Method for preparing high-purity sugammadex sodium

Abstract

A method for preparing high-purity sugammadex sodium, which realizes the preparation by using inositol phosphate and derivatives thereof, includes: adding a specific type of protective agent to crude sugammadex sodium, and performing recrystallization under the protection of inert gas to obtain pure sugammadex sodium. The protective agent is selected from inositol phosphate and derivatives thereof, such as inositol hexaphosphate and salts or esters thereof; one or a mixture of two or more of partial degradation products of inositol hexaphosphate, such as inositol pentaphosphate, inositol tetraphosphate, inositol triphosphate, inositol diphosphate, inositol monophosphate, and salts or esters thereof, in any ratio. The method has the advantages of simple operation, high product purity, good safety and less allergic reaction, and the method is cost-effective and more suitable for industrial production.

Claims

1. A method for preparing high-purity sugammadex sodium, comprising: adding a protective agent to crude sugammadex sodium, and performing a recrystallization under a protection of inert gas to obtain pure sugammadex sodium, wherein the protective agent is selected from inositol phosphate expressed by the following general formula and derivatives thereof: ##STR00006##

2. The method for preparing the high-purity sugammadex sodium according to claim 1, wherein the inositol phosphate and the derivatives thereof are inositol hexaphosphate and salts or esters thereof; or one or a mixture of two or more of partial degradation products of the inositol hexaphosphate, comprising inositol pentaphosphate, inositol tetraphosphate, inositol triphosphate, inositol diphosphate, inositol monophosphate, and salts or esters thereof, in any ratio.

3. The method for preparing the high-purity sugammadex sodium according to claim 1, wherein a mass ratio of the protective agent to the crude sugammadex sodium is 0.001% or above.

4. The method for preparing the high-purity sugammadex sodium according to claim 3, wherein the mass ratio of the protective agent to the crude sugammadex sodium is 0.1%-1%.

5. The method for preparing the high-purity sugammadex sodium according to claim 1, wherein a solvent for the recrystallization is selected from a combination of water and a poor solvent for sugammadex sodium.

6. The method for preparing the high-purity sugammadex sodium according to claim 5, wherein the solvent for the recrystallization is selected from the combination of water and the poor solvent for sugammadex sodium, and the poor solvent for sugammadex sodium is one solvent or a mixture of more than one solvent selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and N,N-dimethylformamide.

7. The method for preparing the high-purity sugammadex sodium according to claim 6, wherein the method comprises the following specific process steps: dissolving the crude sugammadex sodium in water, adding the protective agent, increasing a temperature under the protection of the inert gas, then adding the poor solvent for sugammadex sodium, then performing stirring to decrease the temperature to −20° C. to 30° C., and performing a filtration to obtain the pure sugammadex sodium.

8. The method for preparing the high-purity sugammadex sodium according to claim 1, wherein the inert gas is selected from the group consisting of nitrogen, argon, helium, and carbon dioxide.

9. The method for preparing the high-purity sugammadex sodium according to claim 2, wherein a solvent for the recrystallization is selected from a combination of water and a poor solvent for sugammadex sodium, and the poor solvent for sugammadex sodium is one solvent or a mixture of more than one solvent selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and N,N-dimethylformamide.

10. The method for preparing the high-purity sugammadex sodium according to claim 3, wherein a solvent for the recrystallization is selected from a combination of water and a poor solvent for sugammadex sodium, and the poor solvent for sugammadex sodium is one solvent or a mixture of more than one solvent selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and N,N-dimethylformamide.

11. The method for preparing the high-purity sugammadex sodium according to claim 4, wherein a solvent for the recrystallization is selected from a combination of water and a poor solvent for sugammadex sodium, and the poor solvent for sugammadex sodium is one solvent or a mixture of more than one solvent selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and N,N-dimethylformamide.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates an HPLC pattern of crude sugammadex sodium according to the present invention.

(2) FIG. 2 illustrates an HPLC pattern of pure sugammadex sodium obtained by adopting a method according to the present invention.

(3) FIG. 3 illustrates an HPLC pattern of a commercially available sugammadex sodium injection.

DETAILED DESCRIPTION OF THE EMBODIMENTS

(4) More detailed descriptions of exemplary implementations of the method of the present invention are provided below. It should be correctly understood that the method in the embodiments of the present invention is merely used for further describing the present invention, but is not intended to limit the present invention, Therefore, all simple improvements made to the present invention based on the method of the present invention shall fall within the protection scope of the present invention.

(5) Unless otherwise stated in the present invention, the reagents, instruments and equipment used are all commercially available products.

(6) Crude sugammadex sodium is produced with reference to the method disclosed in U.S. Pat. No. 6,670,340.

Reference Embodiment

(7) Preparation of Crude Sugammadex Sodium

(8) 3-mercaptopropionic acid (12.2 mL, 140 mol) was put into a reaction flask, 450 mL of N,N-dimethylformamide was added, sodium hydride (12.3 g, 308 mol, 60%) was added in three batches under the protection of nitrogen at room temperature. Then stirring was performed for 30 minutes at room temperature, gamma-iodocyclodextrin (31.2 g, 14 mmol, dissolved in 450 mL of N,N-dimethylformamide) was dropped, and then the temperature was increased to 70° C. for reaction for 12 h. After the reaction was completed, cooling to room temperature was performed, 100 mL of water were added, stirring was performed, and reduced pressure distillation was performed until the amount of a remaining solvent was 400 mL, 2 L of ethanol was added, filtration was performed, a solid was collected, and vacuum drying was performed to obtain 45 g of off-white solid with a purity of 91.92%. Test results of crude sugammadex sodium were as shown in FIG. 1.

(9) Sterilization Color Investigation Test of Sugammadex Sodium Injection:

(10) 1 g of sugammadex sodium sample was taken, filled with nitrogen for protection, and then dissolved in 8 ml of water for injection, heating was performed for dissolution, the pH value was regulated, and water for injection was added to fix the volume to 10 ml. The above liquid was enabled to pass through a 0.22 m filter membrane and then was filled into a vial, a rubber stopper was added for capping, and the vial was placed in a sterilizer for sterilization at 121° C. for 30 min. Whether the color was changed was checked.

(11) Sugammadex Sodium Protein Residue Detection Test (Coomassie Brilliant Blue G-250 Method):

(12) 0, 6, 12, 24, 36, 48 and 60 μl of standard protein solution were respectively added to test tubes, 3 ml of Coomassie Brilliant Blue G-250 staining solution was added, uniform mixing was performed, heat preservation was performed at room temperature for 15 min, colorimetric determination was performed at wavelength of 595 nm. and a standard curve was drawn.

(13) 1 g of sugammadex sodium sample to be tested was taken and dissolved in 8 ml of water for injection, heating was performed for dissolution, the pH value was regulated, water for injection was added to fix the volume to 10 ml, the above liquid was enabled to pass through a 0.22 μm filter membrane, and then a sample solution to be tested was prepared. 60 μl of the solution was taken and the above determination was performed to obtain the concentration thereof.

Embodiment 1: Refining of Sugammadex Sodium

(14) 100.0 g of crude sugammadex sodium was taken and dissolved with 0.3 L of water until it was clear, 2.0 g of inositol hexaphosphate (50% aqueous solution) was added under stirring, the temperature was increased to 80° C. under the protection of nitrogen, 0.8 L of N,N-dimethylformamide was added to the solution, then stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 39.8 g of pure sugammadex sodium with a purity of 99.8%, as shown in FIG. 2.

(15) Of course, stirring may also be performed to decrease the temperature to −20° C. to 30° C.

Embodiment 2: Refining of Sugammadex Sodium

(16) 100 g of crude sugammadex sodium was taken and dissolved with 1 L of water until it was clear, 1 g of inositol diphosphate was added under stirring, the temperature was increased to 70° C. under the protection of nitrogen, and 6 L of acetonitrile was added to the solution. Then, stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 32.3 g of pure sugammadex sodium with a purity of 99.5%.

(17) The protective gas may also be selected from one of nitrogen, argon, helium, and carbon dioxide.

Embodiment 3: Refining of Sugammadex Sodium

(18) 100 g of crude sugammadex sodium was taken and dissolved with 0.5 L of water until it was clear, 3 g of inositol monophosphate was added under stirring, the temperature was increased to reflux under the protection of nitrogen, and 2 L of ethanol was added to the solution. Then, stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 29.9 g of pure sugammadex sodium with a purity of 99.6%.

Embodiment 4: Refining of Sugammadex Sodium

(19) 100 g of crude sugammadex sodium was taken and dissolved with 0.3 L of water until it was clear, 0.5 g of inositol triphosphate was added under stirring, the temperature was increased to 60° C. under the protection of nitrogen, and 2 L of acetone was added to the solution. Then, stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 32.1 g of pure sugammadex sodium with a purity of 99.7%.

Embodiment 5: Refining of Sugammadex Sodium

(20) 100 g of crude sugammadex sodium was taken and dissolved with 0.3 L of water until it was clear, 0.8 g of inositol tetraphosphate was added under stirring, the temperature was increased to 80° C. under the protection of nitrogen, and 1 L of N,N-dimethylformamide was added to the solution. Then, stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 37.2 g of pure sugammadex sodium with a purity of 99.7%.

Embodiment 6: Refining of Sugammadex Sodium

(21) 100 g of crude sugammadex sodium was taken and dissolved with 3 L of water until it was clear, 0.2 g of inositol pentaphosphate was added under stirring, the temperature was increased to 70° C. under the protection of nitrogen, and 8 L of acetonitrile was added to the solution. Then, stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 34.7 g of pure sugammadex sodium with a purity of 99.6%.

Embodiment 7: Refining of Sugammadex Sodium

(22) 100 g of crude sugammadex sodium was taken and dissolved with 0.3 L of water until it was clear, 0.8 g of CPPM (CAS No. 2271351-38-1, 1,2,3,4,5-Cyclohexanepentol,6-[(phosphonooxy)methyl]) was added under stirring, the temperature was increased to 80° C. under the protection of nitrogen, and 1 L of N,N-dimethylformamide was added to the solution. Then, stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 36.1 g of pure sugammadex sodium with a purity of 99.7%.

Embodiment 8: Refining of Sugammadex Sodium

(23) 100 g of crude sugammadex sodium was taken and dissolved with 0.3 L of water until it was clear, 0.9 g of L-CIPM (CAS No. 1313195-32-2, L-chiro-Inositol,2,3-dideoxy-3-[(phosphonooxy)methyl]) was added under stirring, the temperature was increased to 80° C. under the protection of nitrogen, and 1 L of N,N-dimethylformamide was added to the solution. Then, stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 37.5 g of pure sugammadex sodium with a purity of 99.6%.

Embodiment 9: Refining of Sugammadex Sodium

(24) 100 g of crude sugammadex sodium was taken and dissolved with 0.3 L of water until it was clear, 0.8 g of CDPM (CAS No. 127233-15-2, 1,2-Cyclohexanediol,4-[(phosphonooxy)methyl],bis(dihydrogen phosphate)) was added under stirring, the temperature was increased to 80° C. under the protection of nitrogen, and 1 L of N,N-dimethylformamide was added to the solution. Then, stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 38.3 g of pure sugammadex sodium with a purity of 99.8%.

Embodiment 10: Sterilization Color Investigation of Sugammadex Sodium Injection

(25) 1 g of the sugammadex sodium product prepared in Embodiments 1-9 was taken respectively, filled with nitrogen for protection, and then dissolved in 8 ml of water for injection, heating was performed for dissolution, the pH value was regulated, and water for injection was added to fix the volume to 10 ml. The above liquid was enabled to pass through a 0.22 m filter membrane and then was filled into a vial, and a rubber stopper was added for capping. The vial was placed in a sterilizer for sterilization at 121° C. for 30 min. It was detected that the sample was colorless and transparent. Compared with the sample before sterilization, the color was not darkened. Compared with the commercially available injections, the color was obviously lighter.

Embodiment 11

(26) 100.0 g of crude sugammadex sodium was taken, added with 0.1% cyclodextrin glucosyltransferase and dissolved with 0.3 L of water until it was clear, 2.0 g of inositol hexaphosphate (50% aqueous solution) was added under stirring, the temperature was increased to 80° C. under the protection of nitrogen, 0.8 L of N,N-dimethylformamide was added to the solution, then stirring was performed to decrease the temperature to room temperature, a large amount of white solid was precipitated, and suction filtration was performed to obtain 39.3 g of pure sugammadex sodium. The sample was detected by the above protein residue detection method (Coomassie Brilliant Blue G-250 Method), and no protein residue was detected.

Comparative Embodiment 1

(27) The purity of a sugammadex sodium injection produced by a commercial original research manufacturer was 98.56% (FIG. 3).

(28) Comparing Comparative Embodiment 1 with Embodiments 1-9, it can be seen that the pure sugammadex sodium obtained in the present invention has higher purity than the commercially available products, and the number of impurities is far less than that of the commercially available preparations.

Comparative Embodiment 2: Comparison of Ability of Protective Agent to Remove Residual Protein

(29) 100 g of crude sugammadex sodium was taken, added with 0.1% cyclodextrin glucosyltransferase and dissolved with 0.3 L of water, the temperature was increased to 80° C. under the protection of nitrogen, 0.8 L of N,N-dimethylformamide was added to the solution, then stirring was performed to decrease the temperature room temperature, a large amount of white solid was precipitated, and filtration was performed to obtain 37.1 g of pure sugammadex sodium. The sample was detected by the above protein residue detection method (Coomassie Brilliant Blue G-250 Method), and the content of protein was 0.06 μg/ml.

(30) The technical means disclosed in the solutions of the present invention are not limited to the technical means disclosed in the foregoing implementations, and also includes technical solutions including any combination of the foregoing technical features. It should be noted that a person of ordinary skill in the art may make several improvements and modifications without departing from the principle of the present invention, and such modifications and modifications shall fall within the protection scope of the present invention.