A method for purifying iodixanol

Abstract

This invention relates to the field of drug purification technology, specifically providing a method for purifying iodixanol. This invention uses polymer porous microspheres as a reversed-phase packing material to purify the iodixanol reaction solution. The process includes: column packing, column equilibration, sample loading, impurity elution, elution and collection of the target analyte, column regeneration, target analyte concentration, and drying. The iodixanol purification method disclosed in this invention requires only one step of chromatographic purification to directly purify the reaction solution to the standard of the active pharmaceutical ingredient. This method is simple to operate, has mild conditions, and low purification cost, making it particularly suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of drug purification technology, specifically to a method for purifying iodixanol. Background Technology

[0002] Iodixanol is a non-ionic contrast agent. It can be used in X-ray angiography and CT contrast-enhanced examinations. It is currently the only contrast agent that is isotonic with plasma when applied intravascularly. It is commonly used in adult cardiovascular angiography, cerebral angiography (conventional and iaDSA), peripheral arterial angiography (conventional and iaDSA), abdominal angiography (iaDSA), urinary tract angiography, and venography. Its structural formula is as follows:

[0003]

[0004] Currently, domestic and international patents and literature mainly describe the purification of iodixanol using methods such as recrystallization, macroporous resin purification-crystallization, and reverse-phase C18 bonded silica gel purification.

[0005] CN1273574A discloses a method for crystallizing iodixanol using methanol / isopropanol / water. The crystallization is carried out under high heat, especially under high pressure and temperatures exceeding the solution's boiling point, making the conditions harsh and requiring sophisticated production equipment. CN101293855B discloses a purification method for iodixanol. This invention employs recrystallization to purify crude iodixanol prepared using a method involving dimerized 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. Repeated crystallization yields an iodixanol product suitable for pharmacopoeia standards. Nycomed's patent EP 0108638 uses a preparative chromatographic purification method; Mallinckrodt Inc.'s patent EP 0470247B1 describes a method for decolorizing, separating, and purifying water-soluble nonionic contrast agents from an aqueous solution containing nonionic compound impurities using reversed-phase chromatography; Bracco SpA's patent EP 0902686B1 describes a method for refining and purifying contrast agents, which includes combining chromatographic and nanofiltration techniques, sequentially separating the crude solution using chromatography and nanofiltration, and finally decolorizing with ion exchange resin. Patent CN111440084A discloses a method for purifying iodixanol using reversed-phase C18 bonded silica gel, using a 2-5% concentration of organic solvent aqueous solution as the mobile phase for equilibration, sample loading, and impurity washing, eluting the target analyte with a 6-9% organic solvent aqueous solution, and regenerating with a 90-100% organic solvent aqueous solution to obtain iodixanol target analyte with a purity greater than 95% and a yield greater than 88%.

[0006] Purification methods involving crystallization or recrystallization require multiple repetitions to obtain high purity and high content of iodixanol, making it difficult to control purity and yield. Purification methods using macroporous resins consume large amounts of mobile phase, resulting in low purity and yield of the target analyte. While reverse-phase C18 bonded silica gel yields good purity, the yield is low, and low-concentration alcohols used as mobile phases are difficult to recover, and the packing material has a short lifespan in high-salt-concentration reaction solutions. Therefore, it is essential to develop a purification method that can be stably applied for extended periods in high-salt-concentration reaction solutions, eliminates the need for low-concentration solvent equilibration and washing, and achieves high purity and high yield. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention discloses a purification method for iodixanol. It utilizes polymer porous microspheres containing long-chain alkyl groups as the reverse-phase packing material to purify the iodixanol reaction solution. This not only solves the lifespan problem of reverse-phase bonded silica gel but also allows water to replace 2-5% of the solvent as the mobile phase for equilibration and impurity washing, thus resolving the difficulty in recovering large quantities of low-concentration solvent. Furthermore, the purification scheme disclosed in this invention significantly improves loading capacity, purity, and yield compared to reverse-phase C18 bonded silica gel. The process is stable, requires minimal equipment, and can be used for large-scale production, greatly reducing production costs.

[0008] Specifically, the present invention provides a method for purifying iodixanol, comprising the step of using polymer porous microspheres as reversed-phase packing material to perform reversed-phase chromatography purification of the iodixanol reaction solution, wherein the polymer porous microspheres have the structural unit shown in formula (I):

[0009]

[0010] Where R1 is absent or selected from R2 is

[0011] R3 is R4 is absent or selected from methylene or carbonyl groups;

[0012] n1 is an integer from 0 to 4, n2 is an integer from 1 to 4, n3 is an integer from 7 to 17, and n4 is an integer from 0 to 4.

[0013] Furthermore, the polymer porous microspheres have the structural unit shown in formula (II):

[0014]

[0015] R1, R3, and n3 are as defined above.

[0016] Furthermore, the polymer porous microspheres have structural units represented by formula (III) or (IV):

[0017]

[0018]

[0019] Where n3 is as defined above.

[0020] The present invention also provides a method for purifying iodixanol, comprising the step of using polymer porous microspheres as reversed-phase packing material to perform reversed-phase chromatography purification of the iodixanol reaction solution, wherein the polymer porous microspheres contain, based on the total mass of monomer units as 100%, 35-95% aromatic divinyl monomer units and 5-65% vinyl monomer units containing alkyl side chains of 8-18 carbon atoms.

[0021] Preferably, the polymer porous microspheres contain 40-80% aromatic divinyl monomer units; preferably, the polymer porous microspheres contain 20-60% vinyl monomer units with alkyl side chains containing 8-18 carbon atoms.

[0022] In this invention, the aromatic divinyl monomers include, but are not limited to, divinylbenzene. This includes one or a mixture of several of p-divinylbenzene, m-divinylbenzene, di(4-vinylphenyl)methane, 1,2-di(4-vinylphenyl)ethane, 1,3-di(4-vinylphenyl)propane, and 1,4-di(4'-vinylphenoxy)butane. Preferred aromatic divinyl monomers are p-divinylbenzene, m-divinylbenzene, and 1,2-di(4-vinylphenyl)ethane.

[0023] In this invention, the vinyl monomer containing an alkyl side chain of 8-18 carbon atoms is a vinyl functional monomer containing a long side chain alkyl (C8-C18), specifically a C8-C18 alkyl ester of methacrylic acid.

[0024] Furthermore, the polymer porous microspheres are polymer porous microspheres copolymerized from C8-C18 alkyl esters of methacrylate and aromatic divinyl monomers; preferably, the aromatic divinyl monomer is divinylbenzene or P,P'-divinyl-1,2-diphenylethane; more preferably, the polymer porous microspheres include one or more of poly(divinylbenzene-octadecyl methacrylate), poly(P,P'-divinyl-1,2-diphenylethane-octyl methacrylate), or poly(divinylbenzene-octyl methacrylate).

[0025] Furthermore, the average particle size of the polymer porous microspheres is 30-150 μm, and the pore size is... Specific surface area is 100-500 m² 2 / g; preferably, the polymer porous microspheres have an average particle size of 50-100 μm and a pore size of Specific surface area is 200-400m² 2 / g.

[0026] Furthermore, the degree of crosslinking of the polymer porous microspheres is 50-80% (W / W), preferably 60-70% (W / W).

[0027] Furthermore, the method includes a one-step chromatographic purification method, comprising: using polymer porous microspheres as reversed-phase packing material to perform reversed-phase chromatographic purification of the iodixanol reaction solution, concentrating the collected target analyte, and drying to obtain iodixanol powder.

[0028] Furthermore, the method for preparing the polymer porous microspheres includes the following steps:

[0029] Step S1: Prepare an aqueous phase by mixing water and a surfactant; prepare an oil phase by mixing an aromatic divinyl monomer, a vinyl monomer having 8-18 alkyl side chains, a porogen, and an initiator; or prepare an oil phase by mixing an aromatic divinyl monomer, a vinyl monomer having 8-18 alkyl side chains, other vinyl monomers, a porogen, and an initiator.

[0030] Step S2: Using aqueous and oil phases as raw materials, free radical polymerization is carried out using template swelling method, precipitation polymerization method, suspension polymerization or dispersion polymerization to form microspheres;

[0031] Step S3: After the polymerization reaction is complete, the porogen is removed to obtain polymer porous microspheres.

[0032] In this invention, the initiator used in the microsphere preparation method disclosed herein is an organic peroxide or azo compound, including but not limited to benzoyl peroxide, lauroyl peroxide, tert-butyl peroxide-2-ethylhexanoate, azobisisobutyronitrile, azobisisovalerate, and azobisisoheptanenitrile. The amount of initiator used is 0.5-5% of the total weight of the monomers.

[0033] In the microsphere preparation method disclosed in this invention, the porogen is an organic solvent, linear polymer, or surfactant that does not participate in the polymerization reaction and is insoluble or slightly soluble in water. More specifically, the porogen includes:

[0034] 1) Aromatic hydrocarbons, such as benzene, toluene, and ethylbenzene;

[0035] 2) Aliphatic hydrocarbons, such as straight-chain, branched, or cycloalkanes containing 6 to 12 carbons, such as hexane, heptane, octane, dodecane, isooctane, isododecane, cyclohexane, etc.

[0036] 3) Halogenated hydrocarbons, such as chloroform and chlorobenzene;

[0037] 4) Esters containing four or more carbons, such as ethyl acetate, butyl acetate, and dibutyl phthalate;

[0038] 5) Alcohols, such as straight-chain, branched, or cycloalkanols containing 4 to 12 carbons, such as hexanol, cyclohexanol, octanol, isooctanol, decanol, and dodecanol.

[0039] 6) Oil-soluble surfactants, such as sorbitan trioleate, polyoxyethylene sorbitan beeswax derivatives, sorbitan tristearate, polyoxyethylene sorbitan hexastearate, ethylene glycol fatty acid esters, propylene glycol fatty acid esters, propylene glycol monostearate, sorbitan sesquioleate, polyoxyethylene sorbitan oleate, glyceryl monostearate, hydroxylated lanolin, sorbitan monooleate, and propylene glycol monolaurate;

[0040] 7) Linear polymers with a molecular weight not exceeding 100 kDa, such as polyethylene, polyvinyl chloride, polypropylene, polyurethane, polyethylene glycol, polystyrene, polymethacrylate, poly(meth)acrylate, poly(meth)acrylic acid, poly(meth)acrylonitrile, and poly(meth)acrylate.

[0041] In this invention, the surfactant refers to a water-soluble polymeric surfactant, including but not limited to one or more of polyvinyl alcohol, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, sodium polyacrylate, and polyvinylpyrrolidone. The amount of surfactant used is 0.1-5% of the weight of the aqueous phase.

[0042] Inorganic salts can also be added to the aqueous phase. The function of these inorganic salts is to adjust the density of the aqueous phase and reduce the solubility of the components in the oil phase within the aqueous phase, thus allowing the oil droplets to be more stably dispersed in the aqueous phase. These include, but are not limited to, one or more of sodium chloride, potassium chloride, calcium chloride, sodium sulfate, potassium sulfate, and calcium sulfate. The amount of inorganic salt used should not exceed 20% of the amount of the aqueous phase.

[0043] In this invention, to reduce adhesion between resins, improve the conduction of polymerization heat, and simultaneously increase equipment utilization and production efficiency, the weight ratio of the oil phase to the water phase is set to 1:3-1:20. A preferred weight ratio is 1:6-1:10.

[0044] In the microsphere preparation method disclosed in this invention, the weight of the initiator is 0.3-3.0% of the total weight of the monomers, preferably 0.5-1.5%; the weight of the porogen initially present in the oil phase is 80-200% of the weight of the monomers, preferably 120-180%.

[0045] In the microsphere preparation method disclosed in this invention, the polymerization temperature is 50-90℃, preferably 60-85℃.

[0046] The above method can be used to obtain the polymer porous microspheres of this invention, namely polymer porous beads containing long-chain alkyl groups. In this invention, the content of long-chain alkyl groups is determined by the proportion of the functional monomer (i.e., vinyl monomers containing alkyl side chains of 8-18 carbon atoms) in the monomer weight. By adjusting the amount of functional monomer, a series of polymer porous microspheres with different hydrophilicity and hydrophobicity can be obtained. This method is applicable to the reverse-phase separation and purification of compounds with different hydrophilicity and hydrophobicity.

[0047] In this invention, the particle size of the polymer porous microspheres is detected using a particle image processing instrument. Specifically, the microspheres are uniformly distributed on a glass slide, the carrier particles are magnified using a microscope, and a camera simultaneously captures magnified images of the microsphere particles. The morphological characteristics and particle size of the microspheres are then analyzed and calculated using a computer.

[0048] The particle size of the carrier mainly depends on the polymerization method. Taking template-based swelling polymerization as an example, the particle size of the microspheres can be controlled by adjusting the ratio between the template and the swollen oil phase during the swelling process. Taking suspension polymerization as an example, the particle size of the carrier can also be adjusted by changing the type and amount of the surfactant in the aqueous phase, as well as the stirring speed during suspension polymerization. Taking precipitation polymerization as an example, adjusting the type of surfactant, the amount of oil phase, and the amount of initiator can all control the particle size of the microspheres. If the particle size of the microspheres is too large, the specific surface area decreases, the mass transfer time inside the microspheres increases, and the space between the microspheres increases, all of which reduce the separation efficiency when used as a purification packing material. If the particle size of the microspheres is too small, it will cause excessively high pressure during the purification process, increasing equipment costs. In this invention, the particle size range of the carrier is 30-150 μm, preferably 50-100 μm.

[0049] The specific surface area of ​​the polymer porous microspheres was measured using the nitrogen adsorption method. Specifically, 0.1500-0.2000 g of dried polymer porous microspheres were accurately weighed and placed in an ASAP 2020 fully automated specific surface area and porosity analyzer (Micromeritics Instrument Co.). The specific surface area was measured under these conditions with an inlet gas rate of 5-10 kPa. The specific surface area was then determined using the nitrogen physical adsorption method and calculated using the BET model. In this invention, the BET specific surface area of ​​the microspheres was 100-500 m² / g. 2 / g, with a preferred micro specific surface area of ​​200-400m². 2 / g.

[0050] The average pore size of the polymer porous microspheres was measured using mercury porosimetry. Specifically, 0.1500-0.3000 g of sample was accurately weighed and placed in an automated mercury porosimetry instrument, AutoPoreⅣ9500 (Micromeritics Instrument Co.), with the mercury contact angle set to 130° and the surface tension to 485 dyn / cm. The average pore size of the polymer porous microspheres mainly depends on the type and amount of porogen, the type and amount of crosslinking agent, and the reaction temperature and time. By adjusting these conditions, the average pore size of the polymer porous microspheres can be adjusted. If the average pore size of the polymer porous microspheres is too small, mass transfer will be difficult, affecting the purification results when used as a reverse-phase packing material; if the average pore size of the carrier is too large, the specific surface area will decrease, affecting the loading capacity when used as a reverse-phase packing material. In this invention, the average pore size of the microspheres is... Its preferred microsphere pore size is 80-

[0051] Furthermore, the reversed-phase chromatography purification includes the following steps:

[0052] 1) Column packing: The chromatographic column is packed with polymer porous microspheres;

[0053] 2) Equilibrate the chromatographic column with water;

[0054] 3) Load the filtered iodixanol reaction solution into a chromatographic column packed with polymer porous microspheres;

[0055] 4) Use water to wash away impurities;

[0056] 5) Elute the target analyte using a low-concentration solvent with a mass percentage of 5-25%;

[0057] 6) Collect the target iodixanol solution in segments to obtain the purified iodixanol solution;

[0058] 7) Regenerate the chromatographic column with a high-concentration solvent with a mass percentage concentration higher than 50%.

[0059] In other words, the reversed-phase chromatography purification process involves packing porous polymer microspheres into a chromatographic column and equilibrating it with water; loading the filtered iodixanol reaction solution onto the column; using water as the mobile phase to wash away impurities; and eluting with a low-concentration alcohol solution of 5-25% by mass to obtain the purified iodixanol solution.

[0060] After purification, the chromatographic packing material is regenerated using a high-concentration solvent aqueous solution with a mass percentage concentration higher than 50%.

[0061] Furthermore, the target concentration method includes one or more of the following: vacuum distillation, rotary evaporation, thin-film evaporation, and nanofiltration, with nanofiltration being the preferred concentration method.

[0062] Furthermore, the purity of the iodixanol reaction solution is 70-85%.

[0063] In this invention, the purity of the iodixanol reaction solution or iodixanol refers to the purity calculated by the peak area normalization method obtained by measuring the peak area using HPLC.

[0064] Furthermore, the purity of the iodixanol reaction solution is 75-85%.

[0065] Furthermore, the filtration is performed by filtering the reaction solution with iodixanol using a filter membrane with a pore size of 0.1–1 μm.

[0066] Furthermore, the pore size of the filter membrane is 0.22-0.45 μm.

[0067] Further, the column packing is performed by adding 0.6-1.6 times the weight of the polymer porous microspheres to a homogenized alcohol-water solution with a volume percentage of 30-70% (V / V), using a wet packing method, and a column packing pressure of 0.2-40 MPa;

[0068] Furthermore, the water-equilibrated chromatographic column is washed with 2-6 column volumes of water, and the flow rate of the equilibration process line is 2-10 cm / min.

[0069] Furthermore, the loading refers to injecting the filtered iodixanol reaction solution into the chromatographic column at a flow rate of 1-5 cm / min and a loading volume of 40-80 g / L.

[0070] Furthermore, the impurity elution is a process of washing the chromatographic column with 12-36 column volumes of purified water to remove polar impurities, with a process flow rate of 2-10 cm / min.

[0071] Further, in step 5), the elution is a process of rinsing the chromatographic column with 6-12 column volumes of low-concentration solvent solution to elute the target analyte iodixanol, with a process flow rate of 2-10 cm / min.

[0072] Furthermore, the regeneration is a process of rinsing the chromatographic column with 2-5 column volumes of high-concentration solvent solution to elute all target analytes and impurities, with a process flow rate of 2-10 cm / min.

[0073] Further, in step 5) or step 7), the solvent refers to alcohols, esters, ethers, ketones, amides, and sulfones that are soluble in water and have no more than 4 carbon atoms, including but not limited to methanol, ethanol, isopropanol, butanol, ethyl formate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, dioxane, diethyl ether, anisole, acetone, methyl ethyl ketone, butanone, methyl isobutyl ketone, diisobutyl ketone, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, or a mixture of several of these.

[0074] Furthermore, the solvent is one or a mixture of several of methanol, ethanol, acetonitrile, and acetone.

[0075] Furthermore, the solvent is one or a mixture of two of methanol and ethanol.

[0076] Furthermore, the mass percentage concentration of the low-concentration solvent is 5-25% (w / w).

[0077] Furthermore, the mass percentage concentration of the high-concentration solvent is greater than 50% (W / W).

[0078] Furthermore, the reversed-phase chromatography purification includes the following steps:

[0079] 1) Column packing: Use polymer porous microspheres as packing material to pack the chromatographic column: Add 0.6-1.6 times the weight of 30-70% (V / V) alcohol-water slurry to the polymer porous microspheres, homogenize, wet pack the column, and pack the column at a pressure of 0.2-5.0 MPa;

[0080] 2) Equilibrate the column with water: Rinse the column with 2-6 column volumes of water, with a flow rate of 2-10 cm / min during the equilibration process;

[0081] 3) The reaction solution with iodixanol is filtered using a filter membrane with a pore size of 0.1-1 μm, preferably 0.22-0.45 μm; the filtered iodixanol reaction solution is loaded into a chromatographic column packed with polymer porous microspheres; the flow rate during loading is 1-5 cm / min, and the loading volume is 40-80 g / L;

[0082] 4) Eluting with water: Wash the column with 12-36 column volumes of purified water, with a flow rate of 2-10 cm / min during the elution process;

[0083] 5) Elution of the target analyte with a low-concentration solvent: Wash the column with 6-12 column volumes of a low-concentration solvent solution, and maintain a flow rate of 2-10 cm / min during the elution process;

[0084] 6) Collect the target iodixanol solution in segments, and summarize the components that meet the requirements to obtain the purified iodixanol solution.

[0085] 7) Regenerate the column with a high-concentration solvent: Rinse the column with 2-5 column volumes of high-concentration solvent solution, with a flow rate of 2-10 cm / min during the regeneration process.

[0086] Furthermore, the solvent refers to alcohols, esters, ethers, ketones, amides, and sulfones that are soluble in water and have no more than 4 carbon atoms, including but not limited to one or a mixture of methanol, ethanol, isopropanol, butanol, ethyl formate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, dioxane, diethyl ether, anisole, acetone, methyl ethyl ketone, butanone, methyl isobutyl ketone, diisobutyl ketone, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. Preferably, it is one or a mixture of methanol, ethanol, acetonitrile, and acetone, with methanol and ethanol being the most preferred.

[0087] The low-concentration solvent has a mass percentage concentration of 5-25% (w / w); the high-concentration solvent has a mass percentage concentration of more than 65% (w / w).

[0088] The purity of the iodixanol reaction solution is 70-85%; preferably, the purity is 75-85%.

[0089] After reversed-phase chromatography purification, the concentration methods for the collected target analytes include one or a combination of vacuum distillation, rotary evaporation, thin-film evaporation, and nanofiltration, with nanofiltration being the preferred concentration method.

[0090] After concentration, the liquid enters the drying step. The methods for drying the concentrate include, but are not limited to, precipitation, distillation, vacuum distillation, rotary evaporation, freeze drying, and spray drying. Spray drying is the preferred drying method.

[0091] The reversed-phase chromatography purification method includes: using 60-110 parts by weight of poly(divinylbenzene-octadecyl methacrylate) polymer porous microspheres or poly(P,P'-divinyl-1,2-diphenylethane-octyl methacrylate) polymer porous microspheres as chromatographic packing material, adding 30-60 parts by volume of 40-60% ethanol or 40-60% methanol to homogenize, packing the column with a column volume of 40-140 parts by volume, and a column packing pressure of 7.5-200 bar; after packing, using 190-400 parts by volume of water to equilibrate the column, with a linear flow rate of 2-10 cm / min; and taking a concentration of 200-400 g. A solution of iodixanol of / L was filtered through a 0.45-micron pore size filter membrane. 10.5-40 volume fractions of the filtrate were loaded onto the chromatographic column using an infusion pump at a flow rate of 1-5 cm / min. After loading, impurities were eluted with water for 190-220 min at a flow rate of 2-10 cm / min. After impurity elution, the target analyte, iodixanol, was eluted with 13%-18% ethanol or 13%-18% methanol for 80-100 min at a flow rate of 2-10 cm / min. The eluent was collected and analyzed by liquid chromatography. The weight to volume ratio was g / mL.

[0092] 1. The purification method for iodixanol disclosed in this invention uses polymer porous microspheres as shown in Formula (I) instead of traditional macroporous resin and reversed-phase bonded silica gel as the stationary phase. Only one-step chromatographic purification is required to achieve iodixanol with a main impurity content of less than 0.15%, a residual impurity content of less than 0.05%, a purity greater than 98.5%, and a yield greater than 92%. Compared with existing technologies, this invention not only solves the application limitations of macroporous resin and reversed-phase bonded silica gel and reduces the amount of low-concentration solvent used, but also solves the problem of difficulty in recovering large amounts of low-concentration solvent. Furthermore, the purification method disclosed in this invention significantly improves loading capacity, purity, and yield compared to macroporous resin and reversed-phase C18 bonded silica gel. Unlike conventional polystyrene-divinylbenzene polymer porous microspheres, this invention uses a "comb-like structure" formed by long side-chain alkyl groups to impede the interaction between the solute and the high-density electron cloud brought by the phenyl group. This invention expands the applicability of porous polymer resins in reversed-phase chromatography, particularly for the separation of hydrophobic small molecules containing straight-chain alkyl groups, such as iodixanol, where the separation effect is far superior to conventional polystyrene-divinylbenzene porous microspheres. Compared to oil-absorbing or oil-removing resins, this invention solves the problem of excessive swelling in polymers with long alkyl side chains, enabling the application of porous polymer microspheres in reversed-phase chromatography.

[0093] 2. The purification method for iodixanol disclosed in this invention uses polymer porous microspheres containing long-chain alkyl groups to replace reverse-phase C18 bonded silica gel as the reverse-phase packing material for purifying the iodixanol reaction solution. This not only solves the lifespan problem of reverse-phase bonded silica gel but also allows water to replace 2-5% concentration solvent as the mobile phase for equilibration and impurity washing processes, thus solving the problem of difficulty in recovering large amounts of low-concentration solvent. Furthermore, the purification scheme disclosed in this invention significantly improves loading capacity, purity, and yield compared to reverse-phase C18 bonded silica gel. The process is stable, requires minimal equipment, and can be used for large-scale production, greatly reducing production costs.

[0094] 3. The purification method for iodixanol disclosed in this invention adjusts the binding force (interaction force) between the packing material and the target analyte by adjusting the structure and composition of the polymer porous microspheres used as the reverse-phase packing material. If the binding force is too low, the loading capacity will be low; if the binding force is too strong, water will be unable to wash away impurities. Using low-concentration solvents to wash away impurities will increase costs. In a preferred embodiment of this invention, the polymer porous microspheres are copolymerized with 35-95% aromatic divinyl monomer units and 5-65% vinyl monomer units with alkyl side chains containing 8-18 carbon atoms, based on the total mass of the monomer units (100%). By controlling the mass percentage of monomers within the above range, the binding force between the microspheres and the target analyte is controlled, ultimately achieving the highest loading capacity, higher purification efficiency, and lower purification cost by washing away impurities with water and eluting the target analyte with low-concentration solvents.

[0095] 4. This invention uses a polymerization method to prepare polymer porous microspheres containing long-chain alkyl groups. Compared to methods that first prepare the framework and then perform bonding, polymer porous microspheres have a higher content of long-chain alkyl groups, lower cost, and more ideal purification effect as a reverse-phase packing material. Compared to monolithic columns, the polymer porous microspheres disclosed in this invention can adapt to reverse-phase purification requirements of various scales, solving the problem of monolithic columns being difficult to industrialize. At the same time, industrial-scale production of polymer porous microspheres also avoids the problems of high cost and poor batch stability of monolithic columns. Therefore, it is an ideal reverse-phase purification packing material. Attached Figure Description

[0096] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0097] Figure 1 The liquid chromatogram of the iodixanol reaction solution in Example 3 (detection wavelength 254 nm);

[0098] Figure 2 The liquid chromatogram of iodixanol after purification in Example 3 (detection wavelength 254 nm);

[0099] Figure 3 This is a SEM image of the polymer porous microspheres in Example 1. Detailed Implementation

[0100] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0101] Where specific experimental steps or conditions are not specified in the examples, they can be performed according to the conventional experimental steps or conditions described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products. The divinylbenzene used in this invention can be a raw material containing more than 55%, 63%, or 80% by mass of the main components m-divinylbenzene and p-divinylbenzene. This raw material may also contain impurities such as ethylstyrene, methylstyrene, and diethylbenzene. The mass ratio of m-divinylbenzene to p-divinylbenzene in the raw material can be 1:3 to 3:1.

[0102] In Example 1, the mass percentage of intermediate-divinylbenzene and p-divinylbenzene used in the divinylbenzene raw materials was 80%, and the mass ratio of intermediate-divinylbenzene to p-divinylbenzene was 2:1.

[0103] In Example 5, the divinylbenzene raw materials used had a mass percentage of 96% for intermediate divinylbenzene and p-divinylbenzene, and a mass ratio of 1:1 for intermediate divinylbenzene and p-divinylbenzene.

[0104] The iodixanol reaction solution in this invention is prepared using the method described in patent WO0047549. Specifically, it is obtained by the dimerization reaction of 5,5′-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N′-bis(2,3-dihydroxypropyl)-1,3-phenylenediamine] with epichlorohydrin under alkaline conditions. The purity of the target compound iodixanol in the reaction product is 74.8-80.8%.

[0105] Example 1

[0106] This embodiment provides a purification method for iodixanol, comprising the following steps: 60g of poly(divinylbenzene-octadecyl methacrylate) polymer porous microspheres are used as chromatographic packing material. 40ml of 50% (w / w) methanol slurry is added and homogenized, then packed into a 10×600mm column with a packing volume of 47ml and a packing pressure of 200bar. After packing, the column is equilibrated with 200ml of pure water at a flow rate of 4.7ml / min. Iodixanol reaction solution with a concentration of 313g / L (purity 77.5%) is taken and filtered through a 0.45-micron filter membrane. 10.5ml of the filtrate is loaded onto the column (capacity 70g / L) using an infusion pump at a flow rate of 2.4ml / min. After loading, impurities are eluted with water for 200min at a flow rate of 4.7ml / min. After impurity elution, the target compound iodixanol was eluted with 18% (w / w) methanol for 100 min at a flow rate of 4.7 mL / min. The eluent was collected and analyzed by high-performance liquid chromatography (HPLC). The column was regenerated using 80% methanol at a flow rate of 4.7 mL / min for 30 min. HPLC analysis showed that the purity of iodixanol was 99.5%, with single impurities A, B, D, and G less than 0.05%, impurity C less than 0.1%, and unknown impurities less than 0.05%, with a yield of 94.6%. The impurities met the requirements of the European Pharmacopoeia. A Dairy DK3838C30 nanofiltration membrane with a molecular weight cutoff of 150-300 Da was used to concentrate the target compound by nanofiltration and spray-drying at 70 °C to obtain 2.97 g of iodixanol powder.

[0107] The preparation method of porous microspheres of poly(divinylbenzene-octadecyl methacrylate) polymer is as follows:

[0108] In a 5L reactor equipped with a condenser, stirrer, and thermometer, add 2.4L of purified water, 24g of polyvinyl alcohol 1788, and 36g of sodium chloride, dissolve, and set aside; this is the aqueous phase. Weigh out 68.8g of divinylbenzene (80% purity), 45.9g of octadecyl methacrylate, 1.7g of benzoyl peroxide, 172.1g of dibutyl phthalate, and 11.5g of polystyrene (manufacturer: Shanghai Aladdin Biochemical Technology Co., Ltd., molecular weight: 35000, product number: P434450), mix thoroughly, and this is the oil phase. Add the oil phase to the reactor, start stirring, and heat to 70℃ for polymerization for 12 hours. After the reaction, wash with hot water, reflux with ethanol to remove pore-forming agents, sieve and collect polymer porous microspheres with a particle size of 50-100μm (see...). Figure 3 It is a porous polymer resin containing octadecyl side chain alkyl groups. Its average pore size was determined using mercury porosimetry. Its specific surface area (BET) was determined to be 320 m² using nitrogen adsorption method. 2 / g. The resulting polymer porous microspheres have the structural unit shown in formula (III), where n3 is 17.

[0109] Example 2

[0110] This embodiment provides a purification method for iodixanol, comprising the following steps: 60g of poly(divinylbenzene-octadecyl methacrylate) polymer porous microspheres are used as chromatographic packing material. 60ml of 50% (w / w) ethanol is added to form a homogenate, which is then packed into a 10×600mm chromatographic column with a packing volume of 47ml and a packing pressure of 150bar. After packing, a 190ml water-equilibrated column is used at a flow rate of 5ml / min. Iodixanol at a concentration of 276g / L (purity 74.8%) is filtered through a 0.45-micron pore size filter membrane. 11.5ml of the filtrate is loaded onto the chromatographic column (capacity 67.5g / L) using an infusion pump at a flow rate of 2.5ml / min. After loading, impurities are eluted with water for 220min at a flow rate of 5ml / min. After impurity elution, the target compound iodixanol was eluted with 13% ethanol for 80 min at a flow rate of 5 mL / min. The eluent was collected and analyzed by high-performance liquid chromatography (HPLC). The column was regenerated using 65% ethanol at a flow rate of 5 mL / min for 30 min. HPLC analysis showed that the purity of iodixanol was 99.2%, with single impurities A, B, D, and G less than 0.05%, impurity C less than 0.15%, and unknown impurities less than 0.05%, with a yield of 95.1%. The impurities met the requirements of the European Pharmacopoeia. A Dairy DK3838C30 nanofiltration membrane with a molecular weight cutoff of 150-300 Da was selected. The collected target compound was concentrated by nanofiltration and spray-dried at 70°C to obtain 2.9 g of iodixanol powder.

[0111] The preparation method of the poly(divinylbenzene-octadecyl methacrylate) polymer porous microspheres is the same as in Example 1.

[0112] Example 3

[0113] This embodiment provides a method for purifying iodixanol, comprising the following steps: 1100g of poly(divinylbenzene-octadecyl methacrylate) polymer porous microspheres are used as the chromatographic packing material. 600ml of 50% (w / w) ethanol is added to form a homogenate, and a 50×900mm DAC column is packed at a packing pressure of 7.5 bar with a packing volume of 1217ml. After packing, a 4L water-equilibrated column is used at a flow rate of 121ml / min. The iodixanol reaction solution (its HPLC chromatogram is shown in...) is then collected. Figure 1The concentration was 216 g / L (purity 80.8%), and the solution was filtered through a 0.45 μm filter membrane. 394.5 ml of the filtrate was loaded onto the column (capacity 70 g / L) using an infusion pump at a flow rate of 60 ml / min. After loading, water was used for elution of impurities for 190 min at a flow rate of 121 ml / min. After elution of impurities, iodixanol was eluted with 18% methanol for 90 min at a flow rate of 121 ml / min. The eluent was collected and analyzed by high-performance liquid chromatography (HPLC). The column was regenerated with 65% methanol at a flow rate of 121 ml / min for 30 min. The results were analyzed by HPLC (see [link to HPLC analysis]). Figure 2 The purity of iodixanol was 99.4%, with single impurities A, B, D, and G less than 0.05%, impurity C less than 0.15%, and unknown impurities less than 0.05%, resulting in a yield of 94.1%. The relevant impurities met the requirements of the European Pharmacopoeia. A Dairy DK3838C30 nanofiltration membrane with a molecular weight cutoff of 150-300 Da was selected. The collected solution was concentrated by nanofiltration and spray-dried at 70°C to obtain 80.4 g of iodixanol powder.

[0114] The preparation method of the poly(divinylbenzene-octadecyl methacrylate) polymer porous microspheres is the same as in Example 1.

[0115] Example 4

[0116] This embodiment provides a method for purifying iodixanol, comprising the following steps: 60g of poly(P,P'-divinyl-1,2-diphenylethane-octyl methacrylate) polymer porous microspheres are used as chromatographic packing material. 50ml of 50% (w / w) methanol is added to form a homogenate, and a 10×600mm column is packed at a packing pressure of 150 bar and a packing volume of 47ml. After packing, the column is equilibrated with 200ml of water at a flow rate of 4.7ml / min. Iodixanol reaction solution with a concentration of 216g / L (purity 80.8%) is taken and filtered through a 0.45-micron pore size filter membrane. 17.4ml of the filtrate is loaded onto the column (capacity 80g / L) using an infusion pump at a flow rate of 4.7ml / min. After loading, impurities are eluted with water for 220min at a flow rate of 4.7ml / min. After impurity elution, the target compound, iodixanol, was eluted with 18% methanol for 90 min at a flow rate of 4.7 mL / min. The eluent was collected and analyzed by high-performance liquid chromatography (HPLC). The column was regenerated using anhydrous methanol at a flow rate of 4.7 mL / min for 40 min. HPLC analysis showed that the purity of iodixanol was 99.1%, with single impurities A, B, D, and G less than 0.05%, impurity C less than 0.15%, and unknown impurities less than 0.05%, resulting in a yield of 97.1%. The impurities met the requirements of the European Pharmacopoeia. A Dairy DK3838C30 nanofiltration membrane with a molecular weight cutoff of 150-300 Da was used to concentrate the target compound solution via nanofiltration and spray-dry at 70 °C to obtain 3.5 g of iodixanol powder.

[0117] The preparation method of porous microspheres of poly(P,P'-divinyl-1,2-diphenylethane-octyl methacrylate) polymer is as follows: 2.4L of purified water, 24g of polyvinyl alcohol 1788, and 12g of sodium dodecyl sulfate are added to a 5L reactor equipped with a condenser, stirrer, and thermometer, and dissolved for later use; this is the aqueous phase. 47.7g of P,P'-divinyl-1,2-diphenylethane (BVPE), 38.2g of octyl methacrylate, 1.4g of azobisisobutyronitrile, 95.4g of toluene, and 47.7g of isododecane are weighed and mixed evenly; this is the oil phase. The oil phase and aqueous phase are added to the reactor and emulsified at 5℃. After emulsification, the droplet diameter did not exceed 1 μm. 10 g of 15 μm linear polystyrene seed microspheres obtained by seed swelling polymerization (prepared according to the following literature: Zhang Li et al., "Preparation of Micron-Sized Polystyrene Microspheres by Seed Swelling Polymerization," *Chinese Journal of Powder Technology*, Vol. 17, No. 3, June 2011) were added, and swelling was allowed to occur for 12 h. After swelling, polymerization was carried out at 70℃ for 12 h. After the reaction, the mixture was washed with hot water and extracted with acetone under reflux to remove the pore-forming agent, yielding polymer porous microspheres with a particle size of 45 μm, which are polymer porous resins containing octyl alkyl side chains. The average pore size was determined using mercury porosimetry. The specific surface area (BET) detected by nitrogen adsorption method is 240 m². 2 / g. The resulting polymer porous microspheres have the structural unit shown in formula (IV), where n3 is 7.

[0118] The preparation method of 15μm linear polystyrene seed microspheres is as follows:

[0119] In a 250 mL four-necked reaction flask equipped with a condenser, 60 g of anhydrous ethanol, 30 g of styrene, 0.3 g of azobisisobutyronitrile (AIBN), and 1.2 g of polyvinylpyrrolidone (PVP K-30) were added to prepare a transparent solution. N2 was bubbled through the solution for 15 min, and the reaction system was heated to 70 °C. Timing was started after the temperature reached 70 °C. After one hour of reaction, 1 mL of a 10 g / L ethanol solution of p-benzoquinone was added. The reaction was continued for another 12 hours and then stopped. The resulting emulsion was separated by centrifugation, the supernatant was removed, and the mixture was washed repeatedly with ethanol and water. Finally, the product was dried at low temperature to obtain porous polymer microspheres with a particle size of 6.2 μm and a dispersion index of 1.03.

[0120] 5g of sodium dodecyl sulfonate was dissolved in 880g of water, and 10g of benzoyl peroxide was dissolved in 200g of styrene. The two phases were mixed and emulsified in a homogenizer at 4°C for 120 minutes. 18g of the aforementioned monodisperse polystyrene particles with a particle size of 6.2μm were added as seeds. After stirring at 25°C for 24 hours, 206g of 5% polyvinyl alcohol (model 1788) was added to the reactor. The dispersion was then polymerized at 60°C for 1 hour and then at 70°C for 20 hours, forming monodisperse seeds with a particle size of 15μm. The seeds were separated by centrifugation, the supernatant was removed, and the mixture was washed repeatedly with ethanol and water. Finally, the product was dried at low temperature to obtain polystyrene seed microspheres with a particle size of 15μm and a dispersion coefficient of 1.04.

[0121] Example 5

[0122] This embodiment provides a purification method for iodixanol, comprising the following steps: 1100g of poly(divinylbenzene-dodecyl methacrylate) polymer porous microspheres are used as chromatographic packing material. 600ml of 50% (w / w) acetonitrile slurry is added and homogenized, then packed into a 50×900mm DAC column at a packing pressure of 8.0 bar and a packing volume of 1200ml. After packing, a 4L water-equilibrated column is used at a flow rate of 120ml / min. Iodixanol reaction solution with a concentration of 216g / L (purity 80.8%) is taken and filtered through a 0.45-micron pore size filter membrane. 333ml of the filtrate is loaded onto the column (capacity 60g / L) using an infusion pump at a flow rate of 60ml / min. After loading, impurities are eluted with water for 120min at a flow rate of 120ml / min. After impurity elution, the target compound iodixanol was eluted with 15% (v / v) methanol for 70 min at a flow rate of 120 mL / min. The eluent was collected and analyzed by high-performance liquid chromatography (HPLC). The column was regenerated using 80% methanol at a flow rate of 120 mL / min for 20 min. HPLC analysis showed that the purity of iodixanol was 99.2%, with single impurities A, B, D, and G less than 0.05%, impurity C less than 0.15%, and unknown impurities less than 0.05%, with a yield of 92.1%. The impurities met the requirements of the European Pharmacopoeia. A Dairy DK3838C30 nanofiltration membrane with a molecular weight cutoff of 150-300 Da was used to concentrate the target compound by nanofiltration and spray-drying at 70 °C to obtain 66.1 g of iodixanol powder.

[0123] The preparation method of porous microspheres of poly(divinylbenzene-dodecyl methacrylate) polymer is as follows:

[0124] Add 300L of purified water and 4.35kg of polyvinylpyrrolidone K-90 to a 500L reactor equipped with a condenser, stirrer, and thermometer, dissolve, and set aside as the aqueous phase. Weigh out 20.3kg of divinylbenzene (96% purity), 20.3kg of dodecyl methacrylate, 600g of azobisisobutyronitrile, 35.5kg of heptane, and 35.5kg of isooctanol, and mix thoroughly to form the oil phase. Add the oil phase and aqueous phase to the reactor, sonicate for 30min, stir slowly, and heat to 70℃ for polymerization for 20h. After the reaction, wash with hot water, and reflux with ethanol to remove the pore-forming agent. Collect polymer porous microspheres with a particle size of 33.3-50μm, which are polymer porous resins containing dodecyl side chains. The average pore size was determined using mercury porosimetry. The specific surface area (BET) detected using nitrogen adsorption method is 285 m². 2 / g. The resulting polymer porous microspheres have the structural unit shown in formula (III), where n3 is 11.

[0125] Comparative Example 1

[0126] 60g of hydrophilic polyacrylate-hexyl microspheres (purchased from Tosoh Corporation, Japan, model ToyopearlHexyl-650M) were packed into a 10×600mm column at a packing pressure of 15 bar and a packing volume of 47ml. After packing, the column was equilibrated with 200ml of water at a flow rate of 4.7ml / min. Iodixanol reaction solution with a concentration of 216g / L (purity 80.8%) was filtered through a 0.45μm filter membrane. 2.0ml of the filtrate was loaded onto the column (load capacity 9.1g / L) using an infusion pump at a flow rate of 4.7ml / min. After loading, the column was washed with water at a flow rate of 4.7ml / min for 40min. Fractional collection was performed, and the flow-through fraction of 94mL was collected. Using external standard liquid chromatography, the concentration was 4.16mg / mL, equivalent to 391mg, representing 90.5% of the total. No separation was observed in the flow-through fraction. A 47 mL fraction with a purity of 99.6% was collected, and the concentration obtained using liquid chromatography with external standard method was 0.51 mg / mL, equivalent to 24 mg, representing 5.5% of the total. Another 47 mL fraction with a purity of 60.5% was collected, and the concentration obtained using liquid chromatography with external standard method was 0.38 mg / mL, equivalent to 18 mg, representing 4% of the total. This indicates that the loading capacity of this packing material is less than 9.1 g / L, and the maximum loading capacity of the target analyte that this packing material can achieve for separation is 0.5 g / L.

[0127] Comparative Example 2

[0128] 60g of hydrophilic polyacrylate-hexyl microspheres (purchased from Tosoh Corporation, Japan, model ToyopearlHexyl-650M) were packed into a 10×600mm column at a packing pressure of 15 bar and a packing volume of 47ml. After packing, the column was equilibrated with 200ml of water at a flow rate of 4.7ml / min. Iodixanol reaction solution, concentration 216g / L (purity 80.8%), was filtered through a 0.45μm filter membrane. 0.1mL of the filtrate was loaded onto the column (load capacity 0.5g / L) using an infusion pump at a flow rate of 0.5ml / min. After loading, the column was rinsed with water at a flow rate of 4.7ml / min for 30min. Impurities appeared between 4-17min, and the target analyte appeared between 17-26min. The eluent from 17-26min was collected and analyzed by liquid chromatography. The column was regenerated using 20% ​​methanol at a flow rate of 3ml / min for 30min. High-performance liquid chromatography (HPLC) analysis showed that the purity of the collected iodixanol was 98.7%, with single impurities A, B, D, and G less than 0.10%, impurity C less than 0.15%, and unknown impurities less than 0.05%, with a yield of 90.1%. The impurities met the requirements of the European Pharmacopoeia. The collected liquid was freeze-dried to obtain 19.3 mg of solid.

[0129] As can be seen from the comparison of the various embodiments with Comparative Examples 1 and 2, the purification method of iodixanol provided in the various embodiments of the present invention can significantly improve the purification effect of iodixanol by using specific polymer porous microspheres, and the loading and yield are significantly improved, especially the loading, which is increased by more than 120 times.

[0130] Among them, Example 4 had the highest yield and loading capacity.

[0131] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for purifying iodixanol, characterized in that, The step includes using polymer porous microspheres as a reversed-phase packing material to purify the iodixanol reaction solution by reversed-phase chromatography, wherein the reversed-phase chromatography purification includes the following steps: 1) Column packing: The chromatographic column is packed with polymer porous microspheres; 2) Equilibrate the chromatographic column with water; 3) Load the filtered iodixanol reaction solution into a chromatographic column packed with polymer porous microspheres; 4) Use water to wash away impurities; 5) Elute the target analyte using a low-concentration solvent with a mass percentage of 5-25%; 6) Collect the target iodixanol solution in segments to obtain the purified iodixanol solution; 7) Regenerate the chromatographic column with a high-concentration solvent (mass percentage concentration higher than 50%); in steps 5) and 7), the solvent refers to an alcohol solvent that is soluble in water and has no more than 4 carbon atoms; the average particle size of the polymer porous microspheres is 30-150 μm, the pore size is 50-300 Å, and the specific surface area is 100-500 m². 2 / g, the polymer porous microspheres have structural units shown in formula (III) or (IV): (III); (IV); Where n3 is an integer between 7 and 17.

2. A method for purifying iodixanol, characterized in that, The step includes using polymer porous microspheres as a reversed-phase packing material to purify the iodixanol reaction solution by reversed-phase chromatography, wherein the reversed-phase chromatography purification includes the following steps: 1) Column packing: The chromatographic column is packed with polymer porous microspheres; 2) Equilibrate the chromatographic column with water; 3) Load the filtered iodixanol reaction solution into a chromatographic column packed with polymer porous microspheres; 4) Use water to wash away impurities; 5) Elute the target analyte using a low-concentration solvent with a mass percentage of 5-25%; 6) Collect the target iodixanol solution in segments to obtain the purified iodixanol solution; 7) Regenerate the chromatographic column with a high-concentration solvent (greater than 50% by mass); in steps 5) and 7), the solvent refers to an alcohol solvent that is soluble in water and has no more than 4 carbon atoms; the polymer porous microspheres are selected from one or more of poly(divinylbenzene-octadecyl methacrylate), poly(P,P'-divinyl-1,2-diphenylethane-octyl methacrylate), or poly(divinylbenzene-octyl methacrylate); the average particle size of the polymer porous microspheres is 30-150 μm, the pore size is 50-300 Å, and the specific surface area is 100-500 m². 2 / g.

3. A method for purifying iodixanol, characterized in that, The step includes using polymer porous microspheres as a reversed-phase packing material to purify the iodixanol reaction solution by reversed-phase chromatography, wherein the reversed-phase chromatography purification includes the following steps: 1) Column packing: The chromatographic column is packed with polymer porous microspheres; 2) Equilibrate the chromatographic column with water; 3) Load the filtered iodixanol reaction solution into a chromatographic column packed with polymer porous microspheres; 4) Use water to wash away impurities; 5) Elute the target analyte using a low-concentration solvent with a mass percentage of 5-25%; 6) Collect the target iodixanol solution in segments to obtain the purified iodixanol solution; 7) Regenerate the chromatographic column with a high-concentration solvent (mass percentage concentration higher than 50%); in steps 5) and 7), the solvent refers to an alcohol solvent that is soluble in water and has no more than 4 carbon atoms; the average particle size of the polymer porous microspheres is 30-150 μm, the pore size is 50-300 Å, and the specific surface area is 100-500 m². 2 / g, based on the total mass of monomer units as 100%, the polymer porous microspheres contain: 35-95% aromatic divinyl monomer units, 5-65% vinyl monomer units with alkyl side chains containing 8-18 carbon atoms, the vinyl monomers with alkyl side chains containing 8-18 carbon atoms are C8-C18 alkyl esters of methacrylic acid, and the polymer porous microspheres are polymer porous microspheres copolymerized from C8-C18 alkyl esters of methacrylic acid and aromatic divinyl monomers; the aromatic divinyl monomers are divinylbenzene or P,P'-divinyl-1,2-diphenylethane.

4. The purification method of iodixanol according to claim 3, characterized in that, The polymer porous microspheres are selected from one or more of poly(divinylbenzene-octadecyl methacrylate), poly(P,P'-divinyl-1,2-diphenylethane-octyl methacrylate), or poly(divinylbenzene-octyl methacrylate).

5. The purification method of iodixanol according to any one of claims 1-4, characterized in that, The average particle size is 50-100 μm, the pore size is 80-250 Å, and the specific surface area is 200-400 m². 2 / g.

6. The purification method of iodixanol according to any one of claims 3-4, characterized in that, The method for preparing the polymer porous microspheres includes the following steps: Step S1: Prepare an aqueous phase by mixing water and surfactant; prepare an oil phase by mixing aromatic divinyl monomer, vinyl monomer with 8-18 alkyl side chains, pore-forming agent and initiator. Step S2: Using aqueous and oil phases as raw materials, free radical polymerization is carried out using template swelling method, precipitation polymerization method, suspension polymerization or dispersion polymerization to form microspheres; Step S3: After the polymerization reaction is complete, the porogen is removed to obtain polymer porous microspheres.

7. The purification method of iodixanol according to any one of claims 1-4, characterized in that, The purity of the iodixanol reaction solution is 70-85%.

8. The purification method of iodixanol according to any one of claims 1-4, characterized in that, The purity of the iodixanol reaction solution is 75-85%.

9. The purification method of iodixanol according to any one of claims 1-4, characterized in that, The column packing process involves adding 0.6-1.6 times the weight of a 30-70% (v / v) alcohol-water slurry to the polymer porous microspheres, followed by wet packing at a pressure of 0.2-40 MPa.

10. The purification method of iodixanol according to any one of claims 1-4, characterized in that, The water-equilibrium chromatographic column is washed with 2-6 column volumes of water, and the flow rate during the equilibrium process is 2-10 cm / min.

11. The purification method of iodixanol according to any one of claims 1-4, characterized in that, The loading process refers to injecting the filtered iodixanol reaction solution into the chromatographic column at a flow rate of 1-5 cm / min and a loading volume of 40-80 g / L.

12. The purification method of iodixanol according to any one of claims 1-4, characterized in that, The impurity elution is performed by washing the chromatographic column with 12-36 column volumes of purified water to remove polar impurities, with a process flow rate of 2-10 cm / min.

13. The purification method of iodixanol according to any one of claims 1-4, characterized in that, In step 5), the elution is a process of washing the chromatographic column with 6-12 column volumes of low-concentration solvent solution to elute the target analyte iodixanol, with a process flow rate of 2-10 cm / min.

14. The purification method of iodixanol according to any one of claims 1-4, characterized in that, The regeneration process involves rinsing the column with 2-5 column volumes of a high-concentration solvent solution to elute all target analytes and impurities, with a process flow rate of 2-10 cm / min.

15. The purification method of iodixanol according to any one of claims 1-4, characterized in that, In step 5) or step 7), the solvent is selected from one or a mixture of methanol, ethanol, and isopropanol.

16. The purification method of iodixanol according to any one of claims 1-4, characterized in that, In step 5) or step 7), the solvent is one or a mixture of two of methanol and ethanol.

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