JPH09249692A - Crystallization of alpha-l-aspartyl-l-phenylalanine methyl ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for cooling and crystallizing an aqueous solution of α-L-aspartyl-L-phenylalanine methyl ester (AMP) by which the forced fluidization is interrupted during a part of the crystallization time in order to obtain the large-sized and uniform AMP crystal, good in filterability and dryability and excellent in handling of production, packaging, transportation, etc., quality, etc.

SOLUTION: This method for crystallizing AMP comprises initially cooling a transparent aqueous solution of the AMP under conditions of forced fluidization, interrupting the forced fluidization before the formed crystal concentration attains 0.5wt.% after staring the crystallization, interrupting the forced fluidization until the formed crystal concentration attains ≥10wt.% and ≤50wt.%, interrupting the cooling at the same time as or for a short time after the interruption of the forced fluidization and continuing the interruption time for the cooling during at least a part of the interruption time for the forced fluidization in the method for interrupting the forced fluidization during a part of crystallization time and cooling and crystallizing the aqueous solution of the AMP.

COPYRIGHT: (C)1997,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention provides
By interrupting forced flow, α-L-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as APM) has a sweetness of about 200 times that of sucrose, and is a high-quality sweetener, and therefore, as a low-calorie sweetener. Widely used.

[0002]

BACKGROUND OF THE INVENTION Aspartame can be produced by various methods. The industrial process for manufacturing APM includes
A process in which N-protected-L-aspartic acid and L-phenylalanine methyl ester are condensed in the presence of an enzyme and the protective group is subsequently eliminated (US-A-4,282).
721) and N-protected-L-aspartic anhydride and L
-A process of coupling with phenylalanine methyl ester in an organic solvent and leaving the protective group according to the usual methods (US-A-3,786,039).

In any of the processes, a crystallization step is essential to obtain the final product by isolating APM from the reaction mixture. In this crystallization step, (a) APM solution (aqueous solution, organic solvent or water-containing organic solvent) or crude APM product obtained through (1) synthesis step and purification step is redissolved in water, organic solvent or water-containing organic solvent. By cooling the (b) APM solution produced by
It is usually carried out by depositing M crystals, (2) solid-liquid separation or dehydration of the deposited crystals using, for example, a centrifuge, and (3) drying the dehydrated crystals to obtain a final product. .

Hereinafter, unless otherwise defined, the "APM solution" is used as an APM aqueous solution, an APM organic solution or an APM organic solution containing water, and the term "aqueous solution" is used as a solution consisting only of water. It

According to the prior art, precipitation of APM crystals by cooling (cooling crystallization) is usually (i) stirrer and cooling / heat-
It is carried out using a crystallizer with a moving surface or (2) a crystallizer with an external circulation heat exchanger. In other known methods, APM
In order to improve the crystal properties of the above, crystallization is carried out by heat conduction without forced flow (EP-B-0091787,
Hereinafter, abbreviated as' 787).

In Example 3 of JP-A-2-243699 (hereinafter abbreviated as' 699), it was accidentally apparent that if forced flow was interrupted at the same time as the start of crystallization, cooling crystallization without forced flow would proceed. became. Thus, in the above example, stirring was interrupted at the same time as the start of crystallization, and
It describes an experiment involving crystallization from an APM aqueous solution by cooling without continuous stirring for 5 minutes with continuous cooling.

When APM is crystallized by cooling in a crystallizer using forced flow, for example, normal mechanical stirring or forced flow created by external circulation, solid-liquid separation and dehydration are poor. Fine needle crystals are obtained. Such crystals also easily adhere to the cooling / heat transfer surface and form so-called scales, which impair the efficiency of heat transfer and must be removed by interrupting the crystallization run at regular intervals. I won't. Furthermore, since the crystals are fine and have a high water content, various problems occur during drying and subsequent handling. For example, in the drying step, since there is a large amount of mother liquor containing impurities remaining attached to the APM crystals,
An undesirably high impurity product is obtained. The dried product also contains a lot of fine powder, which in the form of fine powder is highly scattered.

In order to avoid such a problem, the above-mentioned '787 which is considered to be the closest prior patent to the present invention.
Is a process in which an APM solution, which may be an aqueous solution, is cooled through conduction heat transfer to generate a pseudo-solid phase without forced flow created by mechanical stirring, etc., and then cooled with stirring if necessary. Is proposed. In the method of cooling crystallization according to '787, at least the first 75% of the crystallization must maintain the conditions of static crystallization. Because of this, poor quality crystals are produced. Even if continuous cooling is performed using the method of Example 3 of '699, crystals of even worse quality are produced.

The methods of '787 and' 699 may provide APM crystals with favorable filtration and dewatering performance. However, the cooling efficiency of these methods is relatively low because cooling or most of that cooling is carried out by conduction heat transfer without forced flow. Such a method requires a large conduction area, a sorbet-like pseudo-solid phase is generated, and stirring cannot be performed until the final part of crystallization. Therefore, for example, a special solid such as shown in FIG. 9 of '787 is used. Equipment is required. For these reasons, for example, '78
The cost of method 7 is high.

Furthermore, especially in the considerable range of '787 or' 699, the temperature near the cooling surface is low and the temperature far from the cooling surface is high. Thus, the solution or system as a whole is heterogeneous, and under normal conditions the actual APM concentration in the solution-saturation, which means the solubility of APM, is non-uniformly distributed in the crystallizer. For this reason, the degree of saturation becomes high in a place where the temperature is low, crystallization of APM starts in such a place, and the system becomes more and more heterogeneous. This inevitably leads to inhomogeneities in the crystals obtained.

[0011]

The object of the present invention is to provide large and relatively uniform APM crystals which have good filterability and dryability, and which have advantages in handling, quality in manufacturing, for example, packaging or transportation, and the like. In order to obtain the above, it is an object of the present invention to provide a method of crystallizing APM by interrupting forced flow during a certain portion of crystallization and cooling the aqueous solution containing APM.

[0012]

In view of the above points, the inventors of the present invention have enthusiastically studied to solve the above problems for improving the industrial production of APM crystals, and as a result, Suitable, large size APM crystals can be obtained by interrupting forced flow and cooling the aqueous solution containing APM during certain parts of the crystallization.
The clear aqueous solution containing PM is first cooled under forced flow, the forced flow is stopped until the concentration of the produced crystals reaches 0.5% by weight, and the amount of produced crystals is at least 10% by weight, Discontinue the forced flow until it becomes 50% or less, and stop the cooling at the same time as or after the stop of the forced flow, and continue the cooling interruption time for at least a part of the forced flow interruption time. It has been clarified that the above-mentioned problems can be surprisingly solved by. The present invention has been completed based on the above findings.

Therefore, according to the present invention, for a part of the crystallization time, the forced flow is stopped, and α-L-aspartyl-L
In the crystallization method of α-L-aspartyl-L-phenylalanine methyl ester by cooling the aqueous solution containing phenylalanine methyl ester, α-L-aspartyl-
The transparent aqueous solution containing L-phenylalanine methyl ester was first cooled under forced flow to start the crystallization of α-L-aspartyl-L-phenylalanine methyl ester, but the concentration of the produced crystal was 0.5% by weight. %, The forced flow is stopped before reaching the%, the forced flow is interrupted until the amount of produced crystals becomes at least 10% by weight, but 50% or less, and cooling is performed at the same time as the forced flow is stopped or after a while. There is provided a process for crystallization of α-L-aspartyl-L-phenylalanine methyl ester characterized in that it is stopped and this cooling interruption time continues for at least part of the forced flow interruption time.

The present invention will be further described below.

The transparent APM aqueous solution is effectively cooled by forced flow. Such forced flow is created, for example, by applying an external circulation pump, a mechanical stirrer using various stirring blades, or vacuum evaporation. Preference is given to using stirring blades. The optimum cooling effect is obtained by using a device equipped with cooling coils, cooling plates, cooling jackets or external circulation coolers.

The APM aqueous solution suitable for use in the present invention is
Initially it is a clear solution, whose temperature is (i) above the temperature at which the APM crystals precipitate and (ii) below the temperature at which significant decomposition of APM occurs, for example the formation of diketopiperazine. But it's okay.

Generally, a large amount of APM can be dissolved in a solution, while the decomposition into diketopiperazine is small, so that 50
Temperatures in the range of ~ 65 ° C are preferred.

The pH of the solution is preferably 3 to 6 and more preferably 4 to 5 in order to minimize the decomposition of APM. The APM concentration of the solution is preferably 2 to 6% by weight in order to obtain APM crystals in high yield.

The cooling rate of the cooling accompanied by the forced flow before the forced flow is stopped (hereinafter, abbreviated as "initial cooling rate") is 2 ° C. in order to shorten the cooling time and suppress the decomposition of APM. / Hour or more is preferable, the degree of saturation increases, and the APM crystal grows at a high speed, so that a large APM crystal can be obtained. Further, the cooling rate is preferably 5 ° C./hour or more, more preferably 10 ° C./hour. However,
Very high cooling rates require enormous cooling capacity and increase the cost of the cooling system. Therefore, an initial cooling rate of 50 ° C./hour or less is generally preferable.

According to the present invention, after the precipitation of the APM crystal is started, the forced flow is interrupted until the concentration of the generated crystal reaches 0.5% by weight, and the cooling is stopped at the same time as or immediately after the stop. Stop. Further, it is preferable to stop the cooling after the forced flow is stopped and before the temperature is lowered by 3 ° C. or more. Therefore, the time between the interruption of forced flow and the interruption of cooling is preferably up to about 30 minutes.

In Example 3 of '699, the stirring was stopped at the same time as the precipitation of the APM crystals was started, and then the stirring was interrupted for 45 minutes while continuing the cooling to crystallize the APM aqueous solution by cooling. Is described. According to the method of the present invention, it is preferable that the time from the first precipitation of APM crystals to the stop of forced flow and the time to stop cooling at the same time and immediately thereafter are shorter, and the concentration thereof is 0.5% by weight. % Must not exceed the time required for APM crystal precipitation. In particular, the crystal concentration in the system is 0.01 to
It is preferred to start the forced flow and the interruption of cooling at the same time or shortly after reaching 0.4% by weight. If the time to stop is too short, the total crystallization time becomes unnecessarily long, the obtained APM crystal becomes small, and the crystal growth becomes insufficient. If the forced flow and cooling are interrupted before the precipitation of APM crystals, the results are even worse. If the time until the interruption is too long, that is, if the interruption is continued until 0.5% by weight or more of crystals are produced, the crystal nucleus generation rate is too fast and too many APM crystals are obtained. Since it is short, the filterability becomes poor. Therefore, this result is related to the degree of saturation, the formation rate of crystal nuclei, and the formation rate of APM crystals.

The detection of the start of APM crystal precipitation can be carried out visually or by a change in pH, that is, when the APM crystals precipitate, the pH decreases or increases depending on the initial pH. However, it is preferable to use a turbidimeter that measures changes in light transmittance because it is easier and more accurate. Turbidity changes differentially when APM precipitation begins.

Using a turbidimeter, the preferred amount of APM present can be estimated by the turbidity in the system in which the APM is deposited, before interruption of forced flow or interruption of cooling. As a result, when the initial amount of APM crystals reaches the most preferable range, forced flow or cooling can be stopped. In the above most preferred range,
APM crystal nuclei are generated at a suitable rate, and the initial APM crystals grow well after the termination of forced flow.
PM crystals are obtained. Therefore, the APM finally obtained
The crystals have a very good filterability.

After the forced flow interruption (or even the cooling interruption), the precipitation of APM crystals continues until the supersaturation is eliminated. According to the present invention, forced flow (or cooling) is
It should not be restarted until the amount of PM crystals reaches at least 10% of the target amount, but it is not particularly necessary to restart forced flow and cooling at the same time. Although cooling may be restarted immediately before restarting forced flow, it is preferable to restart forced flow before restarting cooling. Since a large amount of APM crystals can be obtained by prolonging the interruption time, the interruption time of the forced flow is 0.
2 hours or more, preferably at least 0.5 hours. on the other hand,
The upper limit of this interruption time is 5 hours, because it is interrupted further and no more crystals are formed,
After 2 hours, a slight amount of crystals are formed, so the interruption time is preferably 2 hours.

The present inventors have found that sherbet-like pseudo-solid phases as described in '787 do not form during the interruption of forced flow. It is considered that such a difference occurred in '787 because the forced flow was not carried out until at least 75% of the crystals were precipitated.

The cooling of the APM solution may be stopped at the same time when the forced flow is stopped, or after the forced flow is stopped and before the temperature is lowered by 3 ° C. or more. However, in order to obtain the most uniform and large APM crystals, it is preferable to interrupt the cooling during the interruption of the forced flow. Temporarily, '69
As in Example 3 of 9, cooling was not interrupted during forced flow and A
When the temperature of the PM solution is lowered, there is no forced flow,
The temperature distribution becomes non-uniform and the degree of supersaturation also becomes non-uniform. As a result, there is a difference between the crystal nucleation rate and the growth rate,
The resulting APM crystals are less uniform and the number of relatively small crystals increases. If the cooling is interrupted or the temperature is not lowered during the forced flow interruption, the temperature and supersaturation will be more uniform. Therefore, there is almost no difference between the crystal nucleation rate and the growth rate in the entire system, and a large and uniform APM crystal with good filterability can be obtained. In general, by interrupting the cooling, the temperature can be kept constant, and special operations and equipment are usually unnecessary since the temperature is almost constant during the interruption of forced flow. The meaning of this constant is understood here that the temperature does not decrease by 3 ° C. or more. The cooling water or the refrigerant remains as it is, for example, in the cooling jacket, the cooling coil, or the cooling plate. Since such a refrigerant is very small compared to the volume of the entire apparatus, there is no substantial change in the temperature distribution. Does not happen.

A temperature drop of about 3 ° C. does not interfere with the actual operation for the preferred practice of the present invention. However, in order to keep the temperature constant, when the forced flow is interrupted,
It is preferable to replace the circulating refrigerant with a refrigerant having the temperature of the entire system.

Forced flow should be resumed when the amount of crystals reaches at least 10% of the target amount. This crystal amount is 2
0% or more is preferable, and 30% or more is particularly preferable, but the upper limit thereof is about 50% in consideration of the overall efficiency.

The target amount of APM crystals can be easily estimated based on the solubilities at various temperatures. This amount initially varies with the final temperature and to a lesser extent also with the impurity concentration. The exact solubility of APM in the actual system to be crystallized can be determined in advance or separately by crystallization experiments using the initial solution as a sample. In a more preferred practice of the invention, upon resuming forced flow, the APM slurry is withdrawn from the system while simultaneously adding the same amount of fresh solution.

Almost at the same time when the forced flow is restarted, the APM
The solution (crystallization system) may be further cooled at an initial cooling rate or a rate lower than that. In order to obtain a large amount of APM crystals in a short time, such further cooling should be applied. Such optional further cooling should be considered when determining the target amount of crystals. In this case, the relatively thick and precipitated APM crystals have already grown as seed crystals and have good filterability.
PM crystals are obtained in good yield. Final cooling to 5-10 ° C is preferred to increase the yield of crystals.

In the present invention, there is almost no scaling problem, and even if slight scaling occurs, the scale can be easily removed by forced flow.

In the present invention, the pH of the starting APM solution
Is not particularly limited, but is preferably 3 to 6 and more preferably 4 to 5 because the amount of the APM crystals precipitated and the growth rate increase.

After the batch crystallization of the APM solution is completed,
If necessary, after changing the obtained crystallization system into a slurry that easily flows, or in a preferred method of continuously extracting the crystal slurry after the forced flow is restarted, the slurry of the APM crystals obtained is Solid-liquid separation is carried out by batch operation or continuous operation, and high dehydration degree can be achieved in a short time.

As described above, in the preferred embodiment of the present invention, the slurry obtained in the crystallization step is continuously withdrawn immediately after the forced flow is resumed. Then, in this continuous method, crystallization is continuously continued, during which the amount of new AP corresponding to the amount of slurry extracted for solid-liquid separation is increased.
Supply M solution. The mother liquor in the solid-liquid separation step may be returned to the crystallizer, or may be further cooled in order to increase the amount of APM crystals obtained.

As the solid-liquid separator, any type of centrifugal separator or filter such as a filter press, belt filter and drum filter usually used in industrial operation can be used. If necessary, the resulting crystal cake may be washed with water or APM solution. To minimize redissolution of APM, add water or APM solution, for example 5 to 1
It is preferable to cool to 0 ° C. Easy to clean,
Since the mother liquor adhering to the APM is removed, the quality of the APM crystal is improved. The resulting wet cake, after granulation,
Alternatively, it may be dried as it is. As the dryer, a blast dryer, a fluidized bed dryer, a drum dryer and a high speed rotary paddle dryer can be used. Drying may be performed under reduced pressure.

In the present invention, the average particle size of the APM crystal becomes extremely large, and the particles are very uniform and uniform. The resulting APM crystal is a crystal that grows well in its minor axis direction. The reason for this cannot be completely explained, but because of the uniform temperature and uniform supersaturation when forced flow is applied,
Uniform and favorable nucleation of APM crystals occurs. Therefore, a uniform and large APM crystal having good filterability can be obtained because of the high growth rate especially in the minor axis direction.

[0037]

INDUSTRIAL APPLICABILITY In the present invention, since the cooling is carried out under the forced flow for the main time or the entire time of the crystallization, the cooling efficiency is extremely high and no special equipment is required. The cooling device can be made compact. Furthermore, the method of the present invention is economically very advantageous because of its short cooling time and low cooling energy requirement. Under forced flow, the APM solution is uniform while being cooled, and the crystallization of APM is carried out in the absence of a significant temperature difference. As a result, APM precipitation occurs throughout the system and AP
The M crystal grows uniformly. Therefore, uniform and large APM crystals with good filterability can be obtained. The effects obtained by the method of the present invention can be summarized as follows.

(1) Crystallization can be carried out in a single process, and the apparatus can be made compact. Moreover, the device is easy to operate and the energy required for the process is very low. Therefore, the present invention can be applied to the production of a large amount of APM on an industrial scale and is effective.

(2) APM obtained by this crystallization method
The crystals are largely even, with a small amount of water adhering to the crystals, and a wet cake of APM with a small amount of impurities:
APM crystals can be obtained in a short time because they are extremely easy to filter and wash.

(3) Since the amount of water adhering to the APM crystals is small, it is easy to dry the APM cake, and very little energy is used to obtain the APM crystals at an appropriate temperature and in a short time. You can dry the cake. Moreover, during such drying, no product degradation is observed and a high quality APM is obtained. Furthermore, the amount of fine particles produced in the drying process is very small, which is very convenient for practical operation.

(4) Little dispersion of the dry product occurs, which is very advantageous for handling the final product.

(5) If desired, the quality of the APM crystals deposited using conventional crystallization methods can be improved by adding the resulting APM as seed crystals and wet grinding.

As described above, the present invention has many advantages in terms of actual operation, economics, quality of the obtained product and handling.

[0044]

The present invention will be described with reference to the following examples and comparative examples, but the present invention is not limited to these examples.

In the following examples and comparative examples, the APM
The crystal filtration rate was measured by the following method: 500 ml of the slurry containing the APM precipitated crystals obtained in each example was sampled and 5 ml / cm ² seconds (1
A polypropylene filter cloth having an air permeability of ₂ mmH ₂ O; 117 Pascal) was laid and filtered using a suction filter consisting of a double-walled glass flask equipped with a stirrer, that is, a leaf tester. The slurry is carefully poured into the filter cloth so that the slurry can be continuously dried without being completely dried on the filter cloth, and each slurry is -400 mmHg.
It was filtered at a specific pressure of (= 53.3 kPa).
The filtration rate was calculated from the time elapsed from the start to the end of filtration (the filter is considered to have finished when no liquid was visible on the filter cloth) and the volume of the filtrate at the end of filtration.

EXAMPLE 1 2 liters of a 60 ° C. APM solution containing 3.5% by weight of APM, 2.5 equipped with an external cooling jacket and a stirrer.
It was placed in a liter glass flask and the pH of the solution was adjusted to 4.5 with 1N NaOH. Then add the solution 3
The solution was cooled by circulating cooling water through an external cooling jacket at a cooling rate of 15 ° C./hour while stirring at 00 rpm. Stirring and cooling were stopped as soon as it was observed that APM crystals began to precipitate (which occurred at 42.5 ° C).
The deposited APM concentration at that time was 0.08% by weight. After 1 hour, restart stirring and cooling (at that time, the target amount of 2
6% of APM crystals were deposited. ), The system at 10 ℃
Cooled down. Sherbet-like pseudo-solid phases as described in '787 did not form in that system. The crystal growth was good and no scaling was observed after extracting the finally obtained APM crystals. Table 1 shows the crystal morphology and filtration rate of the APM crystals obtained in this example.

Example 2 This example was carried out in the same manner as Example 1 except that stirring and cooling were interrupted for 2 hours. Also in this embodiment, the AP
Stirring and cooling were stopped as soon as it was observed that M crystals began to precipitate (which occurred at 42.5 ° C). The deposited APM concentration at that time was 0.08% by weight. Other observations were the same as in Example 1 (about 28% of the final crystal amount was obtained before restarting stirring and cooling). Again, the crystal growth was good and no scaling problems were observed after extracting the finally obtained APM crystals. Table 1 shows the crystal morphology and filtration rate of the APM crystals obtained in this example.

Example 3 In this example, APM crystals started to precipitate (42.5 ° C.).
Was carried out in the same manner as in Example 1, except that only stirring was stopped instantaneously when the phenomenon (1) was observed. After a while, cooling was stopped when the temperature dropped to 41 ° C., and stirring and cooling were restarted 1 hour after the stirring was stopped. The concentration of the deposited APM at the time when the stirring was stopped was 0.
It was 05% by weight, and a well-grown APM crystal was observed. The temperature of the system after restarting the stirring was 40 ° C. No scaling was observed at the end of the experiment. Table 1 shows the results
Shown in

Example 4 In this example, a turbidimeter (COMITITE-10, manufactured by Hiranuma Kogyo Co., Ltd.) was used instead of visually confirming the start of precipitation of APM crystals.
Example 1 was carried out in the same manner as in Example 1 except that the determination was performed using a type 1 recording titrator). Stirring and cooling were stopped instantly after the light transmittance changed by 100 mV. It is extremely easy to detect the precipitation of APM crystals, and the concentration of APM initially deposited is 0.05% by weight when stirring and cooling are stopped.
Met. No scaling was observed after withdrawing the finally obtained slurry. The results are shown in Table 1.

Comparative Example 1 This comparative example was carried out in the same manner as in Example 1 except that APM crystallization was carried out without interruption of stirring and cooling.
The crystals obtained were fine and acicular, with considerable scaling. Table 1 shows the shape and filtration rate of the obtained APM crystals. Comparative Example 2 In this Comparative Example, both stirring and cooling were continued even after visually confirming the start of APM crystal precipitation (42.5 ° C.), and stirring was instantaneously performed after the temperature of the system reached 40 ° C. The same procedure as in Example 1 was performed except that the cooling was stopped. At that time, the concentration of the deposited APM was 1.0% by weight. The resulting APM crystals were finely needle-shaped and many scalings occurred. Stirring and cooling was resumed after 1 hour, after which
The APM slurry was further cooled to 10 ° C. Despite stirring, the part with scale could not be removed. Table 1 shows the shape and filtration rate of the obtained APM crystals.

Comparative Example 3 In this comparative example, Example 1 was repeated except that stirring and cooling were stopped at 44 ° C. before visually confirming the start of APM crystal precipitation.
Was carried out in the same manner as described above. An extremely small scale was observed, and the APM crystals deposited after restarting stirring and cooling were fine needle-shaped. Some of the scale could not be removed. Table 1 shows the shape and filtration rate of the obtained APM crystals.

Comparative Example 4 This comparative example was carried out in the same manner as in Example 1 except that cooling was not interrupted at all in 699 as in Example. A
When it was observed that PM crystals began to precipitate (43 ° C.), stirring was stopped instantaneously. At that time, it was found that the concentration of deposited APM was 0.08% by weight. Cooling continued uninterrupted. However, the cooling efficiency drops considerably,
Significant scaling has occurred. When the temperature reached 36.5 ° C (stirring was interrupted for about 1 hour), stirring was resumed and cooling was continued to 10 ° C. Despite stirring, the part with scale could not be removed. The AP obtained
The shape of M crystal and the filtration rate are shown in Table 1.

[0053]

[Table 1]

As is clear from this table, the APM obtained
The filtration rate of the crystals was at the same level as the filtration rate of the present invention, but the length of the crystals was shorter than that of the crystals of the present invention. The particle size distribution of the obtained crystals was slightly wider than that of the crystals obtained in the examples.

In all the above examples, it was revealed that large and uniform APM crystals were obtained because the particle sizes were fairly uniform. By the subsequent treatment, the crystals show good filterability and dryness, and are easily handled during production (for example,
Packaging or shipping) and quality.

Claims (14)

[Claims] 1. A part of the crystallization time, the forced flow is stopped, and the aqueous solution containing α-L-aspartyl-L-phenylalanine methyl ester is cooled to obtain α-L-aspartyl-L-phenylalanine methyl ester. In the crystallization method, a transparent aqueous solution containing α-L-aspartyl-L-phenylalanine methyl ester was first cooled under forced flow to start the crystallization of α-L-aspartyl-L-phenylalanine methyl ester. Forced flow is stopped before the concentration of the produced crystals reaches 0.5% by weight, forced flow is interrupted until the amount of produced crystals is at least 10% by weight, but 50% or less, and the forced flow is stopped. Α-characterized in that cooling is stopped at the same time as or after a while, and this cooling interruption time continues for at least a part of the forced flow interruption time. A method for crystallizing L-aspartyl-L-phenylalanine methyl ester. 2. The α-L-aspartyl- according to claim 1.
In the crystallization method of L-phenylalanine methyl ester, the interruption of forced flow is started when the concentration of the produced crystal reaches 0.01 to 0.4% by weight.
A crystallization method of -L-aspartyl-L-phenylalanine methyl ester. 3. A method for crystallizing α-L-aspartyl-L-phenylalanine methyl ester according to claim 1 or 2, wherein the α-L-aspartyl-L-phenylalanine methyl ester in the solution is Concentration is 2
The method for crystallizing α-L-aspartyl-L-phenylalanine methyl ester is characterized in that the content is ˜6% by weight. 4. The α-L- according to claim 1.
In the crystallization method of aspartyl-L-phenylalanine methyl ester, the temperature of the solution does not decrease by 3 ° C or more at least while the forced flow is interrupted, and α-L-aspartyl-L-phenylalanine methyl ester is characterized. Crystallization method. 5. The α-L- according to any one of claims 1 to 4,
In the crystallization method of aspartyl-L-phenylalanine methyl ester, cooling is interrupted at least while forced flow is interrupted, and the method of crystallization of α-L-aspartyl-L-phenylalanine methyl ester is characterized. 6. The α-L- according to any one of claims 1 to 5,
In the crystallization method of aspartyl-L-phenylalanine methyl ester, α-L-aspartyl-L is replenished with the same amount of aqueous solution as soon as the forced flow is restarted.
Α-L-aspartyl-L, characterized by continuously extracting a slurry of phenylalanine methyl ester
-A crystallization method of phenylalanine methyl ester. 7. The α-L- according to any one of claims 5 to 6.
In the crystallization method of aspartyl-L-phenylalanine methyl ester, α-L-aspartyl- characterized in that cooling is restarted almost at the same time when forced flow is restarted.
A method for crystallizing L-phenylalanine methyl ester. 8. The α-L- according to any one of claims 1 to 7,
In the crystallization method of aspartyl-L-phenylalanine methyl ester, α-L-aspartyl-L- is characterized in that cooling is carried out until the temperature reaches 5 to 10 ° C.
A method for crystallizing phenylalanine methyl ester. 9. The α-L- according to any one of claims 1 to 8,
In the crystallization method of aspartyl-L-phenylalanine methyl ester, the initial cooling rate is 2 ° C / hour to 50 ° C.
A method for crystallizing α-L-aspartyl-L-phenylalanine methyl ester, which is in the range of ° C / hour. 10. The method for crystallization of α-L-aspartyl-L-phenylalanine methyl ester according to claim 1, wherein the start of crystallization is detected by using a turbidimeter. A crystallization method of α-L-aspartyl-L-phenylalanine methyl ester. 11. The α- according to any one of claims 1 to 10,
In the crystallization method of L-aspartyl-L-phenylalanine methyl ester, forced flow is restarted when the amount of the obtained crystals of α-L-aspartyl-L-phenylalanine methyl ester is 20% to 50% of the target amount. A method for crystallization of α-L-aspartyl-L-phenylalanine methyl ester, which comprises: 12. α- according to any one of claims 1 to 10.
In the crystallization method of L-aspartyl-L-phenylalanine methyl ester, the pH of the aqueous solution of α-L-aspartyl-L-phenylalanine methyl ester is 3 to 6.
Α-L-aspartyl-characterized in that
A method for crystallizing L-phenylalanine methyl ester. 13. The method for crystallizing α-L-aspartyl-L-phenylalanine methyl ester according to claim 12, wherein the pH of the aqueous solution of α-L-aspartyl-L-phenylalanine methyl ester is in the range of 4 to 5. A method for crystallization of α-L-aspartyl-L-phenylalanine methyl ester, which is characterized by being present. 14. A method for crystallization of α-L-aspartyl-L-phenylalanine methyl ester substantially as described in the description and examples.