EP1183085A1

EP1183085A1 - Method for crystallizing an aqueous solution

Info

Publication number: EP1183085A1
Application number: EP00931332A
Authority: EP
Inventors: Gérard Antonini; Olivier Bals
Original assignee: Association Gradient
Current assignee: Association Gradient
Priority date: 1999-05-28
Filing date: 2000-05-22
Publication date: 2002-03-06
Also published as: FR2794031B1; FR2794031A1; AU4930000A; WO2000072934A1

Abstract

The invention relates to a method for crystallizing an aqueous solution. According to the invention, said method consists in the following steps: at least one surfactant is initially added to the aqueous solution if the aqueous solution does not at least already contain one natural surfactant; the volume of the medium is subsequently swollen to form foam, whereupon crystallization occurs in a structured medium in the form of foam and said structured medium is used as a provisional material support for crystals undergoing a process of formation, after which the crystals or agglomerates of crystals are recovered by destructuring said foam.

Description

Process for crystallizing an aqueous solution.

The present invention relates to the crystallization of an aqueous solution with a view to obtaining crystals or crystal agglomerates which can be used in industry, for example the pharmaceutical industry or the cosmetic industry.

The criteria usually sought by the industry for the crystals which are recovered at the end of a crystallization process, are usually the purity, and possibly the flowability of the product (in order to facilitate its handling), as well as the suitability has a rapid dissolution. Controlled particle size is also a very important parameter. In the pharmaceutical industry, for example, putting capsules for the assimilation of active ingredients requires a particle size which is determined as precisely as possible.

It is known that the solubility (that is to say the maximum quantity of product capable of dissolving, at a given temperature, in a given quantity of solvent) generally increases when the temperature increases. Therefore, when one wishes not to dissolve a substance, but to crystallize it, it is necessary to cool the solution in order to modify the initial equilibrium thereof. The difference in concentration of the solution at a given temperature, compared to that at equilibrium at this same temperature, is called supersaturation, which is a metastable state for a body which remains liquid while its concentration is greater than saturation. This supersaturation is a necessary condition for crystallization, and this is most of the time generated by cooling. The cooling rate therefore conditions the supersaturation of the solution. If the cooling speed is too high important with regard to the kinetics of crystallization, the supersaturation increases, but the imbalance which is then generated may become too large, in which case the number of crystals formed per unit of time and per unit of volume (what specialists call the frequency of nucleation ) increases in an uncontrolled manner, with the risk of solidification of the solution. The solidification of a solution is the result of a very significant increase in its viscosity, by the appearance of more and more crystallites leading to the formation of a solid block which is very difficult to remove from the reactor and then to reuse. This solidification must therefore be avoided at all costs, since the solid block is generally unusable, even after mechanical grinding, for the applications concerned.

Thus, with conventional crystallization techniques, if the cooling temperature is low, a mediocre distribution of the particle size is obtained, that is to say that the particle size thereof corresponds to a very spread spectrum. In addition, the time required is very important, since it is necessary to adapt the speed to the kinetics, which leads to process times reaching for example forty hours. Of course, the temperature must not be too low, in particular in order to avoid the above-mentioned solidification which would render the product unusable.

As a result, the cooling crystallization processes currently used are carried out with stirring (in order to avoid any high local supersaturation), continuously, and with precise temperature control in order to avoid approaching the temperature zone or the we would find a risk of initiating a solidification.

The cooling rates are thus limited by the kinetics of crystallization, and in particular by the nucleation frequency.

To treat very concentrated solutions, which would allow the crystallization of a large quantity of product, but which would also cause an increase in viscosity, one can provide for a massive addition of solvent (in which the crystallized phase is sparingly or not soluble) in order to to reduce the risks of solidification, and to improve the kinetics of transfer of the solute towards the crystal. However, this procedure of adding solvent causes additional costs, as well as safety and environmental problems. Despite these drawbacks, this solution is often used by specialists, who do not have other crystallization methods in the range of high concentrations. The state of the art is also illustrated by document US-A-5,338,519.

This document describes a crystallization process using a three-dimensional carrier matrix through which the solution to be crystallized passes, said matrix having a large specific surface (2000 to 10000 m ² / m ³ ). The structure of this solid matrix is an "open-pored foam" whose porosity ranges from 0.3 to 3 mm, and it is expressly said that said matrix must have a high mechanical resistance to resist a centπfugation, the constituent materials being ceramic materials, aluminum oxides, glass or polymers.

The use of such a solid cellular material is however delicate, and makes it difficult to control the crystallization process.

Finally, under the technological background, gold may cite the documents GB-A-976,457 and US-A-3,917,801, which illustrate skim flotation techniques, which techniques are in fact very far away from α ' ur controlled crystallization process. The object of the present invention is to design a method for crystallizing an aqueous solution which makes it possible both to control the apparent particle size of the crystals and to reduce the time required to obtain crystals having the desired particle size, while eliminating the risk of solidification without addition of solvent.

This problem is solved in accordance with the invention by a method of crystallizing an aqueous solution, characterized in that it comprises the initial addition to the aqueous solution of at least one surfactant, at least in the case where the aqueous solution does not already contain a natural surfactant, then the medium is abundant for the formation of foam, the crystallization then being carried out in a structured medium in the form of foam, said structured medium then serving as a temporary material support for the crystals in formation , after which the crystals or the crystal agglomerates are recovered by destructuring the foam. The process of the invention thus offers a very interesting alternative to so-called volume crystallizations, in so far as one takes maximum advantage of the geometry of polyhedral type presented by the cells of the structured medium in the form of foam. It will be understood that the term "foam" here refers to liquid or aqueous foams, practically without own mechanical resistance, such as soapy compositions, which has nothing to do with three-dimensional structures with open porosity or "open-pored foam "(such as those described in US-A-5,338,519). Indeed, thanks to a beneficial effect of capillary drainage, the liquid is depleted, which leads to the appearance of polyhedral cells whose flat faces form liquid films. This formation of liquid films allows precisely to control the crystallization process by avoiding any interference, in particular any agglo-coalescence which would lead to the solidification that we just want to avoid.

The crystallization process is then no longer carried out in volume as in conventional techniques, but in a two-dimensional manner at the level of each of the plane faces of the polyhedral cells forming the structured medium.

We thus use in an original and surprising way the presence of a medium structured in the form of foam, not solid and practically without mechanical resistance, which ensures for the first time a function of provisional material support for crystals in formation, which does not had never been considered. It should be noted that the crystallization process, whether it is a conventional crystallization without chemical reaction or a crystallization with chemical reaction between the components of the aqueous phase, in particular precipitation, has nothing to do with see with other mechanisms of the polymerization type. Thus, it has already been proposed to use a polymerization in a foaming medium to obtain an aerated polymer structure of the alveolar elastomer type (see for example the document US-A-4 312 960), but this has nothing to do with a crystallization process, or a fortiori with the process of the invention in which the foam is destructured to recover crystals or crystal agglomerates, unlike the recovery of an aeref er structure. alveolar elastomer which it is obviously not a question of destructuring.

Depending on the case, provision may be made for the initial addition of at least one stabilizing agent for better structuring of the foam.

In a particular embodiment, provision may be made after the proliferation of the medium for the foaming, the foam obtained as a result of the expansion is cooled to create a supersaturated solution, until the final recovery of the crystals or crystal agglomerates by destructuring the foam.

It is also possible to provide a seeding, that is to say an addition of a few percent of the cπstallisable mass, before or after the expansion.

The expansion is preferably carried out by mechanical stirring with the addition of a gas, in particular air. Mechanical stirring can be stopped as soon as the desired expansion is obtained, before the initiation of cooling, or as a variant be maintained during crystallization. The expansion rate, that is to say the ratio between the volume of air and the volume of product, will be chosen according to the desired particle size of the crystals. This gives very advantageous control over the particle size of the crystals obtained by the simple choice of the expansion rate, this resulting from the fact that the expansion rate associated with a given initial formulation directly regulates the liquid thickness of the faces of the polyhedral cells constituting the structured medium in the form of foam. The destructuring of the foam to recover the crystals or the agglomerates αe crystals can be carried out by mechanical means, in particular by crushing or by restarting the agitator.

Alternatively, this destructuring can be achieved by adding solvent, or even pa ¹ -: 0itratιcr after pumping the foam.

It can also be shown that the crystals or the agglomerates of recovered crystals are washed to remove the impurities. In the case of destructuring of the foam produced by adding solvent, washing the crystals and crystal agglomerates can then be produced in a single operation.

The process of the invention obviously applies as well to the case of a crystallization carried out in a structured medium in the form of foam which is a conventional crystallization without chemical reaction, as to the case of a crystallization with chemical reaction between the components of the aqueous phase, in particular precipitation. Other characteristics and advantages of the invention will appear more clearly in the light of the description which follows, and of specific examples which will be given by way of illustration.

In its most general definition, the process of crystallization of an aqueous solution is remarkable in that the crystallization is carried out in a structured medium in the form of foam, said structured medium then serving as a temporary material support for the crystals in formation, after whereby the crystals or the crystal agglomerates are recovered by destructuring the foam.

By previously structuring the medium in the form of a foam, it then becomes possible to confer on the crystallized product particular properties inherent in the very structure of the medium (modification of the final particle size distribution of the crystals) and / or of limiting the harmful effects of the significant increase in viscosity when the solution solidifies.

The presence of polyhedral cells for the structured medium in the form of foam makes it possible to easily obtain thicknesses of the constituent faces which are very small and thus make it possible to exercise control over the particle size of the crystals in formation.

Once formed, the foam undergoes more or less slow degradation (a few minutes to a few hours * at in which come a series of complex mechanisms such as vertical bubble segregation, gravitational drainage, and capillary suction. Vertical bubble segregation can occur because Archimedes' thrust is greater for large bubbles than for small ones, which is found at the start of foam formation. Gravitational drainage occurs during the entire life of the foam: it is a true natural liquid flow within the film. The proportion of liquid present in the foam decreases, and the bubbles lose their spherical shape to become polyhedral. Specialists then say that we go from a so-called wet foam (that is to say containing 15 to 20% by volume of liquid) to a so-called dry foam (that is to say with less 10% by volume of liquid). The quantity of liquid continues to decrease, because the difference in curvature between the edges of the Plateau (space at the junction of several bubbles) and the flat part of the films produces, according to Laplace's law, a pressure gradient. This pressure gradient is the driving force that moves the liquid from the center of the films to the edges of the tray, thanks to the capillary suction mechanism that is also encountered during the degradation of the foam. The foam can then start to degrade by breaking relatively thin films (at least a few μm thick), if there is no mechanism for stabilizing disturbances in the inter-bubble film. The destabilization of the foam can be slowed by increasing the viscosity of the medium, if the polyhedral bubbles are large, or by the presence of solid or liquid particles of another phase (the size of which is of course less than the thickness of the film) within the liquid film.

In the case of sparingly concentrated solutions, the crystals will form orerentially at the edges of Plateau, and their size will be limited by the space available at the intersection of several cells (micrometric size). In this case, crystals of very small particle size are obtained, with the advantage of being able to limit the growth rate of the compound. In this case, however, it is impossible to have very large crystals.

In the case of more concentrated solutions, the crystallization can extend to the entire liquid film. If the final cooling temperature is low (minus 20 ° C for example), a foam is obtained in the long term, the honeycomb structure of which does not prevent the recovery of the crystals since the mechanical resistance of this three-dimensional building is relatively low. A real three-dimensional wireframe structure is then produced which can be easily collapsed by mechanical or other means, contrary to what could be encountered in the case of a solid block, for which recovery is practically impossible. The crystals obtained then are relatively fine, that is to say a few microns, and can be found in the form of agglomerates whose size can go up to the millimeter. This method therefore makes it possible to recover the crystals contained in a solid solution and, moreover, to form agglomerates capable of improving the flow properties of the product.

We will now describe different particular embodiments of the crystallization process according to the invention, in the case of a so-called conventional crystallization without chemical reaction, it being understood that the person skilled in the art can easily use the same principle in the case of 'A crystallization with chemical reaction between the components of the aqueous phase, for example of the precipitation type. In this case, the aqueous solution already contains the product to be crystallized, whereas in the case of precipitation, the product to be crystallized is formed only during the chemical reaction.

Apart from certain special cases where the aqueous solution already contains a natural surfactant, the first phase of the crystallization process according to the invention comprises the initial addition to the aqueous solution of at least one surfactant, and optionally also of a stabilizing agent. , such as a gelling agent or a polymer (for example polyoxyethylene), or optionally a polymer of plant origin such as carboxymethylcellulose (CMC). In the case of an aqueous solution already containing a natural surfactant, provision may naturally be made for the addition of other complementary surfactants in order to have the desired additional effect. In practice, gold will provide for the addition of a surfactant representing from 1 to 6% of the water mass of the concentrated saturated solution used as a starting point. This quantity however depends on the balance between the surface and the liquid phase, insofar as the foamability (that is to say the increase in volume resulting from the foam) increases up to a concentration of surfactant corresponding to the critical micellar concentration. As an indication, s. using a saturated glucose solution at 60 ° C, the addition of surfactant represents a mass of about 0,; gram per 200 grams of solution, which then corresponds to about 1% of the water mass of said solution.

We can naturally use various types of surfactants tre- possibly of plant origin, including those already used in Îa ^r foam technology. By way of example, there may be mentioned the sulframine qu_ is manufactured by the company ITCO, which constitutes u; interesting surfactant. It is of course possible to envisage the addition of nonionic surfactants, which must however be chemically compatible with the product concerned, and also compatible with the purity of the final product sought.

After this addition of surfactant, and optionally of stabilizing agent, the medium is expanded to form foam. The expansion is preferably carried out by mechanical stirring with the addition of a gas, in particular air or nitrogen. The degree of agitation will naturally depend on the activity of the surfactant used. The addition of gas can be done by direct injection of a liquid / gas mixture either through a block of sintered material (static mixer), or by dynamic expansion in a continuous device of stator-rotor type, or alternatively using a gas taken from the surface by the middle sky.

In general, mechanical stirring will be stopped, or, as the case may be, the residence time in the dynamic mixer will be fixed, as soon as the desired expansion is obtained, before initiating the cooling of the medium. However, it is also possible, as a variant, to prolong the agitation during the actual crystallization.

It is also possible to provide for seeding of the solution, that is to say an addition of a few percent of the crystallizable mass. This step, which is not compulsory, can be carried out before or after the expansion.

The expansion rate will preferably be chosen directly as a function of the granulometry of the crystals sought. This expansion rate, which is represented by the air / liquid volume ratio in fact regulates the liquid thickness of the faces of the polyhedral cells, and thus directly controls the particle size of the crystals in formation or of the agglomerates of these crystals by confining the particles in the liquid plate constituting the faces of the polyhedral cells. The foam obtained is then cooled to create a supersaturated solution, after which the final recovery of the crystals or crystal agglomerates is carried out by destructuring the foam. This destructuring can be carried out by purely mechanical means, for example by crushing or by restarting the agitator. As a variant, this destructuring can be carried out by adding solvent or even by filtration after pumping the foam. It should be noted that the three-dimensional structure in which the crystals or crystal agglomerates are embedded has an extremely low mechanical strength, which has nothing to do with that of a solidification block which would be obtained by a lack of control. of the crystallization process. Thus, a simple pressurization (continuous or by impact) on the three-dimensional structure is sufficient to carry out the crushing to recover the crystals and crystal agglomerates.

In general, with very concentrated solutions, purely mechanical means will be used to deconstruct the foam in order to recover the crystals or the crystal agglomerates. The addition of solvent is also an interesting possibility, especially insofar as a washing process making it possible to remove the impurities can be carried out simultaneously with the recovery of the crystals or crystal agglomerates.

In the case of poorly concentrated solutions, it is advantageous to provide for pumping of the foam in order to bring it to a filter. Indeed, in this case, the crystals are essentially confined at the edges of the plateau of the polyhedral cells of the medium structured in the form of foam. However, it should be noted that the same could be done with highly concentrated solutions by cooling less or treating the foam faster (for example a few hours instead of ten hours), because the foams obtained generally remain pumpable for at least two hours.

Finally, provision may be made for washing the crystals and agglomerates of crystals recovered in order to remove the impurities therefrom. As has been said above, in the case of a destructuring of the foam carried out by adding solvent, this washing process is then obtained simultaneously with the destructuring.

At the end of the destructuring of the foam, it is thus possible to easily recover crystals or agglomerates of crystals whose particle size is perfectly controlled. It should be noted that the aggregates of crystals thus obtained are advantageous insofar as they are rapidly soluble, since they are formed of microcrystals. The network formed by the skeleton obtained at the end of the crystallization process is easy to deconstruct, even when the process is carried out until all the faces of the polyhedral cells solidify. We will now mention various tests carried out by the Applicant, which make it possible to demonstrate the superiority of the results obtained compared to traditional crystallization techniques.

Various tests have thus been carried out on the one hand on a saturated glucose solution at 60 ° C (290 grams of glucose per 100 grams of water), that is to say a very concentrated solution, and on the other hand on a saturated solution of glycine at 50 ° C (39.1 grams of glycine per 100 grams of water), that is to say a solution that is not very concentrated. For each of these solutions, provision has been made for adding a surfactant with different percentages of the water mass, essentially between 1 and 6 0. The surfactant used was the sulfram already mentioned above.

The medium was then expanded by stirring, with the introduction of gas bubbles within the liquid. For both solutions, stirring was carried out in a few minutes using a food processor.

The foam was then cooled to create a supersaturated solution. The saturated solutions were thus cooled to 20 ° C or to - 20 ° C for about 10 hours without stirring. A test was also carried out on a concentrated glucose solution cooled to 20 ° C with stirring to improve the transfer coefficient to the wall.

For the recovery of the crystals and crystal agglomerates contained in the film, a mechanical crushing and stirring technique was used for the concentrated glucose solutions, and a filtration technique after pumping for the glycine solutions.

The results of these tests tend to show that the particle size distribution of the crystals recovered initially varies very little with the initial amount of surfactant for a given cooling temperature. It was further observed that the average size increased at lower temperature, the crystals formed are certainly smaller, but agglomerating better. Thus, the average volume size of the sample varied between 422 and 470 μ for concentrated glucose solutions, and between 90 and 180 μ for low concentrated glycine solutions. The solubility of glycine being very much lower than that of glucose in water, it was found that the crystals were found in individualized form at the end of crystallization, without the formation of crystal agglomerates. The size of the crystals was then small (average size approximately 100 μm at -20 ° C.). Thanks to a comparative test carried out according to a traditional crystallization technique, using the same surfactant with the same content, and with the same cooling temperature, it has been found that the average size of the crystals obtained with traditional techniques was close to 720 μm, which is much greater than the average size of the crystals presently obtained with the method according to the invention. The formation of a honeycomb medium therefore made it possible to limit the kinetics of growth of the glycine crystals.

In practice, rather concentrated solutions will be used rather to have small particle sizes. We are thus assured, thanks to the principle of a temporary support by a structured foam medium, of having crystallites of small sizes, that is to say of the order of 100 to 200 μm, while the crystals obtained from the same solution with a traditional crystallization technique have an average size of the order of a millimeter.

On the other hand, fairly or very concentrated solutions will be used to obtain a medium or large size of crystals, the particle size being always perfectly controlled, and moreover without there being any risk of solidification. Of course, with these same concentrated solutions, it is possible to obtain fine particles if the cooling time is short, or medium or large particles with long times, and this without risk of solidification. It has thus been possible to obtain agglomerates of crystallites in the foam which make it possible to produce easily dispersible powders with short dissolution times. The control of the apparent particle size, as well as the notable increase in flowability, with greatly reduced cooling times, constitute quite remarkable advantages of the process of the invention. In addition, this original mode of crystallization constitutes a very attractive alternative to the conventional techniques of adding solvent intended to avoid the risks of caking. The invention is not limited to the embodiments which have just been described, but on the contrary encompasses any variant incorporating, with equivalent means, the essential characteristics set out above.

Claims

1. Method for crystallizing an aqueous solution, characterized in that it comprises the initial addition to the aqueous solution of at least one surfactant, at least in the case where the aqueous solution does not already contain a natural surfactant , then the medium is abundant for the formation of foam, the crystallization then being carried out in a structured medium in the form of foam, said structured medium then serving as a temporary material support for the crystals in formation, after which the crystals or the crystal agglomerates are recovered by destructuring the foam.

2. Method according to claim 1, characterized in that it also comprises the initial addition of at least one stabilizing agent.

3. Method according to claim 1 or claim 2, characterized in that after the expansion of the medium for foaming, the foam obtained as a result of the expansion is cooled to create a supersaturated solution, until the final recovery of crystals or crystal agglomerates by destructuring the foam.

4. Method according to one of claims 1 to 3, characterized in that it further comprises a seeding before or after the expansion.

5. Method according to one of claims 1 to 4, characterized in that the expansion is achieved by mechanical stirring with the addition of a gas, in particular air.

6. Method according to claim 5, characterized in that the mechanical stirring can be maintained during crystallization.

7. Method according to claim 5 or claim 6, characterized in that the rate of expansion is chosen according to the desired particle size of the crystals.

8. Method according to one of claims 1 to 7, characterized in that the destructuring of the foam to recover the crystals or the crystal agglomerates is carried out by mechanical means, in particular by crushing or by restarting the stirring .

9. Method according to one of claims 1 to 7, characterized in that the destructuring of the foam to recover the crystals or the crystal agglomerates is carried out by adding solvent.

10. Method according to one of claims 1 to 7, characterized in that the destructuring of the foam to recover the crystals or the crystal agglomerates is carried out by filtration after pumping the foam.

11. Method according to one of claims 8 to 10, characterized in that the crystals or the agglomerates of crystals recovered are washed to remove the impurities.

12. Method according to one of claims 1 to 11, characterized in that the crystallization carried out in the medium structured in the form of foam is a conventional crystallization without chemical reaction.

13. Method according to one of claims 1 to 11, characterized in that the crystallization carried out in the structured medium in the form of foam is a crystallization with chemical reaction, in particular precipitation.