The method of crystallization-l-aspartyl-l-phenylalanine methyl ester from the aqueous solution and the device

 

(57) Abstract:

The invention relates to a method of cooling an aqueous solution of aspartame and crystallization from him aspartame, excluding mobilizatio in water crystallization system by (i) filing of a hot aqueous solution of aspartame in the means for dispersing droplets; (ii) dispersion of droplets in an immiscible with water, the fluid whose temperature is at least 20C lower for drops there was no formation of crystallization centers while passing them through immiscible with water, liquid; (iii) cooling mentioned immiscible with water fluid with the for the drops effectively cooled to achieve an initial supersaturation-L-aspartyl-L-phenylalanine methyl ester inside the drops in the range from 1 to 6, preferably from 1.2 to 4; (iv) collecting the cooled droplets for crystallization aspartame; and (v) provide sufficient time for this. Under the proposed method is rapid crystallization arm, which, in addition, allows to obtain crystals suitable for processing in the process of wet granulation, and there are other acceptable properties of the crystal. 2 S. and 19 C.p. f-crystals, 1 Il., table 1.

Isobm description also referred to as aspartame or workstation) and crystallization of L-aspartyl-L-phenylalanine methyl ester from its aqueous solution with the exception of turbulence in the water of crystallization system.

Aspartame is a dipeptide ester L-aspartyl-L-phenylalanine methyl ester (APM) is an important synthetic low-calorie sugary substance, which is approximately 200 times sweeter than sugar and has exceptionally good taste, for example, without a bitter aftertaste. Used for sweetening a wide range of products or products such as soft drinks, sweets.

Aspartame may be prepared in various known ways. There is, for example, the way in which the N-protected L-aspartic acid or its anhydride and L-phenylalanine or its methyl ester chemically connected, a protective group, optionally, be removed later, and arm are obtained by esterification, if necessary. Examples of such a process is described, for example, in patent US-A-3786039. In processes for chemical compounds usually a relatively large number of arm are formed as a by-product, and the gradual formation of the desired arm often occurs through the formation, for example, HCl salts and neutralization crystallization. These methods inevitably lead to a large number of inorganic salts.

There are also enzymatic processes for the production workstation, through to the m-derived LL-dipeptide and then converted to a workstation. This method is described, for example, in U.S. patent US-A-4116768.

Any way of getting arm one end or the final stages is to obtain AWS in crystalline form from the solvent in which it is present and in which are also and other reaction by-products and/or cleavage products. Typically, the solvent is an aqueous solvent, i.e. water or mixed with water solvent concentration miscible with water, an organic solvent up to 25 wt%, in particular, the lower alcohol with one to three carbon atoms. Used in the present description, the term "water", therefore, exactly what is supposed to mean "water and water containing up to about 25% weight. C1-3alcohol".

The meaning of the term "arm" is used in this description for the source material does not include physiologically acceptable salt workstation, such as its salt of hydrochloric acid ("HCl"), but may include AWS, obtained after neutralization of such salts.

The method of crystallization workstation from aqueous solutions is described in European patent EP-A-91787 (hereinafter in the description referred to as the '787). According to this method AWS crystallizes, at least for the most part crtdate forced flow, i.e. in conditions where turbulence in the water system are excluded. This method requires special equipment and leads to the formation of a solid, carbetapentane Pseudomonas phase. Due to the fact that the required cooling method is not adapted to receive thermal conductivity, at best, higher than the average 100 W/m2during the cooling process. The cooling time is relatively long. Moreover, it was found that the APM crystals obtained by method '787, it is difficult to manipulate in the process of wet granulation. This is a significant disadvantage of this known method.

Accordingly, the present invention is to provide a method of rapid crystallization workstation by cooling from its aqueous solutions, which, in addition, allows to obtain crystals suitable for processing in the process of wet granulation and still have acceptable properties of the crystal.

Summary of invention

The solution to this problem is provided by the fact that the method of cooling an aqueous solution-L-aspartyl-L-phenylalanine methyl ester and crystallization of L-aspartyl-L-phenylalanine methyl ester with drop the thief-L-aspartyl-L-phenylalanine methyl ester in the means for dispersing droplets of the above-mentioned solution; (ii) mentioned dispersion of droplets in a water-immiscible liquid having a temperature of at least about 20oC lower than the temperature mentioned the hot solution, and this temperature difference with the said hot solution that drops there is no formation of crystallization centers at a time when they are water-immiscible liquid; water-immiscible liquid has a density less than the density of the aqueous solution at the same temperature, and a viscosity of less than 10 mPas; (iii) cooling the aforementioned water-immiscible liquid so for the droplets effectively cooled to achieve an initial relative supersaturation-L-aspartyl-L-phenylalanine methyl ester inside the drops in the range from 1 to 6, preferably from 1.2 to 4; (iv) collecting the cooled droplets after passing through the water-immiscible liquid for crystallization of L-aspartyl-L-phenylalanine methyl ester without any mechanical mixing; (v) and provide sufficient time for crystallization of L-aspartyl-L-phenylalanine methyl ester from the collected aqueous phase.

This method provides an elegant and Bystrice wet granulation and at the same time having other acceptable properties of the crystal. In addition to aspartame, according to the present invention can also be crystallized and other products exhibiting good crystallization properties with strong saturation. However, it is preferable to crystallize aspartame.

In addition, it was found that the present method when the resulting crystalline product is dried, gives particles of aspartame, which has a smooth surface, whereas the product obtained by a known static crystallization, has a rough uneven surface; smooth surface is especially preferred in case of high moisture product, for example by wet granulation. It is noticed that the rate of melting of the crystals obtained according to the present invention, there can be few worse than those of the crystals obtained according to the method of the '787, but it is well known that the rate of melting can be improved by further processing of the crystals, for example by reducing the average size or by adding additives or additives that increase the speed of melting.

Therefore, the present invention relates to a method of cooling an aqueous solution APM and crystallization from his arm with iltor-L-aspartyl-L-phenylalanine methyl ester in the means for dispersing droplets of the above-mentioned solution; (ii) mentioned dispersion of droplets in a water-immiscible liquid having a temperature of at least about 20oC lower than the temperature mentioned the hot solution, and with the temperature difference between the hot solution, in which there is no formation of crystallization centers in the droplets at the time when they pass through the water-immiscible liquid; water-immiscible liquid has a density lower than the density of the aqueous solution at the same temperature, and a viscosity of less than 10 mPas; (iii) cooling the aforementioned water-immiscible liquid is thus so that droplets effectively cooled to achieve the initial relative supersaturation-L-aspartyl-L-phenylalanine methyl ester inside the droplets in the range from 1 to 6, preferably from 1.2 to 4; (iv) collecting the cooled droplets after passing through the water-immiscible liquid for crystallization of L-aspartyl-L-phenylalanine methyl ester without any mechanical mixing; (v) and provide sufficient time for crystallization of L-aspartyl-L-phenylalanine methyl ester from the collected aqueous phase.

The relative saturation, ispolzuemogo a) difference (c) the actual concentration of dissolved arm before crystallization and intense concentration workstation (c*in the mother liquor at a temperature of crystallization, and (b) referred to a saturated concentration AWS in the uterine fluid (c*). Hence = c/c*. Value before crystallization is the initial relative saturation. The value of c*used in this application, is calculated (for workstation solutions in pure water in the temperature range of the suspension obtained in this way) according to the following formula:

c*= 0,436 100,017 T(in wt%),

where T is the temperature inoC. In the relevant temperature range, this formula agrees well with the formula proposed by Kishimoto and others in "J. Chem. Tech. Biotechnol", 1988, 43, pp. 71-82, which is

c*= 4,36 100,017 T(in g/l, ToC).

The last formula (g/l), however, is a bit more uncertain.

As already explained above, the term aqueous solvent is water or mixed with water, the solvent concentration miscible with water solvent, for example, C1-3alcohol, up to about 25% weight. Moreover, the presence of a lower alcohol may be useful in further stages of the method, for example when further processing of the suspension, for example, removed by the fact that a source solutions can be achieved a higher concentration (dissolved) workstation. Water-immiscible liquid, which are generally used are poor solvents for the workstation, and can dissolve only a very small amount of water.

It is observed that the density of the aqueous solution APM depends on the composition of this solution. The presence of a lower alcohol provides a trend of decreasing density. The density of the aqueous solution APM (measured with the temperature of the water-immiscible liquid), therefore, is normally in the range of 0.95 to 1.00 g/cm3.

The temperature difference between the hot aqueous solution APM and (colder) water-immiscible organic liquid must be significant, for example not less than about 20oC, so that in the lower layer (i.e., under water-immiscible liquid), it was possible to get acceptable output or the production of crystals. However, the temperature difference should not be too large, to avoid excessive formation of crystallization centers in the droplets as they move through the water-immiscible liquid. This should lead to undesirable formation of small crystal is cooled when passing through the said liquid. This cooling is very effective, and can be calculated so that it was carried out with the heat transfer coefficient in the range from about 800 to about 3000 W/m2In contrast to the heat transfer coefficient according to a known method for cooling heat conductivity, which at best, is about 100 W/m2K.

It should be noted that another way of rapid cooling and crystallization workstation from aqueous solutions is described in European patent EP-A-0523813 in which such cooling is provided by direct contact with ice. However, this method is very disadvantageous, because, on the one hand, the cooling is not equally effective across the AWS solution and, on the other hand, is extensive dilution of the initial solution AWP because of the need to melt large amounts of ice.

In a preferred embodiment of the invention the means for dispersing droplets selected from, for example, different types of nozzles (for example, spray nozzles or injectors, nozzles, high pressure rotating nozzles, rotary atomizers, gazoraspredelitelnyh nozzle or nozzles, vibrating nozzle, or pulsed nozzles or FD is x means the formation of droplets, located near the upper level of water-immiscible liquid; means for forming and dispersing droplets usually relatively simple, inexpensive and accessible, and the specialists can easily determine which of these types are most suitable for this purpose. It is preferable to choose this type dispersing means, which gives exactly the same drops, or so-called monodisperse droplets. The size of the formed droplets can be adjusted in a wide range by selection of the dispersing means. Preferably, the selected range average size (diameter) of the droplets was narrow.

It is most preferable to have a means for dispersing droplets at a small distance from the upper layer of water-immiscible liquid, but does not contact directly with the said liquid. This eliminates the situation in which the outlet nozzle (or similar) occurs crystallization and/or clogging of the nozzle, which leads to unwanted interruption. The distance from the dispersive tools to the upper surface of the water-immiscible liquid is not critical, but usually it should not be more than 2 meters of water liquid can rise in the implementation of the method of the invention (and it certainly is in the process dosed feed or download when from the bottom of the crystallization equipment doesn't remove the suspension), it is preferable that the means for dispersion could move in a vertical direction and is adjustable in height during the process in accordance with the position of the upper liquid level. Such vertical adjustment of the dispersing means less important or even unnecessary in the case where the method of the invention is carried out in a continuous mode, i.e., by (semi)continuous removal of the crystal slurry formed in the lower part of the unit, while on top of a freshly prepared aqueous solution APM.

In order to ensure that educated dispersing agent droplets will have sufficient cooling time when passing through the water-immiscible, it is preferable that the dispersion was carried out at least at a distance of 10 cm above the bottom level of water-immiscible liquid. The minimum distance will depend on the size of the droplets.

To achieve good results the temperature of the hot aqueous solution APM must be at least 50oC and the concentration of the arm should be at measures is stylizacji becomes too low, also, if the concentration of AWS in it too low, relative saturation, which can be achieved in the method according to the invention, will also be relatively low, in the result we will get bad results. As stated above, the temperature difference between the hot aqueous solution APM and (colder) water-immiscible organic liquid should be at least about 20oC, so that there was no education, no crystallization centers in the droplets as they move through the immiscible with water liquid.

Droplets, falling in immiscible with water, the liquid (lower temperature) is cooled when passing through the said liquid. This cooling is very effective, and you can calculate that it was carried out with the overall heat transfer coefficient in the range from about 800 to about 3000 W/m2K.

Lower the temperature of the immiscible with water fluid (in comparison with a hot aqueous solution APM) is maintained at an approximately constant level, mainly by cooling; preferably this cooling to be implemented through indirect cooling. Indirect cooling as it is understood immiscible with water, liquid, or cooled by external circulation of immiscible with water fluid through the heat exchanger; the latter is preferable to perform by submission (and removal) of immiscible with water fluid in a counter so that the aqueous phase does not protrude in the outer or external heat exchanger, and into the mould (or from it). This can easily be ensured through adequate design, for example through the use of tangential feed lines and perechodnik channels.

The temperature of the refrigerant used for cooling immiscible with water, liquid should be between -10 and +20oC. the Specialists can easily determine the optimum conditions depending on the equipment used, the temperature of the hot aqueous solution APM and used immiscible with water liquid.

Thus, in the case of circulation and external cooling immiscible with water is liquid, it is preferable to carry out by way of diversion from the top layer of immiscible with water liquid without contact of the aqueous phase and feed it in a counter near the lower level of said liquid. More profitable to make such objection and filing thus, in order to be achieved, for example, through the use of demolition of partitions, turbulizer, a tangential feed, etc.

In a preferred embodiment of the present invention Vodorezova liquid is in (one or more) of the tubular column(s), equipped with means for dispersing droplets.

The dispersion of the droplets should preferably be carried out at such a distance from the inner side walls of crystallization equipment, especially in the case of tubular columns (columns), so that the droplets created dispersing means is not in contact with the said side walls at their downward movement. This engagement with the side walls may lead to an increase in exposure time and unwanted crystallization and nataliopravde on these walls. Specialists can easily determine the optimal configuration and the design of the equipment.

The diameter of droplets of the solution AWP created dispersing agent, can be chosen quite arbitrarily, although it is preferable that the diameter of the droplets were in the range from 0.05 to 5 mm, and most preferably from 0.1 to 3 mm on average. The best results are obtained if drops of monodisperse, i.e. imewe the desired residence time of the droplets in an immiscible with water liquid. When the diameter of the droplets is smaller, the cooling is faster. Good crystalline properties get when dispersed droplets with a diameter of 0.1 to 3 mm. Specialists can easily determine the optimal combination of dispersing funds, droplet size, immiscible with water, fluids and equipment.

Immiscible with water, the fluid may be selected from a wide range of liquids having low or negligible solubility in water, specific gravity which is much lower than the density of the aqueous solution at the same temperature. Preferably it is chosen from the group of aliphatic hydrocarbons and/or aromatic series, having from 5 to 12 carbon atoms, and most preferred that it be selected from the group comprising toluene or n-heptane. The first of them, having a density close to the density of water, has the advantage that water droplets falling into the liquid, are inhibited more effectively, so that their impact when they reach the bottom of the water crystallized suspension is very weak, and the crystals formed or present in the lower part of the installation, at least not impacted and are not affected. The last of these has advantages the organic liquid component, than in the case of, for example, toluene. Usually, however, found that passion immiscible with water, the liquid in the crystallizing system should be weaker, if the collision of drops with crystal layer is weaker. This collision or push when the layer is immiscible with water the liquid is too thin, it is not depends on the height of this layer, as the droplets move through the layer with approximately linear velocity (final sedimentation rate). The measurement of final sedimentation rate enable determination of the diameter of the drops, because the final sedimentation rate refers to the diameter according to Stokes ' law.

Preferably, the droplets passing through the immiscible with water, the liquid was cooled from a temperature 50oC and above to a temperature in the range from 35 to 20oC or below. When the aqueous solution also contains a lower alcohol, the concentration of the arm may be higher, and the beginning of formation of centers of crystallization occurs when the relative saturation, different from the relative supersaturation when using water as the sole solvent arm under other identical conditions.

The aqueous phase after prohozhdenie is INEE in low or negligible mixing or mechanical disturbance, that could happen crystallization. Optionally, the collected aqueous phase can additionally be cooled by indirect cooling.

Preferably, the residence time of the aqueous phase collected at the bottom of the installation, subject to the maintenance in the absence of mechanical mixing or like him, was at least 30 minutes. During the mentioned time is formed spatial structure of crystals workstation, which may be stronger or weaker depending on the amount present aspartame, but which, if necessary, can be easily destroyed by mechanical treatment. In any case, the spatial structure formed according to the present method differs from the so-called dermatopathology Pseudomonas phase formed during static crystallization: the last in the formation in a beaker retains or holds the entire water solvent at turning chemical glass upside down.

Spatial structure (the lower part of the arm formed by the present method, therefore, can be removed in the form of a slurry or suspension without affecting the upper part of about what about the screw feeder. The preferred continuous operation.

The method of the present invention can be carried out in batch or semi-continuous mode. The last mode is more preferable from the viewpoint of industrial feasibility and can be carried out mainly by the continuous discharge of any amounts of crystalline suspension arm from the lower portion of the collected aqueous phase, either continuously or periodically after keeping her without mechanical mixing for at least 30 minutes on average.

As noted above, optionally, the collected aqueous phase can additionally be cooled by indirect cooling. As a result of this additional cooling output of the obtained crystals can be increased. This can be done either by further cooling the bottom of the crystallization setup, or by diversion of crystalline suspension of the installation in another vessel, cooled to a lower temperature in the range of 0 - 20oC, and implementation of additional crystallization in said additional vessel. Preferred additional crystallization to be carried out during mixing, because it is the crystals obtained without negative impact on the size and properties of crystals.

After crystallization workstation, optional with additional cooling, the collected aqueous phase and an immiscible with water, the liquid parts, and any immiscible with water, the liquid retained in the aqueous phase can be removed from it by a known method, such as evaporation.

The method of the invention can be easily implemented in the installation shown diagrammatically in the attached drawing (Fig. 1). This drawing shows the situation of the work in the preferred continuous operation, the number of items marked with the following:

(1) denotes a supply pipe through which the hot aqueous solution APM, prepared and maintained at an elevated temperature in the storage tank (not shown) is fed from above into the vessel or column, (2), which is partially filled immiscible with water liquid. Mentioned food passes through the metering system (3) comprising means for dispersing droplets. The dosing system can be regulated and adjusted vertically in accordance with the upper level immiscible with water, the liquid in the vessel. Position (4) designated area immiscible with water, the liquid in the vessel (2) and item (5) designated area WM is provodnosti (5a). Immiscible with water, the liquid can circulate through an external cooler (6) to maintain an approximately constant temperature, loading or applying a hot aqueous solution AWP. The passion of the aqueous phase into the external cooler (6), which works with a fridge (7) is eliminated through the appropriate location of the circulation piping and vessel design, i.e., through installation perechodnik channels. At the bottom of the vessel (2) provided by the tool (8) for discharging the formed suspension and transport it into another vessel (9), equipped with a stirrer (10), which may, but not necessarily, be extra cooling. Received in the end of the crystal slurry produced through the output (11) in subsequent processing steps to extract and drying APM crystals.

The present invention therefore relates to such equipment or facility which is schematically depicted in Fig. 1. However, the equipment in any case is not limited to the apparatus shown in the above drawing. Specialists can easily construct the equipment according to the present invention; please note that this equipment is very much the campaign is xtraction column.

Further, the invention is additionally illustrated by the following experiments are presented below in the form of examples and comparative examples, but in no way limited to them.

Almost all experiments were performed using glass equipment, including a tubular column (height 75 cm, diameter 10 cm), the middle part which is equipped with a jacket, which can circulate the refrigerant, which is a column of one litre of supply vessel containing an aqueous solution AWP. In the lower part of the column is provided a discharge valve through which can be issued the suspension. In the initial experiments the solution was applied to a column of droplets or through 0.9 mm syringe (for drops with diameter of about 3 mm on average) or blowing into the column through a dedicated nozzle (for droplets with an average diameter of 0.5 mm). For each type of experiments and used the hot solution was determined by the diameter of the droplets or by counting drops and weighing, or by measuring the final sedimentation rate according to Stokes ' law. At the beginning of each experiment, the column was filled with approximately 4 liters of immiscible with water Giacosa zone suspension or suspension, and the experiment continued until, while in the lower part of the column of water suspension reached a height of about 15 cm (i.e., volume of about 1 liter). However, it should be noted that the effective time of the experiment is determined by the time of passing through the immiscible with water, the liquid falling in drops. Additional time spent in the lower part is not determinative and is intended only to ensure complete crystallization.

During the experiments the temperature gradient is immiscible with water, the liquid was held to a minimum, as described above, by cooling the Central part of the zone immiscible with water fluid through the circulation of the refrigerant with the appropriate temperature through the jacket. The temperature of the resulting suspension was continuously monitored by a thermometer located at the bottom of the column. It was also found that the temperature of the suspension was only slightly higher (at most 4oC) than the temperature of the lower part of immiscible with water liquid. Properties of the resulting crystalline suspension was determined at the temperature of the suspension after separation of the layer of suspension from the layer of immiscible liquid by determining the resistivity Phi is La better comparison all values of specific resistance of filter pressey cakes made (or certain restated) when the differential pressure P = 0.25 bar (25 kPa). For some suspensions (experiments 1, 2 and 3) were also determined by the compressibility of the filter pressey cakes (respectively component to 0.56 and 0.50 and 0.64, i.e., the average of 0.57); this was carried out in accordance with standard methods after determining the specific resistance of filter pressey pellet with 5 preset differential pressure.

Details of experiments and comparative experiments, the conditions of the experiments and their results are shown in table.

In the table the first column shows the number of Experience or Comparative experience (C.), and also specifies the immiscible with water, solvent: T - toluene or N - n-heptane. The second column refers to the nutrient solution and indicates the content AWP (% wt.) and temperature (oC). It is noted that the Experience of 9 was carried out, using as solvent of water/methanol, whereas in all other experiments the solvent used clean water. In addition, in experiment 3 the resulting suspension was further cooled with stirring to a temperature of 10.5oC prior to determination of specific resistance of filter pressey tortillas. In the third column lists the temperature of the obtained suspension. Column 4 shows the data related to the c*c; the go values of specific resistance of filter pressey pellet at 25 kPa (for example, "1,9" means "1,9 109m/kg").

From these experiments it is seen that according to the method of the invention, the crystals of aspartame with good properties is produced in the process with efficient and rapid cooling. In comparative examples 1 and 2, which were conducted during the initial relative saturation of 8.09 and 0.74, respectively, were obtained poor results for specific resistance of filter pressey cakes.

It was found that the products obtained in the above experiments according to the invention, it is possible to easily manage the process of wet granulation. Equally favorable results when the wet granulation can also be obtained for aspartame, crystallized by static crystallization according to European patent EP-A-91787.

Tests on wet granulation was carried out in the granulator of Ariha (Eirich), includes a rotating vessel volume 5 DM3situated at an angle 30oto the vertical and having an inner rotor rotating in the opposite direction. In the experiments, the vessel was rotated with a speed of 42 rpm, while the circumferential speed of the rotor was 2.8 m/s water Content in the initial product for the wet grain is the exploits of passing a flow of air with a temperature of 65oC above the layer of product. Real granulation was started when the water content in the product was about 45 - 40% weight. or below. Were determined particle size distributions, bulk (bulk) weight and crosscontact obtained granular products, as well as the possibility of the mechanical seal. Crosscontact is a measure of the resistance to abrasion of the particles; the higher values crackaveli, the less the resistance, i.e., above the dust when tested in crosscontact. These tests can be carried out, for example, in rotating drums, possibly with the help of solid bodies moving inside the drum. It is established that the aspartame crystals obtained by the method of the present invention, can granulomatosa for about 4-5 hours to obtain a granulated product having the properties as listed in square brackets properties of granular products manufactured similarly1from aspartame, crystallized by the way '787, as shown below:

*the distribution of particle size (psd, in mm):

d100,6 - 0,8 [< 0,02]

d502,0 - 3,0 [0,05]

d903,0 - 8,9 [0,56]

*crosscontact (in %, must be < 20): 6 - 10 [60]

the awn tablets (N/cm2): 330 - 420 [170]

1Please note that the moisture content at the beginning of this experiment was 32%, the wet granulation was possible without adding water; due to the lower water content of the granulation was carried out quickly, about 2 hours, and the final moisture content was about 23%.

1. The method of cooling an aqueous solution-L-aspartyl-L-phenylalanine methyl ester and crystallization of L-aspartyl-L-phenylalanine methyl ester, eliminating turbulence in the water of crystallization system, characterized in that it comprises the following stages: (i) serves a hot aqueous solution of L-aspartyl-L-phenylalanine methyl ester in a device for dispersing droplets of the solution; (ii) is dispersed droplets in a water-immiscible liquid having a temperature of at least about 20oC below the temperature of the hot solution, and the temperature difference between the water-immiscible liquid and the hot solution is that, in drops, there is no formation of crystallization centers when passing through the water-immiscible liquid, the density of water-immiscible liquid is less than the density of the aqueous solution at the same temperature the liquid thus to effectively drops was cooled to achieve initiating crystallization of glut-L-aspartyl-L-phenylalanine methyl ester droplets in the range from 1 to 6, preferably from 1.2 to 4; (iv) collecting the cooled droplets after passing through the water-immiscible liquid for crystallization of L-aspartyl-L-phenylalanine methyl ester without mechanical mixing, and (v) provides sufficient time for crystallization of L-aspartyl-L-phenylalanine methyl ester from the collected aqueous phase.

2. The method according to p. 1, characterized in that the device for dispersion of the droplets is located near the upper level of water-immiscible liquid.

3. The method according to p. 1 or 2, characterized in that the device for dispersion of the droplets is located a short distance above the upper level of water-immiscible liquid and is not in direct contact with the liquid.

4. The method according to any of paragraphs.1 to 3, characterized in that the device for dispersion can be moved vertically to adjust the height during the process depending on the position of the upper liquid level.

5. The method according to any of paragraphs.1 to 4, characterized in that the dispersion Ob according to any one of paragraphs.1 - 5, wherein the hot aqueous solution of L-aspartyl-L-phenylalanine methyl ester has a temperature of at least 50oC and the concentration of L-aspartyl-L-phenylalanine methyl ester, at least 2.5 percent by weight.

7. The method according to any of paragraphs.1 - 6, characterized in that the cooling water-immiscible liquid is carried out by indirect cooling.

8. The method according to any of paragraphs.1 to 7, characterized in that the part of the water-immiscible liquid circulates and is cooled on the outside by lead her from the upper level of water-immiscible liquid without increasing the aqueous phase and is served in a counter near the lower liquid level.

9. The method according to any of paragraphs.1 to 8, characterized in that the water-immiscible liquid is enclosed in (one or more) cylindrical column(s).

10. The method according to p. 9, characterized in that the dispersion of drops perform at such a distance from the inner side wall that formed droplets are not in contact with the inner side walls during movement down.

11. The method according to any of paragraphs.1 to 10, characterized in that the diameter of the drops-L-aspartyl-L-phenylalanine methyl ester, formed in dis 12. The method according to any of paragraphs.1 - 11, characterized in that the water-immiscible liquid is selected from aliphatic, aromatic or alifaticheskih hydrocarbons having from 5 to 12 carbon atoms.

13. The method according to any of paragraphs.1 - 12, characterized in that the water-immiscible liquid is toluene or n-heptane.

14. The method according to any of paragraphs.1 - 13, characterized in that the drops when passing through the water-immiscible liquid is cooled to a temperature in the range from 35 to 20oC or below.

15. The method according to any of paragraphs.1 to 14, characterized in that the collected aqueous phase is additionally cooled by indirect cooling.

16. The method according to any of paragraphs.1 - 15, characterized in that the collected aqueous phase can withstand without mechanical mixing for at least 30 minutes

17. The method according to p. 16, characterized in that the lower part of the collected aqueous phase is subjected to processing for careful disrupting the structure of the resulting crystals.

18. The method according to any of paragraphs.1 to 17, characterized in that the process is carried out continuously diverting a certain amount of crystalline suspension-L-aspartyl-L-phenylalanine methyl ester from the bottom h is the air traffic management for at least 30 minutes

19. The method according to p. 18, characterized in that allotted crystalline suspension is additionally cooled in an additional vessel with mechanical stirring or without mechanical agitation to a temperature in the range from 0 to 20oC.

20. The method according to any of paragraphs.1 to 19, characterized in that after the crystallization of L-aspartyl-L-phenylalanine methyl ester collected aqueous phase and a water-immiscible liquid are separated and the rest in the aqueous phase of water-immiscible liquid is removed by a known method such as evaporation.

21. Device for cooling the aqueous solution of L-aspartyl-L-phenylalanine methyl ester and crystallization of L-aspartyl-L-phenylalanine methyl ester, comprising a first vessel containing water-immiscible liquid, equipped with a metering system that includes a device for dispersing droplets of a solution, and a device for discharging the formed slurry in the second vessel equipped with a stirrer and yield of the final product, and the water-immiscible liquid may additionally circulate through an external cooler with refrigerator.

 

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The invention relates to the satisfaction of vital needs of the person associated with the destruction of the viability of protein drugs using heat exposure, including within multi-media

The invention relates to biotechnology

The invention relates to a device for the catalytic dehydrogenation of hydrocarbons, in particular for radial flow reactors, and can be used in the petrochemical industry for the dehydrogenation of ethylbenzene to styrene

The invention relates to a device for the catalytic dehydrogenation of hydrocarbons, in particular for radial flow reactors, and can be used in the petrochemical industry for the dehydrogenation of ethylbenzene to styrene
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