CN117843818A - Oxidation composition for dextrin oxidation and method for preparing carboxymaltodextrin - Google Patents
Oxidation composition for dextrin oxidation and method for preparing carboxymaltodextrin Download PDFInfo
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- 238000007254 oxidation reaction Methods 0.000 title claims abstract description 95
- 230000003647 oxidation Effects 0.000 title claims abstract description 93
- 239000000203 mixture Substances 0.000 title claims abstract description 59
- 229920001353 Dextrin Polymers 0.000 title claims abstract description 48
- 239000004375 Dextrin Substances 0.000 title claims abstract description 48
- 235000019425 dextrin Nutrition 0.000 title claims abstract description 48
- 238000000034 method Methods 0.000 title claims abstract description 27
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 82
- 230000001590 oxidative effect Effects 0.000 claims abstract description 45
- -1 organic acid sodium salt Chemical class 0.000 claims abstract description 41
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 30
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims abstract description 16
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims abstract description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 229920002774 Maltodextrin Polymers 0.000 claims description 16
- 239000005913 Maltodextrin Substances 0.000 claims description 16
- 229940035034 maltodextrin Drugs 0.000 claims description 16
- 239000001433 sodium tartrate Substances 0.000 claims description 15
- 230000001276 controlling effect Effects 0.000 claims description 13
- 235000019524 disodium tartrate Nutrition 0.000 claims description 13
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 235000019265 sodium DL-malate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- WPUMTJGUQUYPIV-UHFFFAOYSA-L sodium malate Chemical compound [Na+].[Na+].[O-]C(=O)C(O)CC([O-])=O WPUMTJGUQUYPIV-UHFFFAOYSA-L 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 3
- 239000002351 wastewater Substances 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 32
- 229910052742 iron Inorganic materials 0.000 description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- MFBBZTDYOYZJGB-HAONTEFVSA-L (2s,3s,4s,5r)-4-[(2r,3r,4r,5s,6r)-5-[(2r,3r,4r,5s,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2,3,5,6-tetrahydroxyhexanoate;iron(3+);oxyg Chemical compound O.[OH-].[O-2].[Fe+3].O[C@@H]1[C@@H](O)[C@@H](O[C@@H]([C@H](O)CO)[C@@H](O)[C@H](O)C([O-])=O)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@@H](CO)O1 MFBBZTDYOYZJGB-HAONTEFVSA-L 0.000 description 6
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 6
- 229960004131 ferric carboxymaltose Drugs 0.000 description 6
- 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 5
- 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 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000005708 Sodium hypochlorite Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 4
- 208000007502 anemia Diseases 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940124274 edetate disodium Drugs 0.000 description 2
- MSNWSDPPULHLDL-UHFFFAOYSA-K ferric hydroxide Chemical compound [OH-].[OH-].[OH-].[Fe+3] MSNWSDPPULHLDL-UHFFFAOYSA-K 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000012085 test solution Substances 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
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical group [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 229910015189 FeOx Inorganic materials 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 102000018434 Iron-Regulatory Proteins Human genes 0.000 description 1
- 108010066420 Iron-Regulatory Proteins Proteins 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- LDNOWZOWQPKCKK-UHFFFAOYSA-N OO.[Na].[Na] Chemical group OO.[Na].[Na] LDNOWZOWQPKCKK-UHFFFAOYSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007865 diluting Methods 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
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 239000005417 food ingredient Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229940032961 iron sucrose Drugs 0.000 description 1
- MVZXTUSAYBWAAM-UHFFFAOYSA-N iron;sulfuric acid Chemical compound [Fe].OS(O)(=O)=O MVZXTUSAYBWAAM-UHFFFAOYSA-N 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
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000018343 nutrient deficiency Nutrition 0.000 description 1
- 208000030212 nutrition disease Diseases 0.000 description 1
- 208000019180 nutritional disease Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- MQBDAEHWGRMADS-XNHLMZCASA-M sodium;(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-);(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate Chemical compound [O-2].[O-2].[O-2].[Na+].[Fe+3].[Fe+3].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.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.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.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.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.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 MQBDAEHWGRMADS-XNHLMZCASA-M 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention belongs to the field of medicine synthesis, and discloses an oxidation composition for dextrin oxidation, which contains 90-99 parts by weight of hydrogen peroxide, 1-4 parts by weight of disodium ethylenediamine tetraacetate and 0.5-4 parts by weight of organic acid sodium salt. According to the invention, the defects of poor stability and severe oxidation process of hydrogen peroxide under an alkaline system can be effectively overcome by combining disodium ethylenediamine tetraacetate with part of organic acid sodium salt. In the dextrin oxidation link, the reaction is stable by controlling the temperature and the dropping speed, the whole process is consistent with the traditional sodium hypochlorite-sodium bromide oxidant combination phenomenon, and the dextrin oxidation link has an equivalent effect and can effectively replace the sodium hypochlorite-sodium bromide oxidant combination; and the consumption of the oxidant can be reduced, the oxidation reaction temperature is reduced, the energy consumption is reduced, the cost is saved, less waste water is generated, the discharge of chloride ions is directly reduced, and the environment protection is facilitated.
Description
Technical Field
The invention belongs to the field of medicine synthesis, relates to an oxidation composition for dextrin oxidation and a method for preparing carboxymaltodextrin, and in particular relates to an oxidation composition for dextrin oxidation in iron carboxymaltose medicine synthesis and a method for preparing carboxymaltodextrin by dextrin oxidation.
Background
Iron deficiency anemia is a common nutritional disorder, which is one of the world-recognized nutritional deficiencies. Iron deficiency anemia is anemia that occurs due to the inability of iron storage in the body to meet the needs of normal erythropoiesis.
Currently, about 20 hundred million people worldwide suffer from anemia, of which more than 90% are iron deficiency anemia from a clinical statistical perspective, that is, 9 out of 10 anemia patients are iron deficiency anemia patients.
For treating iron deficiency anemia, it is most commonly used to take orally or inject iron. The oral iron preparation often has obvious gastrointestinal discomfort symptoms, and patients can interrupt treatment due to intolerance; oral iron agents are also affected by the disturbance of food ingredients and iron reserves in the body, especially in many chronic disease and tumor patients, the inflammatory mediators in the body are increased, and the inflammatory mediators can induce the liver to synthesize iron regulatory proteins which down regulate the expression of iron transport proteins on the surface membrane of gastrointestinal tracts and iron storage cells in the body, thereby affecting the absorption and utilization of iron, and the effect of the oral iron agents is often poor or ineffective at all. In addition, in gastrointestinal diseases, when the iron reservoir needs to be quickly restored and the oral administration is insufficient to supplement the human needs, intravenous iron supplement is needed under the conditions that the oral iron agent cannot be tolerated and cannot be complied with.
Currently, common intravenous iron agents used in the world for clinical applications include iron dextran, iron sodium gluconate complex, iron sucrose, iron isomalt 1000 and iron carboxyl maltose.
Iron carboxymaltose is a novel medicine for treating or preventing iron deficiency anemia. The iron carboxyl maltose is a colloidal iron (III) hydroxide compounded with carboxyl maltose, is a sugar polymer releasing iron, and has the chemical name of polynuclear iron (III) hydroxide 4 (R) - [ poly- (1- & gt 4) -O-alpha-D-glucopyranosyl]-oxy-2 (R), 3 (S), 5 (R), 6-tetrahydroxyhexanoic acid complex, formula: [ FeOx (OH) y (H) 2 O)z]n[{(C 6 H 10 O 5 )m(C 6 H 12 O 7 )}l]k, where n.apprxeq.103, m.apprxeq. 8,l.apprxeq.11, k.apprxeq.4 (l represents the average degree of branching of the ligand) with a relative molecular weight of 110000 ～ 230000Da.
The synthesis of ferric carboxymaltose uses dextrin and ferric trichloride as starting materials. The dextrin is carboxylated after oxidation under certain conditions, and then is complexed with iron ions in ferric trichloride to form a macromolecular compound ferric carboxymaltose with the carboxyl maltodextrin as a sugar shell and iron ions.
Oxidation of dextrins is a critical first step in the synthesis of iron carboxymaltose, a stage of sugar shell formation. By establishing the oxidation endpoint control, consistency in sugar shell formation is ensured. The key intermediate produced in the step is carboxyl maltodextrin formed after dextrin is oxidized, and the weight average molecular weight and the oxidation degree are key quality attributes. The size of the molecular weight and the oxidation degree directly influence the size of the sugar shell, and further influence the molecular weight and in-vivo distribution of the final product carboxyl maltose iron.
Currently, the oxidation of dextrins is only an oxidation process with a combination of sodium hypochlorite-sodium bromide oxidizing agent. The oxidation process needs sodium hypochlorite with high concentration (the effective chlorine content is more than or equal to 9%) and sodium bromide with high price, the cost is high, unpleasant and pungent smell can be generated in production, a large amount of wastewater containing chloride ions and bromide ions can be discharged, and the environmental protection treatment cost is high.
Hydrogen peroxide is widely used as an oxidant and is not suitable for the oxidation of dextrin directly. The main reasons are that the oxidation capacity of hydrogen peroxide is far stronger than that of sodium hypochlorite, the oxidation process is too severe, the molecular weight of the oxidized product carboxyl maltodextrin is not uniform, the hydrogen peroxide is quickly decomposed under alkaline conditions, the stability is poor, the oxidation process of the dextrin is uncontrollable, the consistency of the molecular weight of the oxidized product and the oxidation degree is poor, and the requirements of stable and controllable quality cannot be met. So far, no technology report on the production of ferric carboxymaltose by oxidizing dextrin with hydrogen peroxide is seen.
Disclosure of Invention
The invention aims to provide an oxidation composition for oxidizing dextrin in the synthesis of iron carboxyl maltose drugs.
The purpose of the invention is realized by the following technical scheme:
an oxidation composition for dextrin oxidation, which contains 90-99 parts by weight of hydrogen peroxide, 1-4 parts by weight of disodium ethylenediamine tetraacetate and 0.5-4 parts by weight of organic acid sodium salt; the total amount of the hydrogen peroxide, the disodium ethylenediamine tetraacetate and the organic acid sodium salt is 100 parts by weight.
Preferably, the oxidizing composition contains 94 to 97 parts by weight of hydrogen peroxide, 1.9 to 4 parts by weight of disodium ethylenediamine tetraacetate and 0.95 to 4 parts by weight of organic acid sodium salt.
Specifically, the oxidizing composition contains 97 parts by weight of hydrogen peroxide, 2 parts by weight of disodium edetate, 1 part by weight of organic acid sodium salt, 95.10 parts by weight of hydrogen peroxide, 3.92 parts by weight of disodium edetate, 0.98 part by weight of organic acid sodium salt, 95 parts by weight of hydrogen peroxide, 4 parts by weight of disodium edetate, 1 part by weight of organic acid sodium salt, 96.04 parts by weight of hydrogen peroxide, 1.98 parts by weight of disodium edetate, 1.98 parts by weight of organic acid sodium salt, 96 parts by weight of hydrogen peroxide, 2 parts by weight of disodium edetate, 2 parts by weight of organic acid sodium salt, 94.18 parts by weight of hydrogen peroxide, 1.94 parts by weight of disodium edetate, 3.88 parts by weight of organic acid sodium salt, 94 parts by weight of hydrogen peroxide, 2 parts by weight of disodium edetate, and 2 parts by weight of organic acid sodium salt.
Most preferably, the oxidizing composition comprises 97 parts by weight of hydrogen peroxide, 2 parts by weight of disodium edetate and 1 part by weight of sodium salt of an organic acid.
The mass fraction of the hydrogen peroxide is 3-10%, preferably 5%.
The organic acid sodium salt is selected from one or more of sodium citrate, disodium tartrate or disodium malate, and is preferably disodium tartrate.
A method of preparing the oxidizing composition for dextrin oxidation, comprising: sequentially adding hydrogen peroxide and disodium ethylenediamine tetraacetate into the purification space, controlling the temperature to be not more than 30 ℃, and uniformly stirring; adding organic acid sodium salt, controlling the temperature not to exceed 30 ℃, stirring and dissolving.
It is another object of the present invention to provide a process for preparing carboxymaltodextrins comprising the steps of:
taking 100 parts by weight of maltodextrin and 38-45 parts by weight of oxidizing composition; preparing a dextrin solution by using purified water, regulating the pH of the dextrin solution to 10.5-11.5 by using a sodium hydroxide solution, then dripping an oxidation composition, dripping the oxidation composition while dripping the sodium hydroxide solution to maintain the pH of the system to 10.5-11.5, controlling the temperature of the system to 20-30 ℃ in the dripping process, and controlling the dripping time to be 1-1.5 hours; after the dripping is finished, maintaining the temperature of the system at 20-30 ℃, firstly maintaining the pH value of the system at 11.5+/-0.5 within 10 minutes, and then continuously stirring for 1-1.5 hours; and after the reaction is finished, dropwise adding hydrochloric acid to adjust the pH value of the system to 6.5+/-0.5.
Preferably, 40 to 42 parts by weight of the oxidizing composition are used per 100 parts by weight of maltodextrin.
Specifically, for every 100 weight parts of maltodextrin, 40, 40.05, 40.45, 40.50, 40.85, 40.90, 41 or 41.25 weight parts of the oxidizing composition are used.
More preferably, 40 parts by weight of the oxidizing composition are used per 100 parts by weight of maltodextrin.
The mass fraction of the dextrin solution is 28-30%.
The mass fraction of the sodium hydroxide solution is 30%.
Compared with the prior art, the invention has the beneficial effects that:
compared with other oxidants, hydrogen peroxide is used as the widely applied oxidant, and has the following advantages: the residue after the hydrogen peroxide is water, is environment-friendly, has strong self-oxidability, and generally has relatively smaller dosage under the condition of achieving the same oxidation effect. However, hydrogen peroxide has defects, mainly has poor stability under an alkaline system, has a severe oxidation process, has obvious bubbles, has dangerousness, and is not easy to control the process progress. In the synthesis of ferric carboxymaltose, the oxidation of the initial material dextrin needs a continuous and stable oxidation process, so that carboxylated dextrin with stable molecular weight and oxidation number can be produced, and further a sugar shell with relatively uniform molecular weight is formed, so that the final ferric carboxymaltose has stable and uniform molecular weight and iron content.
Aiming at the characteristics of hydrogen peroxide, the invention discovers that the combination of disodium ethylenediamine tetraacetate and partial organic acid sodium salt can effectively make up the defects of poor stability and more severe oxidation process of hydrogen peroxide under an alkaline system through a large number of screening. In the dextrin oxidation link, the reaction is stable by controlling the temperature and the dropping speed, the whole process is consistent with the traditional sodium hypochlorite-sodium bromide oxidant combination phenomenon, and the dextrin oxidation link has an equivalent effect and can effectively replace the sodium hypochlorite-sodium bromide oxidant combination; and the consumption of the oxidant can be reduced, the oxidation reaction temperature is reduced, the cost is saved, the energy consumption is reduced, less waste water is generated, the discharge of chloride ions is directly reduced, and the environment protection is facilitated.
Detailed Description
The following examples are presented to specifically illustrate the oxidizing agent compositions for the oxidation of dextrins in the synthesis of ferric carboxymaltose and the methods of their use for the oxidation of dextrins.
The effectiveness of the present oxidizer combination is determined by comparing the oxidation process of the sodium hypochlorite-sodium bromide oxidizer combination with the detection of the key index "oxidation number, molecular weight" of the dextrin oxide carboxymaltodextrin.
[ molecular weight ] is measured by reference to size exclusion chromatography (rule 0514 of the fourth edition of Chinese pharmacopoeia 2020).
Test solution: precisely measuring the proper amount of the product (about 200mg corresponding to maltodextrin), placing in a 10mL measuring flask, diluting with water to scale, shaking, filtering with 0.45 μm filter membrane, and collecting the filtrate.
Mobile phase: phosphate buffer solution is used as a mobile phase, the flow rate is 0.5mL/min, and the column temperature is 45 ℃.
Assay: precisely measuring the solution of the sample, injecting into a liquid chromatograph, and recording the chromatogram. The weight average molecular weight of the product was calculated by GPC software.
0.45g of maltodextrin is taken, precisely weighed, placed in a 200mL measuring flask, heated to be dissolved in water, cooled, diluted to scale with water and shaken uniformly to be used as a reference solution. The other amount of dextrin oxide 7mL was measured, put in a 50mL measuring flask, diluted with water to the scale, and shaken well to obtain a sample solution. The oxidation degree of the product was calculated as follows.
Oxidation degree (%) = (1-C1V 1/C2V 2) ×100%
Wherein, C1 is the concentration of maltodextrin in the reference substance solution, and the unit is mg/mL; v1 is the total volume of the consumed reference substance solution, and the unit is mL; c2 is the concentration of maltodextrin in the dextrin oxide solution in mg/mL; v2 is the total volume of the consumed test solution in mL.
The current oxidation process for sodium hypochlorite-sodium bromide oxidizer combination is as follows:
840g of purified water was added to the reaction flask, 350g of maltodextrin and 10g of sodium bromide were added with stirring, and the mixture was stirred until the dextrin was completely dissolved.
And (3) dropwise adding 30% sodium hydroxide solution into the dextrin solution to adjust the pH to 11.5, then dropwise adding 170g of sodium hypochlorite solution (the available chlorine is not less than 9%), simultaneously dropwise adding 30% sodium hydroxide solution to maintain the pH of the solution to be 11.5+/-0.5, controlling the system temperature to be 30-40 ℃ in the dropwise adding process, and dropwise adding the sodium hypochlorite solution for about 90 minutes. After the dripping is finished, maintaining the temperature of the system at 20-30 ℃, monitoring the pH of the solution within 10 minutes, adding a proper amount of 30% sodium hydroxide solution to adjust the pH of the dextrin solution to 11.5+/-0.5, and stirring for 1 hour. And dropwise adding 20% hydrochloric acid to adjust the pH of the system to 6.5+/-0.5, sampling after the reaction is finished, and checking the oxidation value and the molecular weight.
Detection results of multiple sets of experiments: the oxidation number is more than or equal to 91 percent (the internal control standard is more than or equal to 90 percent), and the molecular weight is 16000-16500 (the internal control standard is 16000-17000).
Example 1
Carboxymaltodextrins were prepared according to the oxidation composition ratios of table 1, their oxidation numbers and molecular weights were determined and compared with current sodium hypochlorite-sodium bromide oxidant combination processes.
The preparation process of the carboxymaltodextrine comprises the following steps:
840g of purified water was added to the reaction flask, 350g of maltodextrin was added with stirring, and stirring was performed until the dextrin was completely dissolved.
Preparing an oxidation composition solution of hydrogen peroxide-disodium ethylenediamine tetraacetate-disodium tartrate according to the prescription amount of the table 1: adding hydrogen peroxide and disodium ethylenediamine tetraacetate in sequence in the purifying space, controlling the temperature to be not more than 30 ℃, and uniformly stirring; adding disodium tartrate, controlling the temperature to be not more than 30 ℃, stirring and dissolving.
To the dextrin solution was added dropwise 30% sodium hydroxide solution, and the pH of the dextrin solution was adjusted to 11.5. And then dropwise adding the oxidizing composition solution, dropwise adding 30% sodium hydroxide solution while dropwise adding the oxidizing composition to maintain the pH of the solution at 11.5+/-0.5, controlling the system temperature to be 20-28 ℃ in the dropwise adding process, and dropwise adding the oxidizing composition solution for about 90 minutes.
After the dripping is finished, maintaining the temperature of the system at 20-28 ℃, monitoring the pH of the solution within 10 minutes, adding a proper amount of 30% sodium hydroxide solution to adjust the pH of the dextrin solution to 11.5+/-0.5, and continuously stirring for 1 hour. After the reaction, dropwise adding 20% hydrochloric acid to adjust the pH of the system to 6.5+/-0.5, sampling, and inspecting the oxidation value and the molecular weight.
TABLE 1 influence of Hydrogen peroxide concentration in oxidizing compositions on carboxymaltodextrin oxidation number and molecular weight
The results are shown in Table 1, and it can be seen that, except for the oxidation composition of hydrogen peroxide-disodium ethylenediamine tetraacetate-disodium tartrate, the effect of carboxymaltodextrin obtained by using the oxidation composition of the invention is equivalent to that of the sodium hypochlorite-sodium bromide oxidation composition, the oxidation values reach the internal control standard, the molecular weight is stable, and the oxidation composition is consistent with that of the sodium hypochlorite-sodium bromide oxidation composition; and the total consumption of the oxydol-disodium ethylenediamine tetraacetate-disodium tartrate oxidation composition is 140.2g, which is less than 180g of sodium hypochlorite-sodium bromide oxidation composition. From the analysis of the oxidation number, the hydrogen peroxide concentration is not less than 3%, so that the internal control standard of 90% can be achieved, and the oxidation number is not obviously increased after the hydrogen peroxide concentration exceeds 5%. In view of safety and cost, it is preferable to use 5% hydrogen peroxide to prepare an oxidizing composition of disodium edetate-disodium tartrate.
Example 2
An oxidation composition solution of hydrogen peroxide-disodium ethylenediamine tetraacetate-disodium tartrate was prepared according to the prescription of table 2, carboxymaltodextrins were prepared according to the preparation process of example 1, and the oxidation number and molecular weight of carboxymaltodextrins were measured and are shown in table 2.
TABLE 2 influence of disodium edetate usage in oxidizing compositions on carboxymaltodextrin oxidation number and molecular weight
Note that: prescription 5 did not measure molecular weight because the oxidation number was well below the internal control standard.
The results are shown in Table 2, and it can be seen that the oxidation number is only 42% when disodium ethylenediamine tetraacetate is not added, and the oxidation number may be related to too fast decomposition of hydrogen peroxide, i.e. disodium ethylenediamine tetraacetate plays a role in stabilizing hydrogen peroxide in combination. However, when the amount of disodium edetate reaches 4% (i.e., the amount of disodium edetate is 5.6 g), the oxidation number is slightly reduced, probably because the stability of disodium edetate to hydrogen peroxide is too strong, and the oxidizing property of hydrogen peroxide is inhibited. In combination with practical situations and cost, an oxidizing composition of hydrogen peroxide-disodium ethylenediamine tetraacetate-disodium tartrate with disodium ethylenediamine tetraacetate content of 2% is preferably used.
Example 3
An oxidation composition solution of hydrogen peroxide-disodium ethylenediamine tetraacetate-disodium tartrate was prepared according to the prescription of table 3, carboxymaltodextrins were prepared according to the preparation process of example 1, and the oxidation number and molecular weight of carboxymaltodextrins were determined as shown in table 3.
TABLE 3 influence of the amount of disodium tartrate in the oxidized compositions on the oxidation number and molecular weight of carboxymaltodextrins
Note that: prescription 8 did not measure molecular weight because the oxidation number was well below the internal control standard.
The results are shown in Table 3, and it can be seen that when the oxidizing composition does not contain disodium tartrate, the oxidation number of carboxymaltodextrine is only 66%, which indicates that the combination of disodium tartrate and disodium ethylenediamine tetraacetate can more effectively maintain the stability of hydrogen peroxide and prevent the hydrogen peroxide from decomposing too fast. When the content of the disodium tartrate is 1 percent of the oxidation composition (namely, the using amount of the disodium tartrate is 1.4 g), the expected effect can be achieved; when the content of the disodium tartrate exceeds 2% (i.e., the amount of the disodium tartrate is 2.8 g), the oxidation number is not substantially affected. In combination with the actual situation, it is preferable to use an oxidizing composition of hydrogen peroxide-disodium edetate-disodium tartrate with a disodium tartrate content of 1%.
Example 4
Carboxymaltodextrins were prepared according to the preparation procedure of example 1, with the oxidation number and molecular weight determined by gradually increasing the amounts according to the recipe for each batch of table 4, and the oxidation number and molecular weight of carboxymaltodextrins are shown in table 4.
TABLE 4 oxidation number and molecular weight of carboxymaltodextrins of different batches
As shown in Table 4, the result of the whole amplification process completely meets the expectations, the oxidation number and molecular weight of the carboxymaltodextrins reach the internal control standard, and the result is stable. Illustrating that the oxidizing composition of the present invention is fully capable of replacing current sodium hypochlorite-sodium bromide oxidizing compositions.
Claims (10)
1. An oxidizing composition for the oxidation of dextrins, characterized in that: the oxidizing composition contains 90-99 parts by weight of hydrogen peroxide, 1-4 parts by weight of disodium ethylenediamine tetraacetate and 0.5-4 parts by weight of organic acid sodium salt.
2. Oxidizing composition for the oxidation of dextrins according to claim 1, characterized in that: the oxidizing composition contains 94-97 parts by weight of hydrogen peroxide, 1.9-4 parts by weight of disodium ethylenediamine tetraacetate and 0.95-4 parts by weight of organic acid sodium salt.
3. Oxidizing composition for the oxidation of dextrins according to claim 2, characterized in that: the oxidizing composition contains 97 parts by weight of hydrogen peroxide, 2 parts by weight of disodium ethylenediamine tetraacetate and 1 part by weight of organic acid sodium salt.
4. An oxidizing composition for the oxidation of dextrins according to claim 1, 2 or 3, characterized in that: the mass fraction of the hydrogen peroxide is 3-10%.
5. The oxidizing composition for dextrin oxidation as claimed in claim 4, wherein: the mass fraction of the hydrogen peroxide is 5%.
6. An oxidizing composition for the oxidation of dextrins according to claim 1, 2 or 3, characterized in that: the organic acid sodium salt is selected from one or more of sodium citrate, disodium tartrate or disodium malate.
7. The oxidizing composition for dextrin oxidation according to claim 6, characterized in that: the organic acid sodium salt is disodium tartrate.
8. A process for preparing an oxidizing composition for the oxidation of dextrins according to claim 1, characterized in that: comprising the following steps: sequentially adding hydrogen peroxide and disodium ethylenediamine tetraacetate into the purification space, controlling the temperature to be not more than 30 ℃, and uniformly stirring; adding organic acid sodium salt, controlling the temperature not to exceed 30 ℃, stirring and dissolving.
9. A process for preparing carboxymaltodextrins, characterized in that: the method comprises the following steps: taking 100 parts by weight of maltodextrin, 38-45 parts by weight of the oxidizing composition according to any one of claims 1-7; preparing a dextrin solution by using purified water, regulating the pH of the dextrin solution to 10.5-11.5 by using a sodium hydroxide solution, then dripping an oxidation composition, dripping the oxidation composition while dripping the sodium hydroxide solution to maintain the pH of the system to 10.5-11.5, controlling the temperature of the system to 20-30 ℃ in the dripping process, and controlling the dripping time to be 1-1.5 hours; after the dripping is finished, maintaining the temperature of the system at 20-30 ℃, firstly maintaining the pH value of the system at 11.5+/-0.5 within 10 minutes, and then continuously stirring for 1-1.5 hours; and dropwise adding hydrochloric acid to adjust the pH of the system to 6.5+/-0.5.
10. The process for preparing carboxymaltodextrins according to claim 9, characterized in that: 40 to 42 parts by weight of the oxidizing composition per 100 parts by weight of maltodextrin; preferably, 40 parts by weight of the oxidizing composition are used per 100 parts by weight of maltodextrin.
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