Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-12-06
2002-06-18
Gitomer, Ralph (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C426S658000, C514S025000, C514S053000
Reexamination Certificate
active
06407227
ABSTRACT:
The present invention relates to a process for the production of structurally pure lactitol crystal forms. Especially, the invention comprises a process for the crystallization of lactitol from an aqueous lactitol solution as any one of the crystalline lactitol forms selected from the group consisting of anhydrous lactitol, lactitol monohydrate, lactitol dihydrate and lactitol trihydrate.
Lactitol is a bulk sweetener which can be used as a total or partial replacement for sucrose, however, its energy content is only about half of that of sucrose, and it does not cause increased blood glucose content; furthermore, it is tooth-friendly (see Developments in Sweeteners, Ed. Grenby, T. H., Vol. 3, 1987, p. 65-81).
The preparation of lactitol from lactose has been known for a long time. Industrially, lactitol is prepared analogously with the preparation of sorbitol from glucose by hydrogenation in the presence of a Raney nickel catalyst. The preparation is described e.g. in Wolfrom, M. L., et al., J. Am. Chem. Soc. 60, (1938) p. 571-573.
Crystalline lactitol is reported to occur in the anhydrous form as well as in the form of a monohydrate and dihydrate. Lactitol also crystallizes as a trihydrate. There seem to exist more then one distinct crystalline form at least of the anhydrous form and the monohydrate. In the crystallization, however, the more stable form generally crystallizes predominantly.
Crystalline lactitol monohydrate as well as the di- and trihydrate and the anhydrous form may be used as sweetening agents resembling sugar. For instance, crystalline lactitol monohydrate may be used in dietetic products, confectionery, bakery products, cereals, desserts, jams, beverages, chocolate, chewing gum and ice-cream. The lactitol crystals may also be used in the production of cosmetic products and in the manufacture of pharmaceuticals, such as tooth paste.
According to the above mentioned Wolfrom et al. article anhydrous lactitol can be crystallized by adding ethanol to a lactitol solution evaporated to a high concentration. After a long crystallization time anhydrous lactitol crystals melting between 144 and 146° C. were obtained.
Anhydrous lactitol may also be crystallized from an aqueous solution as described in WO 92/16542, incorporated herein by reference. The process comprises cooling or evaporating a supersaturated lactitol solution at a temperature above 70° C. to provide anhydrous lactitol having a melting range of 149-152° C.
Lactitol hydrate powders anhydrated to a moisture content of less than 3% have been prepared by drying both lactitol solution and crystalline hydrate. The hygroscopicity of these powders is utilized in drying moist mixtures (European Patent Application 0231643).
The crystallization of lactitol dihydrate was presumably mentioned for the first time by Senderens, J. B., Compt. Rend 170, (1920) p. 47-50. Lactitol solution obtained by hydrogenation was evaporated slowly at room temperature so that crystallization was initiated. The melting point of the resulting product was 78° C., and Senderens mistakenly regarded it as a monohydrate. However, it appears obvious from Wolfrom, M. L , et al., J. Am. Chem. Soc. 74 (1952) p. 1105 that the product obtained by Senderers was a dihydrate having a moisture content of 9.5%, determined by a Karl Fischer method, and a melting point between 76 and 78° C.
An attempt to prepare lactitol monohydrate by crystallization was made in 1979, see van Velthuijsen, J. A., J. Agric. Food Chem. 27, (1979) p. 680. The product, however, was an impure hydrate structure containing 4.5% of other sugars.
Another attempt to crystallize lactitol monohydrate was made in 1981 as disclosed in European Patent 0 039 981. The inventors believed that they had obtained pule lactitol monohydrate having a melting point of 121-123° C. However, the crystallization was performed at a constant temperature of 45° C. or 20° C. which, in fact, resulted in the precipitation of a mixture of lactitol-water structures. This product was then dried to provide crystals melting between 110° C. and 125° C. The temperature range indicates that the products were partially anhydrated lactitol hydrate forms. The present applicant has found that it is not possible to produce structurally pure lactitol monohydrate by the processes disclosed in said EP Patent.
EP 0 039 981 also discloses a process for the production of lactitol dihydrate by seeding an aqueous lactitol solution with lactitol dihydrate and crystallizing at a constant temperature between 10 and 25° C. The obtained dihydrates had a melting range of 78-83° C. According to said Patent a lactitol solution provides monohydrate at 25° C. if seeded with monohydrate but dihydrate if seeded with dihydrate. This is contrary to the findings of the present inventors. According to J. Kivikoski et al. in Carbohydrate Research, 233 (1992) 53-59, pure crystalline lactitol dihydrate melts at 70-72° C., which indicates that the dihydrate product of the EP Patent was not structurally pure lactitol dihydrate.
The preparation of lactitol trihydrate is described, for instance, in EP Patent Application 0 381 483. The process comprises crystallization of an aqueous or solvent-containing lactitol solution at a temperature of 0-30° C. The processes according to the Examples use a very high lactitol concentration and obviously may have precipitated besides lactitol trihydrate also a mixture of dihydrate and trihydrate. The melting range of the product was 52-56°C. The structure of lactitol trihydrate has been disclosed in Carbohydrate Research, 233 (1992), 189-195.
The preparation of pure lactitol monohydrate having lattice cell constants a=7.815 Å, b=12.682 Å, and c=15.927 Å; and a melting range between 90 and 100° C., preferably between 94 and 98° C., succeeded for the first time according to the process described in EP Patent 0456636, the disclosure of which is incorporated herein by reference. The melting range was determined, as in the present invention, with a Büchi Tottol melting point apparatus. The lactitol content of the structurally pure lactitol monohydrate was more than 99.5% on a dry substance basis, and its moisture content was between 4.85 and 5.15%.
In the crystallization process according to the invention disclosed in EP 0456636, the crystallization temperatures is in the range from 80 to 30° C. and the crystallization is performed as a cooling crystallization or as an evaporative crystallization. In the examples of said EP Patent 0456636 the lactitol monohydrate of the cooling crystallization was recovered at about 40° C. Since the cooling was rapid at the end of the crystallization and since the crystals present in the solution were pure lactitol monohydrate crystals, the product was pure lactitol monohydrate despite the fact that the temperature was lowered to as low as 40° C. or lower.
The crystallization tests of said EP Patent 0456636 showed that if the crystallization of lactitol monohydrate was to occur in a controlled manner for obtaining a desired crystal size without a wide crystal size distribution, the crystallization should be effected in such a manner that the supersaturation of the mother liquor remained below 1.3 (preferably 1.2) with respect to lactitol throughout the crystallization.
According to JP Application 13220/89 lactitol monohydrate may be produced by crystallizing at a temperature of 20-70° C. to obtain a crystalline product melting at 102-105° C.
The above description of the prior art clearly shows that the crystallization of lactitol is a complex matter, wherein a crystalline product obtained may well be a pure crystalline compound in the form of the pure anhydrous, monohydrate, dihydrate or trihydrate but the crystals may also comprise mixtures of various lactitol-water structures.
Since the literature is full of contradictory statements as regards which temperature ranges and crystallization conditions provide which crystal form, it is evident that the person skilled in the art would benefit from having an exact tool for monitoring the conditio
Kaira Miika
Nurmi Juha
Gitomer Ralph
Khare Devesh
Scully Scott Murphy & Presser
Xyrofin Oy
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