Preparation method of ferric carboxymaltose

Abstract

The invention discloses a preparation method of ferric carboxymaltose, which comprises the following steps: mixing a ferric carboxymaltose aqueous solution with absolute ethyl alcohol, carrying out alcohol precipitation and centrifugal filtration to obtain a wet ferric carboxymaltose product, adding water into the wet ferric carboxymaltose product for dissolving, adding a small amount of absolute ethyl alcohol to obtain a reconstitution fluid, and directly carrying out spray drying on the reconstitution fluid to obtain the ferric carboxymaltose. Obtaining a powdery finished product of the ferric carboxymaltose; wherein the dosage of the alcohol precipitation absolute ethyl alcohol is 70%-100% w / w of the weight of the ferric carboxymaltose aqueous solution; the alcohol precipitation is performed once; the wet carboxyl maltose iron product is added into water which is 250-350% w / w of the weight of the wet carboxyl maltose iron product to be dissolved, then absolute ethyl alcohol which is 10-20% w / w of the weight of the wet carboxyl maltose iron product is added, and a reconstitution fluid is obtained. The method disclosed by the invention is simple, obviously simplifies the process steps, shortens the production cycle, obviously reduces the energy and material consumption, reduces organic waste liquid, is beneficial to environmental protection, and also reduces the total production cost.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry and relates to a method for preparing carboxylated maltose iron. Background Technology

[0002] Iron deficiency anemia is a common nutritional disorder caused by insufficient iron stores in the body to meet the needs of normal red blood cell production. Currently, approximately 2 billion people worldwide suffer from anemia, and clinical statistics show that more than 90% of them have iron deficiency anemia.

[0003] Oral or injectable iron supplements are the most common treatments for iron deficiency anemia. Oral iron supplements are often the first-line treatment due to their effectiveness, low cost, and safety, and remain the primary treatment in China. However, oral iron supplements frequently cause significant gastrointestinal discomfort, leading some patients to discontinue treatment due to intolerance. Furthermore, oral iron supplementation is affected by food composition and the body's iron reserves, especially in patients with many chronic diseases and cancers. Increased inflammatory mediators in the body can induce the liver to synthesize iron-regulating proteins, which downregulate the expression of iron transporters on the surface membranes of iron-storing cells in the gastrointestinal tract and the body, thus affecting iron absorption and utilization. In such cases, oral iron supplementation is often ineffective or even completely useless. Additionally, in cases of gastrointestinal diseases requiring rapid restoration of iron reserves where oral supplementation is insufficient, or in situations where oral iron supplementation is intolerant or cannot be adhered to, intravenous iron supplementation is necessary.

[0004] In carboxymaltose iron injection, iron is complexed with carbohydrate polymers in a stable ferric state to release usable iron into iron transport and storage proteins (ferritin and transferrin) in the body. It is a novel polysaccharide intravenous iron agent and has become a representative drug of new intravenous iron agents.

[0005] The synthesis of carboxymaltose iron begins with maltodextrin as the starting material. After oxidation, carboxymaltodextrin is obtained, which is then complexed with raw materials containing ferric ions to generate carboxymaltose iron.

[0006] Related patents CN106977621A, CN108129582A, and CN1705682A all involve the process and refining of carboxymethyl maltose iron, but the descriptions of the preparation methods for carboxymethyl maltose iron differ significantly. The final drying of the material generally employs vacuum drying, which is ineffective and can easily lead to significant changes in the molecular weight of the material. CN106977621A's refining process is complex: the resulting carboxymethyl maltose iron aqueous solution requires continuous pH adjustment during alcohol precipitation, and is repeatedly washed with icy ethanol, dried, dissolved again in water, and then precipitated with anhydrous ethanol. The filter cake undergoes repeated washing with icy ethanol and pH adjustment, finally being vacuum dried. The entire process involves numerous moisture components and does not meet industrial requirements. CN108129582A and CN1705682A do not address the drying process. Summary of the Invention

[0007] The synthesis of carboxymaltose iron begins with maltodextrin as the starting material. After oxidation, carboxymaltodextrin is obtained, which is then complexed with raw materials containing ferric ions to generate carboxymaltose iron.

[0008] The inventors prepared carboxylated maltodextrin iron of a specific molecular weight using the following technical solution: maltodextrin was dissolved in 1-2 times its weight of water; sodium bromide at 1%-2% of the maltodextrin mass was used as a catalyst; the pH was adjusted to 9.0-11.0 with 30% sodium hydroxide solution; the temperature was controlled at 25-40℃; and 0.8-1 times the weight of maltodextrin in 10% sodium hypochlorite solution was added under stirring to obtain a carboxylated maltodextrin solution; the mass ratio of ferric chloride hexahydrate to maltodextrin was 1:2. 2. The mass ratio of ferric chloride hexahydrate to sodium carbonate is 2:1 to 3:1. Weigh out ferric chloride hexahydrate and sodium carbonate to prepare ferric chloride solutions with a concentration of 70-80% w / w and sodium carbonate solutions with a concentration of 20-35% w / w, respectively. Mix the carboxymethyl maltodextrin solution with the ferric chloride solution, stir, control the temperature at 50-70℃, set the flow rate, and add sodium carbonate solution dropwise at a uniform rate over 1 hour. Then, perform alkali curing, acid curing, and high-temperature curing in sequence to obtain a stable carboxymethyl maltodextrin-iron aqueous solution.

[0009] The purpose of this invention is to provide a simple and effective method for preparing carboxylated maltose iron.

[0010] The objective of this invention is achieved through the following technical solution:

[0011] A method for preparing carboxymethyl maltose iron includes: first, mixing an aqueous solution of carboxymethyl maltose iron with anhydrous ethanol for alcohol precipitation, centrifuging and filtering to obtain a wet carboxymethyl maltose iron product; dissolving the wet carboxymethyl maltose iron product in water and adding a small amount of anhydrous ethanol to obtain a complex solution; and directly spray-drying the complex solution to obtain a powdered carboxymethyl maltose iron product.

[0012] The amount of anhydrous ethanol used for alcohol precipitation is 70% to 100% (w / w) of the weight of the carboxymaltose iron aqueous solution. Compared with conventional alcohol precipitation, this invention increases the alcohol content, controlling the alcohol content during precipitation to about 40% to 50%, which can ensure the thorough removal of small molecule impurities.

[0013] The alcohol precipitation temperature is 0–30°C.

[0014] The alcohol precipitation was performed once.

[0015] Preferably, the carboxymaltose iron wet product is dissolved in 250%–350% (w / w) of water by weight of the carboxymaltose iron wet product, and then 10%–20% (w / w) of anhydrous ethanol by weight of the carboxymaltose iron wet product is added to obtain a complex solution. The complex solution of this invention contains alcohol, which can prevent the small carboxymaltose iron particles from sticking together and clumping during spray drying.

[0016] More preferably, the carboxymaltose iron wet product is dissolved in water at 290% to 320% (w / w) of the carboxymaltose iron wet product weight, and then anhydrous ethanol at 14% to 16% (w / w) of the carboxymaltose iron wet product weight is added to obtain a complex solution.

[0017] Preferably, the temperature of the reconstituted solution is 60–70°C. This temperature ensures complete dissolution of carboxymethyl maltose iron while reducing the temperature difference between the reconstituted solution and the drying chamber of the spray dryer, thereby improving the drying efficiency after atomization.

[0018] Preferably, the reconstituted solution is spray-dried using a spray dryer, wherein the inlet air temperature of the drying chamber is 150–200°C and the outlet air temperature is 80–100°C. The spray drying parameters described in this invention ensure effective liquid atomization, prevent the formation of tiny particles from sticking together, and achieve effective gas-solid separation.

[0019] Specifically, the preparation method of carboxylated maltose iron according to the present invention includes the following steps:

[0020] Step (1): The amount of anhydrous ethanol is 70% to 100% (w / w) of the weight of the carboxymaltose iron aqueous solution. The carboxymaltose iron aqueous solution is mixed with anhydrous ethanol. At a temperature of 0 to 30°C, the mixture is stirred for 5 to 15 minutes, then allowed to stand for ethanol precipitation for 1.5 to 2.0 hours. After centrifugation and filtration, the carboxymaltose iron wet product is obtained.

[0021] Step (2): Dissolve the carboxymaltose iron in water at 250%–350% (w / w) of the carboxymaltose iron, then add anhydrous ethanol at 10%–20% (w / w) of the carboxymaltose iron, stir for 30–60 minutes at 0–30°C, then raise the temperature to 60–70°C to ensure complete dissolution and obtain a complex solution.

[0022] Step (3): Keep the temperature of the reconstituted solution at 60-70℃, pump it into the spray dryer for spray drying, keep the air inlet temperature in the drying chamber at 150-200℃, adjust the flow rate, keep the outlet temperature at 80-100℃, and obtain the carboxymaltose iron product.

[0023] The beneficial effects of this invention are:

[0024] The current mainstream method for refining carboxymaltose iron generally involves mixing an aqueous solution of carboxymaltose iron with anhydrous ethanol to precipitate carboxymaltose iron. After filtration, the precipitate is redissolved in water and then precipitated with alcohol 1-3 times to thoroughly remove moisture. The filter cake is then washed with anhydrous ethanol 1-3 times and dried in an oven to obtain a powdered product of carboxymaltose iron. This method involves numerous production steps, a long cycle, high energy and material consumption, and generates a significant amount of organic wastewater with high recycling and treatment costs, resulting in a high overall production cost. Carboxymaltose iron is highly soluble in water but practically insoluble in ethanol. The purpose of multiple alcohol precipitations is to remove moisture from the carboxymaltose iron and prevent the material from clumping together during drying.

[0025] This invention uses a spray drying method, which involves increasing the solution temperature, adding a certain amount of ethanol, and controlling process parameters such as inlet and outlet temperatures, air volume, and material flow rate during the process, ultimately obtaining a powdered solid material with excellent uniformity.

[0026] Compared with existing mainstream processes, the method of this invention is simple, significantly simplifies the process steps, shortens the production cycle, significantly reduces energy and material consumption, reduces organic waste liquid, is beneficial to environmental protection, and also reduces the overall production cost.

[0027] This invention has low requirements for equipment and technology, is fully suitable for industrial operation, and has great practical significance in actual production. Detailed Implementation

[0028] The technical solution of the present invention will be further described below through specific embodiments.

[0029] The maltodextrin described in this invention has a DE value of 10 to 15.

[0030] The example uses a small spray dryer from Shanghai Oumeng Industrial Co., Ltd.: Model: OM-QPG-3-B (glass type), drying tower: φ500mm high borosilicate glass GG-17, feeding method: stepless speed regulating peristaltic pump.

[0031] Example 1

[0032] Take 1000g of maltodextrin, add 2000g of water, stir and dissolve to obtain a maltodextrin solution; add 10g of sodium bromide to the maltodextrin solution, add 30% sodium hydroxide solution to adjust the pH of the maltodextrin solution to 9.0-11.0, control the temperature at 25-40℃, and add 800g of 10% sodium hypochlorite solution under stirring to obtain a carboxylated maltodextrin solution.

[0033] Ferric chloride solution: 2200g of ferric chloride hexahydrate is mixed with water to prepare a 75% (w / w) solution.

[0034] Sodium carbonate solution: 1100g of sodium carbonate is mixed with water to prepare a 25% (w / w) solution.

[0035] The carboxylated maltodextrin solution and ferric chloride solution were first mixed and stirred. The temperature was controlled at 50–70°C, and a sodium carbonate solution was added dropwise using a peristaltic pump at a set flow rate, completing the addition within 1 hour. After the addition was complete, 30% sodium hydroxide solution was added to adjust the pH to 10.0–12.0, and the temperature was controlled at 50–70°C, stirring for 0.5 hours (alkali solidification). Then, 20% hydrochloric acid solution was added to adjust the pH to 5.0–6.0, and the temperature was controlled at 50–70°C, stirring for 0.5 hours (acid solidification). The temperature was then raised to 90–100°C, and stirring continued for 0.5 hours (high-temperature solidification), yielding 12410 g of a stable carboxylated maltodextrin-ferric aqueous solution.

[0036] Add 10,000 g of anhydrous ethanol to the above carboxymaltose iron aqueous solution, stir at 20°C for 10 minutes, and then let stand at 20°C for 90 minutes for alcohol precipitation; centrifuge and filter, weigh, and obtain 2,940 g of filter cake (i.e., carboxymaltose iron wet product). Add 8,800 g of water to the filter cake and stir to dissolve, then add 450 g of anhydrous ethanol, stir at 20°C for 45 minutes, and then heat to 70°C to obtain a reconstituted solution. Maintain the temperature of the reconstituted solution at 70°C; set the inlet air temperature of the drying chamber of the spray dryer to 190°C, pump the reconstituted solution into the spray dryer, adjust the flow rate to 140 mL / min, and maintain the outlet air temperature at 80-100°C to obtain 1,580 g of carboxymaltose iron powder product.

[0037] Example 2

[0038] Following the process described in Example 1, the scale-up of each material was doubled to obtain 24770g of a stable carboxylated maltose iron aqueous solution.

[0039] Add 20,000 g of anhydrous ethanol to the above carboxymaltose iron aqueous solution, stir at room temperature for 10 minutes, and let stand at room temperature for alcohol precipitation for 90 minutes; centrifuge and filter, weigh, and obtain 5,840 g of filter cake. Add 17,600 g of water to the filter cake, stir at room temperature to dissolve, then add 900 g of anhydrous ethanol, stir at room temperature for 45 minutes, heat the solution to 70°C to obtain a reconstituted solution, and maintain the temperature of the reconstituted solution at 70°C.

[0040] The inlet air temperature of the drying chamber of the spray dryer was set to 190℃. The reconstituted solution was pumped into the spray dryer, the flow rate was adjusted to 140mL / min, and the outlet air temperature was maintained at 80~100℃ to obtain 3140g of carboxymaltose iron powder.

[0041] Example 3

[0042] Following the process described in Example 1, each material was scaled up 5 times to obtain 62,100 g of a stable carboxylated maltose iron aqueous solution.

[0043] Add 50,000 g of anhydrous ethanol to the above carboxymaltose iron aqueous solution, stir at room temperature for 10 minutes, and let stand at room temperature for alcohol precipitation for 90 minutes; filter to obtain 14,850 g of filter cake, add 44,000 g of water to the filter cake, stir at room temperature to dissolve, then add 2,250 g of anhydrous ethanol, stir at room temperature for 45 minutes, heat the solution (total 61,100 g) to 70°C to obtain a reconstituted solution, and keep the temperature of the reconstituted solution at 70°C.

[0044] The inlet air temperature of the drying chamber of the spray dryer was set to 190℃. 20,000g of the reconstituted solution was pumped into the spray dryer, the flow rate was adjusted to 140mL / min, and the outlet air temperature was maintained at 80-100℃. 2,586g of carboxymaltose iron powder was obtained (the total reconstituted solution should yield 7,900g).

[0045] Table 1: Key Indicators of Carboxymaltose Iron Products from Examples 1-3

[0046]

[0047] Comparative Example 1

[0048] Take 1000g of maltodextrin, add 2000g of water, stir and dissolve to obtain a maltodextrin solution; add 10g of sodium bromide to the maltodextrin solution, add 30% sodium hydroxide solution to adjust the pH of the maltodextrin solution to 9.0-11.0, control the temperature at 25-40℃, and add 800g of 10% sodium hypochlorite solution under stirring to obtain a carboxylated maltodextrin solution.

[0049] Ferric chloride solution: 2200g of ferric chloride hexahydrate is mixed with water to prepare a 75% (w / w) solution.

[0050] Sodium carbonate solution: 1100g of sodium carbonate is mixed with water to prepare a 25% (w / w) solution.

[0051] The carboxylated maltodextrin solution and ferric chloride solution were first mixed and stirred. The temperature was controlled at 50–70°C, and a sodium carbonate solution was added dropwise using a peristaltic pump at a set flow rate, completing the addition within 1 hour. After the addition was complete, 30% sodium hydroxide solution was added to adjust the pH to 10.0–12.0, and the temperature was controlled at 50–70°C, stirring for 0.5 hours (alkali curing). Then, 20% hydrochloric acid solution was added to adjust the pH to 5.0–6.0, and the temperature was controlled at 50–70°C, stirring for 0.5 hours (acid curing). The temperature was then raised to 90–100°C, and stirring continued for 0.5 hours (high-temperature curing), yielding 12390 g of a stable carboxylated maltodextrin-ferric aqueous solution.

[0052] Add 6000g of anhydrous ethanol to the above carboxymaltose iron aqueous solution, stir for 10 minutes, and allow to stand at 20℃ for alcohol precipitation for 90 minutes; centrifuge and filter, add 8000g of water to the filter cake, stir to dissolve, add 6000g of anhydrous ethanol, stir for 10 minutes, and allow to stand at 20℃ for alcohol precipitation for 90 minutes; centrifuge and filter, adding 3000g of anhydrous ethanol during filtration, washing twice with 1500g each time, to obtain 2660g of filter cake (i.e., carboxymaltose iron moist product). Dry the filter cake in a drying oven (temperature 50℃, vacuum degree -0.08MPa) for 5 hours to obtain 1446g of finished product.

[0053] Comparative Example 2

[0054] Following the process of Comparative Example 1, the scale-up of each material was doubled to obtain 25010g of a stable carboxymethyl maltose iron aqueous solution.

[0055] Add 12000g of anhydrous ethanol to the above carboxymaltose iron aqueous solution, stir for 10 minutes, and allow to stand at 20℃ for alcohol precipitation for 90 minutes; centrifuge and filter, add 16000g of water to the filter cake, stir to dissolve, add 12000g of anhydrous ethanol, stir for 10 minutes, and allow to stand at 20℃ for alcohol precipitation for 90 minutes; centrifuge and filter, adding 6000g of anhydrous ethanol during filtration, washing twice with 3000g each time, to obtain 5410g of filter cake (i.e., carboxymaltose iron moist product). Dry the filter cake in a drying oven (temperature 50℃, vacuum degree -0.08MPa) for 5 hours to obtain 2952g of finished product.

[0056] Comparative Example 3

[0057] Following the process of Comparative Example 1, the materials were scaled up 5 times to obtain 62,200 g of a stable carboxymethyl maltose iron aqueous solution.

[0058] Add 30,000 g of anhydrous ethanol to the above carboxymaltose iron aqueous solution, stir for 10 minutes, and allow to stand at 20°C for alcohol precipitation for 90 minutes; centrifuge and filter, add 40,000 g of water to the filter cake, stir to dissolve, add 30,000 g of anhydrous ethanol, stir for 10 minutes, and allow to stand at 20°C for alcohol precipitation for 90 minutes; centrifuge and filter, adding 15,000 g of anhydrous ethanol during filtration, washing twice with 7,500 g each time, to obtain 5,410 g of filter cake (i.e., carboxymaltose iron moist product). Dry the filter cake in a drying oven (temperature 50°C, vacuum degree -0.08 MPa) for 5 hours to obtain 7,198 g of the finished product.

[0059] Table 2: Comparison of Yield and Ethanol Consumption between This Process and Other Conventional Methods

[0060]

[0061] Note: Comparative Examples 1-3 of the conventional process correspond to the same amount of raw and auxiliary materials used in Examples 1-3 of the present invention.

[0062] As can be seen from Table 1, the key indicators of carboxymaltose iron obtained by the process of this invention all meet the relevant standards of the original research, fully satisfy the requirements of pharmaceutical raw materials for the production of carboxymaltose iron injection, and are suitable as raw materials for carboxymaltose iron injection.

[0063] As can be seen from Table 2, under the same conditions, the yield of the final product of the process of this invention is about 5 to 10% higher than that of the current mainstream process. This is mainly because the number of alcohol precipitation times is reduced, the alcohol washing process is eliminated, and the yield is improved. The amount of ethanol used is greatly reduced, and the corresponding amount of organic waste liquid is significantly reduced, thus reducing both the material cost and the waste liquid treatment cost.

Claims

1. A method for preparing carboxylated maltose iron, characterized in that: include: First, the aqueous solution of carboxymaltose iron is mixed with anhydrous ethanol for alcohol precipitation, centrifuged and filtered to obtain a wet carboxymaltose iron product. The wet carboxymaltose iron product is dissolved in water and a small amount of anhydrous ethanol is added to obtain a complex solution. The complex solution is directly spray-dried to obtain a powdered carboxymaltose iron product.

2. The method for preparing carboxylated maltose iron according to claim 1, characterized in that: The amount of anhydrous ethanol used for precipitation is 70% to 100% w / w of the weight of the carboxymaltose iron aqueous solution.

3. The method for preparing carboxylated maltose iron according to claim 1, characterized in that: The alcohol precipitation temperature is 0–30°C.

4. The method for preparing carboxylated maltose iron according to claim 1, characterized in that: The alcohol precipitation was performed once.

5. The method for preparing carboxylated maltose iron according to claim 1, characterized in that: The carboxymaltose iron wet product is dissolved in 250% to 350% w / w of water by weight of the carboxymaltose iron wet product, and then 10% to 20% w / w of anhydrous ethanol by weight of the carboxymaltose iron wet product is added to obtain a complex solution.

6. The method for preparing carboxylated maltose iron according to claim 1 or 5, characterized in that: The carboxymaltose iron wet product is dissolved in 290% to 320% w / w of water by weight of the carboxymaltose iron wet product, and then 14% to 16% w / w of anhydrous ethanol by weight of the carboxymaltose iron wet product is added to obtain a complex solution.

7. The method for preparing carboxylated maltose iron according to claim 1, characterized in that: The temperature of the reconstituted solution is 60–70°C.

8. The method for preparing carboxylated maltose iron according to claim 1, characterized in that: The reconstituted solution was spray-dried using a spray dryer.

9. The method for preparing carboxylated maltose iron according to claim 8, characterized in that: The inlet air temperature of the drying chamber of the spray dryer is 150-200℃, and the outlet air temperature is 80-100℃.

10. A method for preparing carboxylated maltose iron according to claim 1, characterized in that: Includes the following steps: Step (1): The amount of anhydrous ethanol is 70% to 100% (w / w) of the weight of the carboxymaltose iron aqueous solution. The carboxymaltose iron aqueous solution is mixed with anhydrous ethanol. At a temperature of 0 to 30°C, the mixture is stirred for 5 to 15 minutes, then allowed to stand for ethanol precipitation for 1.5 to 2.0 hours. After centrifugation and filtration, the carboxymaltose iron wet product is obtained. Step (2): Dissolve the carboxymaltose iron in water at 250%–350% w / w of the carboxymaltose iron, then add anhydrous ethanol at 10%–20% w / w of the carboxymaltose iron, stir for 30–60 minutes at 0–30°C, and then raise the temperature to 60–70°C to obtain a complex solution; Step (3): Keep the temperature of the reconstituted solution at 60-70℃, pump it into the spray dryer for spray drying, keep the air inlet temperature in the drying chamber at 150-200℃, adjust the flow rate, keep the outlet temperature at 80-100℃, and obtain the carboxymaltose iron product.

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