CN108498539A - A kind of preparation method of water solubility chalybeate complex bulk pharmaceutical chemicals - Google Patents
A kind of preparation method of water solubility chalybeate complex bulk pharmaceutical chemicals Download PDFInfo
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- CN108498539A CN108498539A CN201810413638.6A CN201810413638A CN108498539A CN 108498539 A CN108498539 A CN 108498539A CN 201810413638 A CN201810413638 A CN 201810413638A CN 108498539 A CN108498539 A CN 108498539A
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- maltodextrin
- heating stirring
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- iron
- soluble
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- 239000000126 substance Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 229920002774 Maltodextrin Polymers 0.000 claims abstract description 55
- 239000005913 Maltodextrin Substances 0.000 claims abstract description 55
- 229940035034 maltodextrin Drugs 0.000 claims abstract description 55
- 238000003756 stirring Methods 0.000 claims abstract description 54
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 43
- 238000010438 heat treatment Methods 0.000 claims abstract description 41
- 229960004887 ferric hydroxide Drugs 0.000 claims abstract description 40
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 claims abstract description 40
- 239000000084 colloidal system Substances 0.000 claims abstract description 39
- 238000002604 ultrasonography Methods 0.000 claims abstract description 28
- 239000002245 particle Substances 0.000 claims abstract description 26
- 239000003513 alkali Substances 0.000 claims abstract description 13
- 235000014413 iron hydroxide Nutrition 0.000 claims abstract description 11
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 claims abstract description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 76
- 229910052742 iron Inorganic materials 0.000 claims description 42
- -1 alkali metal salt Chemical class 0.000 claims description 38
- 229910052783 alkali metal Inorganic materials 0.000 claims description 28
- 239000007788 liquid Substances 0.000 claims description 14
- 238000009938 salting Methods 0.000 claims description 12
- 238000010792 warming Methods 0.000 claims description 9
- 230000033228 biological regulation Effects 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 3
- 239000003292 glue Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 9
- 239000002253 acid Substances 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 6
- 239000006185 dispersion Substances 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 40
- 230000000052 comparative effect Effects 0.000 description 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- 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 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 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 16
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 16
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 12
- 239000005708 Sodium hypochlorite Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000012869 ethanol precipitation Methods 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 238000002441 X-ray diffraction Methods 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 150000002505 iron Chemical class 0.000 description 6
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- LGZDNJBUAAXEMN-UHFFFAOYSA-N 1,2,2,3-tetramethyl-1-oxidopiperidin-1-ium Chemical class CC1CCC[N+](C)([O-])C1(C)C LGZDNJBUAAXEMN-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- 239000013049 sediment Substances 0.000 description 4
- 239000002356 single layer Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920001353 Dextrin Polymers 0.000 description 3
- 239000004375 Dextrin Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 235000019425 dextrin Nutrition 0.000 description 3
- 238000002270 exclusion chromatography Methods 0.000 description 3
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 3
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000012905 visible particle Substances 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- ICGDKKACLISIAM-UHFFFAOYSA-N 2,3,5,6-tetramethylpiperazine Chemical class CC1NC(C)C(C)NC1C ICGDKKACLISIAM-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- LLSKXGRDUPMXLC-UHFFFAOYSA-N 1-phenylpiperidine Chemical class C1CCCCN1C1=CC=CC=C1 LLSKXGRDUPMXLC-UHFFFAOYSA-N 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- FWZTTZUKDVJDCM-CEJAUHOTSA-M disodium;(2r,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;iron(3+);oxygen(2-);hydroxide;trihydrate Chemical compound O.O.O.[OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Na+].[Na+].[Fe+3].[Fe+3].[Fe+3].[Fe+3].[Fe+3].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 FWZTTZUKDVJDCM-CEJAUHOTSA-M 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- 229940032961 iron sucrose Drugs 0.000 description 1
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000005186 women's health Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Nutrition Science (AREA)
- Inorganic Chemistry (AREA)
- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of preparation methods of water-soluble chalybeate complex bulk pharmaceutical chemicals, including：S1) maltodextrin is aoxidized to obtain carboxyl maltodextrin；S2 carboxyl maltodextrin and ferric hydroxide colloid) are subjected to complex reaction under conditions of heating stirring is with ultrasound, obtain water-soluble chalybeate complex bulk pharmaceutical chemicals.Compared with prior art, the present invention prepares water-soluble chalybeate complex bulk pharmaceutical chemicals using ferric hydroxide colloid and carboxyl maltodextrin under conditions of heating stirring and ultrasound, it is omitted in complex reaction by the adjusting of acid to alkali, processing step is reduced, pass through the ultrasonic dissolution dispersity for greatly improving iron hydroxide simultaneously, keep its dispersion more uniform, so that the product arrived has dissolubility excellent, degree of stability higher, molecular weight is more uniform with distribution of particles, improves the safety of technology stability and later stage medication.
Description
Technical field
The invention belongs to field of medicine preparing technology more particularly to a kind of preparation sides of water-soluble chalybeate complex bulk pharmaceutical chemicals
Method.
Background technology
Water-soluble chalybeate complex bulk pharmaceutical chemicals especially ferric iron, is ground with the dimension good fortune medicine under Galenica groups of Switzerland
The carboxyl maltose iron of system is that a kind of novel non-dextran of representative is injected intravenously chalybeate.The third generation iron supplementary its pacifying
Ideal value is all reached in terms of full property and validity.It is reported according to the research of Evstatiev etc., in therapeutics of iron deficiency anemia side
Face, carboxyl maltose iron curative effect are better than iron sucrose, and advantageously, tolerance is good for cost, it has also become speedup is most on American market
Fast Intravenous Supplement chalybeate.Currently, Wei Fu pharmaceuticals assessing its treatment chronic kidney disease, tumour (anemia of cancer patient),
The therapeutic effect of the different fields such as heart disease (chronic heart failure), women's health.
There are mainly two types of methods for the synthesis of existing carboxyl maltose iron：One is be original with maltodextrin and trivalent iron salt
Material, first with suitable oxidant (such as sodium hypochlorite, TEMPO/NaClO/NaBr) by maltodextrin (DE values be 5~20) oxygen
Change, then the maltodextrin that oxidation obtains is mixed with ferric aqueous solution (iron chloride, ferric sulfate etc.), then adjusts solution
PH value raises simultaneously temperature of reaction system to promote to be complexed, then adjusts reaction solution pH with HCl and to neutrality and be heated to alkalinity
It boils certain time, ethyl alcohol sedimentation separation is added after reaction, is dried in vacuo at 50 DEG C, you can obtain carboxyl maltose iron
Product；Another method needs preparative separation iron hydroxide solid, by FeCl3Na is gradually added into solution2CO3, through filtering
Isolated ferric hydroxide precipitate, then the maltodextrin solution that oxidation obtains is sufficiently mixed with brand-new iron hydroxide, with NaOH
Solution ph is adjusted to 11, and heats 30min at 50 DEG C, solution ph is then adjusted to 6 with HCl, keeps the temperature 30min, then rise
Temperature obtains carboxyl maltose ferrous solution, carboxyl maltose iron is obtained through refrigerated separation to 96 DEG C of heating 30min.
Such as Patent No. WO2004/037865, WO2008/087135, WO2008/145586 and WO2016/151367
Patent take molysite to be mixed with carboxyl maltodextrin after on the basis of acidity gradually alkali tune complex products.But when the method is reacted
Between it is longer, and in preparation process using more amount acid repeatedly adjusted with alkali, dosage is big, and processing route is long.
Although process of the second method without repeatedly adjusting soda acid, obtained product stability are poor.
Invention content
In view of this, the technical problem to be solved in the present invention is to provide a kind of system of water-soluble chalybeate complex bulk pharmaceutical chemicals
Preparation Method, the preparation method is simple and obtained product stability is higher.
The present invention provides a kind of preparation methods of water-soluble chalybeate complex bulk pharmaceutical chemicals, including：
S1) maltodextrin is aoxidized to obtain carboxyl maltodextrin；
S2 carboxyl maltodextrin and ferric hydroxide colloid) are subjected to complex reaction under conditions of heating stirring is with ultrasound,
Obtain water-soluble chalybeate complex bulk pharmaceutical chemicals.
Preferably, ferric hydroxide colloid is prepared according to the following steps：
A1 soluble iron salting liquid is mixed with alkali metal salt soln), is reacted under cryogenic conditions, hydroxide is obtained after filtering
Iron colloidal solid；The alkali metal salt soln is alkali carbonate and/or alkali metal hydrogencarbonate；
A2 after) mixing ferric hydroxide colloid particle with water, disperseed under conditions of heating stirring is with ultrasound, obtained
Ferric hydroxide colloid.
Preferably, in the soluble iron salting liquid iron ion a concentration of 20~30wt%；The alkali metal salt soln
A concentration of 10~20wt% of middle alkali metal salt；Iron ion and alkali carbonate and/or alkali in the soluble iron salting liquid
The molar ratio of alkali metal bicarbonate salt is 1：(1~2).
Preferably, the step A1) be specially：
Alkali metal salt soln is added dropwise in soluble iron salting liquid, the control of reaction process ice bath keeps the temperature of system
No more than 4 DEG C, after alkali metal salt soln is added dropwise, it is stirred to react 10~30min, ferric hydroxide colloid particle after filtering.
Preferably, a concentration of the 20 of iron ion in the mixed liquor that the iron hydroxide particle obtains after being mixed with water~
30wt%.
Preferably, the step A2) in heating stirring temperature be 40 DEG C~80 DEG C；The rate of heating stirring be 800~
1200rpm；The frequency of ultrasound is 40~80KHz.
Preferably, the step S2) in heating stirring temperature be 50 DEG C~100 DEG C；The rotating speed of heating stirring be 800~
1200rpm；The frequency of ultrasound is 40~80KHz；The pH value of system is 5~11 when heating stirring.
Preferably, the step S2) temperature of heating stirring is warming up to 80 DEG C~100 DEG C from 50 DEG C~70 DEG C, and is adding
At least constant temperature 1h or more when thermal agitation.
Preferably, the step S2) heating stirring when first by the pH value of system be adjusted to 10~12 progress complex reactions, wait for
The temperature of heating stirring is warming up to the pH value of regulation system before maximum temperature to 5~7.
Preferably, the pH value of regulation system is at least reacting 30min after 5~7.
The present invention provides a kind of preparation methods of water-soluble chalybeate complex bulk pharmaceutical chemicals, including：S1) by maltodextrin oxygen
Change obtains carboxyl maltodextrin；S2) by carboxyl maltodextrin and ferric hydroxide colloid under conditions of heating stirring is with ultrasound into
Row complex reaction obtains water-soluble chalybeate complex bulk pharmaceutical chemicals.Compared with prior art, the present invention using ferric hydroxide colloid with
Carboxyl maltodextrin prepares water-soluble chalybeate complex bulk pharmaceutical chemicals under conditions of heating stirring and ultrasound, and complex reaction is omitted
In the adjusting of alkali is arrived by acid, processing step is reduced, while by the very big dissolution dispersity for improving iron hydroxide of ultrasound, making it
Dispersion is more uniform, so that the product arrived has dissolubility excellent, degree of stability higher, molecular weight and distribution of particles are more
Uniformly, the safety of technology stability and later stage medication is improved.
Description of the drawings
Fig. 1 is the XRD spectra of the water-soluble chalybeate complex bulk pharmaceutical chemicals obtained in the embodiment of the present invention 1；
Fig. 2 is the XRD spectra of the carboxyl maltose iron obtained in comparative example 1 of the present invention；
Fig. 3 is the XRD spectra of the carboxyl maltose iron obtained in comparative example 2 of the present invention；
Fig. 4 is the XRD spectra of the carboxyl maltose iron obtained in comparative example 3 of the present invention；
Fig. 5 is the sample dissolution time and dissolving Size Trends that the embodiment of the present invention 1, comparative example 1 and comparative example 2 obtain
Figure；
Fig. 6 is the particle diameter distribution spectrogram for the sample that the embodiment of the present invention 1, comparative example 1 and comparative example 2 obtain.
Specific implementation mode
Below in conjunction with the embodiment of the present invention, technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
The present invention provides a kind of preparation methods of water-soluble chalybeate complex bulk pharmaceutical chemicals, including：S1) by maltodextrin oxygen
Change obtains carboxyl maltodextrin；S2) by carboxyl maltodextrin and ferric hydroxide colloid under conditions of heating stirring is with ultrasound into
Row complex reaction obtains water-soluble chalybeate complex bulk pharmaceutical chemicals.
Wherein, the present invention is not particularly limited the source of all raw materials, is commercially available.
Maltodextrin is aoxidized to obtain carboxyl maltodextrin；The maltodextrin is malt well known to those skilled in the art
Dextrin has no special limitation, and the DE of heretofore described maltodextrin is preferably 5~22, and more preferably 10~22；Institute
The method for stating oxidation is method well known to those skilled in the art, has no special limitation, preferably uses in the present invention
Tetramethyl piperidine oxides/sodium bromide/sodium hypochlorite system or sodium hypochlorite；By oxidation system by maltodextrin end, make
Content of reducing sugar is down to 2% or less；In the present invention, it is preferred to which maltodextrin is first dissolved to the molten of a concentration of 20~30wt%
Then liquid is being aoxidized；The temperature of the oxidation is preferably 0~10 DEG C；When oxidation system is tetramethyl piperidine oxides/bromine
When changing sodium/sodium hypochlorite system, preferably first maltodextrin solution, tetramethyl piperidine oxides are mixed with sodium bromide, then again
Sodium hypochlorite is added dropwise；After being added dropwise, the pH value of system is adjusted to alkalinity, it is preferably adjusted to 9~11, more preferably 9.5~
10.5, further preferably reacted for 10；The time of the reaction is preferably 30~80min, more preferably 40~60min, then excellent
It is selected as 50min；After reaction, reaction preferably is quenched with ethyl alcohol, obtains carboxyl maltodextrin；In the present invention, the carboxyl
Maltodextrin preferably also passes through 1~4 organic solvent deposit and purifies；The organic solvent has to be well known to those skilled in the art
Solvent has no special limitation, is preferably one or more in methanol, ethyl alcohol and acetone in the present invention.
Carboxyl maltodextrin and ferric hydroxide colloid are subjected to complex reaction under conditions of heating stirring is with ultrasound；It is described
Ferric hydroxide colloid is preferably freshly prepd ferric hydroxide colloid；The ferric hydroxide colloid is preferably prepared in accordance with the following methods：
A1 soluble iron salting liquid is mixed with alkali metal salt soln), is reacted under cryogenic conditions, ferric hydroxide colloid is obtained after filtering
Grain；The alkali metal salt soln is alkali carbonate and/or alkali metal hydrogencarbonate；A2) by ferric hydroxide colloid particle with
After water mixing, is disperseed under conditions of heating stirring is with ultrasound, obtain ferric hydroxide colloid.
Soluble iron salting liquid is mixed with alkali metal salt soln；The soluble ferric iron salt is known to those skilled in the art
Soluble ferric iron salt, have no special limitation, preferably ferric sulfate, ferric trichloride and Iron(III) chloride hexahydrate in the present invention
In it is one or more；A concentration of 20~30wt% of soluble ferric iron salt in the soluble iron salting liquid, more preferably 20~
25wt%；The alkali metal salt be alkali carbonate well known to those skilled in the art and/or alkali metal hydrogencarbonate,
Special limitation is had no, is preferably one or more in sodium carbonate, sodium bicarbonate, potassium carbonate and saleratus in the present invention；
The concentration of alkali metal salt is preferably 10~20wt% in the alkali metal salt soln, more preferably 13~18wt%, further preferably for
15~18wt%；Iron ion and alkali carbonate and/or mole of alkali metal hydrogencarbonate in the soluble iron salting liquid
Than being preferably 1：(1~2), more preferably 1：(1.5~2), most preferably 1:1.5；The method of the mixing is art technology
Method known to personnel, has no special limitation, and it is molten that alkali metal salt soln is preferably added to soluble ferric iron salt in the present invention
In liquid；The addition speed of the alkali metal salt soln is preferably 50~90ml/h, more preferably 55~88ml/h, is further preferably 58
~88ml/h；The rotating speed of the mixing is preferably 200~350rpm；Entire mixed process ice bath control, preferably remains system
Temperature is no more than 4 DEG C；After alkali metal salt soln is added dropwise, continue to be stirred to react, ferric hydroxide colloid particle is obtained after filtering；
The time being stirred to react is preferably 10~30min.
The iron hydroxide particle is mixed with water；The concentration of iron ion is preferably 20~30wt% in mixed liquor, more excellent
It is selected as 22~28wt%, is further preferably 24~26wt%, most preferably 25wt%；After mixing, in the item of heating stirring and ultrasound
Disperseed under part, obtains ferric hydroxide colloid；The temperature of the heating stirring is preferably 40 DEG C~80 DEG C, more preferably 50 DEG C
~60 DEG C；The rotating speed of the heating stirring is preferably 800~1200rpm；The frequency of the ultrasound is preferably 40~80KHz, more
Preferably 60~80KHz；The time of the dispersion is preferably 30~60min, more preferably 30~40min.
Carboxyl maltodextrin and ferric hydroxide colloid are subjected to complex reaction under conditions of heating stirring is with ultrasound；It is preferred that
After carboxyl maltodextrin is first dissolved in water, then with ferric hydroxide colloid under conditions of heating stirring is with ultrasound be complexed anti-
It answers；It is preferably 20~35wt% that the carboxyl maltodextrin, which is dissolved in its concentration in the solution of water, more preferably 20~30wt%, then
Preferably 25wt%；The mass ratio of the carboxyl maltodextrin and ferric hydroxide colloid is preferably 1：(0.5~1.5), more preferably
It is 1：(0.5~1.2) is further preferably 1：(0.6~1), most preferably 1：0.8；The temperature of the heating stirring is preferably 50 DEG C
~100 DEG C；In the present invention, the heating stirring is preferably gradually warming up to 80 DEG C~100 DEG C from 50 DEG C~70 DEG C, and is heating
At least constant temperature 1h or more when stirring, so that the bond energy between glycosyl ligand and iron hydroxide ligand becomes firm；The heating is stirred
The rotating speed mixed is preferably 800~1200rpm；The pH value of system is preferably 5~11 when the heating stirring, more preferably first by system
PH value be adjusted to 10~12, preferably 11 progress complex reactions, preferably 30~50min of complex reaction, the temperature of thermal agitation to be added
The pH value of regulation system before rising to maximum temperature is spent to 5~7, with the requirement suitable for human injection；The pH of more preferable regulation system
It is worth to after 5~7, at least keeps 30min；Further preferably the pH value of regulation system is to after 5~7, heating stirring maximum temperature extremely
30min is kept less；The frequency of the ultrasound is preferably 40~80KHz, preferably the continual ultrasonic when system pH is 10~12
30min or more, 30~60min of more preferable ultrasound, further preferably 40~45min of ultrasound, then stops ultrasound, the purpose is to fully divide
Dissipate ferric hydroxide colloid particle.
After complex reaction, between 5~7, ethanol precipitation obtains pH value that is preferably cooling and continuing regulation system after dry
Water-soluble chalybeate complex bulk pharmaceutical chemicals；The method of the drying is method well known to those skilled in the art, and it is special to have no
Limitation, the present invention in can centrifuge drying, vacuum drying or be that dissolved solid powder particle is lyophilized or is spray-dried.
The present invention is prepared with carboxyl maltodextrin under conditions of heating stirring and ultrasound water-soluble using ferric hydroxide colloid
Property chalybeate complex bulk pharmaceutical chemicals, the adjusting for arriving alkali in complex reaction by acid is omitted, processing step reduction while passing through ultrasonic pole
The big dissolution dispersity for improving iron hydroxide, keeps its dispersion more uniform, so that the product arrived has dissolubility excellent,
Degree of stability higher, molecular weight is more uniform with distribution of particles, improves the safety of technology stability and later stage medication.
Water-soluble chalybeate complex bulk pharmaceutical chemicals prepared by the present invention can be used for treating hypoferric anemia or chronic kidney disease.
In order to further illustrate the present invention, with reference to embodiments to a kind of water-soluble chalybeate complex provided by the invention
The preparation method of bulk pharmaceutical chemicals is described in detail.
Reagent used in following embodiment is commercially available.
Embodiment 1
The material 24g that maltodextrin DE is 10 is weighed, TEMPO (tetramethyl piperazines are added in molten 25% concentration under the conditions of 4 DEG C
Pyridine oxide) 0.110g and NaBr 4.26g and maltodextrin stirring it is equal, after 13.8% sodium hypochlorite 160mL is added dropwise at a slow speed, use
It is 10.0 holding 50min that 1mol/L sodium hydroxide solutions, which adjust pH value,.Reaction finishes 3 times of reaction system precipitations of ethyl alcohol and is quenched instead
It answers, continues to dissolve sediment to 25wt% concentration, ethanol precipitation twice, abandons supernatant, and dissolving 25wt% is carboxyl malt for use
Dextrin solution.
It is 20% solution that it is molten, which to weigh 25.38g ferric trichlorides, and ice-water bath stirs 30min, sodium carbonate 26.42g weighed, by it
Molten is 15wt% concentration, is added in iron salt solutions with constant speed (be at the uniform velocity added and finish in 2~3h), reacts overall process ice bath control
System keeps the temperature of reaction system to be no more than 4 DEG C.It waits for that sodium carbonate is added dropwise, continues reaction solution stirring 26min, use Bu Shi
Funnel single layer filter paper filters reaction solution, continues to filter after washing, operate repeatedly three times.Finally obtained ferric hydroxide colloid particle.
Obtained ferric hydroxide colloid particle is molten for 25wt% concentration, ultrasonic 30min, frequency 80KHz；Then carboxyl is added
Maltodextrin solution carries out complex reaction, adjusts 60 DEG C of reaction temperature, and pH value to 11.0 stirs quasi- rotating speed 1200rpm, reacts
45min waits for stopping ultrasound without visible particle in visual reaction system；PH value is adjusted to 7.0,98 DEG C is warming up to and is reacted
30min stops cooling ethanol precipitation and collects taking precipitate to be dried to get to water-soluble chalybeate complex bulk pharmaceutical chemicals.
The water-soluble chalybeate complex bulk pharmaceutical chemicals obtained in embodiment 1 are analyzed using XRD, obtain its XRD spectra,
As shown in Figure 1.
The water-soluble chalybeate complex bulk pharmaceutical chemicals obtained in embodiment 1 are detected, its performance parameter such as 1 institute of table is obtained
Show.
The performance parameter of water-soluble chalybeate complex bulk pharmaceutical chemicals in 1 embodiment 1 of table
| Molecular weight (molecular-exclusion chromatography) | Iron content | Carbohydrate content |
| 13.8KD | 26.3% | 42.3% |
The water-soluble chalybeate complex bulk pharmaceutical chemicals obtained in embodiment 1 and commercially available original are ground into injection product in comparable sodium
Under, its light absorption is detected by 1mol/L salt acid degradations and evaluates palliating degradation degree, it is as shown in table 2 to obtain testing result.
2 palliating degradation degree testing result of table
As shown in Table 2, within 20h, 290nm detects absorbance value, it is found that original grinds product and reduces by 67.06%, and implements
Example 1 reduces by 81.8%, illustrates that the water-soluble chalybeate complex bulk pharmaceutical chemicals that embodiment 1 obtains more are stablized in acid condition, tool
There are longer stationary phase and storage phase.
Embodiment 2
The material 22g that maltodextrin DE is 22 is weighed, TEMPO (tetramethyls are added in molten 25% concentration under the conditions of 0~10 DEG C
Phenylpiperidines oxide) 0.134g and NaBr 4.85g and maltodextrin stirring it is equal, after 14.5% sodium hypochlorite is added dropwise at a slow speed
160mL adjusts pH value 10.0 with 1mol/L sodium hydroxide solutions and keeps 50min.Reaction finishes 3 times of reaction system precipitations of ethyl alcohol and quenches
It goes out reaction, continues to dissolve sediment to 25wt% concentration, ethanol precipitation twice, abandons supernatant, and dissolving 25wt% is carboxyl for use
Maltodextrin solution.
It is 20wt% solution that it is molten, which to weigh 25.35g ferric trichlorides, and ice-water bath stirs 30min, weighs sodium carbonate 28.33g, will
It is 15wt% concentration that its is molten, is added in iron salt solutions with constant speed (be at the uniform velocity added and finish in 2~3h), reacts overall process ice bath
Control keeps the temperature of reaction system to be no more than 4 DEG C.It waits for that sodium carbonate is added dropwise, continues reaction solution stirring 14min, use cloth
Family name's funnel single layer filter paper filters reaction solution, continues to filter after washing, operate repeatedly three times.Finally obtained ferric hydroxide colloid
Grain.
Obtained ferric hydroxide colloid particle is molten for 25wt% concentration, ultrasonic 30min, frequency 80KHz；Then carboxyl is added
Maltodextrin solution carries out complex reaction, adjusts 60 DEG C of reaction temperature, and pH value to 11.0 stirs quasi- rotating speed 1200rpm, reacts
40min waits for stopping ultrasound without visible particle in visual reaction system；PH value is adjusted to 7.0,100 DEG C is warming up to and is reacted
30min stops cooling ethanol precipitation and collects taking precipitate to be dried to get to water-soluble chalybeate complex bulk pharmaceutical chemicals.
The water-soluble chalybeate complex bulk pharmaceutical chemicals obtained in embodiment 2 are detected, its performance parameter such as 3 institute of table is obtained
Show.
The performance parameter of water-soluble chalybeate complex bulk pharmaceutical chemicals in 3 embodiment 2 of table
| Molecular weight (molecular-exclusion chromatography) | Iron content | Carbohydrate content |
| 16.6KD | 27.9% | 38.3% |
Embodiment 3
The material 20.5g that maltodextrin DE is 19 is weighed, TEMPO is added under the conditions of 0~10 DEG C in molten 25wt% concentration
(tetramethyl piperidine oxides) 0.100g and NaBr 4.83g and maltodextrin stirring are equal, after 14.5% sodium hypochlorite is added dropwise at a slow speed
160mL adjusts pH value 10.0 with 1mol/L sodium hydroxide solutions and keeps 50min.Reaction finishes 3 times of reaction system precipitations of ethyl alcohol and quenches
It goes out reaction, continues to dissolve sediment to 25wt% concentration, ethanol precipitation twice, abandons supernatant, and dissolving 25wt% is carboxyl for use
Maltodextrin solution.
It is 20% solution that it is molten, which to weigh 28.38g ferric trichlorides, and ice-water bath stirs 30min, sodium carbonate 30.14g weighed, by it
Molten is 15wt% concentration, is added in iron salt solutions with constant speed (be at the uniform velocity added and finish in 2~3h), reacts overall process ice bath control
System keeps the temperature of reaction system to be no more than 4 DEG C.It waits for that sodium carbonate is added dropwise, continues reaction solution stirring 30min, use Bu Shi
Funnel single layer filter paper filters reaction solution, continues to filter after washing, operate repeatedly three times.Finally obtained ferric hydroxide colloid particle.
Obtained ferric hydroxide colloid particle is molten for 25wt% concentration, ultrasonic 30min, frequency 80KHz；Then carboxyl is added
Maltodextrin solution carries out complex reaction, adjusts 60 DEG C of reaction temperature, and pH value to 11.0 stirs quasi- rotating speed 1200rpm, reacts
40min waits for stopping ultrasound without visible particle in visual reaction system；PH value is adjusted to 6.8,100 DEG C is warming up to and is reacted
30min stops cooling ethanol precipitation and collects taking precipitate to be dried to get to water-soluble chalybeate complex bulk pharmaceutical chemicals.
The water-soluble chalybeate complex bulk pharmaceutical chemicals obtained in embodiment 3 are detected, its performance parameter such as 4 institute of table is obtained
Show.
The performance parameter of water-soluble chalybeate complex bulk pharmaceutical chemicals in 4 embodiment 3 of table
| Molecular weight (molecular-exclusion chromatography) | Iron content | Carbohydrate content |
| 19.5KD | 29.86% | 38.45% |
Comparative example 1
Using maltodextrin and trivalent iron salt as raw material, first with suitable oxidant (such as sodium hypochlorite, TEMPO/NaClO/
NaBr etc.) by maltodextrin (DE values are 5~20) oxidation, then obtained maltodextrin and ferric aqueous solution (chlorine will be aoxidized
Change iron, ferric sulfate etc.) mixing, the pH of solution is then adjusted to alkalinity, raises simultaneously temperature of reaction system to promote to be complexed, then
Reaction solution pH is adjusted to neutrality with HCl and is heated to boiling certain time.Ethyl alcohol sedimentation separation is added after reaction, in 50 DEG C
Lower vacuum drying, you can obtain carboxyl maltose iron product.
The carboxyl maltose iron obtained in comparative example 1 is analyzed using XRD, obtains its XRD spectra, as shown in Figure 2.
Comparative example 2
By to FeCl3Na is gradually added into solution2CO3, it is separated by filtration to obtain ferric hydroxide precipitate, then will aoxidize
To maltodextrin solution be sufficiently mixed with brand-new iron hydroxide, pH value of solution is adjusted to 11 with NaOH, and is heated at 50 DEG C
30min then adjusts pH value of solution to 6 with HCl, keeps the temperature 30min, then is warming up to 96 DEG C of heating 30min, obtains carboxyl maltose iron
Solution obtains carboxyl maltose iron through refrigerated separation.
The carboxyl maltose iron obtained in comparative example 2 is analyzed using XRD, obtains its XRD spectra, as shown in Figure 3.
Comparative example 3
The material 24g that maltodextrin DE is 10 is weighed, TEMPO (tetramethyl piperazines are added in molten 25% concentration under the conditions of 4 DEG C
Pyridine oxide) 0.110g and NaBr 4.26g and maltodextrin stirring it is equal, after 13.8% sodium hypochlorite 160mL is added dropwise at a slow speed, use
It is 10.0 holding 50min that 1mol/L sodium hydroxide solutions, which adjust pH value,.Reaction finishes 3 times of reaction system precipitations of ethyl alcohol and is quenched instead
It answers, continues to dissolve sediment to 25wt% concentration, ethanol precipitation twice, abandons supernatant, and dissolving 25wt% is carboxyl malt for use
Dextrin solution.
It is 20% solution that it is molten, which to weigh 25.38g ferric trichlorides, and ice-water bath stirs 30min, sodium carbonate 26.42g weighed, by it
Molten is 15wt% concentration, is added in iron salt solutions with constant speed (be at the uniform velocity added and finish in 2~3h), reacts overall process ice bath control
System keeps the temperature of reaction system to be no more than 4 DEG C.It waits for that sodium carbonate is added dropwise, continues reaction solution stirring 26min, use Bu Shi
Funnel single layer filter paper filters reaction solution, continues to filter after washing, operate repeatedly three times.Finally obtained ferric hydroxide colloid particle.
By obtained ferric hydroxide colloid particle it is molten be 25wt% concentration, then be added carboxyl maltodextrin solution be complexed
Reaction adjusts 60 DEG C of reaction temperature, and pH value to 11.0 stirs quasi- rotating speed 1200rpm, reacts 45min；PH value is adjusted to 7.0, is risen
Temperature carries out reaction 30min to 98 DEG C, stops cooling ethanol precipitation and collect taking precipitate to be dried to get to carboxyl maltose
Iron.
The carboxyl maltose iron obtained in comparative example 3 is analyzed using XRD, obtains its XRD spectra, as shown in Figure 4.
The water-soluble chalybeate complex bulk pharmaceutical chemicals of the preparation of embodiment 1 are can be seen that by Fig. 1~Fig. 4 under equal conditions
Higher relative to 1~3 response of comparative example, peak shape is clearly sharp keen, and single degree is high, this makes sample show good associativity
With stability.
The sample that embodiment 1, comparative example 1 and comparative example 2 are obtained under equal conditions (60 DEG C, 300rpm) dissolvings, obtain
It is as shown in Figure 5 to its dissolution time and dissolving Size Trends figure.As seen from Figure 5, under the same conditions, embodiment 1 obtains
Sample solution rate be substantially better than comparative example 1 and comparative example 2.
The sample that embodiment 1, comparative example 1 and comparative example 2 are obtained carries out the comparison of grain size and molecular weight concentration degree, obtains
Particle diameter distribution spectrogram is as shown in Figure 6.Particle diameter distribution is corresponding with molecular weight concentration degree, and the particle diameter distribution of high concentration necessarily corresponds to
The molecular weight distribution of concentration.As seen from Figure 6, due in embodiment 1 ferric hydroxide colloid complexing when use ultrasonic disperse
System, obtained ferric hydroxide colloid granulation uniformity is higher, and reflection is high to final molecular weight product concentration degree, and molecular weight is steady
It is fixed, be convenient for drug dispersion when later stage medication to absorb, effective grain size close in the case of, the sample grain that obtains in embodiment 1
Diameter concentration degree distribution concentration degree is better than comparative example 1 and comparative example 2.
Claims (10)
1. a kind of preparation method of water solubility chalybeate complex bulk pharmaceutical chemicals, which is characterized in that including：
S1) maltodextrin is aoxidized to obtain carboxyl maltodextrin；
S2 carboxyl maltodextrin and ferric hydroxide colloid) are subjected to complex reaction under conditions of heating stirring is with ultrasound, obtained
Water-soluble chalybeate complex bulk pharmaceutical chemicals.
2. preparation method according to claim 1, which is characterized in that ferric hydroxide colloid is prepared according to the following steps：
A1 soluble iron salting liquid is mixed with alkali metal salt soln), is reacted under cryogenic conditions, iron hydroxide glue is obtained after filtering
Body particle；The alkali metal salt soln is alkali carbonate and/or alkali metal hydrogencarbonate；
A2 after) mixing ferric hydroxide colloid particle with water, disperseed under conditions of heating stirring is with ultrasound, obtain hydrogen-oxygen
Change iron colloid.
3. preparation method according to claim 2, which is characterized in that the concentration of iron ion in the soluble iron salting liquid
For 20~30wt%；A concentration of 10~20wt% of alkali metal salt in the alkali metal salt soln；The soluble iron salting liquid
Middle iron ion is 1 with the molar ratio of alkali carbonate and/or alkali metal hydrogencarbonate：(1~2).
4. preparation method according to claim 2, which is characterized in that the step A1) be specially：
Alkali metal salt soln is added dropwise in soluble iron salting liquid, the control of reaction process ice bath keeps the temperature of system not surpass
4 DEG C, after alkali metal salt soln is added dropwise are crossed, 10~30min is stirred to react, ferric hydroxide colloid particle after filtering.
5. preparation method according to claim 2, which is characterized in that the iron hydroxide particle obtained after being mixed with water
A concentration of 20~30wt% of iron ion in mixed liquor.
6. preparation method according to claim 2, which is characterized in that the step A2) in heating stirring temperature be 40
DEG C~80 DEG C；The rate of heating stirring is 800~1200rpm；The frequency of ultrasound is 40~80KHz.
7. preparation method according to claim 1, which is characterized in that the step S2) in heating stirring temperature be 50
DEG C~100 DEG C；The rotating speed of heating stirring is 800~1200rpm；The frequency of ultrasound is 40~80KHz；System when heating stirring
PH value is 5~11.
8. preparation method according to claim 1, which is characterized in that the step S2) temperature of heating stirring is from 50 DEG C
~70 DEG C are warming up to 80 DEG C~100 DEG C, and at least constant temperature 1h or more in heating stirring.
9. preparation method according to claim 1, which is characterized in that the step S2) heating stirring when first by system
PH value is adjusted to 10~12 progress complex reactions, and the temperature of thermal agitation to be added is warming up to the pH value of regulation system before maximum temperature extremely
5~7.
10. preparation method according to claim 9, which is characterized in that at least reacted after the pH value of regulation system to 5~7
30min。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113004428A (en) * | 2019-12-20 | 2021-06-22 | 金陵药业股份有限公司 | Preparation method of carboxyl ferric maltose |
| CN115322265A (en) * | 2022-08-29 | 2022-11-11 | 滨州学院 | Carboxyl maltose controlled oxidation and purification process |
| CN115403675A (en) * | 2022-08-29 | 2022-11-29 | 滨州学院 | A kind of complexation and refining process of carboxymaltose iron |
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| US3794722A (en) * | 1968-11-20 | 1974-02-26 | M Taya | Iron composition for treating anemia |
| CN1705682A (en) * | 2002-10-23 | 2005-12-07 | 维福（国际）股份公司 | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing said complexes |
| CN1798754A (en) * | 2003-05-30 | 2006-07-05 | 色品先进技术股份有限公司 | Synthesis of high molecular weight iron-saccharidic complexes |
| CN105125578A (en) * | 2015-07-29 | 2015-12-09 | 南京生命能科技开发有限公司 | High-dissolution-rate sugar-iron compound and preparation method thereof |
| CN105125577A (en) * | 2015-07-29 | 2015-12-09 | 南京生命能科技开发有限公司 | Stable sugar-iron compound and preparation method thereof |
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| US3794722A (en) * | 1968-11-20 | 1974-02-26 | M Taya | Iron composition for treating anemia |
| CN1705682A (en) * | 2002-10-23 | 2005-12-07 | 维福（国际）股份公司 | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing said complexes |
| CN1798754A (en) * | 2003-05-30 | 2006-07-05 | 色品先进技术股份有限公司 | Synthesis of high molecular weight iron-saccharidic complexes |
| CN105125578A (en) * | 2015-07-29 | 2015-12-09 | 南京生命能科技开发有限公司 | High-dissolution-rate sugar-iron compound and preparation method thereof |
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| CN113004428A (en) * | 2019-12-20 | 2021-06-22 | 金陵药业股份有限公司 | Preparation method of carboxyl ferric maltose |
| CN115322265A (en) * | 2022-08-29 | 2022-11-11 | 滨州学院 | Carboxyl maltose controlled oxidation and purification process |
| CN115403675A (en) * | 2022-08-29 | 2022-11-29 | 滨州学院 | A kind of complexation and refining process of carboxymaltose iron |
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