CN114276414A - Method for purifying cetrorelix - Google Patents
Method for purifying cetrorelix Download PDFInfo
- Publication number
- CN114276414A CN114276414A CN202111661596.6A CN202111661596A CN114276414A CN 114276414 A CN114276414 A CN 114276414A CN 202111661596 A CN202111661596 A CN 202111661596A CN 114276414 A CN114276414 A CN 114276414A
- Authority
- CN
- China
- Prior art keywords
- cetrorelix
- mobile phase
- acetic acid
- sample
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Peptides Or Proteins (AREA)
Abstract
The invention relates to a purification method for solid-phase synthesis of cetrorelix, belonging to the technical field of polypeptide synthesis. Mainly solves the technical problems of low purity and low yield of the cetrorelix obtained by separation in the prior art and easy separation of a sample in the purification process. According to the method, crude peptide obtained by solid phase synthesis is dissolved in 30% acetic acid aqueous solution, then octadecylsilane chemically bonded silica filler is used as a stationary phase, two purification steps of different systems are combined, and acetic acid aqueous solution with higher concentration is introduced in each step, so that the problem that a sample is easy to separate out in the purification process is solved, and the cetrorelix bulk drug with high purity, high quality and high yield is obtained.
Description
Technical Field
The invention relates to the field of polypeptide purification, in particular to a method for purifying cetrorelix.
Background
The name of Chinese: cetrorelix; the name of English: cetrorelix acetate; cetrorelix is an LHRH antagonist developed by Asta Medica, Germany, and can control the stimulation of ovary, prevent premature follicle from discharging early, and help conception. A large number of researches show that cetrorelix has better curative effect on diseases such as ovarian cancer, prostatic cancer, uterine fibrocarcinoma, endometriosis and the like, and has prevention and improvement effects on benign prostatic hypertrophy and ovarian hyperstimulation syndrome.
The cetrorelix is synthesized by a solid phase, a plurality of impurities which influence the purity and yield of a sample can be generated in a synthesized substance, the cetrorelix sample obtained by separation by the existing purification technology has low purity and yield, and meanwhile, the cetrorelix contains a plurality of amino acids with strong hydrophobicity, so the cetrorelix has poor solubility and is easy to be separated out in the production process, thereby influencing the yield and the quality.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a method for purifying cetrorelix, which improves the purity and yield of the cetrorelix by two times of HPLC purification.
In order to achieve the above object, the present invention adopts the following technical solutions:
the invention relates to a method for purifying cetrorelix, which comprises the following steps:
step one, preprocessing a crude product of cetrorelix to obtain a crude peptide solution of cetrorelix;
step two, using octadecylsilane chemically bonded silica filler as a stationary phase, trifluoroacetic acid as a mobile phase A and acetonitrile as a mobile phase B, and carrying out first HPLC purification to remove impurities before the cetrorelix peak;
adding an equal volume of acetic acid aqueous solution to prevent the sample from being separated out, so as to obtain a cetrorelix first-step sample solution;
step four, taking octadecylsilane chemically bonded silica filler as a stationary phase and acetic acid as a mobile phase A; performing HPLC purification for the second time by taking acetonitrile as a mobile phase B to remove impurities after the cetrorelix peak so as to obtain a cetrorelix second-step sample solution;
step five, using octadecylsilane chemically bonded silica filler as a stationary phase and ammonium acetate as a mobile phase A1Acetic acid aqueous solution as mobile phase A2(ii) a Taking acetonitrile as a mobile phase B, carrying out salt transfer, and taking cetrorelix salt transfer as an acetate to obtain a cetrorelix salt transfer sample solution;
and step six, adding an equal volume of acetic acid aqueous solution into the salt conversion sample solution for concentration to obtain a salt conversion concentrated solution.
And step seven, pouring the salt-converted concentrated solution into a freeze-drying tray, and putting the freeze-drying tray into a freeze dryer for freeze-drying.
The preferable technical scheme of the method for purifying cetrorelix is as follows:
in the first step, a crude product of cetrorelix is pretreated to obtain a crude peptide aqueous solution of cetrorelix; the pretreatment step comprises the following steps:
1) dissolving the crude product of cetrorelix in 30% acetic acid aqueous solution to obtain a crude peptide solution of cetrorelix;
2) filtering the crude cetrorelix peptide solution by using a filter membrane to remove insoluble particles, and collecting the filtrate for later use.
In the second step, octadecylsilane chemically bonded silica filler is used as a stationary phase, 0.1% trifluoroacetic acid is used as a mobile phase A, acetonitrile is used as a mobile phase B, the detection wavelength is 260nm, the first HPLC linear gradient elution is carried out, and fractions containing the cetrorelix sample are collected; the granularity of the stationary phase is 8 mu m, and the preparation method of the 0.1% trifluoroacetic acid comprises the following steps: 1000ml of water was taken and 1ml of trifluoroacetic acid was added.
In the third step, an equal volume of 10% acetic acid aqueous solution was added to the sample obtained in the first purification step to prevent precipitation of the sample.
In the fourth step, octadecylsilane chemically bonded silica filler is used as a stationary phase, 10% acetic acid aqueous solution is used as a mobile phase A, acetonitrile is used as a mobile phase B, the detection wavelength is 260nm, and the second HPLC gradient elution is carried out to collect fraction containing a cetrorelix sample; the preparation method of the 10% acetic acid aqueous solution comprises the following steps: adding acetic acid 100ml into 900ml water.
In the fifth step, octadecylsilane chemically bonded silica filler is used as a stationary phase, and 50mmol/L ammonium acetate is used as a mobile phase A 110% acetic acid aqueous solution as mobile phase A2(ii) a And (3) carrying out salt transfer by taking acetonitrile as a mobile phase B, and taking cetrorelix salt transfer as acetate to obtain a cetrorelix salt transfer sample solution.
And step six, adding an equal volume of 20% acetic acid aqueous solution into the salt transfer sample solution for concentration, wherein the operation can ensure that the sample cannot be separated out in the concentration process, so that a clear salt transfer concentrated solution is obtained.
And step seven, pouring the salt-converted concentrated solution into a freeze-drying tray, and putting the freeze-drying tray into a freeze dryer for freeze-drying. The temperature of the freeze-drying curve in the sublimation drying stage is set to be less than the eutectic point of the salt-transferring concentrated solution.
Compared with the prior art, the invention has the advantages that:
1. in the invention, the acetic acid aqueous solution (higher concentration can be controlled) is added in each production step, so that the precipitation of the sample in the production process can be effectively prevented;
2. octadecylsilane chemically bonded silica filler is combined with 0.1% trifluoroacetic acid of a mobile phase, so that most of impurities before peaks of cetrorelix can be removed; the purity of the collected sample reaches 99.0%.
3. Gradient elution is carried out by using octadecylsilane chemically bonded silica filler as a fixed phase and combining with 10% acetic acid aqueous solution under chromatographic conditions, so that impurities after cetrorelix peak can be removed, and the yield of a sample with the purity of over 99.8% is over 70%; the purity and the yield of the finished products of the cetrorelix are improved.
Drawings
FIG. 1 is an HPLC chart of crude cetrorelix in example 1;
FIG. 2 is an HPLC plot of cetrorelix after the first HPLC purification of example 1;
FIG. 3 is an HPLC plot of cetrorelix after a second HPLC purification of example 1;
figure 4 is an HPLC plot of cetrorelix after salt transfer of example 1.
Detailed Description
The invention is described in detail below with reference to the figures and the embodiments.
Example 1:
the HPLC chart of the crude cetrorelix product is shown in figure 1.
Sample treatment: a sample containing 20g of crude cetrorelix peptide (crude peptide: 30 g) was dissolved in a 30% aqueous acetic acid solution, and after complete dissolution, it was filtered through a 0.22 μm filter. And collecting the filtered crude cetrorelix peptide solution for later use.
First step HPLC purification, whose HPLC scheme is referenced to fig. 2.
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (50mm × 250 mm); using 0.1% trifluoroacetic acid (1000 ml of water, 1ml of trifluoroacetic acid and uniform mixing) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate was 50mL per minute; the detection wavelength is 260 nm; the amount of the sample loaded on a single needle was 3 g. Elution is performed with the following table elution gradient.
Collecting the fraction of the cetrorelix sample with the purity of more than 99.0 percent and the precursor impurity of less than 0.1 percent, and adding an equal volume of 10 percent acetic acid aqueous solution to obtain a cetrorelix first-step sample solution.
Second step HPLC purification, the HPLC chart is referred to FIG. 3.
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (50mm × 250 mm); taking 10% acetic acid solution (900 ml water added acetic acid 100ml) as mobile phase A; acetonitrile is used as a mobile phase B; the flow rate was 50mL per minute; the detection wavelength is 260 nm; the amount of the sample was 2 g. Elution is performed with the following table elution gradient.
Fractions of the cetrorelix sample with a purity of greater than 99.8% and less than 0.1% single impurity were collected.
The HPLC chart is shown in FIG. 4.
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (50mm × 250 mm); taking 50mmol/L ammonium acetate as mobile phase A 110% acetic acid aqueous solution as mobile phase A2(ii) a Acetonitrile is used as a mobile phase B; the flow rate was 50mL per minute; the detection wavelength is 260 nm; the amount of the sample was 5 g. Elution is performed with the following table elution gradient.
Fractions of the cetrorelix sample with a purity of greater than 99.8% and less than 0.1% single impurity were collected. The solution contains 14.0g of cetrorelix quantitatively by a reference substance, and the purification yield reaches 70.0 percent.
Concentrated freeze-drying
Adding the salt-transfer peak top solution into an isovolumetric 20% acetic acid aqueous solution, concentrating to 25 +/-5 g/L with a rotary evaporator water bath temperature of 30-35 ℃ and a vacuum degree of-0.09 Mpa, and freeze-drying according to the following freeze-drying curve:
example 2:
taking cetrorelix crude product
Sample treatment: a sample containing 70g of crude cetrorelix peptide (crude peptide: 100 g) was dissolved in a 30% aqueous acetic acid solution, and after complete dissolution, it was filtered through a 0.22 μm filter. And collecting the filtered crude cetrorelix peptide solution for later use.
First step HPLC purification
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (100mm × 250 mm); using 0.1% trifluoroacetic acid (1000 ml of water, 1ml of trifluoroacetic acid and uniform mixing) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 200mL per minute; the detection wavelength is 260 nm; the loading of a single needle was 12 g. Elution is performed with the following table elution gradient.
Collecting the fraction of the cetrorelix sample with the purity of more than 99.0 percent and the precursor impurity of less than 0.1 percent, and adding an equal volume of 10 percent acetic acid aqueous solution to obtain a cetrorelix first-step sample solution.
Second step HPLC purification
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (100mm × 250 mm); taking 10% acetic acid solution (900 ml water added acetic acid 100ml) as mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 200mL per minute; the detection wavelength is 260 nm; the amount of the sample was 8 g. Elution is performed with the following table elution gradient.
Fractions of the cetrorelix sample with a purity of greater than 99.8% and less than 0.1% single impurity were collected.
Salt conversion
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (100mm × 250 mm); taking 50mmol/L ammonium acetate as mobile phase A110% acetic acid aqueous solution as mobile phase A2(ii) a Acetonitrile is used as a mobile phase B; the flow rate is 200mL per minute; the detection wavelength is 260 nm; the amount of the sample was 20 g. Elution is performed with the following table elution gradient.
Fractions of the cetrorelix sample with a purity of greater than 99.8% and less than 0.1% single impurity were collected. The solution contains 50.0g of cetrorelix quantitatively by a reference substance, and the purification yield reaches 71.4 percent.
Concentrated freeze-drying
Adding the salt-transfer peak top solution into an isovolumetric 20% acetic acid aqueous solution, concentrating to 25 +/-5 g/L with a rotary evaporator water bath temperature of 30-35 ℃ and a vacuum degree of-0.09 Mpa, and freeze-drying according to the following freeze-drying curve:
example 3:
taking cetrorelix crude product
Sample treatment: a sample containing 180g of crude cetrorelix peptide (crude peptide: 250 g) was dissolved in a 30% aqueous acetic acid solution, and after complete dissolution, it was filtered through a 0.22 μm filter. And collecting the filtered crude cetrorelix peptide aqueous solution for later use.
First step HPLC purification
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (200mm × 250 mm); using 0.1% trifluoroacetic acid (1000 ml of water, 1ml of trifluoroacetic acid and uniform mixing) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 800mL per minute; the detection wavelength is 260 nm; the loading of a single needle was 48 g. Elution is performed with the following table elution gradient.
Collecting the fraction of the cetrorelix sample with the purity of more than 99.0 percent and the precursor impurity of less than 0.1 percent, and adding an equal volume of 10 percent acetic acid aqueous solution to obtain a cetrorelix first-step sample solution.
Second step HPLC purification
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (200mm × 250 mm); taking 10% acetic acid solution (900 ml water added acetic acid 100ml) as mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 800mL per minute; the detection wavelength is 260 nm; the amount of the sample was 32 g. Elution is performed with the following table elution gradient.
Fractions of the cetrorelix sample with a purity of greater than 99.8% and less than 0.1% single impurity were collected.
Salt conversion
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (200mm × 250 mm); taking 50mmol/L ammonium acetate as mobile phase A110% acetic acid aqueous solution as mobile phase A2(ii) a Acetonitrile is used as a mobile phase B; the flow rate is 800mL per minute; the detection wavelength is 260 nm; the amount of the sample was 80 g. Elution is performed with the following table elution gradient.
Fractions of the cetrorelix sample with a purity of greater than 99.8% and less than 0.1% single impurity were collected. The solution contains 130.0g of cetrorelix quantitatively by a reference substance, and the purification yield reaches 72.2 percent.
Concentrated freeze-drying
Adding the salt-transfer peak top solution into an isovolumetric 20% acetic acid aqueous solution, concentrating to 25 +/-5 g/L with a rotary evaporator water bath temperature of 30-35 ℃ and a vacuum degree of-0.09 Mpa, and freeze-drying according to the following freeze-drying curve:
according to 3 embodiments, the purity of the cetrorelix crude product purified by the method is more than 99.8%, the yield is more than 70%, and the three embodiments have no precipitation phenomenon in the production process.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. It should be understood by those skilled in the art that the above embodiments do not limit the present invention in any way, and all technical solutions obtained by using equivalent alternatives or equivalent variations fall within the scope of the present invention.
Claims (8)
1. A method of purifying cetrorelix, comprising the steps of:
step one, preprocessing a crude product of cetrorelix to obtain a crude peptide solution of cetrorelix;
step two, using octadecylsilane chemically bonded silica filler as a stationary phase, trifluoroacetic acid as a mobile phase A and acetonitrile as a mobile phase B, and carrying out first HPLC purification to remove impurities before the cetrorelix peak;
adding an equal volume of acetic acid aqueous solution to prevent the sample from being separated out, so as to obtain a cetrorelix first-step sample solution;
step four, taking octadecylsilane chemically bonded silica filler as a stationary phase and taking acetic acid solution as a mobile phase A; performing HPLC purification for the second time by taking acetonitrile as a mobile phase B to remove impurities after the cetrorelix peak so as to obtain a cetrorelix second-step sample solution;
step five, using octadecylsilane chemically bonded silica filler as a stationary phase and ammonium acetate as a mobile phase A1Acetic acid aqueous solution as mobile phase A2(ii) a Taking acetonitrile as a mobile phase B, carrying out salt transfer, and taking cetrorelix salt transfer as an acetate to obtain a cetrorelix salt transfer sample solution;
step six, adding an equal volume of acetic acid aqueous solution into the salt conversion sample solution for concentration to obtain a salt conversion concentrated solution;
and step seven, pouring the salt-transfer concentrated solution into a freeze-drying tray, and putting the freeze-drying tray into a freeze dryer for freeze-drying to obtain the purified cetrorelix freeze-dried powder.
2. The method of claim 1, wherein in step one,
pre-treating the crude product of cetrorelix to obtain a crude peptide solution of cetrorelix; the step of pre-treating comprises:
1) dissolving the crude product of cetrorelix in an acetic acid aqueous solution to obtain a crude peptide solution of cetrorelix;
2) filtering the crude cetrorelix peptide solution by using a filter membrane to remove insoluble particles, and collecting the filtrate for later use.
3. The method for purifying cetrorelix according to claim 1, wherein in the second step, octadecylsilane chemically bonded silica filler is used as a stationary phase, 0.1% trifluoroacetic acid is used as a mobile phase A, acetonitrile is used as a mobile phase B, the detection wavelength is 260nm, and the first HPLC linear gradient elution is carried out to collect fractions containing cetrorelix samples; the granularity of the stationary phase is 8 mu m, and the preparation method of the 0.1% trifluoroacetic acid comprises the following steps: 1000ml of water was taken and 1ml of trifluoroacetic acid was added.
4. The method for purifying cetrorelix according to claim 1, wherein an equal volume of 10% aqueous acetic acid is added to the sample obtained in the first purification step in the third step to prevent precipitation of the sample.
5. The method for purifying cetrorelix according to claim 1, characterized in that in step four, a second HPLC gradient elution is performed with octadecylsilane chemically bonded silica filler as a stationary phase, 10% acetic acid aqueous solution as a mobile phase a, acetonitrile as a mobile phase B, and a detection wavelength of 260nm, to collect a fraction containing a cetrorelix sample; the preparation method of the 10% acetic acid aqueous solution comprises the following steps: adding acetic acid 100ml into 900ml water.
6. The method for purifying cetrorelix according to claim 1, wherein in step five, octadecylsilane chemically bonded silica filler is used as a stationary phase, and 50mmol/L ammonium acetate is used as a mobile phase A110% acetic acid aqueous solution as mobile phase A2(ii) a And (3) carrying out salt transfer by taking acetonitrile as a mobile phase B, and taking cetrorelix salt transfer as acetate to obtain a cetrorelix salt transfer sample solution.
7. The method for purifying cetrorelix according to claim 1, wherein in the sixth step, an equal volume of 20% acetic acid aqueous solution is added to the trans-salt sample solution for concentration, and the sample does not precipitate during concentration, so that a clear trans-salt concentrated solution is obtained.
8. The method of claim 1, wherein in step seven, the temperature of the sublimation drying stage of the lyophilization curve is set to be less than the eutectic point of the trans-salt concentrate during lyophilization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111661596.6A CN114276414A (en) | 2021-12-30 | 2021-12-30 | Method for purifying cetrorelix |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111661596.6A CN114276414A (en) | 2021-12-30 | 2021-12-30 | Method for purifying cetrorelix |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114276414A true CN114276414A (en) | 2022-04-05 |
Family
ID=80879108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111661596.6A Pending CN114276414A (en) | 2021-12-30 | 2021-12-30 | Method for purifying cetrorelix |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114276414A (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6258933B1 (en) * | 1998-03-27 | 2001-07-10 | Degussa-Huls Aktiengesellschaft | Process for the one-stage resalting and purification of oligopeptides |
| CN104086632A (en) * | 2014-08-05 | 2014-10-08 | 杭州诺泰制药技术有限公司 | Method for preparing cetrorelix |
| CN105693844A (en) * | 2016-03-10 | 2016-06-22 | 泰州施美康多肽药物技术有限公司 | Preparation method of gonadotrophin-releasing hormone analogue acetate |
| CN107312073A (en) * | 2017-06-20 | 2017-11-03 | 浙江湃肽生物有限公司 | A kind of method of purifies and separates Cetrorelix |
| CN107759667A (en) * | 2017-11-29 | 2018-03-06 | 苏州纳微科技有限公司 | A kind of isolation and purification method of Cetrorelix |
| CN109467591A (en) * | 2018-12-27 | 2019-03-15 | 苏州天马医药集团天吉生物制药有限公司 | A kind of purification process of Cetrorelix |
| US20190382447A1 (en) * | 2018-06-16 | 2019-12-19 | Biophore India Pharmaceuticals Private Limited | Process for the preparation of cetrorelix acetate |
| CN112250735A (en) * | 2020-09-29 | 2021-01-22 | 开封明仁药业有限公司 | Salt transfer method of cetrorelix |
-
2021
- 2021-12-30 CN CN202111661596.6A patent/CN114276414A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6258933B1 (en) * | 1998-03-27 | 2001-07-10 | Degussa-Huls Aktiengesellschaft | Process for the one-stage resalting and purification of oligopeptides |
| CN104086632A (en) * | 2014-08-05 | 2014-10-08 | 杭州诺泰制药技术有限公司 | Method for preparing cetrorelix |
| CN105693844A (en) * | 2016-03-10 | 2016-06-22 | 泰州施美康多肽药物技术有限公司 | Preparation method of gonadotrophin-releasing hormone analogue acetate |
| CN107312073A (en) * | 2017-06-20 | 2017-11-03 | 浙江湃肽生物有限公司 | A kind of method of purifies and separates Cetrorelix |
| CN107759667A (en) * | 2017-11-29 | 2018-03-06 | 苏州纳微科技有限公司 | A kind of isolation and purification method of Cetrorelix |
| US20190382447A1 (en) * | 2018-06-16 | 2019-12-19 | Biophore India Pharmaceuticals Private Limited | Process for the preparation of cetrorelix acetate |
| CN109467591A (en) * | 2018-12-27 | 2019-03-15 | 苏州天马医药集团天吉生物制药有限公司 | A kind of purification process of Cetrorelix |
| CN112250735A (en) * | 2020-09-29 | 2021-01-22 | 开封明仁药业有限公司 | Salt transfer method of cetrorelix |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112552376B (en) | Method for purifying vilacatide | |
| CN111057142B (en) | Purification method of teriparatide | |
| CN112724241B (en) | Purification method of abamectin | |
| CN110845599B (en) | Preparation and purification method of polypeptide | |
| CN114276414A (en) | Method for purifying cetrorelix | |
| CN109467591B (en) | Purification method of cetrorelix | |
| CN109206486B (en) | Polymyxin B sulfate impurity and preparation method thereof | |
| CN108409806B (en) | Method for separating and preparing petunidin-3-O-glucoside | |
| CN111454333B (en) | Preparation method of high-purity oxytocin | |
| CN114349824A (en) | Method for purifying linaclotide | |
| CN111777650B (en) | Method for extracting and separating baicalin by using mixed micelle | |
| CN108516999B (en) | method for separating and preparing petunidin-3-O-galactoside | |
| CN108517000B (en) | Method for separating and preparing petunidin-3-O-arabinoside | |
| SU1207396A3 (en) | Method of isolating vincristine | |
| CN111909176B (en) | Method for recovering ascomycin and tacrolimus 8-propyl analogue from tacrolimus separation waste liquid | |
| CN104829695A (en) | Purifying method for alarelin | |
| CN112250735A (en) | Salt transfer method of cetrorelix | |
| CN110590586A (en) | Method for separating and purifying lysine fermentation liquor | |
| CN116162124B (en) | Preparation method of continuous glutamine polypeptide | |
| CN111233944B (en) | High performance liquid phase method for simultaneously preparing and separating four lignans components | |
| CN110903346B (en) | Method for preparing vancomycin hydrochloride impurity impC | |
| CN117659127A (en) | Method for purifying octreotide | |
| CN111662362B (en) | Method for purifying carbetocin | |
| CN216321130U (en) | Extraction and concentration device for clavulanic acid fermentation liquor | |
| CA3076793C (en) | Integrated automated filtration for separation, washing and drying of peptide crystals |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |