CA1223580A - Process for preparing lactulose from lactose, in the form of a syrup or a crystalline product - Google Patents
Process for preparing lactulose from lactose, in the form of a syrup or a crystalline productInfo
- Publication number
- CA1223580A CA1223580A CA000456736A CA456736A CA1223580A CA 1223580 A CA1223580 A CA 1223580A CA 000456736 A CA000456736 A CA 000456736A CA 456736 A CA456736 A CA 456736A CA 1223580 A CA1223580 A CA 1223580A
- Authority
- CA
- Canada
- Prior art keywords
- lactulose
- lactose
- syrup
- ethanol
- solution containing
- Prior art date
- 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.)
- Expired
Links
Abstract
ABSTRACT
A process for preparing lactulose from lactose, in the form of a concentrated syrup or high purity crystals, for pharmaceutical use or for use as a sweetener.
The process is characterised by using as the lactose epimerising agent a mixture of equal parts of MgO and sodium hydrosulphite, each component being used to the extent of between 0.05 and 0.2%
by weight with respect to the lactulose, at a temperature of about 100°C. The epimerisation is complete in a few minutes.
The crystalline lactulose is obtained by crystallisation from ethanol.
A process for preparing lactulose from lactose, in the form of a concentrated syrup or high purity crystals, for pharmaceutical use or for use as a sweetener.
The process is characterised by using as the lactose epimerising agent a mixture of equal parts of MgO and sodium hydrosulphite, each component being used to the extent of between 0.05 and 0.2%
by weight with respect to the lactulose, at a temperature of about 100°C. The epimerisation is complete in a few minutes.
The crystalline lactulose is obtained by crystallisation from ethanol.
Description
~223~
PROCESS FOR PREPARING LACTULOSE FROM LACTOSE, TN THE FORM OF A
SYRUP OR A CRYSTALLINE PRODUCT
This invention relates to a new process for preparing lactulose from lactose, in the form of a syrup or a pure crystalline product.
Lactulose or 4-0-~-D-galactopyranosyl-D-fructose is known to be a synthetic disaccharide which is currently used in the form of syrup in the treatment of intestinal affections, or in the form of a crystalline product as a sweeter replacing succors.
Many processes are also known for preparing iactulose by the epimerisation of lookout which is a widely available natural disaccharide of formula 4-0-~-D-galactopyranosyl-D-glucose.
lo Some of these processes are based essentially on the epimerisation of lactose by strong alkalis such as Kiwi, Noah, OH and strong organic bases.
These processes have the drawback of leading to the formation of large percentages of by-products which are difficult to separate and are colored, and which not only strongly decrease the lactulose yield but also make it difficult both to use the lactulose syrup as such, and to prepare it as a crystalline product. - -A further group of processes uses sodium tetraborate or sodium I
P
acuminate as the epimerising agent.
Although these processes lead to a higher lactulose yield and a more pure product, they are industrially unsatisfactory both because of the difficulty of filtering off the aluninium hydrate and because of the difficulty of quantitatively removing the boric acid.
Finally, processes which use strongly alkaline ion exchange resins for the epimerisation are too costly, and do not allow lactulose to be produced at market prices.
A lactulose production process has also been proposed in which lactulose is treated with a basic My derivative in an inert gaseous 15 atmosphere (Spanish patent 397,810).
This process bus never been used in practice because it utilizes initial lactose solutions which are relatively dilute and is extremely slow, requiring between 10 and 20 hours for the completion of epimerisation. Both these factors make the process insignificant from an industrial viewpoint.
ye have now discovered the subject matter of the present invention, namely that it is possible to obtain lactulose on an industrial scale with high yields and high purity by epimerising lactose with a mixture of equal parts of a basic magnesium salt and sodium hydrosulphite at a temperature of 90 -100 C.
The basic My salt can be the oxide, hydroxide or carbonate, and preferably My The reaction is conducted in the homogeneous phase using an aqueous lactose solution at a concentration of between 60 and I and ` adding to the solution sodium hydrosulphite and magnesium oxide to 35 the extent of between 0.05 and 0.2% by weight for each of said .
- /
~2235~0 components with respect to the lactose, The solution obtained is heated to 100 C and then cooled. The reaction is generally complete in ten minutes The lactose which separates out on cooling the aqueous solution is separated by filtration, and the solution is then passed through a column of strong cat ionic resin and a column of weak anionic resin in order to remove the My and No ions and the relative anions.
The purified solution is concentrated under vacuum at 60 C until a density of 1~4 at the concentration temperature is obtained, Further lactose crystallizes on cooling the aqueous concentrate, and is separated by filtration or centrifuging.
The syrup composition at this stage is on average the following:
lactulose 5~/0 by weight galactose 4-5%
lactose 4-5% "
other sugars Lowe I
The yield at this stage is 35-4~/. of lactulose with respect to the initial lactose, The syrup is absolutely free from coloration and can be used as such for all normal pharmaceutical uses, If lactulose is required in the crystalline state, the syrup can be further processed as follows.
The syrup is further concentrated to obtain a spongy mass with owe of residual moisture, after which ethanol is added in the proportion of about 1:15 with respect to the solid residue, and the mixture heated under reflex until the mass has dissolved. The I
ethanol used must not contain more than 5% of H20.
On cooling to a temperature of around 15-20 C7 the syrup stratifies into a solid mass which decants and into an overlying alcoholic solution The solid mass, which contains essentially all the lactose and the other sugars together with part of the lactulose, is separated and recycled.
on concentrating the clear solution at ordinary pressure, possibly after seeding, crystalline lactulose is separated with the following average composition:
lactulose 98-99%
other sugars Lowe/, Crystalline lactulose at such a high purity has not been obtained with any of the industrial processes carried out up to the present time.
The crystalline lactulose yield is 35-40~/~ with respect to that contained in the starting syrup, which had approximately I of lactulose.
Thus on an overall basis, taking account of the recycled quantities, the effective loss of lactulose does not exceed 3-5~.
The ethanol is also recovered by distillation, with a loss not exceeding Lowe. It is recycled after making-up the missing quantity, A practical example is described hereinafter in order to clarify the operational details of the process according to the present invention, but it must in no way be considered as limitative of 35 the inventive concept of the present invention.
~2;~5~
The scope of the invention covers all those embodiments and equivalent means which are apparent to an expert of the art.
EXAMPLE
0.750 kg of lactose, 0.750 g of sodium hydrosulphite and 0.400 kg of deionized water are fed into a two lithe flask fitted with an agitator. The lactose is dissolved by heating to 95 C, and 0.750 g of magnesium oxide are added.
The reaction mixture is heated to 100C and kept at this temperature for 10 minutes.
It is cooled, and the unrequited lactose is filtered off and reused for a second preparation.
The clear solution is passed firstly through a column of strong cat ionic resin and then through a column of weak anionic resin.
The solution is concentrated under vacuum to a density of about 1.4 at okay, is cooled firstly with running utter and then with brine to 5 C, and the additional lactose which precipitates is lit-toned off.
In this manner 0.530 kg of a clear solution of pi between 4 and 6 is obtained, having the following weight composition:
Lactulose 5070 Galactose 4.3%
Lactose 4.5 Other sugars 2 Yield approximately 35% with respect to the initial lactose.
.
This syrup can be used as such, The solution was analyzed by HPLC under the following experimental conditions:
351~
Column: p mm. 1 = 250 mm Filling: Lichrosorb NH2 (10 microns) Column temperature: 40 0.5 C
detector: W spectrophotometer - reading at 192 no Mobile phase: owe aqueous solution of 0.01 M monobasic potassium phosphate and owe of acetonitrile Flow: 2.5 ml/minute Quantity injected: 20 ye of a solution having an approximate concentration of owe total sugars I
0.5 kg of I lactulose syrup obtained in the previous stage is fed into a 5 lithe flask, and dried under a vacuum of 1-5 Torn until a white spongy mass is obtained with a residual moisture content of less than 77v.
I liters of 9~/c ethanol are added, and the mixture heated under reflex until a clear solution is obtained.
It is cooled to 15-20C until a viscous mass forms and deposits on 20 the container base, after which the overlying alcoholic solution is decanted and the clear solution concentrated at ordinary pressure after adding lactulose seed crystals.
When 2.5 liters of alcohol have distilled off, heating is stopped and agitation is continued, allowing the temperature to fall to The crystallized lactulose is filtered off, washed with ethanol and dried under vacuum at okay.
Yield 0.100 kg ox crystalline product of the following composition:
lactulose 98.5%
other sugars owe Yield approximately 40~/. with respect to the lactulose contained in the syrup.
~2Z3S8~) _ 7 _ .
This crystalline lactulose can be used as a sweetener.
Both the residue from the first alcohol extraction and the sugars contained in the etbanolic mother liquor from the final lactulose crystallization were taken up in water and reused for further processing.
The total lactulose loss was about 3%.
The ethyl alcohol was also recovered both during the solution concentration and during the drying of the lactulose crystals.
The alcohol loss was 7%, and was made-up by adding alcohol.
PROCESS FOR PREPARING LACTULOSE FROM LACTOSE, TN THE FORM OF A
SYRUP OR A CRYSTALLINE PRODUCT
This invention relates to a new process for preparing lactulose from lactose, in the form of a syrup or a pure crystalline product.
Lactulose or 4-0-~-D-galactopyranosyl-D-fructose is known to be a synthetic disaccharide which is currently used in the form of syrup in the treatment of intestinal affections, or in the form of a crystalline product as a sweeter replacing succors.
Many processes are also known for preparing iactulose by the epimerisation of lookout which is a widely available natural disaccharide of formula 4-0-~-D-galactopyranosyl-D-glucose.
lo Some of these processes are based essentially on the epimerisation of lactose by strong alkalis such as Kiwi, Noah, OH and strong organic bases.
These processes have the drawback of leading to the formation of large percentages of by-products which are difficult to separate and are colored, and which not only strongly decrease the lactulose yield but also make it difficult both to use the lactulose syrup as such, and to prepare it as a crystalline product. - -A further group of processes uses sodium tetraborate or sodium I
P
acuminate as the epimerising agent.
Although these processes lead to a higher lactulose yield and a more pure product, they are industrially unsatisfactory both because of the difficulty of filtering off the aluninium hydrate and because of the difficulty of quantitatively removing the boric acid.
Finally, processes which use strongly alkaline ion exchange resins for the epimerisation are too costly, and do not allow lactulose to be produced at market prices.
A lactulose production process has also been proposed in which lactulose is treated with a basic My derivative in an inert gaseous 15 atmosphere (Spanish patent 397,810).
This process bus never been used in practice because it utilizes initial lactose solutions which are relatively dilute and is extremely slow, requiring between 10 and 20 hours for the completion of epimerisation. Both these factors make the process insignificant from an industrial viewpoint.
ye have now discovered the subject matter of the present invention, namely that it is possible to obtain lactulose on an industrial scale with high yields and high purity by epimerising lactose with a mixture of equal parts of a basic magnesium salt and sodium hydrosulphite at a temperature of 90 -100 C.
The basic My salt can be the oxide, hydroxide or carbonate, and preferably My The reaction is conducted in the homogeneous phase using an aqueous lactose solution at a concentration of between 60 and I and ` adding to the solution sodium hydrosulphite and magnesium oxide to 35 the extent of between 0.05 and 0.2% by weight for each of said .
- /
~2235~0 components with respect to the lactose, The solution obtained is heated to 100 C and then cooled. The reaction is generally complete in ten minutes The lactose which separates out on cooling the aqueous solution is separated by filtration, and the solution is then passed through a column of strong cat ionic resin and a column of weak anionic resin in order to remove the My and No ions and the relative anions.
The purified solution is concentrated under vacuum at 60 C until a density of 1~4 at the concentration temperature is obtained, Further lactose crystallizes on cooling the aqueous concentrate, and is separated by filtration or centrifuging.
The syrup composition at this stage is on average the following:
lactulose 5~/0 by weight galactose 4-5%
lactose 4-5% "
other sugars Lowe I
The yield at this stage is 35-4~/. of lactulose with respect to the initial lactose, The syrup is absolutely free from coloration and can be used as such for all normal pharmaceutical uses, If lactulose is required in the crystalline state, the syrup can be further processed as follows.
The syrup is further concentrated to obtain a spongy mass with owe of residual moisture, after which ethanol is added in the proportion of about 1:15 with respect to the solid residue, and the mixture heated under reflex until the mass has dissolved. The I
ethanol used must not contain more than 5% of H20.
On cooling to a temperature of around 15-20 C7 the syrup stratifies into a solid mass which decants and into an overlying alcoholic solution The solid mass, which contains essentially all the lactose and the other sugars together with part of the lactulose, is separated and recycled.
on concentrating the clear solution at ordinary pressure, possibly after seeding, crystalline lactulose is separated with the following average composition:
lactulose 98-99%
other sugars Lowe/, Crystalline lactulose at such a high purity has not been obtained with any of the industrial processes carried out up to the present time.
The crystalline lactulose yield is 35-40~/~ with respect to that contained in the starting syrup, which had approximately I of lactulose.
Thus on an overall basis, taking account of the recycled quantities, the effective loss of lactulose does not exceed 3-5~.
The ethanol is also recovered by distillation, with a loss not exceeding Lowe. It is recycled after making-up the missing quantity, A practical example is described hereinafter in order to clarify the operational details of the process according to the present invention, but it must in no way be considered as limitative of 35 the inventive concept of the present invention.
~2;~5~
The scope of the invention covers all those embodiments and equivalent means which are apparent to an expert of the art.
EXAMPLE
0.750 kg of lactose, 0.750 g of sodium hydrosulphite and 0.400 kg of deionized water are fed into a two lithe flask fitted with an agitator. The lactose is dissolved by heating to 95 C, and 0.750 g of magnesium oxide are added.
The reaction mixture is heated to 100C and kept at this temperature for 10 minutes.
It is cooled, and the unrequited lactose is filtered off and reused for a second preparation.
The clear solution is passed firstly through a column of strong cat ionic resin and then through a column of weak anionic resin.
The solution is concentrated under vacuum to a density of about 1.4 at okay, is cooled firstly with running utter and then with brine to 5 C, and the additional lactose which precipitates is lit-toned off.
In this manner 0.530 kg of a clear solution of pi between 4 and 6 is obtained, having the following weight composition:
Lactulose 5070 Galactose 4.3%
Lactose 4.5 Other sugars 2 Yield approximately 35% with respect to the initial lactose.
.
This syrup can be used as such, The solution was analyzed by HPLC under the following experimental conditions:
351~
Column: p mm. 1 = 250 mm Filling: Lichrosorb NH2 (10 microns) Column temperature: 40 0.5 C
detector: W spectrophotometer - reading at 192 no Mobile phase: owe aqueous solution of 0.01 M monobasic potassium phosphate and owe of acetonitrile Flow: 2.5 ml/minute Quantity injected: 20 ye of a solution having an approximate concentration of owe total sugars I
0.5 kg of I lactulose syrup obtained in the previous stage is fed into a 5 lithe flask, and dried under a vacuum of 1-5 Torn until a white spongy mass is obtained with a residual moisture content of less than 77v.
I liters of 9~/c ethanol are added, and the mixture heated under reflex until a clear solution is obtained.
It is cooled to 15-20C until a viscous mass forms and deposits on 20 the container base, after which the overlying alcoholic solution is decanted and the clear solution concentrated at ordinary pressure after adding lactulose seed crystals.
When 2.5 liters of alcohol have distilled off, heating is stopped and agitation is continued, allowing the temperature to fall to The crystallized lactulose is filtered off, washed with ethanol and dried under vacuum at okay.
Yield 0.100 kg ox crystalline product of the following composition:
lactulose 98.5%
other sugars owe Yield approximately 40~/. with respect to the lactulose contained in the syrup.
~2Z3S8~) _ 7 _ .
This crystalline lactulose can be used as a sweetener.
Both the residue from the first alcohol extraction and the sugars contained in the etbanolic mother liquor from the final lactulose crystallization were taken up in water and reused for further processing.
The total lactulose loss was about 3%.
The ethyl alcohol was also recovered both during the solution concentration and during the drying of the lactulose crystals.
The alcohol loss was 7%, and was made-up by adding alcohol.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing lactulose from lactose, characterized in that an aqueous solution containing 60-70% of lactose is treated with 0.05-0.2% both of a basic Mg compound and of sodium hydrosulphite, at a temperature of 90-100°C.
2. A process as claimed in claim 1, wherein the Mg compound is MgO.
3. A process as claimed in claim 1, wherein the reac-tion solution containing the lactulose is purified by successive passages through a cationic exchange resin and an anionic exchange resin, and is then concentrated to a density of 1.4.
4. A process as claimed in claim 1, wherein the solu-tion is evaporated until a spongy mass containing 5-10% of mois-ture is obtained, the lactulose being extracted from this mass by hot ethanol, from which it is crystallized.
5. A process as claimed in claim 4, wherein the ethanol contains a maximum of 5% of water.
6. A process as claimed in claim 4, wherein the ethanol is added in the proportion of 1:15 with respect to the solid residue, and the mixture is heated under reflux until com-plete solubilization is obtained.
7. A process as claimed in claim 4, wherein the ethanolic solution containing the lactulose is cooled to about 15-20°C.
8. A process as claimed in claim 7, wherein the crys-talline lactulose is obtained by concentration in the presence of lactulose seed crystals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000456736A CA1223580A (en) | 1984-06-15 | 1984-06-15 | Process for preparing lactulose from lactose, in the form of a syrup or a crystalline product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000456736A CA1223580A (en) | 1984-06-15 | 1984-06-15 | Process for preparing lactulose from lactose, in the form of a syrup or a crystalline product |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1223580A true CA1223580A (en) | 1987-06-30 |
Family
ID=4128111
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000456736A Expired CA1223580A (en) | 1984-06-15 | 1984-06-15 | Process for preparing lactulose from lactose, in the form of a syrup or a crystalline product |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1223580A (en) |
-
1984
- 1984-06-15 CA CA000456736A patent/CA1223580A/en not_active Expired
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|---|---|---|---|
| MKEX | Expiry |