WO1996007331A1 - Composition comprising co-crystals, method for its manufacture, and its use - Google Patents
Composition comprising co-crystals, method for its manufacture, and its use Download PDFInfo
- Publication number
- WO1996007331A1 WO1996007331A1 PCT/FI1995/000490 FI9500490W WO9607331A1 WO 1996007331 A1 WO1996007331 A1 WO 1996007331A1 FI 9500490 W FI9500490 W FI 9500490W WO 9607331 A1 WO9607331 A1 WO 9607331A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- crystals
- grinding
- xylitol
- sorbitol
- Prior art date
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 61
- 239000000203 mixture Substances 0.000 title claims abstract description 50
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title claims description 22
- 238000000227 grinding Methods 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 229920005862 polyol Polymers 0.000 claims abstract description 14
- 150000003077 polyols Chemical class 0.000 claims abstract description 14
- 239000007787 solid Substances 0.000 claims abstract description 12
- 150000002772 monosaccharides Chemical class 0.000 claims abstract description 10
- 150000002482 oligosaccharides Chemical class 0.000 claims abstract description 10
- 229920001542 oligosaccharide Polymers 0.000 claims abstract description 9
- 150000002016 disaccharides Chemical class 0.000 claims abstract description 8
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 48
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 45
- 239000000811 xylitol Substances 0.000 claims description 45
- 235000010447 xylitol Nutrition 0.000 claims description 45
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 45
- 229960002675 xylitol Drugs 0.000 claims description 45
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 39
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 38
- 238000002844 melting Methods 0.000 claims description 31
- 230000008018 melting Effects 0.000 claims description 31
- 239000000600 sorbitol Substances 0.000 claims description 15
- 238000002441 X-ray diffraction Methods 0.000 claims description 8
- 238000002288 cocrystallisation Methods 0.000 claims description 5
- 150000001720 carbohydrates Chemical class 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 3
- 238000005054 agglomeration Methods 0.000 claims description 3
- 230000002776 aggregation Effects 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 238000000113 differential scanning calorimetry Methods 0.000 claims 2
- 235000009508 confectionery Nutrition 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 4
- 235000015173 baked goods and baking mixes Nutrition 0.000 abstract description 2
- 235000013305 food Nutrition 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 229940127557 pharmaceutical product Drugs 0.000 abstract description 2
- 229960002920 sorbitol Drugs 0.000 description 34
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 28
- 239000007858 starting material Substances 0.000 description 24
- 235000010355 mannitol Nutrition 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 8
- 238000010587 phase diagram Methods 0.000 description 8
- 150000005846 sugar alcohols Chemical class 0.000 description 8
- 229930195725 Mannitol Natural products 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000000594 mannitol Substances 0.000 description 6
- 229960001855 mannitol Drugs 0.000 description 6
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical group O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 4
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 101100192215 Arabidopsis thaliana PTAC7 gene Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 235000015218 chewing gum Nutrition 0.000 description 2
- 229940112822 chewing gum Drugs 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 239000013081 microcrystal Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 101100481033 Arabidopsis thaliana TGA7 gene Proteins 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920001908 Hydrogenated starch hydrolysate Polymers 0.000 description 1
- 229920001202 Inulin Polymers 0.000 description 1
- AYRXSINWFIIFAE-SCLMCMATSA-N Isomaltose Natural products OC[C@H]1O[C@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)[C@@H](O)[C@@H](O)[C@@H]1O AYRXSINWFIIFAE-SCLMCMATSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 1
- 229940029339 inulin Drugs 0.000 description 1
- 239000000905 isomalt Substances 0.000 description 1
- 235000010439 isomalt Nutrition 0.000 description 1
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 1
- DLRVVLDZNNYCBX-RTPHMHGBSA-N isomaltose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)C(O)O1 DLRVVLDZNNYCBX-RTPHMHGBSA-N 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229940034008 mannitol / sorbitol Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000010309 melting process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000000930 thermomechanical effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G4/00—Chewing gum
- A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
- A23G4/10—Chewing gum characterised by the composition containing organic or inorganic compounds characterised by the carbohydrates used, e.g. polysaccharides
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
- A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
- A23G3/346—Finished or semi-finished products in the form of powders, paste or liquids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/30—Artificial sweetening agents
- A23L27/33—Artificial sweetening agents containing sugars or derivatives
- A23L27/34—Sugar alcohols
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G2200/00—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF containing organic compounds, e.g. synthetic flavouring agents
- A23G2200/06—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF containing organic compounds, e.g. synthetic flavouring agents containing beet sugar or cane sugar if specifically mentioned or containing other carbohydrates, e.g. starches, gums, alcohol sugar, polysaccharides, dextrin or containing high or low amount of carbohydrate
Definitions
- Composition comprising co-crystals, method for its manufacture, and its use
- the present invention relates to compositions comprising co-crystals of at least two compounds, prepared by grinding.
- the compounds forming these co- crystals comprised in the composition of the invention are selected from a group consisting of monosaccharides, disaccharides and oligosaccharides and physiologically acceptable polyols.
- the invention also relates to a method for producing such a composition, in which at least two crystalline compounds selected from mono ⁇ saccharides, disaccharides and oligosaccharides and physiologically acceptable polyols are ground as a mix- ture in a solid state at a temperature substantially lower than the melting points of the components.
- Co-crystals are crystals formed by two or more compounds.
- a co-crystal has a unique crystal structure, which is different from the crystal structure of its components.
- a physiologically acceptable polyol in this context means a hydrogenated product corresponding to a monosaccharide, disaccharide or oligosaccharide, i.e. a sugar alcohol.
- the compounds from which co-crystals have been prepared in the study concerned are substituted benzoic acid derivatives wherefrom co- crystals have been obtained both by crystallization from a solution and by grinding.
- co- crystals can be produced from sugars and sugar alcohols by grinding also in cases where crystallization from a solution will not produce co-crystals, but the compounds are separable in a pure form by crystallization from the solution.
- particulate, i.e. powdery or granular, products having sugars and sugar alcohols as raw mater ⁇ ials have been developed for the needs of the sweets and tableting industries.
- Granular products in which the sugar or sugar alcohol is agglomerated with the aid of a binder and which are suitable for preparing tablets by the direct compression method are described for example in Finnish Patent 81 004 (xylitol with polyol as a binder), Finnish Patent Application 892797 (fructose with polyol as a binder) and Finnish Patent Application 932696 (xylitol with polymerized reducing sugar, alkali metal carboxymethyl cellulose or hydrogenated starch hydrolysate as a binder).
- the main component of the product is granulated by adding thereto an aqueous solution of a binder, and after granulation the product is dried and possibly sifted.
- U.S. Patent 5 158 789 relates to a sorbitol/xyl- itol co-crystal produced by melt crystallization.
- the co-crystal is produced by melting the starting materials into a homogeneous melt, cooling the melt with simultaneous stirring until a viscous mass has been obtained, and slowly cooling this mass until the sorbitol/xylitol mixture is crystal ⁇ lized throughout.
- the resultant co-crystal product is reported to be easier to tablet and to compound into chewing-gum, and also easier to handle in the sweets industry and/or in pharmaceutical compositions, to make use of the advantageous effects of xylitol.
- the method for preparing co-crystals as disclosed in this patent publication is, however, expensive and slow and requires high temperatures in the melting step. Furthermore, the crystallized solid mass must be crushed and possibly ground as a last step to make it usable.
- the product thus prepared by melting crystallization is an agglomer ⁇ ate in its physical properties. It is composed of numerous microcrystals adhering together.
- U.S. Patent 5 075 291 discloses a similar method for preparing a pharmaceutical composition, the com ⁇ position comprising a crystalline sugar alcohol derived from at least one monosaccharide or polysaccharide and having particles of at least one pharmaceutically active compound homogeneously dispersed in its crystal matrix.
- the product in accordance with this patent comprises 5-35% by weight of mannitol.
- the starting materials are melted, stirred, the slightly cooled mass is extruded and allowed to cool for several days at room temperature and ground.
- Finnish Patent Application 915876 relates to a directly compressible powdery composition based on xyl ⁇ itol.
- Xylitol is stated to be present in an amount of at least 60% by weight of the composition, and possible other components of the composition include a sacchar- ide, oligosaccharide or polysaccharide or a correspond- ing hydrogenated compound thereof.
- the process disclosed comprises thermomechanical treatment in which the start ⁇ ing material mixture partly melts and is extruded.
- the residence time in the heat zone is 5-300 seconds, and the extruded partly molten mass is cooled, crushed and sifted; the particle size of the resultant product is in excess of 50 ⁇ , typically in excess of 100 ⁇ m.
- a substantially dry composition in accordance with the invention which comprises co-crystals formed by at least two compounds selected from monosaccharides, disaccharides and oligo- saccharides and physiologically acceptable polyols, said co-crystals being produced by grinding a mixture of crystalline starting materials in a solid state.
- the expression "substantially dry” in this con ⁇ text means that the amount of free water is less than about 5% by weight, preferably less than 1% by weight.
- the invention also relates to a method for form ⁇ ing co-crystals from at least two compounds selected from monosaccharides, disaccharides and oligosaccharides and physiologically acceptable polyols, the method being characterized in that a mixture of crystalline starting materials is ground in a solid state at a temperature substantially lower than the melting points of the com ⁇ ponents until a fine product consisting of co-crystals is produced.
- the grinding temperature in the method of the invention is not critical, as long as it is substan ⁇ tially lower than the melting point of any of the com ⁇ ponents in the mixture.
- a grinding temper ⁇ ature suitable for a mixture of xylitol and sorbitol is in the range 15-50 °C. As a rule, the grinding is prefer ⁇ ably carried out at room temperature.
- the invention is based on the finding that co- crystals can be obtained from compounds of the above type by grinding a mixture of starting materials in a solid state, provided that the melting points of the starting materials are sufficiently close to one an ⁇ other.
- the difference between melting points should normally be less than about 30 °C, preferably less than 20 °C.
- Monosaccharides, disaccharides and oligosacchar ⁇ ides that are possible in the preparation of the product of the invention include glucose, fructose, galactose, xylose, sucrose, mannose, lactose, maltose, isomaltose and raffinose.
- the physiologically acceptable polyol(s) can be selected for instance from the following; sor ⁇ bitol, xylitol, maltitol, lactitol, mannitol, galactitol and isomalt.
- the co-crystals are formed of sorbitol and xylitol, in which case the product is also suitable for diabetics and the special advantages of xylitol are also gained for example in regard to caries prevention.
- Formation of a xylitol/sorbitol co-crystal by the method of the invention is particularly unexpected for the reason that the generally employed method for purifying xylitol from sorbitol is to crystallize it from an aque ⁇ ous solution containing these compounds, that is, such co-crystals are not formed from an aqueous solution. This completely deviates from what is to be anticipated on the basis of the above dissertation by G. M. Franken- bach.
- the proximity of the melting points referred to above must be taken into account in the selection of the starting materials.
- grinding did not produce co- crystals from a mannitol/sorbitol mixture (difference between melting points about 65 °C) or from a mannitol/ xylitol mixture (difference between melting points about 70 °C).
- the grinding is carried out in a pulverizer wherein a large amount of energy is bound to the material to be ground and the particles are in intimate contact with one another for relatively long periods of time; the comminuting being based mainly on abrasion (rather than compression, impact or prall).
- Suitable grinding devices include rod mills, ball mills and tube mills.
- the composi- tion of the invention comprises 5-100% of co-crystals.
- the product obtained by grinding may also include pure starting materials. If, for example, a mixture of sor ⁇ bitol and xylitol having 20 molar per cent of sorbitol and a balance of xylitol is ground, a product can be obtained in which all sorbitol is co-crystallized with an amount of xylitol corresponding to the co-crystal form, and thus the product comprises both co-crystals and free xylitol.
- Co-crystallization of xylitol and sorbitol will take place at least at a molar ratio about 1:1, which in the above case will yield a product comprising 40% of co-crystals, the remainder being xylitol.
- a powdery co- crystallized product is directly obtained from the crys- talline starting materials by grinding.
- the particle size of the product is below 50 ⁇ m.
- the product can be used as such for instance for tableting and as a raw material for the sweets industry, or it may be agglomerated into granules by methods known in the art, possibly employing binders as an aid in the agglomeration.
- the scope of the present invention encompasses a product obtained by co-crystallization grinding and also granules obtained therefrom by agglomeration, as well as the use thereof in the preparation of pharmaceutical products, sweets and chewing-gum, and in the food industry, for instance in bakery products.
- composition of the invention may also com ⁇ prise additives incorporated into the starting material mixture to be ground or into the product obtained from the grinding step or in connection with the agglomer ⁇ ation.
- additives may be e.g. aromas and dyes, poly- dextrose, inulin, carboxymethyl cellulose etc.
- Sugar alcohol mixtures xylitol/D-sorbitol, xyl- itol/D-mannitol and D-mannitol/D-sorbitol were prepared by weighing these reagents into each mixture in given molar ratios.
- the reagents employed were: D-sorbitol, Fluka art. 85532, D-(-)-mannitol, Merck art. 5982, and xylitol by Cultor Ltd, the purity of which was ascer ⁇ tained.
- the phases of the reagents and their thermal properties were measured prior to and after grinding by DSC and X-ray diffraction methods.
- the D-(-)-mannitol by Merck was in the monoclinic 6-form
- the D-sorbitol by Fluka was a mixture of A and r-polymorphs.
- the mixtures of crystalline reagents were ground in a ball mill pulverizer FRITSCH Pulverizette type 07.302 with a speed setting 8-9 (scale 1-10) for 20 minutes.
- TG Thermogravimetric
- DSC differential scanning calorimetric
- X-ray diffraction analyses were performed on each sample.
- HP Plotter 7475A, PE DSC7 (software). The TG analyses were performed in platinum crucibles in an air flow, flow rate 40-60 cm 3 /min. The samples weighed 3 to 9 mg, the heating rate was 2 °C/ min, and the temperature range was 25-200 °C.
- the DSC analyses were performed in 50 ⁇ l perforated aluminium crucibles in nitrogen flow, flow rate 50-60 cm 3 /min.
- the samples weighed 3 to 9 g, the heating rate was 2 °C/min, and the temperature range was varied from the range 25-120 °C to the range 25-180 °C in accordance with the sample.
- the X-ray diffraction patterns were measured with the ENRAF NONIUS PDS120 diffractometer furnished with an INEL CPS120 detector.
- the radiation applied was mono ⁇ chromatic CuK ⁇ x radiation (wavelength 1.54056A).
- the samples did not contain any appreciable amounts of moisture.
- the "onset" and peak values for melting and the heats of fusion were measured from pure starting materials and ground pure starting materials by DSC.
- the mean values and their standard deviations from two analyses are shown in Table 1 (standard deviation values in paren ⁇ theses).
- the polymorphic forms of the starting materials were determined by DSC and X-ray diffraction.
- the melting points of the starting materials employed were as follows: xylitol 93.0 °C, D-sorbitol 97.0 °C and D-mannitol 164.4 °C.
- phase diagrams for the xylitol/D-mannitol, D- mannitol/D-sorbitol and xylitol/D-sorbitol systems were drawn up by using the melting peak values obtained from the DSC graphs, and they are shown in Figures 1, 2 and 3 in which
- Figure 1 is a phase diagram for the system xyl ⁇ itol/D-mannitol
- Figure 2 is a phase diagram for the system D- mannitol/D-sorbitol
- Figure 3 is a phase diagram for the system xylitol/D-sorbitol.
- the horizontal line shown in Figure 3 is the mean value of the melting points of the xylitol/D-sorbitol co-crystals in the zone 0.25/0.75-0.75/0.25 of the molar ratios (xylitol/D-sorbitol) of the co-crystal.
- xylitol/D- mannitol and D-sorbitol/D-mannitol showed no signs of co-crystal formation in the solid state.
- the melting point for the sugar alcohol having the lower melting point (xylitol and D-sorbitol, respectively) changed only very little when a sugar alcohol having a higher melting point (D-mannitol) was present.
- the melting point of D-mannitol decreased when the molar ratio of xylitol or D-sorbitol, respectively, increased, in which situation xylitol and D-sorbitol were present as im ⁇ purities in D-mannitol.
- the total heats of fusion of the melting process as measured for these samples were equi- valent to the values calculated from the heats of fusion of pure samples when the molar ratios of the samples were taken into account.
- the DSC graphs determined for samples in which the starting materials had been separ ⁇ ately ground and thereafter mixed were equivalent to the DSC graphs for samples in which the starting materials had been ground together.
- phase diagram for the xylitol/D-sorbitol sys- tem differed from the phase diagrams of the two previous systems. It complied with the shape of the phase dia ⁇ grams of two such components as do not form solid solu ⁇ tions with one another. However, the DSC patterns showed no characteristic configuration of eutectic melting, which would have been perceived as a sharp melting peak in the DSC graph.
- the DSC graphs that were measured from samples in which the starting materials had been separ ⁇ ately ground and thereafter mixed differed from the DSC curves of samples in which the starting materials had been ground together.
- Figure 4 shows the normalized DSC curves of xyl- itol/sorbitol mixtures for a case where the starting materials have been ground separately and for a case where they have been ground together.
- the intersection of the two lines gives 76.2 °C as the melting point for the co-crystal of these compounds and 0.495/0.505 as the molar ratio (xyl ⁇ itol/D-sorbitol) thereof.
- the mean value and standard deviation for the melting peak values calculated for molar ratios 0.25/0.75 and 0.75/0.25 was 76.1 (0.3) °C.
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Abstract
The invention relates to a dry composition comprising co-crystals. The co-crystals have been produced by grinding a mixture comprising at least two crystalline compounds selected from monosaccharides, disaccharides and oligosaccharides and physiologically acceptable polyols in a solid state. The invention also relates to a method for producing such a composition. The composition may be used in the preparation of pharmaceutical products, sweets and chewing-gun, and in the food industry, for example in bakery products.
Description
Composition comprising co-crystals, method for its manufacture, and its use
The present invention relates to compositions comprising co-crystals of at least two compounds, prepared by grinding. The compounds forming these co- crystals comprised in the composition of the invention are selected from a group consisting of monosaccharides, disaccharides and oligosaccharides and physiologically acceptable polyols. The invention also relates to a method for producing such a composition, in which at least two crystalline compounds selected from mono¬ saccharides, disaccharides and oligosaccharides and physiologically acceptable polyols are ground as a mix- ture in a solid state at a temperature substantially lower than the melting points of the components.
Co-crystals are crystals formed by two or more compounds. A co-crystal has a unique crystal structure, which is different from the crystal structure of its components.
A physiologically acceptable polyol in this context means a hydrogenated product corresponding to a monosaccharide, disaccharide or oligosaccharide, i.e. a sugar alcohol. Formation and characterization of co-crystals and their application to scientific research has been described in the doctoral dissertation of Gayle Marie Frankenbach, The Preparation and Characterization of Hydrogen-Bonded Cocrystals with Applications to Mater- ials Science, 1989, University of Minnesota. The disser¬ tation discloses as co-crystal producing methods co- crystallization from a solution, sublimation, and co- crystallization in a solid state, the last-mentioned being performed by grinding. The compounds from which co-crystals have been prepared in the study concerned
are substituted benzoic acid derivatives wherefrom co- crystals have been obtained both by crystallization from a solution and by grinding. In connection with the pres¬ ent invention, it has been unexpectedly found that co- crystals can be produced from sugars and sugar alcohols by grinding also in cases where crystallization from a solution will not produce co-crystals, but the compounds are separable in a pure form by crystallization from the solution. Several particulate, i.e. powdery or granular, products having sugars and sugar alcohols as raw mater¬ ials have been developed for the needs of the sweets and tableting industries. Granular products in which the sugar or sugar alcohol is agglomerated with the aid of a binder and which are suitable for preparing tablets by the direct compression method are described for example in Finnish Patent 81 004 (xylitol with polyol as a binder), Finnish Patent Application 892797 (fructose with polyol as a binder) and Finnish Patent Application 932696 (xylitol with polymerized reducing sugar, alkali metal carboxymethyl cellulose or hydrogenated starch hydrolysate as a binder). In all these cases, the main component of the product is granulated by adding thereto an aqueous solution of a binder, and after granulation the product is dried and possibly sifted.
U.S. Patent 5 158 789 relates to a sorbitol/xyl- itol co-crystal produced by melt crystallization. In accordance with this patent, the co-crystal is produced by melting the starting materials into a homogeneous melt, cooling the melt with simultaneous stirring until a viscous mass has been obtained, and slowly cooling this mass until the sorbitol/xylitol mixture is crystal¬ lized throughout. The resultant co-crystal product is reported to be easier to tablet and to compound into chewing-gum, and also easier to handle in the sweets
industry and/or in pharmaceutical compositions, to make use of the advantageous effects of xylitol. The method for preparing co-crystals as disclosed in this patent publication is, however, expensive and slow and requires high temperatures in the melting step. Furthermore, the crystallized solid mass must be crushed and possibly ground as a last step to make it usable. The product thus prepared by melting crystallization is an agglomer¬ ate in its physical properties. It is composed of numerous microcrystals adhering together.
U.S. Patent 5 075 291 discloses a similar method for preparing a pharmaceutical composition, the com¬ position comprising a crystalline sugar alcohol derived from at least one monosaccharide or polysaccharide and having particles of at least one pharmaceutically active compound homogeneously dispersed in its crystal matrix.
The forming of a sorbitol/mannitol co-crystal by melt crystallization is disclosed in U.S. Patent
5 023 092. The product in accordance with this patent comprises 5-35% by weight of mannitol. In this case, the starting materials are melted, stirred, the slightly cooled mass is extruded and allowed to cool for several days at room temperature and ground.
Finnish Patent Application 915876 relates to a directly compressible powdery composition based on xyl¬ itol. Xylitol is stated to be present in an amount of at least 60% by weight of the composition, and possible other components of the composition include a sacchar- ide, oligosaccharide or polysaccharide or a correspond- ing hydrogenated compound thereof. The process disclosed comprises thermomechanical treatment in which the start¬ ing material mixture partly melts and is extruded. In accordance with the examples, the residence time in the heat zone is 5-300 seconds, and the extruded partly molten mass is cooled, crushed and sifted; the particle
size of the resultant product is in excess of 50 μ , typically in excess of 100 μm.
It is an object of the present invention to pro¬ vide a composition comprising co-crystals formed by at least two compounds selected from monosaccharides, di¬ saccharides and oligosaccharides and physiologically acceptable polyols, which co-crystals can be prepared directly from solid starting materials without using solvents or high temperatures at which the risk of de- gradation of the materials being treated would exist. Simultaneously, time-consuming and energy-consuming heating and cooling steps are avoided. It is a further object of the present invention to provide a product comprising such co-crystals that is sufficiently fine without being subjected to any separate grinding step.
. These objects are achieved with a substantially dry composition in accordance with the invention, which comprises co-crystals formed by at least two compounds selected from monosaccharides, disaccharides and oligo- saccharides and physiologically acceptable polyols, said co-crystals being produced by grinding a mixture of crystalline starting materials in a solid state.
The expression "substantially dry" in this con¬ text means that the amount of free water is less than about 5% by weight, preferably less than 1% by weight. The invention also relates to a method for form¬ ing co-crystals from at least two compounds selected from monosaccharides, disaccharides and oligosaccharides and physiologically acceptable polyols, the method being characterized in that a mixture of crystalline starting materials is ground in a solid state at a temperature substantially lower than the melting points of the com¬ ponents until a fine product consisting of co-crystals is produced. The grinding temperature in the method of the
invention is not critical, as long as it is substan¬ tially lower than the melting point of any of the com¬ ponents in the mixture. For example, a grinding temper¬ ature suitable for a mixture of xylitol and sorbitol is in the range 15-50 °C. As a rule, the grinding is prefer¬ ably carried out at room temperature.
The invention is based on the finding that co- crystals can be obtained from compounds of the above type by grinding a mixture of starting materials in a solid state, provided that the melting points of the starting materials are sufficiently close to one an¬ other. The difference between melting points should normally be less than about 30 °C, preferably less than 20 °C. Monosaccharides, disaccharides and oligosacchar¬ ides that are possible in the preparation of the product of the invention include glucose, fructose, galactose, xylose, sucrose, mannose, lactose, maltose, isomaltose and raffinose. The physiologically acceptable polyol(s) can be selected for instance from the following; sor¬ bitol, xylitol, maltitol, lactitol, mannitol, galactitol and isomalt.
In a particularly preferred embodiment of the invention, the co-crystals are formed of sorbitol and xylitol, in which case the product is also suitable for diabetics and the special advantages of xylitol are also gained for example in regard to caries prevention. Formation of a xylitol/sorbitol co-crystal by the method of the invention is particularly unexpected for the reason that the generally employed method for purifying xylitol from sorbitol is to crystallize it from an aque¬ ous solution containing these compounds, that is, such co-crystals are not formed from an aqueous solution. This completely deviates from what is to be anticipated on the basis of the above dissertation by G. M. Franken-
bach.
In addition to the intended use of the product, the proximity of the melting points referred to above must be taken into account in the selection of the starting materials. Hence, grinding did not produce co- crystals from a mannitol/sorbitol mixture (difference between melting points about 65 °C) or from a mannitol/ xylitol mixture (difference between melting points about 70 °C). In the method of the invention, the grinding is carried out in a pulverizer wherein a large amount of energy is bound to the material to be ground and the particles are in intimate contact with one another for relatively long periods of time; the comminuting being based mainly on abrasion (rather than compression, impact or prall). Suitable grinding devices include rod mills, ball mills and tube mills.
The formation mechanism of co-crystals is con¬ sidered to be - yet without being bound to this theory - such that as a result of the energy carried into the mixture in grinding, changes occur in the lattice struc¬ ture of the crystalline starting materials, and when the difference in the melting points of the starting mater¬ ials is small, the change in the lattice structure oc- curs nearly simultaneously in all of the crystalline starting materials. On account of rearrangement, co- crystals of the different components are produced. The fact that genuine co-crystals are involved, and not for instance a product formed by adherence of microcrystals of the different materials, has been ascertained with X- ray diffraction analyses (powder method) and differen¬ tial scanning calorimetry (DSC), as will be explained in greater detail in the working example below.
In accordance with one embodiment, the composi- tion of the invention comprises 5-100% of co-crystals.
The product obtained by grinding may also include pure starting materials. If, for example, a mixture of sor¬ bitol and xylitol having 20 molar per cent of sorbitol and a balance of xylitol is ground, a product can be obtained in which all sorbitol is co-crystallized with an amount of xylitol corresponding to the co-crystal form, and thus the product comprises both co-crystals and free xylitol.
Co-crystallization of xylitol and sorbitol will take place at least at a molar ratio about 1:1, which in the above case will yield a product comprising 40% of co-crystals, the remainder being xylitol.
In accordance with the invention, a powdery co- crystallized product is directly obtained from the crys- talline starting materials by grinding. In accordance with one embodiment of the invention, the particle size of the product is below 50 μm. The product can be used as such for instance for tableting and as a raw material for the sweets industry, or it may be agglomerated into granules by methods known in the art, possibly employing binders as an aid in the agglomeration.
The scope of the present invention encompasses a product obtained by co-crystallization grinding and also granules obtained therefrom by agglomeration, as well as the use thereof in the preparation of pharmaceutical products, sweets and chewing-gum, and in the food industry, for instance in bakery products.
The composition of the invention may also com¬ prise additives incorporated into the starting material mixture to be ground or into the product obtained from the grinding step or in connection with the agglomer¬ ation. Such additives may be e.g. aromas and dyes, poly- dextrose, inulin, carboxymethyl cellulose etc.
The invention will be illustrated in greater detail in the following example.
Example
Sugar alcohol mixtures xylitol/D-sorbitol, xyl- itol/D-mannitol and D-mannitol/D-sorbitol were prepared by weighing these reagents into each mixture in given molar ratios. The reagents employed were: D-sorbitol, Fluka art. 85532, D-(-)-mannitol, Merck art. 5982, and xylitol by Cultor Ltd, the purity of which was ascer¬ tained. The phases of the reagents and their thermal properties were measured prior to and after grinding by DSC and X-ray diffraction methods. The D-(-)-mannitol by Merck was in the monoclinic 6-form, and the D-sorbitol by Fluka was a mixture of A and r-polymorphs.
The mixtures of crystalline reagents were ground in a ball mill pulverizer FRITSCH Pulverizette type 07.302 with a speed setting 8-9 (scale 1-10) for 20 minutes.
Thermogravimetric (TG), differential scanning calorimetric (DSC), and X-ray diffraction analyses were performed on each sample. The TG and DSC equipment was the following (PE = Perkin-Elmer, HP ■ Hewlett-Packard):
TG: PE TGA7, TAC7/DX, IBM PS/2 Model 55SX,
HP Plotter 7475A, PE TADS.TGS (software) DSC: PE DSC-7, TAC7/PC, EPSON PC AX 2,
HP Plotter 7475A, PE DSC7 (software). The TG analyses were performed in platinum crucibles in an air flow, flow rate 40-60 cm3/min. The samples weighed 3 to 9 mg, the heating rate was 2 °C/ min, and the temperature range was 25-200 °C.
The DSC analyses were performed in 50 μl perforated aluminium crucibles in nitrogen flow, flow rate 50-60 cm3/min. The samples weighed 3 to 9 g, the heating rate was 2 °C/min, and the temperature range was varied from the range 25-120 °C to the range 25-180 °C in accordance with the sample. The X-ray diffraction patterns were measured with
the ENRAF NONIUS PDS120 diffractometer furnished with an INEL CPS120 detector. The radiation applied was mono¬ chromatic CuKαx radiation (wavelength 1.54056A).
In accordance with the TG analyses, the samples did not contain any appreciable amounts of moisture. The "onset" and peak values for melting and the heats of fusion were measured from pure starting materials and ground pure starting materials by DSC. The mean values and their standard deviations from two analyses are shown in Table 1 (standard deviation values in paren¬ theses). The polymorphic forms of the starting materials were determined by DSC and X-ray diffraction.
The melting points of the starting materials employed ("onset", DSC) were as follows: xylitol 93.0 °C, D-sorbitol 97.0 °C and D-mannitol 164.4 °C.
. The phase diagrams for the xylitol/D-mannitol, D- mannitol/D-sorbitol and xylitol/D-sorbitol systems were drawn up by using the melting peak values obtained from the DSC graphs, and they are shown in Figures 1, 2 and 3 in which
Figure 1 is a phase diagram for the system xyl¬ itol/D-mannitol,
Figure 2 is a phase diagram for the system D- mannitol/D-sorbitol, and Figure 3 is a phase diagram for the system xylitol/D-sorbitol.
The horizontal line shown in Figure 3 is the mean value of the melting points of the xylitol/D-sorbitol co-crystals in the zone 0.25/0.75-0.75/0.25 of the molar ratios (xylitol/D-sorbitol) of the co-crystal.
A. Systems xylitol/D-mannitol and D-sorbitol/D- mannitol (comparison)
In accordance with the phase diagrams, xylitol/D- mannitol and D-sorbitol/D-mannitol showed no signs of co-crystal formation in the solid state. The melting
point for the sugar alcohol having the lower melting point (xylitol and D-sorbitol, respectively) changed only very little when a sugar alcohol having a higher melting point (D-mannitol) was present. The melting point of D-mannitol decreased when the molar ratio of xylitol or D-sorbitol, respectively, increased, in which situation xylitol and D-sorbitol were present as im¬ purities in D-mannitol. The total heats of fusion of the melting process as measured for these samples were equi- valent to the values calculated from the heats of fusion of pure samples when the molar ratios of the samples were taken into account. The DSC graphs determined for samples in which the starting materials had been separ¬ ately ground and thereafter mixed were equivalent to the DSC graphs for samples in which the starting materials had been ground together.
B. System xylitol/D-sorbitol (in accordance with invention)
The phase diagram for the xylitol/D-sorbitol sys- tem differed from the phase diagrams of the two previous systems. It complied with the shape of the phase dia¬ grams of two such components as do not form solid solu¬ tions with one another. However, the DSC patterns showed no characteristic configuration of eutectic melting, which would have been perceived as a sharp melting peak in the DSC graph. The DSC graphs that were measured from samples in which the starting materials had been separ¬ ately ground and thereafter mixed differed from the DSC curves of samples in which the starting materials had been ground together.
Figure 4 shows the normalized DSC curves of xyl- itol/sorbitol mixtures for a case where the starting materials have been ground separately and for a case where they have been ground together. In the phase diagram for the xylitol/D-sorbitol
system (Figure 3), the intersection of the two lines gives 76.2 °C as the melting point for the co-crystal of these compounds and 0.495/0.505 as the molar ratio (xyl¬ itol/D-sorbitol) thereof. The mean value and standard deviation for the melting peak values calculated for molar ratios 0.25/0.75 and 0.75/0.25 was 76.1 (0.3) °C. A small slope can be seen in the molar ratio range 0.8/0.2-0.95/0.05 (xylitol/D-sorbitol) in Figure 3. In this molar ratio range, also the melting point of the co-crystal changes. It is possible that there is also another co-crystal that is formed in this range.
The analysis results clearly show that the samples obtained by grinding together xylitol and D- sorbitol in a ball mill pulverizer for 20 minutes contained a co-crystal product. The X-ray diffraction analyses confirmed that these samples contained a new product along with the pure starting materials. The presence of this product can be seen as an additional peak in Figure 5 which shows X-ray diffraction patterns for xylitol, D-sorbitol and a product prepared from these compounds that contains a co-crystal.
The effect of the grinding time on a sample con¬ taining xylitol and D-sorbitol in a molar ratio 1:1 was also studied. It was found that the melting peak for the co-crystal in the DSC graphs became sharper when the grinding time was increased, which indicated an increase in co-crystallized material. The whole heat of fusion was decreased with incresing grinding time: with 20 minutes grinding time, the whole heat of fusion was 29.8 kJ/mol and with 60 minutes grinding time 27.7 kJ/mol.
Table 1
Mean values for starting material melting "onset" and peak valu Standard deviations of mean values in arentheses.
References: [1] A. Reamy and F. Schweizer, J. Thermal Anal., Vol. 28 (1983) 9
[2] H. S. Kim and G. A. Jeffrey, Acta Cryst. B25 (1969) 2607.
[3] Y. J. Park, G. A. Jeffrey and W. C. Hamilton, Acta Cryst. B27
[4] I. Pitkanen, P. Perkkalainen and H. Rautiainen, Thermochim. A
Claims
Claims: 1. A substantially dry composition comprising co- crystals, c h a r a c t e r i z e d in that the co- crystals have been prepared by grinding a mixture com- prising at least two crystalline compounds selected from monosaccharides, disaccharides and oligosaccharides and physiologically acceptable polyols in a solid state, the difference between the melting points of said compounds being less than about 30°C.
2. A composition as claimed in claim 1, c h a r a c t e r i z e d in that the difference between the melting points is less than 20"C.
3. A composition as claimed in claim 1 or claim 2, c h a r a c t e r i z e d in that the co-crystals comprise two polyols.
.
4. A composition as claimed in claim 3, c h a r a c t e r i z e d in that the polyols are xylitol and sorbitol.
5. A composition as claimed in claim 4, c h a r a c t e r i z e d in that the molar ratio of xylitol and sorbitol in the composition is from 9:1 to 1:9.
6. A composition as claimed in claim 5, c h a r a c t e r i z e d in that the molar ratio of xylitol and sorbitol in the co-crystals is about 1:1.
7. A composition as claimed in claim 6, c h a r a c t e r i z e d in that the co-crystals have a melting point in the range 70-80βC as determined by DSC (differential scanning calorimetry).
8. A composition as claimed in claim 6, c h a r a c t e r i z e d in that the co-crystals have an X-ray diffraction pattern essentially as shown in Figure 5 by the uppermost curve.
9. A composition as claimed in any one of the preceding claims, c h a r a c t e r i z e d in that the amount of co-crystals contained therein is 5-100% by weight of the composition.
10. A method for producing a substantially dry composition comprising co-crystals, c h a r a c t e r - i z e d by grinding a mixture comprising at least two crystalline compounds selected from monosaccharides, di¬ saccharides and oligosaccharides and physiologically acceptable polyols in a solid state until a fine product consisting of co-crystals is produced.
11. A method as claimed in claim 10, c h a r ¬ a c t e r i z e d in that the grinding temperature is substantially lower than the melting points of the com¬ ponents of the mixture.
12. A method as claimed in claim 10 or claim 11, c h a r a c t e r i z e d in that said two compounds are xylitol and sorbitol.
13. A method as claimed in claim 12, c h a r ¬ a c t e r i z e d in that the grinding is carried out at a temperature of 15-50°C.
14. A method as claimed in any one of claims 10-
13, c h a r a c t e r i z e d in that the grinding is carried out by a ball mill.
15. A method as claimed in any one of claims 10-
14, c h a r a c t e r i z e d in that it further com- prises a step in which the product prepared by grinding is agglomerated into granules.
16. A method as claimed in any one of claims 10-
15, c h a r a c t e r i z e d in that additives not involved in the co-crystallization are added to the mix- ture to be treated prior to grinding, after grinding or in connection with agglomeration.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI944182 | 1994-09-09 | ||
FI944182A FI944182L (en) | 1994-09-09 | 1994-09-09 | Composition containing single crystals, method for its preparation and use |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996007331A1 true WO1996007331A1 (en) | 1996-03-14 |
Family
ID=8541339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FI1995/000490 WO1996007331A1 (en) | 1994-09-09 | 1995-09-08 | Composition comprising co-crystals, method for its manufacture, and its use |
Country Status (2)
Country | Link |
---|---|
FI (1) | FI944182L (en) |
WO (1) | WO1996007331A1 (en) |
Cited By (13)
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FR2888129A1 (en) * | 2005-07-08 | 2007-01-12 | Roquette Freres | PROCESS FOR PRODUCING A POWDER CONTAINING CRYSTALLINE PARTICLES OF XYLITOL WITH ANOTHER POLYOL |
WO2007144683A1 (en) * | 2006-06-13 | 2007-12-21 | Ingenio Del Cauca S.A. - Incauca S.A. | Process for cocrystallization of saccharose and a natural sweetener and the product obtained |
WO2008153945A3 (en) * | 2007-06-06 | 2009-02-12 | Univ South Florida | Nutraceutical co-crystal compositions |
WO2010013035A1 (en) * | 2008-07-26 | 2010-02-04 | University Of Bradford | Method and product |
US7790905B2 (en) | 2002-02-15 | 2010-09-07 | Mcneil-Ppc, Inc. | Pharmaceutical propylene glycol solvate compositions |
US7927613B2 (en) | 2002-02-15 | 2011-04-19 | University Of South Florida | Pharmaceutical co-crystal compositions |
US8183290B2 (en) | 2002-12-30 | 2012-05-22 | Mcneil-Ppc, Inc. | Pharmaceutically acceptable propylene glycol solvate of naproxen |
CN101717325B (en) * | 2009-11-25 | 2012-12-05 | 山东蜜福堂食品有限公司 | Method for preparing eutectic xylitol |
US8362062B2 (en) | 2002-02-15 | 2013-01-29 | Mcneil-Ppc, Inc. | Pharmaceutical compositions with improved dissolution |
EP1842436A4 (en) * | 2005-01-24 | 2014-02-19 | Food Science Co Ltd B | Sugar alcohol eutectic and process for producing the same |
WO2014031162A1 (en) * | 2012-08-20 | 2014-02-27 | Forest Laboratories Holdings Limited | Crystalline form of carbamoyl-cyclohexane derivatives |
US10501817B2 (en) | 2010-03-16 | 2019-12-10 | Imperial Sugar Company | Process for the manufacture of co-crystallized sucrose natural sweeteners and the products thereof |
US10633344B2 (en) | 2002-03-01 | 2020-04-28 | University Of South Florida | Multiple-component solid phases containing at least one active pharmaceutical ingredient |
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EP0528604A1 (en) * | 1991-08-09 | 1993-02-24 | SPI POLYOLS, Inc. | Melt cocrystallized sorbitol/xylitol compositions |
WO1994021827A1 (en) * | 1993-03-19 | 1994-09-29 | Xyrofin Oy | Sweetening agent, process for its production, and its use |
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1994
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1995
- 1995-09-08 WO PCT/FI1995/000490 patent/WO1996007331A1/en active Application Filing
Patent Citations (2)
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EP0528604A1 (en) * | 1991-08-09 | 1993-02-24 | SPI POLYOLS, Inc. | Melt cocrystallized sorbitol/xylitol compositions |
WO1994021827A1 (en) * | 1993-03-19 | 1994-09-29 | Xyrofin Oy | Sweetening agent, process for its production, and its use |
Cited By (19)
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---|---|---|---|---|
US7790905B2 (en) | 2002-02-15 | 2010-09-07 | Mcneil-Ppc, Inc. | Pharmaceutical propylene glycol solvate compositions |
US8362062B2 (en) | 2002-02-15 | 2013-01-29 | Mcneil-Ppc, Inc. | Pharmaceutical compositions with improved dissolution |
US7927613B2 (en) | 2002-02-15 | 2011-04-19 | University Of South Florida | Pharmaceutical co-crystal compositions |
US10633344B2 (en) | 2002-03-01 | 2020-04-28 | University Of South Florida | Multiple-component solid phases containing at least one active pharmaceutical ingredient |
US8183290B2 (en) | 2002-12-30 | 2012-05-22 | Mcneil-Ppc, Inc. | Pharmaceutically acceptable propylene glycol solvate of naproxen |
EP1842436A4 (en) * | 2005-01-24 | 2014-02-19 | Food Science Co Ltd B | Sugar alcohol eutectic and process for producing the same |
FR2888129A1 (en) * | 2005-07-08 | 2007-01-12 | Roquette Freres | PROCESS FOR PRODUCING A POWDER CONTAINING CRYSTALLINE PARTICLES OF XYLITOL WITH ANOTHER POLYOL |
US8112935B2 (en) | 2005-07-08 | 2012-02-14 | Roquette Freres | Method for producing a powder containing xylitol crystal particles with another polyol |
WO2007006885A3 (en) * | 2005-07-08 | 2007-03-29 | Roquette Freres | Method for producing a powder containing xylitol crystal particles with another polyol |
US20140154359A1 (en) * | 2006-06-13 | 2014-06-05 | Ingenio Del Cauca S.A. -Incauca S.A. | Process for co-crystallizing sucrose and a natural sweetener and the product thereof |
WO2007144683A1 (en) * | 2006-06-13 | 2007-12-21 | Ingenio Del Cauca S.A. - Incauca S.A. | Process for cocrystallization of saccharose and a natural sweetener and the product obtained |
US8404297B2 (en) | 2006-06-13 | 2013-03-26 | Ingenio del Cauca S.A.—Incauca S.A. | Process for co-crystallizing sucrose and a natural sweetener and the product thereof |
US10376521B2 (en) | 2007-06-06 | 2019-08-13 | University Of South Florida | Nutraceutical co-crystal compositions |
WO2008153945A3 (en) * | 2007-06-06 | 2009-02-12 | Univ South Florida | Nutraceutical co-crystal compositions |
US10842797B2 (en) | 2007-06-06 | 2020-11-24 | University Of South Florida | Nutraceutical co-crystal compositions |
WO2010013035A1 (en) * | 2008-07-26 | 2010-02-04 | University Of Bradford | Method and product |
CN101717325B (en) * | 2009-11-25 | 2012-12-05 | 山东蜜福堂食品有限公司 | Method for preparing eutectic xylitol |
US10501817B2 (en) | 2010-03-16 | 2019-12-10 | Imperial Sugar Company | Process for the manufacture of co-crystallized sucrose natural sweeteners and the products thereof |
WO2014031162A1 (en) * | 2012-08-20 | 2014-02-27 | Forest Laboratories Holdings Limited | Crystalline form of carbamoyl-cyclohexane derivatives |
Also Published As
Publication number | Publication date |
---|---|
FI944182A0 (en) | 1994-09-09 |
FI944182L (en) | 1996-03-10 |
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