AU603122B2 – Process for producing stable alpha-L-aspartyl-L- phenylalanine methyl ester
– Google Patents
AU603122B2 – Process for producing stable alpha-L-aspartyl-L- phenylalanine methyl ester
– Google Patents
Process for producing stable alpha-L-aspartyl-L- phenylalanine methyl ester
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Publication number
AU603122B2
AU603122B2
AU76820/87A
AU7682087A
AU603122B2
AU 603122 B2
AU603122 B2
AU 603122B2
AU 76820/87 A
AU76820/87 A
AU 76820/87A
AU 7682087 A
AU7682087 A
AU 7682087A
AU 603122 B2
AU603122 B2
AU 603122B2
Authority
AU
Australia
Prior art keywords
crystals
aspartyl
phenylalanine methyl
methyl ester
aspartame
Prior art date
1986-08-13
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU76820/87A
Other versions
AU7682087A
(en
Inventor
Tsuneo Harada
Shigeaki Irino
Kiyotaka Oyama
Akira Tokuda
Hidetoshi Wakamatsu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tosoh Corp
Original Assignee
Tosoh Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1986-08-13
Filing date
1987-08-12
Publication date
1990-11-08
1987-08-12
Application filed by Tosoh Corp
filed
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Tosoh Corp
1988-02-18
Publication of AU7682087A
publication
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patent/AU7682087A/en
1990-11-08
Application granted
granted
Critical
1990-11-08
Publication of AU603122B2
publication
Critical
patent/AU603122B2/en
2007-08-12
Anticipated expiration
legal-status
Critical
Status
Ceased
legal-status
Critical
Current
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Classifications
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07K—PEPTIDES
C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
C07K5/06—Dipeptides
C07K5/06104—Dipeptides with the first amino acid being acidic
C07K5/06113—Asp- or Asn-amino acid
C07K5/06121—Asp- or Asn-amino acid the second amino acid being aromatic or cycloaliphatic
C07K5/0613—Aspartame
Description
I
a i a -~L13~- COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION FOR OFFICE USE Form Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: 6a312 2 Related Art: f k Name of Applican Address of Applic SActual Inventor: Address for Servic TO BE COMPLETED BY APPLICANT CO/Po/PTtO t: *-TOY-SDBA-MAN.UFAGC-T-U-R-ING-G.-,,T-D–* ant: No. 4560, Oaza-tonda, Shin-nanyo-shi, Yamaguchi-ken, JAPAN Hidetoshi Wakamatsu; Shigeaki Irino; Tsuneo Harada; Akira Tokuda and Kiyotaka Oyama GRIFFITH HASSEL FRAZER 71 YORK STREET SYDNEY NSW 2000
AUSTRALIA
Complete Specification for the invention entitled: PROCESS FOR PRODUCING STABLE a-L-ASPARTYL- L-PHENYLALANINE METHYL ESTER The following statement is a full description of this invention, including the best method of performing it known to me/us:- 0962A:rk t Our Ref.: TS-230 PROCESS FOR PRODUCING STABLE a-L-ASPARTYL-L-PHENYLALANINE METHYL ESTER The present invention relates to a process for producing a-L-aspartyl-L-phenylalanine methyl ester s 5 (hereinafter referred to as Aspartame) having excellent storage stability.
Aspartame has two types of crystal forms i.e. I and II types. The I type crystals are hygroscopic, and they are likely to undergo color change or decomposition 10 during storage. Whereas, the II type crystals are less hygroscopic, and it has been taught that they have good flowability and storage stability.
Heretofore, a method has been proposed wherein wet Aspartame crystals are dried at a temperature of at least 15 80°C to obtain the II type crystals of Aspartame (Japanese Unexamined Patent Publications No. 172441/1984 and No. 37949/1985), or a method for preparing granules has been known in which dried II type crystals are hydrated to have a water content of from 35 to 45% by weight, followed by extrusion granulation and drying 2 again (Japanese Unexamined Patent Publication No.
95862/1984).
In the conventional processes, crystals are dried at a high temperature to obtain the II type crystals, and it is likely that a decomposition product of Aspartame i.e.
a diketopiperadine derivative, is likely to form.
Further, in order to obtain granules, a dried product of the II type crystals of Aspartame is required to be hydrated once, followed by granulation and drying again, 10 such being disadvantageous from the viewpoint of the process control and a cost for energy.
It is an object of the present invention to solve such problems and to provide a process for producing Aspartame having excellent storage stability without requiring high temperature drying and redrying as required in the conventional processes.
The present inventors have conducted extensive to research to solve the above-mentioned problems, and have found it possible to obtain stable II type crystals of Aspartame by heating I type crystals of Aspartame in a specific range of the water content without requiring high temperature drying or redrying.
Thus, the present invention provides a process for producing stable a-L-aspartyl-L-phenylalanine methyl ester, which comprises heat-treating crystals of o-L-aspartyl-L-phenylalanine methyl ester having a water content of from 5 to 15% by weight based on wet crystals, ::r 3 at a temperature in the range from 50 0 °C and lower than 80 0 C for at least 30 minutes.
Throughout the specification stable aspartame means that the aspartame comprises at least 70% of type II crystals.
Now, the present invention will be described in detail with reference to the preferred embodiments.
The wet Aspartame crystals prior to drying in accordance with the process of the present invention may be prepared by any precipitation and separation methods.
There is no restriction as to the method for the preparation of the wet Aspartame crystals.
The wet Aspartame crystals thus obtained may or. may not be treated by a granulator. When it is treated by a granulator, any type of granulator such as an extrusion type granulator or a compression type granulator may be employed. When the wet Aspartame crystals are treated by extrusion by means of an extrusion type granulator, granules of a cylindrical shape can be obtained by passing the wet Aspartame crystals through a screen having a mesh size of from 0.1 to 10.0 mm in diameter.
It is preferred to pass the wet crystals through a screen having a mesh size of from 1.0 to 4.0 mm in diameter.
Such wet Aspartame crystals usually contain far more than 15% by weight of water. Therefore, the wet crystals are firstly dried to a water content of from 5 to 15% by weight. There is no particular restriction as to the temperature and the drying method for the drying of wet Aspartame crystals (which may or may not be granulated) to a water content of from 5 to 15% by weight based on 4 wet crystals. For example, the drying machine may be of a usual type, but is preferably an air stream drier or a fluidized-bed drier whereby the retention time is long.
If the temperature is too high, a diketopiperadine derivative as a decomposition product of Aspartame is likely to form. Therefore, the drying is preferably conducted at a temperature of lower than 80 C. The wet Aspartame crystals having a water content of from 5 to by weight is then heat-treated at a temperature of higher than 50°C and lower than 80°C. The heat treatment may be conducted by an air stream drier or a fluidized bed drier. However, it is preferred to conduct the treatment in a sealed container for from 30 minutes to 48 «hours. The heat treatment is continued until the crystal 15 form of Aspartame is changed to the stable crystal form, and the heat treatment time is dependent on the water 9 So content and the temperature. Once the change to the stable Aspartame has been completed, further drying can V0W be conducted at any temperature within a range where Aspartame udergoes no substantial decomposition. Thus, it is possible to obtain dry Aspartame having excellent stability.
Now, the present invention will be described in further detail with reference to Examples. However, it should be understood that the present invention is by no means restricted to such specific Examples.
In the Examples, the ratio of II type crystals (the b 5 ratio of the II type crystals to the total amount of the I and II type crystals) was determined as follows: Standard samples of the I and II type crystals were mixed at various ratios, and calibration curve was prepared based on the ratios in the strength of the specific peaks at the respective X-ray diffraction angles (2 8 of 4.4° (I type) and 5.0° (II type). Then, the ratio of the II type crystals was determined by compairing the strength ratio of each sample with the calibration curve.
Further, in the Examples, the hygroscopicity of Aspartame was determined by storing a sample in an air at a temperature of 25°C under a humidity of 78%, and the storage stability was determined by placing from 2 to 3 g of Aspartame in a sealed container (20 ml), which was then stored in a constant temperature tank of 55 C and measuring the water content and the diketopiperadine content after an expiration of a predetermined period of Stime.
EXAMPLE 1 Wet Aspartame crystals (5 kg) obtained by solid-liquid separation by means of a centrifugal separator, was extruded through a screen having a mesh size of 2.0 mm in diameter, and granulated. The wet granules (60 g) thus obtained were dried in an air stream drier by means of a hot air stream of 60°C to a water content of 10.1% by weight. The granules (5 g) were placed in a sealed container and heat-treated at 60 0 C for p.i 6 about 1 hour, and then dried in an air stream drier by means of a hot air stream of 60 0 C. (Yield: 4.6 g, Example 1) On the other hand, for the purpose of comparison, the above wet granules (60 g) were dried under reduced pressure at 40 0 C for 6 hours. (Yield: 24.6 g, Comparative Example 1) The results of the storage stability and the hygroscopicity are shown in Table 1.
*s ee so s *o *c C i L i I~ ii
S
Table 1 Number Ratio of Hygroscopicity Storage stability of II type Water content M% Content of Example or crystals _______diketopiperadine M% Comparative Immediately After 24 Immediately After 79 Example after, drying hours test after drying days test Example 1 100 2.0 5.4 0.20 0.94 Comparative 0 2.3 8.7 0.23 1.21 Example 1 8 EXAMPLES 2 to 11 Wet Aspartame granules (250 g) prepared in the same manner as in Exmaple 1 were dried at 60 C under reduced pressure to obtain granules having water contents of (1) 19.5% by weight (20 15.4% by weight (17 (3) 10.1% by weight (23 5.5% by weight (18 g) and 2.3% by weight (20 g respectively. They were respectively treated by heating at various temperatures in sealed containers, followed by drying at 60 0 C under S. 10 reduced pressure, to obtain dry Aspartame products having water contents of 2.1% by weight (from 19.5% by weight), 1.5% by weight (from 15.4% by weight), (3) by weight (from 10.1% by weight) and 2.0% by weight (from 5.5% by weight), respectively. The increases in the water contents of the dry Aspartame products during the storage were measured, and the results are shown in Table 2.
*e
I
AL,~
x U C
I
U
UUO *e* U*.Tab l U S U U *eO U US U U U U S S S U U U SUe Number of Heat treatment Water content at the Ratio of II type Hygroscopicity Example or Temper- 0 TimeW initiation of heat crystals c Water content Comparative ature (hr) treatment M% increase M% Example (After 48 hours Comparative Example 2 40 17 5.5 0 9.9 Coparative Example’ 3 510.1 45 xample 2 50 3 to78 5.3 w3 K 10.1 100 Comparative Example ‘4 «19.5 0 Example .4 60 1 10.1 100 3.7 -3 5.5 4.1 u6 «3 10.1 Comparative Example 5- 3 15.4 0 9.8 Example 7 70 1 5.5 100 3.8 1 10.1 3.8 Comparative Example 6 N1 15.4 10 a»7 a 16 2.3 0 Example 9 «5.5 100 3.8 10 U 10.1 3.8 Comparative Example 8 U19.5 0 U9 80 17 2.3 10 9.1 19.5 8 i 10 EXAMPLE 11 Wet Aspartame crystals (80 kg) prepared in the same manner as in Example 1, were dried in a conical drier as a sealed container at 60°C under reduced pressure, to a water content of 9.4% by weight. Then, the heat treatment was conducted at 60 C for 1 hour, followed by drying again under reduced pressure for 3 hours, to obtain 32.5 kg of a dried product of stable Aspartame (composed of 100% of II type crystals) having a water content of 1.8%.
As is apparent from the foregoing description, according to the present invention, it is possible to :0.
obtain dry Aspartame having excellent storage stability without necessity of high temperature drying, or reducing which is disadvantageous from the viewpoint of the process control and costs for energy.
0* The dry Aspartame product having excellent storage stability of the present invention is particularly useful when it is used as a table sweetener in the form of granules or tablets together with sugars or other substances.
Claims (11)
1. p 0* S. a. 0 4r S S S. 11 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A process for producing stable a-L-aspartyl-L- phenylalanine methyl ester, which comprises heat-treating crystals of a-L-aspartyl-L-phenylalanine methyl ester S having a water content of from 5 to 15% by weight based on wet crystals, at a temperature in the range from 500C and lower than 80 0 C for at least 30 minutes.
2. The process according to Claim 1, wherein the heat treatment is conducted within 48 hours. 10
3. The process according to Claim 1, wherein the crystals of a-L-aspartyl-L-phenylalanine methyl ester having a water content of from 5 to 15% by weight, are granulated by a granulator prior to the heat treatment.
4. The process according to Claim 3, wherein the granules have a diameter of from 0.1 to 10.0 mm.
The process according to Claim 1, wherein the crystals of a-L-aspartyl-L-phenylalanine methyl ester having a water content of from 5 to 15% by weight, are not treated by granulator. 20
6. The process according to Claim 1, wherein the heat treatment is conducted in a sealed container.
7. The process according to Claim 1, wherein the heat treatment is conducted in an air stream drier.
8. The process according to Claim 1, wherein the heat treatment is conducted in a fluidized-bed drier. _-rl r _i i– -12-
9. A process for producing stable a-L-aspartyl- L-phenylalanine methyl ester substantially as herein described with reference to any one or more of Examples 1 to 13 (excluding Comparative Examples). r*o *a 1. 08’*
10. Stable o-L-aspartyl-L-phenylalanine methyl,
11 A *a ester when produced by a process defined in any one 4 Or of Claims 1 to 9. Dated this 12th day of August 1987 By their Patent Attorney(3 3)) GRIFFITH H-ASSEL FRAZER
AU76820/87A
1986-08-13
1987-08-12
Process for producing stable alpha-L-aspartyl-L- phenylalanine methyl ester
Ceased
AU603122B2
(en)
Applications Claiming Priority (2)
Application Number
Priority Date
Filing Date
Title
JP61188661A
JPH07103154B2
(en)
1986-08-13
1986-08-13
Method for producing stable α-L-aspartyl-L-phenylalanine methyl ester
JP61-188661
1986-08-13
Publications (2)
Publication Number
Publication Date
AU7682087A
AU7682087A
(en)
1988-02-18
AU603122B2
true
AU603122B2
(en)
1990-11-08
Family
ID=16227634
Family Applications (1)
Application Number
Title
Priority Date
Filing Date
AU76820/87A
Ceased
AU603122B2
(en)
1986-08-13
1987-08-12
Process for producing stable alpha-L-aspartyl-L- phenylalanine methyl ester
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Link
US
(1)
US4835301A
(en)
EP
(1)
EP0256517A3
(en)
JP
(1)
JPH07103154B2
(en)
AU
(1)
AU603122B2
(en)
CA
(1)
CA1318751C
(en)
Families Citing this family (8)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
US5543554A
(en)
*
1982-04-12
1996-08-06
Ajinomoto Co., Inc.
Process for preparing dry crystals of the methyl ester of α-L-aspartyl-L-phenylalanine, having improved solubility
JPH0710878B2
(en)
*
1986-07-28
1995-02-08
東ソー株式会社
Process for producing α-L-aspartyl-L-phenylalanine methyl ester with improved solubility
JPH07103152B2
(en)
*
1986-08-12
1995-11-08
東ソー株式会社
Process for producing α-L-aspartyl-L-phenylalanine methyl ester with improved solubility
US4835303A
(en)
*
1986-08-12
1989-05-30
Toyo Soda Manufacturing Company, Ltd.
Process for producing dry α-L-aspartyl-L-phenylalanine methyl ester
JPH07103154B2
(en)
*
1986-08-13
1995-11-08
東ソー株式会社
Method for producing stable α-L-aspartyl-L-phenylalanine methyl ester
JPH0832719B2
(en)
*
1986-12-19
1996-03-29
三井東圧化学株式会社
Method for producing α-L-aspartyl-L-phenylalanine methyl ester having low hygroscopicity
NL9101477A
(en)
*
1991-09-02
1993-04-01
Dsm Nv
METHOD FOR DRYING AND GRANULATING ASPARTAME.
JPH05178889A
(en)
*
1991-10-30
1993-07-20
Ajinomoto Co Inc
Method for crystallizing alpha-l-aspartyl-l-phenylalanine methyl ester
Citations (3)
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Publication number
Priority date
Publication date
Assignee
Title
AU7614787A
(en)
*
1986-07-28
1988-02-04
Tosoh Corporation
Process for producing alpha-l-aspartyl-l-phenylalanine methyl ester having an improved solubility
AU7682087A
(en)
*
1986-08-13
1988-02-18
Tosoh Corporation
Process for producing stable alpha-L-aspartyl-L- phenylalanine methyl ester
AU7681987A
(en)
*
1986-08-12
1988-02-18
Tosoh Corporation
Process for producing alpha-L-aspartyl-L-phenylalanine methyl ester having an improved solubility
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Publication number
Priority date
Publication date
Assignee
Title
JPS5742623A
(en)
*
1980-08-29
1982-03-10
Sawai Seiyaku Kk
Antialcoholic adipohepatic agent
JPS5995862A
(en)
*
1982-11-25
1984-06-02
Ajinomoto Co Inc
Production of dipeptide sweetening agent granule
JPH0631312B2
(en)
*
1983-03-18
1994-04-27
味の素株式会社
Dipeptide crystal and method for producing the same
JPH0637949A
(en)
*
1992-07-17
1994-02-10
Ricoh Co Ltd
Facsimile equipment
1986
1986-08-13
JP
JP61188661A
patent/JPH07103154B2/en
not_active
Expired – Lifetime
1987
1987-08-11
CA
CA000544244A
patent/CA1318751C/en
not_active
Expired – Fee Related
1987-08-11
US
US07/083,802
patent/US4835301A/en
not_active
Expired – Fee Related
1987-08-12
EP
EP87111701A
patent/EP0256517A3/en
not_active
Withdrawn
1987-08-12
AU
AU76820/87A
patent/AU603122B2/en
not_active
Ceased
Patent Citations (3)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
AU7614787A
(en)
*
1986-07-28
1988-02-04
Tosoh Corporation
Process for producing alpha-l-aspartyl-l-phenylalanine methyl ester having an improved solubility
AU7681987A
(en)
*
1986-08-12
1988-02-18
Tosoh Corporation
Process for producing alpha-L-aspartyl-L-phenylalanine methyl ester having an improved solubility
AU7682087A
(en)
*
1986-08-13
1988-02-18
Tosoh Corporation
Process for producing stable alpha-L-aspartyl-L- phenylalanine methyl ester
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Publication number
Publication date
US4835301A
(en)
1989-05-30
JPH07103154B2
(en)
1995-11-08
CA1318751C
(en)
1993-06-01
AU7682087A
(en)
1988-02-18
EP0256517A2
(en)
1988-02-24
EP0256517A3
(en)
1989-04-26
JPS6345296A
(en)
1988-02-26
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