CN114369142A - Method for purifying desmopressin acetate - Google Patents
Method for purifying desmopressin acetate Download PDFInfo
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- CN114369142A CN114369142A CN202111673487.6A CN202111673487A CN114369142A CN 114369142 A CN114369142 A CN 114369142A CN 202111673487 A CN202111673487 A CN 202111673487A CN 114369142 A CN114369142 A CN 114369142A
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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 method for purifying desmopressin acetate, and mainly solves the technical problems that impurities with low purity, low yield and similar physicochemical properties are difficult to remove when desmopressin acetate is separated and obtained in the prior art. According to the method, crude peptide is dissolved in a purified water solution, octadecylsilane chemically bonded silica filler is used as a stationary phase, sodium hydroxide is added into a sample to be purified, and then purification is carried out, so that the desmopressin acetate bulk drug with high purity, high quality and high yield is obtained. In the process of purifying desmopressin acetate by a high performance liquid chromatography, sodium hydroxide is added into a desmopressin acetate solution sample, impurities similar to the physical and chemical properties of the desmopressin acetate are removed by chromatographic gradient elution combining octadecylsilane chemically bonded silica filler and phosphate mobile phase, and the sample with the purity of over 99.0 percent and the yield of 80.0 percent can be obtained at one time; improves the purity and the yield of the finished product of the desmopressin acetate.
Description
Technical Field
The invention relates to the field of peptide purification, in particular to a method for purifying desmopressin acetate.
Background
The name of Chinese: desmopressin acetate; the name of English: desmopressin; peptide sequence:
Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH2
the molecular formula is as follows: c46H64N14O12S2(ii) a Precise molecular weight: 1068.4270 molar molecular weight: 1069.2240 chemical structural formula:
desmopressin acetate is artificially synthesized, and 9 amino acids form cyclic nonapeptide, the effect of the cyclic nonapeptide is similar to that of human vasopressin, but the antidiuretic effect is obviously enhanced, and the effect on smooth muscle is weak, so the adverse effect of boosting pressure is avoided. The ratio of the antidiuretic action/the vasopressin is about 1200-3000 times of that of vasopressin, and the antidiuretic action time is longer than that of vasopressin and can reach 6-24 hours. Its oxytocin activity is also reduced obviously. In addition, the high dose of the product, namely 0.3 mu g/kg of intravenous injection or subcutaneous injection, can increase the activity of procoagulant factor VIII in blood plasma by 2-4 times, and can also increase von Willebrand disease antigen factor (vWF: Ag) in blood and release fibrinogen plasminogen activator (t-PA), so that the product can be used for controlling or preventing hemorrhage of certain diseases during minor surgery or hemorrhage induced by drugs.
The desmopressin acetate composition can generate a plurality of impurities which affect the purity and yield of a 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 overcome the defects in the prior art, the invention aims to provide a novel method for purifying desmopressin acetate, which can effectively improve the purity and yield of the desmopressin acetate.
In order to achieve the above object, the present invention adopts the following technical solutions:
the invention relates to a method for purifying desmopressin acetate, which comprises the following steps: dissolving desmopressin acetate crude peptide in a purified water solution, then using octadecylsilane bonded silica gel filler as a stationary phase, adding sodium hydroxide into a sample to be purified, and purifying twice to obtain purified desmopressin acetate.
The invention relates to a purification method of desmopressin acetate, which adopts a further preferable technical scheme that the purification method comprises the following specific steps:
(1) dissolving the crude desmopressin acetate in a purified water solution to obtain a crude peptide water solution of desmopressin acetate, filtering the aqueous solution of desmopressin acetate with a filter membrane to remove insoluble particles, and collecting the filtrate for later use;
(2) octadecylsilane chemically bonded silica filler is used as a fixed phase, TFA/acetonitrile is used as a mobile phase system for pretreatment, and residual ether or other high-retention substances in the crude desmopressin acetate solution are removed;
(3) removing acetonitrile by adopting a low-pressure distillation mode to obtain a desmopressin acetate first-step sample solution;
(4) adjusting the pH value of the sample solution in the first step to 6.0-6.9 by using an aqueous solution of sodium hydroxide;
(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 to be used as a mobile phase system, and purification is carried out to obtain the desmopressin acetate pure product.
The invention relates to a purification method of desmopressin acetate, which adopts a further preferable technical scheme that 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, first HPLC linear gradient elution is carried out, and residual ether or other high-retention substances in a crude desmopressin acetate crude product solution are removed; collecting a fraction of a sample containing desmopressin acetate; the particle size of the stationary phase was 10 μm.
The purification method of desmopressin acetate, disclosed by the invention, further preferably adopts the technical scheme 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 a further preferable technical scheme, in the step (3), a rotary evaporator is used for removing part of acetonitrile at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 MPa to obtain a first-step sample solution of the desmopressin acetate, wherein the sample solution is acidic.
In the further preferable technical scheme of the method for purifying desmopressin acetate, in the step (4), 0.5mol of aqueous sodium hydroxide solution is used for adjusting the pH value of the first-step sample solution to 6.5.
According to a further preferable technical scheme, 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 the pH value to 6.5/acetonitrile to be used as a mobile phase system, the detection wavelength is 220nm, secondary HPLC gradient elution is carried out, and fractions containing a desmopressin acetate sample are collected.
The purification method of desmopressin acetate provided by the invention further preferably adopts the technical scheme that in the step (5), 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.
The invention also discloses the application of the sodium hydroxide aqueous solution in the purification of the desmopressin acetate, and in the process of purifying the desmopressin acetate by the high performance liquid chromatography, the impurities with the physical and chemical properties similar to that of the desmopressin acetate can be removed by adding a mobile phase system combining sodium hydroxide and phosphate into a desmopressin acetate solution sample to perform gradient elution. 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, and 0.1 percent of phosphoric acid and sodium hydroxide are used for adjusting the pH value to 6.5/acetonitrile to be used as a mobile phase system for purification to obtain a pure desmopressin acetate.
Compared with the prior art, the invention has the advantages that: in the process of purifying desmopressin acetate by a high performance liquid chromatography, sodium hydroxide is added into a desmopressin acetate solution sample, impurities similar to the physical and chemical properties of the desmopressin acetate are removed by chromatographic gradient elution combining octadecylsilane chemically bonded silica filler and phosphate mobile phase, and the sample with the purity of over 99.0 percent and the yield of 80.0 percent can be obtained at one time; improves the purity and the yield of the finished product of the desmopressin acetate.
Drawings
FIG. 1 is an HPLC chart of crude desmopressin acetate of example 2;
FIG. 2 is an HPLC chart of the finished desmopressin acetate of example 2.
Detailed Description
The invention is described in detail below with reference to the figures and the embodiments.
Example 1, a method of purifying desmopressin acetate comprising the steps of:
step one, pretreating a desmopressin acetate crude product to obtain a desmopressin acetate crude peptide aqueous solution;
the pretreatment step comprises the following steps: dissolving the crude desmopressin acetate in a purified water solution to obtain a crude peptide water solution of desmopressin acetate; filtering the desmopressin acetate water solution with a filter membrane to remove insoluble particles, and collecting the filtrate for later use. Preferably, the filter is a 0.45 μm filter.
Step two, using octadecylsilane chemically bonded silica filler as a stationary phase, using 0.1% TFA/acetonitrile as a mobile phase system for pretreatment, wherein the detection wavelength is 220nm, and performing first HPLC linear gradient elution to remove residual ether or other high-retention substances in the desmopressin acetate crude product solution; collecting a fraction of a sample containing desmopressin acetate; 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 obtain 0.1% TFA.
And step three, removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 25-30 ℃ and the vacuum degree of below-0.09 MPa to obtain a first-step sample solution of the desmopressin acetate, 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 HPLC purification for the second time 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 to be used as a mobile phase system, the detection wavelength is 220nm, the HPLC gradient elution is carried out for the second time, and fractions containing desmopressin acetate samples are collected. 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 and obtain a finished desmopressin acetate product with high purity and high yield, the method is used for carrying out purification experiments on crude peptide samples containing 3g, 8g and 33g of desmopressin acetate, and the experimental processes are as follows:
example 2:
taking a desmopressin acetate crude product, wherein an HPLC chart of the desmopressin acetate crude product is shown in figure 1;
sample treatment: a sample containing 3g of desmopressin acetate crude peptide (crude peptide: 4.2 g) was dissolved in a purified aqueous solution, and after complete dissolution, it was filtered through a 0.45 μm filter. Collecting the filtered crude peptide water solution of desmopressin acetate for later use.
First step HPLC purification
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (30mm × 250mm, 10 μm); taking 0.1% TFA (1000 ml of water is taken, 1ml of TFA is added and mixed uniformly) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate was 10mL per minute; the detection wavelength is 220 nm; the loading of the single needle was 1g, and elution was carried out with the elution gradient shown in the following table.
Collecting the fraction of desmopressin acetate sample. And removing part of acetonitrile by using a rotary evaporator at a water bath temperature of 25-30 ℃ and a vacuum degree of below-0.09 Mpa. And obtaining a desmopressin acetate first-step sample solution.
Second step HPLC purification
Adjusting the pH value of the first step sample solution to 6.5 by using 0.5mol of aqueous sodium hydroxide solution;
chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (30mm × 250mm, 10 μm); taking phosphate solution (1000 ml water is added with 1ml phosphoric acid, and the pH value is adjusted to 6.5 by sodium hydroxide) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate was 10mL per minute; the detection wavelength is 220 nm; the loading was 1.5g, and elution was carried out with the elution gradient shown in the following table.
Collecting the fraction of desmopressin acetate sample with the purity of more than 99.0%. The solution contains 2.50g of desmopressin acetate quantitatively through a reference substance, and the yield reaches 83.33 percent. The HPLC chart of the pure desmopressin acetate is shown in FIG. 2.
Example 3
Taking desmopressin acetate crude product
Sample treatment: a sample containing 8g of desmopressin acetate crude peptide (crude peptide: 11.4 g) was dissolved in the purified aqueous solution, and after complete dissolution, it was filtered through a 0.45 μm filter. The filtered crude peptide aqueous solution was collected for use.
First step HPLC purification
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (50mm × 250mm, 10 μm); taking 0.1% TFA (1000 ml of water is taken, 1ml of TFA is added and mixed uniformly) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate was 50mL per minute; the detection wavelength is 220 nm; the loading was 2.7g, and elution was carried out with the elution gradient shown in the following table.
Collecting the fraction of desmopressin acetate sample. And removing part of acetonitrile by using a rotary evaporator at a water bath temperature of 25-30 ℃ and a vacuum degree of below-0.09 Mpa. And obtaining a desmopressin acetate first-step sample solution.
Second step HPLC purification
Adjusting the pH value of the first step sample solution to 6.5 by using 0.5mol of aqueous sodium hydroxide solution;
chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (50mm × 250mm, 10 μm); taking phosphate solution (1000 ml water is added with 1ml phosphoric acid, and the pH value is adjusted to 6.5 by sodium hydroxide) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate was 50mL per minute; the detection wavelength is 220 nm; the loading was 4.1g, and elution was carried out with the elution gradient shown in the following table.
Collecting the fraction of desmopressin acetate sample with the purity of more than 99.0%. The solution contains 6.73g of desmopressin acetate quantitatively through a reference substance, and the yield reaches 84.12 percent.
Example 4
Taking desmopressin acetate crude product
Sample treatment: a sample containing 33g of desmopressin acetate crude peptide (crude peptide: 47.1 g) was dissolved in a purified aqueous solution, and after complete dissolution, it was filtered through a 0.45 μm filter. The filtered crude peptide aqueous solution was collected for use.
First step HPLC purification
Chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler as stationary phase (100mm × 250mm, 10 μm); taking 0.1% TFA (1000 ml of water is taken, 1ml of TFA is added and mixed uniformly) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 150mL per minute; the detection wavelength is 220 nm; the amount of the sample was 11 g.
Elution is performed with the following table elution gradient.
Collecting the fraction containing desmopressin acetate sample. And removing part of acetonitrile by using a rotary evaporator at a water bath temperature of 25-30 ℃ and a vacuum degree of below-0.09 Mpa. And obtaining a desmopressin acetate first-step sample solution.
Adjusting the pH value of the first step sample solution to 6.5 by using 0.5mol of aqueous sodium hydroxide solution;
chromatographic conditions are as follows: chromatographic column with octadecylsilane chemically bonded silica filler stationary phase (100mm × 250mm, 10 μm); taking phosphate solution (1000 ml of water is added with 1ml of phosphoric acid, and the pH value is adjusted to 6.5 by sodium hydroxide) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 150mL per minute; the detection wavelength is 220 nm; the amount of the sample was 16.6 g. Elution is performed with the following table elution gradient.
Collecting the fraction of desmopressin acetate sample with the purity of more than 99.0%. The solution contains 28.2g of desmopressin acetate quantitatively through a reference substance, and the yield reaches 85.45 percent.
| Desmopressin acetate-containing sample/g | Mass/g of purified desmopressin acetate | Yield of | Purity of | |
| Example 2 | 3 | 2.50 | 83.33％ | More than 99.0 percent |
| Example 3 | 8 | 6.73 | 84.12％ | More than 99.0 percent |
| Example 4 | 32 | 28.21 | 85.45％ | More than 99.0 percent |
From the above 3 experimental examples, it can be known that the purity of desmopressin acetate obtained by purifying the desmopressin acetate crude product by the method is more than 99.0%.
The experimental examples verify that the purity of the desmopressin acetate purified by the HPLC method is more than 99.0%, the yield of the desmopressin acetate purified by the HPLC method is more than 80.0%, and the purity and the yield of the desmopressin acetate are improved.
1. 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 (10)
1. A method of purifying desmopressin acetate, comprising: dissolving desmopressin acetate crude peptide in a purified water solution, then using octadecylsilane bonded silica gel filler as a stationary phase, adding sodium hydroxide into a sample to be purified, and purifying twice to obtain purified desmopressin acetate.
2. The method for purifying desmopressin acetate according to claim 1, comprising the following steps:
(1) dissolving the crude desmopressin acetate in a purified water solution to obtain a crude peptide water solution of desmopressin acetate, filtering the aqueous solution of desmopressin acetate with a filter membrane to remove insoluble particles, and collecting the filtrate for later use;
(2) octadecylsilane chemically bonded silica filler is used as a fixed phase, TFA/acetonitrile is used as a mobile phase system for pretreatment, and residual ether or other high-retention substances in the crude desmopressin acetate solution are removed;
(3) removing acetonitrile by adopting a low-pressure distillation mode to obtain a desmopressin acetate first-step sample solution;
(4) adjusting the pH value of the sample solution in the first step to 6.0-6.9 by using an aqueous solution of sodium hydroxide;
(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 to be used as a mobile phase system, and purification is carried out to obtain the desmopressin acetate pure product.
3. 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 first HPLC linear gradient elution is performed to remove residual diethyl ether or other highly-retained substances in the solution of the crude desmopressin acetate; collecting a fraction of a sample containing desmopressin acetate; the particle size of the stationary phase was 10 μm.
4. The method for purifying desmopressin acetate according to claim 1, wherein the 0.1% TFA is prepared by the following steps in step (2): 1000mL of purified water was added with 1mL of TFA and mixed well to give 0.1% TFA.
5. The method for purifying desmopressin acetate according to claim 1, wherein in the step (3), a rotary evaporator is used to remove part of acetonitrile at a water bath temperature of 30-35 ℃ and a vacuum degree of-0.09 MPa or less, so as to obtain a first-step sample solution of desmopressin acetate, wherein the sample solution is acidic.
6. The method of claim 1, wherein in step (4), the pH of the first sample solution is adjusted to 6.5 with 0.5mol of aqueous sodium hydroxide.
7. 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 and sodium hydroxide are used to adjust pH to 6.5/acetonitrile to be used as a mobile phase system, the detection wavelength is 220nm, and a second HPLC gradient elution is performed to collect the fraction containing the desmopressin acetate sample.
8. The method for purifying desmopressin acetate according to claim 1, wherein in the step (5), the phosphate solution is prepared by: 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.
9. The application of the sodium hydroxide water solution in the purification of desmopressin acetate is characterized in that: in the process of purifying desmopressin acetate by a high performance liquid chromatography, a mobile phase system combining sodium hydroxide and phosphate is added into a desmopressin acetate solution sample for gradient elution to remove impurities with similar physicochemical properties to the desmopressin acetate.
10. Use according to claim 9, characterized in that: 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, and 0.1 percent of phosphoric acid and sodium hydroxide are used for adjusting the pH value to 6.5/acetonitrile to be used as a mobile phase system for purification to obtain a pure desmopressin acetate.
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