A method for recovering divalent copper ions and cytarabine

Abstract

The present invention relates to the recovery of divalent copper ions and cytarabine in the process of cytarabine daunorubicin liposomes for injection, and specifically to a method for recovering divalent copper ions and cytarabine. After passively encapsulating cytarabine, the cytarabine daunorubicin liposomes for injection use ultrafiltration to remove free cytarabine, copper gluconate and triethanolamine. Divalent copper ions belong to heavy metals, and cytarabine is an anti-tumor drug with certain genotoxicity. Direct discharge of waste liquid will seriously pollute the environment. The present invention uses alkaline solution to form precipitation with copper ions for removal, then neutralizes with acid, adsorbs through cation exchange resin, elutes with a certain concentration of ammonia water and ethanol, and concentrates under reduced pressure and recrystallizes to obtain a raw material drug that meets the requirements, thereby achieving the purpose of green manufacturing.

Description

Technical Field

[0001] The invention relates to the field of recovery of divalent copper ions and cytarabine in the process of cytarabine daunorubicin liposome for injection, in particular to a method for recovering divalent copper ions and cytarabine. Background Art

[0002] In 2017, the U.S. FDA officially approved the drug Vyxeos for the treatment of related acute myeloid leukemia and acute myeloid leukemia with myelodysplasia-related changes; Vyxeos is a fixed-dose combination drug composed of the chemotherapy drugs daunorubicin and cytarabine. The combination improves the effect of chemotherapy and thus prolongs the patient's survival time.

[0003] Vyxeos is a liposome combination of anthracycline topoisomerase inhibitor daunorubicin and nucleoside metabolic inhibitor cytarabine. Daunorubicin, which has anti-cytotoxic and cytotoxic activities, forms a complex with DNA to inhibit topoisomerase II activity, thereby inhibiting DNA polymerase activity and affecting gene expression regulation; cytarabine only affects cells in the S phase of cell division and is a cell cycle phase-specific antitumor drug that mainly works by inhibiting DNA polymerase.

[0004] Vyxeos is the first approved liposome product that loads two different drugs in the same lipid vesicle. It uses both passive and active drug loading. When the pH is 7.4, cytarabine is passively encapsulated in the liposomes when the liposomes are hydrated with copper gluconate and triethanolamine cytarabine solution. After reducing the particle size and replacing the unencapsulated drug and copper gluconate / triethanolamine solution, daunorubicin is incubated with liposomes encapsulated with cytarabine under neutral pH conditions. Daunorubicin is stored in the liposome lumen by copper gluconate / triethanolamine encapsulation. Daunorubicin diffuses into the liposome through the lipid bilayer, while neutral triethanolamine permeates outside the liposome, establishing a kinetic and stoichiometric relationship between the efflux of daunorubicin and triethanolamine. Copper gluconate / triethanolamine plays an important role in the interaction with the two drugs, regulating the drug release from the liposomes while maintaining retention in the liposomes. In the process of cytarabine daunorubicin liposome technology, copper gluconate, triethanolamine and cytarabine outside the liposome need to be removed by ultrafiltration after hydration, homogenization or extrusion, and all of them will be discharged as waste liquid. Direct discharge will cause great pollution to the environment. Summary of the invention

[0005] The object of the present invention is to provide a method for recovering divalent copper ions and cytarabine to solve the problems in the prior art.

[0006] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0007] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0008] S1: after passive encapsulation of cytarabine by daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid;

[0009] S2: adjusting the pH of the waste liquid with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with hydrochloric acid, and concentrating to obtain a concentrated waste liquid;

[0010] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0011] S4: dissolving the cytarabine recovery product with a hydrochloric acid solution, and adding deionized water to obtain a cytarabine hydrochloride solution;

[0012] S5: adding isopropanol to the cytarabine hydrochloride solution, heating and stirring, and drying to obtain cytarabine hydrochloride.

[0013] Furthermore, the waste liquid contains gluconate, triethanolamine and cytarabine.

[0014] Furthermore, the pH of the waste liquid is adjusted to 6.96-7.2 with alkaline solution.

[0015] Furthermore, the alkali solution is one or a mixture of sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.

[0016] Furthermore, in step S4, deionized water is used as the solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 30-40%.

[0017] Furthermore, the cation exchange resin is one of hydrogen type 001×7 cation exchange resin, D301 weak acid cation exchange resin, and AmerliteIR-116 resin.

[0018] Furthermore, the working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 4-6% alkali solution for 4-6 retention volumes, and then eluting with 60%-80% ethanol for 4-6 retention volumes.

[0019] Furthermore, the alkali solution used in the cation exchange resin is aqueous ammonia.

[0020] Furthermore, the working conditions of heating and stirring are: stirring at 55-60°C for 1-2 hours, and the working conditions of drying are: forced air drying at 55-60°C for 7-8 hours.

[0021] Furthermore, the purity of cytarabine hydrochloride in step S5 is 98.5-100.0%.

[0022] Beneficial effects of the present invention:

[0023] The invention provides a method for recovering divalent copper ions and cytarabine. Alkaline solution is used to form precipitation with copper ions for removal, then acid is used for neutralization, cation exchange resin is used for adsorption, and then ammonia water of a certain concentration is used for elution to obtain cytarabine. After reduced pressure concentration and recrystallization, the recovered cytarabine can be recycled, thereby achieving the purpose of reducing costs and protecting the environment.

[0024] Waste liquid containing copper gluconate, triethanolamine and cytarabine in the process of cytarabine daunorubicin liposome is treated with alkali to remove copper ions, adjusted to neutrality and loaded on a cation exchange column; the column is washed with deionized water, alkali solutions of different concentrations and ethanol of different concentrations respectively; the obtained cytarabine is salified with hydrochloric acid, and then a proper amount of isopropanol is added, heated to dissolve, filtered, and crystallized to obtain cytarabine hydrochloride raw material, thereby achieving the purpose of green manufacturing. DETAILED DESCRIPTION

[0025] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] It should be noted that if the embodiments of the present invention involve directional indications such as up, down, left, right, front, back, etc., the directional indication is only used to explain a specific posture such as the relative position relationship between the components, the movement status, etc. If the specific posture changes, the directional indication will also change accordingly. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the ability of ordinary technicians in this field to implement. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the protection scope required by the present invention.

[0027] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only used to explain the present invention, and are not used to limit the present invention.

[0028] Example 1

[0029] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0030] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0031] S2: adjusting the pH of the waste liquid to 6.96 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid, which contains 40 g of cytarabine;

[0032] The alkali solution is 1 mol / L sodium hydroxide;

[0033] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0034] The cation exchange resin is a hydrogen type 001×7 cation exchange resin;

[0035] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 4% ammonia water for 4 retention volumes, and then eluting with pH 2.5, 60% ethanol for 4 retention volumes;

[0036] S4: dissolving the cytarabine recovered product with a hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (using deionized water as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 35%);

[0037] S5: Add 225 mL of isopropanol to the cytarabine hydrochloride solution, stir at 55°C for 2 h, filter, and cool to room temperature to obtain crystals. Filter to obtain a crystalline filter cake, and air dry at 55°C for 8 h to obtain 36 g of white crystalline powder. The purity of cytarabine hydrochloride determined by liquid phase chromatography is 99.4%.

[0038] Example 2

[0039] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0040] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0041] S2: adjusting the pH of the waste liquid to 7 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid, which contains 40 g of cytarabine;

[0042] The alkali solution is 1 mol / L sodium hydroxide;

[0043] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0044] The cation exchange resin is D301 weak acid cation exchange resin;

[0045] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 5% ammonia water for 4 retention volumes, and then eluting with pH 2, 60% ethanol for 6 retention volumes;

[0046] S4: dissolving the cytarabine recovered product with a hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (using deionized water as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 35%);

[0047] S5: Add 225 mL of isopropanol to the cytarabine hydrochloride solution, stir at 58°C for 1.5 h, filter, cool and crystallize, filter to obtain a crystalline filter cake, and air dry at 58°C for 7.5 h to obtain 35 g of white crystalline powder. The purity of cytarabine hydrochloride determined by liquid phase analysis is 99.1%.

[0048] Example 3

[0049] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0050] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0051] S2: adjusting the pH of the waste liquid to 7.1 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid;

[0052] The alkali solution is 1 mol / L sodium hydroxide;

[0053] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0054] The cation exchange resin was Amerlite IR-116 resin;

[0055] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 5% ammonia water for 5 retention volumes, and then eluting with pH=2.4, 80% ethanol for 4 retention volumes;

[0056] S4: dissolving the cytarabine recovery product with a 4 mol / L hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (using deionized water as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 30%);

[0057] S5: Add 250 mL of isopropanol to the cytarabine hydrochloride solution, stir at 60°C for 1 h, filter, cool and crystallize, filter again to obtain a crystalline filter cake, and air dry at 60°C for 7 h to obtain 35 g of white crystalline powder. The purity of cytarabine hydrochloride determined by liquid phase analysis is 98.5%.

[0058] Example 4

[0059] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0060] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0061] S2: adjusting the pH of the waste liquid to 7.2 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid, which contains 40 g of cytarabine;

[0062] The alkali solution is 1 mol / L sodium hydroxide;

[0063] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0064] The cation exchange resin is a hydrogen type 001×7 cation exchange resin;

[0065] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 5% ammonia water for 4.5 retention volumes, and then eluting with pH 2.1, 70% ethanol for 5 retention volumes;

[0066] S4: dissolving the cytarabine recovery product with a 4 mol / L hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (deionized water is used as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 40%);

[0067] S5: Add 220 mL of isopropanol to the cytarabine hydrochloride solution, stir at 60°C for 1 h, filter, cool and crystallize, filter to obtain a crystalline filter cake, and air dry at 60°C for 7 h to obtain 36 g of white crystalline powder. The purity of cytarabine hydrochloride determined by liquid phase analysis is 99.5%.

[0068] Example 5

[0069] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0070] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0071] S2: adjusting the pH of the waste liquid to 7 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid, which contains 40 g of cytarabine;

[0072] The alkali solution is 1 mol / L sodium hydroxide;

[0073] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0074] The cation exchange resin was Amerlite IR-116 resin;

[0075] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 6% ammonia water for 4 retention volumes, and then eluting with pH=2.6, 80% ethanol for 4 retention volumes;

[0076] S4: dissolving the cytarabine recovery product with a 4 mol / L hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (using deionized water as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 32%);

[0077] S5: Add 220 mL of isopropanol to the cytarabine hydrochloride solution, stir at 60°C for 1 h, filter, cool and crystallize, filter again to obtain a crystalline filter cake, and air dry at 60°C for 7 h to obtain 35 g of white crystalline powder. The purity of cytarabine hydrochloride determined by liquid phase analysis is 100%.

[0078] Comparative Example 1

[0079] Example 5 was used as a control group, deionized water was used as a solvent, the mass fraction of the cytarabine hydrochloride solution was 28%, and other processes were normal.

[0080] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0081] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0082] S2: adjusting the pH of the waste liquid to 7 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid, which contains 40 g of cytarabine;

[0083] The alkali solution is 1 mol / L sodium hydroxide;

[0084] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0085] The cation exchange resin was Amerlite IR-116 resin;

[0086] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 6% ammonia water for 4 retention volumes, and then eluting with pH=2.6, 80% ethanol for 4 retention volumes;

[0087] S4: dissolving the cytarabine recovery product with a 4 mol / L hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (using deionized water as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 28%);

[0088] S5: Add 220 mL of isopropanol to the cytarabine hydrochloride solution, stir at 60°C for 1 h, filter, cool to room temperature to obtain crystals, filter again to obtain a crystalline filter cake, and air dry at 60°C for 7 h to obtain 33 g of white crystalline powder. The purity of cytarabine hydrochloride determined by liquid phase chromatography is 97.2%.

[0089] Comparative Example 2

[0090] Example 5 was used as a control group, deionized water was used as a solvent, the mass fraction of the cytarabine hydrochloride solution was 42%, and other processes were normal.

[0091] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0092] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0093] S2: adjusting the pH of the waste liquid to 7 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid, which contains 40 g of cytarabine;

[0094] The alkali solution is 1 mol / L sodium hydroxide;

[0095] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0096] The cation exchange resin was Amerlite IR-116 resin;

[0097] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 6% ammonia water for 4 retention volumes, and then eluting with pH=2.6, 80% ethanol for 4 retention volumes;

[0098] S4: dissolving the cytarabine recovery product with a 4 mol / L hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (using deionized water as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 42%);

[0099] S5: Add 220 mL of isopropanol to the cytarabine hydrochloride solution, stir at 60°C for 1 h, filter, cool to room temperature to obtain crystals, filter again to obtain a crystalline filter cake, and air-dry at 60°C for 7 h to obtain 36 g of white crystalline powder. The purity of cytarabine hydrochloride determined by liquid phase chromatography is 95.2%.

[0100] Comparative Example 3

[0101] Taking Example 5 as the control group, the pH of the waste liquid was adjusted to 6.8 with alkali solution in step S2, and the other processes were normal.

[0102] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0103] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0104] S2: adjusting the pH of the waste liquid to 6.8 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid, which contains 40 g of cytarabine;

[0105] The alkali solution is 1 mol / L sodium hydroxide;

[0106] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0107] The cation exchange resin was Amerlite IR-116 resin;

[0108] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 6% ammonia water for 4 retention volumes, and then eluting with pH=2.6, 80% ethanol for 4 retention volumes;

[0109] S4: dissolving the cytarabine recovery product with a 4 mol / L hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (using deionized water as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 28%);

[0110] S5: Add 220 mL of isopropanol to the cytarabine hydrochloride solution, stir at 60°C for 1 h, filter, cool to room temperature to obtain crystals, filter the crystal cake again, and air dry it at 60°C for 7 h to obtain 35 g of powder. The purity of cytarabine hydrochloride was 95.2% as determined by liquid phase chromatography. Copper ions were not completely removed, and heavy metal copper ions exceeded the standard.

[0111] Comparative Example 4

[0112] Taking Example 5 as the control group, the working conditions of the cation exchange resin in step S3 are: first eluting with deionized water, discarding the eluent, then eluting with 7% ammonia water for 4 retention volumes, and then eluting with pH=2.6, 80% ethanol for 4 retention volumes, and other processes are normal.

[0113] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0114] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0115] S2: adjusting the pH of the waste liquid to 7 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid, which contains 40 g of cytarabine;

[0116] The alkali solution is 1 mol / L sodium hydroxide;

[0117] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0118] The cation exchange resin was Amerlite IR-116 resin;

[0119] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 7% ammonia water for 4 retention volumes, and then eluting with pH=2.6, 80% ethanol for 4 retention volumes;

[0120] S4: dissolving the cytarabine recovery product with a 4 mol / L hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (using deionized water as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 32%);

[0121] S5: Add 220 mL of isopropanol to the cytarabine hydrochloride solution, stir at 60°C for 1 h, filter, cool to room temperature to obtain crystals, and then filter to obtain a crystalline filter cake. Air-dry at 60°C for 7 h to obtain 35 g of powder. The purity of cytarabine hydrochloride determined by liquid phase chromatography is 90.1%.

[0122] Comparative Example 5

[0123] Taking Example 5 as the control group, the working conditions of the cation exchange resin in step S3 are: first eluting with deionized water, discarding the eluent, then eluting with 6% ammonia water for 4 retention volumes, and then eluting with pH=2.8, 90% ethanol for 4 retention volumes, and other processes are normal.

[0124] A method for recovering divalent copper ions and cytarabine comprises the following steps:

[0125] S1: After actively encapsulating cytarabine in cytarabine daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid, wherein the waste liquid contains gluconate, triethanolamine and cytarabine;

[0126] S2: adjusting the pH of the waste liquid to 7 with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with 1 mol / L hydrochloric acid, and concentrating to obtain a concentrated waste liquid, which contains 40 g of cytarabine;

[0127] The alkali solution is 1 mol / L sodium hydroxide;

[0128] S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product;

[0129] The cation exchange resin was Amerlite IR-116 resin;

[0130] The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 6% ammonia water for 4 retention volumes, and then eluting with pH=2.8, 90% ethanol for 4 retention volumes;

[0131] S4: dissolving the cytarabine recovery product with a 4 mol / L hydrochloric acid solution, adding deionized water, and obtaining a cytarabine hydrochloride solution (using deionized water as a solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 32%);

[0132] S5: Add 220 mL of isopropanol to the cytarabine hydrochloride solution, stir at 60°C for 1 h, filter, cool to room temperature, crystallize, and then filter to obtain a crystalline filter cake. Air-dry at 60°C for 7 h to obtain 35 g of powder. The purity of cytarabine hydrochloride determined by liquid phase chromatography is 92.3%.

[0133] By comparing Example 5 with Comparative Examples 1 and 2, it can be seen that the purity of cytarabine hydrochloride is improved by adjusting the mass fraction of the cytarabine hydrochloride solution in step S4.

[0134] By comparing Example 5 with Comparative Example 3, it can be seen that in step S4, the copper ions are completely precipitated and removed by adjusting the pH, then neutralized with acid, adsorbed on a cation exchange resin, and then eluted with a certain concentration of ammonia water to improve the purity of cytarabine.

[0135] By comparing Example 5 with Comparative Examples 4 and 5, it can be seen that the purity of the recovered cytarabine can be improved by controlling the concentration and pH of ammonia water and ethanol in step S3.

[0136] The invention provides a method for recovering divalent copper ions and cytarabine. The method comprises the following steps: using alkaline solution to form a precipitate with copper ions to remove the precipitate, neutralizing the precipitate with an acid, adsorbing the precipitate on a cation exchange resin, and eluting the precipitate with a certain concentration of ammonia water to obtain cytarabine. The precipitate is concentrated under reduced pressure and then recrystallized. The recovered cytarabine can be recycled to achieve the purpose of reducing costs and protecting the environment. Waste liquid containing copper gluconate, triethanolamine and cytarabine in the process of cytarabine daunorubicin liposome is treated with alkali to remove copper ions, adjusted to be neutral and then applied to a cation exchange column. The column is washed with deionized water, alkaline solutions of different concentrations and ethanol of different concentrations respectively. The obtained cytarabine is salified with hydrochloric acid, an appropriate amount of isopropanol is added, heated to dissolve, filtered and crystallized to obtain cytarabine hydrochloride raw material medicine, thereby achieving the purpose of green manufacturing.

[0137] The above descriptions are only embodiments of the present invention and are not intended to limit the patent scope of the present invention. All equivalent structural changes made using the present invention specification under the inventive concept of the present invention, or direct / indirect applications in other related technical fields, are included in the patent protection scope of the present invention.

Claims

1. A method for recovering divalent copper ions and cytarabine, characterized in that: The following steps are involved: S1: after actively encapsulating cytarabine in daunorubicin liposomes, ultrafiltration is performed to obtain a waste liquid; S2: adjusting the pH of the waste liquid with an alkali solution to form a copper hydroxide precipitate, filtering, and drying to form copper oxide; adjusting the pH of the resulting filtrate to neutral with hydrochloric acid, and concentrating to obtain a concentrated waste liquid; S3: passing the concentrated waste liquid through a cation exchange resin to recover the solvent to obtain a cytarabine recovery product; S4: dissolving the cytarabine recovery product with a hydrochloric acid solution, and adding deionized water to obtain a cytarabine hydrochloride solution; S5: adding isopropanol to the cytarabine hydrochloride solution, heating and stirring, filtering, cooling the filtrate to obtain cytarabine hydrochloride crystals, filtering again to obtain solid crystals, and drying to obtain cytarabine hydrochloride finished product; In step S4, deionized water is used as the solvent, wherein the mass fraction of the cytarabine hydrochloride solution is 30-40%; The working conditions of the cation exchange resin are: first eluting with deionized water, discarding the eluent, then eluting with 4-6% alkali solution for 4-6 retention volumes, and then eluting with 60%-80% ethanol for 4-6 retention volumes.

2. The method for recovering divalent copper ions and cytarabine according to claim 1, characterized in that: The waste liquid contains gluconate, triethanolamine and cytarabine.

3. The method for recovering divalent copper ions and cytarabine according to claim 1, characterized in that: The pH of the waste liquid was adjusted to 6.96-7.2 with alkali solution.

4. The method for recovering divalent copper ions and cytarabine according to claim 1, characterized in that: The alkali solution is one or a mixture of sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.

5. The method for recovering divalent copper ions and cytarabine according to claim 1, characterized in that: The cation exchange resin is one of hydrogen type 001×7 cation exchange resin, D301 weak acid cation exchange resin, and Amerlite IR-116 resin.

6. The method for recovering divalent copper ions and cytarabine according to claim 1, characterized in that: The alkali solution used in cation exchange resin is ammonia water.

7. The method for recovering divalent copper ions and cytarabine according to claim 1, characterized in that: The working conditions for heating and stirring are: stirring at 55-60°C for 1-2 hours, and the working conditions for drying are: forced air drying at 55-60°C for 7-8 hours.

8. The method for recovering divalent copper ions and cytarabine according to claim 1, characterized in that: The purity of cytarabine hydrochloride in step S5 is 98.5-100.0%.