KR910006285B1 - Process for the preparation of dipeptide crystals - Google Patents

Abstract

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Description

Method for preparing dipeptide crystals

1-4 show X-ray diffraction patterns measured with a powder X-ray diffractometer.

5 shows the results of measuring water absorption characteristics of various crystals.

The present invention relates to a method for preparing a dipeptide crystal effective as a sweetener. The present invention also relates to tablets containing dipeptide crystals having good storage stability and having sweetness and methods for their preparation.

Α-L-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as AP), commonly known as aspartame, is a low calorie sweetener with a sweet taste similar to sucrose. In recent years, these sweeteners have been of considerable interest. However, when this material is actually used as a sweetening agent, it has disadvantages of low solubility and dispersibility in general properties of AP.

Moreover, AP is relatively unstable to heat and when heated, it is easily converted to diketopiperadine and loses its sweetness. For example, when a solution of AP is heated to 80 ° C. for about 5 hours, about 20% of the AP decomposes. Therefore, care must be taken not to exceed 60 ° C. in the manufacturing process steps when manufacturing the AP.

To date, it is known that there are two types of AP crystals. The decision is generally a type I crystal, and more specifically, is known as an I _A or I _B type crystals. Both type I crystals are highly hygroscopic, causing coloring and degradation during storage. In addition, the pelletizing ability and fluidizing ability of the powder containing these I type crystals are very poor.

The hygroscopic properties of these crystals are a problem when formulated into usable AP tablets. For example, in the case of effervescent tablets, the moisture absorbed or generated internally by the chemical reaction between the blowing agent (basic) and the neutralizing agent (acidic) causes adhesion between each tablet or between the tablet and the container. In addition, since the reaction of the blowing agent with the neutralizing agent reduces the foamability of the tablet during storage, the foamability of the tablet in use is reduced. Due to the reduced foamability, the solubility of the tablets is significantly lowered.

Therefore, there is a constant demand for obtaining AP crystals having excellent storage stability and very stable in the presence of excipients, blowing agents or neutralizing agents. In addition, there is a continuous demand for AP tablets, which exhibit a decreasing rate of neutralization reaction, which maintains the foamability of the tablets and the high solubility of the tablets.

Accordingly, an object of the present invention is to provide an AP crystal having excellent storage stability and stable even in the presence of an excipient, a foaming agent or a neutralizing agent.

It is also an object of the present invention to provide a method for preparing such AP crystals.

Furthermore, it is an object of the present invention to provide an AP tablet which exhibits a rate of reduction of neutralization which can maintain the foamability and high tablet solubility of the tablet as it is.

It is also an object of the present invention to provide a method for providing such a tablet.

According to the present invention, one form of crystal (type II _A ), determined by X-ray diffraction using Cuk α-rays, shows X-ray diffraction at diffraction angles of at least 20.6 °, 21.2 °, 5.0 ° and 11.1 °. represents the peak, the determination of the different forms (ⅱ _B type) are in a form according to the equilibrium water content of the crystals representing the X- ray diffraction peaks at least 15.2 °, 11.1 °, 19.6 ° and 4.5 ° diffraction angle, in other forms Obtaining the interconverting α-L-aspartyl-L-phenylalanine methyl ester type II crystals, namely II _A and II _X type, achieves the above and other objects (crystals at 78% relative humidity above). Equilibrium moisture content is less than 3%).

First to FIG. In FIG. 4, the first turning Ⅱ _A-type crystal, and the second turning Ⅱ _B-type crystal, a third turn the X- ray diffraction pattern for Ⅰ _A type crystals and _B-type crystals Ⅰ fourth turn. In FIG claim 5, reference numeral "○" is Ⅱ _B-type crystals, "X" shows the Ⅱ _A-type crystal, and "△" is Ⅰ _B-type crystals.

According to the present invention, two new types of crystals are obtained in which conventional I type crystals, namely I _A or I _V type crystals, respectively or together as a mixture, are dried at a temperature of about 80 ° C. or more, thereby converting themselves according to humidity. It is a wonderful thing to discover. These new crystal type, Ⅱ _A and Ⅱ _B type is quite absorb small amounts of moisture, even when said pellet upset easily and Gini excellent fluidization ability, has excellent storage stability, drying the Ⅰ type determination at 80 ℃ these It is a surprising finding that the amount of AP decomposed during preparation of new crystals is extremely small.

Accordingly, the present invention relates to the interconversion from one form to another form depending on the water content, the two types of crystals, type _A and AP Ⅱ Ⅱ type determination made in Ⅱ _B type.

Using Cuk α- line X- ray diffraction to step a result, Ⅱ type _A crystal was measured 20.6 °, 21.2 °, 5.0 ° and represents an X- ray diffraction peaks at the diffraction angle 11.1 ° or more, Ⅱ _B-type crystals 15.2 X-ray diffraction peaks are shown at diffraction angles of at least 11.1 °, 19.6 ° and 4.5 °. Moreover, all crystals at 78% relative humidity had an equilibrium moisture content of about 3% or less.

Type II determination of an AP can be characterized by its physical properties.

(1) X-ray diffraction

Cuk using α- ray powder X- ray diffraction measurement to step a Ⅱ _A-type crystal of the X- ray diffraction pattern of the first degree in Ⅱ _B type the X- ray diffraction pattern for a crystalline form of claim 2, the conventional Ⅰ _A X- ray diffraction pattern of type determination is X- ray diffraction pattern of a third degree, ⅰ _B type crystals are shown in FIG. 4.

As clearly shown in the drawing, Ⅱ _A type determination 20.6 °, 21.2 ° in, 5.0 °, and the 11.1 ° of 15.2 °, 11.1 ° in the indicated peak and Ⅱ _B-type crystals in the diffraction angle, 19.6 ° and 4.5 ° diffraction peak shown in each is because not show any conventional ⅰ type _a crystals and type _B crystals from ⅰ is ⅱ _a type crystals and ⅱ _B-type crystals are distinct and ⅰ _B type crystals by these X- ray diffraction.

(2) melting point

Ⅱ _A type crystal 163 ℃ (decomposition)

Ⅱ _결정 Type Crystal 171 ℃ (Decomposition)

Ⅰ _B type crystals 172 ℃ (decomposition)

(3) optical rotation

II Type _A Determination [α] _D ²⁰ = 15.9

Ⅱ _결정 Type determination [α] _D ²⁰ = 16.1

Ⅰ _Ｂ Type determination [α] _D ²⁰ = 16.0

(4) moisture content

Ⅱ _A-type crystal is from about 0.9 to about 3% and Ⅱ _B-type crystals is less than about 0.9%, is continuously changed according to the humidity within the range. On the other hand, Ⅰ type _A crystal is at least about 6% Ⅰ _B-type crystal is from about 2 to about 6%, and continues to change according to the humidity within the range. The wet crystal obtained by the conventional crystallization method is a determination of Ⅰ _A type.

(5) water absorption

50 g of each AP crystal was spread out on a tray, placed in a constant temperature and humidity cell maintained at a temperature of 34 ° C. and a relative humidity of 78%, and the results obtained by measuring the change in moisture content over time were described in Table 5. In the table, the sign "○" will shown the Ⅱ _B-type crystals used in the start of the measurement, the sign "X" is the Ⅱ _A-type crystal, and reference numeral "S" shows a Ⅰ _B-type crystals.

(6) crystal transition

After 48 hours of water absorption test carried out in the preceding paragraph, each crystal was measured by a powder X-ray diffractometer, and these crystals were changed into the crystals described in the following table.

(7) storage stability

0.7 to 1.2 g of AP crystals were placed in 100 ml glass ampoules, sealed, and stored in a constant temperature cell at 55 ° C. and 80 ° C., respectively. The results are shown in the following table.

Storage at 55 ℃

Storage at 80 ℃

(8) fluidization degree

Crystalline Karl Flow [R] ^*

II _A 21.3

Ⅱ _Ｂ 23.1

Ⅰ _Ｂ 18.2

) - 69.445sinθ* R = 39.017 + 78.485 (

)-69.445sinθ

V _E = apparent specific volume

V _ｎ = Tapped specific volume

θ = friction angle

(9) Pelletization degree

The following examples are only intended to illustrate the preparation of type II crystals, and the examples are not intended to limit the present invention.

Example 1

Allowed to stand for 2 hours and then drying the crystalline sludge of AP obtained by separating into solid and liquid by centrifugation 2 to 3 seconds in the air flow in the dryer of 100 ℃ constant temperature drier, to obtain a crystalline powder Ⅱ _B type AP. 323 g of water are added to 600 g of powder and kneaded for 15 minutes on a kneader (the dough product has a moisture content of 35%). This kneaded product is extruded through a 2.0 m / m screen to pelletize. This pelletized product is dried in a fluid bed dryer using hot air at 85 ° C. to obtain a dried pelletized product of AP.

On the other hand, the dough was added to 291g of water in Ⅰ _B type crystal powder, and 600g in order to control: it (the water content of the dough product 35%) similar to and performs pelletization and drying. The obtained results are shown in the following table.

[Rough Specific Volume]

Measure with a bulk density meter in accordance with JIS L 6721. The figures represent the ratio of volume to weight of the contents filled in a 100 ml cylindrical container.

[Filled specific volume]

It is measured after taping 150 times using a taping device for powder tester (manufactured by Hosokawa Tekko Co.). Figures shown are the same as for the rough specific volume.

Dispersibility and Solubility

0.05 g of AP is added to 150 ml of warm water with stirring at 60 ° C., and the time until the AP is dispersed in water (dispersity) and the time until complete dissolution (solubility) are measured.

As described above, when the Ⅱ _B-type crystals, the particulate material having a uniform size are obtained, whose solubility is less fugitive (fly), since greatly increased compared to a starting material powder with a loss, and better fluidization ability for the other hand, ⅰ _a type crystals in that they have the physical characteristics, easy to handle, pelletization is difficult pelletized product buseojyeoseo dryness changes to a fine powder.

Example 2

The crystalline sludge of AP obtained by separating into a solid and a liquid by centrifugation is dried with aeration at a rate of 1 m / sec at a hot air temperature of 100 ° C. If the exhaust air temperature is a constant temperature in 96 ℃ left in 30 minutes more to give a Ⅱ _A-type crystal, and pelleted as in Example 1. In analogy to this. The obtained results are shown in the following table.

Example 3

1.4 kg of water was added to 2.5 kg of Ⅱ _Ｂ type AP crystalline powder (water content of the mixture: 35%), mixed, pelletized using a granulator (manufactured by Fuji Sangyo Co.), and then granulated. Dry in a fluidization drier similar to Example 1. On the other hand, 1.3g of water was added to a to-be-verified Ⅰ _B type crystal 2.5kg: The (water content of the mixture was 35%) of a pelletized and dried in a similar manner.

Crystal of the present invention two types of crystal, i.e. Ⅱ _A would consisting of a type and Ⅱ _B type, these decisions because it is very similar in structure and easily interchangeable depending on the humidity, and these crystals are considered to belong to the same group It is referred to as Type II crystal as a whole. These Ⅱ type determination, Ⅱ _A type and _B type Ⅱ both conventional Ⅰ type crystal, that is Ⅰ _A type and _B type Ⅰ and X- ray diffraction pattern, and so the equilibrium phase Ⅱ type crystals in the water content is determined if the new to be.

The type II crystals of the present invention can be obtained by drying the type I crystals at about 80 ° C. or higher.

Since various methods for preparing AP are known, such as synthetic methods and enzymatic methods, the crystals of the present invention can be obtained without regard to the method used to prepare AP. Ⅰ type determination may be Ⅰ _A type or _B type Ⅰ.

Drying temperature is about 80 degreeC, for example, type II crystal | crystallization cannot be obtained at 70 degreeC. On the contrary, in consideration of decomposition of the AP, it is not preferable to raise the temperature to 150 ° C or higher, and about 85 to 120 ° C is particularly preferable. The drying time should choose a suitable time for the crystal to be converted to type II crystal. For example, for 80 ° C., the drying time is generally about 6 hours, and for 90 ° C., about 1 hour may be sufficient.

Similar to the method of Example 1, the crystals obtained by neutralization, crystallization, centrifugation and water washing were dried under reduced pressure at various temperatures and contained in the desired crystal form and crystals according to drying temperature and time. Measure the amount of Dean. The results are shown in the following table.

The figures in parentheses in the table above refer to the amount of diketo-piperadine contained in the crystals.

Conventional dryers may be used, but types that allow relatively long residence times are preferred, such as tray dryers, air dryers, fluidization dryers and the like.

Gasstream dryers, such as spare dryers and micron dryers, are not suitable because of their short residence times. However, in the case of using such a dryer, type II crystals can be obtained by connecting a solid heater such as a raised disk type, paddle heater type, etc., for holding the dryer powder at about 80 ° C. or higher.

The type II crystals obtained can be made into the product itself or pelletized again. It is not necessary to add a binder such as a binder even when pelleting. However, type II crystals can be converted to type I crystals by spraying about 25-45% of the water with water, and then extruded and dried again. The re-dried product may be type II crystals, but it is desirable to change these crystals to type II crystals in terms of water absorption properties. An important aspect of the pelletization method is the use of the caking properties exhibited when converting type II crystals to type I crystals. This caking property is presumed to be caused in the crystal transition process involving recrystallization from solution so that firstly, the fine branched crystals are separated during recrystallization and they can entangle and increase in apparent viscosity.

The crystal of the present invention has several advantages, such as low water absorption, stable upon storage, and easy to pelletize. Moreover, the crystal has a good fluidization capability and thus excellent powder handling characteristics.

The following example illustrates the preparation of type II crystals.

[Production of Type II Crystals]

Example 1

37 g of AP hydrochloride crystals were dissolved in 500 ml of water at normal temperature and then neutralized to pH 5.0 with 10% sodium carbonate solution to induce the separation of AP crystals. The crystals were separated by centrifugation and washed with water, and the obtained crystals were divided into two parts and dried overnight. One was dried in a reduced pressure dryer controlled at 70 DEG C and the other in a reduced pressure dryer controlled at 90 DEG C. 11.8 g of A (70 ° C. drier) and 11.2 g of Crystal B (90 ° C. drier) are obtained. As a result of measuring a powder X- ray diffraction of these crystals, crystal A has a crystal structure of Ⅰ type _B, crystal B showed a crystal structure of Ⅱ _B type.

Example 2

43 g of N-carbobenzoxy-α-L-aspartyl-L-phenylalanine methyl ester were dissolved in 400 ml of methanol-water (1: 1) and 0.4 g of 5% Pd-C catalyst at normal pressure and 55 ° C. After 4 hours of catalytic hydrogenation, the catalyst is filtered off, and the reaction mixture is left overnight in the refrigerator to separate the AP crystals. These crystals are filtered through a Buchner funnel and dried in a constant temperature drier at 85 ° C. for 6 hours to yield 23.4 g of crystals. Powder X- ray diffraction measurement results, these crystals exhibited a crystal form of Ⅱ _B type.

Example 3

Example 1 Take the AP of Ⅰ type _B crystal obtained in 3.00g in petri dishes and then allowed to stand overnight in a thermostatic chamber controlled at 80 ℃ decision result of measuring a powder X- ray diffraction of these decisions are converted into _B-type Ⅱ It became.

Example 4

500 g of AP was dissolved in 12 L of water at 60 ° C. and cooled to 50 ° C. with stirring to separate the crystals, and the crystals were separated by centrifugation to yield 677 g of wet crystals (water content 45.3%). 500 g of these wet crystals are placed in an air drier having an effective dry surface area of 0.08 m 2 and dried for 1 hour under an air flow rate of 1.0 m / sec and hot air conditions of 90 ° C. At the end, the exhaust air temperature is 87 ° C., at which temperature the constant temperature is maintained.

The obtained crystals were pulverized and subjected to powder X-ray diffraction measurement to find II _A crystals.

[Storage Stability Purification or Granulation of AP]

Many attempts to formulate AP as a commercial sweetener have continued to date. For example, as a known AP formulation method, there is a method of granulating AP together with an excipient having high solubility. Another known method is a method of formulating an effervescent tablet that foams upon dissolution of the AP.

However, in such granulation or tableting, other problems arise due to the excipients used. In other words, since sugar, dextrin, etc. are generally used as excipients, aminocarbonylation reactions occur between aspartame and the excipients described above during storage, and browning may damage the appearance and cause loss of sweetness due to decomposition of aspartame. do. Moreover, small amounts of water or atmospheric humidity incorporated during storage tend to reduce fluidization or solubility in the case of granules or to reduce degradation properties and dispersibility or solubility when added to water in the case of tablets. Particularly in the case of effervescent tablets, since the reaction occurs between the blowing agent (carbonate, bicarbonate, etc.) and the neutralizing agent (acidic material) during storage, the effervescence after storage is reduced, solubility is markedly decreased, and the tablets are purified due to the water generated or the water absorbed by the neutralization reaction. Adhesion occurs between itself or between the tablet and the container.

The present inventors have found that conventional aspartame Ⅰ type crystal, that is Ⅰ a type _A crystal or Ⅰ _B-type crystals by heating at more than 80 ℃ There are two types of crystals of the novel to interconvertible to each other can be obtained, and these crystals are excellent physical properties and It has been found to have storage stability. In addition, these crystals, namely, aspartame type II crystals, are very stable even when the above-mentioned excipients, blowing agents, neutralizing agents, etc. coexist, and in the case of effervescent tablets, the neutralization process tends to be significantly suppressed compared to the case of conventional type I crystals. It has also been found by the present inventors.

When aspartame Ⅱ type crystals used in the present invention can be measured with two types of crystal, i.e., according to the humidity and the interconversion Ⅱ type _A crystals and type _B crystals of Ⅱ, powder X- ray using the Cuk α--ray diffraction, ⅱ _a-type crystal is 20.6 °, 21.2 °, while showing an X- ray diffraction peaks at least 5.6 ° and 11.1 ° diffraction angle, ⅱ _B-type crystals are 15.2 °, 11.1 °, 19.6 ° and 4.5 ° in a diffraction angle of the X -Ray diffraction peaks, both of which have an equilibrium moisture content of 3% or less at a temperature of 34 ° C and a relative humidity of 78%. More specifically, these crystals can be obtained, for example, by drying aspartame type I crystals at about 80 ° C or higher.

Physical properties of the aspartame type II crystals obtained in Preparation Examples 1 to 4 are as follows:

(1) X-ray diffraction

Powder X- ray diffraction pattern in X- ray diffraction measurement to step a Ⅱ _A type determination using the Cuk α- line is a first degree, X- ray diffraction pattern of claim 2, the conventional Ⅰ _A type _B type crystal Ⅱ X- ray diffraction pattern of the crystals X- ray diffraction pattern of the crystal of the third and ⅰ _B-type crystals were each shown in FIG. 4.

As clearly shown in the drawing, Ⅱ _A type determination 20.6 °, 21.2 ° in, 5.0 °, and the 11.1 ° of 15.2 °, 11.1 ° in the indicated peak and Ⅱ _B-type crystals in the diffraction angle, 19.6 ° and 4.5 ° diffraction peak appeared in each of the conventional _a-type crystals and ⅰ ⅰ _B type crystal from which therefore also has not been found, ⅱ type _a crystal and ⅱ _B-type crystals can be clearly distinguished from the ⅱ _B-type crystals such as X- ray diffraction .

(2) melting point

Ⅱ _A type crystal 163 ℃ (decomposition)

Ⅱ _결정 Type Crystal 171 ℃ (Decomposition)

Ⅰ _A type crystals 172 ℃ (decomposition)

(3) optical rotation

II Type _A Determination [α] _D ²⁰ = 15.9

Ⅱ _결정 Type determination [α] _D ²⁰ = 16.1

Ⅰ _Ｂ Type determination [α] _D ²⁰ = 16.0

(4) moisture content

Ⅱ _A-type crystal is from about 0.9 to about 3% and Ⅱ _B-type crystals is less than about 0.9%, is continuously changed according to the humidity within the range. On the other hand, Ⅰ _B-type crystal is from about 2 to about 6%, and continues to change according to the humidity within the range. The wet crystals obtained by conventional crystallization are crystals of type I _A.

The dipeptide sweetener-containing tablets or granules of the present invention use the aspartame type II crystals described above as a whole or as part of a sweetener. Aspartame II crystals may also be mixed with other natural or artificial sweeteners such as sugar, sugar alcohols, steviosides or as an auxiliary sweetener such as Acetultan K. In addition, aspartame type I crystals may be additionally used, but aspartame type II crystals are preferably used alone.

The preparation of tablets or granules and other starting materials is not particularly limited. In fact, it can be prepared according to the preparation methods and starting material formulations described below.

As excipients, one or more sugars other than aspartame, such as sucrose, glucose, lactose, mannitol, sorbitol, dextrin or cyclodextrin, or inorganic substances such as, for example, calcium phosphate or calcium sulfate, can be used.

When granulating or molding into a granule or cube using a binder, water, an alcohol, an aqueous solution of sugar or an inorganic substance, etc. are appropriately selected and used as the binder.

In the foamed tablet, a blowing agent such as sodium bicarbonate and the like, and a neutralizing agent such as malic acid, citric acid, fumaric acid, tartaric acid, or the like can be added as appropriate.

In addition to the above components, leucine, isoleucine, L-valine, sugar esters, magnesium stearate and the like, and a disintegrating agent suitable as an adjuvant for the preparation of tablets may be incorporated as the tablet lubricant, or, if necessary, flavors and flavoring ingredients that are not sweeteners. Can be mixed.

The shape and size of the tablets or granules is also not limited. Tablets herein include in the same form as the adsorbent.

The method for producing the granules can be any of mixed granulation, compression granulation, extrusion granulation, flow granulation, tempering granulation, crushing granulation, and the like.

The manufacturing method of a tablet can also use a well-known method, These tablets can be manufactured by mixing the above-mentioned components for purification, and applying a direct powder compression method, a dry granular compression method, etc.

In the preparation of granules or tablets, granulation is carried out using aspartame type II crystals obtained as a starting material obtained by conversion from aspartame type I crystals by first drying at 80 ° C. or higher, or granulating or forming aspartame type I crystals first. The granulation or shaped product may then be dried at about 80 ° C. or higher during the granulation or molding step. The drying temperature should be at least about 80 ° C. For example, in the case of 70 ° C., storage stability cannot be obtained. On the contrary, heating to 150 ° C. or higher is undesirable because aspartame decomposes, and about 80 to 120 ° C. is particularly suitable. The drying time is a time at which a complete transition to type II crystals can be achieved, for example at 80 ° C., about 6 hours can be satisfied, and at 90 ° C., about 1 hour can be sufficient.

Preparation Example 1

37 g of aspartame hydrochloride crystals are dissolved in 500 ml of water at normal temperature and neutralized to pH 5.0 with 10% sodium carbonate solution to induce the separation of aspartame crystals. The crystals obtained by separating these crystals by centrifugation and washing with water are divided into two parts, one side is dried in a reduced pressure drier controlled at 70 DEG C and the other in a reduced pressure drier controlled at 90 DEG C overnight, to crystall 11.8 g. (Dry at 70 ° C.) and 11.2 g of crystal B (dry at 90 ° C.) are obtained. Powder X- ray diffraction measurement of these determination results, determining A represents the crystal structure of _B-type crystals Ⅰ B exhibited a crystal structure of the type _B Ⅱ.

Production Example 2

43 g N-carbobenzoxy-α-L-aspartyl-L-phenylalanine methyl ester was dissolved in 400 ml of methanol-water (1: 1) and normal pressure and 55 using 0.4 g of 5% Pd-C catalyst After 4 hours of catalytic hydrogenation at < RTI ID = 0.0 > C, < / RTI > the catalyst is filtered off and the reaction mixture is left overnight in the refrigerator to induce the separation of aspartame crystals. These crystals are filtered through a Buchner funnel and dried for 6 hours in a constant temperature drier at 85 ° C. to yield 23.4 g of crystals. Crystal form is Ⅱ _B type.

Preparation Example 3

After putting the aspartame Ⅰ _B-type crystals obtained in Production Example 1 3.00g in petri plates for storage in a constant temperature cell controlled at 80 ℃ overnight and measure the powder X- ray diffraction of these crystals. These crystals were converted into Ⅱ _B type.

Production Example 4

500 g of aspartame was dissolved in 12 liters of water at 60 ° C., cooled to 50 ° C. with stirring to induce crystals to separate, and the crystals were separated by centrifugation to yield 677 g of wet crystals (water content 45.3%). 500 g of these wet crystals are placed in an air drier having an effective air dry surface area of 0.08 m 2 and dried for 1 hour under an air flow rate of 1.0 m / sec and hot air conditions of 90 ° C. The exhaust air temperature at the end is 87 ° C., and the constant temperature is maintained at this temperature.

A powder X- ray diffraction measurement was pulverized and the obtained results was determined by Ⅱ _A crystal.

Example 1

Effervescent tablets having the compositions shown in the following table are prepared by dry granular compression.

TABLE 1

Tablet composition

^* 1 The Ⅱ _B-type crystal obtained in Example 1

^* 2 Ⅰ _B-type crystal obtained in Example 2

^* 3 Product Name: RINGDEX-B (Sanraku Ocean Co.)

Each sample exhibited smooth machine operation and excellent manufacturing characteristics during the sludge purification and main purification steps.

The tablets obtained are stored under open conditions (50 tablets are placed in each basis bottle and left uncovered). Storage conditions are adverse conditions of 44 ° C. and RH 78%, and the results are shown in Table 2 below.

TABLE 2

Storage test result of effervescent tablet

^* 1 roughness and cracking of the stagnant surface visually observed

○: Excellent, △: Normal, X: Poor

^* 2: Time to complete dissolution when added to 500 ml of warm water at 60 ℃

^* 3 b value is a value obtained by measuring with a color control system, and a larger b value shows darker yellow color.

That is, as can be clearly seen in Table 2, the tablet of the present invention showed little change in appearance or solubility due to storage, and only slight browning. Since Ⅰ _A-type crystals as compared to the case of the quiet purified for use, the reaction of the blowing agent due to the moisture absorption is lowered to get up Borax comprehension of dissolution, solubility is decreased. Moreover, the b-value was greatly increased, and the appearance also gave flexibility and a wet feeling.

Example 2

Non-foamed tablets having the compositions in the following table are prepared by dry granular compression.

TABLE 3

Tablet composition

^* 1 The Ⅱ _B-type crystal obtained in Example 3

^* 2 Ⅰ _B-type crystal obtained in Example 4

^* 3 crystalline cellulose manufactured by Asahi Chemical

Each sample exhibited smooth machine operation and good fabrication during both sludge purification and main purification steps. The tablet thus obtained is subjected to a storage test in a similar manner as in Example 1 to compare the storage capacity. The results are shown in Table 4 below.

TABLE 4

Storage test results of disintegrating tablets

^* 1 loss of drying for 4 hours at 105 ℃

^* Hardness at crushing, measured on 2 gable-type hardness testers (5 kg)

That is, as can be clearly seen in Table 4, the tablets of the present invention had a lower increase in moisture and a lower decrease in hardness as compared to the control. For the control, the water absorption was high and the tablets coalesced with each other even after only about one week of storage. Their appearance and shape did not remain intact in the tablets.

Example 3

The Aspartame II _A type crystals obtained in Production Example 4 were subjected to a roller Confitter (model TF-MINI from Freunt Sangyo) using an X-type screw, a rotation of 15 rpm, an S-type roll, a rotation of 3 rpm and a pressure of 0.66 to 0.94. Compression molding under t / cm conditions yields compression flakes. These flakes are crushed on a speed mill and pelletized on a pelletizer ("Oscillator" 16 mesh screen) to obtain aspartame granules.

To contrast, the granulated Aspartame Ⅰ _B-type crystal obtained in Example 1 in a similar manner to produce the granules. The granules obtained are subjected to a storage test similarly as in Examples 1 and 2 to compare the storage capacity. The results are shown in Table 5.

TABLE 5

Storage test result of aspartame granulation

That is, aspartame Ⅱ _B lower the granules is increased moisture of the present invention using the type determination, high and almost been reached equilibrium, for verification granules increases moisture by storage with Ⅰ _B-type crystals of about 2.8% to about 24 hours After this time, equilibrium was not reached and water absorption continued.

Example 4

Aspartame-containing granules are prepared according to the following composition using a flow pelletization method.

TABLE 6

Granule formulation

* (Dextrin manufactured by Nichiden Kagaku)

As a result, the result of having measured the granular strength (powderization degree) of the obtained granule is shown in Table 7. I.e., granules of the present invention with Ⅱ _B-type crystal as a starting material is a granular strength higher when compared to the control and one for (a lower degree of powder), and further excellent in the stability of the product at the time of dispersion.

TABLE 7

Strength of the granules ^-

* Granular strength

The 80 mesh-phase granules are filled up to 80% by volume in a pre-measured cylindrical vessel with vibration of 4 cm for 1 hour.

After shaking, sift through an 80 mesh sieve (10 minutes). The degree of powdering is calculated according to the following equation.

The powdering degree measured above is important because the granularity is higher as the powdering degree is lower.

Although the present invention has been described fully herein, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

Claims (2)

A-L-aspartyl-L-phenylalanine methyl ester I crystal is dried at a temperature of about 80-150 ° C., thereby producing a-L-aspartyl-L-phenylalanine methyl ester II crystal. A starting material containing α-L-aspartyl-Lphenylalanine methyl ester II crystals obtained by drying the α-L-aspartyl-L-phenylalanine methyl ester I crystal at a temperature of 80 to 150 ° C. is molded or granulated , α-L-aspartyl-L-phenylalanine methyl ester Forming or granulating the starting material containing the crystals of type I and dried at a temperature of 80 to 150 ℃, α-L-aspartyl-L A process for preparing a dipeptide sweetener-containing tablet containing as a whole or part of a sweetener phenylalanine methyl ester II crystals.

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