JPH02243699A - Preparation of dry crystal of alpha-l-aspartyl-l-phenylala-nine methyl ester having improved solubility - Google Patents

Abstract

PURPOSE:To industrially readily provide the subject crystal of IB type having good solubility by continuously air-drying the wet crystal of alpha-L-aspartyl-L- phenylalanine methyl ester having a specific water content with hot air having a specific temperature. CONSTITUTION:alpha-L-Aspartyl-L-phenylalanine methyl ester (hereinafter referred to as aspartame) having a water content of <=50wt.% is dried with hot air of 80-120 deg.C, preferably 130-160 deg.C, to a water content of 2-6wt.% to provide the objective crystal. It is preferable to prepare the aspartame wet crystal as the raw material by a stationary crystallization method, since the objective crystal is effectively prepared because the crystal having a water content of 20-50wt.% is obtained only by the centrifugal separation of the crystal after the crystallization.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides α-L-aspartyl-
The present invention relates to a method for producing dry crystals of L-phenylalanine methyl ester (hereinafter abbreviated as aspartame).

(Prior art) Aspartame is widely used as a low-calorie sweetener because it has a mild sweetness with less bitterness and aftertaste that is commonly found in high-intensity sweeteners.
It has been pointed out that aspartame has low dispersibility and solubility in water, and in order to obtain aspartame with excellent solubility, methods such as granulation with excipients and disintegrants, foaming tablets, etc. have been considered. However, depending on the application, the presence of excipients and the like is often a problem, and there is a strong demand for aspartame that is highly pure and has good solubility.

Attempts to improve the solubility of aspartame while maintaining high purity include a method of spray-drying slurry-like aspartame (Japanese Patent Publication No. 58-20588), and a method of granulating aspartame with water added to a specific water content (Japanese Patent Publication No. 58-20588). 59
-95862), etc., but regarding the solubility of aspartame crystal itself, JP-A-59-17244
1 in No. 4, the type crystal has good solubility as a dry crystal.

Therefore, as for the aspartame crystal itself, it is desirable to industrially obtain pure summer square type crystals, but there is still insufficient research on how to efficiently obtain highly pure TI type crystals.

[Problem to be solved by the invention]

According to the research of the present inventors, in order to produce high-purity aspartame type Is crystals free of excipients, blowing agents, etc., wet aspartame crystals must be dried at a relatively low temperature of 80°C or less. I know what I should do.

However, it takes a long time to dry aspartame wet crystals at a low temperature below 80°C, and it is difficult to say that this is an industrially efficient drying method. , complex operation management is also required. Therefore,
Developing a process for industrially producing Type 1 crystals with excellent solubility in a short period of time and continuously is an important challenge both technically and economically.

[Means and effects for solving the problem] As a result of extensive research into the above-mentioned problem, the present inventors adjusted the water content of aspartame wet crystals to a specific amount or less, and
The present invention was completed based on the finding that 1-type crystalline aspartame with good solubility can be easily produced industrially by continuous ventilation drying using hot air at 200°C. be.

Both standing crystallization and stirring crystallization are possible, but wet crystals obtained by standing crystallization are preferably used.

In order to obtain aspartame wet crystals by static crystallization, it is sufficient to follow the crystallization method disclosed in JP-A-58-177952. Specifically, when aspartame is cooled and crystallized from an aspartame solution, Solvent present If
On the other hand, it consists of a step of cooling by conduction heat transfer without applying forced flow such as mechanical stirring so that the amount of the precipitated solid phase after cooling is about 10 g or more to generate a pseudo-solid phase. After the formation of the pseudo-solid phase, aspartame wet crystals can be obtained by static crystallization by directly performing solid-liquid separation, or by further cooling and solid-liquid separation if necessary.

Aspartame crystals obtained by static crystallization are bundles of fine needle-shaped crystals that appear to form a single crystal, and exhibit very good dehydration properties in solid-liquid separation. . On the other hand, according to the studies of the present inventors, in order to obtain aspartame wet crystals, stirring crystallization, which is most widely used industrially (i.e., when aspartame is cooled and crystallized from aspartame solution, mechanical stirring, etc. (The aspartame crystals obtained are needle-shaped crystals), the water content of the wet crystals heated in the furnace is about 75%, Even after centrifugation, the water content remains just over 50%. Therefore,
If aspartame wet crystals obtained by stirring crystallization are directly fed to a flash dryer, etc., the wet crystals will inevitably adhere to the inner wall of the dryer, resulting in overdrying and scorching of the adhered crystals, which can be fatal in the product manufacturing process. It becomes a serious obstacle. Furthermore, because of poor dispersibility in airflow, the proportion of large clumps produced increases.

In addition, when wet crystals are fed to a dryer, they tend to adhere to the feed screw, causing problems in quantitative supply. In contrast, aspartame wet crystals produced by static crystallization are left as they are after centrifugation (i.e. , moisture content is usually 20-5
Even if it is fed to a flash dryer (about 10-20% if dehydrating), it can be dried smoothly without causing the above problems, and high purity aspartame. It can be manufactured efficiently. still,
Aspartame wet crystals also include granules in a wet crystal state (ie, those obtained by extruding wet crystals through a screen, etc.).

Aspartame wet crystals obtained by stirring crystallization used in the present invention are produced by mechanically stirring the solution, which is a commonly used industrial method when aspartame is cooled and crystallized from an aspartame solution. - Obtained by cooling and crystallizing a crystal mixture, followed by solid-liquid separation.

In the case of stirring crystallization, the water content of the filtered wet crystals is 75
%, and since the water content is over 50% by normal centrifugation, the water content of aspartame wet crystals is adjusted to 50% or less on a weight basis by forced dehydration such as centrifugation for an even longer period of time. do. The aspartame wet crystals also include granules in a wet crystal state (that is, those obtained by extruding wet crystals through a screen, etc.).

In the method of the present invention, the apparatus for performing continuous aeration drying includes dryers commonly used for continuous aeration drying, such as a flash dryer and a micro dryer, and the type of these dryers does not matter at all.

Originally, when aspartame is dried at high temperatures, a portion of it tends to convert into diketopiperazine derivatives, which lack sweetness, resulting in a loss of sweetness overall. According to the method of the present invention, 80 to 200°
C1 Even if hot air at a high temperature of preferably 130 to 160°C is used, continuous air drying is carried out in which drying is completed in a short time of about 1 minute, so there is almost no change to the diketopiperazine derivative, and Formation of crystals is also small. Therefore, aspartame L-type crystals can be produced extremely efficiently (and stably). However, if the hot air temperature is lower than 80°C, it will take a long time to dry, and if it is higher than 200°C,
■Since the rate of transition to type crystals increases, both I
, is not preferred for industrially and stably obtaining type crystals.

Aspartame dry crystals (!, shaped crystals) having a water content of about 2 to 6% are obtained by the above continuous air drying.

Obtained aspartame 1. The mold crystal is aspartame■
It has better solubility than molded crystals, and has excellent powder properties with less scattering when handled.

Next, the present invention will be further explained by examples.

〔Example〕

Example 1 17.7 kg of aspartame was placed in a stainless steel crystallizer with a diameter of 400 mm and equipped with a jacket and a cooling plate inside.
Pour 380L of raw material aqueous solution (55°C, initial aspartame concentration 4.4% by weight) into which the aspartame is dissolved, and raise the temperature to O''C.
of refrigerant was circulated through the jacket and cold plate and cooled for 3 hours. After about 1 hour, the entire solution became a pseudo-solid phase. The quasi-solid-phase aspartame crystals were dropped into a paddle equipped with a cooling coil and a stirrer, crushed, turned into a slurry, and further cooled (the receiver was cooled from 16°C to 7°C in the tank). The slurry thus obtained was filtered and dehydrated using a centrifugal separator with a diameter of 36 inches, and aspartame wet crystals with a water content of 30% were obtained. The aspartame wet crystals obtained by such a static crystallization method were continuously supplied to a micro dryer (manufactured by Hosokawa Micron) using a screw feeder.

(Drying conditions) Dryer inlet hot air temperature: 135°C Dryer outlet exhaust air temperature: 104°C The proportion of type 18 crystals after drying is I
It was determined from the characteristic peak ratio of powder X-ray diffraction of type 8 crystal and n type crystal.

(The same applies to the following examples.) (Drying results) Moisture content 1, type crystal ratio diketopiperazine derivative Example 2 2.6% 95% 0.05 or less Static crystallization method as in Example 1 Aspartame wet crystals (moisture content based on the weight of aspartame wet crystals: 30
%) was supplied to the same micro dryer as in Example 1 using a screw feeder, and air-dried under the following drying conditions.

(Drying conditions) Dryer inlet hot air temperature 160°C Dryer outlet exhaust air temperature 109°C (Drying results) Moisture content 2.4% L-type crystallized crystals 87% Diketopiperazine derivative 0.05% or less Examples 3. An aqueous aspartame solution (55° C., aspartame concentration 44% by weight) was prepared in a stainless steel crystallization can with a cooling jacket and a stirrer, and a refrigerant at a temperature of 0° C. was circulated through the jacket. 4
When aspartame reached an extremely high level at 4°C, stirring was stopped and crystals were allowed to grow for 45 minutes without stirring, and then cooled to 7°C by cooling again with stirring. When this slurry was filtered and dehydrated using a centrifuge, aspartame wet crystals with a water content of 38% based on the weight of aspartame wet crystals were obtained. The wet crystals were continuously supplied to a micro dryer (manufactured by Hosokawa Micron) using a screw feeder.

(Drying conditions) Dryer inlet hot air temperature 135°C Dryer outlet exhaust air temperature 77"C (Drying results) Moisture content 3.5% TI type crystal percentage 94% Diketopiperazine derivative 0.23% Example 4 Example Prepare an aspartame solution with the same concentration as in 3 in a crystallizer (55°C) equipped with a cooling jacket and a stirrer, circulate a refrigerant at a temperature of 0°C through the jacket while stirring, and cool to 7''C for crystallization. did. This slurry was subjected to solid-liquid separation using a centrifuge, and then dehydrated for 1 hour to obtain aspartame wet crystals with a water content of 46%. The aspartame wet crystals were fed to the same micro dryer as in Example 3 using a screw feeder.

(Drying conditions) Dryer inlet hot air temperature 159°C Dryer outlet exhaust air temperature 87°C (Drying results) Moisture level i 2.7% Type Il crystal percentage 85% Diketopiperazine derivative 0.82% Example 5~ 7 The aspartame stirring crystallization slurry obtained by the same method and conditions as in Example 3 was separated into solid and liquid, and then pre-dried to obtain aspartame wet crystals with moisture content of 30% and 45%.

The obtained wet crystals and the aspartame stirred crystallized wet crystals with a moisture content of 60% as a comparative example were dried using a micro dryer.
It was dried under the conditions shown in Table 1. The results are shown in Table 1.

Claims (1)

[Claims] 1. A method for producing dried α-L-aspartyl-L-phenylalanine methyl ester by drying wet crystals of α-L-aspartyl-L-phenylalanine methyl ester, the water content being α-L-aspartyl-L-phenylalanine methyl ester. L-phenylalanine methyl ester α-L- characterized by using wet crystals of 50% or less based on the wet crystal weight and continuously air drying them with hot air at 80 to 200°C to a moisture content of about 2 to 6%. A method for producing dry crystals of aspartyl-L-phenylalanine methyl ester.