Iron removal method for anthracycline drugs

Abstract

The invention belongs to the technical field of medicine, and particularly relates to an iron removal method for anthracycline drugs, according to the method, iron in the anthracycline drugs is removed through macroporous cationic resin and a treating agent, the purity of products can be improved, the product quality of the anthracycline drugs is remarkably improved, and operation is easy. The reaction yield and purity are stable, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for removing iron from anthracycline drugs. Background Technology

[0002] Anthracycline drugs, characterized by anthracene rings and glycosyl ligands, are widely used clinically to treat breast cancer, acute lymphoblastic leukemia, non-lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and other solid tumors. Common anthracene-based antitumor drugs include daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, and pentorubicin.

[0003]

[0004]

[0005] Anthracycline drug molecules themselves have a certain ability to complex metal ions. For example, the following structure is disclosed in US4138480A:

[0006]

[0007] The letter "Me" represents a metal ion, indicating that metal ions can be complexed at three sites. Therefore, such compounds often lead to excessive residue on ignition. Especially during production, if this type of material comes into contact with iron ions in pipelines, reaction vessels, and other contact equipment, it will cause the characteristic color change of phenols, changing from orange-red to blackish-red, forming corresponding iron complexes. CN201010150067.5 discloses a method for preparing the antitumor drug daunorubicin. This invention's fermentation broth extraction and purification includes several processes: fermentation broth filtration, macroporous resin adsorption purification, and ethylenediaminetetraacetic acid (EDTA) complexation to remove impurities. By controlling the pH value and pretreating the fermentation broth and resin column, good purification results for daunorubicin are achieved, reducing impurity B to below 0.5% and residue on ignition to below 0.1%. Using EDTA to compete for the complexed metal ions requires adjusting the pH to alkaline. This effectively reduces residue on ignition.

[0008] Currently, the purification process of anthracycline drugs mostly requires resin purification, involving steps such as elution, concentration, and extraction. The resin removes most impurities through adsorption. While it effectively adsorbs and removes free metal ions from the reactants, it struggles to remove some complexes, leading to excessive residues on ignition. This is particularly true for complexes formed between iron ions and anthracyclines. Therefore, there is an urgent need to develop a simple, industrially viable method for iron removal from anthracyclines. Summary of the Invention

[0009] To address the problems existing in current technologies, this invention provides a method for iron removal from anthracycline drugs. The method of this invention is simple to operate, avoids the cumbersome steps of resin column adsorption and elution, has low production costs, and is very suitable for industrial production.

[0010] The specific technical solution of the present invention is as follows:

[0011] At room temperature, iron-containing anthracycline compounds are added to a reaction vessel, dissolved in water, and then a treatment agent is added and stirred until homogeneous. Macroporous cation exchange resin is then added, and the mixture is stirred while maintaining a controlled temperature. The iron ion concentration is monitored until it reaches the acceptable level. Once iron removal is complete, stirring is stopped, the mixture is filtered, and the filtrate is collected. The filtrate is then further processed to obtain qualified anthracycline compounds.

[0012] Preferably, the anthracycline compound is one of daunorubicin hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, and epirubicin hydrochloride.

[0013] Preferably, the mass ratio of water to anthracycline compound is 10-500:1, more preferably 100-300:1.

[0014] Preferably, the amount of the treatment agent is 0.1%-10% of the mass of the anthracycline compound, more preferably 0.2%-1%.

[0015] Preferably, the treatment agent is one of vitamin C, vitamin E, catechol, hydroquinone, sodium bisulfite, sodium sulfite, sodium dithionite, and sodium metabisulfite, with vitamin C and sodium bisulfite being preferred.

[0016] Preferably, the mass-to-volume ratio of the anthracycline compound to the macroporous cation exchange resin is 1:0.01-10 g / ml, more preferably 1:1-5 g / ml.

[0017] Preferably, the macroporous cation exchange resin is IRA 200 (Na) or IR-120(H).

[0018] Preferably, the temperature for temperature control and stirring is 0-30℃; particularly preferably 15-30℃.

[0019] Preferably, the post-treatment of the filtrate is as follows: the filtrate is concentrated under reduced pressure at 40-50°C until it becomes gel-like, the temperature is maintained, anhydrous ethanol is slowly added dropwise, the mixture is stirred, the temperature is lowered to 15-30°C until anthracycline compounds precipitate, and the mixture is filtered to obtain the corresponding qualified anthracycline compounds.

[0020] Preferably, the mass-to-volume ratio of anthracycline compounds to anhydrous ethanol is 1:5-50 g / ml, more preferably 1:15-20 g / ml.

[0021] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0022] (1) This invention provides a method for removing iron from anthracycline drugs using macroporous cation exchange resin and a treatment agent. The method is simple to operate and has a high yield. It avoids the cumbersome process of repeated resin purification in the prior art.

[0023] (2) The present invention has a significant iron removal effect and can significantly improve the product quality of anthracycline drugs. Detailed Implementation

[0024] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0025] Materials used in the experiment: Vitamin C and other treatment agents, IRA 200(Na), IR-120(H) is available for purchase or can be prepared using existing publicly available technologies.

[0026] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0027] Example 1

[0028] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of doxorubicin hydrochloride with a 1% (mass fraction) iron content. The liquid phase purity is 99.1% (black in color). Continue stirring for 10-30 minutes until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) vitamin C and stir for 10-30 minutes. Add 60mL of activated macroporous cation exchange resin. IRA 200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by suction filtration to obtain orange-red doxorubicin hydrochloride with a liquid phase purity of 99.8%, an iron ion content of 0.04 ppm, and a yield of 95%.

[0029] Example 2

[0030] At room temperature, add 4L of purified water to the reaction vessel, and while stirring, add 20g of epirubicin hydrochloride with an iron content of 0.5% (mass fraction), liquid phase purity 99.5% (black color), continue stirring for 10-30 min until the solid is completely dissolved and the color is dark red. Add 0.1% (0.02g) vitamin C and stir for 10-30 min; add 40mL of activated macroporous cation exchange resin. [IR-120(H)], stirring at a controlled temperature of 15-30℃, monitoring the iron ion concentration during the process. When the iron ion concentration is below 0.05 μg / g (ICP-MS detection), the filtrate is considered qualified, iron removal is complete, stirring is stopped, and the filtrate is collected. The filtrate is concentrated under reduced pressure at 40-50℃ until it becomes gel-like. While maintaining the temperature, 300 ml of anhydrous ethanol is slowly added dropwise, stirring for 1 hour. The temperature is then lowered to 15-30℃, and the filtrate is collected by suction filtration to obtain orange-red doxorubicin hydrochloride with a liquid phase purity of 99.7%, an iron ion content of 0.08 ppm, and a yield of 97%.

[0031] Example 3

[0032] At room temperature, add 9L of purified water to the reaction vessel, and while stirring, add 30g of doxorubicin hydrochloride containing 1% (mass fraction) iron, with a liquid phase purity of 99.1% (black color). Continue stirring for 10-30 minutes until the solid is completely dissolved and the color is dark red. Add 1% (0.3g) of vitamin C and stir for 10-30 minutes. Add 150mL of activated macroporous cation exchange resin. IRA200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by suction filtration to obtain orange-red doxorubicin hydrochloride with a liquid phase purity of 99.8%, an iron ion content of 0.08 ppm, and a yield of 93%.

[0033] Example 4

[0034] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of doxorubicin hydrochloride with a 1% (mass fraction) iron content, 99.1% purity (black color) in liquid chromatography. Continue stirring for 10-30 minutes until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) sodium bisulfite and stir for 10-30 minutes. Add 60mL of activated macroporous cation exchange resin. IRA200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by suction filtration to obtain orange-red doxorubicin hydrochloride with a liquid phase purity of 99.6%, an iron ion content of 0.1 ppm, and a yield of 94%.

[0035] Example 5

[0036] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of doxorubicin hydrochloride with a 1% (mass fraction) iron content. The liquid phase purity is 99.1% (black in color). Continue stirring for 10-30 minutes until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) vitamin C and stir for 10-30 minutes. Add 30mL of activated macroporous cation exchange resin. IRA 200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by suction filtration to obtain orange-red doxorubicin hydrochloride with a liquid phase purity of 99.7%, an iron ion content of 0.09 ppm, and a yield of 93%.

[0037] Example 6

[0038] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of doxorubicin hydrochloride with a 1% (mass fraction) iron content. The liquid phase purity is 99.1% (black in color). Continue stirring for 10-30 minutes until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) of catechol and stir for 10-30 minutes. Add 60mL of activated macroporous cation exchange resin. IRA200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by suction filtration to obtain orange-red doxorubicin hydrochloride with a liquid phase purity of 99.6%, an iron ion content of 0.1 ppm, and a yield of 95%.

[0039] Example 7

[0040] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of daunorubicin hydrochloride with an iron content of 0.8% (mass fraction), liquid phase purity 99.3% (black color). Continue stirring for 10-30 minutes until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) of vitamin C and stir for 10-30 minutes. Add 60mL of activated macroporous cation exchange resin. IRA200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by suction filtration to obtain orange-red daunorubicin hydrochloride with a liquid phase purity of 99.8%, an iron ion content of 0.06 ppm, and a yield of 94%.

[0041] Example 8

[0042] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of daunorubicin hydrochloride with an iron content of 0.8% (mass fraction), liquid phase purity 99.3% (black color), continue stirring for 10-30 min until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) sodium bisulfite, and stir for 10-30 min; add 60mL of activated macroporous cation exchange resin. IRA 200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by suction filtration to obtain orange-red daunorubicin hydrochloride with a liquid phase purity of 99.6%, an iron ion content of 0.08 ppm, and a yield of 93%.

[0043] Example 9

[0044] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of daunorubicin hydrochloride with an iron content of 0.8% (mass fraction), liquid phase purity 99.3% (black color), continue stirring for 10-30 min until the solid is completely dissolved and the color is dark red. Add 0.1% (0.3g) of vitamin C and stir for 10-30 min; add 60mL of activated macroporous cation exchange resin. [IR-120(H)], stirring at a controlled temperature of 15-30℃, monitoring the iron ion concentration during the process. When the iron ion concentration is below 0.05 μg / g (ICP-MS detection), the filtrate is considered qualified, iron removal is complete, stirring is stopped, and the filtrate is collected. The filtrate is concentrated under reduced pressure at 40-50℃ until it becomes gel-like. While maintaining the temperature, 450 ml of anhydrous ethanol is slowly added dropwise, stirring for 1 hour. The temperature is then lowered to 15-30℃, and the filtrate is collected by suction filtration to obtain orange-red daunorubicin hydrochloride with a liquid phase purity of 99.6%, an iron ion content of 0.09 ppm, and a yield of 95%.

[0045] Example 10

[0046] At room temperature, add 9L of purified water to the reaction vessel, and while stirring, add 30g of idarubicin hydrochloride with an iron content of 0.1% (mass fraction), liquid phase purity 99.5% (black color), continue stirring for 10-30 min until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) vitamin C and stir for 10-30 min; add 60mL of activated macroporous cation exchange resin. IRA 200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by suction filtration to obtain orange-red idarubicin hydrochloride with a liquid phase purity of 99.7%, an iron ion content of 0.05 ppm, and a yield of 96%.

[0047] Example 11

[0048] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of idarubicin hydrochloride with an iron content of 0.1% (mass fraction), liquid phase purity 99.5% (black color), continue stirring for 10-30 min until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) catechol, and stir for 10-30 min; add 60mL of activated macroporous cation exchange resin. IRA 200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by vacuum filtration to obtain orange-red idarubicin hydrochloride with a liquid phase purity of 99.5%, an iron ion content of 0.1 ppm, and a yield of 93%.

[0049] Example 12

[0050] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of idarubicin hydrochloride with an iron content of 0.1% (mass fraction), liquid phase purity 99.5% (black color), continue stirring for 10-30 min until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) sodium bisulfite, and stir for 10-30 min; add 150mL of activated macroporous cation exchange resin. IRA 200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored intermittently. When the iron ion concentration was below 0.05 μg / g (detected by ICP-MS), the filtrate was considered qualified, iron removal was complete, stirring was stopped, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the filtrate was collected by vacuum filtration to obtain orange-red idarubicin hydrochloride with a liquid phase purity of 99.8%, an iron ion content of 0.07 ppm, and a yield of 94%.

[0051] Example 13

[0052] At room temperature, add 6L of purified water to the reaction vessel, and while stirring, add 30g of idarubicin hydrochloride with an iron content of 0.1% (mass fraction), liquid phase purity 99.5% (black color), continue stirring for 10-30 min until the solid is completely dissolved and the color is dark red. Add 0.2% (0.06g) sodium bisulfite, and stir for 10-30 min; add 60mL of activated macroporous cation exchange resin. [IR-120(H)], stirring at a controlled temperature of 15-30℃, monitoring the iron ion concentration during the process. When the iron ion concentration is below 0.05 μg / g (ICP-MS detection), the filtrate is considered qualified, iron removal is complete, stirring is stopped, and the filtrate is collected. The filtrate is concentrated under reduced pressure at 40-50℃ until it becomes gel-like. While maintaining the temperature, 450 ml of anhydrous ethanol is slowly added dropwise, stirring for 1 hour. The temperature is then lowered to 15-30℃, and the filtrate is collected by suction filtration to obtain orange-red idarubicin hydrochloride with a liquid phase purity of 99.7%, an iron ion content of 0.07 ppm, and a yield of 96%.

[0053] Comparative Example 1

[0054] At room temperature, add 6 L of purified water to the reaction vessel, and while stirring, add 30 g of doxorubicin hydrochloride containing 1% iron (mass fraction), with a liquid phase purity of 99.1% (blackish color). Continue stirring for 10-30 min until the solid is completely dissolved and the color is dark red. Add 100 mL of activated macroporous cation exchange resin. IRA 200(Na)] was stirred at a controlled temperature of 15-30℃, with the iron ion concentration monitored throughout. ICP-MS analysis showed the iron ion concentration remained above 0.3 μg / g. After stirring for 24 hours, stirring was stopped, and the mixture was filtered. The filtrate was collected. The filtrate was concentrated under reduced pressure at 40-50℃ until it reached a gel-like state. While maintaining the temperature, 450 ml of anhydrous ethanol was slowly added dropwise, and the mixture was stirred for 1 hour. The temperature was then lowered to 15-30℃, and the mixture was filtered to obtain doxorubicin hydrochloride with a liquid chromatography purity of 99.2%, an iron ion content of 0.5 ppm, and a yield of 90%.

Claims

1. A method for removing iron from anthracycline drugs, characterized in that, At room temperature, iron-containing anthracycline compounds are added to a reaction vessel, dissolved in water, and then a treatment agent is added and stirred until homogeneous. Macroporous cation exchange resin is then added, and the mixture is stirred while maintaining a controlled temperature. The iron ion concentration is monitored until it reaches the acceptable level. Once iron removal is complete, stirring is stopped, the mixture is filtered, and the filtrate is collected. The filtrate is then further processed to obtain qualified anthracycline compounds.

2. The synthesis method according to claim 1, characterized in that, The anthracycline compound mentioned is one of daunorubicin hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, and epirubicin hydrochloride.

3. The synthesis method according to claim 1, characterized in that, The mass ratio of water to anthracycline compound is 10-500:1, preferably 100-300:

1.

4. The synthesis method according to claim 1, characterized in that, The amount of the treatment agent used is 0.1%-10% of the mass of the anthracycline compound, preferably 0.2%-1%.

5. The synthesis method according to claim 1, characterized in that, The treatment agent is one of vitamin C, vitamin E, catechol, hydroquinone, sodium bisulfite, sodium sulfite, sodium dithionite, and sodium metabisulfite, preferably vitamin C or sodium bisulfite.

6. The synthesis method according to claim 1, characterized in that, The mass-volume ratio of the anthracycline compound to the macroporous cation exchange resin is 1:0.01-10 g / ml, preferably 1:1-5 g / ml.

7. The synthesis method according to claim 1, characterized in that, The macroporous cation exchange resin is IRA200(Na)or IR-120(H).

8. The synthesis method according to claim 1, characterized in that, The temperature for temperature control and stirring is 0-30℃; preferably 15-30℃.

9. The synthesis method according to claim 1, characterized in that, The filtrate post-treatment is as follows: the filtrate is concentrated under reduced pressure at 40-50℃ to a gel state, the temperature is maintained, anhydrous ethanol is slowly added dropwise, the mixture is stirred, and the temperature is lowered to 15-30℃ until anthracycline compounds precipitate. The mixture is then filtered to obtain the corresponding qualified anthracycline compounds.

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