WO2020077927A1

WO2020077927A1 - Post-processing method for gonadotropin-releasing hormone antagonist

Info

Publication number: WO2020077927A1
Application number: PCT/CN2019/075757
Authority: WO
Inventors: 付玉清; 张利香; 李世东; 舒遂智; 王宏欣
Original assignee: 深圳市健元医药科技有限公司
Priority date: 2018-10-14
Filing date: 2019-02-21
Publication date: 2020-04-23
Also published as: CN111036078B; CN111036078A

Abstract

A post-processing method for a GnRH antagonist, comprising the following steps: (1) preparing before nanofiltration, installing a nanofiltration membrane, using purified water to clean a nanofiltration machine, and preparing nanofiltration; (2) starting nanofiltration, controlling the temperature of a sample solution, and adding acetic acid during the nanofiltration process to control the acetic acid content of the sample solution; (3) ending nanofiltration, discharging the nanofiltered solution, and diluting the nanofiltered solution using an acetic acid aqueous solution to control the concentration of the sample; (4) upper freeze-drying, pouring the nanofiltered and concentrated solution into a freeze-drying dish to control the thickness of the solution, and then pre-freezing to control the pre-freezing temperature; (5) sublimation drying; (6) desorption drying; (7) lower freeze-drying, and subpackaging and putting the sample into storage.

Description

Post-processing method of gonadotropin-releasing hormone antagonist

Technical field

The invention relates to a post-treatment method of GnRH antagonist. It belongs to the field of biomedical technology.

Background technique

Gonadotropin-releasing hormone (GnRH) antagonists are synthetic gonadotropin-releasing hormone analogs that inhibit the proliferation and metastasis of prostate cancer by inhibiting testosterone. GnRH antagonists mainly include abarelix, cetrorelix, Nal-Glu, ganirelix and degarelix. The post-processing method involved in the present invention mainly refers to the concentration method and lyophilization process of the purified sample solution. The post-processing method is a very important link in the process of preparing the GnRH antagonist API and directly affects the quality of the active ingredient of the drug.

In the prior art, the patent CN102428097 uses the method of column concentration + vacuum rotary evaporation to condense the sample of Digarek after purification, and then freeze-dry. The patent CN201380028448 proposes three concentration methods, which are through vacuum rotary evaporation. Through column concentration or lyophilization to achieve the purpose of concentrating the sample after purification, and finally using lyophilization to obtain qualified pharmaceutical active ingredients.

Although the patent CN201380028448 mentions three concentration methods, when using vacuum rotary evaporation to concentrate the sample, the concentration speed is slow, the efficiency is low, the concentration time is long, and the relatively high rotary evaporation temperature may cause the degradation of the sample. Not suitable for large-scale industrial production; the use of freeze-drying to concentrate samples is not only time-consuming, but also has high requirements for the performance of the freeze dryer, and is also not suitable for industrial production; although the method of column concentration is to a certain extent It can achieve the purpose of concentration, but the shortcomings are also obvious. The use of organic solvents in the process of column concentration will cause harm to human health and the natural environment, and there must be some loss of samples during the process of column concentration. The treatment of the liquid also directly increases the cost of concentration. The method of column concentration + vacuum rotary evaporation mentioned in the patent CN102428097 not only has complicated steps, but also increases the use of organic solvents, and the concentration cost is higher. In particular, due to the high viscosity of GnRH antagonists, samples of the above-mentioned post-treatment methods will undergo self-polymerization during use. The self-polymerization in the synthesis will introduce new impurities, affecting the purity of the drug and increasing the risk of patients. Although it can be depolymerized by adding acetic acid after self-polymerization in the synthesis, whether it can be completely depolymerized and whether the sample is stable is also an important issue to be considered.

Combining the above problems, the present invention creatively uses nanofiltration technology to concentrate the sample after purification of the GnRH antagonist, while adding an appropriate amount of acetic acid during the nanofiltration process to prevent the sample from undergoing self-polymerization reaction, thereby achieving the purpose of concentration, and according to freeze-drying It is required to nanofilter the sample to the required concentration. The use of organic solvents such as ethanol and acetonitrile is not involved in the nanofiltration process. The cost is lower, the yield is higher, the sample is more stable, and it is more suitable for large-scale industrial production.

Summary of the invention

The object of the present invention is to provide a method for concentrating samples after purification of GnRH antagonists using nanofiltration technology, so as to overcome the above-mentioned deficiencies in the prior art.

The post-processing method of the GnRH antagonist provided by the present invention includes the following steps:

(1) Prepare before nanofiltration, install nanofiltration membrane, wash the nanofiltration machine with purified water, prepare nanofiltration;

(2) Start nanofiltration, control the temperature of the sample solution, and add an appropriate amount of acetic acid during the nanofiltration process to control the acetic acid content of the sample solution;

(3) At the end of nanofiltration, discharge all sample nanofiltration solutions, dilute the nanofiltration solution with acetic acid aqueous solution, and control the sample concentration;

(4) Upper lyophilization, pour the sample solution after nanofiltration concentration into the lyophilization tray, control the thickness of the solution, then pre-freeze, and control the pre-freezing temperature;

(5) Sublimation and drying;

(6) Parsing and drying;

(7) Lyophilize and load the sample into the library.

In some embodiments, the nanofiltration membrane in step (1) above is characterized by a pore size of 1-20 nm and a molecular weight cut-off of 200-1000 Daltons.

In some embodiments, the temperature of the sample solution in the above step (2) is: 0 ° C to 35 ° C.

In some embodiments, the acetic acid content of the sample solution in the above step (2) is: 0% -50%.

In some embodiments, the sample concentration in the above step (3) is: 5 g / L to 75 g / L.

In some embodiments, the thickness of the solution in the above step (4) is: 0.5-2.5 cm.

In some embodiments, the pre-freezing temperature in the above step (4) is: -65 ° C to -25 ° C.

In some embodiments, the above step (5) is characterized in that the sublimation drying temperature is -15 ° C to 15 ° C, and the sublimation drying time is 10h to 35h.

In some embodiments, the above step (6) is characterized in that the analytical drying temperature is 15 ° C to 40 ° C, and the analytical drying time is 5h to 30h.

In some embodiments, the above step (7) is characterized by controlling the ambient temperature to 15 ° C to 35 ° C and the ambient humidity to be 0% to 60%.

In the method described above, the nanofiltration membrane is selected from polyamide nanofiltration membrane, polyethersulfone nanofiltration membrane, cellulose acetate nanofiltration membrane, polyvinyl alcohol nanofiltration membrane, and polypiperazine nanofiltration membrane.

In the method described above, the GnRH antagonist is selected from the group consisting of degarelix, cetrorelix, ganirelix, abarelix, and Nal-Glu. .

Compared with the prior art, the present invention has the following beneficial effects:

Compared with vacuum rotary evaporation concentration, the nanofiltration process used in this patent has shorter concentration time, higher efficiency and higher productivity. The relatively low concentration temperature makes the sample more stable and more suitable for large-scale industrial production; Compared with the vacuum rotary evaporation concentration process, the nanofiltration process used in this patent avoids the use of organic solvents such as acetonitrile, the steps are simpler, the cost is lower, the yield can reach more than 93%, and the sample concentration that can be achieved after concentration is higher . More importantly, the addition of acetic acid during the nanofiltration process can effectively prevent the sample from undergoing self-polymerization and make the sample more stable. Compared with the prior art, the nanofiltration process combined with the subsequent freeze-drying process can not only obtain samples with controllable moisture, acetic acid and optical density, but also have lower cost, more stable samples, and are more suitable for large-scale industrial production.

detailed description

The application of the technical solution in the present invention will be further described in detail below in conjunction with specific embodiments, so that those skilled in the art can further understand the present invention. The embodiments should not be limited to the scope of protection.

Example 1

(1) Prepare before nanofiltration, wash the nanofiltration machine with purified water, the nanofiltration membrane material is polyamide nanofiltration membrane, prepare nanofiltration;

(2) Take 20L of Digaric sample solution, add 10.7L of acetic acid to make the acetic acid content in the sample solution 35%, and start nanofiltration;

(3) After the nanofiltration is completed, the nano filtrate is discharged, the nano filter is washed with a 35% acetic acid aqueous solution, the nano filtrate and the cleaning solution are mixed, and then diluted with a 35% acetic acid aqueous solution, the diluted sample concentration is 15g / L, and the acetic acid content is 35 %, Nanofiltration time 4h;

(4) Pour the diluted sample into the lyophilization tray, the thickness of the sample solution is 0.65cm, and then pre-freeze, the pre-freezing temperature is -35 ℃;

(5) Sublimation drying, sublimation drying temperature is -10 ℃, sublimation drying time is 15h;

(6) Analysis drying, analysis drying temperature 20 ℃, analysis drying time 10h;

(7) Freeze-dried and stored separately in a warehouse with an ambient temperature of 15 ° C and an ambient humidity of 60%.

Samples were collected after lyophilization, of which water content was 6.6%, acetic acid was 7.8%, optical density was 0.02, and concentrated yield was 94.26%.

Example 2

(1) Prepare before nanofiltration, wash the nanofiltration machine with purified water, the material of the nanofiltration membrane is polyethersulfone nanofiltration membrane, prepare nanofiltration;

(2) 30L of degarelix sample solution, add 3.3L of acetic acid to make the acetic acid content in the sample solution 10%, and start nanofiltration;

(3) After 6 hours of nanofiltration, the nanofiltrate is discharged, and the nanofiltration machine is washed with 10% acetic acid aqueous solution, the nanofiltrate and the cleaning solution are mixed, and then diluted with a 10% acetic acid aqueous solution. %

(5) Sublimation drying, sublimation drying temperature is 0 ℃, sublimation drying time is 15h;

(6) Analysis drying, analysis drying temperature 30 ℃, analysis drying time 10h;

Samples were collected after lyophilization, of which water content was 8.6%, acetic acid was 8.8%, optical density was 0.02, and concentrated yield was 94.56%.

Example 3

(2) The volume of the ganerlix sample solution is 30 L, and 3.3 L of acetic acid is added to make the acetic acid content in the sample solution 10%, and nanofiltration is started. When the volume of the sample solution is nanofiltration to 15L, add 3L of acetic acid to control the content of acetic acid in the sample solution to 25%, and then continue the nanofiltration;

(3) Nanofiltration is discharged after 6.5h of nanofiltration, the nanofiltration machine is washed with 25% acetic acid aqueous solution, the nanofiltrate and the cleaning solution are mixed, and then diluted with 25% acetic acid aqueous solution, the sample concentration after dilution is 26g / L, and the acetic acid content is 25%.

(4) Pour the diluted sample into the lyophilization tray, the thickness of the sample solution is 0.85cm, and then pre-freeze, the pre-freezing temperature is -40 ℃;

(5) Sublimation drying, sublimation drying temperature is -5 ℃, sublimation drying time is 20h;

(6) Analysis drying, analysis drying temperature 29 ℃, analysis drying time 10h;

(7) Freeze-dried and stored separately in a warehouse with an ambient temperature of 25 ° C and an ambient humidity of 55%.

Samples were collected after freeze-drying, of which water content was 8.6%, acetic acid was 8.3%, optical density was 0.02, and concentrated yield was 93.58%.

Example 4

(2) Take 30L of Abarelix sample solution, add 1.5L of acetic acid to make the acetic acid content in the sample solution 5%, and start nanofiltration. When the volume of the sample solution is 15L, add 1.8L of acetic acid to make acetic acid in the sample solution The content is 15%, continue nanofiltration;

(3) After 7h of nanofiltration, the nano filtrate is discharged. The nano filter is washed with 15% acetic acid aqueous solution, the nano filtrate and the cleaning solution are mixed, and then diluted with a 15% acetic acid aqueous solution. %

(4) Pour the diluted sample into the lyophilization tray, the thickness of the sample solution is 0.85cm, and then pre-freeze, the pre-freezing temperature is -35 ℃;

(5) Sublimation drying, sublimation drying temperature is -20 ℃, sublimation drying time is 15h;

(6) Analysis drying, analysis drying temperature 25 ℃, analysis drying time 10h;

(7) Freeze-dried and stored separately in a warehouse with an ambient temperature of 15 ° C and an ambient humidity of 39%.

After lyophilization, the samples were analyzed as follows, including moisture 7.6%, acetic acid 9.3%, optical density 0.02, and concentrated yield 97.02%.

Example 5

(1) Prepare before nanofiltration, wash the nanofiltration machine with purified water, the material of the nanofiltration membrane is cellulose acetate nanofiltration membrane, prepare nanofiltration;

(2) Digaric sample solution 30L, add 1.5L acetic acid to make the acetic acid content in the sample solution 5%, start nanofiltration, when nanofiltration is to the sample solution volume is 15L, add 1.8L acetic acid to make the acetic acid content in the sample solution 15%, continue the nanofiltration, when the nanofiltration reaches the sample solution volume of 7.5L, add 1.6L of acetic acid to make the acetic acid content in the sample solution 30%, continue the nanofiltration;

(3) The nanofiltrate is discharged after 7h of nanofiltration, the nanofiltration machine is washed with 30% acetic acid aqueous solution, the nanofiltrate and the cleaning solution are mixed, the sample concentration after mixing is 30g / L, and the acetic acid content is 30%;

(4) Pour the diluted sample into the lyophilization tray, the thickness of the sample solution is 1.0cm, and then pre-freeze, the pre-freezing temperature is -45 ℃;

(6) Analysis drying, analysis drying temperature 27 ℃, analysis drying time 15h;

(7) Freeze-dried and stored separately in a warehouse with an ambient temperature of 23 ° C and an ambient humidity of 44%.

After lyophilization, the sample analysis is as follows, including 7.1% moisture, 8.6% acetic acid, 0.02 optical density, and 97.19% concentrated yield.

Example 6

(2) 30L of degarelix sample solution, add 1.5L of acetic acid to make the acetic acid content in the sample solution 5%, and start nanofiltration. When the volume of the sample solution is nanofiltration to 15L, add 1.8L of acetic acid to make the content of acetic acid in the sample solution 15%, and continue nanofiltration; When the volume of the sample solution is nanofiltration to 7.5L, add 3.2L of acetic acid to make the content of acetic acid in the sample solution 40%, and continue nanofiltration;

(3) After the nanofiltration is completed, the nanofiltrate is discharged, the nanofiltration machine is washed with a 40% acetic acid aqueous solution, and the nanofiltrate and the cleaning solution are mixed. After mixing, the sample concentration is 40 g / L and the acetic acid content is 40%;

(4) Pour the diluted sample into the lyophilization tray, the thickness of the sample solution is 1.8cm, and then pre-freeze, the pre-freezing temperature is -60 ℃;

(5) Sublimation drying, sublimation drying temperature is -13 ℃, sublimation drying time is 35h;

(6) Analysis drying, analysis drying temperature 35 ℃, analysis drying time 15h;

(7) Freeze-dried and stored separately in a warehouse with an ambient temperature of 35 ° C and an ambient humidity of 35%.

After lyophilization, the samples were analyzed as follows. Among them, the water content was 12.6%, acetic acid 16.3%, optical density 0.02, and concentrated yield 95.33%.

Example 7

(1) Preparation before nanofiltration, add water to the purified Ganirelix sample solution, the material of the nanofiltration membrane is a polyvinyl alcohol nanofiltration membrane, and the content of acetonitrile in the solution is controlled to 2%;

(2) 40L of Ganirelix sample solution, add 4.5L of acetic acid to make the acetic acid content in the sample solution 10%, and start nanofiltration;

(4) Pour the diluted sample into the lyophilization dish, the thickness of the sample solution is 1.25cm, and then pre-freeze, the pre-freezing temperature is -40 ℃;

(5) Sublimation drying, sublimation drying temperature is -5 ℃, sublimation drying time is 15h;

(6) Analysis drying, analysis drying temperature 28 ℃, analysis drying time 15h;

(7) Freeze-dried and stored separately in a warehouse with an ambient temperature of 26 ° C and an ambient humidity of 51%.

After lyophilization, the samples were analyzed, including 7.7% moisture, 7.9% acetic acid, 0.06 optical density, and 98.02% concentrated yield.

Example 8

(2) 30L of Garnirec sample solution, adding 1.5L of acetic acid to make the acetic acid content in the sample solution 5%, start nanofiltration. When the volume of the sample solution is 15L, add 1.8L of acetic acid to make the acetic acid content in the sample solution 15%, continue nanofiltration;

(3) After 7h of nanofiltration, the nano filtrate is discharged. The nano filter is washed with 15% acetic acid aqueous solution, the nano filtrate and the cleaning solution are mixed, and then diluted with a 15% acetic acid aqueous solution. The sample concentration after dilution is 10g / L and the acetic acid content is 15 %

(4) Pour the diluted sample into the lyophilization tray, the thickness of the sample solution is 1.5cm, and then pre-freeze, the pre-freezing temperature is -28 ℃;

(5) Sublimation drying, sublimation drying temperature is -15 ℃, sublimation drying time is 20h;

(6) Analysis drying, analysis drying temperature 15 ℃, analysis drying time 12h;

(7) Freeze-dried and stored separately in a warehouse with an ambient temperature of 20 ° C and an ambient humidity of 42%.

Samples were collected after lyophilization, of which water content was 9.6%, acetic acid was 7.3%, optical density was 0.09, and concentrated yield was 94.39%.

Example 9

(2) 40L of cetrorelix sample solution, add 21.5L of acetic acid to make the acetic acid content in the sample solution 35%, and start nanofiltration;

(4) Pour the diluted sample into the lyophilization tray, the thickness of the sample solution is 0.80cm, and then pre-freeze, the pre-freezing temperature is -55 ℃;

(5) Sublimation drying, sublimation drying temperature is -20 ℃, sublimation drying time is 25h;

(6) Analysis drying, analysis drying temperature 30 ℃, analysis drying time 20h;

(7) Freeze-dried and stored separately in a warehouse with an ambient temperature of 20 ° C and an ambient humidity of 45%.

Samples were collected after freeze-drying, in which the water content was 5.6%, acetic acid 10.8%, optical density 0.12, and concentrated yield 95.89%.

Example 10

(2) 40L of cetrorelix sample solution, add 2.1L of acetic acid to make the acetic acid content in the sample solution 5%, start nanofiltration. When the volume of the sample solution is 20L, add 2.4L of acetic acid to make the acetic acid content in the sample solution 15%, continue the nanofiltration. When the volume of the sample solution is 10L, add 2.2L of acetic acid to make the content of acetic acid in the sample solution 30%, and continue the nanofiltration;

(3) Nanofiltration is discharged after 7.5h of nanofiltration, the nanofiltration machine is washed with 30% acetic acid aqueous solution, and the nanofiltrate and the cleaning solution are mixed. After mixing, the sample concentration is 30g / L and the acetic acid content is 30%;

(4) Pour the diluted sample into the lyophilization dish, the thickness of the sample solution is 1.15cm, and then pre-freeze, the pre-freezing temperature is -43 ℃;

(5) Sublimation drying, sublimation drying temperature is -15 ℃, sublimation drying time is 25h;

(7) Freeze-dried and stored separately in a warehouse with an ambient temperature of 35 ° C and an ambient humidity of 55%.

Samples were collected after lyophilization, in which the moisture was 5.1%, acetic acid was 6.6%, the optical density was 0.06, and the concentrated yield was 94.19%.

Comparative Example 1

Take a total of 16L of purified degarelix sample solution, containing 48 g of degarelix, perform vacuum rotary evaporation concentration, and remove the organic solvent in the sample solution by vacuum rotary evaporation. This step is preferably a BUCHI rotary evaporator. The concentration process takes 9h After concentration, the sample is depolymerized by adding appropriate amount of acetic acid, and then filtered and lyophilized under the following conditions:

a. Vacuum concentration temperature: 35 ℃;

b. Vacuum concentration time: 11h;

c. The acetic acid concentration in the sample solution is 24%;

d. The concentration of Digaric sample before lyophilization is 18g / L;

After concentration, the sample is subjected to a freeze-drying step, in which the thickness of the freeze-dried solution is 0.75 cm, the sublimation temperature is -5 ° C, and the analytical drying temperature is 25 ° C. The concentrated yield was 93.5%. After freeze-drying, the sample was detected by the above method, in which the water content was 8.5%, acetic acid 10.5%, and optical density 0.12.

Comparative Example 2

Take 8.0L of purified degarelix sample, dilute with water and use it for reversed-phase chromatography column, then elute degarelix sample with 15% acetic acid aqueous solution: acetonitrile = 40:60 solution, collect qualified fractions, The fraction was concentrated by vacuum rotary evaporation to remove the acetonitrile inside, filtered and lyophilized. The thickness of the lyophilized solution was 0.75 cm, the sublimation temperature was -8 ° C, and the analytical drying temperature was 23 ° C. After lyophilization, the sample was tested by the method in Example 1, wherein the concentrated yield was calibrated to 85.25%, moisture 9.5%, acetic acid 12.5%, and optical density 0.06.

Comparative Example 3

Purified Ganarik sample 4.0L, diluted with water and used in reversed-phase chromatography column, and then eluted Ganarik sample with 10% acetic acid aqueous solution: ethanol = 50: 50 solution, collected qualified fractions, and then collected The fraction was concentrated by vacuum rotary evaporation to remove the ethanol inside, filtered and lyophilized. The thickness of the lyophilized solution was 0.55 cm, the sublimation temperature was -12 ° C, and the analytical drying temperature was 20 ° C. After lyophilization, the sample was tested using the method in Example 1, wherein the concentrated yield was 81.82%, moisture 6.5%, acetic acid 7.5%, and optical density 0.18.

Comparative Example 4

Take 30L of purified abaric sample solution, containing 68g of abaric, and perform vacuum rotary evaporation to condense the organic solvent in the sample solution by vacuum rotary evaporation. In this step, the BUCHI rotary evaporator is preferred. After concentration, the sample is depolymerized by adding appropriate amount of acetic acid, and then filtered and lyophilized under the following conditions:

a. Vacuum concentration temperature: 28 ℃;

b. Vacuum concentration time: 15h;

c. The acetic acid concentration in the sample solution is 12%;

d. The concentration of Abarek sample before lyophilization is 35g / L;

After concentration, the sample is subjected to a lyophilization step, in which the thickness of the lyophilized solution is 0.75 cm, the sublimation temperature is -15 ° C, and the analytical drying temperature is 27 ° C. The concentrated yield was 92.9%, of which moisture was 7.5%, acetic acid was 8.7%, and optical density was 0.10.

It can be seen from the concentration yield and optical density results of the examples and comparative examples that the yield can reach more than 93% and the concentration time of the nanofiltration process is shorter compared with the vacuum rotary evaporation concentration and the column concentration + vacuum rotary evaporation concentration process. Higher efficiency and productivity. Compared with the column concentration + vacuum rotary evaporation concentration process, the nanofiltration process used in this patent avoids the use of organic solvents such as acetonitrile, the steps are simpler and the cost is lower. The nanofiltration process combined with the subsequent freeze-drying process can not only obtain samples with controllable moisture, acetic acid and optical density, the samples are more stable and more suitable for large-scale industrial production.

The above is only a preferred embodiment of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principles of the present invention, several improvements and retouches can be made. These improvements and retouches also It should be regarded as the protection scope of the present invention.

Claims

A post-processing method for GnRH antagonists, characterized in that it includes the following steps:

(1) Prepare before nanofiltration, install nanofiltration membrane, wash the nanofiltration machine with purified water, prepare nanofiltration;

(2) Start nanofiltration, control the temperature of the sample solution, and add acetic acid during the nanofiltration process to control the acetic acid content of the sample solution;

(3) At the end of nanofiltration, discharge the nanofiltration solution, dilute the nanofiltration solution with acetic acid aqueous solution, and control the sample concentration;

(4) Upper freeze-drying, pour the solution after nanofiltration concentration into the freeze-drying tray, control the thickness of the solution, then pre-freeze, and control the pre-freezing temperature;

(5) Sublimation and drying;

(6) Parsing and drying;

(7) Lyophilize and load the sample into the library.
The method of step (2) according to claim 1, wherein the temperature of the sample solution is: 0 ° C to 35 ° C.
The method of step (2) according to claim 1, wherein the acetic acid content of the sample solution is: 0% to 50%.
The method of step (3) according to claim 1, wherein the sample concentration is: 5 g / L to 75 g / L.
The method of step (4) according to claim 1, wherein the thickness of the solution is: 0.5 to 2.5 cm.
The method of step (4) according to claim 1, wherein the pre-freezing temperature is: -65 ° C to -25 ° C.
The method of step (5) according to claim 1, wherein the sublimation drying temperature is -15 ° C to 15 ° C, and the sublimation drying time is 10h to 35h.
The method of step (6) according to claim 1, wherein the analytical drying temperature is 15 ° C to 40 ° C, and the analytical drying time is 5h to 30h.
The method of step (7) according to claim 1, wherein the ambient temperature is controlled to be 15 ° C to 35 ° C, and the ambient humidity is 0% to 60%.
A post-treatment method for GnRH antagonists as claimed in claim 1, characterized in that the nanofiltration membrane used for nanofiltration is selected from polyamide nanofiltration membrane, polyethersulfone nanofiltration membrane, cellulose acetate nanofiltration membrane, poly Vinyl alcohol nanofiltration membrane, polypiperazine nanofiltration membrane.
The method of any one of the preceding claims, wherein the GnRH antagonist is selected from the group consisting of degarelix, cetrorelix, ganirelix, abarelix, and Nal-Glu.