CN114315973A - Method for purifying procatide - Google Patents
Method for purifying procatide Download PDFInfo
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- CN114315973A CN114315973A CN202111661557.6A CN202111661557A CN114315973A CN 114315973 A CN114315973 A CN 114315973A CN 202111661557 A CN202111661557 A CN 202111661557A CN 114315973 A CN114315973 A CN 114315973A
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- mobile phase
- procatide
- acetonitrile
- procapsipeptide
- purifying
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- 238000000034 method Methods 0.000 title claims abstract description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 63
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 26
- 238000000746 purification Methods 0.000 claims abstract description 26
- 238000010828 elution Methods 0.000 claims abstract description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000005526 G1 to G0 transition Effects 0.000 claims abstract description 16
- 239000000945 filler Substances 0.000 claims abstract description 16
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 16
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 14
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000005695 Ammonium acetate Substances 0.000 claims abstract description 10
- 229940043376 ammonium acetate Drugs 0.000 claims abstract description 10
- 235000019257 ammonium acetate Nutrition 0.000 claims abstract description 10
- 239000012264 purified product Substances 0.000 claims abstract description 9
- 239000000047 product Substances 0.000 claims abstract description 5
- 238000004108 freeze drying Methods 0.000 claims abstract description 4
- 239000012528 membrane Substances 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- 229920001184 polypeptide Polymers 0.000 abstract description 2
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 2
- 238000002390 rotary evaporation Methods 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 22
- 239000000523 sample Substances 0.000 description 18
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 239000012521 purified sample Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 230000006978 adaptation Effects 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 230000012495 positive regulation of renal sodium excretion Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- SJMPVWVIVWEWJK-AXEIBBKLSA-N uroguanylin Chemical class SC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(N)=O SJMPVWVIVWEWJK-AXEIBBKLSA-N 0.000 description 1
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Abstract
The invention discloses a method for purifying procatide, belonging to the technical field of polypeptide purification. In the method, a procapsipeptide cyclization solution is filtered by a 0.45 mu m microporous filter membrane to obtain a crude peptide solution. Carrying out first HPLC purification on the crude peptide solution by using octadecylsilane chemically bonded silica filler as a stationary phase, ammonium acetate as a mobile phase A and acetonitrile as a mobile phase B, and collecting an elution peak to obtain a first purified substance; carrying out HPLC purification on the first purified product by taking octadecylsilane chemically bonded silica filler as a stationary phase, acetic acid as a mobile phase A and acetonitrile as a mobile phase B, and collecting an elution peak to obtain a second purified product; and (5) carrying out reduced pressure rotary evaporation concentration and freeze drying on the secondary purified product to obtain a finished product of the procatide.
Description
Technical Field
The invention relates to the field of peptide purification, in particular to a method for purifying procatide.
Background
The name of Chinese: a peptide procaine; the name of English: plectanatide; the peptide sequence is as follows:
H-Asn-Asp-Glu-Cys(13)-Glu-Leu-Cys(10)-Val-Asn-Val-Ala-Cys(5)-Thr-Gly-Cys(2)-Leu-OH
structure diagram:
the procatide is developed by Synergy pharmaceutical company in America, is an analogue of uroguanylin, contains cyclic polypeptide of 16 amino acids, has the function of guanylate cyclase receptor agonist for promoting natriuresis, can regulate acid-base ions in gastrointestinal tract, induces liquid to be transported into gastrointestinal tract, increases the peristalsis of the gastrointestinal tract, and is suitable for treating adult chronic idiopathic constipation. The united states Food and Drug Administration (FDA) approved for marketing on 2017, month 1 and 19, under the trade name truulance.
At present, the procapsipeptide is synthesized by a secondary cyclization solid phase, the synthesized product has more byproducts and more impurities influencing purification, and the procapsipeptide sample obtained by separation by the existing purification technology has low purity and low yield.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a method for purifying procainatide, which is simple to operate and improves the purity and yield of the procainatide.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a method of purifying procainatide comprising the steps of:
step one, filtering the cyclized solution of the procatide by using a 0.45 mu m microporous filter membrane to obtain a crude peptide solution.
Taking the crude peptide solution, taking octadecylsilane chemically bonded silica filler as a stationary phase, ammonium acetate as a mobile phase A and acetonitrile as a mobile phase B, carrying out first HPLC purification, and collecting an elution peak to obtain a first purified substance;
taking the first purified product, taking octadecylsilane chemically bonded silica filler as a stationary phase, taking acetic acid as a mobile phase A and acetonitrile as a mobile phase B, carrying out second HPLC purification, and collecting an elution peak to obtain a second purified product;
and step four, carrying out reduced pressure rotary steaming concentration and freeze drying on the second purified product to obtain a finished product of the procatide.
In the second step of the method for purifying procapsipeptide, preferably, octadecylsilane chemically bonded silica filler is used as a stationary phase, 50mmol/L ammonium acetate and ammonia water are used to adjust the pH to 8.3 to be a mobile phase a, acetonitrile is used to be a mobile phase B, the detection wavelength is 220nm, the flow rate is 50mL/min, and a first HPLC linear gradient elution is performed to collect fractions containing a procapsipeptide sample; the preparation method of the mobile phase A comprises the following steps: 3.85g of ammonium acetate was weighed and dissolved in 1L of pure water, and the pH was adjusted to 8.3 with aqueous ammonia.
In the third step, preferably, octadecylsilane chemically bonded silica filler is used as a stationary phase, 2% acetic acid aqueous solution is used as a mobile phase a, acetonitrile is used as a mobile phase B, the detection wavelength is 220nm, the flow rate is 50mL/min, and the second HPLC gradient elution is performed to collect fractions containing the procainatide sample; the preparation method of the mobile phase A comprises the following steps: 2mL of acetic acid is weighed out and dissolved in 1L of pure water, and the mixture is uniformly mixed.
In the fourth step, the water bath temperature of the rotary evaporator is preferably 30-33 ℃, and the vacuum degree is below-0.09 MPa to remove acetonitrile and part of water, so as to obtain the procatide concentrated solution.
Compared with the prior art, the invention has the following beneficial effects:
the method for purifying the procainatide obtains a finished product of the procainatide by purifying the procainatide cyclization solution in two steps. The obtained procapsipeptide has high purity, the yield of the procapsipeptide is obviously improved, the operation is simple, and the large-scale preparation of the procapsipeptide is favorably realized.
Drawings
FIG. 1 is an HPLC chart of crude procatide in example 1;
FIG. 2 is an HPLC plot of procainatide after the first HPLC purification in example 1;
FIG. 3 is an HPLC plot of procainatide after a second HPLC purification in example 1.
Detailed Description
The invention discloses a purification method of procatide. The method may be carried out by those skilled in the art with reference to the disclosure herein, and it is specifically intended that all such alterations and modifications as are obvious to those skilled in the art are deemed to be included in the invention. While the purification methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as appropriate variations and combinations thereof, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
The reagents used in the purification method of the procatide provided by the invention are all available in the market.
In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention is further described below with reference to the following embodiments:
example 1: purification of procatide
Sample treatment: the cyclized solution containing 2.1g of procapsipeptide was filtered through a 0.45 μm filter. And collecting the filtered crude peptide solution of the procapsipeptide for later use. The HPLC chart of the crude procatide is shown in FIG. 1.
First step HPLC purification:
chromatographic conditions are as follows: the chromatographic column using octadecylsilane chemically bonded silica filler as a stationary phase has the following diameter and length: 50mm × 250 mm; using 50mmol/L ammonium acetate, ammonia water to adjust pH to 8.3 as mobile phase A, acetonitrile as mobile phase B, detection wavelength of 220nm, flow rate of 50mL/min, and sample loading amount of 1.1 g. Elution is performed with the following table elution gradient. The HPLC profile of procapsipeptide after the first HPLC purification is shown in FIG. 2.
Fractions of the procatide sample with a purity of greater than 80% were collected. And adding the collected fractions meeting the requirements into an equal volume of purified water to dilute the fractions twice, and using the fractions as a second-step purified sample.
Second step HPLC purification
Chromatographic conditions are as follows: the chromatographic column using octadecylsilane chemically bonded silica filler as a stationary phase has the following diameter and length: 50mm × 250 mm; taking 2% acetic acid water solution as a mobile phase A, acetonitrile as a mobile phase B, detecting wavelength of 220nm and flow rate of 50 mL/min; the amount of the sample was 1.0 g. Elution is performed with the following table elution gradient. The HPLC profile of procapsipeptide after the second HPLC purification is shown in FIG. 3.
Fractions of the procatide sample with a purity of greater than 98% were collected. And removing acetonitrile and part of water by using a rotary evaporator at the water bath temperature of 30-33 ℃ and the vacuum degree of below-0.09 Mpa to obtain the procatide concentrated solution. The procatide concentrated solution is frozen and dried to obtain 1.5g of procatide, and the yield reaches 71.4%.
Example 2: purification of procatide
Sample treatment: the cyclized solution containing 8.6g of procapsipeptide was filtered through a 0.45 μm filter. And collecting the filtered crude peptide solution of the procapsipeptide for later use.
First step HPLC purification:
chromatographic conditions are as follows: the chromatographic column using octadecylsilane chemically bonded silica filler as a stationary phase has the following diameter and length: 50mm × 250 mm; using 50mmol/L ammonium acetate, ammonia water to adjust pH to 8.3 as mobile phase A, acetonitrile as mobile phase B, detection wavelength of 220nm, flow rate of 50mL/min, and sample loading amount of 1.1 g. Elution is performed with the following table elution gradient.
Fractions of the procatide sample with a purity of greater than 80% were collected. Adding the collected fraction meeting the requirement into the purified water with the same volume to dilute the fraction by one time to be used as a second step of purified sample
Second step HPLC purification
Chromatographic conditions are as follows: the chromatographic column using octadecylsilane chemically bonded silica filler as a stationary phase has the following diameter and length: 50mm × 250 mm; taking 2% acetic acid water solution as a mobile phase A, acetonitrile as a mobile phase B, detecting wavelength of 220nm and flow rate of 50 mL/min; the amount of the sample was 1.0 g. Elution is performed with the following table elution gradient.
Fractions of the procatide sample with a purity of greater than 98% were collected. And removing acetonitrile and part of water by using a rotary evaporator at the water bath temperature of 30-33 ℃ and the vacuum degree of below-0.09 Mpa to obtain the procatide concentrated solution. 6.4g of procapsipeptide is obtained by freeze drying the procapsipeptide concentrated solution, and the yield reaches 74.4%.
Example 3: purification of procatide
Sample treatment: the cyclized solution containing 16.8g of procapsipeptide was filtered through a 0.45 μm filter. And collecting the filtered crude peptide solution of the procapsipeptide for later use.
First step HPLC purification:
chromatographic conditions are as follows: the chromatographic column using octadecylsilane chemically bonded silica filler as a stationary phase has the following diameter and length: 50mm × 250 mm; using 50mmol/L ammonium acetate, ammonia water to adjust pH to 8.3 as mobile phase A, acetonitrile as mobile phase B, detection wavelength of 220nm, flow rate of 50mL/min, and sample loading amount of 1.1 g. Elution is performed with the following table elution gradient.
Fractions of the procatide sample with a purity of greater than 80% were collected. Adding the collected fraction meeting the requirement into the purified water with the same volume to dilute the fraction by one time to be used as a second step of purified sample
Second step HPLC purification
Chromatographic conditions are as follows: the chromatographic column using octadecylsilane chemically bonded silica filler as a stationary phase has the following diameter and length: 50mm × 250 mm; taking 2% acetic acid water solution as a mobile phase A, acetonitrile as a mobile phase B, detecting wavelength of 220nm and flow rate of 50 mL/min; the amount of the sample was 1.0 g. Elution is performed with the following table elution gradient.
Fractions of the procatide sample with a purity of greater than 98% were collected. And removing acetonitrile and part of water by using a rotary evaporator at the water bath temperature of 30-33 ℃ and the vacuum degree of below-0.09 Mpa to obtain the procatide concentrated solution. The procatide concentrated solution is frozen and dried to obtain 12.7g of procatide, and the yield reaches 75.6%.
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and these modifications and adaptations should be considered within the scope of the invention.
Claims (4)
1. A method of purifying procainatide, comprising: the method comprises the following steps:
step one, filtering the cyclized solution of the procatide by using a 0.45 mu m microporous filter membrane to obtain a crude peptide solution.
Taking the crude peptide solution, taking octadecylsilane chemically bonded silica filler as a stationary phase, ammonium acetate as a mobile phase A and acetonitrile as a mobile phase B, carrying out first HPLC purification, and collecting an elution peak to obtain a first purified substance;
taking the first purified product, taking octadecylsilane chemically bonded silica filler as a stationary phase, taking acetic acid as a mobile phase A and acetonitrile as a mobile phase B, carrying out second HPLC purification, and collecting an elution peak to obtain a second purified product;
and step four, carrying out reduced pressure rotary steaming concentration and freeze drying on the second purified product to obtain a finished product of the procatide.
2. The method for purifying procapsipeptide of claim 1, wherein in step two, octadecylsilane chemically bonded silica filler is used as stationary phase, 50mmol/L ammonium acetate and ammonia water are used to adjust pH to 8.3 to be mobile phase A, acetonitrile is used to be mobile phase B, the detection wavelength is 220nm, the flow rate is 50mL/min, and first HPLC linear gradient elution is performed to collect fraction containing procapsipeptide sample; the preparation method of the mobile phase A comprises the following steps: 3.85g of ammonium acetate was weighed and dissolved in 1L of pure water, and the pH was adjusted to 8.3 with aqueous ammonia.
3. The method for purifying procapsipeptide of claim 1, wherein in step three, octadecylsilane chemically bonded silica filler is used as stationary phase, 2% acetic acid aqueous solution is used as mobile phase A, acetonitrile is used as mobile phase B, detection wavelength is 220nm, flow rate is 50mL/min, and second HPLC gradient elution is performed to collect fraction containing procapsipeptide sample; the preparation method of the mobile phase A comprises the following steps: 2mL of acetic acid is weighed out and dissolved in 1L of pure water, and the mixture is uniformly mixed.
4. The method for purifying procatide according to claim 1, wherein in step four, acetonitrile and part of water are removed by a rotary evaporator at a water bath temperature of 30-33 ℃ and a vacuum degree of-0.09 MPa or less to obtain a procatide concentrate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107383171A (en) * | 2017-08-15 | 2017-11-24 | 苏州科技大学 | A kind of method by secondary cyclization synthesis in solid state Pu Kana peptides |
| CN108440652A (en) * | 2018-04-02 | 2018-08-24 | 杭州固拓生物科技有限公司 | A kind of solid phase synthesis process of Pu Kana peptides |
| CN112194708A (en) * | 2020-10-28 | 2021-01-08 | 杭州信海医药科技有限公司 | Preparation method of procatide |
| CN114573662A (en) * | 2021-09-30 | 2022-06-03 | 深圳翰宇药业股份有限公司 | Preparation method of procainatide ammonium salt |
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- 2021-12-30 CN CN202111661557.6A patent/CN114315973A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107383171A (en) * | 2017-08-15 | 2017-11-24 | 苏州科技大学 | A kind of method by secondary cyclization synthesis in solid state Pu Kana peptides |
| CN108440652A (en) * | 2018-04-02 | 2018-08-24 | 杭州固拓生物科技有限公司 | A kind of solid phase synthesis process of Pu Kana peptides |
| CN112194708A (en) * | 2020-10-28 | 2021-01-08 | 杭州信海医药科技有限公司 | Preparation method of procatide |
| CN114573662A (en) * | 2021-09-30 | 2022-06-03 | 深圳翰宇药业股份有限公司 | Preparation method of procainatide ammonium salt |
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Application publication date: 20220412 |