WO1999064445A1

WO1999064445A1 - Preparation and purification of a salt of aspartame with acesulfam k

Info

Publication number: WO1999064445A1
Application number: PCT/NL1999/000339
Authority: WO
Inventors: Carina Sascha Snijder; Gerardus Mathias Cornelus Wagemans; Christiaan Groeneveld
Original assignee: Holland Sweetener Company V.O.F.
Priority date: 1998-06-05
Filing date: 1999-06-01
Publication date: 1999-12-16
Also published as: AU4173899A; EP1084140A1; JP2002517511A; CN1304415A; NL1009323C2; KR20010052586A

Abstract

The invention relates to a process for the preparation of the salt of aspartame and acesulphamic acid wherein the salt of aspartame and acesulphamic acid is made available as a wet solid crystalline product which upon drying results in a product having a particle-size distribution in which at least 10 wt.% of the particles is larger than 200 νm. This crystalline product has an improved stability as compared with the product of the state of the art. In one embodiment the wet solid crystalline product is also subjected, prior to the drying operation, to a washing operation with a basic aqueous solution having a pH of 8 or higher. The invention also relates to the salt of aspartame and acesulphamic acid having such an increased stability that the acetoacetamide 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. In dried form, such salt of aspartame and acesulphamic acid has a particle-size distribution in which at least 10 wt.%, and more in particular at least 25 wt.%, of the particles is larger than 200 νm.

Description

PREPARATION AND PURIFICATION OF A SALT OF ASPARTAME WITH ACESULFAM K

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 APM and AceH will also be referred to as APM.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. It follows from the description in said patent application that the dosing sequence of the components in the reaction and the way in which first solid APM.Ace is obtained as a slurry are not critical. EP-A-0768041 does not give much information on the recovery, drying and/or further purification of the APM.Ace formed, either. The processes described in said patent application and the standard methods further 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 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 salt of aspartame and acesulphamic acid is made available as a wet solid crystalline product which upon drying results in a product having a particle-size distribution in dried form in which at least 10 wt.% of the particles is larger than 200 μm.

The APM.Ace, which in dried form has a particle-size distribution (hereinafter also referred to as p.s.d.) in which at least 10 wt.% of the particles is larger than 200 μm, meets - in this dry form - the criterion to be set, i.e. that upon prolonged exposure in dry form to an elevated temperature, viz. for 48 hours at 80 °C, the APM.Ace must not have a 3A content 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. Upon 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. 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 .

The particle-size distribution (p.s.d.) of the APM.Ace in dried form can be determined in any manner customarily employed by one skilled in the art. A very simple method for the determination of the wt.% of APM.Ace in dried form which has a particle size of 200 μm or more consists of screening off in a customary manner of an amount of, say, 10 g of the APM.Ace on a screen having a mesh width of 200 μm, and determining the weight fraction that is left behind on the screen. APM.Ace in dried form is in this patent application understood to mean, depending on the manner in which the APM.Ace has been prepared, either APM.Ace after normal drying under mild conditions when the APM.Ace has been obtained as a wet slurry, or after normal evaporation using a rotavapor when the APM.Ace is recovered by evaporation from a solution. The applicant has now found that in none of the APM.Ace preparation methods described so far has a product been obtained which in dry form has a p.s.d. in which at least 10 wt.% of the particles is larger than 200 urn. In the framework of the research for the present invention the inventors have established that, in order to obtain APM.Ace which in dry form has a p.s.d. in which at least 10 wt.% of the particles is larger than 200 μm, special measures are to be observed, as will be explained below. Thus, EP-A-0768041 does describe a large number of experiments for the preparation of APM.Ace, but in all cases either the reaction to obtain the APM.Ace is carried out at room temperature (using all sorts of dosing sequences for the various components used) , or all reacting components are always fed in the full amounts to be used of them when the reaction is carried out at elevated temperature, for instance at 50 °C. The applicant has now found that all these processes described lead to the formation of APM.Ace which in dried form has a p.s.d. in which less than 10 wt.% of the particles is larger than 200 μm. In the cited literature no indication whatsoever can be found that any effect as regards the stability of APM.Ace in dried form, let alone as regards the stability with respect to the formation of 3A, is to be expected from variation of the p.s.d., and in particular from the advantageous effects of a p.s.d. in at least 10 wt.% of the particles is larger than 200 μm.

It is noted that if APM.Ace were to be prepared according to the teachings of ES-A-8604766 (which, incidentally, does not describe any example of the formation of APM.Ace) , isolation of the APM.Ace would take place by evaporation from an organic solvent. This probably first gives rise to the formation of an amorphous material, which bears no comparison whatsoever to a crystalline product having a p.s.d. in at least 10 wt.% of the particles is larger than 200 μm.

However, insofar as EP-A-0768041 does refer to particle size, it is noted here that with respect to the particle size said patent application merely establishes a relationship with the desired 'sweetness release' and with effects of segregation in powder mixtures. However, nothing whatsoever is taught about the effects on the stability as regards the possible formation of 3A.

With special preference the APM.Ace according to the present invention is made available as a wet solid crystalline product which upon drying results in a product having a particle-size distribution in which at least 15 wt.%, and even more preferably at least 25 wt.%, of the particles is larger than 200 μm.

For the preparation in a liquid medium of the APM.Ace used in the context of the invention any suitable process can be used, provided it is ensured that the solid APM.Ace that is first obtained, i.e. immediately prior to the drying step, meets the p.s.d. specifications now found to be essential, namely that in dried form it has a p.s.d. in which at least 10 wt.% of the particles is larger than 200 μm. Examples of such processes are described in a general sense in EP-A-0768041. For a further explanation of the liquid media and conditions that can be used in these processes, and of solid-liquid separation methods the contents of said patent applications is therefore also referred to. Special points to be observed in order to obtain a wet solid crystalline APM.Ace product which upon drying results in a product having particles of which at least 10 wt.% is larger than 200 μm will be elucidated below.

The inventors have now found that APM.Ace having an improved stability, in particular as regards the formation of 3A, can be obtained if the following measures are successively taken in the preparation of the APM.Ace: a) a quantity of the inorganic salt of AceH, for example and by preference AceK, that is required in the reaction yielding APM.Ace, is supplied, in full or in part (i.e. at least 5 wt.%, but mostly at least 40 wt.%, of the total amount of this salt that is to be used) , if desired with stirring, in an aqueous medium, at a temperature of 40 to 65 °C, preferably at approximately 50 °C; b) subsequently, at the same temperature and with stirring or with stirring being continued, an amount of approximately 2 to 50% APM is added, calculated as molar equivalents relative to the amount of molar equivalents of the inorganic salt of AceH used in a) ; this addition may take place rapidly, but also in smaller portions; as a rule about 10 to 30 wt.% of the total amount of APM to be used will be added in this process step; c) subsequently, again at the same temperature and with stirring being continued, a strong acid, for example an aqueous solution of HC1 , is gradually or in small portions dosed in, for example, half an hour, the amount used being such that the total amount of strong acid dosed is a small molar deficiency, for example a 5-10% deficiency, with respect to the APM added in b) , - d) in a next step, again at the same temperature and with stirring being continued, if necessary the further amount of the inorganic salt of AceH is added, at once or in portions, and a further amount of APM and strong acid is added, optionally in the form of the salt of APM with that strong acid, this addition taking place gradually, it being constantly ensured that the total amount of APM supplied remains lower than the dose of the inorganic salt of AceH, these materials being added together or separately, and in mutually more or less equivalent amounts, this addition being continued until the total amount of APM used is approximately equivalent to the total amount supplied of the inorganic salt of AceH ; e) then the gradual dosing of the strong acid, still at the same temperature and with stirring being continued, is continued until there no longer is a deficiency with respect to the total amount of APM dosed. In doing so, it is specially preferred to ensure that f ) the steps c) , d) and optionally also e) proceed with such pH control during the reaction that this pH, measured using a pH meter calibrated at the reaction temperature, remains as long as possible at a level higher than 3; this may, for example, being effected by controlling the dosing of the strong acid at a lower pace; g) the residence time at the said temperature, from the first addition of the strong acid up to the end of the addition of the strong acid, is at least one hour, and h) during the formation of the APM.Ace the reaction system is continuously stirred so that at no single moment during the reaction a viscous slurry that is not well stirrable is being formed, so that at all times a stirrable slurry is present. This prevents the occurrence of so- called hot spots as a consequence of locally too high concentrations of strong acid, which may lead to the formation of a detectable amount of 3A during the reaction.

After the above-mentioned process steps have been performed, the formed APM.Ace can be separated as a wet solid product from the liquid reaction medium at the temperature used. Alternatively, the reaction system can first be allowed to cool to ambient temperature, or even, through some additional cooling, also to a temperature of the order of 5-20 °C, before the formed solid APM.Ace is separated from the liquid reaction medium as a wet solid crystalline product.

Drying of the thus separated wet solid crystalline APM.Ace preferably takes place under mild conditions, that is to say, at a temperature of 60 °C or lower, preferably at about 50 °C, optionally at somewhat reduced pressure or with inert gas being passed through. Preferably, the APM.Ace is dried to a moisture content of 0.1 wt.% or lower, calculated relative to the total weight of dried product .

When the APM.Ace is prepared in conformity with the above directions and the reaction conditions during the synthesis step (for example during the trans-salification process) and subsequent drying are chosen so that APM.Ace is formed which upon the drying results in a product having a particle-size distribution in which at least 10 wt.% of the particles is larger than 200 μm, the risk of 3A formation is limited to a bare minimum, not only during the synthesis but also upon prolonged heating (48 hours, 80 °C) of the dried product.

In a special embodiment of the invention the APM.Ace which, while observing the above measures, is made available as a wet solid crystalline product which upon drying results in a product having a particle-size distribution in which at least 10 wt.% of the particles is larger than 200 μm, is also subjected, prior to drying, to a washing operation in one or more steps, 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. In this special embodiment of the process according to the invention it is possible to carry out this 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 a pH, in all cases the pH of the solution in question is meant, as measured at room temperature (20 °C) using a calibrated pH meter. To one skilled in the art it is 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 context of the invention in the basic aqueous solution 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 diketopiperazme 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 m 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 m the art can readily 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, in 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 over-pressure above the filter or underpressure 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 filter cloth 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 otherwise 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 invention also relates to dried crystalline APM.Ace having a particle-size distribution in which at least 10 wt.% of the particles is larger than 200 μm, in particular at least 15 wt.%, and more in particular at least 25 wt.%, of the particles being larger than 200 μm, optionally also having been treated by means of a basic washing operation prior to drying. The wet solid crystalline APM.Ace can, in conformity with the above, 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, while observing the above with respect to the measures to be taken to obtain APM.Ace as a wet solid crystalline product which upon drying results in a product having a particle-size distribution in which at least 10 wt.% of the particles is larger than 200 μm, dry 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 which has an increased stability, in particular an 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) tetrabutylammonium hydrogen sulphate (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 of demineralized water, 141 g of AceK (0.70 moles) and 65 g of 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 of 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 HCl solution. After all the APM had been dosed, the last amount of 33% HCl was dosed, so that in total 77 g of 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 of 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.%. 41.6 wt.% of the particles were larger than 200 μm. No acetoacetamide (3A) could be demonstrated in this product.

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

Example II In a 30-litre crystallizer with a wall temperature of 50 °C 10 kg of demineralized water and 3.015 kg of AceK were combined with stirring. After 20 minutes 1.3 kg of APM (moisture content 4%) was dosed. After 30 minutes dosing of a 33% HCl solution in water was started. In total, 1.646 kg HCl of solution had to be added. After about 1 hour 24 wt.% of the HCl solution had been added and 28.3 wt.% of the total amount of APM. Subsequently, 165 g of APM was dosed every 5 minutes. After 3 hours in total 4.6 kg of APM had been dosed and also all of the HCl solution had been dosed. About 3 hours after the start of the experiment the cooling was started (cryostat at 10°C).

After 2 hours' cooling the slurry temperature was 11 °C.

The slurry was filtered off in a cooled Bύchner funnel with a wall temperature of 10 °C in 1.75 kg portions.

Two of these portions were washed, with 2 x 200 ml demineralized water of 10 °C; the other portions were first washed with 200 ml demineralized water and subsequently with 200 ml demineralized water the pH of which had been raised to 10.7 by means of solid KOH. 750 g portions were then dried in a fluid bed at 50 °C for 1 hour. After this drying the moisture content was < 0.1 wt.%. About 31 wt.% of the particles was larger than 200 μm. No acetoacetamide (3A) could be demonstrated in these portions.

Samples of the dried product portions were kept at 80 °C for 48 hours, upon which the 3A content was re-determined. In none of the cases could 3A be detected. After 13 weeks, and even after one year, of storage at 60 °C no 3A could be detected.

Comparative Example A A 25-litre crystallizer with a shell temperature of 20 °C was charged with 20 1 of demineralized water, to which 6.03 kg of 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 of 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 of water was added. After 10 minutes the mixture could again be stirred. Another 10 minutes later 500 g of APM was added. Then for 20 minutes each 5 minutes a portion of 500 g of APM was added. As the reaction mixture thickened again, APM dosing was stopped for 15 minutes. Then for 30 minutes each 5 minutes a portion of 500 g of APM was added, followed by a last portion of 630 g of 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 of 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 of dried APM.Ace was obtained. The moisture content upon drying was < 0.1 wt.%. About 2.8 wt.% of the particles was larger than 200 μm. No acetoacetamide (3A) could be demonstrated in this product. The dried product was kept at 80 °C for 48 hours, after which the 3A content was re-determined. 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 of 3A was found. After 13 weeks of storage at 60 °C the concentration of 3A had increased to 32 ppm.

Comparative Example B

With stirring, 688 g of demineralized water, 141 g of AceK (0.70 moles) and 215 g of APM (0.70 moles; moisture content 4%) were combined in a 1- litre crystallizer. Subsequently, heating to 50 °C took place and 127.7 g of a 20% HCl solution in water was added dropwise by means of a pipette in 33 minutes. Initially, a slurry was formed that was difficult to stir; later it became thinner. After the addition of the HCl solution, cooling was started (cryostat at 10 °C. After 2 hours cooling, in total a 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 of demineralized water of 10 °C. The moisture content of the collected wet cake was 34 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.%. 8.7 wt.% of the particles were larger than 200 μm.

The dried product was kept at 80 °C for 48 hours, upon which the 3A content was re-determined. 3A could be observed.

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 the salt of aspartame and acesulphamic acid is made available as a wet solid crystalline product which upon drying results in a product having a particle-size distribution in which at least 10 wt.% of the particles is larger than 200 ╬╝m.

2. Process according to claim 1, characterized in that the salt of aspartame and acesulphamic acid is made available as a wet solid crystalline product which upon drying results in a product having a particle-size distribution in which at least 15 wt.%, in particular at least 25 wt.%, of the particles is larger than 200 ╬╝m.

3. Process according to claim 1 or claim 2, characterized in that the salt of aspartame and acesulphamic acid is prepared by successively: a) supplying the full amount of the inorganic salt of acesulphamic acid (AceH) that is required in the reaction yielding the salt of aspartame and acesulphamic acid (APM.Ace) , or part thereof, if desired with stirring, in an aqueous medium, at a temperature of 40 to

65 ┬░C, preferably at approximately 50 ┬░C; b) adding, at the same temperature and with stirring or with stirring being continued, an amount of approximately 2 to 50% APM, calculated as molar equivalents relative to the amount of molar equivalents of the inorganic salt of AceH supplied in a) ; c) slowly dosing a strong acid to the reaction system, at the same temperature and with stirring being continued, in such an amount that the total amount of strong acid dosed is a small molar deficiency with respect to the APM added in b) ; d) if necessary adding the further amount of the inorganic salt of AceH and slowly further dosing APM and strong acid, in mutually more or less equivalent amounts, at the same temperature and with stirring being continued, it being constantly ensured that the total amount of APM supplied remains lower than the dose of the inorganic salt of AceH, until the total amount of APM used is approximately equivalent to the total amount supplied of the inorganic salt of AceH; e) slowly continuing the dosing of the strong acid, at the same temperature and with stirring being continued, until there no longer is a deficiency with respect to the total amount of APM dosed.

4. Process according to of claim 3, characterized in that the steps c) and d) , and optionally also e) , proceed under such monitoring of the pH during the reaction that said pH remains at a level higher than 3 for as long as possible.

5. Process according to claim 3 or claim 4, characterized in that the residence time at the said temperature, from the first addition of the strong acid to the end of the addition of the strong acid, is at least one hour.

6. Process according to any one of claims 3-5, characterized in that the reaction system is stirred in such a way during the formation of the salt of aspartame and acesulphamic acid that throughout the reaction a stirrable slurry is present .

7. Process according to any one of claims 3-6, characterized in that the salt of aspartame and acesulphamic acid that is formed is separated as a wet solid crystalline product from the liquid medium and is subsequently dried at a temperature of 60┬░C or lower, preferably at about 50┬░C.

8. Process according to claim 7, characterized in that the salt of aspartame and acesulphamic acid is dried to a moisture content of 0.1 wt.% or lower, calculated relative to the total weight of dried product .

9. Process according to any one of claims 3-8, characterized in that the product obtained in solid form upon preparation in a liquid medium of the salt of aspartame and acesulphamic acid and separated as a wet solid product from the liquid medium by means of solid- liquid separation is also subjected, prior to drying, 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.

10. Process according to claim 9, characterized in that the basic aqueous solution is a solution of sodium hydroxide and/or potassium hydroxide.

11. Process according to claim 9 or claim 10, 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.

12. Process according to any one of claims 9-11, 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.

13. Process according to any one of claims 9-12, 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.

14. Process according to any one of claims 9-13, 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.

15. Process according to any one of claims 9-14, 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.

16. Process according to any one of claims 9-15, characterized in that use is made of at least

10 wt.% of the basic aqueous solution, relative to the amount of the salt of aspartame and acesulphamic acid (calculated as dry weight) .

17. 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 .

18. Salt of aspartame and acesulphamic acid with in dried form a particle-size distribution in which a least 10 wt.% of the particles is larger than

200 ╬╝m.

19. Salt of aspartame and acesulphamic acid according to claim 18, with in dried form a particle-size distribution in which a least 15 wt.%, in particular at least 25 wt.%, of the particles is larger than 200 ╬╝m.