JP2002517510A - Process for producing organic salts of aspartame - Google Patents

Abstract

  (57) [Summary] The present invention relates to a process for producing a salt of aspartame and acesulfameic acid in solid and dry form by production in a liquid medium, separation therefrom as a wet solid product by solid-liquid separation and subsequent drying. The wet solid product is subjected to one or more steps of washing before drying, wherein at least the last step of these washing operations is performed with a basic aqueous solution having a pH of 8 or more. To a method characterized by the following. The resulting solid dry product has improved stability compared to prior art products. The present invention also relates to an aspartame having an increased stability such that the acetoacetamide content after heating the salt in dry form at a temperature of 80 ° C. for 48 hours remains below 10 ppm relative to the dry weight of the salt With acesulfameic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a process for producing a salt of aspartame and acesulfamic acid in solid and dry form by production in a liquid medium, separation therefrom as a wet solid product by solid-liquid separation and subsequent drying. According to the present invention, aspartame and acesulfameic acid having improved stability in dry form, in particular by exhibiting a reduced risk of acetoacetamide formation after exposure of the salt to elevated temperatures. A salt is obtained. The invention also relates to such novel salts of aspartame and acesulfameic acid.

[0002]

[Prior art]

The salt of aspartame and acesulfameic acid is a sweetener having a sweetness of about 200 times the weight of sugar, especially in powder mixes, chewing gum, sweet confectionery and dry foods, and in particular, such as aspartame It is suitable for use in various products that contain compounds other than sweeteners, such as aldehydes, that can cause undesirable reactions with sweeteners.

[0003] The salt of aspartame and acesulfameic acid is composed of the high-potency sweetener aspartame, which has been known for a long time, namely α-L-aspartyl-L-phenylalanine methyl ester (hereinafter also referred to as APM), and acesulfamic acid. Is done. Acesulfame acid is a high-potency sweetener Acesulfame-K, also known for a long time, ie of the formula 6-methyl-1,2,3-oxathiazine-4 (3K)-
It is an acid derived from a potassium salt having on-2,2-dioxide (hereinafter also referred to as AceK). Acesulfameic acid is hereinafter also referred to as AceH, APM
And AceH are salts of APM. Also called Ace.

[0004] APM with excellent thermal stability and low hygroscopicity. The manufacture of Ace is disclosed in European patent EP-A-0 768 041. EP-A-0768041 discloses an APM. In the method of making Ace, the salt is exchanged in a liquid medium for salt exchange (
transsalification) obtained as a solid as a result of the process. As components in the reaction system (usually a slurry) used, in particular, (i) aspartame, (
ii) inorganic salts of acesulfamic acid, such as potassium salts, and (iii) strong acids, such as hydrochloric acid. The components can be added to the reaction system in any desired order and the system is moved constantly so that a relatively uniform distribution of the components occurs and that undesired too high local concentrations of acid can be present. And remain stirrable. The production of APM.Ace according to the above-mentioned patent application always takes place by a relatively fast process, preferably in an aqueous medium, at a temperature in the range of -20 to + 90 ° C., as described in the above-mentioned application. EP-A-0768041 describes the production of APM. It does not provide much information on Ace recovery, drying and / or further purification. The standard methods used, such as washing of the solid obtained by filtration with ice water, can be used for the salt A
The requirements for obtaining a product with excellent thermal stability with respect to the thermal properties of the PM part were completely fulfilled.

[0005] EP-A-0768041 paid particular attention to the thermal stability of the APM portion of the salt, as it is known that the thermal stability of APM is generally lower than AceK. Incidentally, an acid corresponding to AceK, that is, acesulfamic acid (AceK)
H) itself was also known to have lower stability than, for example, AceK. AP
M. The Ace part in Ace exists as in AceK, and
. No attention was paid to the degradation products of the Ace portion of Ace.

[0006] According to EP-A-0768041, APM. Ace (dry form) is 120 ° C
Has good thermal stability if less than 0.5% decomposition occurs when heated for 1 hour or at 70 ° C. for 70 hours. APM. Decomposition of the Ace portion of Ace was confirmed in Comparative Examples 1C and 1D performed in methanol, as is clear from the table of the above-mentioned patent application.
Only in.

[0007]

However, in the meantime, a dried APM. Produced according to the method of EP-A-07668041. Even at low water content of Ace, the elevated temperature, especially
At a temperature of, for example, 80 ° C., which is considered to be a standard condition, for example for 48 hours,
Prolonged exposure in dry form can result in a detectable acetoacetamide concentration, ie, APM
. An acetoacetamide concentration above the detection limit of 10 ppm based on the dry weight of Ace. It was found to occur during Ace. Acetoacetamide is hereinafter also referred to as 3A.

[0008] In foods, and thus in substances used in foods, in particular the presence of acetoacetamide should be limited to low concentrations for toxicological reasons. For example, from the reference in the European Pharmacopoeia for acetoacetamide (Supplement 1998), 12
The maximum allowable concentration is 50 ppm. In this context, therefore, the Applicant has confirmed, on the one hand, that the acetoacetamide formation proceeds autocatalytically, i.e., the higher the concentration present, the faster it proceeds. , A
PM. It seems important that the production of detectable concentrations of 3A in Ace be prevented.

It is an object of the present invention to address the above problems, in particular APM. The solution is to prevent or prevent the production of 3A in Ace.

[0010]

[Means for Solving the Problems]

Surprisingly, this object is achieved according to the invention by subjecting the wet solid product obtained by solid-liquid separation to one or more washing steps before drying, wherein these washing operations are carried out. At least the last step is performed with a basic aqueous solution having a pH of 8 or more.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION

After drying, the thus obtained APM. Ace has a prolonged exposure to elevated temperatures in dry form, ie, when exposed to 80 ° C. for 48 hours, the 3A content has an APM. A
The criterion to be set is 10 ppm or less based on the dry weight of ce.

At temperatures below 80 ° C., for example 70 ° C., APM. The formation of 3A in Ace, according to the applicant's observations, proceeds more slowly, and at lower temperatures, the effects of its formation are almost negligible. APM. (Made according to the invention). Ace, for example stored at 60 ° C. for 12 months, does not produce a detectable concentration of 3A, but does not produce APM. Ace is already 1 month after 1 month at 60 ° C.
Contains 0-20 ppm of 3A. APM. During storage of Ace for 1 year at 40 ° C., APM. There is no detectable amount of 3A in Ace.

According to the applicant, the production of 3A can now be explained as a result of the reaction of the small amount of AceH present. The reason for this is that under the influence of water (two molecules) acetoacetamide-N-sulfonic acid is formed from AceH (one molecule), which acid can then in particular react to give acetoacetamide. . Applicants have now found that this reaction is autocatalytic

As described in the above-mentioned EP-A-0768041, APM. Ac
The moisture content of e is always higher than in accordance with the method according to EP-A-07688041, provided that it was produced analogously to the method shown in Spanish patent ES-A-8604766. Thus, the above problems of 3A production under conditions of storage and prolonged heating are much greater in such cases.

As used in the context of the present invention, APM. For production of Ace in a liquid medium, any suitable process may be used. Examples of such a process are described in EP-A-0768041 and Spanish patent ES-A-86 cited herein.
04766. Accordingly, reference is made to the contents of the above-mentioned patent applications for a further description of the liquid media and process conditions that can be used in those processes, and solid-liquid separation methods. The same is true for APM. The description also applies to the drying operation to be performed after the washing operation to be performed in the context of the present invention in order to obtain Ace in dry form.

In the method according to the invention, the washing operation can be carried out in one or more steps, wherein the last washing step uses a basic solution having a pH of 8 or more in all cases. It is understood that it is performed. If the washing operation is performed in one step, and therefore the washing is performed immediately with such a basic solution, special care will have to be taken to wash out the inorganic salts present in the product. In that case, more basic cleaning solution is required to achieve the same cleaning result.

As the basic aqueous solution having a pH of 8 or more, it is possible in principle to select any solution of an inorganic or organic compound which results in a solution having a pH of 8 or more at the concentration used. When the present patent application refers to pH, it means in all cases that the pH of the solution is measured at room temperature (20 ° C.) using a calibrated pH meter. Those skilled in the art will understand, in the context of the present invention, that APM. It will be clear that no base is used which reacts in an undesired manner with Ace or which leaves, after use, undesired contaminants or undesired odor or flavor characteristics in the resulting product. Preferably, the recovered APM. A base that leaves no or little residue in Ace is used.

In the context of the present invention, examples of bases which may be used in basic aqueous solutions include inorganic hydroxides, such as alkali metal hydroxides and alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide , Calcium and magnesium,
Also included are ammonium hydroxide, and organic bases such as sodium or potassium benzoate, and similar bases suitable for use in the manufacture of food products.

The basic aqueous solution is preferably a solution of sodium hydroxide and / or potassium hydroxide.

Preferably, the basic washing operation is carried out at a pH between 8 and 13, especially between about 10.5 and about 11.5.
The reaction is carried out using an aqueous solution of a base having a pH in the range of If a very high pH, for example a value of 13.5 or higher, is selected, the APM. There is a risk that the APM in Ace will begin to racemize and / or undergo an increased degree of undesirable side reactions such as ester hydrolysis or diketopiperazine formation. If the pH of the basic aqueous solution used for the washing operation is selected to be less than 8, the effect of the washing operation is too small.

Usually, the temperature of the basic solution used in the washing operation is 20 ° C. or lower, preferably 15 to 5 ° C. The washing operation itself is also preferably performed at the temperatures described above for the basic solution. This prevents unnecessary temperature changes during the cleaning operation. The higher the temperature at which the washing operation is performed, the greater the amount of desired product (APM.Ace) lost through the mother liquor that is separated off. Dissolved APM. Removed via mother liquor. While it is true that such amounts of ace can be recovered, this requires unnecessary additional process steps.

The time used for the base washing operation, ie the recovered solid APM. In the presence of a basic aqueous solution. Ace's stay time is not very decisive. One skilled in the art can easily determine the optimal conditions for the washing operation. As can be seen, the risk of decomposition and / or formation of unwanted by-products increases as the basic washing operation takes more time. Generally, APM. Ace for at least a few seconds
It is usually contacted with the basic aqueous solution for a few minutes or less, for example for 2 to 20 minutes. The time to be used for a basic washing operation, where the liquid medium present in the wet crystal cake is actually replaced by the basic solution at that time, will be known to those skilled in the art. APM to be. It depends in part on the amount of Ace and the equipment used for this.

The washing operation with a basic solution and any preceding washing operation can be performed using any crystal washing method known to those skilled in the art. In one embodiment, for example, the APM. Obtained after solid-liquid separation on a horizontal filter cloth. The Ace crystalline material is treated on the same filter cloth, optionally by using a basic washing solution while applying pressure on the filter cloth or depressurizing under the filter cloth, first removing the crystalline material. In a (small) layer on top of it, then drain it through the crystalline material and filter cloth. The filter cloth can also be attached to a centrifuge.

Before applying the washing operation with a basic aqueous solution according to the invention, preferably at least one washing operation with water is first performed. This makes it possible to limit the amount of basic washing water required according to the invention and the formation of by-products as a result of the basic washing operation itself. If desired, to obtain the desired dry product, the APM. Prior to upgrading Ace, the basic washing operation according to the present invention may be repeated one or more times.

The amount of basic wash used in the method according to the invention is generally not critical. Preferably, APM. A basic aqueous solution of at least 10% by weight, based on the amount of Ace (calculated as dry weight), is used. The optimum amount of the cleaning solution is APM. Ac
e can be readily determined by one skilled in the art depending on the method by which e was produced and the conditions and equipment under which the basic washing operation is performed. For example, the lower the residual moisture content of the wet crystalline material, the smaller the amount of basic cleaning liquid to be used required.

After being subjected to a basic washing operation, the thus obtained APM. Ace is still wet, which can then be dried in any known manner. In particular,
APM. If Ace is prepared according to the embodiment of EP-A-07668041 described above, in which case the preparation is carried out in an aqueous medium, in particular good thermal stability, very low residual moisture content and very low hygroscopicity APM. Ace is obtained,
On the other hand, the risk of formation of 3A when stored for a long time in dry form at elevated temperatures is also greatly reduced.

According to the method of the present invention, a new and improved form of APM. Ace has increased stability, especially APM. Exposing Ace to elevated temperatures for extended periods of time,
That is, it is provided with enhanced stability with respect to the possible formation of 3A under conditions involving exposure to 80 ° C. for 48 hours. This new and improved form of APM
. In Ace, the 3A content after the above exposure was APM. It remains below the detection limit of 10 ppm based on the dry weight of Ace.

This new APM. Ace, that is, APM. After heating Ace at a temperature of 80 ° C. for 48 hours, its acetoacetamide content was reduced to APM. It is characterized by remaining less than 10 ppm based on the dry weight of Ace. APM. Ac
e is a characteristic of the APM.e used prior to the present invention. It corresponds to the characteristics of the product obtained in the ace production process. The new products are distinguished from the products of the prior art only with regard to the danger of producing 3A.

[0029]

【Example】

Next, the present invention will be described with reference to the following Examples and Comparative Examples. The examples do not limit the invention in any way.

All analyzes for 3A were performed using HPLC (High Performance Liquid Chromatography) technology,
In particular, this was done using a gradient elution method. In all cases, the injection volume was 250
μl and the total analysis time was 50 minutes (flow rate 1.5 ml / min).

Apparatus : thermostatically controlled column oven, set at 20 ° C. (Hewlett Pack
ard HP 1090); column length 250 mm, inner diameter 4 mm, LiChrospher 100 RP-18 (5
μm particles, Merck); variable wavelength detector (Spectra Physics, Spectra 20)
0), UV detection at 300 nm; detection limit for 3A: about 10 ppm (dry AP)
M. Ace dry weight)

Mobile phase : the following components: (1) double distilled water (2) methanol, HPLC grade (Chromasolv; Riedel de Haen 34860) (3) tetrabutylammonium hydroxysulfate (TBAHS); Flu
ka 86875 (4) 0.1 M aqueous potassium hydroxide solution

Three kinds of solvents (A, B, C) having the following compositions were prepared.

[Table 1]

The elution gradient used was as follows:

[Table 2]

The pH measurement was performed using a Knick Porta equipped with a ROSS ™ Combination pH electrode 8155SC.
This was done using a mess 752 Calimatic pH meter.

EXAMPLE I In a 1 liter crystallizer at a shell temperature of 50 ° C., the following were combined with stirring: That is, 466 g of deionized water, 141 g of AceK (0.
70 mol) and 65 g of APM (0.21 mol; water content 4%). A 33% HCl solution in water is then pipetted to pH 3.5 for 25 minutes.
Dropped for minutes. 5 g of APM are then added every 5 minutes (150 g in total, ie an additional addition of 0.49 mol), with additional HCl solution being added dropwise by addition of p.
H was controlled at 3.5. After all the APM had been charged, a final amount of 33% HCl was charged, resulting in a total charge of 77 g of 33% HCl (0.70 mol). Approximately 3 hours after the start of the experiment, cooling was started (10 ° C. low temperature bath). After cooling for 3 hours, a total of 716 g of slurry was obtained. After the slurry was filtered off on a cooled Buchner funnel with a wall temperature of 10 ° C., the pH was raised to 1 with solid KOH.
Washed twice with 180 ml each of 10 ° C. deionized water raised to 1.0. The moisture content of the collected wet cake was 19.2% by weight. The wet cake was dried in a fluidized bed at 50 ° C. for 1 hour. The water content after drying was <0.1% by weight. No acetoacetamide (3A) was shown in this product.

After holding the dried product at 80 ° C. for 48 hours, the 3A content was measured again. Still, 3A could not be detected. After storage at 60 ° C. for 13 weeks, 3A could not be detected. After storage at 60 ° C. for 1 year, 3A could still not be detected.

Comparative Example A 6.03 kg of Ac was added to a 25 liter crystallizer having a shell temperature of 20 ° C.
20 liters of deionized water to which eK (30 moles) had been added was charged. Then
The shell temperature thermostat was set at 50 ° C., so that the crystallizer temperature gradually increased during the experiment. Further, 3.07 kg of APM was added over 2 minutes with stirring (10 mol; water content 4%). 33% H in water during the entire APM addition time
The Cl solution was introduced at a rate of 35 g / min. After 9 minutes, the reaction mixture could no longer be stirred. Thereafter, an additional 5 kg of water was added. After 10 minutes, the mixture could be stirred again. After another 10 minutes, 500 g of APM was added. Then
For 20 minutes, 500 g of APM was added every 5 minutes. The APM addition was stopped for 15 minutes as the reaction mixture became viscous again. Then 30 minutes, 50 every 5 minutes
After adding 0 g of APM, the last 630 g of APM was added. A added
The total amount of PM was 9.2 kg (30 mol) and the total amount of added HCl solution was 3.3 kg (30 mol). The thermostat was then set at 10 ° C. After cooling for 3 hours, the crystallizer temperature was 22.8 ° C and the slurry was centrifuged in 3 liter increments. Each portion was washed twice, each wash using 300 ml of 20 ° C. deionized water. The moisture content of the collected wet cake is 5.
7% by weight. The wet cake was dried at 50 ° C. and low speed (about 70 rpm) for 3 hours in a blade dryer. 12.25 kg dry APM in total
. Ace was obtained. The water content after drying was <0.1% by weight. No acetoacetamide (3A) was shown in this product.

After holding the dried product at 80 ° C. for 48 hours, the 3A content was measured again. At this time, the 3A content was 17 ppm. Dried APM. After storing the Ace sample at 40 ° C. for 14 weeks, no 3A was shown in the product. Dried APM. After storing Ace at 60 ° C. for 1 month, 17 ppm of 3A was observed. The concentration of 3A rose to 32 ppm after storage at 60 ° C. for 13 weeks.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW

Claims (9)

[Claims] 1. A process for producing a salt of aspartame and acesulfameic acid in solid and dry form by production in a liquid medium, separation therefrom as a wet solid product by solid-liquid separation and subsequent drying. The wet solid product is
Prior to drying, a method comprising subjecting to one or more washing steps, wherein at least the last step of these washing steps is performed with a basic aqueous solution having a pH of 8 or more. 2. The method according to claim 1, wherein the basic aqueous solution is a solution of sodium hydroxide and / or potassium hydroxide. 3. The method according to claim 1, wherein the basic aqueous solution is in the range from 8 to 13, in particular from about 10.5 to about 11
. 3. The method according to claim 1, wherein the method has a pH in the range of 5. 4. The process as claimed in claim 1, wherein the temperature of the basic aqueous solution is below 20 ° C., in particular in the range from 15 to 5 ° C. 5. The method according to claim 1, wherein the washing operation is carried out at a temperature below 20 ° C., in particular in the range from 15 to 5 ° C. 6. Contacting the salt of aspartame with acesulfameic acid with a basic aqueous solution for at least a few seconds, preferably for 2 to 20 minutes.
The method according to claim 1. 7. The method according to claim 1, wherein at least one washing operation with water is performed first before the washing operation with the basic aqueous solution is applied. Method. 8. APM. 8. The process according to claim 1, wherein at least 10% by weight of the basic aqueous solution, based on the amount of ace (calculated as dry weight), is used. 9. An enhanced acetoacetamide content after heating the salt in dry form at a temperature of 80 ° C. for 48 hours, characterized in that the acetoacetamide content remains below 10 ppm relative to the dry weight of the salt. A stable salt of aspartame and acesulfameic acid.