduced. aqueous, the loop being open; each subsequent sequence being carried out by periodically moving downstream substantially the same increment of volume, the point of introduction of said aqueous solution, the point of introduction of said eluent, the point of withdrawal of the organic acid and the point of withdrawal of the impurity (s) relatively less strongly retained.

According to one embodiment, said anionic resin is an acrylic resin of anionic type, preferably low, having an average size of ₅ o in the range of 300 to 500 μm, preferably 350 to 450 μm, and a coefficient of uniformity less than or equal to 1.30, preferably less than or equal to 1.2.

According to one embodiment, the particle size distribution of said anionic resin is such that at least 98.5% of the particles have a size less than 600 microns.

According to one embodiment, the steps (a), (b), (c) and (d) are implemented according to the sequence (a), then in any order the steps (b), (c) and ( d).

According to one embodiment, steps (b) and (d) are implemented at least partly simultaneously.

According to one embodiment, the steps (a), (b), (c) and (d) are implemented according to the sequence (a), then (c) and then together at least simultaneously (b) and (d) or according to sequence (a), then together at least simultaneously (b) and (d), then (c). 24873PC

4

According to one embodiment, said fixed bed is distributed in cells of the same volume, each zone may comprise one or more cells, said cells being able to correspond to a column or a part of a column.

According to one embodiment, said fixed bed is distributed in cells of the same volume, each zone may comprise one or more cells, Teluant being introduced at the top of the cell of the zone defined in (b), the organic acid being drawn off in leaving the cell of the zone defined in (d), the aqueous solution being introduced at the top of the cell of the zone defined in (b) and the relatively less impurity impurity or impurities being withdrawn at the outlet of the cell of the zone defined in (b). According to one embodiment, the volume increment along which said insertion points and said withdrawal points are displaced substantially corresponds to the volume of a cell.

According to one embodiment, the zones defined in (b) and (d) comprise two or more cells, separated by at least one cell, preferably at least two cells. According to one embodiment, said process is carried out at a pH lower than the first pK of said acid.

According to one embodiment, said eluent is dilute sulfuric acid. According to one embodiment, said aqueous solution is the culture broth obtained by fermentation generating said organic acid. According to one embodiment, the organic acid is citric acid, and preferably the aqueous solution is the culture broth obtained by fermentation of glucose or sucrose generating citric acid.

According to one embodiment, the aqueous solution is obtained by clarifying the culture broth. According to one embodiment, said clarification comprises centrifugation followed by membrane filtration. BRIEF DESCRIPTION OF THE FIGURES

Figures 1 to 4 show schematically an installation implementing the method according to the invention. FIG. 5 represents an installation implementing the method according to the invention;

Figure 6 shows an installation according to the state of the art. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

In what follows, a description is given with reference to the case where said cells correspond to columns. This is not limiting and the invention applies to systems in which the cells, or compartments, are parts of the column. 24873PC

5

For the record, it will be recalled that the organic acid is considered, in chromatography, as more retained and therefore as the extract (X) and that the impurities are less retained and are considered a raffinate (R). In the invention, the purity in the extract is greater than, for example, 95%, preferably greater than 98%, advantageously greater than 99%.

The method of the invention allows a better optimization of the loading sequences of the aqueous solution to be treated and rinsing the separated products; this leads to a reduction in the volume of eluent (desorbent liquid) necessary for separation and / or a decrease in the number of cells (or compartments) during rinsing compared to the conventional SMB process.

Moreover, the process according to the invention makes it possible to substantially reduce the volume of the resin necessary for the desired separation of the organic acid; in addition, it makes it possible to limit the spreading of the elution peaks of the organic acid and of the glucose (one of the main impurities) with respect to that observed with an SMB system, this less spreading resulting in a higher productivity and lower consumption of eluent.

In the SMB process, the aqueous solution to be treated is continuously diluted in the eluent flow. During a sequence, the products introduced then disperse throughout the duration of the sequence in the zone where the aqueous solution to be treated is introduced. The consequence of such a dispersion is that the distance separating the front of the product to be separated from the outlet of said zone is very short, which affects the separation performance.

With regard to the products withdrawn (extract: organic acid and raffinate: impurities), they represent a sampling of the flow passing through the resin. Throughout the duration of the withdrawal, the purity of the products withdrawn can vary and instead of extracting all of a product having the most favorable purity, only a part is taken, the majority being recycled.

In the proposed operation according to the invention, it is a question of the contrary: for the withdrawals, to choose the moment when the desired product is the purest and to take then all the passing flow, for the supply, to interrupt any flow of fluid and directly inject the aqueous solution to be treated without being diluted in a larger volume. The newly introduced elements will then be concentrated in a smaller fraction of the resin bed and the distance to be traveled between the position at the end of injection and the position of the output is increased, which translates into better performance. of seperation. Thus, the invention implements a method according to which the steps comprise: 24873PC

6

(a) maintain a continuous circulation in the closed loop,

(b) introducing a certain volume of said aqueous solution at the head of an area and substantially simultaneously withdrawing the same volume of raffinate at a point downstream of this zone, the loop being open; (c) introducing a certain volume of an eluent capable of displacing the most retained organic acid, at the head of an area situated upstream of the zone in which said aqueous solution is introduced, and substantially simultaneously withdrawing the same volume of raffinate; from the point downstream defined in step (b), in addition to the withdrawal made in step (b), the loop being open; and (d) introducing said eluent in the same zone as that in which it is introduced during the preceding step (c) and withdrawing the extract substantially simultaneously at a point situated between this zone and that into which the aqueous solution is introduced. the loop being open; each subsequent sequence being carried out by periodically moving downstream substantially the same increment of volume, the point of introduction of said aqueous solution, the point of introduction of said eluent, the point of withdrawal of the organic acid and the point of withdrawal of the impurity (s) relatively less strongly retained.

As indicated, the sequence order (b), (c) and (d) may be any after the closed loop circulation step (a). It can be seen that the extract and raffinate withdrawal steps are carried out open loop, unlike the state of the art represented by the SMB.

Note that when the organic acid is citric acid, the aqueous solution may be the culture broth obtained by fermentation of glucose or sucrose generating citric acid and the eluent is then water or preferably the diluted sulfuric acid (in particular of a concentration not higher than 1% by volume, and in particular from 0.01N to IN). It would also be possible to use a crystalline mother water of citric acid or any other solution of citric acid.

Said aqueous solution is preferably obtained by clarifying the culture broth, this clarification may comprise centrifugation followed by membrane filtration.

The pH at which the process is carried out is preferably less than the pKa of the organic acid desired, for example it is between 0.5 and 2. The temperature at which the process is carried out may be between 20 ^° C. C and 80 ° C. The pressure is such that one operates in general in the liquid phase. The anionic resin is preferably an acrylic resin of anionic type, preferably low, having an average size of ₅₀ in the range of 300 to 500 μm, 24873PC

Preferably 350 to 450 μm, and a uniformity coefficient less than or equal to 1.30, preferably less than or equal to 1.2.

The invention uses such a resin having an average size d ₅₀ of about 450 .mu.m, and a uniformity coefficient of about 1.2. It will be recalled that the coefficient of uniformity for the resin balls is the following ratio:

(opening diameter of the sieve allowing 60% by mass of the balls)

(opening diameter of the sieve allowing 10% by mass of the balls)

Advantageously, the particle size distribution of said anionic resin is such that at least 98.5% of the particles have a size of less than 600 μm.

The activating groups of this resin are moreover preferably constituted by tertiary amino groups, such as dimethylamino groups for example; according to one embodiment, the resin is weak.

In addition, the resin is preferably in the salified form with an acid chosen from those which have an anion for which said resin has an affinity equal to or greater than that which it has for the anion of the organic acid to be separated. This salification acid is advantageously a mineral acid and in particular sulfuric acid.

The above characteristics of the anionic resin according to the invention, quite atypical for this type of resin, make it possible to substantially improve the chromatographic separation of the organic acid. This resin is useful in the process according to the invention (SSMB) but also in the methods of the state of the art, represented by US-A-4,720,579 and CA-A-2,007,126.

This resin can be obtained from commercially available resins, which are classified to obtain the desired particle size distribution. It is also possible to use preparation methods such as "jetting" to obtain this narrow particle size distribution.

It will be recalled that in chromatography, citric acid is recognized as being a model fluid of organic acids.

As for glucose, it is a sugar constituting one of the main impurities accompanying the desired organic acid when the latter is manufactured by fermentation of sucrose or glucose.

The resin according to a preferred embodiment leads to a lower spread of the sulfuric acid peak and a faster rinsing of the latter.

This difference in positioning results in a greater gap between the peaks of the sugar and the organic acid and thus leads to a much better separation.

Finally, the resin according to the invention is rinsed much faster than the conventional resin. This makes it possible to reduce the volume of liquid to obtain an identical or 24873PC

8 to reduce the volume of resin in a continuous chromatography system to obtain the same rinse.

The present invention is illustrated by way of example by the following description of two embodiments, with reference to Figures 1 to 4 of the accompanying drawings. As noted above, each column may actually be a column cell or compartment.

More specifically, Figure 1 is a schematic representation of an example of an installation for implementing the method according to the invention.

This installation comprises four columns 1, 2, 3, 4 filled with the same amount of a weak anionic acrylic resin described above. These four columns are arranged in series, each having an inlet 11, 21, 31,

41 and an output 12, 22, 32, 42.

The inputs 21, 31, 41 of the columns 2, 3, 4 are respectively connected to the outputs 12, 22, 32 of the columns 1, 2, 3, via three-way valves Vl, V2, V3 and the output 42 of the last column 4 is connected to the inlet 11 of the column 1 via a three-way valve V4.

Thanks to these various connections, it is possible to form a closed loop comprising, in this order, the elements 1, 12, VI, 21, 2, 22, V 2, 31, 3, 32, V 3, 41, 4, 42, V 4, 11.

Furthermore, the inlets 11, 21, 31, 41 are respectively connected to liquid inlets 13, 23, 33, 43 via valves V5, V6, V7, V8. On the other hand, the outlets 12, 22, 32, 42 are respectively connected to liquid withdrawal conduits 14, 24, 34, 44 respectively via the valves V1, V2, V3, V4. In addition, this installation comprises at least one pump P (eg suction-reducer) for creating and maintaining a flow of liquid at a constant rate in the closed loop referred to above. This pump P may be located between two adjacent columns or between the last and first columns (as shown in FIG. 1). It is also possible, for large volumes, to place a pump per column, and to operate these pumps together.

According to the method of the invention, several successive sequences, four in number in the example chosen, are implemented in this installation, each sequence comprising four successive steps.

The four steps of the first sequence are illustrated in FIG. 2 in which, for reasons of simplification, all the valves and ducts other than those necessary to illustrate the circulation of liquid have been voluntarily omitted.

In the first step, the pump P is turned on and the valves V1 to V8 are set so that the only circulation of liquid takes place in the closed loop mentioned above. 24873PC

9

In the second step, the pump P is stopped and the valves V1 to V8 are adjusted so that the only circulation of liquid takes place according to the circuit 33-V7-31-3-32-V3-34, the arrival 33 being connected to a source of organic acid solution to be treated and the liquid withdrawn through the conduit 34 being rich in impurities (less strongly retained on the resin than the organic acid).

In the third step, the pump P is stopped and the valves V1 to V8 are adjusted so that the only circulation of liquid takes place according to the circuit 13-V5-11-1-12-V1-21-2-22- V2-31-3-32-V3-34, the inlet 13 being connected to a source of dilute sulfuric acid (eluent) and the liquid withdrawn through the conduit 34 being rich in said impurities. In the fourth step, the pump P is stopped and the valves V1 to V8 are adjusted so that only the circulation of liquid takes place according to the circuit 13-V5-11-1-12-V1-14, the arrival 13 being connected to a source of dilute sulfuric acid and the liquid withdrawn through the conduit 14 being rich in organic acid.

We then move on to the second sequence illustrated in FIG. 3 in which, as before, all the valves and ducts other than those necessary to illustrate the circulation of liquid have been intentionally omitted.

This second sequence differs from the first only by the simple downstream movement, of a given volume increment, in this case the volume of a column, the points of entry of liquid in the columns and the drawpoints of these same columns. Thus: in the first step, the pump P is turned on and the valves V1 to V8 are set so that the only circulation of liquid takes place in the closed loop; in the second step, the pump P is stopped and the valves V1 to V8 are adjusted so that the only circulation of liquid takes place according to the circuit 43-V8-41-4-42-V4-44, the arrival 43 being connected to the source of aqueous solution to be treated and the liquid withdrawn through line 44 being the raffinate (rich in impurities); in the third step, the pump P is stopped and the valves V1 to V8 are adjusted so that the only circulation of liquid takes place according to the circuit 23-V6-21-2-22-V2-31-3-32- V3-41-4-42-V4-44, the inlet 23 being connected to the source of dilute sulfuric acid and the liquid withdrawn through line 44 being the raffinate (rich in impurities); in the fourth step, the pump P is stopped and the valves V1 to V8 are adjusted so that the only circulation of liquid takes place according to the circuit 23-V6-21 -2-22-V2-24, the arrival 23 being connected to the source of dilute sulfuric acid and the liquid withdrawn through line 24 being the extract (rich in organic acid). Then we go to the third sequence, then to the fourth sequence by operating in the same way, that is to say by moving each time downstream, an increment of volume 7 000773

24873PC

10 (in this case the volume of a column), the points of entry of liquid into the columns and the withdrawal points from these same columns.

It will be added that in a sequence, the steps may have varying durations from one to the other. Since in each sequence, the second and fourth steps do not use the same liquids, or the same areas of the resin bed, the operations of these steps can be implemented at least in part simultaneously, preferably simultaneously. The fourth step is then integrated in the second step.

In this way, each sequence will comprise only three steps. This is illustrated in FIG. 4, which shows that for the first sequence: in the first step, the only liquid circulation that takes place is in the closed loop. in the second stage (which is carried out at the same time as the fourth stage), the only liquid circulations which take place are on the one hand, according to the circuit 13 (diluted sulfuric acid) -V5-1-1 -12-V1-14 (organic acid withdrawal) and secondly, according to the circuit 33 (aqueous solution to be treated) -V7-31-3-32-V3-34- (withdrawal of impurities), either Charge-Raffinate and Eluent-Extract circuits; in the third stage, the only circulation of liquid which takes place is according to the circuit 13 (diluted sulfuric acid) - V5-11-1-12-V1-21-2-22-V2-31-3-32-V3 -34 (removal of impurities); Eluent to Raffinat.

The plant described above and corresponding to Figures 1 to 4 can be modified according to various parameters such as the nature of the organic acid, the nature of the resin and the nature of the eluent.

Thus, an installation particularly adapted to the separation of citric acid from a broth of clarified culture resulting from the fermentation of sucrose in citric acid comprises 8 columns, the introductions and withdrawals of liquids being carried out as follows during the first sequence (at constant flow rate: first step: circulation in the closed loop, lasting 8 min second step: introduction of the reading broth at the head of the 6 ^th column and withdrawal of a liquid rich in impurities in exit of the 7 ^th column, lasting 13.8 min third step: introduction of the eluent (dilute sulfuric acid) at the head of the ^1st column and withdrawal of a liquid rich in impurities at the outlet of the 7 ^th column, lasting 4.6 min fourth step: introduction of eluent (dilute sulfuric acid) at the top of the 1 ^st column and withdrawal of a liquid rich in citric acid at the outlet of the 3 ^rd column , with a duration of 13.8 min. 24873PC

11

Of course, here again it is possible to incorporate the operations of the second step in the fourth step so that each sequence has only three steps.

In practice, the various sequences of the process according to the invention are repeated until an equilibrium is obtained, that is to say until the withdrawn liquids have substantially constant concentrations of solute.

Once this equilibrium is reached, the fractions of liquid rich in organic acid are preserved to isolate the latter by concentration.

The following table compares the performances of the process according to the invention with those obtained with the SMB process described in the abovementioned Canadian patent CA-A2,007,126, shown schematically in FIGS. 5 and 6, respectively.

The first of these processes uses 8 columns of the same volume and consists of a weakly anionic acrylic resin having the specific particle size characteristics defined above (450 microns and coefficient 1.2).

The second of these processes uses 12 columns of the same volume and consists of acrylic resin AMBERLITE ÏRA-67®.

This table shows that the separation performance of the two processes in question are substantially identical (citric acid of the same purity and neighboring citric acid recovery rate).

On the other hand, the most striking advantage of the process according to the invention lies in reducing the number of resin zones from 12 to 8, which leads to a very significant increase in the specific capacity of the process according to the invention, the productivity (production of citric acid per liter of resin per day) from 0.522 to 0.913.

Claims

24873PC12 CLAIMS

A process for separating an organic acid from an aqueous solution containing such an acid and impurities, by passing this solution over a chromatographic fixed bed comprising an anionic resin and comprising a plurality of zones in series, a flow means of liquid being disposed between adjacent zones and between the last and first zones so as to be able to create a closed-loop fluid flow, said organic acid being selectively more strongly retained by said resin and at least one of the impurities being relatively less strongly retained on this resin as the organic acid, characterized in that it comprises several sequences, each sequence comprising the following steps:

(a) maintain a continuous circulation in the closed loop,

(b) introducing a certain volume of said aqueous solution at the head of an area and substantially simultaneously withdrawing the same volume of a liquid rich in the impurity or impurities relatively less strongly retained, at a point downstream of this zone, the loop being open;

(c) introducing a certain volume of an eluent capable of displacing the more retained organic acid at the head of an area situated upstream of the zone in which said aqueous solution is introduced and withdrawing substantially the same volume of a substantially a liquid rich in the impurity (s) relatively less strongly retained from the downstream point defined in step (b), the loop being open; and

(d) introducing said eluent in the same zone as that in which it is introduced during the preceding step (c) and substantially simultaneously withdrawing the organic acid at a point situated between this zone and that into which the aqueous solution is introduced; the loop being open; each subsequent sequence being carried out by periodically moving downstream substantially the same increment of volume, the point of introduction of said aqueous solution, the point of introduction of said eluent, the point of withdrawal of the organic acid and the point of withdrawal of the impurity (s) relatively less strongly retained.

2. Method according to claim 1, characterized in that said anionic resin is an acrylic resin of anionic type, preferably low, having an average size d ₅₀ in the range of 300 to 500 μm, preferably 350 to 450 μm, and a uniformity coefficient less than or equal to 1.30, preferably less than or equal to 1.2. 24873PC

13

3. Method according to claim 2, characterized in that the particle size distribution of said anionic resin is such that at least 98.5% of the particles have a size less than 600 microns.

4. Method according to one of claims 1 to 3, characterized in that. that steps (a),

(b), (c) and (d) are implemented according to the sequence (a), then in any order the steps (b), (c) and (d).

5. Method according to one of claims 1 to 4, characterized in that steps (b) and (d) are implemented at least partly simultaneously.

6. Method according to one of claims 1 to 5, characterized in that the steps (a), (b), (c) and (d) are implemented according to the sequence (a), then (c) and together at least simultaneously (b) and (d) or in sequence (a), then together at least simultaneously (b) and (d), then (c).

7. Method according to one of claims 1 to 6, characterized in that said fixed bed is distributed in cells of the same volume, each area may comprise one or more cells, said cells may correspond to a column or a portion of a column.

8. Method according to one of claims 1 to 7, characterized in that said fixed bed is distributed in cells of the same volume, each zone may comprise one or more cells, the eluent being introduced at the head of the cell of the zone. defined in (b), the organic acid being withdrawn at the outlet of the cell from the zone defined in (d), the aqueous solution being introduced at the top of the cell of the zone defined in (b) and the relative impurity (s). less strongly retained being withdrawn at the output of the cell of the zone defined in (b).

9. The method of claim 8, characterized in that the increment of volume along which are moved said introduction points and said withdrawal points substantially corresponds to the volume of a cell.

10. The method of claim 8 or 9, characterized in that the areas defined in (b) and (d) comprise two or more cells, separated by at least one cell, preferably at least two cells.

11. Process according to any one of the preceding claims, characterized in that said process is carried out at a pH lower than the first pK of said acid. 24873PC

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12. Method according to any one of the preceding claims, characterized in that said eluent is dilute sulfuric acid.

13. Method according to any one of the preceding claims, characterized in that said aqueous solution is the culture broth obtained by a fermentation generating said organic acid.

14. Process according to any one of the preceding claims, characterized in that the organic acid is citric acid, and preferably the aqueous solution is the culture broth obtained by fermentation of glucose or sucrose generating acid. citric.

15. The method of claim 13 or 14, characterized in that the aqueous solution is obtained by clarification of the culture broth.

16. The method of claim 15, characterized in that said clarification comprises centrifugation followed by membrane filtration.