Patent Publication Number: US-5834018-A

Title: Process for the treatment of aspartame

Description:
This is a continuation of application Ser. No. 08/351,579, filed Dec. 7, 1994 now U.S. Pat. No. 5,587,178 which is a CIP of 08/074,446, filed Jun. 10, 1993, now U.S. Pat. No. 5,411,747. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to a process for the treatment of dried aspartame, and to aspartame thus recovered. 
     2. Description of the Related Art 
     Aspartame is a sweetener that is often used in low-calorie lemonades, sugar-free chewing gum and low-calorie sweeteners. Aspartame is often sold as a &#34;powder&#34; consisting of particles smaller than 1 mm. This powder usually has a wide particle size distribution: there is a significant fraction of particles with sizes between 0 and 20 μm, 20-50 μm, etc. This type of product appears to be (1) relatively poorly soluble, (2) electrostatically chargeable, (3) non-free-flowing, (4) the cause of dust problems, (5) difficult to dose and (6) poorly dispersible in water. 
     In order to prevent some of these problems, aspartame is sometimes sold of which 90 wt. % of the particles are between, say, 250 and 750 μm. This aspartame, however, has a relatively low dissolution rate. In addition, it presents the drawback that a special treatment, for example a granulation step, is required afterwards to process undesired material (aspartame with particle sizes outside this range). 
     The present invention provides a process for the treatment of dried aspartame with which a product of a very high quality and good dissolution rate is obtained and with which only very little material need be reprocessed. 
     SUMMARY OF THE INVENTION 
     The present invention discloses aspartame in particulate form having a particle size distribution within a range of 20 μm to 250 μm, wherein at least 94 wt. % of the aspartame particles are within said range. 
     The present invention also discloses such aspartame, wherein at least 90 wt. % of the particles are larger than 30 μm and such aspartame, wherein at least 90 wt % of the particles are larger than 50 μm. 
     The present invention further discloses such aspartame, wherein at least 97 wt % of the particles are larger than 30 μm and such aspartame, wherein at least 97 wt. % of the particles are larger than 40 μm. 
     The present invention also discloses such aspartame, wherein at least 97 wt. % of the particles are less than 220 μm and such aspartame, wherein at least 97 wt. % of the particles are less than 205 μm. 
     The present invention also discloses a tablet obtained by tableting aspartame particles, wherein at least 94 wt. % of the particles are in a particle size distribution range of 20 μm to 250 μm. 
     The present invention further discloses such a tablet, wherein at least 90 wt. % of the aspartame particles are larger than 30 μm and such a tablet, wherein at least 90 wt. % of the aspartame particles are larger than 50 μm. 
     The present invention further discloses such a tablet, wherein at least 97 wt. % of the aspartame particles are larger than 30 μm and such a tablet, wherein at least 97 wt. % of the aspartame particles are larger than 40 μm. 
     The present invention further discloses such a tablet, wherein at least 97 wt. % of the aspartame particles are less than 220 μm and such a tablet, wherein at least 97 wt. % of the aspartame particles are less than 205 μm. 
     The present invention also discloses a tablet obtained by preparing dried aspartame, wherein in a first separation step, particles smaller than 50 μm are removed, with the aid of a stream of air, from aspartame having a particle size distribution with which more than 5 wt. % of the aspartame has a particle size of less than 20 μm and more than 10 wt. % of the aspartame has a particle size of more than 400 μm and that in a second separation step, the product resulting from the first step is subjected to a screening step using a screen that separates at a value between 150 and 250 μm, after which the fraction of the smaller particles thus obtained is recovered as a first product dried aspartame and the fraction of the larger particles is recovered as a second product dried aspartame or is optionally subjected to a further separation step using a screen that separates at a value between 400 and 1000 μm, the fraction of smaller particles thus obtained being recovered as a second product dried aspartame and preparing a tablet comprising the first product dried aspartame. 
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The process for the treatment of dried aspartame is characterized in that, in a first separation step, particles smaller than 50 μm are removed for the most part, with the aid of a stream of air, from aspartame having a particle size distribution with which more than 5 wt. % of the aspartame has a particle size of less than 20 μm and more than 10 wt. % of the aspartame has a particle size of more than 400 μm and, in a second separation step, the product resulting from the first step is subjected to a screening step using a screen that separates at a value between 150 and 250 μm, after which the fraction of the smaller particles thus obtained is recovered as a first product dried aspartame and the fraction of the larger particles is recovered as a second product dried aspartame or is optionally subjected to a further separation step using a screen that separates at a value between 400 and 1000 μm, the fraction of smaller particles thus obtained being recovered as a second product dried aspartame. 
     In the first step, particles smaller than 40 μm, in particular smaller than 30 μm, more in particular particles smaller than 20 μm, are preferably separated (hereinafter to be referred to as very fine aspartame), the fractions of particles larger than 40 μm, larger than 30 μm and larger than 20 μm, respectively, being the product resulting from the first step. 
     The very fine aspartame is preferably returned to the process. This aspartame may, for example, be dissolved and recrystallized. It is also possible, and preferable, to mix this aspartame with aspartame slurry from a crystallizer or centrifuge for a granulation and drying step. 
     A classifier and a stream of air are used to separate this very fine aspartame. As a rule, more than 1 kg of air per kg of aspartame is used as the stream of air. Preferably, use is made of between 2 and 50 kg of air, in particular of between 5 and 20 kg per kg of aspartame. Very suitable is, for example, a &#34;Sweco Turbo-Screen&#34; (hereinafter also to be referred to as TS) manufactured by Sweco. It is not possible to effect good separation in practice using an ordinary screen, without an additional driving force of a stream of air. 
     In addition, the classifier medium (usually a very fine screen or a plate with very small holes) is preferably continuously cleaned. This can be done, for example, by vibrating the screen or plate or by countercurrently blowing air through the screen or plate in places. 
     In order to separate very fine aspartame, the use of a fluidized bed is also very suitable. As a rule, the rate of fluidization will be chosen between 5 and 25 cm/sec. The thickness of the layer in the fluid bed may vary within a wide range without affecting the separation essentially. 
     For the process according to the invention, it appears to be very important to separate very fine aspartame in a first separation step. This ensures that the next separation step, using a screen that separates at 150-250 μm, takes place without problems in a very efficient manner. When a screening step at for example 200 μm was carried out as the first separation step, the screening apparatus became fouled/blocked and it proved difficult to dose the aspartame. 
     The product resulting from the first separation step is subjected to a second separation step using a screen that separates at a value between 150 and 250 μm. Preferably, the screen separates at a value between 170 and 220 μm, in particular at a value between 180 and 205 μm. 
     The fraction of the larger particles resulting from the second separation step is either directly recovered as a second product or it is subjected to a further separation step to remove relatively coarse material. Use can be made of a screen that separates at a value between 400 and 1000 μm, depending on the desired application of the aspartame product. If only the coarsest material is to be removed, a screen that separates at a value between 900 and 1000 μm is very suitable. Such a screening step may optionally also take place before the second separation step, but that is not preferable because then all of the aspartame (with the exception of the very fine aspartame) is subjected to this screening step, which means that a relatively large screen is required, which is less attractive from an economic point of view. 
     The separated coarse material can be ground and returned to the beginning of the treatment section for the use of the process according to the invention. 
     In this manner several fractions of aspartame are obtained, the fraction recovered as the first product in particular having very good properties. In particular the combination of a high dissolution rate, good flow properties (free flowing), good dispersibility, little dust formation and the virtual absence of electrostatic charging is unique. In addition, this aspartame appears to be extremely suitable for use in tablets, powders and chewing gum in particular, because the absence of larger particles means that a good distribution of aspartame throughout the product is obtained. 
     In commercial scale tableting of aspartame, using standard equipment (direct compression type equipment in general is considered to be the most preferred equipment for tableting) and &#34;state of the art&#34; aspartame products as of the priority date of U.S. patent application Ser. No. 08/074,446 U.S. Pat. No. 5,411,747, many problems occurred, whatever type of excipient and/or tableting agent was added in the process. The main problems were that the tablets tended to &#34;adhere&#34;/&#34;stick&#34; to the punches or dies of the tableting machine (which according to our present understanding may be attributed to the presence of microcrystalline product in the aspartame) and that the tableting equipment could not be run/operated smoothly. 
     The permanent presence of one or more operators, who needed to take many corrective actions during the processing of tablets, was required to run/operate the tableting equipment properly. The equipment often had to be stopped or operating conditions had to be adjusted (e.g., by lowering the rotation speed of the equipment), and feed to the tableting machine had to be kept in motion by tapping/knocking from the outside. It usually turned out to be impossible to continue production of tablets until all of the starting material had been processed; final parts thereof usually could not be pressed into the tableting machine. 
     This conventional tableting process resulted in relatively low production capacity of tablets, and in a high rejection percentage of tablets produced (poor quality). Moreover, the tablets made showed a broad range of distribution of weight and strength, and were not very uniform. In addition, production of tablets caused much noise, because the machinery could not operate smoothly and tapping/knocking was necessary. And last, but not least, the outer appearance of the tablets produced was relatively poor, especially in such cases where one wanted to &#34;imprint&#34; lines, signs, circles or figures, etc., at the surface of the tablets. In those cases, the problems of &#34;adhering/sticking&#34; to the punches and dies were even larger. 
     The above-described problems in the tableting process have now been overcome by using the aspartame made according to the process disclosed herein. This has been demonstrated in production scale experiments using tableting equipment which previously had been used (experiencing the problems mentioned above) for various years with &#34;state of the art&#34; aspartame products. In these experiments performed on a Kilian high speed rotating tableting machine, having 51×6 punches, and a maximum capacity of 1.8×10 6  tablets per hour at a maximum rotation speed of 49 rpm, aspartame was tableted together with &#34;tablettose&#34; (commercially-sold free flowing lactose product, for tableting purposes, from Meggler) as is used in the conventional production runs. 
     Though it is known in principle that relatively large particles of aspartame can be tableted, tablets made from such course products usually tend to be undesirable, i.e., commercially unattractive, due to the poor dissolution rate characteristics of the products obtained. Dissolution rate properties as such would be better if relatively fine aspartame particles would be used, however, such product is very poor in flowing properties, and therefore not very suitable for tableting. It now, surprisingly, has been found that the aspartame product of the present invention is most suitable for tableting purposes, and results in tablets having good dissolution properties. Most surprisingly, it also has been found that the outer appearance of the tablets obtained is much improved as compared with the known tablets, and, especially that lines, signs, circles or figures, etc., could be imprinted at the surface of the tablets during the tableting process in a very exact way. 
     It clearly has been demonstrated that direct compression tableting of aspartame, obtained according to the method of the present application, is very favorable. The tablets obtained are very homogeneous and uniform, both in weight and strength; the tableting machinery can be operated without attendance for many hours, and without problems of undesired noise levels, etc.; no tapping/knocking is necessary, and no adhering/sticking of product to the punches and dies occurs; the rejection percentage of tablets made in this way is extremely low; and finally, production can be continued undisturbed until all of the starting material has been converted into tablets. 
     The aspartame used in the production of these tablets is prepared from the above-described first product dried aspartame and is characterized by a narrow particle size distribution in which 97 wt. % of the particles are larger than 20 μm, preferably larger than 30 μm, in particular larger than 40 μm. In addition, 97 wt. % of the particles are smaller than 250 μm, preferably smaller than 220 μm, in particular smaller than 205 μm. In addition, 90 wt. % of the particles are preferably larger than 30 μm, in particular larger than 50 μm. The different values preferred for the upper and lower limits can be combined with one another in different manners for products that meet specific economic or technical requirements. 
     The second product dried aspartame is a granular type of aspartame that has a good bulk density and is easily processable but dissolves less quickly than the first product. 
     As starting material for the process according to the invention, use is preferably made of dry aspartame with a moisture content of less than 6 wt. %, in particular with a moisture content of 1-4 wt. %. The aspartame is usually recovered through crystallization from an aqueous solution. The slurry finally obtained is filtered off with the aid of for example a centrifuge and the wet cake (containing about 25-60 wt. % water) is dried and optionally granulated. In the granulation step or steps, aspartame may already be formed that has a particle size distribution that makes it suitable for use in the process according to the invention. If, however, a relatively large amount of coarse material is present, for example, if more than 20 wt. % has a particle size of more than 1 mm, then it is preferable to grind the material first. 
     The starting material usually has a wide particle size distribution, which is the result of the mechanical forces exerted during the granulation, reduction and drying steps. As a rule, the aspartame has such a distribution that more than 5 wt. % of the aspartame has a particle size of less than 20 μm and that more than 10 wt. % has a particle size of more than 400 μm. 
     Although it is common to speak of separation at a particular value in the case of, for example, screening, it is of course true that around that value a portion of the material having a smaller particle size will not pass through the screen and a portion of the larger material will, depending on the efficiency of the screen. This is because the holes of a screen are not all as large as one another and the particles are not ideally round. 
    
    
     The invention will be elucidated with reference to the following non-limiting examples. 
     EXAMPLE 1 
     Aspartame obtained through centrifugation, granulation, drying and grinding had the following characteristics: 
     d 10  :40 μm 
     d 50  :180 μm 
     d 90  :820 μm 
     moisture:2.8 wt. % 
     This aspartame was subjected to the following steps: 
     1) treatment in a Sweco TS 18, using a plate that separates at 50 μm and a stream of air of 10 kg of air per kg of aspartame. The fine material was returned to the granulation section where it was dispersed in the centrifuged aspartame slurry; 
     2) the resulting product was passed through a 200-μm screen. The fraction of the smaller particles was recovered as product 1; 
     3) the material consisting of the larger particles was passed through a 900-μm screen. The coarse material was returned to the grinding step; the desired fraction was recovered as product 2. 
     14% very fine and 5% coarse aspartame were separated. 40% product 1 and 40% product 2 were recovered and there was 1% loss. 
     The properties of the products are shown in Table 1. 
     
                       TABLE 1                                                     
______________________________________                                    
           Product 1                                                      
                  Product 2                                               
______________________________________                                    
d.sub.3      32     μm 180       μm                                 
d.sub.10     55     μm 230       μm                                 
d.sub.50     95     μm 400       μm                                 
d.sub.90     180    μm 700       μm                                 
d.sub.97     200    μm 900       μm                                 
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     Further properties of product 1 were: 
     settling angle:24° 
     bulk density:410 kg/m  3   
     outflow time*:9 sec 
     dissolution rate**:4 min 
    
    
     COMPARATIVE EXAMPLE 1 
     Aspartame as described in Example 1 was passed through a 200-μm screen. The screen became blocked several times. The cleaning of the screen caused a 5% loss of product. The screened product presented the following properties: 
     
                       TABLE 2                                                     
______________________________________                                    
         comparative product                                              
______________________________________                                    
       d.sub.10                                                           
            20                                                            
       d.sub.50                                                           
            70                                                            
       d.sub.90                                                           
           160                                                            
       d.sub.99                                                           
           200                                                            
______________________________________                                    
 
    
     settling angle:34° 
     bulk density:385 kg/m 3   
     outflow time:∞ 
     dissolution rate:8 min 
     EXAMPLE 2 AND COMPARATIVE EXAMPLES 2 AND 3 
     The advantages of use of aspartame according to the present invention for the preparation of tablets can be seen by comparing the results of the following example using Holland Sweetener test product according to the present invention (product A), and comparative examples using NutraSweet® powder product (product B) or Holland Sweetener Company powder product (product C). Example 2 and Comparative Examples 2 and 3 were performed under comparable conditions (Kilian; high speed rotating tableting machine; 51×6 punches; maximum capacity of 1.8×10 6  tablets per hour at 49 rpm maximum). The composition of the starting mixture was in each case 35 wt % of aspartame and 65 wt. % of tablettose (Meggler), with minor amounts of other standard ingredients for assisting the tableting process, identical in all cases. 
     Only in the case of use of product A (aspartame particles obtained according to the method of the present invention) was it possible to run the equipment smoothly at maximum capacity for many hours. In the comparative examples, adjustment of rotation speed to about 40 rpm was necessary, and the operation required much attention. The outer appearance of tablets made from product A was much better than of those made from products B and C. 
     Relevant data for starting materials and tablets produced are shown in Table 3. The data for the aspartame (APM) starting material (in the tableting step) also show various values which are important in estimating the flow properties of said product. These data have been determined according to standard methods known to those skilled in the art. The combined criteria for flow properties are usually presented in the form of the &#34;Carr index&#34;, a classification system first presented by Ralph L. Carr, Jr., in &#34;Chemical Engineering&#34;, 1965, pages 163-168, and incorporated herewith by reference. This reference also shows how the various data can be determined. A total &#34;Carr point score&#34; above 70 indicates that the product will flow fairly well without aid (though occasionally some vibration might be needed); a &#34;Carr point score&#34; in the range of 40 to 59 means that flowability is poor and that agitation/vibration is necessary for keeping the product in notion when flowing; a &#34;Carr point score&#34; of 20 to 39 indicates that flowability and performance are very poor, and more positive agitation is required in moving the product. 
     From the results shown in the Table 3, it is clear that tablets comprising aspartame according to the present invention can be produced at a higher production rate and more smoothly, with less spread of results in average tablet weight, aspartame content and strength of tablets, as compared to tablets prepared from conventional aspartame particles. 
     
                       TABLE 3                                                     
______________________________________                                    
TABLETING OF ASPARTAME WITH TABLETTOSE                                    
               Present                                                    
               Invention                                                  
                       Comparative Examples                               
Item                 Product A Product B                                  
                                      Product C                           
______________________________________                                    
     DATA STARTING                                                        
     MATERIAL APM                                                         
1.   particle size                                                        
     % &lt; 20 μm    n.d.      n.d.   11.69%                              
     % &lt; 50 μm    1.81%     99%    n.d.                                
     % &lt; 75 μm    n.d.      n.d.   54.45%                              
     % &gt; 200 μm   0.57%     0%     4.69%                               
     d.sub.50        130 μm         70 μm                           
     d.sub.90        186 μm 21 μm                                   
                                      175 μm                           
     d.sub.95        194 μm 37 μm                                   
                                      199 μm                           
2.   angle of repose 31.6°                                         
                               50.8°                               
                                      48.3°                        
     CARR POINTS     21.8      12.1   13.3                                
3.   Free bulk density                                                    
                     445 kg/m.sup.3                                       
                               215 kg/m.sup.3                             
                                      267 kg/m.sup.3                      
     Tapped bulk density                                                  
                     538 kg/m  355 kg/m.sup.3                             
                                      374 kg/m.sup.3                      
     Compressibility 16.4%     39.6%  28.6%                               
     CARR POINTS     19.3      3.3    12.1                                
4.   Angle of rupture                                                     
                     35.1°                                         
                               56.8°                               
                                      46.0°                        
     CARR POINTS     21.6      14.3   18.0                                
5.   Cohesion        19.1%     36.6%  10.4%                               
     CARR POINTS     11.8      8.4    13.4                                
6.   Total points Carr                                                    
                     74.5      38.1   56.8                                
     DATA ON PRODUCTION                                                   
     OF TABLETS                                                           
     COMPRISING APM                                                       
7.   max. possible speed                                                  
                     49 rpm    &lt;40 rpm                                    
                                      &lt;40 rpm                             
     of rotation for (=limit of                                           
     smooth production                                                    
                     equipment)                                           
8.   outer appearance                                                     
                     ++        +/-    +/-                                 
9.   attention needed                                                     
                     no        yes    yes                                 
     during production                                                    
10.  average tablet  50 mg     47 mg  48 mg                               
     weight                                                               
     standard deviation                                                   
                     1.9%      4.3%   3.0%                                
11.  average APM content                                                  
                     17.64 mg  16.3 mg                                    
                                      n.d.                                
     standard deviation                                                   
                     2.2%      3.8%   n.d.                                
12.  average strength of                                                  
                     20.5 N    21.9 N 10.5 N                              
     tablet                                                               
     standard deviation                                                   
                     11%       21%    26%                                 
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     While the present invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. 
     Thus, it is to be understood that variations in the present invention can be made without departing from the novel aspects of this invention as defined in the claims.