EP1084139A1

EP1084139A1 - Preparation of an organic salt of aspartame with acesulfam h

Info

Publication number: EP1084139A1
Application number: EP99925471A
Authority: EP
Inventors: Christiaan Groeneveld
Original assignee: Holland Sweetener Co VOF
Current assignee: Holland Sweetener Co VOF
Priority date: 1998-06-05
Filing date: 1999-06-01
Publication date: 2001-03-21
Also published as: WO1999064444A1; NL1009324C2; KR20010052585A; AU4173799A; JP2002517510A; CN1304414A

Abstract

The invention relates to a process for the preparation of the salt of aspartame and acesulphamic acid on solid and dried form by preparation in a liquid medium and separation therefrom as a wet solid product by means of solid-liquid separation and subsequent drying, wherein said wet solid product, before being dried, is subjected to a washing operation in one or more steps, with at least the last of these washing oparations being effected with the aid of a basic aqueous solution having a pH of 8 or higher. The obtained solid dried procuct has an improved stability as compared with the product of the state of the art. The invention also relates to salt of aspartame and acesulphamic acid having such an increased stability that the acetoecetamide content upon heating of that salt in dry form at a temperature of 80 °C for 48 hours remains lower than 10 ppm relative to the dry weight of the salt.

Description

PREPARATION OF AN ORGANIC SALT OF ASPARTAME WITH ACESULFAM H

The invention relates to a process for the preparation of the salt of aspartame and acesulphamic acid in solid and dried form by preparation in a liquid medium and separation therefrom as a wet solid product by means of solid liquid separation and subsequent drying. According to this invention the salt of aspartame and acesulphamic acid is obtained having improved stability in dry form, in particular by showing a reduced risk of the formation of acetoacetamide upon exposure of the salt to an elevated temperature. The invention also relates to such a new salt of aspartame and acesulphamic acid.

The salt of aspartame and acesulphamic acid is a sweetener, with a sweetening power of approximately 200 times that of sugar on a weight basis, that is particularly suitable for use in powder mixtures, chewing gums, sweets and dry foodstuffs, in particular also in various products which, besides the sweetener, contain compounds such as aldehydes and the like, which may enter into undesirable reactions with sweeteners such as aspartame.

The salt of aspartame and acesulphamic acid is made up of the intensive sweetener aspartame, alpha- L-aspartyl-L-phenylalanine methyl ester (hereinafter also referred to as APM) , which has been known since a long time, and acesulphamic acid. Acesulphamic acid is the acid that is derived from the intensive sweetener acesulphame-K, the potassium salt having the formula 6- methyl-1, 2 , 3-oxathiazin-4 (3K) -one-2 , 2-dioxide

(hereinafter also referred to as AceK) , which has also been known for a long time. Acesulphamic acid will hereinafter also be referred to as AceH, and the salt of AP and AceH will also be referred to as AP .Ace.

The preparation of APM.Ace in a form having an excellent thermal stability and low hygroscopicity is disclosed in EP-A-0768041. In the preparation processes for APM.Ace disclosed in EP-A-0768041 that salt is obtained as a solid as a result of a trans- salification process carried out in a liquid medium. As components in the reaction system used (usually a slurry) mention is made specifically of (i) aspartame, (ii) an inorganic salt, for example the potassium salt, of acesulphamic acid and (iii) a strong acid, for example hydrochloric acid. Said components can be added to the reaction system in any desired order, the system being constantly kept in motion and remaining stirrable so that a relatively homogeneous distribution of the components takes place and there can be no undesirable too high local concentrations of the acid. The preparation of APM.Ace according to said patent application always takes place, as described in said application, by means of a relatively fast process, preferably in an aqueous medium, at a temperature in the range of -20 to +90°C. EP-A-0768041 does not give much information on the recovery, drying and/or further purification of the APM.Ace formed. The standard methods used, such as for example washing with ice water of the solid obtained by filtration, fully met the requirements for obtaining product having an excellent thermal stability as regards the thermal properties of the APM part of the salt.

EP-A-0768041 paid particular attention to the thermal stability as regards the APM part of the salt, as it was known that the thermal stability of APM is generally lower than that of AceK. It was also known, incidentally, that the acid corresponding to AceK, acesulphamic acid (AceH) , itself has a lower stability than, for example, AceK. The Ace part in APM.Ace is present in the same way as in AceK, and therefore any decomposition products of the Ace part in APM.Ace have never been given any attention.

According to EP-A-0768041 the APM.Ace (in dry form) has a good thermal stability when less than 0.5% decomposition takes place upon heating for 1 hour at 120°C, or for 70 hours at 70°C. Decomposition of the Ace part of APM.Ace was apparent, as is evident from the table in said patent application, only in comparative experiments 1C and ID, which were carried out in methanol . However, it has meanwhile become clear that detectable acetoacetamide concentrations, i.e. higher than the detection limit of 10 ppm on the basis of the dry weight of APM.Ace, are formed in APM.Ace upon prolonged exposure in dry form to an elevated temperature, specifically - as will therefore hereinafter be taken to be standard conditions - of for example 80 °C for, for example, 48 hours, even at the low moisture contents of the dry APM.Ace prepared according to the process of EP-A-0768041. Acetoacetamide will hereinafter also be referred to as 3A.

In foodstuffs, and therefore in substances used in foodstuffs, the presence of, in particular, acetoacetamide, is to be restricted to low concentrations for toxicological reasons. From the reference in the European Pharmacopoeia (Supplement 1998) for acetoacetamide, for example, a maximum allowable- concentration of 1250 ppm follows. In this context it is therefore deemed important according to the applicant - also because the applicant has meanwhile established that the formation of acetoacetamide proceeds autocatalytically, i.e. proceeds faster as the concentration that is present is higher - that the formation of detectable concentrations of 3A in APM.Ace is prevented.

The aim of the present invention is to solve the above-mentioned problems, in particular as regards preventing or impeding the formation of 3A in APM.Ace.

Surprisingly, this aim is achieved according to the invention in that the wet, solid product obtained by the solid-liquid separation, is subjected, before being dried, to a washing operation in one or more steps, with at least the last one of these washing operations being effected with the aid of a basic aqueous solution with a pH of 8 or higher.

After drying, the APM.Ace thus obtained meets the criterion to be set, that upon prolonged exposure in dry form to an elevated temperature, viz. for 48 hours at 80 °C, the 3A content is not higher than

10 ppm on the basis of the dry weight of APM.Ace. At temperatures lower than 80 °C, for example at 70 °C, the formation of 3A in APM.Ace proceeds - according to applicant's observations - more slowly, and at even lower temperatures the effects of its formation are almost negligible. Storage of APM.Ace (prepared according to the invention) for 12 months at 60 °C, for example, results in non-detectable concentrations of 3A, whereas APM.Ace which has not been prepared according to the invention already after one month at 60 °C contains 10-20 ppm of 3A. During storage of APM.Ace for one year at 40 °C no detectable quantities of 3A are formed in APM.Ace which at the beginning does not contain 3A.

According to the applicant, the formation of 3A can now be explained as a consequence of reactions of minute quantities of AceH present. The reason for this is that under the influence of (two molecules of) water acetoacetamide-N-sulphonic acid can be formed from (one molecule of) AceH, and this acid can subsequently, inter alia, react to form acetoacetamide. Applicants now have found that this reaction is autocatalytic .

It is noted that - as also stated in said EP-A-0768041 - the moisture contents of APM.Ace, if this were to be prepared analogously to the process as indicated in ES-A-8604766 , are always higher than in conformity with the process according to EP-A-0768041. The above-mentioned problems of the formation of 3A under conditions of storage and prolonged heating are therefore much greater in such a case. For the preparation in a liquid medium of the APM.Ace used in the context of this invention any suitable process can be employed. Examples of such processes are described in EP-A-0768041 as well as in ES-A-8604766 cited therein. For a further explanation of liquid media and process conditions that can be used in those processes and of solid-liquid separation methods, the contents of said patent applications are therefore referred to. The same holds for an explanation of the drying operation to be carried out after the washing operation (s) to be effected in the context of the present invention in order to obtain the APM.Ace in dry form.

In the process according to the invention it is possible to carry out the washing operation in one or more steps, it being understood that the last washing step is in all cases carried out with a basic solution having a pH of 8 or higher. If the washing operation is carried out in one step, and hence washing is immediately effected with such a basic solution, special attention will have to be paid to the washing out of inorganic salt present in the product. In that case more basic washing liquor will be needed to achieve the same washing result. As basic aqueous solution with a pH of 8 or higher in principle any solution of an inorganic or organic compound can be chosen which, at the concentration used, yields a solution having a pH of 8 or higher. Where this patent application refers to pH, in all cases the pH of the solution m question is meant as measured at room temperature (20 °C) using a calibrated pH meter. To one skilled in the art it will be obvious that in the context of this invention no bases are used that react in an undesirable manner with the APM.Ace, or that after use leave behind undesirable contaminants or undesirable odour or taste properties in the product obtained. Preferably, use is made of bases that leave no or hardly any residues behind in the recovered APM.Ace. Examples of bases that can be used in the basic aqueous solution in the context of the invention include inorganic hydroxides such as alkali hydroxides and alkaline earth hydroxides, for example sodium, potassium, calcium, and magnesium hydroxide, but for example also ammonium hydroxide, as well as organic bases, such as for example sodium or potassium benzoate, and similar bases that are suitable for use in the preparation of foodstuffs. The basic aqueous solution is preferably a solution of sodium hydroxide and/or potassium hydroxide .

Preferably, the basic washing operation is carried out using an aqueous solution of a base with a pH of 8-13, in particular with a pH in the range of about 10.5 to about 11.5. If a very high pH is chosen, for example a value of 13.5 or higher, there is a risk of the APM in APM.Ace starting to racemize and/or being subject to an increased extent to undesirable side reactions such as ester hydrolysis or diketopiperazine formation. If the pH of the basic aqueous solution used for the washing operation is chosen to be lower than 8, the effect of the washing operation is too small. Usually, the temperature of the basic solution used in the washing operation will not be higher than 20 °C, and preferably it will be in the range of 15-5°C. The washing operation itself is also preferably carried out at the temperature mentioned above for the basic solution. This prevents unnecessary temperature changes during the washing operation. As the temperature at which the washing operation is carried out is higher, the quantities of desired product (APM.Ace) lost via the mother liquor that is separated off will increase. It is true that such quantities of dissolved APM.Ace removed via the mother liquor can be recovered, but this requires unnecessary additional process steps.

The time used for the basic washing operation, i.e. the residence time of the recovered solid APM.Ace in the presence of the basic aqueous solution, is not very critical. One skilled in the art can simply determine the optimum conditions for the washing operation. Obviously, the risk of decomposition and/or formation of undesirable by-products increases as the basic washing operation takes more time. In general, the APM.Ace will be contacted with the basic aqueous solution for at least a few seconds, usually not longer than a few minutes, for example for 2 to 20 minutes. The time to be used for the basic washing operation, during which time the liquid medium present in the wet crystal cake is in fact displaced by the basic solution, will - as is obvious to one skilled in the art - depend in part on the amount of APM.Ace to be washed and the equipment used for this.

The washing operation with the basic solution, but also any preceding washing operation, can be carried out using any crystal washing method that is known to one skilled in the art. In one embodiment the APM.Ace crystal mass obtained upon solid-liquid separation, for example on a horizontal filter cloth, will be treated on that same filter cloth, optionally while applying overpressure above the filter or under- pressure below the filter, with the basic wash liquor by first applying this in a (small) layer on top of the crystal mass and subsequently discharging it through the crystal mass and the filter. The filter cloth may also be installed in a centrifuge. Before applying the washing operation with the basic aqueous solution according to the invention, preferably first at least one washing operation with water is carried out. This makes it possible to limit the amount of basic washing water needed according to the invention as well as any formation of by-products as a result of the basic washing operation itself. If desired, the basic washing operation according to the invention can also be repeated one or more times before the APM.Ace is upgraded - via drying in a way known to one skilled in the art - to obtain the desired dry product .

The amount of basic wash liquor used in the process according to the invention will generally not be critical. Preferably, at least 10 wt . % of the basic aqueous solution, relative to the amount of APM.Ace (calculated as dry weight) , is used. The optimum amount of wash liquor can simply be determined by one skilled in the art, depending on the way the APM.Ace has been prepared and depending on the conditions under which and equipment in which the basic washing operation is carried out. The lower, for example, the residual moisture content of the wet crystal mass, the lower the amount of basic wash liquor that needs to be used. The APM.Ace thus obtained after having been subjected to a basic washing operation, which is still wet, can subsequently be dried in any known manner. In particular when the APM.Ace has been prepared according to those embodiments of the above-mentioned EP-0768041 in which the preparation is carried out in an aqueous medium, an APM.Ace is obtained that has a particularly good thermal stability, a very low residual moisture content and a very low hygroscopicity, while there is also a strongly reduced risk of formation of 3A upon prolonged storage in dry form at elevated temperature.

According to the process of the invention thus a new, improved form of APM.Ace is provided with increased stability, in particular with increased stability as regards the possible formation of 3A under conditions involving prolonged exposure of the APM.Ace in dry form to an elevated temperature, viz. at 80 °C for 48 hours. In this new, improved form of APM.Ace, the 3A content upon the said exposure remains below the detection limit of 10 ppm on the basis of the dry weight of APM.Ace.

This new APM.Ace is thus characterized in that its acetoacetamide content remains lower than 10 ppm relative to the dry weight of the APM.Ace upon heating of the APM.Ace in dry form at a temperature of

80°C for 48 hours. The other properties of the APM.Ace correspond to the properties of that product as obtained in the APM.Ace preparation process used prior to the invention. The new product distinguishes itself from state-of-the-art products only with respect to the risk of formation of 3A.

The invention will now be elucidated with reference to the following examples and comparative examples. The examples are in no way meant to limit the invention.

All analyses for 3A were performed using

HPLC (High Performance Liquid Chromatography) techniques, specifically a gradient elution process. Injected volume in all cases 250 microliter; total running time 50 minutes at a flow rate of 1.5 ml/min.

Equipment : thermostatically controlled column oven, set at 20°C (Hewlett Packard HP 1090) ; column length 250 mm, internal diameter 4 mm, packed with LiChrospher 100 RP-18 (5 micrometer particles; Merck); variable wavelength detector (Spectra Physics, Spectra 200) , UV detection at 300 nm. Detection limit for 3A approx. 10 ppm (relative to dry weight of dry APM.Ace) .

Mobile phase: from the following components, viz.

(1) twice distilled water

(2) methanol , HPLC grade (Chromasolv; Riedel de Haen 34860) (3) tetrabutylammoniumhydroxysulphate (TBAHS) ; Fluka 86875

(4) 0.1 M aqueous potassium hydroxide solution, three solvents (A, B, C) were prepared, which had the following compositions:

The elution gradient used was as follows

The pH measurements were made using a Knick Portamess 752 Calimatic pH meter, equipped with a ROSS® Combination pH electrode 8155SC.

Example I

In a 1-litre crystallizer with a shell temperature of 50 °C the following were combined with stirring: 466 g demineralized water, 141 g AceK (0.70 moles) and 65 g APM (0.21 moles; moisture content 4%) Then a 33 % HCl solution in water was added dropwise for 25 minutes using a pipette until the pH was 3.5. Subsequently, 5 g APM was added every five minutes (extra addition in total 150 g, or 0.49 moles), the pH being controlled at 3.5 by the dropwise addition of additional HC1 solution. After all APM had been dosed, the last amount of 33% HCl was dosed, so that in total 77 g 33% HCl (0.70 moles) was dosed. About 3 hours after the start of the experiment, cooling was started

(cryostat at 10 °C) . In total 716 g of slurry was obtained, after 3 hours' cooling. This slurry was filtered off in a cooled Bϋchner funnel with a wall temperature of 10°C, and then washed twice, each time with 180 ml demineralized water of 10 °C, the pH of which had been raised to 11.0 by means of solid KOH. The moisture content of the collected wet cake was 19.2 wt . % . The wet cake was dried for 1 hour in a fluid bed at 50 °C. The moisture content upon drying was <

0.1 wt . % . No acetoacetamide (3A) could be demonstrated in this product.

The dried product was kept for 48 hours at 80 °C, following which the 3A content was re-determined. Still no 3A could be detected. After 13 weeks of storage at 60 °C no 3A could be detected. After one year of storage at 60°C still no 3A could be detected.

Comparative Example A A 25-litre crystallizer with a shell temperature of 20 °C was charged with 20 1 demineralized water, to which 6.03 kg AceK (30 moles) was added. The shell temperature thermostat was then set at 50 °C, so that the crystallizer temperature gradually increased during the experiment. In addition, in 2 minutes

3.07 kg APM was added with stirring (10 moles; moisture content 4%) . During the entire APM addition period a 33 % HCl solution in water was dosed, at a rate of 35 g/minute . After 9 minutes the reaction mixture could no longer be stirred, following which an additional 5 kg water was added. After 10 minutes the mixture could again be stirred. Another 10 minutes later 500 g APM was added. Then for 20 minutes every 5 minutes a portion of 500 g APM was added. As the reaction mixture thickened again, the APM addition was stopped for 15 minutes. Then for 30 minutes every 5 minutes a portion of 500 g APM was added, followed by a last portion of 630 g APM. The total amount of APM added was 9.2 kg (30 moles) , and the total amount of HCl solution added was 3.3 kg (30 moles). The thermostat was subsequently set at 10 °C. After 3 hours' cooling the crystallizer temperature was 22.8°C, and the slurry was centrifuged in three-litre portions. Each portion was washed twice, each time with 300 ml demineralized water of 20 °C. The moisture content of the collected wet cake was 5.7 wt . % . The wet cake was dried for 3 hours in a blade dryer at 50°C and at a low speed (about 70 rpm) . A total amount of 12.25 kg dried APM.Ace was obtained. The moisture content upon drying was < 0.1 wt . % . The presence of acetoacetamide (3A) could not be demonstrated in this product .

The dried product was kept at 80 °C for 48 hours, after which the 3A content was redetermined. This time the 3A content was 17 ppm.

After storage of a sample of the dried APM.Ace for 14 weeks at 40 °C, no 3A could be demonstrated in the product. After 1 month's storage of the dried APM.

Ace at 60 °C 17 ppm 3A was found. The concentration of 3A increased after 13 weeks of storage at 60 °C to 32 ppm .

Claims

1. Process for the preparation of the salt of aspartame and acesulphamic acid in solid and dried form by preparation in a liquid medium and separation therefrom as a wet solid product by means of solid- liquid separation and subsequent drying, characterized in that said wet solid product, before being dried, is subjected to a washing operation in one or more steps, with at least the last of these washing operations being effected with the aid of a basic aqueous solution having a pH of 8 or higher.

2. Process according to claim 1, characterized in that the basic aqueous solution is a solution of sodium hydroxide and/or potassium hydroxide.

3. Process according to claim 1 or claim 2, characterized in that the basic aqueous solution has a pH in the range of 8-13, in particular in the range of approximately 10.5 to approximately 11.5.

4. Process according to any one of claims 1-3, characterized in that the temperature of the basic aqueous solution is not higher than 20 ┬░C, and in particular is in the range of 15-5┬░C.

5. Process according to any one of claims 1-4, characterized in that the washing operation is effected at a temperature that is not higher than 20┬░C, and in particular is in the range of 15-5┬░C.

6. Process according to any one of claims 1-5, characterized in that the salt of aspartame and acesulphamic acid is contacted with the basic aqueous solution for at least a few seconds, preferably for 2 to 20 minutes.

7. Process according to any one of claims 1-6, characterized in that, before the washing operation with a basic aqueous solution is applied, first at least a washing operation with water is carried out .

8. Process according to any one of claims 1-7, characterized in that use is made of at least 10 wt . % of the basic aqueous solution, relative to the amount of APM.Ace (calculated as dry weight) .

9. Salt of aspartame and acesulphamic acid with increased stability, characterized in that upon heating of said salt in dry form at a temperature of 80 ┬░C for 48 hours the acetoacetamide content remains lower than 10 ppm relative to the dry weight of the salt .