U.S. patent application number 13/554050 was filed with the patent office on 2012-11-15 for hydrate crystals.
This patent application is currently assigned to AJINOMOTO CO., INC.. Invention is credited to Kenichi MORI, Eriko ONO.
Application Number | 20120289574 13/554050 |
Document ID | / |
Family ID | 40940485 |
Filed Date | 2012-11-15 |
United States Patent
Application |
20120289574 |
Kind Code |
A1 |
MORI; Kenichi ; et
al. |
November 15, 2012 |
HYDRATE CRYSTALS
Abstract
New (2R,4R) monatin monosodium salt hydrate crystals
characterized by having specific characteristic X-ray diffraction
peaks provide general-purpose, stable, and safe monatin sodium salt
crystals incorporating no organic solvent. These crystal may be
prepared by a method that requires no organic solvent in the
crystallization, separation, and drying steps. These crystal are
useful as sweeteners and for the preparation of orally consumed
products, such as foods, beverages, pharmaceutical products,
topical pharmaceutical products, and feeds containing
general-purpose, stable, and safe monatin sodium salt crystals.
Inventors: |
MORI; Kenichi;
(Kawasaki-shi, JP) ; ONO; Eriko; (Kawasaki-shi,
JP) |
Assignee: |
AJINOMOTO CO., INC.
Chuo-ku
JP
|
Family ID: |
40940485 |
Appl. No.: |
13/554050 |
Filed: |
July 20, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13104547 |
May 10, 2011 |
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13554050 |
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12401997 |
Mar 11, 2009 |
7973070 |
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13104547 |
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61036349 |
Mar 13, 2008 |
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61119396 |
Dec 3, 2008 |
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Current U.S.
Class: |
514/419 ;
548/495 |
Current CPC
Class: |
C07D 209/20 20130101;
A61P 3/10 20180101; A61P 3/00 20180101 |
Class at
Publication: |
514/419 ;
548/495 |
International
Class: |
C07D 209/20 20060101
C07D209/20; A61P 3/00 20060101 A61P003/00; A61P 3/10 20060101
A61P003/10; A61K 31/405 20060101 A61K031/405 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 11, 2008 |
JP |
2008-060859 |
Dec 2, 2008 |
JP |
2008-307637 |
Claims
1. (2R,4R) Monatin monosodium salt hydrate crystals, having
characteristic X-ray diffraction peaks at angles of diffraction
(2.theta..+-.0.2.degree., CuK.alpha.) of either: group (A)
7.7.degree., 10.9.degree., 16.7.degree., and 17.0.degree.; or group
(B) 4.7.degree., 12.4.degree., 18.8.degree., and 22.6.degree..
2. Monatin crystals, having characteristic X-ray diffraction peaks
at angles of diffraction (2.theta..+-.0.2.degree., CuK.alpha.) of
either: group (A) 7.7.degree., 10.9.degree., 16.7.degree., and
17.0.degree. or group (B) 43.degree., 12.4.degree., 18.8.degree.,
and 22.6.degree..
3. Monatin crystals, which comprise (2R,4R) monatin monosodium salt
hydrate crystals according to claim 1.
4. The monatin crystals according to claim 2, wheerin the
enantiomer excess rate of the (2R,4R) monatin monosodium salt
hydrate crystals is 10 to 100% ee.
5. The monatin crystals according to claim 2, wherein the
diastereomer excess rate of the (2R,4R) monatin monosodium salt
hydrate crystals is 10 to 100% de.
6. The monatin crystals according to claim 2, wherein the sweetness
intensity thereof is 200-fold or more that of a 5 percent sucrose
aqueous solution.
7. The monatin crystals according to claim 2, wherein the chemical
purity thereof is 50 to 100 weight percent.
8. The monatin crystals according to claim 3, wherein the
enantiomer excess rate of the (2R,4R) monatin monosodium salt
hydrate crystals is 10 to 100% ee.
9. The monatin crystals according to claim 3, wherein the
diastereomer excess rate of the (2R,4R) monatin monosodium salt
hydrate crystals is 10 to 100% de.
10. The monatin crystals according to claim 3, wherein the
sweetness intensity thereof is 200-fold or more that of a 5 percent
sucrose aqueous solution.
11. The monatin crystals according to claim 3, wherein the chemical
purity thereof is 50 to 100 weight percent.
12. An orally consumed product, comprising (2R,4R) monatin
monosodium salt hydrate crystals according to claim 1.
13. An orally consumed product, comprising monatin crystals
according to claim 2.
14. A method for making an orally consumed product, comprising
adding (2R,4R) monatin monosodium salt hydrate crystals according
to claim 1 to at least one ingredient for an orally consumed
product.
15. A method for making an orally consumed product, comprising
adding (2R,4R) monatin monosodium salt hydrate crystals according
to claim 2 to at least one ingredient for an orally consumed
product.
16. A method for making (2R,4R) Monatin monosodium salt hydrate
crystals, having characteristic X-ray diffraction peaks at angles
of diffraction (2.theta..+-.0.2.degree., CuK.alpha.) of
7.7.degree., 10.9.degree., 16.7.degree., and 17.0.degree., said
method comprising: allowing an aqueous solution containing a high
concentration of (2R,4R) monatin monosodium salt to stand or
subjecting it to stirring precipitation to obtain said
crystals.
17. A method for making (2R,4R) Monatin monosodium salt hydrate
crystals, having characteristic X-ray diffraction peaks at angles
of diffraction (2.theta..+-.0.2.degree., CuK.alpha.) of
4,7.degree., 12.4.degree., 18.8.degree., and 22.6.degree., said
method comprising: concentrating an aqueous solution containing a
high concentration of (2R,4R) monatin monosodium salt, to obtain a
concentrated solution; introducing a water-miscible solvent into
said concentrated solution, to obtain a mixture; and allowing said
mixture to stand or inducing crystallization by stirring.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application No. 61/036,349, filed on Mar. 13, 2008; U.S.
Provisional Application No. 61/119,396, filed on Dec. 3, 2008;
Japanese Patent Application No. 060859/2008, filed on Mar. 11,
2008; and Japanese Patent Application No. 307637/2008, filed on
Dec. 2, 2008, all of which are incorporated herein by reference in
their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to new (2R,4R) monatin
monosodium salt hydrate crystals, characterized by having specific,
characteristic X-ray diffraction peaks. It also relates to monatin
crystals comprising these crystals, and to orally consumed products
comprising these crystals.
[0004] 2. Discussion of the Background
[0005] Monatin is a naturally occurring amino acid derivative
isolated from the bark of the roots of Schlerochiton ilicifollus,
which is a plant naturally grown in the area of northern Transvaal
of South Africa. The structure of monatin was reported to be
(2S,4S)-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl)-pentanoic acid
((2S,4S)-4-hydroxy-4-(3-indolylmethyl)-glutamic acid) by R.
Vleggaar et al. (see, R. Vleggaar et al., J. Chem. Soc. Perkin
Trans., 3095-3098 (1992)). The intensity of the sweet taste of the
(2S,4S) substance (natural-type monatin) derived from the natural
plant is reported in R. Vleggaar et al., J. Chem. Soc. Perkin
Trans., 3095-3098 (1992) to be 800 to 1,400-fold that of sucrose.
Although various methods of synthesizing monatin have been
reported, many of these relate to methods of synthesizing a mixture
of stereoisomers. There have been almost no reports in which each
of four stereoisomers having the same chemical structural formulae
as natural-type monatin is synthesized and isolated as a pure
substance and the properties thereof are investigated in detail
(see, ZA 87/4288; ZA 88/4220; U.S. Pat. No. 5,994,559; Holzapfel et
al., Synthetic Communications, vol. 24 (22), 3197-3211 (1994); and
K. Nakamura et al., Organic Letters, 2, 2967-2970 (2000)).
[0006] A number of studies have been conducted in recent years into
methods of manufacturing monatin (see, WO 2003-056026 and WO
2003-059865). A certain amount of information has been reported on
monatin crystals, but much of this relates to potassium salts.
There have been only limited reports on sodium salts, which are of
the greatest general utility (see, WO 2003-045914, U.S. Published
Patent Application No. 2005-272939, Japanese Patent Application
Publication No. 2005-154291, and Japanese Patent Application
Publication No. 2006-052213). The crystals of the characteristic
existing (2R,4R) monatin sodium salt are fine, the salt is
difficult to handle, and its thermal stability is somewhat lacking
(see, WO 2003-045914).
SUMMARY OF THE INVENTION
[0007] Accordingly, it is one object of the present invention to
provide novel crystals of (2R,4R) monatin monosodium salt.
[0008] It is another object of the present invention to provide
novel, stable (2R,4R) monatin sodium salt crystals.
[0009] It is another object of the present invention to provide
novel, stable (2R,4R) monatin sodium salt hydrate crystals.
[0010] It is another object of the present invention to provide
novel monatin crystals which contain such crystals of (2R,4R)
monatin monosodium salt hydrate.
[0011] It is another object of the present invention to provided
novel orally consumed products which contain such these
crystals.
[0012] It is another object of the present invention to provide
novel uses of such crystals as sweeteners.
[0013] It is another object of the present invention to provide
orally consumed products such as foods, beverages, pharmaceutical
products, topical pharmaceutical products, and feeds which
containing general-purpose, stable, and safe new sodium salt
crystals of (2R,4R) monatin.
[0014] These and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventors' obtaining new (2R,4R) monatin monosodium salt hydrate
crystals characterized by having specific characteristic X-ray
diffraction peaks, and discovered that the above problems were
solved by these crystals.
[0015] Thus, the present invention provides:
[0016] (1) (2R,4R) Monatin monosodium salt hydrate crystals,
characterized by having characteristic X-ray diffraction peaks at
angles of diffraction (2.theta..+-.0.2.degree., CuK.alpha.) of
either:
[0017] group (A) 7.7.degree., 10.9.degree., 16.7.degree., and
17.0.degree.; or
[0018] group (B) 4.7.degree., 12.4.degree., 18.8.degree., and
22.6.degree..
[0019] (2) Monatin crystals characterized by having characteristic
X-ray diffraction peaks at angles of diffraction
(2.theta..+-.0.2.degree., CuK.alpha.) of either:
[0020] group (A) 7.7.degree., 10.9.degree., 16.7.degree., and
17.0.degree.; or
[0021] group (B) 4.7.degree., 12.4.degree., 18.8.degree., and
22.6.degree..
[0022] (3) Monatin crystals, which comprise (2R,4R) monatin
monosodium salt hydrate crystals according to (1).
[0023] (4) The monatin crystals according to (2) or (3), wherein
the enantiomer excess rate of the (2R,4R) monatin monosodium salt
hydrate crystals is 10 to 100% ee.
[0024] (5) The monatin crystals according to (2) or (3), wherein
the diastereomer excess rate of the (2R,4R) monatin monosodium salt
hydrate crystals is 10 to 100% de.
[0025] (6) The monatin crystals according to (2) or (3), wherein
the sweetness intensity thereof is 200-fold or more that of a 5
percent sucrose aqueous solution.
[0026] (7) The monatin crystals according to (2) or (3), wherein
the chemical purity thereof is 50 to 100 weight percent.
[0027] (8) An orally consumed product, characterized by comprising
the (2R,4R) monatin monosodium salt hydrate crystals according to
(1).
[0028] (9) An orally consumed product, characterized by comprising
the monatin crystals of any one of (2) to (7).
[0029] The new (2R,4R) monatin monosodium hydrate crystals
characterized by having specific characteristic X-ray diffraction
peaks make it possible to provide stable monatin sodium salt
crystals. They also make it possible to clarify the utility and
various physical properties of these stereoisomers as sweeteners.
And they make it possible to provide orally consumed products such
as foods, beverages, pharmaceutical products, topical
pharmaceutical products, and feeds containing general-purpose,
stable, and safe monatin sodium salt crystals. This invention can
also be applied to (2S,4S) monatin, of course.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] A more complete appreciation of the invention and many of
the attendant advantages thereof will be readily obtained as the
same become better understood by reference to the following
detailed description when considered in connection with the
accompanying drawings, wherein:
[0031] FIG. 1 is a powder X-ray diffraction chart of (2R,4R)
monatin monosodium salt hydrate crystals (A) after drying (Example
1).
[0032] FIG. 2 is an optical microphotograph of (2R,4R) monatin
monosodium salt hydrate crystals (A) immediately prior to
separation from a crystallized solution (200-fold magnification)
(Example 1),
[0033] FIG. 3 is an optical microphotograph of (2R,4R) monatin
monosodium salt hydrate crystals (A) following drying and
pulverizing in a mortar (200-fold magnification) (Example 1).
[0034] FIG. 4 is a powder X-ray diffraction chart of (2R,4R)
monatin monosodium salt hydrate crystals (A) after a redrying test
(Example 2).
[0035] FIG. 5 is the plot of a water vapor adsorption/desorption
curve for (2R,4R) monatin monosodium salt hydrate crystals (A)
(Example 3).
[0036] FIG. 6 is a powder X-ray diffraction chart of (2R,4R)
monatin monosodium salt monohydrate crystals (B) after drying
(Example 4).
[0037] FIG. 7 is an optical microphotograph of (2R,4R) monatin
monosodium salt monohydrate crystals (B) immediately prior to
separation from a crystallized solution (200-fold magnification)
(Example 4).
[0038] FIG. 8 is a plot of the rate of decomposition over time into
the decomposition product X (lactone compound) of Example 4 and
Comparative Example 1.
[0039] FIG. 9 is a plot of the rate of decomposition over time into
the decomposition product Y (lactam compound) of Example 4 and
Comparative Example 1,
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0040] The present invention relates to new (2R,4R) monatin
monosodium salt hydrate crystals characterized by having specific
characteristic X-ray diffraction peaks.
[0041] In the present invention, the term "natural-type monatin"
refers to the (2S,4S) form of the stereo structure. All compounds
having the same chemical structural formula are collectively
referred to as "monatin." Accordingly, the term "non-natural-type
stereoisomers of monatin" refers to "stereoisomers of natural-type
monatin," "non-natural-type monatin," "(2S,4R) monatin," "(2R,4S)
monatin," "(2R,4R) monatin," and the like. Monatin ((2S,4S) form)
is included with these stereoisomers by referring to "the four
stereoisomers," and in particular, the natural form of monatin is
referred to as "(2S,4S) monatin" or "`(2S,4S) monatin` or the
like."
[0042] The (2R,4R) monatin employed in the present invention can be
prepared by known methods; the method employed is not limited. For
example, it can be enzymatically obtained from tryptophan via
indolepyruvic acid (see, WO 2003-056026), or obtained from
tryptophan, passing via indolepyruvic acid, by reduction from an
oxime (see, WO 2003-059865). In the manufacturing process, the
natural-type monatin (2S,4S) form and the non-natural-type
stereoisomer (2S,4R) and (2R,4S) forms can be contained in addition
to (2R,4R) monatin.
[0043] The monatin thus obtained may be employed as a mixture
containing the four isomers of monatin, or may be separated and
purified for use by known methods, such as with adsorption resin or
ion-exchange resin. Generally, it can be incorporated as a free
compound, ammonium salt, potassium salt, basic amino acid salt, or
some other known salt. The method of obtaining an aqueous solution
containing a high concentration of monatin monosodium salt is not
specifically limited. Free compounds and salts of monatin obtained
in the form of sodium salts by neutralization or salt exchange, as
well as those obtained by salt exchange by means of an ion-exchange
resin, can be employed. When an even higher concentration is
required, a known method such as solvent distillation under reduced
pressure can be employed.
[0044] The sodium employed in the present invention is not
specifically limited. It can be derived from inorganic sodium
compounds such as sodium hydroxide, sodium carbonate, sodium
bicarbonate, and sodium iodide, as well as from organic sodium
compounds such as sodium acetate, sodium oxalate, and sodium
lactate, by various methods such as neutralization and salt
exchange. These may be employed separately, or in combinations of
two or more.
[0045] Methods of precipitating the (2R,4R) monatin monosodium salt
hydrate crystals of the present invention that have the
characteristic X-ray peaks of (A) 7.7, 10.9.degree., 16.7.degree.,
and 17.0.degree. (also abbreviated hereinafter to (2R,4R) monatin
monosodium salt hydrate crystals (A) or (2R,4R) monatin monosodium
hydrate crystals (A)) will be described.
[0046] Allowing an aqueous solution containing a high concentration
of (2R,4R) monatin monosodium salt to stand or subjecting it to
stirring precipitation will cause the crystals to precipitate out.
Sowing seed crystals of (2R,4R) monatin monosodium salt hydrate is
desirable because it promotes stable and efficient
precipitation.
[0047] The precipitating crystals can be readily obtained as wet
crystals by subjecting them to a separation process such as
filtration. Washing the crystals is not specifically limited, so
long as a crystal-solvent exchange is not induced; water can be
employed. So long as a crystal solvent exchange is not induced, a
water-miscible solvent, such as methanol, ethanol, n-propanol,
isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol,
acetonitrile, or THF; inorganic salts; and the like can be
incorporated. Since the precipitation yield is higher when no
crystal-solvent exchange is induced, washing with water alone is
desirable, washing with cold water is preferred, washing with 0 to
20.degree. C. cold water is of greater preference, washing with 0
to 15.degree. C. cold water is of even greater preference, washing
with 0 to 10.degree. C. cold water is of still greater preference,
and washing with 0 to 5.degree. C. cold water is of particular
preference.
[0048] The wet crystals thus obtained can be subjected to a known
drying process to derive dry crystals. The drying equipment
employed in the drying process is not specifically limited. A
temperature range that does not melt the (2R,4R) monatin monosodium
salt can be employed. Drying under reduced pressure, drying under
an airflow, hot blow-drying, and the like can be employed.
[0049] The (2R,4R) monatin monosodium salt hydrate crystals thus
obtained are acicular and have characteristic X-ray diffraction
peaks at angles of diffraction (2.theta..+-.0.2.degree.,
CuK.alpha.) of 7.7.degree., 10.9.degree., 16.7.degree., and
17.0.degree..
[0050] The (2R,4R) monatin monopotassium salt monohydrate crystals
described in Example 17 of WO 2003-045914 have a solid crystalline
shape. In contrast to these (2R,4R) monatin monopotassium salt
monohydrate crystals, which cannot be mixed into a quality powder
with an excipient without a pulverizing step, the (2R,4R) monatin
monosodium salt hydrate crystals (A) of the present invention, even
when mixed as is into a powder with an excipient, are characterized
by yielding a sweetener composition producing a good taste
sensation without creating a gritty sensation on the tip of the
tongue, affording good mouth feel, and having a good initial
sweetness that are of the same quality as those of granulated
sugar.
[0051] In a water vapor adsorption/desorption test of (2R,4R)
monatin monosodium salt hydrate crystals (A), the trihydrate
exhibited the greatest stability. However, the crystalline
structure is thought to have the singular property of gradually
losing water of crystallization as is. Although the crystalline
lattice that is formed by (2R,4R) monatin monosodium salt and
trihydrate is itself rigid, perhaps because the hydrogen bonds of
the water of crystallization that is present within it are
relatively loose, the crystalline lattice is thought to have the
property of being able to gradually lose its water of
crystallization under the effect of just a vacuum pump at
40.degree. C. or the like. Accordingly, despite identical
characteristic X-ray diffraction peaks, it can be denoted as
(2R,4R) monatin monosodium salt n-hydrate crystals (n=0.1 to 3.0).
That is, when referred to as (2R,4R) monatin monosodium salt
hydrate crystals (A), what is meant in a narrow sense is (2R,4R)
monatin monosodium salt trihydrate crystals, and what is meant in a
broad sense is (2R,4R) monatin monosodium salt n-hydrate crystals
(n=0.1 to 4.0).
[0052] The differences between the (2R,4R) monatin monosodium salt
hydrate crystals (A) of the present invention and the (2R,4R)
monatin monosodium salt crystals of Examples 14 and 20 in WO
2003-045914 will be examined. The crystals described in Example 14
of WO 2003-045914, which are (2R,4R) monatin monosodium salt 0.2
ethanolate, are described as "exhibiting characteristic X-ray
diffraction peaks at diffraction angles (2.theta., CuK.alpha.) of
4.4.degree., 15.3.degree., 17.5.degree., 19.1.degree., and
24.6.degree.". The crystals described in Example 20 of WO
2003-045914, when traced, exhibit hydrates of (2R,4R) monatin
monosodium salt corresponding to 2.5 hydrates. These crystals are
described as "exhibiting characteristic X-ray diffraction peaks at
diffraction angles (2.theta., CuK.alpha.) of 4.4.degree.,
15.2.degree., 17.8.degree., 20.6.degree., and 24.1.degree.". When
these are examined, once the crystals have been constructed, the
fact that crystalline transition tends not to occur even once the
crystal solvent has been removed is thought to be a singular
property of monatins, particularly (2R,4R) monatin, or (2R,4R)
monatin monosodium salt. Accordingly, in the course of obtaining
the new (2R,4R) monatin monosodium salt hydrate crystals (A) having
characteristic X-ray diffraction peaks at angles of diffraction
(2.theta..+-.0.2.degree., CuK.alpha.) of 7.7.degree., 10.9.degree.,
16.7.degree., and 17.0.degree. of the present invention, an organic
solvent capable of forming a solvate, such as ethanol, must not be
present in large quantity during the crystallization stage. That
is, it is desirable to employ just water during the crystallization
stage, and it is preferable to employ just water during both the
crystallization and washing stages.
[0053] The new (2R,4R) monatin monosodium salt hydrate crystals (A)
having characteristic X-ray diffraction peaks at angles of
diffraction (2.theta..+-.0.2.degree., CuK.alpha.) of (A)
7.7.degree., 10.9.degree., 16.7.degree., and 17.0.degree. make it
possible to provide general-purpose, stable, and safe monatin
sodium salt crystals in which organic solvents are not
incorporated. They also make it possible to provide a manufacturing
method in which organic solvent is not required in either the
crystallization, separation, or drying step.
[0054] The method of crystallizing those (2R,4R) monatin monosodium
salt hydrate crystals having characteristic X-ray peaks at (B)
4.7.degree., 12.4.degree., 18.8.degree., and 22.6.degree. among the
crystals of the present invention (sometimes abbreviated
hereinafter to "(2R,4R) monatin monosodium salt hydrate crystals
(B)" or "(2R,4R) monatin monosodium salt monohydrate crystals (B)")
will be described next.
[0055] The crystals can be precipitated by concentrating an aqueous
solution containing a high concentration of (2R,4R) monatin and
sodium source as mentioned above, introducing a water-miscible
solvent, and allowing the mixture to stand or inducing
crystallization by stirring. Specifically, water-miscible solvents
in the form of lower monohydric alcohols such as methanol, ethanol,
isopropanol, n-butanol, and t-butanol; ketones such as acetone and
methyl ethyl ketone; and the like can be employed. Some residual
water may also be present. The concentration of (2R,4R) monatin
crystals in the solvent is not specifically limited so long as it
is supersaturated, causing crystals to precipitate out, but 20 to
60 weight percent is desirable. From the viewpoint of achieving a
solution viscosity suited to manufacturing, 30 to 50 weight percent
is preferable, and 35 to 45 weight percent is of greater
preference. The temperature of dissolution is not specifically
limited so long as the crystals continue to dissolve; 40 to
100.degree. C. is desirable. Allowing an aqueous solution
containing a high concentration of (2R,4R) monatin and sodium
source as mentioned above to stand or subjecting it to stirring
precipitation will cause the crystals to precipitate out. Sowing
seed crystals of (2R,4R) monatin monosodium salt hydrate is
desirable because it promotes stable and efficient precipitation.
The concentration of (2R,4R) monatin crystals in the solvent is not
specifically limited so long as it is supersaturated, causing
crystals to precipitate out, but 20 to 60 weight percent is
desirable. From the viewpoint of achieving a solution viscosity
suited to manufacturing, 30 to 50 weight percent is preferable, and
35 to 45 weight percent is of greater preference. The temperature
of dissolution is not specifically limited so long as the crystals
continue to dissolve; 40 to 100.degree. C. is desirable.
[0056] Sowing seed crystals of (2R,4R) monatin monosodium salt
monohydrate at a high crystallization starting temperature makes it
possible to stably obtain the targeted crystals. From the
perspective of producing the targeted crystals without dissolving
the seed crystals, the crystallization starting temperature must be
lower than the temperature at which the solvent exhibits
solubility. Additionally, from the perspective of promoting crystal
growth and obtaining large crystals, the lower limit of the
crystallization starting temperature is desirably 35.degree. C.,
preferably 40.degree. C., more preferably 43.degree. C., still more
preferably 45.degree. C., yet more preferably 48.degree. C., and
particularly preferably, 50.degree. C. From the perspective of
producing the targeted crystals without dissolving the seed
crystals, the crystallization starting temperature must be lower
than the temperature at which the solvent exhibits solubility.
Additionally, from the perspective of promoting crystal growth and
obtaining large crystals, the upper limit of the crystallization
starting temperature is desirably 80.degree. C., preferably
70.degree. C., and more preferably, 60.degree. C.
[0057] The crystals that precipitate can be readily obtained as wet
crystals by subjecting them to a separation process such as
filtration. Washing the crystals is not specifically limited, so
long as a crystal solvent exchange is not induced. Specific
solvents that can be employed so long as a crystal solvent exchange
is not induced are water-miscible solvents, such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, t-butanol,
sec-butanol, propylene glycol, acetonitrile, and THF; inorganic
salts; and the like.
[0058] Dry crystals can be derived by subjecting the wet crystals
that have thus been obtained to a known drying process. The drying
equipment employed in the drying process is not specifically
limited. A temperature range over which the (2R,4R) monatin
monosodium salt (B) does not melt can be employed. Drying under
reduced pressure, drying under an airflow, hot blow-drying, and the
like can be employed.
[0059] The (2R,4R) monatin monosodium salt monohydrate crystals (B)
thus obtained are acicular and have characteristic X-ray
diffraction peaks at angles of diffraction
(2.theta..+-.0.2.degree., CuK.alpha.) of 4.7.degree., 12.4.degree.,
18.8.degree., and 22.6.degree..
[0060] The differences between the (2R,4R) monatin monosodium salt
monohydrate crystals (B) of the present invention and the (2R,4R)
monatin monosodium salt crystals of Examples 14 and 20 in WO
2003-045914 will be examined. The crystals described in Example 14
of WO 2003-045914 are (2R,4R) monatin monosodium salt 0.2
ethanolate, and when traced, start to crystallize at 20.degree. C.
or lower. They are described as "exhibiting characteristic X-ray
diffraction peaks at diffraction angles (2.theta., CuK.alpha.) of
4.4.degree., 15.3.degree., 17.5.degree., 19.1.degree., and
24.6.degree.". The crystals described in Example 20 of WO
2003-045914, when traced, exhibit hydrates of (2R,4R) monatin
monosodium salt corresponding to 2.5 hydrates. These crystals are
described as "exhibiting characteristic X-ray diffraction peaks at
diffraction angles (2.theta., CuK.alpha.) of 4.4.degree.,
15.2.degree., 17.8.degree., 20.6.degree., and 24.1.degree.". When
these are examined, once the crystals have been constructed, the
fact that crystalline transition tends not to occur even once the
crystal solvent has been removed is thought to be a singular
property of monatins, particularly (2R,4R) monatin, or (2R,4R)
monatin monosodium salt. Accordingly, in the course of obtaining
the new (2R,4R) monatin monosodium monohydrate crystals (B) having
characteristic X-ray diffraction peaks at angles of diffraction
(2.theta..+-.0.2.degree., CuK.alpha.) of 4.7.degree., 12.4.degree.,
18.8.degree., and 22.6.degree. of the present invention, the
above-described high crystallization starting temperature range is
extremely important; this characteristic is clearly different from
the crystallization starting temperature (20.degree. C.) of the
sodium salt of WO 2003-045914. As a result, different crystalline
forms are obtained. The crystals are larger than has conventionally
been the case, and their stability, at 20-fold or greater, is
extremely high. This was a surprising discovery.
[0061] The (2R,4R) monatin monosodium salt monohydrate crystals (B)
characterized by having characteristic X-ray diffraction peaks at
4.7.degree., 12.4.degree., 18.8.degree., and 22.6.degree. make it
possible to provide monatin sodium salt crystals that are large in
crystalline shape and have good thermal stability.
[0062] The (2R,4R) monatin monosodium salt hydrate crystals of the
present invention ((A) or (B)) can form monatin crystals with
another monatin isomer in the form of (2S,4S) monatin monosodium
salt. In that case, the enantiomer excess rate is not specifically
limited. From the perspectives of having stable crystals and
performing as an effective sweetener in small quantities, the
enantiomer excess rate is desirably 10 to 100% ee, preferably 30 to
100% ee, more preferably 50 to 100% ee, still more preferably 70 to
100% ee, yet more preferably 90 to 100% ee, and particularly
preferably, 95 to 100% ee.
[0063] The (2R,4R) monatin monosodium salt hydrate crystals of the
present invention ((A) or (B)) can form monatin crystals with other
monatin isomers in the form of (2S,4R) monatin monosodium salt and
(2R,4S) monatin monosodium salt. The diastereomer excess rate is
not specifically limited. From the perspectives of having stable
crystals and performing as an effective sweetener in small
quantities, the diastereomer excess rate is desirably 10 to 100%
de, preferably 30 to 100% de, more preferably 50 to 100% de, still
more preferably 70 to 100% de, yet more preferably 90 to 100% de,
and particularly preferably, 95 to 100% de.
[0064] The (2R,4R) monatin monosodium salt hydrate crystals of the
present invention ((A) or (B)) can form monatin crystals with
organic and inorganic impurities. The lower limit of chemical
purity of monatin crystals containing the (2R,4R) monatin
monosodium salt hydrate crystals of the present invention is not
specifically limited so long as crystals are formed. However, from
the perspective of forming stable crystals, 50 weight percent is
desirable, 60 weight percent is preferable, 70 weight percent is
more preferable, 80 weight percent is still more preferable, 90
weight percent is yet more preferable, and 95 weight percent is
particularly preferable. Additionally, the upper limit of chemical
purity is desirably 100 weight percent from the perspective of
achieving sweetness intensity when formulated in small quantities.
The "chemical purity" referred to here is the ratio of the weight
of the "monatin monosodium salt hydrate crystals" to the weight of
the monatin crystals as a whole. Examples of items that decrease
purity are impurities (including other isomers) in the monatin
itself, inorganic salts, and salts of metals other than sodium.
This is not an exhaustive list of impurities.
[0065] The (2R,4R) monatin monosodium salt hydrate crystals of the
present invention ((A) or (B)) can form monatin crystals with other
monatin isomers in the form of (2S,4S) monatin monosodium salt,
(2S,4R) monatin monosodium salt, (2R,4S) monatin monosodium salt,
and other organic and inorganic impurities. The sweetness intensity
of monatin crystals containing the (2R,4R) monatin monosodium salt
hydrate crystals of the present invention ((A) or (B)) is not
specifically limited. From the perspective of having stable
crystals and being an effective sweetener in small quantities, a
sweetness intensity relative to a 5 percent sucrose aqueous
solution of 200-fold or greater is desirable, 500-fold or greater
is preferred, 1,000-fold or greater is of greater preference,
1,500-fold or greater is of still greater preference, 2,000-fold or
greater is of even greater preference, and 2,500-fold or greater is
of particular preference.
[0066] Additional sweeteners (excluding monatins and their salts)
can be combined with monatin crystals containing the (2R,4R)
monatin monosodium salt hydrate crystals of the present invention
((A) or (B)) of the present invention to obtain sweetening
compositions. These sweeteners are not specifically limited.
Specific examples are monosaccharides such as xylose, glucose, and
fructose; disaccharides such as sucrose, lactose, and maltose;
oligosaccharides such as fructooligosaccharides,
maltooligosaccharides, isomaltooligosaccharides, and
galactooligosaccharides; sugar alcohols such as xylitol, lactitol,
sorbitol, erythritol, mannitol, maltitol, reduced palatinose, and
reduced starch saccharification products; and high-intensity
sweeteners (HIS) such as aspartame, acesulfame-K, sucralose,
saccharin, stevioside, neotame, sodium cyclohexylsulfamate, stevia,
glycyrrhizin, monellin, thaumatin, dulcin, brazzein, neoculin, and
MHPPAPM
(N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-aspartyl]-phenylala-
nine 1-methylester monohydrate (Advantame (CAS No. 714229-20-6)).
These may be employed singly, or in combinations of two or more.
From the perspective of achieving a synergistic sweetening effect,
aspartame, acesulfame-K, sucralose, saccharin, sodium
cyclohexylsulfamate, stevioside, and neotame are desirable;
aspartame, acesulfame-K, sucralose, saccharin, stevioside, and
neotame are preferable; aspartame, acesulfame-K, sucralose,
stevioside, and neotame are of greater preference; aspartame,
acesulfame-K, sucralose, and neotome are of even greater
preference; aspartame, acesulfame-K, and sucralose are of still
greater preference; and aspartame and sucralose are of particular
preference. From the perspectives of quality of flavor and
achieving a synergistic sweetening effect, aspartame is of
particular preference.
[0067] In addition to various food materials, various additives
that can be employed in orally consumed products, such as foods,
beverages, pharmaceuticals, topical pharmaceutical products, and
feeds, can be employed to a degree that does not impede the effect
of the present invention. Specific examples are excipients in the
form of dextrins such as dextrin, maltodextrin, starch
decomposition products, reduced starch decomposition products,
cyclodextrin, and hard-to-digest dextrins, and in the form of
polysaccharides such as crystalline cellulose and polydextrose; pH
regulating agents such as citric acid, phosphoric acid, lactic
acid, malic acid, tartaric acid, gluconic acid, and salts thereof;
antioxidants such as L-ascorbic acid, erysorbic acid, and
tocopherol (vitamin E); quality-enhancing agents such as sodium
acetate, glycine, glycerine fatty acid esters, and lysozyme;
preservatives such as sodium benzoate and potassium sorbate;
stabilizers such as pectin, gum arabic, carageenan, soy
polysaccharides, and hydroxypropyl cellulose (HPC); thickening
stabilizers such as xanthan gum, locust bean gum, guar gum,
tamarind gum, and caraya gum; anticaking agents such as calcium
phosphate, calcium carbonate, magnesium carbonate, silicon dioxide,
and shell calcium; fragrances in the form of natural fragrance
materials such as cinnamon oil, lemon oil, mint oil, orange oil,
and vanilla, in the form of synthetic fragrance materials such as
menthol, citral, cinnamic alcohol, terpineol, and vanillin, and in
the form of mixed fragrances blended therefrom; coloring materials
such as kuchinashi dye, caramel dye, cochineal dye, annatto dye,
safflower dye, .beta.-carotene, and various tar-based synthetic
dyes; anticaking agents such as sodium bicarbonate, starch, agar
powder, gelatin powder, and crystalline cellulose; gloss-imparting
agents such as stearic acid, sugar esters, benzoic acid, and talc;
leavening agents such as sodium bicarbonate and glucono
delta-lactone; and emulsifiers such as lecithin, sucrose fatty acid
esters, glycerine fatty acid esters, and sorbitan fatty acid
esters. These may be employed in any combination, and may be
employed singly or in mixtures of two or more.
[0068] The monatin crystals or sweetener composition of the present
invention can be employed in orally consumed products such as
foods, beverages, pharmaceutical products, topical pharmaceutical
products, and feeds. The formulation thereof is not specifically
limited. Examples are powders, granules, cubes, pastes, and
liquids. Specific examples are beverages typified by liquid
beverages such as fruit drinks, vegetable drinks, cola, carbonated
beverages, sports drinks, coffee, black tea, cocoa, and dairy
beverages; powdered drinks such as powdered juices; and liquors
such as plum wine, medicinal wine, fruit wine, and sake. Further
specific examples are foods typified by snacks such as chocolate,
cookies, cakes, doughnuts, chewing gum, jelly, pudding, mousse, and
Japanese snacks; baked goods such as French bread and croissants;
dairy products such as coffee-flavored milk and yogurt; frozen
confections such as ice cream and sherbet; powder mixes such as
baking mixes and dessert mixes; table sweeteners such as liquid
table sweeteners and powdered table sweeteners; dried shellfish
products; salted shellfish products; foods boiled down in soy;
processed meat and seafood products such as ham, bacon, and
sausage; seasonings such as dressings, sauces, soy sauce, miso,
sweet sake, ketchup, and steeped barley; spices such as curry
powder; processed grain products such as instant noodles; and
cereals. Still further specific examples are pharmaceutical
products typified by table pharmaceuticals, powdered
pharmaceuticals, syrup pharmaceuticals, and drop pharmaceuticals.
Still further specific examples are topical pharmaceutical products
such as breath fresheners, mouthwashes, toothpastes, and drinks.
And still further specific examples are feeds such as pet foods,
liquid feeds, and powdered feeds. In particular, from the
perspective of maintaining the quality and stability of the
sweetness of monatin, those foods, beverages, pharmaceutical
products, topical pharmaceutical products, and feeds in which
monatin is maintained in crystalline form are desirable; powdered
beverages, snacks, powdered mixes, powdered table sweeteners, table
pharmaceuticals, powdered pharmaceuticals, and powdered feeds are
preferred; and powdered beverages, powdered table sweeteners, and
powdered mixes are of greater preference.
[0069] The monatin crystals and sweetener composition of the
present invention are extremely useful as preventive agents and
treatments for metabolic syndromes; preventive agents and
treatments for obesity; preventive agents and treatments for
diabetes; and cavity-preventing agents. They also have synergistic
sweetening effects, synergistic flavoring effects,
bitterness-masking effects, and photodecomposition stabilizing
effects.
[0070] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments which
are given for illustration of the invention and are not intended to
be limiting thereof.
EXAMPLES
Measuring Methods.
[0071] The various measuring methods will be described first.
Powder X-Ray Diffraction Measuring Method.
[0072] 1) A 0.5 g quantity of sample was collected and ground for
60 seconds in an agate mortar. The powder obtained was placed on a
glass plate, and pressure was applied from above to level the
powder. The powder was then immediately placed in a powder X-ray
diffractometer and measurements were made under the conditions
given below.
[0073] 2) A PW3050 X-ray diffractometer made by Spectris Co., Ltd.
was employed in powder X-ray diffraction measurement with
CuK.alpha. radiation. Measurements were made under the following
conditions: tube: Cu; tube current: 30 mA; tube voltage: 40 kV;
sampling width: 0.020.degree.; scan rate: 3.degree./minute;
wavelength: 1.54056 .ANG.; and measurement diffraction angle range
(2.theta.): 4 to 30.degree.. [0074] Measurement program: X'PERT
DATA COLLECTION [0075] Analysis program: X'PERT High Score
[0076] 3) The data obtained were plotted in Excel and
characteristic acute maximum peaks were read over the range of 4 to
18.degree.. The diffraction angle error for this method was
.+-.0.2.degree..
Method of Measuring Monatin Content.
[0077] The molar ratio of (2R,4R) monatin and sodium was determined
as a concentration ratio by HPLC measurement of the monatin content
in a (2R,4R) monatin sodium salt crystal solution of prescribed
concentration under the following conditions: Equipment
employed.
TABLE-US-00001 Pump: LC-9A made by Shimadzu Corporation Column
oven: CTO-10A made by Shimadzu Corporation Detector: SPD-10A made
by Shimadzu Corporation Autosampler: SIL-9A made by Shimadzu
Corporation Gradientor: LPG-1000 made by Tokyo Rikakikai Co.
Column: CAPCELL PAK C18 TYPE MGII 5 .mu.m 4.6 mm .times. 250 mm
made by Shiseido Column temperature: 40.degree. C. Detection
wavelength: 210 nm Mobile phase composition: Liquid A 20
mMKH2PO4/acetonitrile = 100/5 Liquid B Only acetonitrile Time (min)
Liquid A (%) Liquid B (%) Gradient pattern: 0 100 0 15 100 0 40 63
37 45 63 37 Retention time: (2S,4R) Monatin: 11.8 minutes (2R,4R)
Monatin: 15.1 minutes Quantity introduced: 10 .mu.L Analysis cycle:
70 min/sample Standard substance for monatin content measurement:
(2R,4R) Monatin potassium 348.4 salt monohydrate Molecular weight:
Monatin content in (2R,4R) monatin sodium salt crystal solution =
(292.3/348.4) * (Wstd * Qs)/(Ws * Qstd) * 100 (%) Wstd: Standard
substance concentration (mg/mL) Qstd: Area value of standard
substance Ws: (2R,4R) Monatin sodium salt concentration (mg/mL) Qs:
Area value of (2R,4R) monatin sodium salt (2R,4R) Monatin free
292.3 compound Molecular weight:
Sodium Ion Measurement Method.
[0078] The molar ratio of (2R,4R) monatin and sodium was determined
as a concentration ratio by measuring the sodium ion concentration
in a (2R,4R) monatin sodium salt crystal solution of prescribed
concentration by ion chromatography under the following conditions:
[0079] Device: Ion chromatograph IC-2001 made by Toso Co., Ltd.
[0080] Cation measurement column: TSKgeI SuperIC-Cation, inner
diameter 4.6 mm, length 150 mm, made by Toso Co., Ltd. [0081] Guard
column: TSKguardcolumn SuperIC-C, inner diameter 4.6 mm, length 10
mm, made by Toso Co., Ltd. [0082] Eluant: 2.5 mmol/LHNO3+0.5
mmol/L-histidine [0083] Column temperature: 40.degree. C. [0084]
Flow rate: 1 mL/minute [0085] Standard solution: Cation standard
solution made by Kanto Chemical Co., Inc. [0086] .sup.1H-NMR
spectral measurement method. [0087] Device: AVANCE400 made by
Bruker .sup.1H, 400 MHz [0088] Solvent: Heavy water [0089]
Temperature Room temperature [0090] Concentration: About 7 weight
percent
MS Spectral Measurement Method.
[0090] [0091] Device: TSQ700 made by Thermo Quest [0092]
Measurement mode: ESI mode
Moisture Measurement Method.
[0093] The concentration of water in a (2R,4R) monatin sodium salt
crystal solution of prescribed concentration was measured by the
Karl Fisher method under the following conditions, and the ratio of
(2R,4R) monatin and water was calculated from the titration value
obtained: [0094] Device: Automatic moisture detector AQV-2000 made
by Hiranuma Sangyo Co., Ltd. [0095] Titrant: Hydranal-composite 5
(made by Riedel-deHaen) [0096] Solvent: Methanol [0097]
Temperature: Room temperature
Manufacturing Example 1
Preparation of (2R,4R) Monatin Monopotassium Salt Monohydrate
[0098] In accordance with Example 17 of WO 2003-045914, 10 g of
(2R,4R) monatin monoammonium salt crystals were dissolved in water
and the solution was processed with cation-exchange resin DIAION
PK228 (potassium type, made by Mitsubishi Chemical Corp.). The
exiting solution was concentrated, ethanol was added dropwise at
35.degree. C., the crystals were separated, and the mixture was
dried under reduced pressure, yielding (2R,4R) monatin
monopotassium salt monohydrate crystals (9.3 g).
[0099] Melting point: 220.0 to 222.3.degree. C.
Example 1
Preparation of (2R,4R) Monatin Monosodium Salt Hydrate Crystals
(A)
[0100] A 4 g (11.5 mmol) quantity of the (2R,4R) monatin
monopotassium salt monohydrate crystals of Manufacturing Example 1
was dissolved in 40 mL of water, the solution was passed through a
column packed with 20 mL of cation-exchange resin DIAION UBK550
(sodium type, made by Mitsubishi Chemical Corp.) for replacement
with sodium, and the exiting solution was condensed to 6.4 g. The
condensed solution obtained was left standing for 6 hours at
5.degree. C. The crystals were separated from the crystallization
solution and washed with 2 mL of cold water. The wet crystals were
then dried overnight in a reduced pressure drier at 40.degree. C.,
yielding 2.28 g (6.4 mmols) of (2R,4R) monatin monosodium salt
hydrate crystals (A).
[0101] .sup.1HNMR (D2O) .delta.: 1.94-2.01 (q 1H), 2.57-2.61 (q
1H), 2.99-3.03 (d 1H), 3.19-3.23 (d 1H), 3.54-3.57 (q 1H),
7.05-7.17 (m 3H), 7.40-7.42 (m 1H), 7.64-7.66 (m 1H).
[0102] ESI-MS: 293.1 (M+H).sup.+, 291.1 (M-H).sup.-
[0103] Moisture content: 12.4 wt % (corresponds to 2.5 hydrate)
[0104] Sodium content: 6.3 wt %
[0105] Characteristic X-ray diffraction peaks
(2.theta..+-.0.2.degree., CuK.alpha.): 7.7.degree., 10.9.degree.,
16.7.degree., and 17.0.degree. (see, FIG. 1)
[0106] Diastereomer excess rate: 96.4% de
[0107] ((2R,4R): (2S,4R)=98.2:1.8)
Example 2
Hydrate Crystallization and Redrying Test
[0108] The (2R,4R) monatin monosodium salt hydrate crystals (A)
(corresponding to 2.5 hydrate) obtained in Example 1 were dried for
another 24 hours under reduced pressure at 40.degree. C. and cooled
overnight to room temperature in a desiccator in the presence of
silica gel to obtain the following (2R,4R) monatin monosodium salt
hydrate crystals (A):
[0109] Moisture content (immediately after drying): 6.9 wt %
(corresponding to 1.3 hydrate)
[0110] Moisture content (immediately following powder X-ray
measurement of crystals stored in desiccator): 8.0 wt %
(corresponding to 1.5 hydrate)
[0111] Characteristic X-ray diffraction peaks
(2.theta..+-.0.2.degree., CuK.alpha.): 7.8.degree., 10.9.degree.,
16.7.degree., and 17.1.degree. (see, FIG. 4)
[0112] This test revealed that a change in the hydrate from 2.5 to
1.5 had almost no effect on the characteristic X-ray diffraction
peaks.
Example 3
Water Vapor Adsorption/Desorption Test of (2R,4R) Monatin
Monosodium Salt Hydrate Crystals (A)
[0113] A water vapor adsorption/desorption curve was plotted for
the (2R,4R) monatin monosodium salt hydrate crystals (A) obtained
in Example 1. The measurement conditions were as follows. The
measured values are given in FIG. 5. [0114] Device: Automatic vapor
adsorption measuring device BELSORP18 made by Bel Japan Inc. [0115]
Measurement method: Volumetric gas adsorption method
Measurement Conditions:
[0115] [0116] Adsorbed gas: H.sub.2O [0117] Air thermostat
temperature (K): 353 [0118] Adsorption temperature (K): 298 [0119]
Saturation vapor pressure (kPa): 3.169 [0120] Adsorption
cross-sectional area (nm.sup.2): 0.125 [0121] Maximum adsorption
pressure (relative pressure P/PO): desorption: 0.90; adsorption:
0.95 [0122] Minimum adsorption pressure (relative pressure P/PO):
desorption: 0.10; adsorption: 0.05 [0123] Equilibration period: 500
s
[0124] FIG. 5 shows that the most stable hydrate of (2R,4R) monatin
monosodium salt (A) is trihydrate. It also reveals that water of
crystallization is gradually released under relatively mild
conditions.
Example 4
Preparation of (2R,4R) Monatin Monosodium Salt Monohydrate Crystals
(B).
[0125] A 40 g (115 mmol) quantity of the (2R,4R) monatin
monopotassium salt monohydrate crystals of Manufacturing Example 1
was dissolved in water, the solution was passed through a column
packed with 150 mL of cation-exchange resin DIAION UBK550 (sodium
type, made by Mitsubishi Chemical Corp.) for replacement with
sodium, and the exiting solution was condensed to 99.2 g. While
stirring the condensed solution obtained at 50.degree. C., 400 mL
of ethanol was added dropwise, and the mixture was calmly stirred
overnight at 50.degree. C. The crystals were separated from the
crystallization solution and dried overnight in a reduced pressure
drier at 40.degree. C., yielding 35.0 g (104 mmols) of (2R,4R)
monatin monosodium salt monohydrate crystals (B).
[0126] .sup.1HNMR (D2O) .delta.: 1.94-2.01 (q 1H), 2.57-2.61 (q
1H), 2.99-3.03 (d 1H), 3.19-3.23 (d 1H), 3.54-3.57 (q 1H),
7.05-7.17 (m 3H), 7.40-7.42 (m 1H), 7.64-7.66 (m 1H).
[0127] ESI-MS: 293.1 (M+H).sup.+, 291.1 (M-H).sup.-
[0128] Moisture content: 6.6 wt % (corresponds to monohydrate)
[0129] Sodium content: 6.8 wt % (corresponds to monosodium)
[0130] Characteristic X-ray diffraction peaks
(2.theta..+-.0.2.degree., CuK.alpha.): 4.7.degree., 12.4.degree.,
18.8.degree., and 22.6.degree. (see, FIG. 6)
[0131] Sweetness intensity: 2,700-fold (average of values provided
by seven panelists relative to 5 percent sucrose aqueous
solution)
Example 5
Evaluation of Thermal Stability.
[0132] The thermal stability of the monatin crystals (B) obtained
in Example 4 and the monatin crystals obtained in Comparative
Example 1 (Example 14 of WO 2003-045914) was evaluated by the
following method.
Evaluation Method.
[0133] A 50 mg quantity of the crystals of Example 4 and an
identical quantity of the crystals of Comparative Example 1 were
placed in separate 4 mL vials and stored at a temperature of
120.degree. C. During this storage, the vials were left open.
Following storage periods of 3 hours, 7 hours, and 24 hours, 2 mg
of sample was removed and the rate of decomposition of the samples
was determined by HPLC. Specifically, decomposition product X was a
lactone compound (RT=21 minutes) and decomposition product Y was a
lactam compound (RT=26 minutes). The individual area ratios
(percentages) were calculated relative to the area of monatin. The
results are given in Tables 1 and 2. (For example, for Example 4 at
hour 3, the decomposition rates of decomposition products X and Y
were calculated as 0.11% and 0.11%, respectively, based on
decomposition product X (7432) and decomposition Y (7201).)
TABLE-US-00002 TABLE 1 Rate of decomposition over time into the
decomposition product X (lactone) Storage time (hr) 0 3 7 24
Example 4 0% 0.11% 0.23% 0.24% (a) Comp. Ex. 1 0% 3.38% 4.64% 6.67%
(b) Comparison of -- 30-fold 21-fold 27-fold decomposition rates
((b)/(a))
TABLE-US-00003 TABLE 2 Rate of decomposition over time into the
decomposition product Y (lactam) Storage time (hr) 0 3 7 24 Example
4 0% 0.11% 0.21% 0.38% (a) Comp. Ex. 1 0% 2.08% 3.63% 7.46% (b)
Comparison of -- 19-fold 17-fold 20-fold decomposition rates
((b)/(a))
[0134] This test revealed that the rate of decomposition (at 24
hours) of the monatin crystals of Comparative Example 1 into
decomposition product X (lactone compound) was 27-fold, and the
rate of decomposition (at 24 hours) into decomposition product Y
(lactam compound) was 20-fold, those of the monatin crystals of
Example 4. The test also revealed that the thermal stability of the
(2R,4R) monatin monosodium salt monohydrate crystals (B) of the
present invention was drastically better. FIGS. 8 and 9 are plots
of the rates of decomposition over time into decomposition product
X (lactone compound) and Y (lactam compound) for Example 4 and
Comparative Example 1; the differences are immediately
apparent.
Formulation Example 1
Table Sweetener
TABLE-US-00004 [0135] TABLE Weight percent. Hydrate crystals (A)
described in Example 1 0.12 Erythritol 20 Reduced maltose remainder
Total 100
[0136] A table sweetener was prepared by mixing the above powders.
When tested by addition to coffee, it exhibited a good quality of
sweetness similar to that of sugar. It was also tested by being
sprinkled on hot cakes, producing a pleasant taste sensation
without creating a gritty sensation on the tip of the tongue,
dissolving well in the mouth, having a good initial sweetness, and
exhibiting sweetness of the same good quality as granulated
sugar.
INDUSTRIAL APPLICABILITY.
[0137] (2R,4R) Monatin monosodium salt hydrate crystals ((A) and
(B)) make it possible to provide stable sodium salt crystals of
monatin. The utility and various physical properties of these
stereoisomers as sweeteners have been clarified. They also make it
possible to provide orally consumed products, such as foods,
beverages, pharmaceutical products, topical pharmaceutical
products, and feeds that contain general-purpose, stable, and safe
monatin sodium salt crystals, which is of great significance.
[0138] Where a numerical limit or range is stated herein, the
endpoints are included. Also, all values and subranges within a
numerical limit or range are specifically included as if explicitly
written out.
[0139] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that, within the scope of the
appended claims, the invention may be practiced otherwise than as
specifically described herein.
[0140] All patents and other references mentioned above are
incorporated in full herein by this reference, the same as if set
forth at length.
* * * * *