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Lactitol Monohydrate and a Method for the Production of Crystalline Lactitol

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Lactitol Monohydrate and a Method for the Production of Crystalline Lactitol Europâisches Patentamt European Patent Office (iT) Publication number : 0 039 981 Office européen des brevets B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication of patent spécification : % Int. Cl.3 : C 07 H 15/08 03.08.83 (2?) Application number : 81200505.6 (22) Date of filing : 11.05.81 (54) Lactitol monohydrate and a method for the production of crystalline lactitol. (30) Priority : 14.05.80 NL 8002823 (73) Proprietor : C.V. CHEMIE COMBINATIE AMSTERDAM C.C.A. (43) Date of publication of application : Arkelsedijk 46 P.O. Box 21 18.11.81 Bulletin 81/46 NL-4200 AA Gorinchem (NL) (45) Publication of the grant of the patent : (72) Inventor : Wijnman, Christiaan Frederik 03.08.83 Bulletin 83/31 Fintstraat 2 NL-4285 XS Woudrichem (NL) (§4) Designated contracting states : Inventor : van Velthuijsen, John Adriaan AT BE CH DE FR GB IT Ll LU NL SE H.M. van Randwijksingel 2 NL-4205 JS Gorinchem (NL) Inventor : van den Berg, Hendrik (56) Références cited : Mussenlaan 25 COMPTES RENDUS, 1920, 170, M.J.B. SENDE- NL-4214 EG Vuren (NL) RENS « Hydrogénation catalytlque du lactose », pages 47-50 JOURNAL OF THE AMERICAN CHEMICAL (74) Représentative : van der Beek, George Frans et al SOCIETY, February20, 1952, vol. M.L. Wol- Nederlandsch Octrooibureau Johan de Wittlaan 15 74, P.O. fram et al. « Lactitol Dihydrate » Box 29720 JOURNAL OF THE AMERICAN CHEMICAL NL-2502 LS Den Haag (NL) SOCIETY, March 1938 vol. 60 M.L. WOLFROM et al. « Crystalline lactositol », pages 571-573 CHEMICAL ABSTRACTS, vol. 90, 1979 page 391, abstract 37738f Columbus, Ohio, USA T. SAIJON- MAA et al. « Lactitolsmilk sugar alcohols » 00 O) O) o o o Note : Within nine months f rom the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in CL a written reasoned statëment. It shall not be deemed to have been filed until the opposition fee has been paid (Art. 99(1) Ul European patent convention). Jouve, 18, rue St-Denis, 75001 Paris, France The invention relates to a method for the production of lactitol monohydrate and to a method for the production of crystalline lactitol by crystallization from an aqueous solution of lactitol. Lactitol is lactose the glucose portion of which has been hydrogenated to sorbitol. Lactitol has the systematical name 4-β-D-galactopyranosyl-D-sorbitol. The preparation of lactitol is of general knowledge. As described in « Agricultural and Food Chemistry •, July-August 1979, 27, 680-686 a 30-40 percent by weight lactose solution (based on the sum total) is normally used as the starting material such solution being hydrogenated at 100 °C and under a hydrogen pressure of 40 atmospheres in the presence of Raney-nickel. Upon the sedimentation of the catalyst the hydrogenated solution is filtered and purified by means of ion-exchangers and activated carbon. The relative sweetness of lactitol amounts to 36 % when compared with the sweetness of a 5 % saccharose solution. it thus is clearly less sweet than sorbitol (relative sweetness of 55 %) and xylitol (relative sweetness of 96 %) (vide « Agricultural and Food Chemistry », July-August 1979, 27, 680-686). As reported in a German Patent (Maizena, 1974) the hydrolysis of lactitol by a-glucosidase (maltase) is much slower than that of lactose and maltose. Whereas lactose is hydrolyzed completely by S-galactosidase within 45 minutes lactitol is only hydrolyzed for 10-15 % within the same period of time. Hence lactitol will only be decomposed to a minor degree in the alimentary track so that it is suitable as a replacement for sugar in products to be used by diabetics. Lactitol is also suitable for use in low-caloric foods. Lactitol is less hygroscopic than sorbitol, glycerol and xylitol and may consequently be used in the preparation of certain bakery products for diabetics such as light biscuits (Dutch patent Application 78.11204). Lactitol may therefore also be used in moisture insensitive coatings for chewing gum, gellies, fondant etc. Furthermore lactitol possesses properties in view of which it is also well suited for several applications. Due to the absence of a carbonyl group lactitol exibits a good stability against the exposure to head and to alkali. Heating an aqueous solution of 10 percent by weight of lactitol adjusted to a pH-value of 13 with NaOH (1 hour at 100 °C) does not produce any discoloration whereas a lactose solution when heated under the same conditions shows a strong discoloration. The stability of lactitol in acidic medium is comparable to that of lactose. After heating solutions of 10 percent by weight of lactitol adjusted to a pH-value of 1 and 2, respectively, with HCI (4 hours at 100 °C) it appeared that 5.1 % and 1.4 % respectively, of the lactitol was hydrolyzed. Lactose solutions appear to be hydrolyzed for 5.4 % and 1.3 %, respectively, when heated under the same conditions. Heating at higher temperatures (170-240 °C) caused anhydrisation of lactitol (production of lactitan). Lactitol is soluble in water, dimethylsulfoxide and dimethylformamide and is miscible with other polyols (sorbitol, glycerol). It is slightly soluble in ethanol and diethylether. Notwithstanding the fact that recent literature (Saijonmaa, T., Heikonen, M., Linko, P., Milchwis- senschaft33 (1978) 733-736, Schiweck, H., Süsswaren 14 (1978) 13-21) considers lactitol to be a substance that may be crystallized only with difficulty or not at all, nevertheless there are also reports to be found in the literature referring to a crystalline dihydrate (Wolfrom, M. L., Hann, Raymond M., Hudson, C.S., J. Am. Chem. Soc. 74 (1952) 1105) as well as to crystalline anhydrous lactitol. Crystalline anhydrous lactitol has been obtained by the repeated extraction of a concentrated aqueous lactitol solution with absolute ethanol (removal of water). The amorphous hyroscopic mass thus obtained was combined with absolute ethanol whereby Iactitol.0 aq crystallized in a yield of 80 % in a period of about one month. Upon recrystallisation (dissolution in little water and additon of the same volume of ethanol) there were obtained small tetrahedric crystals having a melting point of 146 °C and a specific rotation of + 14°. Heating these crystals at 140 °C under reduced pressure above Pz05 for a period of 54 hours caused almost no loss of weight. Lactitol dihydrate possesses a melting point of 76-78 °C and was presumably first described by Senderens, J. B., Compt. Rend. 170 (1920) 47-50. This investigator evaporated a hydrogenated lactose solution on a water bath until a syrupy mass was obtained, which mass kept at room temperature started to crystallize after some days ; the product showed a melting point of 78 °C and specific rotation of + 12.2°. Since drying the crystals at 130 °C to a constant weight caused a weight loss of 5 % (water) Senderens thought he had obtained the monohydrate. It has now become apparent that when drying lactitol dihydrate at 130 °C for three days there will be a loss of weight of only 5 %. The publication by Senderens does not disclose any determination of the moisture content according to the Karl Fischer method ; such a determination would presumably have yielded a higher water content corresponding to the dihydrate (containing about 9.5 percent by weight of water). Also in view of the low melting point (78 °C) it may thus be assumed that at that time Senderens had recovered the dihydrate instead of the monohydrate (the melting point indicated by him is 78 °C, whereas lactitol monohydrate has a melting point of 121-123 °C and the dihydrate has a melting point of 76-78 °C). Wolfrom, M. L. Hann, Raymond M., Hudson, C. S., (J. Am. Chem. Soc. 74 (1952) 1105) have also obtained the dihydrate and confirmed the composition thereof on the basis of the elementary analysis. They found a melting point of 72.5-74 °C and a specific rotation of + 11.5°. Van Velthuijsen in Agriculture and Food Chemistry 27 (1979) 680-686 describes an impure lactitol monohydrate which contains 3 % mannitol, 0.5 % sorbitol, 0.5 % dulcitol and 0.5 % lower polyols. The melting point of this substance is 94-97 °C. According to the invention there has now been found a crystalline lactitol monohydrate Formula C12H24011 . H20 ; melting point 121-123°C; crystal system orthorhombic ; dimensions of unit cell a = 7.808 A, b = 12.685 A, c = 15.931 A ; space group P 2, 2, 2 ; 4 molecules per unit cell having a volume 1 577.9 A3, as well as a method for the production of crystalline lactitol by crystallization from an aqueous solution of lactitol by means of which lactitol monohydrate as well as lactitol dihydrate may be produced on an industrial scale, said method being characterized by a) seeding an aqueous solution of from 70 to 85 percent by weight, preferably from 78 to 82 percent by weight, of lactitol with lactitol monohydrate at from 45 °C to 55 °C and causing lactitol monohydrate +0 crystallize at from 40 °C to 50 °C, preferably between 43 °C and 47 °C, said lactitol monohydrate optionally being recovered, b) optionally subsequently cooling the mother liquor to from 15 °C to 25 °C, preferably to from 18 °C to 22°C, seeding the same with crystalline lactitol monohydrate seeds and causing the lactitol monohydrate to crystallize at this temperature, said lactitol monohydrate optionally being recovered, c) optionally causing the mother liquor obtained under b) to crystallize further at from 10 °C to 25 °C, preferably at from 15 °C to 20 °C and recovering lactitol dihydrate, or d) seeding an aqueous solution of from 57 to 76 percent by weight, preferably of from 68 to 76 percent by weight, in particular of from 72 to 74 percent by weight, of lactitol with crystalline lactitol dihydrate seeds and causing lactitol dihydrate to crystallize and recovering the same.
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