阅读说明：本技术 一种舒更葡糖钠晶型 (Crystal form of sugammadex sodium ) 是由 张贵民 彭祥龙 鲍广龙 刘云娜 于 2019-09-20 设计创作，主要内容包括：本发明提供了一种舒更葡糖钠晶型,涉及晶型药物分子技术领域。该舒更葡糖钠晶型使用Cu-Kα辐射,以2θ表示的X射线衍射谱图5.74±0.2°,7.51±0.2°,10.36±0.2°,12.67±0.2°,16.16±0.2°,17.20±0.2,17.92±0.2°,19.43±0.2°,20.45±0.2°,21.83±0.2°,22.63±0.2°有特征峰；并提供了相关制备方法和应用。本发明的舒更葡糖钠晶型稳定性好,其溶液澄清度与颜色符合注射液原料药标准,提高了舒更葡糖钠注射制剂的安全性和稳定性。(The invention provides a sugammadex crystal form, and relates to the technical field of crystal form drug molecules. The sugammadex sodium crystal form uses Cu-Kalpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta shows that the crystal form has characteristic peaks at 5.74 +/-0.2 degrees, 7.51 +/-0.2 degrees, 10.36 +/-0.2 degrees, 12.67 +/-0.2 degrees, 16.16 +/-0.2 degrees, 17.20 +/-0.2 degrees, 17.92 +/-0.2 degrees, 19.43 +/-0.2 degrees, 20.45 +/-0.2 degrees, 21.83 +/-0.2 degrees and 22.63 +/-0.2 degrees; and provides related preparation method and application. The sugammadex sodium crystal form has good stability, the clarity and the color of the solution meet the raw material medicine standard of the injection, and the safety and the stability of the sugammadex sodium injection preparation are improved.)

1. The sugammadex sodium crystal form is characterized in that the sugammadex sodium crystal form uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks and characteristic peaks at 7.51 +/-0.2 degrees, 10.36 +/-0.2 degrees, 16.16 +/-0.2 degrees, 17.20 +/-0.2 degrees, 17.92 +/-0.2 degrees.

2. The sugammadex crystal form of claim 1, wherein the sugammadex crystal form has characteristic peaks at 5.74 ± 0.2 °, 7.51 ± 0.2 °, 10.36 ± 0.2 °, 12.67 ± 0.2 °, 16.16 ± 0.2 °, 16.64 ± 0.2 °, 17.20 ± 0.2 °, 17.92 ± 0.2 °, 19.00 ± 0.2 °, 19.43 ± 0.2 °, 20.45 ± 0.2 °, 21.83 ± 0.2 °, 22.63 ± 0.2 ° in an X-ray diffraction pattern expressed in terms of 2 Θ using Cu-ka radiation.

3. The crystalline form of sugammadex sodium of claim 1, wherein said crystalline form has an X-ray powder diffraction pattern as shown in figure 1.

4. A process for preparing the crystalline form of sugammadex sodium according to any one of claims 1 to 3, characterized in that the preparation process comprises the following steps:

under the protection of inert gas, adding sugammadex sodium into a mixed solution of an organic solvent A and purified water, controlling the temperature, carrying out reflux reaction, after the reaction is finished, filtering, and slowly cooling the filtrate; after the temperature reduction is finished, stirring and dripping the organic solvent B under the condition of heat preservation, and after the dripping is finished, stirring and crystallizing under the condition of heat preservation; after crystallization, filtering and drying the filter cake, white crystal sodium sugammadex is obtained.

5. The method for preparing sugammadex sodium crystal form according to claim 4, wherein the organic solvent A is one or two of methanol, ethanol, isopropanol, tert-butanol, ethylene glycol and propylene glycol.

6. The process for preparing crystalline form of sugammadex sodium according to claim 4, wherein the volume ratio of said organic solvent A to purified water is 1: 1-2; the mass-volume ratio of the sugammadex sodium to the mixed solution is 1: 3-5 g/ml.

7. The process for the preparation of the crystal form of sugammadex sodium according to claim 4, wherein the slow cooling of the filtrate is a programmed cooling, preferably at a cooling rate of 0.5 ℃/min; and slowly cooling the filtrate to 20-30 ℃.

8. The method for preparing sugammadex sodium crystal form according to claim 4, wherein the organic solvent B is one or two of methanol, ethanol, acetonitrile, acetone, N-dimethylformamide, isopropanol, tert-butanol, tetrahydrofuran, 1, 4-dioxane, ethylene glycol and propylene glycol; the mass-volume ratio of the sugammadex sodium to the organic solvent B is 1: 10-20, and g/ml.

9. The preparation method of the sugammadex sodium crystal form according to claim 4, wherein the temperature for dropping the organic solvent B and stirring for crystallization is 20-30 ℃.

10. Use of the crystalline form of sugammadex sodium according to any of claims 1 to 3 as active ingredient for the preparation of a muscle relaxant antagonist medicament.

Technical Field

The invention relates to the technical field of crystal form drug molecules, in particular to a sugammadex crystal form.

Background

Sugammadex Sodium (Sugammadex Sodium), chemical name octa-6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin Sodium salt, CAS number: 343306-79-6, the specific structural formula is as follows:

the sugammadex sodium is a novel muscle relaxant reversal agent, is firstly developed by Organon corporation in the Netherlands, is used for reversing the blocking effect of a conventionally used neuromuscular blocking drug rocuronium bromide or vecuronium bromide, and can immediately reverse the effect of rocuronium bromide used by adults and the effect of rocuronium bromide used by children and teenagers (2-17 years old). Sugammadex sodium is the first and only Selective Relaxation Binding Agent (SRBA), the first major drug development in the field of narcotics over 20 years, and is known as a milestone muscle relaxation antagonist.

Akzo Nobel owns a patent right on 6-mercaptocyclodextrin derivatives (publication No. CN1402737A), which was incorporated into Xianlingbao-ya, Mlingbao-ya and later developed sumamadex by Ougangong, Netherlands, the department of human health and health, in 2007, and was purchased by Miner Shadong, Mblend, in 2009. The product has been approved in the european union and japan in 2008 and 2010, respectively. Sodium sugammadex injection (trade name: Bridion) is approved by the FDA at 12 months and 15 days 2015 for sale.

In recent years, researches show that the crystal forms of the drugs are different, and the physicochemical properties (density, hardness, solubility, stability, optical property, electrical property and the like), dissolution rate, biological effect and the like of the drug can be changed, so that the research on the crystal forms of the drugs has important practical value in medicine and pharmacology. The crystal form drug molecules comprise polymorphism, hydrate, solvate, salt and the like of the drug molecules, and through the way of drug crystallization, the crystallography parameters of the crystal form drug molecules can be determined, and the types and the number of the solvent molecules (such as crystal water molecules) in the crystal form can be determined, so that the crystal form drug molecules have very important effects on understanding and mastering the spatial arrangement and the physicochemical properties of the drug molecules.

In the current study report of the crystal form of sugammadex sodium, CN107400182 reports that alcohol such as methanol and ethanol is dripped into a sugammadex sodium aqueous solution to prepare a sugammadex sodium crystal form a; patent IN201741012475 reports that methanol is dripped into a methanol/water mixed solution for crystallization to obtain a sugammadex crystal form; patent US9879096 discloses the preparation of an amorphous form of sugammadex sodium; patent CN109053933 reports 5 sugammadex crystal forms and one sugammadex amorphous form, patent TW201912656 discloses sugammadex crystal forms I and II, and reports that sugammadex crystal form III is obtained by heating crystal form II to induce crystal transformation.

As is well known, sugammadex sodium as an effective muscle relaxant is an injection raw material drug, and an injection preparation has strict requirements on various aspects of the raw material drug, and the known sugammadex sodium crystal form cannot well meet the requirements of a pharmaceutical preparation in the aspects of clarity, color, solubility, thermal stability, photostability, dissolution rate, bioavailability and the like, so that more crystal forms need to be developed, on one hand, more sugammadex sodium crystal forms are provided for pharmaceutical application, and on the other hand, the pharmaceutical performance is improved in the aspects of chemical purity, fluidity, solubility, stability (such as storage stability, dehydration stability, polymorphic transformation stability, low hygroscopicity, low residual solvent content), clarity and the like, and a more efficient medicine is developed; on the other hand, the crystal form of sugammadex sodium which is more suitable for industrial production and has high economic benefit is also developed.

Disclosure of Invention

In order to overcome the disadvantages of the prior art, it is an object of the present invention to provide a crystalline form of sugammadex sodium; another object of the present invention is to provide a method for preparing the sugammadex sodium crystal form; still another object of the present invention is to provide a use of a crystalline form of sugammadex sodium for the preparation of a muscle relaxant antagonist medicament.

The specific technical scheme of the invention is as follows:

a sugammadex crystal form uses Cu-Kalpha radiation, and has characteristic peaks at 7.51 +/-0.2 degrees, 10.36 +/-0.2 degrees, 16.16 +/-0.2 degrees, 17.20 +/-0.2 degrees, 17.92 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta.

Preferably, the sugammadex sodium crystal form has characteristic peaks at 5.74 +/-0.2 degrees, 7.51 +/-0.2 degrees, 10.36 +/-0.2 degrees, 12.67 +/-0.2 degrees, 16.16 +/-0.2 degrees, 16.64 +/-0.2 degrees, 17.20 +/-0.2 degrees, 17.92 +/-0.2 degrees, 19.00 +/-0.2 degrees, 19.43 +/-0.2 degrees, 20.45 +/-0.2 degrees, 21.83 +/-0.2 degrees, 22.63 +/-0.2 degrees by using Cu-Ka radiation and an X-ray diffraction spectrum expressed by 2 theta.

Preferably, the sugammadex sodium crystal form, using Cu-ka radiation, has characteristic peaks according to the X-ray powder diffraction pattern shown in fig. 1.

The preparation method of the sugammadex sodium crystal form comprises the following steps:

under the protection of inert gas, adding sugammadex sodium into a mixed solution of an organic solvent A and purified water, controlling the temperature, carrying out reflux reaction, after the reaction is finished, filtering, and slowly cooling the filtrate; after the temperature reduction is finished, stirring and dripping the organic solvent B under the condition of heat preservation, and after the dripping is finished, stirring and crystallizing under the condition of heat preservation; after crystallization, filtering and drying the filter cake, white crystal sodium sugammadex is obtained.

Preferably, the organic solvent A is one or two of methanol, ethanol, isopropanol, tert-butanol, ethylene glycol and propylene glycol; tert-butanol is preferred.

Preferably, the volume ratio of the organic solvent A to the purified water is 1:1 to 2.

Preferably, the mass-volume ratio of the sugammadex sodium to the mixed solution is 1: 3-5 g/ml.

Preferably, the temperature-controlled reflux reaction time is 1-2 hours.

Preferably, the temperature of the filtrate is slowly reduced to 20-30 ℃.

In a preferable scheme, the slow cooling mode of the filtrate is program cooling, and preferably, the cooling rate is 0.5 ℃/min.

Preferably, the organic solvent B is one or two of methanol, ethanol, acetonitrile, acetone, N-dimethylformamide, isopropanol, tert-butanol, tetrahydrofuran, 1, 4-dioxane, ethylene glycol and propylene glycol; acetonitrile is preferred.

Preferably, the amount of the organic solvent B is a proper amount which can ensure that the sugammadex sodium reaches the maximum precipitation amount; the mass volume ratio of the sugammadex sodium to the organic solvent B is preferably 1: 10-20 g/ml.

Preferably, the crystallization time is 2-3 hours.

Preferably, the temperature for dripping the organic solvent B and stirring for crystallization is 20-30 ℃.

In the present invention, the inert gas is generally selected from nitrogen and argon, and argon is particularly preferred.

The sugammadex sodium crystal form is used as an active ingredient for preparing a muscle relaxation antagonist drug.

An injection preparation, which contains the sugammadex sodium crystal form of the invention and other components.

Preferably, the preparation method of the injection preparation of the present invention is as follows: the compounds of the present invention are formulated for injection into a pharmaceutically acceptable solid or liquid carrier, and optionally with pharmaceutically acceptable excipients, using standard and conventional techniques.

Preferably, the preparation can be a ready-to-use liquid injection or a freeze-dried powder injection.

Preferably, the other components of the formulation include other active ingredients, osmotic pressure regulators, pH regulators, solubilizers, solubilizing agents, co-solvents, antioxidants, bacteriostats, emulsifiers, complexing agents, and the like, which may be used in combination.

More preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, fructose, glycerol, sorbitol, xylitol, magnesium chloride, phosphate, sodium citrate and mannitol; the pH value regulator is selected from one or more of hydrochloric acid, sulfuric acid, lactic acid, malic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate and arginine; the solubilizer is selected from one or more of tween 80, tween 60 and poloxamer 68; the cosolvent is selected from sodium benzoate, sodium salicylate, sodium p-aminobenzoate, urethane, urea, erucamide, glucose, meglumine, malic acid, methionine, glycine, arginine, nicotinamide, sodium bicarbonate, phenylalanine, and vitamin B₆One or more of the above; the antioxidant is selected from one or more of L-cysteine hydrochloride, sodium sulfite, sodium bisulfite, propyl gallate, glutathione, sodium thiosulfate, thiourea, mercaptoacetic acid, sodium metabisulfite and vitamin B; the bacteriostatic agent is selected from one or more of the following components; the emulsifier is selected from one or more of lecithin, soybean lecithin, poloxamer 68, cholesterol and glycerol monooleate; the complexing agent is one or more selected from disodium ethylene diamine tetraacetate and calcium disodium ethylene diamine tetraacetate.

The invention has the beneficial effects that:

1. the preparation method of the sugammadex sodium crystal form is simple, the requirement on production equipment is low, and the obtained product has high purity and yield and is suitable for large-scale popularization and application.

2. The sugammadex sodium crystal form has no increase of impurities basically in accelerated test, has better stability, and is beneficial to medicament storage and ensures medicament effect when a dosage form prepared by utilizing the crystal form is utilized.

3. The solution of the sugammadex sodium crystal form is qualified in clarity and color, and the safety and stability of the sugammadex sodium injection preparation are improved.

Drawings

FIG. 1: sugammadex sodium crystal form X-ray powder diffraction pattern.

FIG. 2: a differential scanning calorimetry (DSC/TGA) graph of the sugammadex sodium crystal form.

Detailed Description

The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.

Materials used in the experiment: sugammadex sodium is available commercially and can also be prepared by reference to the prior art; all materials used in other experiments, which have not been indicated for their origin and specification, are commercially available, analytically pure or chemically pure.

The purity of the sugammadex sodium is measured by HPLC, and the chromatographic conditions are as follows:

a chromatographic column: phenomenex, Aqua-C₁₈₍2.0mm×150mm,3.0μm)；

Mobile phase: mobile phase A: 25.0mmol/L phosphate buffer (pH 3.0) (3.45 g sodium dihydrogen phosphate monohydrate taken in a 1000ml volumetric flask, 950ml water added, pH adjusted to 3.00 ± 0.03 with 1.5mol/L phosphoric acid solution and diluted to the mark with water, shake up) -acetonitrile (83: 20); mobile phase B: acetonitrile;

column temperature: 40 ℃;

detection wavelength: 200 nm;

flow rate: 0.27 ml/min;

sample introduction amount: 2.5 mul;

the elution gradient is shown in table 1, where the sugammadex sodium (8-substituent) retention time is between about 20.5min and 23.0min, the minor active ingredient 7-substituent is at about 0.65 times the main peak retention time, and the sugammadex sodium purity is calculated as the area and the calculation of 7-substituent and 8-substituent.

TABLE 1 elution gradiometer

Example 1

Sodium sugammadex (5.05g) was added to tert-butanol/purified water (V) under argon_{Tert-butyl alcohol}:V_{Water (W)}1:1.5, 20ml), carrying out reflux reaction for 1 hour at controlled temperature, finishing the reaction, filtering, and cooling the filtrate to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding acetonitrile (75ml) while stirring, and after dropwise adding, keeping the temperature and stirring for crystallization for 2 hours; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex, with yield of 97.8% and purity of 99.89%.

Example 2

Sodium sugammadex (5.02g) was added to methanol/purified water (V) under argon_Methanol:V_{Water (W)}1:1, 25ml) is added into the mixed solution, the temperature is controlled, reflux reaction is carried out for 2 hours, the reaction is finished, filtration is carried out, and the temperature of the filtrate is reduced to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding methanol (60ml) while stirring, and after dropwise adding, keeping the temperature and stirring for crystallization for 2 hours; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex, with yield 95.6% and purity 99.78%.

Example 3

Sodium sugammadex (5.08g) was added to ethanol/purified water (V) under argon_Ethanol:V_{Water (W)}15ml) is added into the mixed solution, the temperature is controlled, the reflux reaction is carried out for 1 hour, the reaction is finished, the filtration is carried out, and the temperature of the filtrate is reduced to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding methanol (80ml) while stirring, and finishing dropwise addingAfter finishing, stirring and crystallizing for 3 hours under the condition of heat preservation; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex, with yield 95.8% and purity 99.76%.

Example 4

Sodium sugammadex (5.01g) was added to isopropanol/purified water (V) under argon_{Isopropanol (I-propanol)}:V_{Water (W)}22ml) is added into the mixed solution, the temperature is controlled, the reflux reaction is carried out for 1 hour, the reaction is finished, the filtration is carried out, and the temperature of the filtrate is reduced to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding N, N-dimethylformamide (85ml) while stirring, and after dropwise adding, keeping the temperature and stirring for crystallization for 3 hours; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex, with yield of 96.2% and purity of 99.74%.

Example 5

Sodium sugammadex (5.03g) was added to ethylene glycol/purified water (V) under argon_{Ethylene glycol}:V_{Water (W)}1:1.2, 25ml), carrying out reflux reaction for 2 hours at controlled temperature, finishing the reaction, filtering, and cooling the filtrate to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding acetone (70ml) while stirring, and after dropwise adding, keeping the temperature and stirring for crystallization for 2 hours; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex with yield of 96.3% and purity of 99.72%.

Example 6

Sodium sugammadex (5.06g) was added to propylene glycol/purified water (V) under argon_{Propylene glycol}:V_{Water (W)}1:1.5, 20ml), carrying out reflux reaction for 2 hours at controlled temperature, finishing the reaction, filtering, and cooling the filtrate to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding isopropanol (90ml) while stirring, and after dropwise adding, keeping the temperature and stirring for crystallization for 3 hours; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex, with yield 95.9% and purity 99.78%.

Example 7

Sodium sugammadex (5.05g) was added to methanol/purified water (V) under argon_Methanol:V_{Water (W)}1:1, 20ml) ofCarrying out temperature-controlled reflux reaction on the mixed solution for 2 hours, filtering after the reaction is finished, and cooling the filtrate to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding tetrahydrofuran (100ml) while stirring, and after dropwise adding, keeping the temperature and stirring for crystallization for 2 hours; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex, with yield of 96.3% and purity of 99.74%.

Example 8

Sodium sugammadex (5.02g) was added to tert-butanol/purified water (V) under argon_{Tert-butyl alcohol}:V_{Water (W)}1:1.5, 20ml), carrying out reflux reaction for 2 hours at controlled temperature, finishing the reaction, filtering, and cooling the filtrate to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding 1, 4-dioxane (80ml) while stirring, and after dropwise adding, keeping the temperature and stirring for crystallization for 3 hours; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex, with yield of 96.4% and purity of 99.76%.

Example 9

Sodium sugammadex (5.07g) was added to ethanol/purified water (V) under argon_Ethanol:V_{Water (W)}1:1.5, 20ml), carrying out reflux reaction for 2 hours at controlled temperature, finishing the reaction, filtering, and cooling the filtrate to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding ethylene glycol (65ml) while stirring, and after dropwise adding, keeping the temperature and stirring for crystallization for 2 hours; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex, with yield 95.6% and purity 99.73%.

Example 10

Sodium sugammadex (5.04g) was added to isopropanol/purified water (V) under argon_{Isopropanol (I-propanol)}:V_{Water (W)}1:1.5, 20ml), carrying out reflux reaction for 2 hours at controlled temperature, finishing the reaction, filtering, and cooling the filtrate to 20-30 ℃ at the speed of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding propylene glycol (70ml) while stirring, and after dropwise adding, keeping the temperature and stirring for crystallization for 2 hours; after crystallization, filtering, drying filter cake under reduced pressure at 40 ℃ to constant weight to obtain white crystal sodium sugammadex, with yield of 96.1% and purity of 99.80%.

Confirmation of Crystal form Structure

The X-ray powder diffraction test instrument and the test conditions involved in the invention are as follows: x-ray powder diffractometer PANalytical E; Cu-K alpha; a sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45 kv and current 40 mA; a diverging slot 1/4; an anti-scatter slit 1; 0.04rad of cable pull slit; step length: 0.5 s; scanning range: 3 to 50 degrees. The characteristic peaks in the X-ray powder diffraction pattern (Cu-Ka) corresponding to the crystal form of sugammadex sodium are shown in figure 1 and table 2 in detail.

Table 2 sugammadex crystal PXRD peaks

The samples of examples 1-10 all had the same X-ray powder diffraction pattern.

According to the existing reported preparation method of the sugammadex sodium crystal form, the sugammadex sodium in comparative examples 1-11 is prepared.

Comparative example 1

Adding sugammadex sodium (46g) into a mixed solution of purified water (69 ml)/methanol (69ml), stirring and dissolving at 25-35 ℃, adding activated carbon (11.5g), stirring for 30min at 25-35 ℃, filtering, washing a filter cake by using water (23 ml)/methanol (23ml), controlling the temperature of the filtrate at 25-35 ℃, adding methanol (598ml), stirring for 2 hours, filtering, washing the filter cake by using methanol (184ml), and drying for 14 hours at 55-60 ℃ to obtain crystalline sugammadex sodium, wherein the yield is 55.3 percent and the pure 99.62 percent.

Comparative example 2

Adding sugammadex sodium (10.9g) into a mixed solution of purified water (15 ml)/methanol (15ml), adding activated carbon (2g), filtering, and washing filter cake purified water (5 ml); controlling the temperature of the filtrate to be 50-55 ℃, adding methanol (135ml), stirring for 2 hours at 50-55 ℃, separating out solids, filtering, washing a filter cake by using methanol (20ml), and drying for 24 hours at 70-75 ℃ in vacuum to obtain the amorphous sugammadex sodium, wherein the yield is 62.4%, and the purity is 99.53%.

Comparative example 3

Adding sugammadex sodium (5g) into purified water (10ml), stirring for dissolving, heating to 50-60 ℃, slowly dripping methanol (60ml), precipitating solid after adding, naturally cooling to room temperature, further cooling to 0-5 ℃, preserving heat for 1 hour, filtering, and drying to obtain crystalline sugammadex sodium, wherein the yield is 86.2%, and the purity is 99.64%.

Comparative example 4

Adding sugammadex sodium (10g) into purified water (20ml), stirring for dissolving, heating to 60 ℃, adding ethanol (120ml) while stirring, and separating out a large amount of white solid; naturally cooling to room temperature, further cooling to 0 ℃, keeping the temperature and stirring for 1 hour, performing suction filtration, and drying a filter cake to obtain crystalline sodium sugammadex with the yield of 88.4 percent and the purity of 99.56 percent.

Comparative example 5

Adding sugammadex sodium (10g) into purified water (20ml), stirring for dissolving, heating to 75 ℃, adding DMF (60ml) while stirring, and separating out a large amount of white solid; naturally cooling to room temperature, filtering, drying the filter cake to obtain crystalline sodium sugammadex with the yield of 88.7 percent and the purity of 99.62 percent.

Comparative example 6

Adding sugammadex sodium (10g) into purified water (20ml), stirring for dissolving, heating to 50 ℃, adding acetone (160ml) while stirring, and separating out a large amount of white solid; naturally cooling to room temperature, further cooling to 0 ℃, keeping the temperature and stirring for 1 hour, performing suction filtration, and drying a filter cake to obtain crystalline sodium sugammadex, wherein the yield is 87.3 percent, and the purity is 99.58 percent.

Comparative example 7

Adding sugammadex sodium (10g) into purified water (20ml), stirring to dissolve, placing the solution into a flat-bottom tray, placing the flat-bottom tray into a freeze dryer, pre-freezing to-80 ℃, then heating in a gradient manner, and performing freeze-drying for 24 hours to obtain the sugammadex sodium crystal with the purity of 99.34%.

Comparative example 8

Adding sugammadex sodium (10g) into purified water (50ml), stirring to dissolve, heating to 75 ℃ under stirring, stirring at the rotating speed of 200r/min, dropwise adding 1, 4-dioxane (300ml) into the solution, stirring to reduce the temperature to room temperature, separating out a large amount of white solids, performing suction filtration, and drying a filter cake in vacuum to dryness to obtain the amorphous sugammadex sodium, wherein the yield is 90.8%, and the purity is 99.66%.

Comparative example 9

Adding sugammadex sodium (10g) into purified water (30ml), stirring and dissolving to obtain a sugammadex sodium water solution; DMF (75ml) was added to an aqueous solution of sugammadex sodium to crystallize, and after crystallization at 25 ℃ for 1 hour with stirring, the crystal was filtered, and the filter cake was washed with a mixed solution of water/DMF (20 ml. times.2), whereby crystalline sugammadex sodium was obtained in a yield of 86.7% and a purity of 99.58%.

Comparative example 10

Crystalline sodium sugammadex was prepared according to the preparation method of comparative example 9, and the crystalline sodium sugammadex prepared (93g) was added to purified water (3ml), followed by addition of methanol (480 ml); heating the reaction liquid to 65 ℃ to ensure that the reaction liquid becomes clear, and slowly cooling; cooling to 42-45 deg.C, stirring for 2 hr, and crystallizing; the reaction solution is continuously cooled to 25 ℃, kept at 25 ℃, stirred and crystallized for 2 hours, filtered, and the filter cake is washed by a water/methanol (20ml multiplied by 2) mixed solution to obtain the crystalline sodium sugammadex, the yield is 80.2 percent, and the purity is 99.62 percent.

Comparative example 11

Crystalline sodium sugammadex (5g) prepared in comparative example 10 was dried under vacuum (15mmHg) by heating to 80-90 deg.C for 12 hours to obtain crystalline sodium sugammadex with a purity of 99.64%.

Heat stability test

The sugammadex sodium prepared in example 1 and comparative examples 1 to 11 were dissolved in water, and then stored in the dark at 25 ℃ for 6 months, and samples were taken for 1 month, 3 months and 6 months to measure the impurity content, and the purity of sugammadex sodium was measured by HPLC. The results are shown in Table 3.

TABLE 3 stability test results of sugammadex sodium solution

As shown in table 3, the stability test results of the sugammadex sodium solution stored in the dark at 25 ℃ show that the impurities of the amorphous sugammadex sodium of comparative example 2 and comparative example 8 are significantly increased, and the impurities are more than 1% after 3 months stability test; after the crystal forms of other comparative examples are inspected for 6 months, the results show that the impurities are all more than 0.5; the stability test result of the sugammadex sodium crystal form solution shows that the impurity change is not obvious and is basically stable; the examination found that the examples 1 to 10 of the present invention have similar stability test results.

The sugammadex sodium prepared in example 1 and comparative examples 1 to 11 were subjected to accelerated testing at 40 ℃ (RH 45%) in the dark for 6 months, sampled for 1 month, 3 months, and 6 months, respectively, to detect the impurity content, and then the purity determination method for sugammadex sodium by HPLC was used for detection. The results are shown in Table 4.

Table 4 results of accelerated test at 40 ℃ in solid state of sugammadex sodium

The solid stability test result shows that the impurities of the amorphous sugammadex sodium in the comparative examples 2 and 8 are obviously increased, and after 3-month stability test, the impurities are more than 1 percent; after the crystal forms of other comparative examples are inspected for 6 months, the results show that the impurities are all more than 0.5; the test result of the crystal form solid stability of sugammadex sodium shows that the impurity change is not obvious and is basically stable; the examination found that the examples 1 to 10 of the present invention have similar stability test results.

Light stability test

The sugammadex sodium prepared in example 1 and comparative examples 1 to 11 were respectively taken, and the impurity content was measured and detected under strong light irradiation (4500Lx ± 500Lx) for 0, 15 and 30 days, respectively, and the purity measurement method of sugammadex sodium was referred to HPLC. The results are shown in Table 5.

TABLE 5 light stability test results for sugammadex sodium

The photostability test result shows that under the condition of strong light irradiation, the crystal form impurities of the sugammadex sodium are not obviously changed, the light irradiation stability is good, and the dosage form prepared by utilizing the crystal form is beneficial to medicine storage and ensures the medicine effect; the results of the sodium amorphous sugammadex illumination test of comparative example 2 and comparative example 8 show that the impurities are significantly increased and the photostability is poor; the examination found that the examples 1 to 10 of the present invention have similar photostability test results.

Clarity and color test

The sugammadex sodium prepared in example 1 and comparative examples 1-11 were subjected to accelerated testing at 40 ℃ in the dark for 6 months, and samples were taken at the initial stage, 1 month, 3 months, and 6 months to determine clarity and color of the sample solutions. Referring to the registration label of sugammadex sodium injection (JX20140183), the clarity detection of a sample solution refers to "0902 of the general rules of the four departments of the chinese pharmacopoeia 2015 edition"; and (3) detecting the color of the sample solution, and measuring the absorbance (which should be less than 0.75) at the wavelength of 350nm by using ultra pure water as a blank solution and adopting an ultraviolet-visible spectrophotometry (0401 in the fourth part of the pharmacopoeia 2015). The results are shown in Table 6.

TABLE 6 results of accelerated test at 40 ℃ in the solid state of sugammadex sodium

After the sugammadex crystal form is inspected for 6 months, the clarity is less than 0.5 turbidity, the color detection absorbance is less than 0.75, and the sugammadex crystal form reaches the raw material drug standard of injection. Examination found that inventive examples 1-10 have similar clarity and color test results.