CN115403675A - Complexing and refining process of ferric carboxymaltose - Google Patents
Complexing and refining process of ferric carboxymaltose Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 230000000536 complexating effect Effects 0.000 title claims abstract description 18
- 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 title claims abstract description 14
- 229960004131 ferric carboxymaltose Drugs 0.000 title claims abstract description 14
- 238000007670 refining Methods 0.000 title claims abstract description 13
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 33
- 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 claims abstract description 28
- 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 claims abstract description 28
- 238000003756 stirring Methods 0.000 claims abstract description 26
- 238000010438 heat treatment Methods 0.000 claims abstract description 18
- 229910052742 iron Inorganic materials 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 15
- 238000004108 freeze drying Methods 0.000 claims abstract description 11
- 238000005374 membrane filtration Methods 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 238000001556 precipitation Methods 0.000 claims description 31
- 239000000463 material Substances 0.000 claims description 24
- 239000007788 liquid Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000005913 Maltodextrin Substances 0.000 claims description 17
- 229920002774 Maltodextrin Polymers 0.000 claims description 17
- 229940035034 maltodextrin Drugs 0.000 claims description 17
- 239000006228 supernatant Substances 0.000 claims description 15
- 238000000108 ultra-filtration Methods 0.000 claims description 14
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 230000003647 oxidation Effects 0.000 claims description 7
- 239000000919 ceramic Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000010668 complexation reaction Methods 0.000 claims description 5
- 238000002161 passivation Methods 0.000 claims description 5
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 229960004887 ferric hydroxide Drugs 0.000 claims description 4
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 230000002572 peristaltic effect Effects 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000000084 colloidal system Substances 0.000 claims description 3
- 239000000498 cooling water Substances 0.000 claims description 3
- 238000007599 discharging Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 238000004806 packaging method and process Methods 0.000 claims description 3
- 239000012466 permeate Substances 0.000 claims description 3
- 238000005057 refrigeration Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 239000012530 fluid Substances 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 238000009826 distribution Methods 0.000 abstract description 5
- 239000002105 nanoparticle Substances 0.000 abstract description 4
- 239000013585 weight reducing agent Substances 0.000 abstract description 4
- 239000002245 particle Substances 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000012869 ethanol precipitation Methods 0.000 abstract description 2
- 230000007774 longterm Effects 0.000 abstract description 2
- 238000001471 micro-filtration Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 102000008857 Ferritin Human genes 0.000 description 2
- 108050000784 Ferritin Proteins 0.000 description 2
- 238000008416 Ferritin Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000011344 liquid material Substances 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- -1 iron ions Chemical class 0.000 description 1
- MVZXTUSAYBWAAM-UHFFFAOYSA-N iron;sulfuric acid Chemical compound [Fe].OS(O)(=O)=O MVZXTUSAYBWAAM-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B31/00—Preparation of derivatives of starch
- C08B31/18—Oxidised starch
- C08B31/185—Derivatives of oxidised starch, e.g. crosslinked oxidised starch
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention belongs to the field of medicines, and particularly relates to a complexing and refining process of carboxyl ferric maltose. According to the invention, the temperature, the pH value, the alkali dripping speed and the stirring speed which influence the complexing are accurately controlled, so that the ferric carboxymaltose nanoparticles are uniformly assembled, the molecular weight distribution meets the requirement, and the iron carboxymaltose nanoparticles are not obviously changed in the placing process; the ferric carboxyl maltose particles are passivated by adopting a programmed heating method, so that the molecular weight reduction trend of the finished product is effectively controlled; the ethanol precipitation, the microfiltration membrane filtration and the programmed freeze-drying process are comprehensively adopted to effectively control visible foreign matters, solvent residues, water and the like in the carboxyl ferric maltose, so that the stability of the product is further improved, and the molecular weight reduction trend of long-term stability is solved.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a complexing and refining process of carboxyl ferric maltose.
Background
Ferric carboxymaltose is a novel nano-iron complex, ferric hydroxide colloidal particles are stably complexed in the ferric carboxymaltose by oxidized maltodextrin (namely, the ferric carboxymaltose in the application document), the release of iron is controlled, iron ions can be combined with iron transport protein and ferritin to play a role, a large amount of free iron is prevented from being released, the formation of toxic oxides is reduced, and the Hb and serum ferritin concentrations of patients with light to moderate iron deficiency anemia can be effectively improved.
Therefore, compared with the current clinically common iron supplement, the ferric carboxymaltose has the similar iron utilization efficiency as the ferric sucrose, but does not have the defect that the iron dextran can cause anaphylactic reaction.
The key starting material for preparing the carboxyl ferric maltose is maltodextrin, and the finished product of the carboxyl ferric maltose is prepared by using the maltodextrin as the starting material through oxidation, complexation and refining.
At present, the maltodextrin raw materials in the industry have large quality fluctuation range and unstable molecular weight, the molecular weight descending trend in the stable placement process is obvious, and great troubles are brought to the preparation and process amplification of the carboxyl maltose iron, for example, the product carboxyl maltose iron has large batch fluctuation of molecular weight distribution, low molecular weight distribution concentration, unstable molecular weight and the like.
Disclosure of Invention
Aiming at the technical problems, the invention precisely controls each parameter of the key complexing process which influences the molecular weight of the product, then passivates the complexed polyferose by adopting a programmed heating method to ensure that the molecular weight of the polyferose tends to be stable, and strictly controls the residual solvent and water in the ferric carboxymaltose by adopting a freeze-drying process to ensure that the molecular weight of the ferric carboxymaltose keeps stable in the process of placing stability.
A complexing and refining process of carboxyl maltose iron specifically comprises the following steps:
(1) And (3) oxidation:
a) Dissolving maltodextrin, heating to 30-40 deg.C (preferably 30 deg.C), and adding NaClO water solution dropwise under stirring;
b) After the NaClO aqueous solution is dripped, adding sodium bromide solid into the NaClO aqueous solution under stirring, monitoring the pH value of the reaction solution on line by using a pH meter in the reaction process, and always adjusting the pH value of the solution to 10.0-11.0; simultaneously, detecting the viscosity change of the reaction solution on line, and adjusting the final pH value of the reaction solution to 3.0-5.0 to terminate the reaction when the viscosity is reduced to 65-70 mPa.s;
c) After the reaction is stopped, adding absolute ethyl alcohol into the mixture for precipitation, removing supernatant after the precipitation is completed, and adding water for dissolution; then, continuously adding absolute ethyl alcohol into the dissolved solution until the precipitation is complete; after the precipitation is finished, removing supernatant, adding water to dissolve the supernatant to obtain 25wt% -30wt% of intermediate solution, and performing the next ceramic membrane filtration step;
(2) Ceramic membrane filtration and purification:
A. selecting an ultrafiltration membrane with the pore diameter of 3Kd-5Kd to carry out ultrafiltration on the intermediate solution obtained in the step (1); when the volume of the permeate liquid accounts for 30-40% of the total weight of the materials through ultrafiltration, taking a material sample of the trapped liquid for molecular weight detection, and stopping ultrafiltration when the peak height ratio of the molecular weight of the detected intermediate is more than or equal to 1.5 and more than or equal to 1.2;
B. b, adding absolute ethyl alcohol into the trapped fluid obtained in the step A for precipitation, removing supernatant after complete precipitation, and then drying in vacuum at 30-40 ℃ to obtain an intermediate carboxyl maltose;
(3) The carboxyl maltose iron is prepared by utilizing the obtained intermediate carboxyl maltose through complexation passivation, refining and freeze-drying.
Further, the precipitation conditions are: adding absolute ethyl alcohol with the volume 5-6 times of that of the dissolving solution, wherein the precipitation time is 5-8h, and the precipitation operation is as follows: adding anhydrous ethanol, stirring for 15min, and standing for 50min.
Further, the maltodextrin has a DE value of 16-20.
Further, the addition ratio of the maltodextrin to the NaClO and the sodium bromide is 100: (10-15): 1, preferably 100:10.4:1.
furthermore, the concentration of the NaClO aqueous solution is 5.2wt%, and the adding speed is (1.5-2.0) L/h.
Further, the specific operation of step (3) is as follows:
the first complexing passivation process comprises the following steps:
a) FeCl is added 3 .6H 2 Preparation of FeCl from O 3 Putting the solution into a reaction tank, adding the intermediate carboxyl maltose obtained in the step (2) into the solution under the stirring state, stirring the mixture until the mixture is uniformly mixed, then adjusting the temperature of the reaction liquid to 30-40 ℃, and stirring the mixture (preferably at the stirring speed of 350 rpm) by using a peristaltic pump to add Na into the reaction liquid 2 CO 3 The solution is quickly dripped into the reaction solution to prepare ferric hydroxide colloid;
b) Above Na 2 CO 3 After the solution is dropwise added, dropwise adding an alkaline solution (preferably 6mol/LNaOH solution) into the solution to adjust the pH of the reaction solution to 10.5-11.0, wherein the dropwise adding speed of the alkaline solution is half of that of the sodium carbonate solution;
c) After the pH value of the feed liquid is adjusted to 10.5-11.0, sealing the reaction tank, and raising the temperature of the feed liquid to 50 +/-2 ℃ and keeping the temperature for 50min; then, the temperature of the feed liquid is increased to 68 +/-2 ℃ and is kept for 1h; after the heat preservation is finished, adjusting the pH =6.0 +/-0.1 of the complexing system, heating to 88 +/-2 ℃ and keeping for 60min, and keeping the pH =6.1 +/-0.1 of the system in the reaction process; then continuously heating to 98 +/-2 ℃ and keeping for 50min, and always adjusting the pH value to 6.1 +/-0.1 in the stage; finally, pressurizing the reaction tank to 5 atmospheric pressures, heating the reaction tank to 121 +/-2 ℃ by steam, and continuously maintaining the temperature for 17min; after the reaction is finished, adding cooling water to cool the materials to room temperature, and then adjusting the pH =6.1 +/-0.1 of the materials for later use;
(II) purification step
Filtering the material obtained in the step (I) (preferably passing through a 0.22 micron filter element), taking a filtrate, adding absolute ethyl alcohol with the same volume as the filtrate into the filtrate, and precipitating; removing supernatant after precipitation is finished, centrifuging the residual materials, collecting the centrifuged precipitate, adding water for dissolution, uniformly stirring, adjusting the pH of the solution to be =6.1 +/-0.1, and then filtering the obtained solid for freeze-drying;
(III) Freeze-drying
a) Front and rear boxes are refrigerated: placing the material obtained in the step (II) in a freeze dryer, closing a door of the freeze dryer, closing an air release valve, opening a heat conduction cycle, starting a compressor, opening a valve, and starting front box refrigeration to-30-35 ℃; closing the heat conduction cycle when the front box is refrigerated to-30 to-35 ℃, opening a valve of the rear box to refrigerate the rear box to-45 to-50 ℃, and keeping the temperature for 2 hours;
b) And then opening an intermediate valve, opening a vacuum pump to reduce the vacuum degree to below 50pa, immediately opening a heat conduction cycle, heating the front box to 35-40 ℃, then keeping the temperature for 2 hours, closing a compressor after finishing heat preservation, closing the vacuum pump, closing the intermediate valve, closing the heat conduction cycle, opening a deflation valve to start discharging, collecting the freeze-dried material, weighing and packaging to obtain the finished product of the carboxyl maltose iron.
Further, in each of the above steps, the pH was adjusted with 6mol/L HCl solution or 6mol/L NaOH solution.
Further, the carboxymaltose and FeCl 3 .6H 2 O、Na 2 CO 3 Is addedThe quantity ratio is 100: (50-70): (50-70), preferably 100:60:57.
further, the Na 2 CO 3 The concentration of the solution is 10 percent, and the adding speed is (1-2.0) L/h.
Compared with the prior art, the invention has the following beneficial effects:
(1) Through accurately controlling the temperature, the pH value, the alkali dripping speed and the stirring rotating speed which influence the complexing, the ferric carboxymaltose nanoparticles are uniformly assembled, the molecular weight distribution meets the requirement, and the iron carboxymaltose nanoparticles are not obviously changed in the placing process.
(2) The ferric carboxymaltose particles are passivated by adopting a programmed heating method, so that the molecular weight reduction trend of the finished product is effectively controlled.
(3) The ethanol precipitation, the microfiltration membrane filtration and the programmed freeze-drying process are comprehensively adopted to effectively control visible foreign matters, solvent residues, water and the like in the carboxyl ferric maltose, so that the stability of the product is further improved, and the molecular weight reduction trend of long-term stability is solved.
Detailed Description
The technical solution of the present invention is further described in detail by the following specific examples.
The starting material used in the examples was maltodextrin available from the West king corporation, DE 18.
Example 1 a process for complexing and refining ferric carboxymaltose, comprising the following steps in sequence:
(1) And (3) oxidation:
a) Weighing 400g of medicinal maltodextrin, adding water into a beaker to dissolve the medicinal maltodextrin to ensure that the mass concentration of the medicinal maltodextrin is 30%, continuously stirring for 4-6h until the medicinal maltodextrin is completely dissolved (stirring for 5 h in the embodiment), then heating to 30 ℃, slowly and uniformly adding 800ml of NaClO solution (with the concentration of 5.2 wt%) into the beaker under stirring, and finishing the adding after 25-30 min.
b) After the NaClO solution is dripped, adding 4g of sodium bromide solid into the NaClO solution under stirring for reaction, monitoring the pH value of the reaction solution on line by using a pH meter in the reaction process, and adjusting the pH value of the solution to 10.0-11.0 by using 6mol/L hydrochloric acid; and simultaneously detecting the viscosity change of the reaction solution on line, and when the viscosity is reduced to 65-70 mPa.s, adjusting the final pH value to 3.0-5.0 by using 6mol/L hydrochloric acid (in the embodiment, when the viscosity is reduced to 68 mPa.s, the pH value is adjusted to 4.0).
c) Then adding absolute ethyl alcohol with the volume 5 times that of the feed liquid into the mixture for precipitation, wherein the precipitation time is 6 hours, removing supernatant after the precipitation is finished, and adding water to dissolve the mixture to 50 percent of concentration; then, 6 times of volume of absolute ethyl alcohol is added into the dissolved solution continuously, and precipitation is continued for 6 hours.
d) And (4) after the precipitation is finished, removing the supernatant, adding water to dissolve the supernatant until 25wt% -30wt% of an intermediate solution is obtained, and performing the next ceramic membrane filtration step.
(2) Ceramic membrane filtration and purification:
a) Ultrafiltration is carried out on the intermediate solution by selecting an ultrafiltration membrane with the aperture of 3 Kd; when the volume of the permeate liquid accounts for 40 percent of the total weight of the materials through ultrafiltration, a trapped liquid material sample is taken for molecular weight detection, and when the peak height ratio of the molecular weight of the detected intermediate is more than or equal to 1.5 and more than or equal to 1.2, the ultrafiltration is stopped.
b) And (b) adding absolute ethyl alcohol with the volume 5 times that of the material liquid into the trapped liquid obtained in the step a) for precipitation for 6 hours, removing supernatant after precipitation is finished, and then drying in vacuum for 9 hours at the temperature of 30 ℃ to obtain the intermediate carboxyl maltose.
(3) And (3) a complexing passivation process:
a) Weighing Na 2 CO 3 228g of Na prepared by adding water to a concentration of 10wt% 2 CO 3 A solution;
b) Weighing FeCl 3 .6H 2 O400 g, adding water to dissolve into FeCl 3 Putting the solution with the concentration of 20% into a reaction tank, adding 240g of the intermediate carboxyl maltose obtained in the step (2) into the reaction tank under the stirring state, continuously stirring for 30min till the mixture is uniform, then adjusting the temperature of the reaction liquid to 40 +/-1 ℃, the stirring speed to be 350rpm, and using a peristaltic pump to mix the Na prepared in the step a) 2 CO 3 The solution is quickly dripped into the reaction solution within 2.0h to prepare ferric hydroxide colloid;
c) Above Na 2 CO 3 After the solution is dripped, 6mol/L NaOH solution is dripped into the solution to adjust the pH of the reaction solution, and the NaOH solution is dripped at a constant speed by a peristaltic pumpAdding the sodium carbonate solution at a speed which is half of the dropping speed of the sodium carbonate solution, and finally adjusting the pH value of the feed liquid to 10.5-11.0;
d) After the pH value of the feed liquid is adjusted to 10.5-11.0, sealing the reaction tank, and raising the temperature of the feed liquid to 50 +/-2 ℃ and keeping the temperature for 50min; then, the temperature of the feed liquid is increased to 68 +/-2 ℃ and is kept for 1h; after the heat preservation is finished, adjusting the pH of the complexing system to be 6.0 +/-0.1 by using 6mol/L HCl solution, heating to 88 +/-2 ℃, keeping the temperature at 88 +/-2 ℃ for 60min, and keeping the pH of the system to be 6.1 +/-0.1 in the reaction process; then continuously heating to 98 +/-2 ℃, keeping the temperature for 50min, and regulating the pH to 6.1 +/-0.1 by using 6mol/L HCl solution all the time in the stage; and finally pressurizing the reaction tank to 5 atmospheric pressures, heating the reaction tank to 121 +/-2 ℃ by steam, and continuously maintaining the reaction tank for 17min.
e) After the reaction is finished, cooling water is added to cool the material to room temperature, and then 6mol/L HCl solution is used for adjusting the pH of the material to be =6.1 +/-0.1 for later use.
(4) Refining step
a) Filtering the material obtained in the step (3) by using a 0.22 micron filter element, accurately measuring the volume of filtrate, adding absolute ethyl alcohol with the same volume as the filtrate into the filtrate for precipitation (the specific precipitation operation is as follows: adding anhydrous ethanol, stirring for 15min, and standing for 50 min).
b) And after the precipitation is finished, removing the supernatant, centrifuging the residual materials, collecting the centrifuged precipitate, dissolving the precipitate with purified water to obtain a 20% concentration solution, uniformly stirring, adjusting the pH to be =6.1 +/-0.1, filtering the solution through a 0.22 micron filter element, and freeze-drying the obtained solid.
(5) Freeze-drying
a) Front and rear boxes are refrigerated: placing the material obtained in the step (4) in a freeze dryer, closing a door of the freeze dryer, closing an air release valve, opening a heat conduction cycle, starting a compressor, opening a valve, and starting front box refrigeration to-30-35 ℃; when the front box is refrigerated to-30 to-35 ℃, the heat conduction cycle is closed, and the valve of the rear box is opened to refrigerate the rear box to-45 to-50 ℃, and the temperature is kept for 2 hours.
b) And then starting an intermediate valve, starting a vacuum pump to reduce the vacuum degree to be below 50pa, immediately opening a heat conduction cycle, heating the front box to 35-40 ℃, keeping the temperature for 2 hours, closing a compressor after finishing heat preservation, closing the vacuum pump, closing the intermediate valve, closing the heat conduction cycle, and opening a vent valve to start discharging.
c) And collecting the freeze-dried material, weighing and packaging to obtain the finished product of the carboxyl ferric maltose.
The applicant finds that when the process is applied to preparation of the carboxyl maltose intermediate product, maltodextrin with the DE value distribution range of 16-20 is selected as the starting raw material, so that the influence on subsequent processes such as oxidation, complexation, purification and the like due to large fluctuation of the DE value of the raw material can be effectively avoided.
According to the method, the oxidation end point can be controlled by controlling the reaction liquid to a specific viscosity, and further, the viscosity of the liquid material is detected on line, so that the complicated off-line detection of the molecular weight is avoided, the oxidation reaction end point is accurately monitored, the production process of the intermediate carboxyl maltose is more controllable, and the influence of the fluctuation of the molecular weight of the intermediate on the subsequent complexation is avoided.
By adopting an ultrafiltration membrane package with the aperture of 3Kd for ultrafiltration, impurities such as oligosaccharide micromolecules and chloride ions generated by oxidation are effectively removed, so that the dispersion coefficient of the intermediate carboxyl maltose is 1.3, and the content of sodium chloride is 4.6%.
TABLE 1
Each sample in Table 1 is a carboxyferric maltose sample prepared in example 1, and the results of the measurement are obtained after the sample is left at room temperature for 6 months and 12 months, respectively.
Claims (9)
1. A complexing and refining process of carboxyl ferric maltose specifically comprises the following steps:
(1) And (3) oxidation:
a) Dissolving maltodextrin, heating to 30-40 ℃, and dropwise adding a NaClO aqueous solution into the maltodextrin under stirring;
b) After the NaClO aqueous solution is dripped, adding sodium bromide solid into the NaClO aqueous solution under stirring, monitoring the pH value of the reaction solution on line by using a pH meter in the reaction process, and always adjusting the pH value of the solution to 10.0-11.0; simultaneously, detecting the viscosity change of the reaction solution on line, and adjusting the final pH value of the reaction solution to 3.0-5.0 to terminate the reaction when the viscosity is reduced to 65-70 mPa.s;
c) After the reaction is stopped, adding absolute ethyl alcohol into the mixture for precipitation, removing supernatant after the precipitation is completed, and adding water for dissolution; then, continuously adding absolute ethyl alcohol into the dissolved solution until the precipitation is complete; after the precipitation is finished, removing supernatant, adding water to dissolve the supernatant to obtain 25wt% -30wt% of intermediate solution, and performing the next ceramic membrane filtration step;
(2) Ceramic membrane filtration and purification:
A. selecting an ultrafiltration membrane with the pore diameter of 3Kd-5Kd to carry out ultrafiltration on the intermediate solution obtained in the step (1); when the volume of the permeate liquid accounts for 30-40% of the total weight of the materials through ultrafiltration, taking a material sample of the trapped liquid for molecular weight detection, and stopping ultrafiltration when the peak height ratio of the molecular weight of the detected intermediate is more than or equal to 1.5 and more than or equal to 1.2;
B. b, adding absolute ethyl alcohol into the trapped fluid obtained in the step A for precipitation, removing supernatant after complete precipitation, and then drying in vacuum at 30-40 ℃ to obtain an intermediate carboxyl maltose;
(3) The carboxyl maltose iron is prepared by utilizing the obtained intermediate carboxyl maltose through complexation passivation, refining and freeze-drying.
2. The process of claim 1, wherein the maltodextrin has a DE value of 16 to 20.
3. The process of claim 2, wherein the maltodextrin is added in a ratio of 100% to NaClO to sodium bromide: (10-15): 1.
4. the process according to claim 3, wherein the concentration of the NaClO aqueous solution is 5.2wt% and the addition rate is (1.5-2.0) L/h.
5. The process for complexing and refining ferric carboxymaltose according to claim 1, wherein said step (3) is specifically operated as follows:
the first complexing passivation process comprises the following steps:
a) FeCl is added 3 .6H 2 Preparation of FeCl from O 3 Putting the solution into a reaction tank, adding the intermediate carboxyl maltose obtained in the step (2) into the solution under the stirring state, stirring the mixture until the mixture is uniformly mixed, then adjusting the temperature of the reaction liquid to 30-40 ℃, and stirring the mixture by utilizing a peristaltic pump to obtain Na 2 CO 3 The solution is quickly dripped into the reaction solution to prepare ferric hydroxide colloid;
b) Above Na 2 CO 3 After the solution is dripped, dripping alkaline solution into the solution to adjust the pH of the reaction solution to 10.5-11.0, wherein the dripping speed of the alkaline solution is half of that of the sodium carbonate solution;
c) After the pH value of the feed liquid is adjusted to 10.5-11.0, sealing the reaction tank, and raising the temperature of the feed liquid to 50 +/-2 ℃ and keeping the temperature for 50min; then, the temperature of the feed liquid is increased to 68 +/-2 ℃ and is kept for 1h; after the heat preservation is finished, adjusting the pH =6.0 +/-0.1 of the complexing system, heating to 88 +/-2 ℃ and keeping for 60min, and in the reaction process, keeping the pH =6.1 +/-0.1 of the system; then continuously heating to 98 +/-2 ℃ and keeping for 50min, and always adjusting the pH value to 6.1 +/-0.1 in the stage; finally, pressurizing the reaction tank to 5 atmospheric pressures, heating the reaction tank to 121 +/-2 ℃ by steam, and continuously maintaining the temperature for 17min; after the reaction is finished, adding cooling water to cool the materials to room temperature, and then adjusting the pH =6.1 +/-0.1 of the materials for later use;
(II) purification step
Filtering the material obtained in the step (I), taking a filtrate, and adding absolute ethyl alcohol with the same volume as the filtrate into the filtrate for precipitation; removing supernatant after precipitation is finished, centrifuging the residual materials, collecting the centrifuged precipitate, adding water for dissolution, uniformly stirring, adjusting the pH of the solution to be =6.1 +/-0.1, and then filtering the obtained solid for freeze-drying;
(III) Freeze-drying
a) Front and rear boxes are refrigerated: placing the material obtained in the step (II) in a freeze dryer, closing a door of the freeze dryer, closing an air release valve, opening a heat conduction cycle, starting a compressor, opening a valve, and starting front box refrigeration to-30-35 ℃; closing the heat conduction cycle when the front box is refrigerated to-30 to-35 ℃, opening a valve of the rear box to refrigerate the rear box to-45 to-50 ℃, and keeping the temperature for 2 hours;
b) And then starting an intermediate valve, starting a vacuum pump to reduce the vacuum degree to be below 50pa, immediately opening a heat conduction cycle, heating the front box to 35-40 ℃, keeping the temperature for 2 hours, closing a compressor after finishing heat preservation, closing the vacuum pump, closing the intermediate valve, closing the heat conduction cycle, opening an air release valve to start discharging, collecting freeze-dried materials, weighing and packaging to obtain the finished product of the carboxyl maltose iron.
6. The process according to claim 5, wherein the pH of the solution is adjusted by 6mol/L HCl solution or 6mol/L NaOH solution.
7. The iron carboxymaltose complex and refinement process according to claim 6, characterized in that said carboxymaltose and FeCl 3 .6H 2 O、Na 2 CO 3 The addition amount ratio of (1) is 100: (50-70): (50-70).
8. The process of claim 7, wherein the Na is added to the iron carboxymaltose 2 CO 3 The concentration of the solution is 10 percent, and the adding speed is (1-2.0) L/h.
9. The process of complexing and refining ferric carboxymaltose according to claim 1 or 5, wherein said precipitation conditions are: adding absolute ethyl alcohol with the volume 5-6 times of that of the dissolving solution, wherein the precipitation time is 5-8h, and the precipitation operation is as follows: adding anhydrous ethanol, stirring for 15min, and standing for 50min.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108498539A (en) * | 2018-05-03 | 2018-09-07 | 东营天东制药有限公司 | A kind of preparation method of water solubility chalybeate complex bulk pharmaceutical chemicals |
| CN113004428A (en) * | 2019-12-20 | 2021-06-22 | 金陵药业股份有限公司 | Preparation method of carboxyl ferric maltose |
| CN113004429A (en) * | 2019-12-20 | 2021-06-22 | 金陵药业股份有限公司 | Refining method of carboxyl ferric maltose |
| CN216499363U (en) * | 2021-12-27 | 2022-05-13 | 滨州学院 | Maltodextrin oxide intermediate separation purification device |
| CN216704374U (en) * | 2021-12-27 | 2022-06-10 | 滨州学院 | But on-line control's carboxyl maltose iron complex apparatus for producing |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108498539A (en) * | 2018-05-03 | 2018-09-07 | 东营天东制药有限公司 | A kind of preparation method of water solubility chalybeate complex bulk pharmaceutical chemicals |
| CN113004428A (en) * | 2019-12-20 | 2021-06-22 | 金陵药业股份有限公司 | Preparation method of carboxyl ferric maltose |
| CN113004429A (en) * | 2019-12-20 | 2021-06-22 | 金陵药业股份有限公司 | Refining method of carboxyl ferric maltose |
| CN216499363U (en) * | 2021-12-27 | 2022-05-13 | 滨州学院 | Maltodextrin oxide intermediate separation purification device |
| CN216704374U (en) * | 2021-12-27 | 2022-06-10 | 滨州学院 | But on-line control's carboxyl maltose iron complex apparatus for producing |
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