CN115403675A - A kind of complexation and refining process of carboxymaltose iron - Google Patents

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

A kind of complexation and refining process of carboxymaltose iron

technical field

The invention belongs to the field of medicines, and in particular relates to a process for complexing and refining iron carboxymaltose.

Background technique

Iron carboxymaltose is a new type of nano-iron complex. Iron hydroxide colloidal particles are stably complexed in it with oxidized maltodextrin (that is, "carboxymaltose" in this application document) to control the concentration of iron. Released, iron ions can combine with iron transport protein and ferritin to play a role, and prevent the release of a large amount of free iron, reduce the formation of toxic oxides, and can effectively improve the Hb and serum levels of patients with mild to moderate iron deficiency anemia ferritin concentration.

Therefore, compared with the current common clinical iron supplements, iron carboxymaltose has iron utilization efficiency similar to iron sucrose, but it does not have the disadvantage of iron dextran that may cause allergic reactions.

The key starting material for preparing carboxymaltose iron is maltodextrin, and the finished carboxymaltose iron is obtained through oxidation, complexation reaction and refining by using maltodextrin as the starting material.

At present, the quality of maltodextrin raw materials in the industry has a large fluctuation range, unstable molecular weight, and a significant decline in molecular weight during the stability storage process, which brings relatively large troubles to the preparation of carboxymaltodextrin iron and process scale-up, for example, it will cause carboxymalt. The molecular weight distribution of iron has large fluctuations in batches, the concentration of molecular weight distribution is not high, and the molecular weight is unstable.

Contents of the invention

The present invention aims at the above-mentioned technical problems, by precisely controlling the parameters of the key complexing process that affect the molecular weight of the product, and then adopting the temperature programming method to passivate the complexed polysaccharide iron to make its molecular weight tend to be stable. The dry process strictly controls the residual solvent and moisture in carboxymaltose iron, so that its molecular weight remains stable during the placement stability process.

A complexing and refining process of carboxymaltose iron, specifically comprising the following steps:

(1) Oxidation:

a) After dissolving the maltodextrin, the temperature is raised to 30-40° C. (preferably 30° C.), and NaClO aqueous solution is added thereto dropwise under stirring;

b) After the NaClO aqueous solution is added dropwise, under stirring, add sodium bromide solid therein, monitor the pH value of the reaction solution online with a pH meter during the reaction, and always adjust the pH of the solution at 10.0-11.0; simultaneously detect the pH of the reaction solution online Viscosity changes, when the viscosity drops to 65-70mPa·s, adjust the final pH value of the reaction solution to 3.0-5.0 to terminate the reaction;

c) After the reaction stops, add absolute ethanol to it for precipitation. After the precipitation is complete, remove the supernatant and add water to dissolve; then continue to add absolute ethanol to the dissolved solution until the precipitation is complete; after the precipitation is complete, remove the supernatant and add water Dissolving to obtain an intermediate solution of 25wt%-30wt%, and performing the next ceramic membrane filtration step;

(2) Ceramic membrane filtration and purification:

A. select the ultrafiltration membrane bag that the pore size is 3Kd-5Kd to carry out ultrafiltration to the intermediate solution that above-mentioned step (1) obtains; The liquid material sample is tested for molecular weight, and when the peak height ratio of the molecular weight of the measured intermediate is 1.5≥H2/H1≥1.2, the ultrafiltration is stopped;

B. Take the retentate obtained in the above step A, add absolute ethanol to it for precipitation, remove the supernatant after the precipitation is complete, and then vacuum-dry at 30°C-40°C to obtain the intermediate carboxymaltose;

(3) Using the obtained intermediate carboxymaltose to prepare carboxymaltose iron through complexation passivation, refining and freeze-drying.

Further, the precipitation condition is: add absolute ethanol with 5-6 times the volume of the solution, and the precipitation time is 5-8 hours. The specific operation of precipitation is: add absolute ethanol, stir for 15 minutes, and then stand still for 50 minutes.

Further, the maltodextrin is maltodextrin with a DE value of 16-20.

Further, the ratio of maltodextrin to NaClO and sodium bromide is 100:(10-15):1, preferably 100:10.4:1.

Further, the concentration of the NaClO aqueous solution is 5.2wt%, and its feeding rate is (1.5-2.0) L/h.

Further, the specific operations of the step (3) are as follows:

(1) Complexation passivation process:

a) Prepare FeCl ₃ .6H ₂ O into a FeCl ₃ solution and put it in a reaction tank, add the intermediate carboxy maltose obtained in step (2) to it under stirring, stir until the mixture is uniform, and then adjust the temperature of the reaction feed liquid To 30-40°C, under stirring (preferably the stirring speed is 350rpm), use a peristaltic pump to quickly drop _Na2CO3 solution into the reaction solution to prepare ferric hydroxide colloid _;

b) above-mentioned Na ₂ CO ₃ After the solution has been added dropwise, an alkaline solution (preferably 6mol/L NaOH solution) is added dropwise thereto to adjust the pH of the reaction solution to 10.5-11.0, and the rate of addition of the alkaline solution is the rate of addition of the sodium carbonate solution half of

c) After the pH value of the feed liquid is adjusted to 10.5-11.0, seal the reaction tank, raise the temperature of the feed liquid to 50±2°C and keep it for 50 minutes; then raise the temperature of the feed liquid to 68±2°C and keep it warm for 1 hour; after the heat preservation is completed , adjust the pH of the complexation system=6.0±0.1, raise the temperature to 88±2°C and keep it for 60min, during the reaction process, keep the pH of the system=6.1±0.1; pH to 6.1±0.1; finally, pressurize the reaction tank to 5 atmospheres, heat the steam to 121±2°C, and keep it for 17 minutes; after the reaction, add cooling water to cool the material to room temperature, and then adjust the pH of the material to 6.1 Reserved after ±0.1;

(2) Refining process

After the material obtained in step (1) is filtered (preferably through a 0.22 micron filter element), the filtrate is taken, and anhydrous ethanol equal to the volume of the filtrate is added to it for precipitation; The final precipitate was dissolved in water, stirred evenly, and then the pH of the solution was adjusted to 6.1 ± 0.1, and then the obtained solid was filtered and freeze-dried;

(3) freeze-drying

a) Cooling of the front and rear boxes: put the material obtained in step (2) in the freeze dryer, close the door of the freeze dryer, close the air release valve, open the heat conduction cycle, turn on the compressor, open the valve, and start the front box refrigeration to - 30—-35°C; when the front box is cooled to -30—-35°C, close the heat conduction cycle, open the valve of the back box to cool the back box to -45—-50°C, and keep at this temperature for 2 hours;

b) Then open the partition valve, turn on the vacuum pump to reduce the vacuum degree to below 50pa, then immediately turn on the heat conduction cycle to raise the temperature of the front box to 35-40°C, and then keep it at this temperature for 2 hours. After the heat preservation is completed, turn off the compressor and turn off Vacuum pump, close the partition valve, close the heat conduction cycle, open the vent valve to start discharging, collect the freeze-dried material, weigh and pack to obtain the finished carboxymaltose iron product.

Further, in each of the above steps, the pH is adjusted with 6 mol/L HCl solution or 6 mol/L NaOH solution.

Further, the ratio of carboxyl maltose to FeCl ₃ .6H ₂ O and Na ₂ CO ₃ is 100:(50-70):(50-70), preferably 100:60:57.

Furthermore, the concentration of the Na ₂ CO ₃ solution is 10%, and its feeding rate is (1-2.0) L/h.

Compared with the prior art, the present invention has the following beneficial effects:

(1) Through precise control of the temperature, pH value, alkali dropping speed, and stirring speed that affect the complexation, the carboxymaltose iron nanoparticles are uniformly assembled, the molecular weight distribution meets the requirements, and there is no significant change during the placement process.

(2) Carboxymaltose iron particles are passivated by temperature programming method, so that the molecular weight reduction trend of the finished product is effectively controlled.

(3) Comprehensively adopt ethanol precipitation, microporous membrane filtration and programmed freeze-drying process to effectively control the visible foreign matter, solvent residue, moisture, etc. in iron carboxymaltose, so that the product stability is further improved, so that the long-term stable molecular weight The downtrend is resolved.

Detailed ways

The technical solution of the present invention will be described in further detail below through specific examples.

The medicinal maltodextrin used in the examples was purchased from Xiwang Group with a DE value of 18.

Embodiment 1 A kind of complexing and refining process of carboxyl maltose iron comprises the following steps successively:

(1) Oxidation:

a) Weigh 400g of medicinal maltodextrin, add water to dissolve it in a beaker to make the mass concentration 30%, continue to stir for 4-6h until it is completely dissolved (stirring for 5 hours in this example), then heat up to 30°C, and stir Slowly and uniformly add 800ml of NaClO solution (concentration: 5.2wt%) thereinto, and finish adding in 25-30min.

b) After the NaClO solution has been added dropwise, under stirring, add 4g of sodium bromide solid to it for reaction, monitor the pH value of the reaction solution online with a pH meter during the reaction, and adjust the pH of the solution at 10.0-11.0 with 6mol/L hydrochloric acid ; Simultaneously on-line detection of the viscosity change of the reaction solution, when the viscosity drops to 65-70m Pa s, adjust the final pH value to 3.0-5.0 with 6mol/L hydrochloric acid (in this embodiment, when the viscosity drops to 68m Pa s , adjust the pH to 4.0).

c) Then add 5 times of absolute ethanol to the volume of the feed solution for precipitation, the precipitation time is 6h, after the precipitation is complete, remove the supernatant, add water to dissolve into a concentration of 50%; then continue to add 6 times the volume of the solution to the dissolved solution Absolute ethanol, continue to precipitate for 6h.

d) After the precipitation is completed, remove the supernatant, add water to dissolve until a 25wt%-30wt% intermediate solution is obtained, and proceed to the next ceramic membrane filtration step.

(2) Ceramic membrane filtration and purification:

a) The 3Kd ultrafiltration membrane package is selected to perform ultrafiltration on the above-mentioned intermediate solution; when the ultrafiltration reaches 40% of the total weight of the permeate, the retentate material sample is taken for molecular weight detection, and when the measured intermediate When the peak height ratio of molecular weight is 1.5≥H2/H1≥1.2, stop ultrafiltration.

b) Take the retentate obtained in the above step a), add 5 times the volume of the feed solution in absolute ethanol for precipitation, the precipitation time is 6h, after the precipitation is complete, remove the supernatant, and then vacuum-dry for 9 hours at 30°C to obtain the intermediate Body carboxy maltose.

(3) Complexation passivation process:

a) Weigh 228g of Na ₂ CO ₃ , add water to prepare a Na ₂ CO ₃ solution with a concentration of 10 wt %;

b) Weigh 400g of FeCl ₃ .6H ₂ O, add water to dissolve it into a solution with a FeCl ₃ concentration of 20%, put it into a reaction tank, and add 240g of the intermediate carboxymaltose obtained in step (2) to it under stirring , continue to stir for 30 minutes until the mixture is uniform, then adjust the temperature of the reaction feed liquid to 40±1°C, and the stirring speed is 350rpm, and use a peristaltic pump to quickly drop the Na ₂ CO ₃ solution prepared in step a) to the In the reaction solution, to prepare ferric hydroxide colloid;

c) above-mentioned Na ₂ CO ₃ After the solution has been added dropwise, add 6mol/L NaOH solution dropwise therein to adjust the pH of the reaction solution, and the NaOH solution is added dropwise at a constant speed with a peristaltic pump, and the drop rate is half of the drop rate of the sodium carbonate solution, finally making The pH value of the feed liquid is adjusted to 10.5-11.0;

d) After the pH value of the feed liquid is adjusted to 10.5-11.0, seal the reaction tank, raise the temperature of the feed liquid to 50±2°C and keep it for 50 minutes; then raise the temperature of the feed liquid to 68±2°C and keep it warm for 1 hour; after the heat preservation is completed , use 6mol/L HCl solution to adjust the pH of the complex system=6.0±0.1, raise the temperature to 88±2°C, and keep it at 88±2°C for 60min, during the reaction, keep the pH of the system=6.1±0.1; then continue Raise the temperature to 98±2°C and keep it at this temperature for 50 minutes. During this stage, use 6mol/L HCl solution to adjust the pH to 6.1±0.1; finally pressurize the reaction tank to 5 atmospheres, heat the steam to 121±2°C , continue to maintain 17min.

e) After the reaction, add cooling water to cool the material to room temperature, and then use 6mol/L HCl solution to adjust the pH of the material to 6.1±0.1 for later use.

(4) Refining process

a) After the material obtained in step (3) is filtered with a 0.22 micron filter element, the volume of the filtrate is accurately measured, and dehydrated alcohol of equal volume to the filtrate is added thereto for precipitation (the specific operation of the precipitation is: stir for 15 minutes after adding dehydrated alcohol, then Stand still for 50min).

b) After the precipitation is complete, remove the supernatant, centrifuge the remaining materials, collect the centrifuged sediment, add purified water to dissolve it to a concentration of 20%, stir it evenly, adjust the pH=6.1±0.1 again, and then filter through a 0.22 micron filter element, The resulting solid was lyophilized.

(5) freeze-dried

a) Cooling of the front and rear boxes: put the material obtained in step (4) in the freeze dryer, close the door of the freeze dryer, close the air release valve, open the heat conduction cycle, turn on the compressor, open the valve, and start the front box refrigeration to - 30—-35°C; when the front box is cooled to -30—-35°C, close the heat conduction cycle, open the valve of the back box to cool the back box to -45—-50°C, and keep at this temperature for 2 hours.

b) Then open the partition valve, turn on the vacuum pump to reduce the vacuum degree to below 50pa, then immediately turn on the heat conduction cycle to raise the temperature of the front box to 35-40°C, and then keep it at this temperature for 2 hours. After the heat preservation is completed, turn off the compressor and turn off Vacuum pump, close the partition valve, close the heat conduction cycle, open the air release valve and start discharging.

c) Collect the freeze-dried materials, weigh and pack to obtain the finished carboxymaltose iron product.

The applicant has found through research that when applying the process of the present invention to the preparation of carboxy maltose intermediates, choosing maltodextrin with a DE value distribution range of 16-20 as the starting material can effectively avoid large fluctuations in the DE value of the raw material, thereby affecting the follow-up Oxidation, complexation, purification and other processes are affected.

The present invention can control the oxidation end point by controlling the reaction liquid to a specific viscosity, and further, through on-line detection of the viscosity of the material liquid, avoid cumbersome off-line detection of the molecular weight, accurately monitor the end point of the oxidation reaction, and make the production process of the intermediate carboxy maltose more efficient. Controllable, avoiding the impact of the molecular weight fluctuation of the intermediate on the subsequent complexation.

By using ultrafiltration membrane bag with a pore size of 3Kd for ultrafiltration, impurities such as small oligosaccharide molecules and chloride ions produced by oxidation are effectively removed, so that the intermediate carboxymaltose has a dispersion coefficient of 1.3 and a sodium chloride content of 4.6%.

Table 1

Each sample in Table 1 is the iron carboxymaltose sample prepared in Example 1, and the test results obtained after the sample was placed at room temperature for 6 months and 12 months.

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.