CN114249800A - Preparation method of pamoic acid polypeptide drug - Google Patents
Preparation method of pamoic acid polypeptide drug Download PDFInfo
- Publication number
- CN114249800A CN114249800A CN202010999282.6A CN202010999282A CN114249800A CN 114249800 A CN114249800 A CN 114249800A CN 202010999282 A CN202010999282 A CN 202010999282A CN 114249800 A CN114249800 A CN 114249800A
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- Prior art keywords
- column
- mobile phase
- phase
- solution
- pamoic acid
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 34
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 31
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 31
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 31
- 229940079593 drug Drugs 0.000 title claims abstract description 28
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 61
- 238000005342 ion exchange Methods 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 11
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 9
- 238000012856 packing Methods 0.000 claims abstract description 6
- 229920000642 polymer Polymers 0.000 claims abstract description 6
- 239000012535 impurity Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 70
- 239000012071 phase Substances 0.000 claims description 69
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- 239000000243 solution Substances 0.000 claims description 50
- 238000010828 elution Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
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- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 claims description 2
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- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 claims description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57563—Vasoactive intestinal peptide [VIP]; Related peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
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- Genetics & Genomics (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
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- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
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- Peptides Or Proteins (AREA)
Abstract
The invention relates to a preparation method of a pamoate medicine, which solves the problems of high impurity content and low yield of the traditional polypeptide-pamoate conversion method. The method is mainly characterized in that in a chromatographic column taking reversed-phase polymer packing as a fixed phase, a pamoic acid inorganic salt aqueous solution and an organic solvent are loaded according to a certain proportion and then are subjected to ion exchange with a polypeptide drug to complete salt conversion, and the yield is improved and the residues of ions and the solvent are reduced by controlling an elution program and post-treatment. The method has the advantages of high yield, high product quality, simple and convenient operation, strong process controllability and the like.
Description
Technical Field
The invention belongs to the technical field of polypeptide medicine preparation, and particularly relates to a preparation method of polypeptide-pamoate.
Background
Pamoic acid, chemical name: 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid) having a molecular weight of 388, pka1Is 2.51 and pka2Is 3.1, and the structural formula is as follows:
the compound is a substance capable of generating salts, is commonly used for preparing insoluble salts of medicines in medicinal preparations, has long retention time in vivo, and can slowly release medicines so as to achieve the purpose of long-acting effect. The polypeptide drug has the defects of poor stability, easy degradation in vivo, short half-life period, continuous administration and the like. Therefore, the polypeptide is prepared into the pamoate type, so that the half-life period in vivo of the polypeptide can be effectively prolonged, and the administration frequency is reduced.
The prior art CN105796501A discloses a preparation method of a pamoic acid leuprorelin sustained-release preparation, which comprises the following steps: dissolving leuprorelin acetate and pamoate respectively with ultrapure water, filtering, adding into a reaction kettle, reacting at-10 deg.C-0 deg.C and pH of 6.5-7.5 for 1-2 hr, filtering, precipitating, washing, and drying to obtain leuprorelin acetate pamoate.
CN102504018A discloses a method for preparing melittin transpamoic acid salt (pamoic acid is also called pamoic acid), the steps of transsalting are as follows: dissolving melittin in water for injection, adding sodium pamoate solution under stirring, crystallizing, filtering to separate crystal precipitate, washing with water for injection, and drying to obtain melittin pamoate.
In the prior art, the pamoate type of the polypeptide is obtained by adopting the modes of dissolution, reaction, crystallization and drying, and the method has certain feasibility, relatively simple process and low cost. However, the reaction process of such methods often involves operations such as pH adjustment and temperature control, and polypeptides sensitive to pH and temperature, such as polypeptides containing amino acids such as Cys, Gln, Asn, Met, which are easily oxidized and hydrolyzed, have difficulty in ensuring the yield of products, residual ions and solvents, and stability of samples. In addition, the packing phenomenon during crystallization also results in high ionic and solvent residues.
At present, besides a traditional crystallization drying method, a common method for transferring salt of a polypeptide drug is a chromatography method, the salt transfer is mainly completed through ion exchange, and compared with the crystallization drying method, the method has the advantage that impurities such as organic solvents, ion residues and the like can be well controlled. However, the solubility of the pamoate sample of the polypeptide is low, and when the pamoate is converted by chromatography, the sample cannot be completely eluted, so that the problems of low yield, overproof organic solvent residues and the like are caused. Therefore, there is no report of using chromatography to convert pamoate.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of a pamoate medicine, which comprises the following technical scheme:
a method for preparing a pamoic acid polypeptide medicament comprises the following steps:
step 1: in the preparative chromatography taking the reversed-phase polymer packing as the stationary phase, under the conditions of certain flow velocity and certain column temperature, after the mobile phase balances the chromatographic column, the polypeptide drug solution is loaded to the chromatographic column;
step 2: under the condition of a certain proportion of mobile phase, loading the pamoic acid inorganic salt aqueous solution and the organic solvent into a chromatographic column according to a certain proportion, so that the pamoic acid inorganic salt and the polypeptide drug are subjected to ion exchange;
and step 3: after ion exchange is finished, carrying out gradient elution by using a mobile phase, and collecting a target peak to obtain a pamoate solution of the polypeptide drug;
and 4, step 4: and (3) concentrating the pamoate solution of the polypeptide, and freeze-drying to obtain the pamoate type polypeptide drug solid.
The inorganic phase A in the mobile phase is water, and the organic phase B is selected from one or more of methanol, acetonitrile and ethanol.
The column temperature is determined by the stability of the polypeptide drug, the separation effect on impurities and the temperature resistance range of the filler.
The mobile phase of the gradient elution in the step 3 for the first time period is consistent with the mobile phase in the step 2.
In the above embodiment, the drug is a polypeptide drug having an amino acid number of 3 to 50.
Specifically, the polypeptide drug is selected from leuprolide, triptorelin, goserelin, cetrorelix, degarelix, abarelix, eptifibatide, etibant, capecitabine, thymalfasin, thymopentin, ammostatin, salmon calcitonin, elcatin, teriparatide, exenatide, tedulpit, liraglutide, limalutatide, somatid, pramlintide, nafarelin, ganirelix, octreotide, somatostatin, terlipressin, bivalirudin, atosiban, carbetocin, aviptadil, desmopressin, caspofungin, ziconotide, lanreotide, taltirelin.
Preferably, the reversed-phase polymer filler in the step 1 is one of polystyrene-divinylbenzene, polystyrene-polymethacrylate and polymethacrylate.
Preferably, the diameter of the chromatographic column in the step 1 is 20mm-300 mm.
Preferably, the flow rate of the mobile phase in the step 1 is 30mL/min-1600 mL/min.
Preferably, the proportion of the organic phase in the mobile phase in step 2 is 25% to 65%.
Preferably, the pamoic acid inorganic salt aqueous solution in the step 2 is a sodium salt or potassium salt solution, and the concentration is 20mM-200mM, and more preferably, the concentration is 50mM-70 mM.
Preferably, the organic solvent in step 2 is selected from one or more of acetonitrile, ethanol and methanol, and the proportion of the organic solvent is 25-65%.
Preferably, the volume of the mobile phase required for the ion exchange between the pamoic acid inorganic salt and the polypeptide drug in the step 2 is 2 to 5 times of the column volume, and more preferably, 3 to 4 times of the column volume.
Preferably, the detection wavelength in step 3 is 230nm, and the specific gradient elution procedure is as follows, wherein A and B are volume percentages,
in order to more clearly understand the technical features and the problems solved by the present invention, the following supplementary comparison tables are provided:
when the drug is converted into pamoate, the solubility of the drug is low, so that a sample cannot be completely eluted during separation by chromatography, the problems of great reduction in yield and large residual quantity of organic solvents and the like are inevitably caused, and the preparation of pamoate of the drug by chromatography cannot be considered by a person skilled in the art. The invention creatively utilizes chromatography to prepare the pamoate of the medicine, in the preparative chromatography taking reversed-phase polymer filler as a fixed phase, the inorganic salt aqueous solution of pamoic acid and organic solvent are loaded according to a certain proportion and then are subjected to ion exchange with the polypeptide medicine to complete salt conversion, and through the control of an elution procedure and post-treatment, unexpectedly, the purification and salt conversion can be completed through one-step chromatography, the yield is improved, the ion residue and the organic solvent residue are reduced, and the existing technical bias is overcome. Compared with the prior art, the method has the advantages of high yield, low ion residual quantity, low organic solvent residual quantity, high product quality, simple and convenient operation, strong process controllability and the like.
Drawings
FIG. 1 is a liquid chromatogram of triptorelin pamoate;
FIG. 2 is a liquid chromatogram of terlipressin pamoate;
FIG. 3 is a liquid chromatogram of leuprorelin pamoate;
Detailed Description
The present invention is described in further detail below with reference to specific examples so that those skilled in the art can further understand the present invention. The examples should not be construed as limiting the scope of protection.
Example 1
The salt conversion condition is as follows: preparing a chromatographic column: the filler was polystyrene-divinylbenzene UniPS 40-300. The diameter of the column is 30mm, the temperature of the column is 25 ℃, the flow rate is 30mL/min, the detection wavelength is 230nm, and the mobile phase: phase A: water, phase B: ethanol, gradient elution procedure is shown in table 1:
table 1 gradient elution procedure of example 1
A salt conversion process:
a, balancing a chromatographic column by using 5% ethanol water solution for 10min, and loading the atosiban crude product solution to the chromatographic column at the flow rate of 30 mL/min;
b. under the condition of 25% ethanol mobile phase, 200mM pamoic acid disodium salt water solution and ethanol pass through a column according to the proportion of 75:25, and ion exchange is carried out on the pamoic acid disodium salt water solution and an atosiban crude product solution, wherein the exchange time is 3 times of the volume of the column;
c. eluting with linear gradient for 75min, collecting target peak, concentrating, and freeze drying.
The yield is 98 percent, the purity is 98.38 percent, the content of sodium ions is 0.05 percent, trifluoroacetic acid radicals are not detected, and the content of ethanol is 0.05 percent.
Example 2
The salt conversion condition is as follows: a chromatographic column: the filler was polystyrene-divinylbenzene UniPS40-300 with a column diameter of 30 mm. The column temperature is 25 ℃, the flow rate is 30mL/min, the detection wavelength is 230nm, and the mobile phase: phase A: water, phase B: ethanol, gradient elution procedure is shown in table 2:
table 2 gradient elution procedure of example 2
A salt conversion process:
a, balancing a chromatographic column by using 5% ethanol water solution for 10min, and loading a triptorelin solution to the chromatographic column at the flow rate of 30 mL/min;
b. under the condition of 25% ethanol mobile phase, 50mM pamoic acid disodium salt water solution and ethanol pass through a column according to the proportion of 75:25, and carry out ion exchange with triptorelin solution, wherein the volume of the passing column exchange is 3 times of the volume of the column;
c. gradient eluting for 75min, collecting target peak, concentrating, and freeze drying.
The yield is 98%, the detection purity is 98.82% (see figure 1), the content of sodium ions is 0.06%, and the content of ethanol is 0.04%;
example 3
The salt conversion condition is as follows: a chromatographic column: the filler was polystyrene-polymethacrylate UniPSN40-300, and the column diameter was 150 mm. Column temperature 25 ℃, flow rate 400mL/min, detection wavelength 230nm, mobile phase: phase A: water, phase B: acetonitrile, gradient elution procedure see table 3:
table 3 gradient elution procedure of example 3
A salt conversion process:
a, balancing the chromatographic column with 5% acetonitrile water solution for 10min, and loading the triptorelin solution to the chromatographic column at the flow rate of 400 mL/min;
b. under the condition of 26% acetonitrile mobile phase, passing 30mM pamoic acid disodium salt water solution and acetonitrile through a column according to the proportion of 75:25, and carrying out ion exchange with triptorelin solution, wherein the volume of the ion exchange after passing through the column is 4 times of the volume of the column;
c. gradient eluting for 75min, collecting target peak, concentrating, and freeze drying.
The yield is 99 percent, and the content of sodium ions and acetonitrile are measured to be 0.06 percent and 0.03 percent respectively;
example 4
The salt conversion condition is as follows: a chromatographic column: the packing material is UniPMM40-500 of polymethacrylate, and the column diameter is 300 mm. Column temperature 25 ℃, flow rate 1600mL/min, detection wavelength 230nm, mobile phase: phase A: water, phase B: ethanol, gradient elution procedure see table 4:
table 4 gradient elution procedure of example 4
A salt conversion process:
a, balancing a chromatographic column by using 5% ethanol water solution for 10min, and loading a triptorelin solution to the chromatographic column at the flow rate of 1600 mL/min;
b. under the condition of 25% ethanol mobile phase, 70mM pamoic acid disodium salt aqueous solution and ethanol pass through a column according to the proportion of 75:25, and carry out ion exchange with triptorelin solution, wherein the volume of the passing column exchange is 5 times of the volume of the column;
c. gradient eluting for 80min, collecting target peak, concentrating, and freeze drying.
The yield is 98 percent, and the content of sodium ions and ethanol are measured to be 0.07 percent and 0.06 percent respectively;
example 5
The salt conversion condition is as follows: a chromatographic column: the filler was polystyrene-divinylbenzene UniPS40-1000 with a column diameter of 30 mm. The column temperature is 25 ℃, the flow rate is 30mL/min, the detection wavelength is 230nm, and the mobile phase: phase A: water, phase B: acetonitrile, gradient elution procedure see table 5:
table 5 gradient elution procedure of example 5
A salt conversion process:
a, balancing the chromatographic column with 5% acetonitrile water solution for 10min, and loading the triptorelin solution to the chromatographic column at the flow rate of 30 mL/min;
b. under the condition of 27% acetonitrile mobile phase, 50mM dipotassium pamoate water solution and acetonitrile pass through a column according to the proportion of 70:30, and ion exchange is carried out on the dipotassium pamoate water solution and the acetonitrile and triptorelin solution, wherein the volume of the passing column exchange is 2 times of the volume of the column;
c. gradient eluting for 90min, collecting target peak, concentrating, and freeze drying.
The yield is 98 percent, and the potassium ion content is measured to be 0.06 percent, and the acetonitrile content is measured to be 0.03 percent;
example 6
The salt conversion condition is as follows: a chromatographic column: the packing was polystyrene-divinylbenzene UniPSA30-300 with a column diameter of 30 mm. The column temperature is 25 ℃, the flow rate is 30mL/min, the detection wavelength is 230nm, and the mobile phase: phase A: water, phase B: ethanol, gradient elution procedure is shown in table 6:
table 6 gradient elution procedure for example 6
A salt conversion process:
equilibrating the column with 5% aqueous ethanol for 10min, loading the terlipressin solution onto the column at a flow rate of 30 mL/min;
b. under the condition of 25% ethanol mobile phase, 50mM pamoic acid disodium salt water solution and ethanol pass through a column according to the proportion of 75:25, and carry out ion exchange with terlipressin solution, wherein the volume of the passing column exchange is 3 times of the volume of the column;
c. eluting with linear gradient for 75min, collecting target peak, concentrating, and freeze drying.
The yield is 97 percent, the purity is 98.44 percent (see figure 2), and the sodium ion content is 0.06 percent and the ethanol content is 0.03 percent;
example 7
The salt conversion condition is as follows: a chromatographic column: the filler was UniNM50-300 from polystyrene-divinylbenzene with a column diameter of 30 mm. The column temperature is 25 ℃, the flow rate is 30mL/min, the detection wavelength is 230nm, and the mobile phase: phase A: water, phase B: ethanol, gradient elution procedure is shown in table 7:
table 7 gradient elution procedure for example 7
A salt conversion process:
a, balancing a chromatographic column by using 5% ethanol water solution for 10min, and loading the leuprorelin solution to the chromatographic column at the flow rate of 30 mL/min;
b. under the condition of 30% ethanol mobile phase, 50mM pamoic acid disodium salt water solution and ethanol pass through a column according to the proportion of 70:30, and are subjected to ion exchange with leuprorelin solution, wherein the volume of the ion exchange after passing through the column is 3 times of the volume of the column;
c. eluting with linear gradient for 75min, collecting target peak, concentrating, and freeze drying.
The yield is 97%, the purity is 98.14% (see figure 3), and the sodium ion content is 0.07%, and the ethanol content is 0.06%.
Example 8
The salt conversion condition is as follows: a chromatographic column: the filler was polystyrene-divinylbenzene UniPS10-300 with a column diameter of 50 mm. The column temperature is 5 ℃, the flow rate is 80mL/min, the detection wavelength is 230nm, and the mobile phase: phase A: water, phase B: ethanol, gradient elution procedure see table 8:
table 8 gradient elution procedure for example 8
A salt conversion process:
a, balancing the chromatographic column with 5% ethanol water solution for 10min, and loading the caspofungin solution to the chromatographic column at the flow rate of 80 mL/min;
b. under the condition of 25% ethanol mobile phase, 50mM pamoic acid disodium salt aqueous solution and ethanol pass through a column according to the proportion of 75:25, and carry out ion exchange with caspofungin solution, wherein the volume of the passing column exchange is 3 times of the volume of the column;
c. eluting with linear gradient for 75min, collecting target peak, concentrating, and freeze drying.
The yield is 98 percent, and the content of sodium ions and ethanol are measured to be 0.07 percent and 0.03 percent respectively;
example 9
The salt conversion condition is as follows: a chromatographic column: the filler was polystyrene-divinylbenzene UniPS40-300 with a column diameter of 100 mm. Column temperature 25 ℃, flow rate 200mL/min, detection wavelength 230nm, mobile phase: phase A: water, phase B: acetonitrile, gradient elution procedure see table 9:
table 9 gradient elution procedure for example 9
A salt conversion process:
equilibrating the column with 5% acetonitrile in water for 10min, loading the teduglutide solution onto the column at a flow rate of 200 mL/min;
b. under the condition of 65% acetonitrile mobile phase, 200mM dipotassium pamoate water solution and acetonitrile pass through a column according to the proportion of 35:65, and ion exchange is carried out on the dipotassium pamoate water solution and the acetonitrile and the tedioutide solution, wherein the volume of the passing through the column is 3 times of the volume of the column;
c. eluting with linear gradient for 75min, collecting target peak, concentrating, and freeze drying.
The yield is 98 percent, and the potassium ion content and the acetonitrile content are measured to be 0.08 percent and 0.03 percent respectively;
example 10
The salt conversion condition is as follows: a chromatographic column: the filler was polystyrene-divinylbenzene UniPS40-300 with a column diameter of 100 mm. Column temperature 38 ℃, flow rate 200mL/min, detection wavelength 230nm, mobile phase: phase A: water, phase B: methanol, gradient elution procedure is shown in table 10:
table 10 gradient elution procedure for example 10
A salt conversion process:
equilibrating the column with 5% aqueous methanol for 10min, loading the exenatide solution onto the column at a flow rate of 200 mL/min;
b. under the condition of 40% methanol mobile phase, 100mM pamoic acid disodium salt aqueous solution and methanol are passed through a column according to the proportion of 60:40, and ion exchange is carried out on the pamoic acid disodium salt aqueous solution and the exendin solution, wherein the volume of the exchange of the passing column is 3 times of the volume of the column;
c. eluting with linear gradient for 75min, collecting target peak, concentrating, and freeze drying.
The yield is 98 percent, and the content of sodium ions and the content of methanol are measured to be 0.08 percent and 0.04 percent respectively;
comparative example 1
With atosiban: the molar ratio of the pamoic acid is 1:1, the alkaline pamoic acid sodium salt solution is added into the atosiban crude product solution, and the solution is stirred until crystallization is separated out. The precipitate was filtered off, washed with water and dried under vacuum to give atosiban pamoate.
The yield is 83 percent, the purity is 90.39 percent, and the sodium ion content is 0.90 percent, the trifluoroacetic acid content is 0.36 percent, and the isopropyl ether content is 0.28 percent. (crude atosiban contains residual trifluoroacetic acid and isopropyl ether impurities during the synthesis process)
Comparative example 2
A salt conversion process: with atosiban: the molar ratio of the pamoic acid is 1:1, the alkaline pamoic acid sodium salt solution is added into the atosiban crude product solution, and the solution is stirred until crystallization is separated out. The precipitate was filtered off, washed with water and dried under vacuum to give atosiban pamoate.
And (3) purification conditions: preparing a chromatographic column: the filler is UniPS40-300 of polystyrene-divinylbenzene, the diameter of a column is 30mm, the temperature of the column is 25 ℃, the flow rate is 30mL/min, the detection wavelength is 230nm, and the mobile phase: phase A: water, phase B: ethanol, gradient elution procedure is shown in table 11:
table 11 gradient elution procedure for comparative example 2
And (3) purification process:
a. dissolving atosiban pamoate obtained by the salt conversion with 25% ethanol;
b, balancing the chromatographic column with 25% ethanol water solution for 10min, loading the ethanol solution of atosiban pamoate onto the chromatographic column at the flow rate of 30mL/min, and performing gradient elution;
c. eluting with linear gradient for 65min, collecting target peak, concentrating, and freeze drying.
The total yield is 81 percent, the purity is 98.17 percent, and the sodium ion content is 0.50 percent and the ethanol content is 0.06 percent.
Claims (13)
1. A preparation method of a pamoic acid polypeptide drug is characterized by comprising the following steps:
step 1: in the preparative chromatography taking the reversed-phase polymer packing as the stationary phase, under the conditions of certain flow velocity and certain column temperature, after the mobile phase balances the chromatographic column, the polypeptide drug solution is loaded to the chromatographic column;
step 2: under the condition of a certain proportion of mobile phase, loading the pamoic acid inorganic salt aqueous solution and the organic solvent into a chromatographic column according to a certain proportion, so that the pamoic acid inorganic salt and the polypeptide drug are subjected to ion exchange;
and step 3: after ion exchange is finished, carrying out gradient elution by using a mobile phase, and collecting a target peak to obtain a pamoate solution of the polypeptide drug;
and 4, step 4: and (3) concentrating the pamoate solution of the polypeptide, and freeze-drying to obtain the pamoate type polypeptide drug solid.
The inorganic phase A in the mobile phase is water, and the organic phase B is selected from one or more of methanol, acetonitrile and ethanol.
The column temperature is determined by the stability of the polypeptide drug, the separation effect on impurities and the temperature resistance range of the filler.
The mobile phase of the gradient elution in the step 3 for the first time period is consistent with the mobile phase in the step 2.
2. The method of claim 1, wherein the drug is a polypeptide drug having an amino acid number of 3 to 50.
3. The process according to claim 1, wherein the drug is selected from the group consisting of leuprorelin, triptorelin, goserelin, cetrorelix, degarelix, abarelix, eptifibatide, icatibant, capecitabine, thymalfasin, thymopentin, ammosteine, salmon calcitonin, elcalcitonin, teriparatide, exenatide, tedulpit, liraglutide, limaludin, somatrum, pramine, nafarelin, ganirelix, octreotide, somatostatin, terlipressin, bilvadine, atosiban, carbetocin, aplidil, desmopressin, caspofungin, ziconotide, lanreotide, and taltirelin.
4. The method of claim 1, wherein the chromatographic column has a diameter of 20mm to 300 mm.
5. The method of claim 1, wherein the reverse phase polymer filler is one of polystyrene-divinylbenzene, polystyrene-polymethacrylate, and polymethacrylate.
6. The method according to claim 1, wherein the flow rate in step 1 is 30mL/min to 1600 mL/min.
7. The method according to claim 1, wherein the proportion of the organic phase in the mobile phase in step 2 is 25% to 65%.
8. The method according to claim 1, wherein the aqueous solution of an inorganic salt of pamoic acid in step 2 is a sodium salt or potassium salt solution, and the concentration of the salt solution is 20mM-200 mM.
9. The method according to claim 1, wherein the concentration of the aqueous solution of pamoic acid in step 2 is 50mM-70 mM.
10. The preparation method according to claim 1, wherein the organic solvent in the step 2 is one or more selected from acetonitrile, ethanol and methanol, and the proportion of the organic solvent is 25-65%.
11. The method according to claim 1, wherein the volume of the mobile phase required for ion exchange in step 2 is 2 to 5 column volumes.
12. The method according to claim 1, wherein the volume of the mobile phase required for the ion exchange in step 2 is 3 to 4 column volumes.
13. The preparation method according to any one of claims 1 and 7, wherein the detection wavelength is 230nm, and the specific gradient elution procedure in step 3 is as follows, wherein A and B are volume percentages:
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| WO2024208829A1 (en) | 2023-04-03 | 2024-10-10 | Ferring B.V. | Methods of manufacturing peptide salts |
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