Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-06-28
2001-09-25
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S040000
Reexamination Certificate
active
06294686
ABSTRACT:
TECHNICAL FIELD
The present invention relates to aspartame. More particularly the present invention relates to a novel method for the preparation of aspartame and a new crystal form of aspartame obtained by this method.
BACKGROUND ART
Aspartame (N-L-a-aspartyl-L-phenylalanine methyl ester) hereinafter referred to as APM, was first described and claimed in U.S. Pat. No. 3,492,131 issued in 1970 by Searle. Since then, it dominates the market of low calorie artificial sweeteners, which are being increasingly used in both low calorie and “normal” food products.
The APM molecule is a dipeptide composed of a highly hydrophilic aspartyl residue and a hydrophobic (phenylaianine methyl ester) entity and is zwitterionic at the aspartyl end. To date four polymorphic forms (IA, IB, IIA and IIB) of APM have been described (European Patent Application 0119837 B1, issued to Ajinomoto in 1988).
Compared to other artificial sweeteners APM has several advantages:
a) high sweetening power (300-400 that of sucrose as compared to 300 for saccharin and 30 for cyclamate);
b) no after taste; and
c) relatively good compatibility to human consumption (the acceptable daily intake in mg/kg/day of APM is 0-40 as compared to cyclamate 0-11, acesulfame 0-9 and saccharin 0-2.5).
DISCLOSURE OF THE INVENTION
In the present invention microemulsions are utilized to prepare new crystal forms of aspartame. Microemulsions are homogeneous, thermo-dynamically stable systems, consisting of submicron-size droplets of water dispersed within an immiscible organic (oil) phase or vice versa, oil droplets dispersed within a continuous aqueous phase. The droplets are protected against coalescence by adsorbed layers of suitable surfactants or a surfactant and cosurfactant, (usually an alcohol), and thus stabilized. Microemulsions can be destabilized by changing the specific conditions under which they are formed (i.e. by changing the temperature, pressure and/or by addition of excess of water or a suitable reagent such as a salt, base, etc).
The term “microemulsion”, as used herein, is intended to denote standard microemulsions, as well as any self-assembly of surfactants capable of solubilizing another liquid phase, i.e., micelles, mixed micelles, liposomes, neosomes, lyotropic liquid crystals, etc.
According to the present invention there is provided a novel method for the crystallization - recrystallization of aspartame. More specifically, the present invention provides a method of preparing new crystal forms of aspartame utilizing microemulsions comprising introducing aspartame into a microemulsion formed from an oil phase, an aqueous phase and at least one emulsifier; destabilizing said microemulsion to effect recrystallization of aspartame; separating solid phase crystals from the liquid phase in which they are contained; and cleaning said crystals to remove traces of the oil phase and surfactant.
This approach provides new possibilities to modify crystallization, thus bringing about new crystal forms.
In preferred embodiments of the present invention said microemulsion is formed from an oil phase, an aqueous phase and an emulsifier. Aspartame is introduced into the microemulsion or into the aqueous phase prior to preparing the microemulsion.
In a first preferred embodiment of the present invention said microemulsion is a water-in-oil microemulsion, stabilized by a zwitterionic, cationic, food-grade nonionic or anionic emulsifier. In preferred embodiments said microemulsion is stabilized by a double-chained anionic emulsifier or by a food-granule nonionic emulsifier. Preferred emulsifiers in this embodiment are sodium diisooctyl sulfosuccinate (AOT) and/or a food-grade surfactant consisting of 10% wt/wt L-&agr;-phosphatydilcholine and 90% wt/wt of monoglycero-oleate dissolved in propyleneglycol (ATMOS 300 from ICI Co).
It is to be noted that said emulsifiers can be used alone, or said microemulsion can be achieved by utilizing mixtures or blends of emulsifiers, including any type of cosolvent or coemulsifier, wherein in the literature alcohol is sometimes referred as a cosolvent and sometimes as a coemulsifier.
Preferably in said embodiments said oil is selected from the group consisting of hydrocarbons, liquid triglycerides, alcohols, acids, ketones, food-grade esters, aldehydes, terpenes, essential oils and oleoresins.
Thus, e.g., based on the above principles, there are now prepared according to the present invention, two new crystal forms, form III and form IV of aspartame. Form III was obtained by solubilization of commercial aspartame in water/isooctane microemulsions stabilized by diisooctyl sulfosuccinate (AOT) and its crystallization by subsequent cooling of the microemulsion. Commercial aspartame obtained by courtesy of NUTRASWEET Co, Switzerland (hereinafter NUTRASWEET® aspartame) was used for all experiments and as a standard for comparison with the new products.
Form III of aspartame, hereinafter referred to as APM III, is characterized by:
(a) an X-ray diffraction powder pattern (angles of diffraction) as set forth in
FIG. 1
b
herein;
(b) an FTIR spectrum as represented in
FIGS. 3
b
and
4
b
herein;
(c) TG/DTA and DSC patterns as represented in
FIG. 5
appended hereto;
(d) The NMR spectrum of the dissolved product is identical to the NHR spectrum of NUTRASWEET® as per
FIG. 8
a
; and
(e) improved dissolution kinetics as compared to commercial NUTRASWEET® aspartame as shown in
FIG. 9
herein.
When kept in a closed vial APM III was stable for at least one year.
Different crystal forms of aspartame can also be obtained by crystallizing commercial aspartame from edible microemulsions, such as water/oil/lecithin/mono and diglycerol oleate and others. Thus another new crystal form, form IV aspartame, hereinafter referred to as APM IV, was obtained from w/o microemulsions comprising soybean oil as the oil phase, stabilized by the food-grade surfactant ATMOS 300. APM IV is an adduct of aspartame with propylene glycol with a 1:1 molar ratio. The product is characterized by:
(a) an X-diffraction powder pattern (
FIG. 1
c
) which is distinctly different from the patterns of forms IA, IB, IIA, IIB as described in European patent No. 0119837B1 and from the pattern of APM III (
FIG. 1
b
).
(b) an FTIR spectrum as shown in
FIGS. 3
c
and
4
c
(c) Thermogravimetric (TG and DTA) and differential scanning calorimetric patterns (
FIG. 6
) and
(d) the H-NMR spectrum of the product dissolved in D2O (
FIG. 8
b
).
While the invention will now be described in connection with certain preferred embodiments in the following examples and with reference to the appended figures so that aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims. Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of formulation procedures as well as of the principles and conceptual aspects of the invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
EXAMPLE 1
22 g of aspartame were solubilized by mechanical stirring in a microemulsion containing 234 g (65%) of isooctane, 36 g (10%) of water and 90 g (25%) AOT at 65° C. The microemulsion was then cooled at a rate of 1° C. per min. with constant stirring to a final temperature of 5° C. and stirred at this temperature for an additional two hours to induce crystallization. After the onset of crystallization stirring was discontinued and the suspension stored overnight at 4° C. to complete crystallization. A gel-like product was obtained which was filtered and then repeatedly washed with hexane until the p
Garti Nissim
Kamishny Alexey
Milhofer Helga F.
Chaudhry Mahreen
Foley & Lardner
Killos Paul J.
Yissum Research Development Company of the Hebrew University of
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