CN115505051B - Method for refining sodium gluconate - Google Patents
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Abstract
The method comprises the steps of separating and refining a crude product of sodium sulmore in a poor solvent/water system, preferentially separating and enriching dimer impurities difficult to remove until solids are removed, separating (separating and filtering) to obtain mother liquor, and further adding the poor solvent for crystallization to obtain the sodium sulmore with high purity. The refining method provided by the application can effectively reduce the content of dimer impurities A and B, improve the purity, ensure that the total purity of refined sodium sugammadex is greater than 99.5%, the impurity A is not detected, the impurity B is less than 0.1%, other single impurities are less than 0.1%, the reagents are conventional and easy to obtain, and the operation is simple and safe, so that the refining method is very suitable for industrial amplification under conventional production conditions.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a refining method of sodium sugammadex, in particular to a method for reducing the content of impurity A or impurity B in sodium sugammadex.
Background
Sodium supreme (Sugammadex Sodium) was originally developed by Organon Biosciences (the European company) which was purchased by the company of first-note, inc. (Schering-Plough) in 2007, and was combined with Merck (Merck) in 2009. Sodium gluconate is currently owned and marketed by merck. In 2008, sodium supreme is marketed for the first time in europe and then in japan, the united states, etc., respectively, and is now marketed in 75 countries. The market is available in China in 4.26.2017.
Sodium supreme glucose, chemical name: 6-perdeoxy-6-per (2-carboxyethyl) thio- γ -cyclodextrin sodium salt, english name: sugammadex, trade name: bridion, a modified gamma-cyclodextrin, was the first and only selective muscle relaxant (SRBA) developed successfully over 20 years, which blocked relaxation by wrapping an amino steroid non-depolarizing muscle relaxant in a completely new and unique way, and could reverse rapidly and predictably any intensity of muscle relaxation caused by rocuronium bromide and vecuronium bromide with less side effects, and could bring the use of muscle relaxant close to ideal, and its reverse neuromuscular blocking effect was faster and more predictable than that of the existing drugs. Is suitable for reversing the neuromuscular blocking effect caused by rocuronium bromide or vecuronium bromide, and can reverse (conventional reverse and immediate reverse) the neuromuscular blocking effect caused by adult rocuronium bromide or vecuronium bromide and the neuromuscular blocking effect caused by conventional reverse child and teenager rocuronium bromide.
The sodium sulmore gluconate and the preparation method thereof are disclosed in the US patent 6670340 for the first time, the prepared sodium sulmore gluconate needs to be dialyzed for 36 hours for purification, the dialysis time is long, the water consumption is large, a large amount of waste liquid is generated, resources are wasted, the environment is not protected, the end product is obtained in water after dialysis, and the further extraction is not facilitated due to the fact that the solubility of the end product in water is large.
During the preparation and placement of the sodium sugammadex, more process impurities and degradation impurities are generated, and the impurities are removed or controlled below 0.1% (w/w) by adopting a purification process so as to obtain the high-purity sodium sugammadex, thereby meeting the quality requirements of medicinal raw materials.
The purification method of the sodium gluconate at home and abroad mainly comprises the following steps:
the purification method disclosed in patent WO2012/025937A1 requires column chromatography with a silica gel column and a dextran gel G25, but the product purity is still low; the patent CN104844732A is purified by a nanofiltration membrane, mainly can remove small molecules, has limited removal of impurities with the structure similar to that of sodium sulmore gluconate, and cannot guarantee high purity.
Patent WO2017084401 treats the crude sodium sulfanilate product with a large amount of adsorbent (20-150% w/w), the adsorbent comprises one or a combination of activated carbon, silica gel, macroporous resin, alumina, molecular sieve, zeolite, has large adsorption loss, low yield, large single impurity amount and is not suitable for industrial scale-up.
The purification method disclosed in patent CN106565858A adopts ion exchange resin to convert the crude sodium sulfacetamide into sodium sulfacetamide, and adopts hot pulping to purify, and then uses ion exchange resin or sodium hydroxide to reconvert the sodium sulfacetamide into sodium sulfacetamide, so that the purification loss is large, and the production cost is high.
The purification method disclosed in patent CN107892727A screens different activated carbon, only adopts special aigrette (TOKUSEI SHIRASAGI) activated carbon and aigrette A (SHIRASAGIA) activated carbon produced by Osaka gas chemical group in Japan, and uses the activated carbon and aigrette A (SHIRASAGIA) activated carbon for small-scale adsorption treatment research of 10g sodium Shuganguna crude product after nitrogen protection heating pretreatment, so that sodium Shuganguna purity is more than 99.5% and single impurity is less than 0.1%. The core of the purification process is the activated carbon required by specific types, and is a single foreign manufacturer, the production cost is high, and the continuous production is greatly limited.
The patent CN105348412A is characterized in that the crude product of the sodium sulmore gluconate is dissociated into the sodium sulmore gluconate under the acid condition, the ammonium salt of the sodium sulmore gluconate and the organic amine or the ammonia substance is recrystallized and purified, and the purified sodium sulmore gluconate salt is dissociated under the acid condition and then salified with sodium hydroxide to obtain the sodium sulmore gluconate. The method uses strong inorganic acid aqueous solution for many times, is easy to generate acid degradation impurities, and has great influence on the stability of the purified substrate.
Patent CN107778383A reports that under the condition of conventional recrystallization purification, the crude product of the sodium sulmore gluconate is added with protective agents such as glutathione, cysteine, triphenylphosphine and the like, so that the purity of the sodium sulmore gluconate is more than 99.0 percent; the inventor of the application finds that the purification loss is large by repeating the purification method disclosed by the patent, and the dimer impurities which are difficult to remove can be directly enriched into a sodium gluconate solid phase under the purification condition, so that the impurity is difficult to remove and has high content.
Therefore, the purification method of the sodium sulfanilamide sodium at home and abroad mainly has the following defects:
1) Column chromatography or adsorbent purification such as silica gel column, sephadex G25, macroporous resin, ion exchange resin and the like is adopted, so that the purification cost is high, the process is limited, the universality is avoided, and the industrial large-scale production is not facilitated;
2) Strong inorganic acid is adopted for dissociation for many times, so that the stability of a cyclodextrin substrate of the sodium sulmore gluconate can be influenced, acid degradation impurities are easy to generate, and the medication safety of the sodium sulmore gluconate product is influenced;
3) Under the conventional recrystallization purification condition, triphenylphosphine, glutathione, cysteine and other protective agents are added, so that the increase of oxidized impurities can be inhibited, and partial easy impurity removal of sodium sugammadex is reduced, but the dimer impurities have very similar physicochemical properties to sodium sugammadex, and are usually enriched in sodium sugammadex and difficult to remove in the conventional recrystallization process.
In order to ensure the safety of subsequent preparations and clinical application, the content of single impurities in the sodium sugammadex needs to be controlled below 0.1 percent, and the sodium sugammadex is preferably removed, but the conventional purification process is not realized. Therefore, there is a need to develop a new refining method to reduce the impurity content in sodium sulmore gluconate, especially for dimer-type impurities, so as to obtain high-purity sodium sulmore gluconate, thereby meeting the quality requirements of drug development.
Disclosure of Invention
In view of the above problems, an object of the present application is to provide a refining method of sodium sugammadex, which can effectively reduce the content of impurities in sodium sugammadex, especially reduce the content of dimer impurities, even remove them, and improve the purity.
Sodium sugammadex produces dimeric impurities during the preparation or placement, mainly represented by impurities a or a 'and impurities B or B'; in addition, non-dimeric impurities such as lactonized impurity C, impurity D, impurity E, impurity F, impurity G, etc. are present, and the structural formula is shown below.
In a first aspect, the present application provides a method for refining sodium sugammadex comprising the steps of:
step (1): under the protection of inert gas, dissolving a sodium gluconate crude product into water, adding a poor solvent at room temperature, standing for layering, and taking an upper mother solution;
step (2): under the protection of inert gas, sequentially adding water into the lower layer of organic solution for dissolution, adding a poor solvent, separating out solids, filtering, and combining filtrate with the upper layer of mother solution;
step (3): under the protection of inert gas, heating the combined mother solution in the step (2), adding a poor solvent, cooling and crystallizing, filtering, and drying to obtain the sodium sugammadex.
As used herein, "crude" of sodium sulmore is relative to a finished product, and includes, but is not limited to, a sample having a purity of less than 99.5% sodium sulmore, or a sample having a purity of less than 99.0%, or a sample having a purity of less than 98.0%, and the like.
As used herein, a "poor solvent" is a solvent that has a weak capacity for dissolving a solute relative to the solute to be dissolved, and has an interaction parameter χ with the solute of greater than 0.5. The "poor solvent" is different for different solutes. The "poor solvent" used in one solute may be the "good solvent" for another solute. For example, the "poor solvent" used in the present application for sugammadex is methanol, and the "good solvent" for the solute biphenyl.
In the above-described sodium sulfer refining method, the poor solvent is for sodium sulfer as a solute. According to a preferred embodiment of the present application, the poor solvent is selected from one or more of DMF, DMSO, NMP, DMAc, acetone, ethyl acetate, n-heptane, acetonitrile, ethanol, methanol, isopropanol, 1, 4-dioxane and tert-butyl methyl ether, preferably DMF or ethanol or a combination thereof.
In the above-mentioned purification method of sodium sulmore, the addition of the poor solvent in the steps (1) to (3) may be carried out by a method conventional in the art, preferably by a method of dropwise addition.
Preferably, in the above-mentioned method for purifying sodium sulmore, no protecting agent is used in any of the steps (1) to (3); the protective agent is selected from the group consisting of: mercaptoethanol, thioglycolate vinegar, mercaptopropionate vinegar, glutathione, cysteine, cystamine, dithioerythritol, and salts of trisubstituted organophosphine compounds.
Further, in the above refining method of sodium sulmore, the mass volume ratio of sodium sulmore to water in the step (1) is 1:0.5 to 1:50, preferably 1:1 to 1:10, more preferably 1:2 to 1:3 in terms of g/ml; the mass volume ratio of the sodium sugammadex to the poor solvent is 1:0.5-1:50, preferably 1:1-1:10, more preferably 1:2-1:5 in grams/milliliter.
Or, in the step (2), the mass volume ratio of the sodium metasilicate to the added water is 1:0.25-1:50, preferably 1:1-1:5, more preferably 1:1-1:2 in terms of gram/milliliter; the mass volume ratio of the sodium sugammadex to the added poor solvent is 1:0.25-1:50, preferably 1:1-1:10, more preferably 1:1.5-1:4 in terms of g/ml;
or, in the step (3), the mass-volume ratio of the sodium metasedge to the added poor solvent is 1:1-1:50, preferably 1:2-1:20, more preferably 1:5-1:10 in terms of gram/milliliter; the temperature rise range is 40-100 ℃, preferably 50-70 ℃; the temperature of the cooling crystallization is-20 to 30 ℃, preferably 0 to 10 ℃.
Optionally, the various steps of the process for refining sodium sulmore are carried out under an inert atmosphere, which includes both group 18 element gases in known definitions and nitrogen commonly used in the chemical industry, preferably under a nitrogen atmosphere.
Preferably, the refining method of sodium sulmore glucose is mainly used for reducing the content of impurity A and/or impurity B in sodium sulmore glucose.
The "content" refers to the mass percent (w/w) of impurity A or impurity B in the total amount of sodium sulfolane.
In a second aspect, the present application also provides sodium sugammadex prepared by the above-mentioned refining method, where the total purity of the sodium sugammadex is not less than 99.5%, and the content of impurity a or impurity B in the sodium sugammadex is less than 0.1%.
In a third aspect, the present application provides a method for reducing the levels of impurity a and impurity B in sodium supreme comprising the steps of:
step (1): under the protection of inert gas, dissolving a sodium gluconate crude product into water, adding a poor solvent at room temperature, standing for layering, and taking an upper mother solution;
step (2): under the protection of inert gas, sequentially adding water into the lower layer of organic solution for dissolution, adding a poor solvent, separating out solids, filtering, and combining filtrate with the upper layer of mother solution;
step (3): under the protection of inert gas, heating the combined mother solution in the step (2), adding a poor solvent, cooling and crystallizing, filtering, and drying to obtain the sodium sugammadex.
In the above method for reducing the content of impurity A and impurity B in sodium sugammadex, the poor solvent is for sodium sugammadex. According to a preferred embodiment of the present application, the poor solvent is selected from one or more of DMF, DMSO, NMP, DMAc, acetone, ethyl acetate, n-heptane, acetonitrile, ethanol, methanol, isopropanol, 1, 4-dioxane and tert-butyl methyl ether, preferably DMF or ethanol or a combination thereof.
In the above-mentioned purification method of sodium sulmore, the addition of the poor solvent in the steps (1) to (3) may be carried out by a method conventional in the art, preferably by a method of dropwise addition.
Preferably, in the above method for reducing the content of impurity a and impurity B in sodium metasedge, no protective agent is used in any of the steps (1) to (3); the protective agent is selected from the group consisting of: mercaptoethanol, thioglycolate vinegar, mercaptopropionate vinegar, glutathione, cysteine, cystamine, dithioerythritol, and salts of trisubstituted organophosphine compounds.
Further, in the method for reducing the content of the impurity A and the impurity B in the sodium metasilicate, the mass volume ratio of the sodium metasilicate to the water in the step (1) is 1:0.5-1:50, preferably 1:1-1:10, more preferably 1:2-1:3 in terms of gram/milliliter; the mass volume ratio of the sodium sugammadex to the poor solvent is 1:0.5-1:50, preferably 1:1-1:10, more preferably 1:2-1:5 in grams/milliliter;
or, in the step (2), the mass volume ratio of the sodium metasilicate to the added water is 1:0.25-1:50, preferably 1:1-1:5, more preferably 1:1-1:2 in terms of gram/milliliter; the mass volume ratio of the sodium sugammadex to the added poor solvent is 1:0.25-1:50, preferably 1:1-1:10, more preferably 1:1.5-1:4 in terms of g/ml;
or, in the step (3), the mass-volume ratio of the sodium metasedge to the added poor solvent is 1:1-1:50, preferably 1:2-1:20, more preferably 1:5-1:10 in terms of gram/milliliter; the temperature rise range is 40-100 ℃, preferably 50-70 ℃; the temperature of the cooling crystallization is-20 to 30 ℃, preferably 0 to 10 ℃.
Optionally, the various steps of the method for reducing the impurity A and impurity B content of sodium supreme glucose described herein are carried out under an inert gas atmosphere, which includes both group 18 element gases in the well known definition and nitrogen commonly used in the chemical industry, preferably under a nitrogen atmosphere.
In still another aspect of the present application, a pharmaceutical formulation is provided, comprising sodium sulfanilamide prepared by the above-described refining method, and pharmaceutically acceptable carriers and excipients.
Pharmaceutically acceptable carriers or excipients are well known in the pharmaceutical arts and are described, for example, in the pharmaceutical sciences of Remington's Pharmaceutical Sciences, mark Publishing co.) (a.r.gnono (a.r.gennaro), eds., 1985). These materials are non-toxic to the recipient at the dosages and concentrations employed.
The pharmaceutical formulations described herein may be administered orally, by injection, by inhalation spray, topically, rectally, nasally, bucally, vaginally or by means of an implantable kit. The preferred mode of administration is intravenous injection.
The pharmaceutical formulations described herein may also be presented in discrete unit form, which may be an aqueous liquid solution or suspension; a solution or suspension in a non-aqueous liquid; or a water-in-oil liquid emulsion; or an oil-in-water liquid emulsion; or encapsulated in liposomes; or in the form of a pill, etc.
The medicaments described herein may be in solid dosage forms including, but not limited to, capsules, tablets, troches, elixirs, pills, granules, powders or suppositories; the medicaments described above in this application may also be in liquid dosage forms including, but not limited to, solutions, suspensions or emulsions.
In yet another aspect of the present application, there is also provided the use of sodium sulfanyl or a pharmaceutical preparation containing the same prepared by the above refining method for preparing a drug for reversing neuromuscular blockade; preferably, the neuromuscular blocking drug is rocuronium or vecuronium.
Specifically, reversing the neuromuscular blocking effect caused by rocuronium bromide or vecuronium bromide; further, the neuromuscular blocking effect caused by adult rocuronium bromide or vecuronium bromide is reversed (both conventional and immediate); alternatively, neuromuscular blockade caused by rocuronium bromide in children and adolescents is routinely reversed.
The sodium sugammadex prepared by the refining process of the present application may be used alone or in combination with one or more other drugs.
The present application also provides a method for preparing the sodium sugammadex prepared by the refining method of the present application for preventing or treating the reverse neuromuscular blocking disease by using the sodium sugammadex singly or in combination with other medicines.
By combination is meant simultaneous, sequential or alternating use, and also includes preparation of pharmaceutical dosage forms or pharmaceutical products in corresponding pharmaceutical units in a suitable combination.
The reversal neuromuscular blocking diseases include reversal of rocuronium bromide induced muscle relaxation, vecuronium bromide induced muscle relaxation, panturonium bromide induced muscle relaxation and the like.
The application also provides a preparation method of the sodium sugammadex impurity A or the impurity A', which comprises the following steps:
step 1: the impurity G and the impurity G' are prepared, and the synthetic route is as follows:
the method comprises the following steps: the octaiodo gamma-cyclodextrin is subjected to substitution reaction by 3-mercaptopropionic acid, and then the impurity G' is prepared and separated; the impurity G' and sodium-containing alkali or sodium carbonate are subjected to acid-base salt formation reaction to obtain the impurity G, wherein the sodium-containing alkali is preferably one or more selected from NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium amide-containing alkali and sodium hydroxide.
In some embodiments of the invention, the substitution reaction is carried out with octaiodo gamma-cyclodextrin in an organic solvent containing sodium base, 3-mercaptopropionic acid. Preferably, the sodium-containing base is selected from one or more of NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium amide-containing base and sodium hydroxide, more preferably NaH. Preferably, the organic solvent is selected from one or more of DMF, DMAC, NMP, DMI; more preferably, the organic solvent is DMF.
In some embodiments of the invention, the reaction temperature of the substitution reaction is room temperature, which refers to about 20 to 30 ℃, preferably about 25 ℃. In the substitution reaction, the molar ratio of the octaiodo gamma-cyclodextrin, the 3-mercaptopropionic acid and the sodium-containing base is 1:7:14.
in some embodiments of the invention, the substitution reaction is followed by purification and then preparative separation. Preferably, the purification is beating purification; more preferably, the slurried purified solvent is one or more of alcohols, organic acids, inorganic solvents (e.g., water), ethers, ketones, nitriles. The alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, 1-butanol, 2-butanol, and t-butanol. The ethers include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole and dimethoxyethane. Nitriles include, but are not limited to, acetonitrile and propionitrile. Ketones include, but are not limited to, acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone. Organic acids include, but are not limited to, formic acid, acetic acid.
In some preferred embodiments of the invention, the slurried purified solvent is a mixed solution of alcohols, inorganic solvents, organic acids; more preferably a mixed solution of ethanol, water, acetic acid; more preferably, the volume ratio is 4-10: 1-2: 1-2, for example, a mixed solution of ethanol, water and acetic acid in a volume ratio of 5:1:1. 4:1: 1. 5:1:1.2, 5:1.2:1.2, 5:1.2:1, water and acetic acid.
In some embodiments of the invention, the temperature of the beaten purification is between 0 and 10 ℃, such as 0 ℃,2 ℃, 5 ℃,6 ℃, 8 ℃,9 ℃, 10 ℃.
Step 2: the impurity F and the impurity F' are prepared, and the synthetic route is as follows:
the method comprises the following steps: the impurity G and thiourea generate an isothiourea intermediate, and then the isothiourea intermediate is hydrolyzed, prepared and separated to obtain an impurity F'; the impurity F' and sodium-containing alkali or sodium carbonate are subjected to acid-base salt formation reaction to obtain the impurity F, wherein the sodium-containing alkali is preferably one or more selected from NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium amide-containing alkali and sodium hydroxide.
In some embodiments of the invention, impurity G and thiourea form an isothiourea intermediate at a reaction temperature of 70-90 ℃, preferably at 80 ℃.
In some embodiments of the invention, the isothiourea intermediate is hydrolyzed in an alkaline solution (e.g., sodium hydroxide solution), preferably at a temperature of 80 to 95 ℃, such as 80 ℃, 82 ℃, 85 ℃, 88 ℃, 90 ℃, 92 ℃, 95 ℃.
In some embodiments of the invention, the isothiourea intermediate is hydrolyzed, purified, and then prepared to isolate impurity F'.
Step 3: the preparation of impurity A and impurity A' is carried out by the following synthetic route:
the method comprises the following steps: carrying out substitution reaction on the impurity G ' and the impurity F ', and then preparing and separating to obtain an impurity A '; the impurity A' and sodium-containing alkali or sodium carbonate are subjected to acid-base salt formation reaction to obtain the impurity A, wherein the sodium-containing alkali is preferably one or more selected from NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium amide-containing alkali and sodium hydroxide.
In some embodiments of the invention, impurity G 'is substituted with impurity F' in a base and an organic solvent. Preferably, the organic solvent is selected from one or more of DMF, DMAC, NMP, DMI; more preferably DMF. Preferably, the base is potassium tert-butoxide.
In some embodiments of the invention, the reaction temperature of the substitution reaction is 60 to 80 ℃, preferably 65 to 70 ℃, such as 65 ℃, 68 ℃, 70 ℃.
The technical scheme provided by the application has the following advantages:
in a poor solvent/water system, the crude product of sodium sulmore is separated and enriched to solid removal by controlling the dosage proportion of the crude product of sodium sulmore and water or the poor solvent within a certain range, the dimer impurities A and B are separated and enriched to solid removal, the mother solution with high purity is obtained after separation (liquid separation and filtration), and the poor solvent is further added for crystallization and separation to obtain sodium sulmore with high yield and high purity; overcomes the defect that under the conventional purification condition, the impurity A and the impurity B can be enriched in the sodium sugammadex and are difficult to remove. The total purity of the sodium sugammadex obtained by the refining method provided by the application can reach more than 99.5%, the impurity A is not detected, the impurity B is less than 0.1%, the other single impurities are less than 0.1%, and the total impurity amount is less than 0.5%. The refining system is simple, the condition is mild, the cost is low, and the method is very suitable for social mass production.
The impurity A or the impurity A 'and the impurity B or the impurity B' of the sodium suger provided by the application can be used as impurity reference substances and applied to quality control of corresponding impurities in sodium suger.
Drawings
Fig. 1: example 1 refined sodium sugammadex HPLC profile.
Fig. 2: HPLC profile of commercially available former-ground sodium gluconate injection.
Detailed Description
The following description of the present invention will be further illustrated by specific examples, but it should not be understood that the scope of the present application is limited to the following examples, and appropriate combinations/substitutions/modifications of raw materials, solvents, reagents, operation steps, reaction conditions, etc. in the following examples may be made according to the inventive concept and the entire contents of the present application, which will be apparent to those skilled in the art, and still fall within the scope of the present application.
In the following examples, as well as in the context of the present specification and claims, the following abbreviations have the following meanings, and for undefined abbreviations they have generally accepted meanings.
Dmf=n, N-dimethylformamide
DMSO = dimethyl sulfoxide
Nmp=n-methylpyrrolidone
Dmac=n, N-dimethylacetamide
HPLC = high performance liquid chromatography
The main components are as follows: sodium sulmore gluconate, octamercapto substitution products
And (3) auxiliary components: mono-hydroxysulfocarbon sodium, heptamercapto-substituted monohydroxy products
According to the pharmacological/toxicological review and evaluation description of FDA sodium sulbactam (Pharmacology/Toxicology Review and Evaluation), mono-hydroxy sodium sulbactam is pharmaceutically equivalent to the main component of sodium sulbactam and can be regarded as an API component. Thus, the total purity described in the examples below is the mass percent of the sum of the amounts of the main component of sodium sulbactos (octamercapto-substituted product) and sodium mono-hydroxy sulbactos (heptamercapto-substituted monohydroxy product) in the product.
Experimental conditions:
the purity of the product is measured by adopting an HPLC method, and the calculation method is as follows: area normalization.
The chromatographic column is C 18 A chromatographic column; detection wavelength is 200nm; the flow rate is 0.8ml/min;
mobile phase a:20mmol/L potassium dihydrogen phosphate buffer solution (pH 2.0-2.5)
Mobile phase B: acetonitrile;
gradient elution procedure was used.
And (3) measuring the structures of the impurity A and the impurity B by nuclear magnetic resonance, and adopting a nuclear magnetic resonance spectrometer: BRUKER AVANCE III HD MHz superconducting nuclear magnetic resonance spectrometer, test conditions: solvent D 2 O, temperature 294.7K.
High resolution mass spectrometry: instrument model: ABSciex TripleTOF 5600+
Test conditions: ionization mode: EI+; scanning range: 600-5000 Da.
Preparation of a crude product of sodium sugammadex:
iodinated gamma-cyclodextrins can be prepared by iodination of gamma-cyclodextrin, see Methods for Selective Modifications of Cyclodextrins, chem. Rev.1998,98,1977-1996.
Step (1): sodium hydride (7.16 kg, 60%) was added to dry DMF (317L) under nitrogen atmosphere with an ice bath. A mixed solution of tri-p-tolylphosphine (1.74 kg) -3-mercaptopropionic acid (9.52 kg) -DMF (12.2L) is slowly added dropwise at the temperature of 0-10 ℃, the mixture is heated to 65-75 ℃ after the addition, the mixture is stirred and reacted, and then a mixed solution of periodate gamma-cyclodextrin (12.16 kg) -tri-p-tolylphosphine (0.46 kg) -DMF (63.4L) is slowly added dropwise, and the reaction is continued for about 4 hours under stirring. The reaction solution is cooled to 0-10 ℃, water (60.9L) is added, the temperature is raised to 55-70 ℃ and the reaction is carried out for about 2 hours under stirring. The reaction solution was cooled to room temperature, suction-filtered, the filter cake was dissolved in water (97.4L), celite was filtered, and ethanol (244L) was added to the filtrate, followed by suction-filtration to give sodium sulfatase (10.96 kg, yield 90%, total purity 92.53%).
Step (2): 10.96kg of sodium sulmore gluconate prepared above was added to a mixed solvent of DMF (21.9L) and water (21.9L) under nitrogen protection. Trip-tolylphosphine (411 g), acrylic acid (1.5 kg) and 10% aqueous sodium hydroxide solution (7.26L) were sequentially added at room temperature, the mixture was heated to 50-60℃after the addition, and reacted for 2-8 hours with stirring, DMF (41L) was added dropwise, and the reaction mixture was cooled to room temperature and suction filtered to give sodium sulmore gluconate (10.74 kg, yield 98%, total purity 94.60%).
Step (3): 10.74kg of sodium sulmore gluconate prepared above is added into a mixed solvent of DMF (21.5L) and water (21.5L) under the protection of nitrogen, tri-p-methylphenyl phosphine (184.5 g) is added, the temperature is raised to 60-70 ℃ after the addition, the reaction is carried out for 2-5 h under stirring, DMF (21.5L) is dropwise added, the reaction solution is cooled to room temperature, suction filtration and drying are carried out, and sodium sulmore gluconate (10.2 kg, yield 95%, three steps total yield: 84% and total purity 98.44%) is obtained.
HPLC detection is carried out on the sodium sugammadex prepared in the step (3), and the detection result shows that the total purity of the sodium sugammadex is 98.44%, the content of impurity A is 0.12%, the content of impurity B is 0.091%, the total impurity is 1.56%, the total impurity number is 28, and the single impurity content is 5 impurities with the content of more than 0.1%. The sodium sulmore prepared in the step (3) is used as a crude product of sodium sulmore and is used in the following examples.
Example 1: refining of sodium Shuganglucose
Step (1): under the protection of nitrogen, 0.2kg of sodium sulmore crude product is dissolved in 0.4L of water, 0.6LDMF is added dropwise at room temperature, the system is turbid, the system is stood for layering, liquid separation is carried out, and the upper mother solution is temporarily stored;
step (2): under the protection of nitrogen, sequentially adding 0.2L of water into the lower viscous organic layer to dissolve, dropwise adding 0.3L of DMF, separating out solids, filtering, and combining filtrate with upper mother liquor;
step (3): under the protection of nitrogen, the mother solution combined in the step (2) is heated to 50-70 ℃, 1.6L of DMF is added dropwise, the temperature is reduced to 0-10 ℃ for crystallization, and the sodium gluconate (0.188 Kg, total yield 94%) after purification is obtained through suction filtration and drying.
HPLC detection was performed on the refined sodium sugammadex product obtained in this example, as shown in FIG. 1, and the experimental data are shown in Table 1. As can be seen from FIG. 1 and Table 1, the total purity was 99.68%, impurity A was not detected, impurity B content was 0.046%, and the other individual impurities were less than 0.1%.
TABLE 1 HPLC detection results for refined sodium sulmore gluconate prepared in example 1
| Sequence number | Retention time (min) | Peak area (mAU s) | Peak area (%) | Impurity numbering |
| 1 | 13.746 | 26.60832 | 0.0657 | / |
| 2 | 18.090 | 27.01808 | 0.0667 | / |
| 3 | 20.376 | 625.67218 | 1.5441 | Mono-hydroxy sodium Shuganglucose |
| 4 | 29.639 | 3.97662e4 | 98.1376 | Sodium gluconate for comfort |
| 5 | 42.138 | 27.69884 | 0.0684 | Impurity E |
| 6 | 44.314 | 7.48801 | 0.0185 | / |
| 7 | 45.579 | 10.11244 | 0.0250 | / |
| 8 | 49.710 | 11.41474 | 0.0282 | / |
| 9 | 54.551 | 18.66687 | 0.0461 | Impurity B |
Example 2: refining of sodium Shuganglucose
Step (1): under the protection of nitrogen, 0.2kg of sodium gluconate crude product is dissolved in 0.4L of water, 0.8L of DMAc is dripped at room temperature, the system is turbid, the system is stood for layering, liquid separation is carried out, and the mother solution at the upper layer is temporarily stored;
step (2): under the protection of nitrogen, sequentially adding 0.2L of water into the lower viscous organic layer to dissolve, dropwise adding 0.4L of DMAc, separating out solids, filtering, and combining filtrate with upper mother liquor;
step (3): under the protection of nitrogen, the mother solution combined in the step (2) is heated to 50-70 ℃, 1.2L of DMAc is dripped, the temperature is reduced to 0-10 ℃ for crystallization, and the purified sodium sulfatase (0.182 Kg, 91% of total yield, 99.54% of total purity, undetected impurity A and 0.065% of impurity B) is obtained through suction filtration and drying.
Example 3: refining of sodium Shuganglucose
Step (1): under the protection of nitrogen, dissolving 0.2kg of sodium sulfanilate crude product in 0.6L of water, dropwise adding 1.0L of ethanol at room temperature, clouding the system, standing for layering, separating liquid, and temporarily storing the upper mother liquid;
step (2): under the protection of nitrogen, sequentially adding 0.4L of water into the lower viscous organic layer to dissolve, dropwise adding 0.8L of ethanol, separating out solids, filtering, and combining filtrate with upper mother liquor;
step (3): under the protection of nitrogen, the mother solution combined in the step (2) is heated to 50-70 ℃, 1.0L of ethanol is added dropwise, the temperature is reduced to 0-10 ℃ for crystallization, and the sodium gluconate is obtained after suction filtration and drying, wherein the purified sodium gluconate (0.184 Kg, 92% of total yield, 99.58% of total purity, undetected impurity A and 0.074% of impurity B) is obtained.
Example 4: refining of sodium Shuganglucose
Step (1): under the protection of nitrogen, 0.2kg of sodium gluconate crude product is dissolved in 0.4L of water, 0.6L of acetonitrile is dripped at room temperature, the system is turbid, the system is stood for layering, liquid separation is carried out, and the upper mother solution is temporarily stored;
step (2): under the protection of nitrogen, sequentially adding 0.2L of water into the lower viscous organic layer to dissolve, dropwise adding 0.3L of acetonitrile, separating out solids, filtering, and combining filtrate with upper mother liquor;
step (3): under the protection of nitrogen, the mother solution combined in the step (2) is heated to 50-70 ℃, 2.0L of acetonitrile is dripped, the temperature is reduced to 0-10 ℃ for crystallization, and the purified sodium sulfatase (0.185 Kg, total yield of 92.5%, total purity of 99.52%, undetected impurity A and 0.071% of impurity B) is obtained through suction filtration and drying.
Example 5: refining of sodium Shuganglucose
Step (1): under the protection of nitrogen, 5.6kg of sodium sulmore gluconate crude product is dissolved in 11.2L of water, 16.8LDMF is added dropwise at room temperature, the system is turbid, the system is stood for layering, liquid separation is carried out, and the upper mother solution is temporarily stored;
step (2): under the protection of nitrogen, sequentially adding 5.6L of water into the lower viscous organic layer to dissolve, dropwise adding 8.4L of DMF, separating out solids, filtering, and combining filtrate with upper mother liquor;
step (3): under the protection of nitrogen, the mother solution combined in the step (2) is heated to 50-70 ℃, 45L of DMF is added dropwise, the temperature is reduced to 0-10 ℃ for crystallization, and the sodium gluconate (5.2 Kg, total yield 93%) after purification is obtained through suction filtration and drying.
HPLC detection is carried out on the refined product of sodium sulmore gluconate obtained in the embodiment, and the detection result shows that the total purity of sodium sulmore gluconate is 99.66%, the impurity A is not detected, the content of the impurity B is 0.069%, and other single impurities are less than 0.1%.
Example 6: medium pressure liquid phase separation and purification of impurity A and impurity B
Recovering the solid precipitated in the step (2) of the example 5, separating the solid by medium-pressure liquid phase, and collecting the fraction with the retention time of 20min to obtain impurity A',65mg and the purity of 93.86%; the fraction with a retention time of 30min was collected to give impurity B' as a white powder, 150mg, with a purity of 91.40%. And the impurity A 'or the impurity B' respectively reacts with sodium hydroxide through acid-base salification to obtain the corresponding impurity A or impurity B.
The preparation and separation method of the medium-pressure liquid phase comprises the following steps:
instrument: biotage lsolera One;
detection wavelength: 200nm;
preparation of the column: flash sphere AQ C18 (20-35 um,330 g);
mobile phase: phase A0.1% formic acid solution, phase B acetonitrile;
flow rate: 25ml/min
Elution gradient:
| time (min) | 0 | 35 | 36 | 42 | 43 |
| A(％) | 82 | 72 | 20 | 20 | 82 |
| B(％) | 18 | 28 | 80 | 80 | 18 |
And (3) confirming the structure of the impurity A':
1 H-NMR(400MHz,D 2 O)：5.11-5.03(8H，m)，4.08-4.02(9H，m)，3.95-3.87(9H，m)，3.61-3.48(16H，m)，3.23-3.15(7H，m)，3.03-2.99(7H，m)，2.93-2.86(14H，m)，2.57-2.52(14H，m)。
ESI + ：m/z 1934.3756[M+2Na] 2+
and (3) confirming the structure of the impurity B':
1 H-NMR(400MHz，D 2 O)：5.14-4.92(16H，m)，3.99(16H，m)，3.90-3.79(16H，m)，3.68-3.44(32H，m)，3.12-3.09(16H，m)，2.94-2.91(16H，m)，2.83-2.80(32H，m)，2.47-2.43(32H，m)。
ESI + ：m/z 2019.4045[M+H+Na] 2+
example 7: preparation of sodium Shuganglucose impurity A
1. Preparation of impurity G'
Step 1: to the reaction flask were added octaiodo gamma-cyclodextrin (10.13 g,1.0 eq) and DMF (30 ml), stirring was started and the temperature was controlled at 0-5 ℃.
Step 2: DMF (300 ml) and 3-mercaptopropionic acid (3.45 g,7.0 eq) were added to another reaction flask, stirring was started, the temperature was controlled at 5-15℃and NaH (2.98 g,74.4mmol,14.0 eq) was added in portions and stirred for 15 minutes after the addition.
Step 3: and (3) controlling the temperature to be 0-5 ℃, slowly dripping the reaction solution in the step (2) into the solution in the step (1), slowly heating the reaction temperature to room temperature after dripping, continuously stirring for 2 hours, and carrying out suction filtration. At the temperature of 0-10 ℃, the filter cake is added into a mixed solution of ethanol (250 ml)/water (50 ml)/acetic acid (50 ml) in batches, stirred for 1 hour, suction filtered, the filter cake is rinsed with ethanol (100 ml), suction dried, and then the filter cake is dried by blowing at the temperature of 35 ℃ to obtain a crude product (6.14 g, white-like powder). The crude product was separated by medium pressure liquid phase preparation, the corresponding fractions were collected and lyophilized to give sodium suger impurity G' (322 mg, white powder).
1 H-NMR(400MHz,D 2 O)：5.08-5.04(8H，m)，4.02-3.98(8H，m)，3.89-3.81(8H，m)，3.55-3.47(16H，m)，3.36-3.31(1H，m)，3.18-3.11(7H，m)，3.05-3.00(1H，m)，2.97-2.92(7H，m)，2.86-2.82(14H，m)，2.49-2.45(14H，m)。
High resolution mass spectrometry (esi+): m/z 2023.3167[ M+H ]] +
2. Preparation of impurity F'
DMF (30 ml), sodium sulmore impurity G (2.18G) and thiourea (0.8G) are added into a reaction bottle, stirring is started, the reaction temperature is slowly increased to 80 ℃ after dripping, stirring is continued for 3 hours, and the reaction temperature is reduced to room temperature; ethanol (100 ml) was then added dropwise, stirred for 1 hour, suction filtered, the wet weight of the filter cake was 6.21g, and the filter cake was used directly in the next step.
To the reaction flask were added aqueous NaOH (50 ml,1g NaOH in 50ml purified water) and the filter cake of the previous step (6.21 g), stirring was turned on, the reaction temperature was slowly increased to 90℃and stirring was continued for 7 hours, and the reaction temperature was lowered to room temperature. Then, after adding celite, filtration was carried out, and the filtrate was dropped into ethanol (150 ml), stirred for 1 hour, suction-filtered, and the cake was air-dried at 35℃to obtain a crude product (2.94 g, pale yellow solid). The crude product was separated by medium pressure liquid phase preparation and the corresponding fractions were collected to give sodium supreme impurity F' (478 mg, white powder).
1 H-NMR(400MHz,D 2 O)：5.04-5.00(8H，m)，4.02(8H，m)，3.88-3.79(8H，m)，3.54-3.43(16H，m)，3.15-3.11(8H，m)，2.95-2.92(8H，m)，2.84-2.81(14H，m)，2.43-2.44(14H，m)。
High resolution mass spectrometry (esi+): m/z 1929.3953[ M+H ]] +
3. Preparation of impurity A and impurity A'
DMF (5 ml), potassium tert-butoxide (0.52 g) and sodium sulmore impurity F' (1.14 g) were added to the tube, stirring was turned on and the reaction temperature was increased to 80 ℃. A solution of sodium sulmore impurity G' (0.54G) in DMF (3 ml) was then added dropwise to the tube and reacted at 65-70℃for 20 hours. After the reaction was completed, the mixture was suction-filtered to obtain a crude product (1.32 g, white solid). The crude product is prepared and separated by medium pressure liquid phase, and the corresponding components are collected to obtain sodium gluconate impurity A' (90 mg, purity is 91.10 percent) and white powder. And carrying out acid-base salification reaction on the impurity A' and sodium hydroxide to obtain the impurity A.
The obtained impurity A 'was measured by nuclear magnetic resonance, and the data were the same as those of the impurity A' in example 6.
Comparative example 1: purification of sodium sulmore gluconate by the method of patent CN107778383a
According to the method disclosed in patent CN107778383A, a crude product of sodium sulmore gluconate is prepared, 100g of the crude product of sodium sulmore gluconate is taken, 3L of water is added for dissolution, 5g of dithiothreitol is added, the temperature is raised to reflux under the protection of nitrogen, 8L of acetonitrile is added, the mixture is stirred to room temperature after the addition, and 30g of sodium sulmore gluconate is obtained through crystallization and suction filtration, and the yield is 30%.
HPLC detection is carried out on the refined sodium sulmore glucose product of the comparative example 1, and the detection result shows that the total purity of the sodium sulmore glucose is 96.70%, the impurity A is 0.22%, the impurity B is 0.071%, the total impurity number is 26, and the single impurity content is 8 impurities with the concentration of > 0.1%.
Comparative example 2: detection of impurity A and impurity B in commercially available original Hushu sodium gluconate injection
HPLC detection was performed on a commercially available sample of the original Meishu sodium gluconate injection (purchased from the company Mitsadon, germany, lot number: M034113), the commercially available product profile is shown in FIG. 2, and the experimental data are shown in Table 2. 98.14% of total purity, 0.24% of impurity A, 0.069% of impurity B, 17 of impurity number and 5 of single impurity content > 0.1%.
TABLE 2 HPLC detection results of commercially available sodium sulfato glucose injection
| Sequence number | Retention time (min) | Peak area (mAU s) | Peak area (%) | Impurity numbering |
| 1 | 10.287 | 13.99252 | 0.0499 | / |
| 2 | 11.568 | 7.04455 | 0.0251 | / |
| 3 | 14.175 | 99.11649 | 0.3534 | / |
| 4 | 15.144 | 7.83262 | 0.0279 | / |
| 5 | 18.637 | 111.28273 | 0.3967 | / |
| 6 | 20.809 | 457.26880 | 1.6302 | Mono-hydroxy sodium Shuganglucose |
| 7 | 28.787 | 68.09583 | 0.2428 | Impurity A |
| 8 | 30.242 | 27070.44845 | 96.5087 | Sodium gluconate for comfort |
| 9 | 38.069 | 5.35789 | 0.0191 | / |
| 10 | 43.067 | 64.92190 | 0.2315 | / |
| 11 | 45.947 | 38.32251 | 0.1366 | / |
| 12 | 49.444 | 8.97157 | 0.0320 | / |
| 13 | 50.538 | 5.08289 | 0.0181 | / |
| 14 | 50.892 | 14.82101 | 0.0528 | / |
| 15 | 53.761 | 19.31502 | 0.0689 | Impurity B |
| 16 | 55.201 | 22.60620 | 0.0806 | / |
| 17 | 55.895 | 12.09314 | 0.0431 | / |
| 18 | 56.908 | 11.60212 | 0.0414 | / |
| 19 | 57.666 | 11.56036 | 0.0412 | / |
HPLC detection results of the crude sodium sulmore gluconate, the example sample, the comparative example 1 sample and the commercially available raw sodium sulmore gluconate injection sample are summarized in Table 3.
Table 3 HPLC assay examples and comparative samples
From table 3, it can be seen that the technical scheme that this application provided can effectively reduce the content of impurity A and impurity B in the sodium sulmore, especially can detach impurity A, has further improved product purity, provides the guarantee for follow-up preparation and clinical medication safety. And the refining system is simple, overcomes the defect that the separated solid can enrich part of impurities which are difficult to purify under the conventional purifying condition, and replaces the method for obtaining high-purity sodium gluconate by using a special adsorbent in the field. Mild condition and low cost, and is very suitable for social mass production.
Claims (7)
1. A method for refining sodium sugammadex, which is characterized by comprising the following steps:
step (1): under the protection of inert gas, dissolving a sodium gluconate crude product into water, adding a poor solvent at room temperature, standing for layering, and taking an upper mother solution; the poor solvent is one or more selected from DMF, DMSO, NMP, DMAc, acetone, ethyl acetate, n-heptane, acetonitrile, ethanol, methanol, isopropanol, 1, 4-dioxane and tert-butyl methyl ether; the mass volume ratio of the crude product of the sodium sulfan to the water in the step (1) is 1:0.5-1:50 in terms of g/ml; the mass volume ratio of the sodium sugammadex crude product to the poor solvent is 1:0.5-1:50 in terms of g/ml;
step (2): under the protection of inert gas, sequentially adding water into the lower layer of organic solution for dissolution, adding a poor solvent, separating out solids, filtering, and combining filtrate with the upper layer of mother solution; in the step (2), the mass volume ratio of the sodium sugammadex crude product to the added water is 1:0.25-1:50 in terms of g/ml; the mass volume ratio of the crude product of the sodium suger and the added poor solvent is 1:0.25-1:50 in terms of g/ml;
step (3): under the protection of inert gas, heating the combined mother solution in the step (2), adding a poor solvent, cooling, crystallizing, filtering, and drying to obtain sodium gluconate; in the step (3), the mass volume ratio of the crude product of the sodium digluconate to the added poor solvent is 1:1-1:50 in terms of g/ml; the temperature rise range is 40-100 ℃; the temperature of the cooling crystallization is-20 to 30 ℃.
2. The method for refining sodium sugammadex according to claim 1, characterized in that: the poor solvent is DMF or ethanol or a combination thereof.
3. The method for refining sodium sulmore according to claim 1, wherein the mass-volume ratio of the crude sodium sulmore in step (1) to water is 1:1-1:10 in terms of g/ml; the mass volume ratio of the sodium suger crude product to the poor solvent is 1:1-1:10 in terms of g/ml;
or in the step (2), the mass volume ratio of the crude product of the sodium digluconate to the added water is 1:1-1:5 in terms of g/ml; the mass volume ratio of the sodium sugammadex crude product to the added poor solvent is 1:1-1:10 in terms of g/ml;
or in the step (3), the mass-volume ratio of the crude sodium sulfan to the added poor solvent is 1:2-1:20 in terms of g/ml; the temperature rise range is 50-70 ℃; the temperature of the cooling crystallization is 0-10 ℃.
4. The method for refining sodium sulmore according to claim 3, wherein the mass-volume ratio of the crude sodium sulmore in step (1) to water is 1:2-1:3 in terms of g/ml; the mass volume ratio of the sodium suger crude product to the poor solvent is 1:2-1:5 in terms of g/ml.
5. The method for refining sodium sulmore according to claim 3, wherein in the step (2), the mass-volume ratio of the crude sodium sulmore to the added water is 1:1-1:2 in terms of g/ml; the mass volume ratio of the crude product of the sodium suger to the added poor solvent is 1:1.5-1:4 in terms of g/ml.
6. The method for purifying sodium sulmore according to claim 3, wherein the mass-to-volume ratio of the crude sodium sulmore to the poor solvent added in the step (3) is 1:5 to 1:10 in g/ml.
7. The method for purifying sodium metagluconate according to any one of claims 1 to 6, wherein the steps (1) to (3) are performed under a nitrogen atmosphere.
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| CN111320712B (en) * | 2020-04-09 | 2022-03-04 | 江苏海悦康医药科技有限公司 | Synthesis method of sugammadex sodium intramolecular thioether impurity |
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| CN116606388B (en) * | 2023-06-09 | 2023-11-28 | 北京阳光诺和药物研究股份有限公司 | Alpha crystal form of sodium sugammadex and preparation method thereof |
| CN116924339B (en) * | 2023-07-24 | 2024-01-23 | 山东华氟化工有限责任公司 | Method for recovering iodine from tail liquid of perfluoroalkyl iodide downstream product production |
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| CN111518229A (en) * | 2020-05-22 | 2020-08-11 | 合肥博思科创医药科技有限公司 | Method for removing element impurities and pigments in refined sugammadex sodium product |
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| CN107325204B (en) * | 2017-07-07 | 2019-09-24 | 中国大冢制药有限公司 | A kind of preparation method for the more glucose sodium that relaxes |
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| WO2014125501A1 (en) * | 2013-02-14 | 2014-08-21 | Neuland Laboratories Limited | An improved process for preparation of sugammadex sodium |
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| CN110627925A (en) * | 2018-06-22 | 2019-12-31 | 天津科伦药物研究有限公司 | Method for refining sugammadex sodium |
| CN111518229A (en) * | 2020-05-22 | 2020-08-11 | 合肥博思科创医药科技有限公司 | Method for removing element impurities and pigments in refined sugammadex sodium product |
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| CN115109172A (en) | 2022-09-27 |
| CN110627925B (en) | 2022-09-06 |
| CN115505051A (en) | 2022-12-23 |
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