CN114369142B - Method for purifying desmopressin acetate - Google Patents
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- CN114369142B CN114369142B CN202111673487.6A CN202111673487A CN114369142B CN 114369142 B CN114369142 B CN 114369142B CN 202111673487 A CN202111673487 A CN 202111673487A CN 114369142 B CN114369142 B CN 114369142B
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/16—Oxytocins; Vasopressins; Related peptides
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a purification method of desmopressin acetate, which mainly solves the technical problems that the desmopressin acetate obtained by separation in the prior art has lower purity, lower yield and difficult removal of impurities with similar physicochemical properties. The method comprises the steps of dissolving crude peptide in a purified water solution, adding sodium hydroxide into a sample to be purified by using octadecylsilane chemically bonded silica filler as a stationary phase, and purifying to obtain the desmopressin acetate bulk drug with high purity, high quality and high yield. In the process of purifying desmopressin acetate by a high-efficiency liquid phase method, sodium hydroxide is added into a desmopressin acetate solution sample, and impurities with similar physicochemical properties to the desmopressin acetate can be removed by adopting chromatographic gradient elution of octadecylsilane chemically bonded silica filler combined with a phosphate mobile phase, so that the sample with the purity of more than 99.0 percent and the yield of 80.0 percent can be obtained at one time; the purity and the yield of the finished desmopressin acetate product are improved.
Description
Technical Field
The invention relates to the field of peptide purification, in particular to a method for purifying desmopressin acetate.
Background
Chinese name: desmopressin acetate; english name: desmopresin; peptide sequence:
Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH 2
the molecular formula: c (C) 46 H 64 N 14 O 12 S 2 The method comprises the steps of carrying out a first treatment on the surface of the Accurate molecular weight: 1068.4270 molar mass: 1069.2240 chemical formula:
desmopressin acetate is artificially synthesized, and cyclic nonapeptide is composed of 9 amino acids, and has similar effect to human vasopressin, but remarkably enhanced antidiuresis effect, and weak effect on smooth muscle, so that adverse effect of boosting is avoided. The antidiuretic effect/pressurizing effect ratio is about 1200-3000 times of that of vasopressin, and the antidiuretic effect time is longer than that of vasopressin and can reach 6-24 hours. The oxytocin activity is also obviously weakened. In addition, the high dose of the product, i.e. intravenous injection or subcutaneous injection of 0.3 mug/kg, can increase the activity of procoagulant factor VIII in blood plasma by 2-4 times, and can also increase von Willebrand factor (vWF: ag) in blood and release fibrinogen activator (t-PA) at the same time, thus being capable of controlling or preventing bleeding of certain diseases during minor surgery or drug-induced bleeding.
The desmopressin acetate composition can generate various impurities which affect the purity and yield of the sample, the impurities with similar physicochemical properties are difficult to remove, and the desmopressin acetate sample obtained by separation through 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 novel method for purifying desmopressin acetate, which can effectively improve the purity and the yield of desmopressin acetate.
In order to achieve the above object, the present invention adopts the following technical scheme:
the invention relates to a method for purifying desmopressin acetate, which comprises the following steps: dissolving crude peptide of desmopressin acetate in a purified water solution, and then adding sodium hydroxide into a sample to be purified by using octadecylsilane chemically bonded silica filler as a stationary phase to perform two purifications to obtain the purified desmopressin acetate.
The invention relates to a purification method of desmopressin acetate, which is further preferably characterized by comprising the following specific steps:
(1) Dissolving the crude desmopressin acetate in a purified water solution to obtain a crude desmopressin acetate water solution, filtering the desmopressin acetate water solution by using a filter membrane to remove insoluble particles, and collecting filtrate for later use;
(2) Pretreating octadecylsilane chemically bonded silica filler serving as a stationary phase and TFA/acetonitrile serving as a mobile phase system to remove residual diethyl ether or other high-retention substances in the crude desmopressin acetate solution;
(3) Removing acetonitrile by adopting a low-pressure distillation mode to obtain a desmopressin acetate first-step sample solution;
(4) Adjusting the pH of the first-step sample solution to 6.0-6.9 by using sodium hydroxide aqueous solution;
(5) Octadecylsilane chemically bonded silica filler is used as a stationary phase, phosphoric acid and sodium hydroxide are used for adjusting the pH value to 6.0-6.9/acetonitrile as a mobile phase system, and the pure desmopressin acetate is obtained by purification.
In the step (2), octadecylsilane chemically bonded silica filler is used as a stationary phase, 0.1% TFA/acetonitrile is used as a mobile phase system for pretreatment, the detection wavelength is 220nm, and the first HPLC linear gradient elution is carried out to remove diethyl ether or other substances with high retention in the crude solution of the desmopressin acetate; collecting a fraction containing desmopressin acetate sample; the particle size of the stationary phase was 10. Mu.m.
The further preferable technical scheme of the purification method of desmopressin acetate provided by the invention is that in the step (2), the preparation method of 0.1% TFA comprises the following steps: 1000mL of purified water was added with 1mL of TFA and mixed well to give 0.1% TFA.
According to the method for purifying desmopressin acetate, in the step (3), partial acetonitrile is removed by using a rotary evaporator at a water bath temperature of 30-35 ℃ and a vacuum degree of less than-0.09 MPa, so that a sample solution of the desmopressin acetate in the first step is obtained, and the sample solution is acidic.
According to the purification method of desmopressin acetate, in the step (4), the pH value of the sample solution in the first step is regulated to 6.5 by using 0.5mol of sodium hydroxide aqueous solution.
In the step (5), octadecylsilane chemically bonded silica filler is used as a stationary phase, 0.1% phosphoric acid and sodium hydroxide are used for adjusting pH to 6.5/acetonitrile as a mobile phase system, the detection wavelength is 220nm, and the second HPLC gradient elution is carried out to collect fractions containing an acetic acid desmopressin sample.
The further preferable technical scheme of the purification method of desmopressin acetate provided by the invention is that in the step (5), the preparation method of the phosphate solution is as follows: 1000ml of water was taken, 1ml of phosphoric acid was added, and the pH of the mobile phase was adjusted to 6.5 with sodium hydroxide to obtain a phosphate solution.
The invention also discloses the application of the sodium hydroxide aqueous solution in the purification of desmopressin acetate, and in the process of purifying desmopressin acetate by a high-efficiency liquid phase method, a mobile phase system combining sodium hydroxide and phosphate is added into a desmopressin acetate solution sample to perform gradient elution, so that impurities with physical and chemical properties similar to those of desmopressin acetate can be removed. In the purification process, 0.5mol of sodium hydroxide aqueous solution is used for adjusting the pH value of a sample to be purified to 6.5, 0.1 percent phosphoric acid and sodium hydroxide are used for adjusting the pH value to 6.5/acetonitrile as a mobile phase system, and the desmopressin acetate pure product is obtained by purification.
Compared with the prior art, the invention has the following advantages: in the process of purifying desmopressin acetate by a high-efficiency liquid phase method, sodium hydroxide is added into a desmopressin acetate solution sample, and impurities with similar physicochemical properties to the desmopressin acetate can be removed by adopting chromatographic gradient elution of octadecylsilane chemically bonded silica filler combined with a phosphate mobile phase, so that the sample with the purity of more than 99.0 percent and the yield of 80.0 percent can be obtained at one time; the purity and the yield of the finished desmopressin acetate product are improved.
Drawings
FIG. 1 is an HPLC chart of crude desmopressin acetate of example 2;
FIG. 2 is an HPLC plot of the final desmopressin acetate product of example 2.
Detailed Description
The invention is described in detail below with reference to the drawings and the specific embodiments.
Example 1, a method of purifying desmopressin acetate, comprising the steps of:
step one, pre-treating a crude desmopressin acetate product to obtain a crude desmopressin acetate peptide aqueous solution;
the pretreatment steps comprise: dissolving the crude desmopressin acetate in the purified water solution to obtain a crude desmopressin acetate peptide water solution; filtering desmopressin acetate aqueous solution with a filter membrane to remove insoluble particles, and collecting filtrate for later use. As a preferred embodiment, the filter is a 0.45 μm filter.
Step two, pretreatment is carried out by taking octadecylsilane chemically bonded silica filler as a stationary phase, 0.1 percent TFA/acetonitrile as a mobile phase system, the detection wavelength is 220nm, and first HPLC linear gradient elution is carried out to remove diethyl ether or other high-retention substances remained in the crude desmopressin acetate solution; collecting a fraction containing desmopressin acetate sample; the particle size of the stationary phase is 10 μm, and the preparation method of 0.1% TFA comprises the following steps: 1000ml of purified water was added with 1ml of TFA and mixed well to give 0.1% TFA.
And thirdly, removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 25-30 ℃ and the vacuum degree of less than-0.09 MPa to obtain a sample solution of desmopressin acetate in the first step, wherein the sample solution is acidic.
Step four, adjusting the pH value of the sample solution in the first step to 6.5 by using 0.5mol of sodium hydroxide aqueous solution;
step five, performing a second HPLC purification to remove impurities with physical and chemical properties similar to those of desmopressin acetate;
octadecylsilane chemically bonded silica filler is used as a stationary phase, 0.1% phosphoric acid and sodium hydroxide are used for adjusting the pH value to 6.5/acetonitrile as a mobile phase system, the detection wavelength is 220nm, and a second HPLC gradient elution is carried out to collect fractions containing desmopressin acetate samples. The preparation method of the phosphate solution comprises the following steps: 1000ml of water was taken, 1ml of phosphoric acid was added, and the pH of the mobile phase was adjusted to 6.5 with sodium hydroxide to obtain a phosphate solution.
In order to prove that the purification method can remove impurities to obtain a finished product of desmopressin acetate with high purity and high yield, the purification experiment is carried out by using a crude peptide sample containing 3g, 8g and 33g desmopressin acetate by using the method, and the experimental process is as follows:
example 2:
taking crude desmopressin acetate, and referring to an HPLC chart of the crude desmopressin acetate as shown in figure 1;
sample treatment: a sample containing 3g of desmopressin acetate crude peptide (crude peptide: 4.2 g) was dissolved in the purified water solution, and after complete dissolution, filtered through a 0.45 μm filter. And collecting the filtered crude peptide aqueous solution of desmopressin acetate for later use.
First step HPLC purification
Chromatographic conditions: a chromatographic column using octadecylsilane chemically bonded silica filler as stationary phase (30 mm. Times.250 mm,10 μm); 0.1% TFA (1000 ml of water, 1ml of TFA, mixed well) was used as mobile phase A; acetonitrile is taken as a mobile phase B; the flow rate was 10mL per minute; the detection wavelength is 220nm; the single needle loading was 1g and elution was performed with the following table elution gradient.
A fraction of desmopressin acetate sample was collected. Removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 25-30 ℃ and the vacuum degree of less than-0.09 Mpa. Obtaining the desmopressin acetate first-step sample solution.
Second step HPLC purification
Adjusting the pH of the first step sample solution to 6.5 with 0.5mol of aqueous sodium hydroxide solution;
chromatographic conditions: a chromatographic column using octadecylsilane chemically bonded silica filler as stationary phase (30 mm. Times.250 mm,10 μm); taking phosphate solution (1000 ml of water is added with 1ml of phosphoric acid, and sodium hydroxide is used for adjusting the pH value to 6.5) as a mobile phase A; acetonitrile is taken as a mobile phase B; the flow rate was 10mL per minute; the detection wavelength is 220nm; the loading was 1.5g and elution was performed with the following table elution gradient.
Collecting the fraction of desmopressin acetate sample with purity higher than 99.0%. The solution contains 2.50g of desmopressin acetate quantitatively by a reference substance, and the yield reaches 83.33%. HPLC of desmopressin acetate pure product is shown in FIG. 2.
Example 3
Taking crude desmopressin acetate
Sample treatment: a sample containing 8g of desmopressin acetate crude peptide (crude peptide: 11.4 g) was dissolved in the purified water solution, and after complete dissolution, filtered through a 0.45 μm filter. The filtered crude peptide aqueous solution was collected for use.
First step HPLC purification
Chromatographic conditions: a chromatographic column using octadecylsilane chemically bonded silica filler as stationary phase (50 mm. Times.250 mm,10 μm); 0.1% TFA (1000 ml of water, 1ml of TFA, mixed well) was used as mobile phase A; acetonitrile is taken as a mobile phase B; the flow rate was 50mL per minute; the detection wavelength is 220nm; the loading was 2.7g and elution was performed with the following table elution gradient.
A fraction of desmopressin acetate sample was collected. Removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 25-30 ℃ and the vacuum degree of less than-0.09 Mpa. Obtaining the desmopressin acetate first-step sample solution.
Second step HPLC purification
Adjusting the pH of the first step sample solution to 6.5 with 0.5mol of aqueous sodium hydroxide solution;
chromatographic conditions: a chromatographic column using octadecylsilane chemically bonded silica filler as stationary phase (50 mm. Times.250 mm,10 μm); taking phosphate solution (1000 ml of water is added with 1ml of phosphoric acid, and sodium hydroxide is used for adjusting the pH value to 6.5) as a mobile phase A; acetonitrile is taken as a mobile phase B; the flow rate was 50mL per minute; the detection wavelength is 220nm; the loading was 4.1g and elution was performed with the following table elution gradient.
Collecting the fraction of desmopressin acetate sample with purity higher than 99.0%. The solution contains 6.73g of desmopressin acetate quantitatively by a reference substance, and the yield reaches 84.12 percent.
Example 4
Taking crude desmopressin acetate
Sample treatment: a sample containing 33g of desmopressin acetate crude peptide (crude peptide: 47.1 g) was dissolved in the purified aqueous solution, and after complete dissolution, filtered through a 0.45 μm filter. The filtered crude peptide aqueous solution was collected for use.
First step HPLC purification
Chromatographic conditions: a chromatographic column using octadecylsilane chemically bonded silica filler as stationary phase (100 mm. Times.250 mm,10 μm); 0.1% TFA (1000 ml of water, 1ml of TFA, mixed well) was used as mobile phase A; acetonitrile is taken as a mobile phase B; the flow rate was 150mL per minute; the detection wavelength is 220nm; the loading was 11g.
Elution was performed with the following table elution gradient.
A fraction containing desmopressin acetate sample was collected. Removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 25-30 ℃ and the vacuum degree of less than-0.09 Mpa. Obtaining the desmopressin acetate first-step sample solution.
Adjusting the pH of the first step sample solution to 6.5 with 0.5mol of aqueous sodium hydroxide solution;
chromatographic conditions: a chromatographic column packed with octadecylsilane chemically bonded silica gel stationary phase (100 mm. Times.250 mm,10 μm); phosphate solution (1000 ml of water plus 1ml of phosphoric acid, sodium hydroxide to adjust ph=6.5) was used as mobile phase a; acetonitrile is taken as a mobile phase B; the flow rate was 150mL per minute; the detection wavelength is 220nm; the loading was 16.6g. Elution was performed with the following table elution gradient.
Collecting the fraction of desmopressin acetate sample with purity higher than 99.0%. The solution quantitatively contains 28.2g of desmopressin acetate by a reference substance, and the yield reaches 85.45 percent.
| Desmopressin acetate containing sample/g | Mass/g of purified desmopressin acetate | Yield is good | Purity of | |
| Example 2 | 3 | 2.50 | 83.33％ | More than 99.0% |
| Example 3 | 8 | 6.73 | 84.12％ | More than 99.0% |
| Example 4 | 32 | 28.21 | 85.45％ | More than 99.0% |
From the above 3 experimental examples, the crude desmopressin acetate was purified by the method, and the purity of the obtained desmopressin acetate was more than 99.0%.
The experimental example proves that the method for purifying desmopressin acetate has the purity of more than 99.0 percent and the yield of more than 80.0 percent after HPLC purification, and improves the purity and the yield of desmopressin acetate.
1. The foregoing has shown and described the basic principles, principal features and advantages of the invention. It will be appreciated by persons skilled in the art that the above embodiments are not intended to limit the invention in any way, and that all technical solutions obtained by means of equivalent substitutions or equivalent transformations fall within the scope of the invention.
Claims (9)
1. A method for purifying desmopressin acetate, characterized by: dissolving crude peptide of desmopressin acetate in a purified water solution, and then adding sodium hydroxide into a sample to be purified by using octadecylsilane chemically bonded silica filler as a stationary phase to perform two purifications to obtain purified desmopressin acetate;
the method comprises the following specific steps:
(1) Dissolving the crude desmopressin acetate in a purified water solution to obtain a crude desmopressin acetate water solution, filtering the desmopressin acetate water solution by using a filter membrane to remove insoluble particles, and collecting filtrate for later use;
(2) Pretreating octadecylsilane chemically bonded silica filler serving as a stationary phase and TFA/acetonitrile serving as a mobile phase system to remove residual diethyl ether or other high-retention substances in the crude desmopressin acetate solution;
(3) Removing acetonitrile by adopting a low-pressure distillation mode to obtain a desmopressin acetate first-step sample solution;
(4) Adjusting the pH of the first-step sample solution to 6.0-6.9 by using sodium hydroxide aqueous solution;
(5) And (3) taking octadecylsilane chemically bonded silica filler as a stationary phase, taking 0.1% phosphoric acid with pH adjusted to 6.0-6.9 by sodium hydroxide as a mobile phase A, and taking acetonitrile as a mobile phase B to perform gradient elution on a sample, and purifying to obtain the desmopressin acetate pure product.
2. The method for purifying desmopressin acetate according to claim 1, wherein in the step (2), octadecylsilane chemically bonded silica filler is used as a stationary phase, 0.1% TFA/acetonitrile is used as a mobile phase system for pretreatment, the detection wavelength is 220nm, and the first HPLC linear gradient elution is carried out to remove diethyl ether or other substances with high retention in the crude desmopressin acetate solution; collecting a fraction containing desmopressin acetate sample; the particle size of the stationary phase was 10. Mu.m.
3. The method for purifying desmopressin acetate according to claim 2, wherein in the step (2), the preparation method of 0.1% tfa is as follows: 1000mL of purified water was added with 1mL of TFA and mixed well to give 0.1% TFA.
4. The method for purifying desmopressin acetate according to claim 1, wherein in the step (3), a part of acetonitrile is removed by using a rotary evaporator at a water bath temperature of 30-35 ℃ and a vacuum degree of less than-0.09 MPa, so as to obtain a sample solution of desmopressin acetate in the first step, wherein the sample solution is acidic.
5. The method for purifying desmopressin acetate according to claim 1, wherein in the step (4), the pH of the sample solution of the first step is adjusted to 6.5 with 0.5mol of an aqueous sodium hydroxide solution.
6. The method for purifying desmopressin acetate according to claim 1, wherein in the step (5), octadecylsilane chemically bonded silica filler is used as a stationary phase, 0.1% phosphoric acid with pH adjusted to 6.5 by sodium hydroxide is used as a mobile phase A, acetonitrile is used as a mobile phase B, gradient elution is performed, detection wavelength is 220nm, and second HPLC gradient elution is performed to collect fractions containing desmopressin acetate samples.
7. The method for purifying desmopressin acetate according to claim 1, wherein in the step (5), the preparation method of the mobile phase a is as follows: 1000ml of water was taken, 1ml of phosphoric acid was added, and the pH of the mobile phase was adjusted to 6.5 with sodium hydroxide to obtain a phosphate solution.
8. Use of aqueous sodium hydroxide solution for desmopressin acetate purification, characterized in that: in the process of purifying desmopressin acetate by a high performance liquid phase method, adding a mobile phase system combining sodium hydroxide and phosphate into a desmopressin acetate solution sample for gradient elution can remove impurities with physical and chemical properties similar to those of desmopressin acetate; in the purification process, the pH of a sample to be purified is regulated to 6.0-6.9 by using a sodium hydroxide aqueous solution, 0.1% phosphoric acid with the pH regulated to 6.0-6.9 by using sodium hydroxide is taken as a mobile phase A, acetonitrile is taken as a mobile phase B, gradient elution is carried out, and the desmopressin acetate pure product is obtained by purification.
9. Use according to claim 8, characterized in that: in the purification process, 0.5mol of sodium hydroxide aqueous solution is used for adjusting the pH of a sample to be purified to 6.5, 0.1% phosphoric acid with the pH adjusted to 6.5 by sodium hydroxide is used as a mobile phase A, and acetonitrile is used as a mobile phase B for gradient elution.
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| CN101372504B (en) * | 2007-08-22 | 2011-05-18 | 深圳翰宇药业股份有限公司 | Method for purifying desmopressin |
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