FR2794031A1 - PROCESS FOR CRYSTALLIZING AN AQUEOUS SOLUTION - Google Patents

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

The present invention relates to the crystallization of an aqueous solution for obtaining crystals or agglomerates of crystals used in industry, for example the pharmaceutical industry <B> or </ B> the cosmetic industry.

The criteria usually sought by industry for the crystals that are recovered <B> at </ B> after a crystallization process, are usually the purity, and possibly the flowability of the product (to facilitate its handling). ), as well as the ability <B> to </ B> a rapid dissolution. The controlled particle size is also a very important parameter. In the pharmaceutical industry, for example, putting in capsules for the assimilation of active ingredients requires a particle size which is determined as accurately as possible.

It is known that solubility (i.e., the maximum amount of product capable of dissolving, <B> at </ B> a given temperature, in a given amount of solvent) generally increases as the temperature increases. Therefore, when it is desired not to solubilize a substance, but to crystallize it, it is necessary to cool the solution in order to modify the initial equilibrium thereof. The concentration difference of the solution <B> at </ B> a given temperature, relative <B> to </ B> at </ B> the equilibrium <B> to </ B> this same temperature is called supersaturation, which is a metastable state for a body that remains liquid while its concentration is greater than saturation. This supersaturation is a necessary condition for crystallization, and this is most often generated by cooling. The cooling rate therefore conditions the supersaturation of the solution. If the cooling rate is too high for the kinetics of crystallization, the supersaturation increases, but the imbalance that is then generated can become too great, in which case the number of crystals formed per unit time and per unit volume (which specialists call the nucleation frequency) increases in an uncontrolled manner, with the risk of a build-up of the solution. The setting in mass of a solution is the result of a very important increase of its viscosity, by appearance of crystallites more and more numerous resulting <B> in </ B> the formation of a very difficult solid block <B > to </ B> remove from the reactor and <B> to </ B> then reuse. This setting in mass must therefore be avoided <B> at </ B> any price, because 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 particle size distribution is obtained, that is to say that the particle size thereof corresponds to <B> to </ B > a very spread spectrum. In addition, the time required is very important, because it is necessary to adapt the speed <B> to the kinetics, which leads <B> to </ B> process times reaching for example forty hours . Of course, the temperature must not be too low, in particular to avoid the aforesaid massing that would make 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 control of the temperature to avoid getting closer to the temperature zone where the we would find a risk of initiating a consolidation.

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 crystallisation of a large quantity of product, but which would also cause an increase in the viscosity, it is possible to provide a massive addition of solvent (in which the crystallized phase is little or not soluble) in order to to reduce the risks of setting in mass, and to improve the kinetics of transfer of the solute towards the crystal. However, this solvent addition procedure entails additional costs, as well as safety and environmental problems. Despite these drawbacks, this solution is often used by specialists, who do not have other methods in crystallization in the high concentration range.

It is an object of the present invention to provide a method of crystallizing an aqueous solution which allows <B> to </ B> both to control the apparent particle size of the crystals and to reduce the time required <B> to </ B> obtaining crystals having the desired particle size, while eliminating the risk of caking without the addition of solvent.

This problem is solved according to the invention thanks to a method of crystallizing an aqueous solution, characterized in that the crystallization is carried out in a structured medium in the form of foam, said structured medium then serving as temporary material support for the crystals in formation, after which the crystals or agglomerates of crystals are recovered by destructuring the foam.

The method of the invention thus provides a very interesting alternative to so-called bulk crystallizations, insofar as one takes full advantage of the polyhedral type geometry that the cells of the structured medium in the form of foam exhibit. 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 makes it possible precisely to control the crystallization process while avoiding any interference, in particular any agglo-coalescence which would result in <B> to </ B> the setting in mass which one just wants to avoid.

The crystallization process is then performed more in volume as in conventional techniques, but in a two-dimensional manner at each of the flat faces of the polyhedral cells forming the structured medium.

The presence of a structured medium in the form of a foam which, for the first time, provides a temporary material support function for crystals in formation, which has never been envisaged, is thus used in an original and surprising manner.

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 a precipitation, has nothing <B> to </ B> to see with other mechanisms of the type polymerization. Thus, it has already been proposed to use a polymerization in a foamy medium to obtain an aerated polymeric structure of the cellular elastomeric type (see, for example, US-A-4 312 960). , But this has nothing to do with a process of crystallization, let alone with the process of the invention in which the foam is destructured to recover crystals or agglomerates of crystals, unlike <B> at </ B> the recovery of an aerated cellular elastomeric structure that it is of course not question of destructuring.

Preferably, the method comprises the initial addition <B> to the aqueous solution of at least one surfactant, at least in the case where the aqueous solution does not contain <B> already </ B> a natural surfactant, and optionally also at least one stabilizing agent, after which the medium is expanded for the formation of foam, the foam obtained then being cooled to create a supersaturated solution, until the final recovery of the crystals or agglomerates of crystals by destructuring the foam.

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

The expansion is preferably carried out by mechanical stirring with the addition of a gas, especially air. The mechanical agitation can be stopped as soon as the desired expansion is obtained, before the initiation of cooling, or alternatively 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 grain size of the crystals. This gives a very interesting control of the particle size of the crystals obtained by the simple choice of the expansion rate, this being due to the fact that the expansion rate associated with a given initial formulation directly adjusts the liquid thickness. faces of the polyhedral cells constituting the structured medium in the form of foam.

The destructuring of the foam to recover the crystals or agglomerates of crystals can be achieved by mechanical means, especially by crushing or restarting the stirrer.

As a variant, this destructuring can be carried out by adding solvent, or else by filtration after pumping the foam.

It may further be provided that the crystals or agglomerates of crystals recovered are washed to remove impurities. In the case of a destructuring of the foam carried out by adding solvent, the washing of the crystals and agglomerates of crystals can then be carried out in a single operation.

The process of the invention is of course applicable both in the case of a crystallization carried out in a structured medium in the form of foam which is a conventional crystallization without chemical reaction, and in the case of a crystallization with a chemical reaction between the components of the aqueous phase, in particular precipitation.

Other features and advantages of the invention will appear more clearly in the light of the description which follows, and particular examples which will be given as an illustrative title.

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

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

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 exert control over the particle size of the crystals in formation.

Once formed, the foam undergoes a more or less slow degradation (a few minutes <B> to </ B> a few hours) during which a series of complex mechanisms come into play such as the vertical segregation of the bubbles, the gravitational drainage , and capillary suction. Vertical segregation of bubbles may occur because buoyancy is greater for large bubbles than for small bubbles, which is found at the beginning of foam formation. Gravitational drainage occurs when it is lifted over the 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. The specialists then say that one goes from a so-called wet foam (that is to say containing from <B> 15 to <B>% </ B> by volume of liquid) <B > to </ B> a so-called dry foam (that is to say with less than <B> 10% </ B> in volume of liquid) <B>. </ B> The quantity of liquid continues <B > to </ B> decrease, because the difference in curvature between the edges of Plateau (space at the junction of several bubbles) and the flat part of the films produced, 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 Plateau edges, thanks to the capillary suction mechanism that is also encountered during the degradation of the foam. The foam can then begin to degrade by breaking relatively thin films (at least a few μm thick), if there is no mechanism for stabilizing the disturbances of the film. -bubbles. The destabilization of the foam can be slowed by increasing the viscosity of the medium, S_ the polyhedral bubbles are large, or by the presence of solid or liquid particles of another phase (whose size is of course less than <B> </ B> - "film thickness" within the liquid film.

In the case of low concentration solutions, the crystals will form preferentially at the edges of Plateau, and their size will be limited by the available space <B> at </ B> the intersection of several cells (micron size). in this case, crystals of very small particle size are obtained, with the advantage of being able to limit the rate of growth of the compound. It is however in this case impossible to have very large crystals.

In the case of more concentrated solutions, the crystallization can extend <B> to </ B> all the liquid film. If the final cooling temperature is low (minus 200C for example), we get, <B> to </ B> term, a foam whose honeycomb structure does not prevent the recovery of crystals since the mechanical strength of this three-dimensional building is relatively weak. a real three-dimensional wire structure is then realized which can be easily co-cut by mechanical or other means, unlike <B> to </ B> what could be encountered in the case of a block taken en masse, for which recovery is virtually impossible. The crystals obtained are then relatively fine, that is to say a few microns, and can be in the form of agglomerates whose size can go up to the millimeter. This method therefore allows the recovery of the crystals contained in a solution taken in mass and, in addition, to form agglomerates likely to improve the flow properties of the product.

We will now describe various 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 skilled person can easily use the same principle in the case of crystallisation with chemical reaction between the components of the aqueous phase, for example of the precipitation type.

In this case, the aqueous solution contains <B> already </ B> the product <B> to </ B> crystallize, whereas <B> there </ B> in the case in the case of a precipitation, the product <B> to </ B> crystallize only forms during the chemical reaction.

Except for 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 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) <B>. < In the case of an aqueous solution containing <B> already </ B> a natural surfactant, it will naturally be possible to add other additional surfactants to have a desired additional effect. In practice, there will be provided a surfactant addition of 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 volume increase resulting from the foam) increases to a corresponding surfactant concentration < B> at </ B> the critical micelle concentration. <B> A </ B> as a guideline, if saturated glucose solution <B> is used at 60 ° C, </ B> addition of surfactant represents a mass of approximately <B> 0.5 </ B> gram per 200 grams of solution, which corresponds then <B> to </ B> approximately <B> 1% </ B> of the water mass of said solution.

Naturally, it is possible to use a wide variety of surfactants, possibly of plant origin, and especially those already used in foam technology. As an example, it is possible to use mention sulframine which is manufactured by the company WITCO, which is an 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 desired final product.

After this addition of surfactant, and optionally stabilizing agent, the medium is swollen for the formation of 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 mixture <B> / </ B> gas either through a block of sintered material (static mixer), or by dynamic expansion in a continuous device of the type stator-rotor, or by means of a gas taken on the surface by the middle sky.

In general, the mechanical stirring will be stopped, or, depending on the case, the residence time in the dynamic mixer will be set as soon as the desired expansion is obtained, before initiating the cooling of the medium. But alternatively can also prolong the stirring during crystallization itself.

In addition, it is possible to seed the solution, that is to say an addition of a few percent of the crystallizable mass. This step, which is not mandatory, can be done before <B> or </ B> after the expansion.

The expansion rate will preferably be chosen directly according to the desired particle size of the crystals. This expansion rate, which is represented by the volume ratio air <B> / </ B> liquid indeed regulates the liquid thickness of the faces of the polyhedral cells, and thus directly controls the particle size of the crystals in formation or agglomerates of these crystals thanks to <B> to </ B> a confinement of 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 agglomerates of crystals is carried out by deconstruction of the foam.

This destructuring can be performed by purely mechanical means, for example by crushing or restarting the agitator. Alternatively, this destructuring can be carried out by adding solvent or by filtration after pumping the foam. It should be noted that the three-dimensional structure in which the crystals or agglomerates of crystals are embedded has an extremely low mechanical resistance, which has nothing to do with that of a blocking block which would be obtained by a lack of control of the crystallization process. Thus, a simple pressurization (continuous <B> or </ B> by shock) on the three-dimensional structure is sufficient <B> to </ B> to perform the crushing to recover the crystals and agglomerates of crystals.

In general, with highly concentrated solutions, purely mechanical means will be used to destructure the foam in order to recover crystals or agglomerates of crystals. The addition of solvent is also an interesting possibility, especially since a washing process for removing impurities can be carried out simultaneously with the recovery of crystals or agglomerates of crystals.

In the case of low concentration solutions, it is advantageous to provide a pumping of the foam to bring it on a filter. Indeed, in this case, the crystals are essentially confined at the plateau edges of the polyhedral cells of the foam-shaped structured medium. It should be noted, however, that one could do the same with very concentrated solutions by cooling less or by treating the foam faster (for example a few hours instead of ten hours), because the foams obtained remain in pumpable for at least two hours.

Finally, the crystals and agglomerates of recovered crystals can be washed to remove impurities. As has been said above, in the case of a destructuration of the foam carried out by adding solvent, this washing process is then obtained simultaneously <B> at </ B> the destructuration.

<B> A </ B> the result of the destructuration of the foam, it is thus possible <B> to </ B> easily recover crystals or agglomerates of crystals whose granulometry is perfectly controlled. It should be noted that the crystal aggregates thus obtained are advantageous to the extent that they are rapidly solubilizable because formed microcrystals. The network formed by the skeleton obtained at the end of the crystallization process is easy to deconstruct, even when the process is conducted until all the faces of the polyhedral cells are solidified.

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 techniques of crystallization.

Various tests were thus carried out on the one hand on a saturated solution of glucose <B> at 60 ° C (290 </ B> grams of glucose for <B> 100 </ B> grams of water), it is ie a very concentrated solution, and secondly on a saturated solution of glycine <B> to </ B> SOOC <B> (39,1 </ B> grams of glycine for <B> 100 </ B> grams of water), that is to say a low concentration solution.

For each of these solutions, a surfactant addition with different percentages of the water mass was provided, essentially between <B> 1 </ B> and <B> 6%. </ B> The surfactant used was sulframine <B> already </ B> mentioned above.

Subsequently, the medium was expanded by stirring, with introduction of gas bubbles into 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 <B> to </ B> 200C or <B> to <200C for about <B> 10 </ B> hours without agitation. An attempt was also made on a concentrated solution of cooled glucose <B> at 20 ° C with stirring to improve the transfer coefficient <B> to the wall.

For the recovery of crystals and crystal agglomerates contained in the film, a mechanical crushing and agitation technique for concentrated glucose solutions, and a pumped filtration technique for glycine solutions were used.

The results of these tests tend to show that the particle size distribution of the recovered crystals initially varies very little with the initial amount of surfactant for a given cooling temperature.

It was further found that the average size increased <B> to </ B> lower temperature, the formed crystals being certainly smaller, but aggregating better. Thus, the average volume size of the sample varied between 422 and 470 pm for concentrated glucose solutions, and between <B> 90 </ B> and <B> 180 p </ B> for solutions. little concentrated glycine. Since the solubility of glycine is very much <B> lower than that of glucose in water, it has been found that the crystals are <B> under individualized form at the end of crystallization, without formation. of agglomerates of crystals. The size of the crystals was then small (average size about <B> 100 </ B> pm <B> to </ B> -200C). </ B> Thanks to <B> to </ B> a try Comparative carried out according to a traditional technique of crystallization, using the same surfactant with the same content, and with the same cooling temperature, it was found that the average size of the crystals obtained with the traditional techniques was close to <B> 720 </ B > pm, which is much greater than the average size of the crystals presently obtained with the process according to the invention. The formation of a honeycomb medium thus made it possible to limit the kinetics of growth of the glycine crystals.

In practice, rather low concentration solutions will be used to have small particle sizes. It is thus ensured, thanks to the principle of a temporary support by a structured foam medium, to have crystallites of small sizes, that is to say of the order of <B> 100 to </ B> 200 μm, whereas the crystals obtained from the same solution with a traditional crystallization technique have an average size of the order of one 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 the risk of caking. 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 caking.

It has thus been possible to obtain agglomerates of crystallites in the foam which make it possible to produce easily dispersible powders with low dissolution times. The control of the apparent particle size, as well as the noticeable increase in flowability, with greatly reduced cooling times, constitute remarkable advantages of the process of the invention. In addition, this original mode of crystallization is a very attractive alternative to conventional techniques for adding solvent to <B> to </ B> avoid the risk of caking.

 The invention is not limited to the embodiments that have just been described, but on the contrary covers any variant using, with equivalent means, the essential characteristics mentioned above.

Claims (1)

<U> CLAIMS </ U> <B> 1. </ B> Process for the crystallization of an aqueous solution, characterized in that the crystallization is carried out in a structured medium in the form of a foam, the said structured medium then serving as a support provisional material for forming crystals, after which crystals or agglomerates of crystals are recovered by destructuring the foam. 2. Method according to claim 1, characterized in that it comprises the initial addition to the aqueous solution of at least one surfactant, at least in the case wherein the aqueous solution does not already contain a natural surfactant, and optionally also at least one stabilizing agent, after which the medium is foamed for foaming, the resulting foam is then cooled to create a supersaturated solution, until the final recovery of the crystals or agglomerates of crystals by destructuring the foam. <B> 3. </ B> The method of claim 2, characterized in that it further comprises a seeding before or after the expansion. 4. Method according to claim 2 or claim <B> 3, </ B> characterized in that the expansion is carried out by mechanical stirring with the addition of a gas, especially air. <B> 5. </ B> Process according to claim 4, characterized in that mechanical agitation can be maintained during crystallization. <B> 6. </ B> Process according to claim 4 or claim <B> 5, </ B> characterized in that the expansion rate is chosen according to the desired grain size of the crystals. '7. Process according to one of Claims 1 to 6, characterized in that the destructuring of the foam to recover the crystals or agglomerates of crystals is carried out by mechanical means, in particular by crushing or by reworking. road of the agitation. <B> 8. </ B> Method according to one of claims <B> 1 to 6, </ B> characterized in that the destructuring of the foam to recover crystals or agglomerates of crystals is achieved by adding solvent. <B> 9. </ B> Process according to one of claims <B> 1 to 6, </ B> characterized in that the destructuring of the foam to recover crystals or agglomerates of crystals is carried out by filtration after pumping the foam. <B> 10. </ B> Method according to one of claims <B> 7 to 9, </ B> characterized in that the crystals or agglomerates of crystals recovered are washed to remove impurities. <B> 11. </ B> The method according to one of claims <B> 1 to 10, </ B> characterized in that the crystallization carried out in the structured medium <B> under foam </ b> is a classical crystallization without chemical reaction. 12. Method according to one of claims <B> 1 to 10, </ B> characterized in that the crystallization carried out in the structured medium <B> under foam form is a crystallization with chemical reaction, in especially a precipitation.