CN115656391B - Method for detecting impurities contained in teriparatide - Google Patents
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- CN115656391B CN115656391B CN202211587185.1A CN202211587185A CN115656391B CN 115656391 B CN115656391 B CN 115656391B CN 202211587185 A CN202211587185 A CN 202211587185A CN 115656391 B CN115656391 B CN 115656391B
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Abstract
The invention discloses a method for detecting impurities contained in teriparatide, and belongs to the technical field of biomedical detection. The invention solves the problems that the existing teriparatide detection standard is easy to oxidize teriparatide in the detection process, the detected oxidation impurity level is higher than the true value, and the detection capability on part of inserted peptide impurities and part of isomeric impurities is unavailable. According to the invention, the anionic active agent sodium dodecyl sulfate is used as a mobile phase, and negative charges carried by the mobile phase can be combined with positive charges on the surface of the polypeptide, so that the elution capability of the mobile phase on the polypeptide is enhanced, the separation capability of impurities and teriparatide is enhanced, and the content of isomeric impurities of insert peptide and isoleucine in teriparatide can be accurately detected. Meanwhile, the invention also adds antioxidant phenol in the mobile phase, thereby ensuring that teriparatide is not oxidized in the detection process and ensuring the accuracy of detection of oxidized impurities.
Description
Technical Field
The invention relates to a method for detecting impurities contained in teriparatide, belonging to the technical field of biomedical detection.
Background
The teriparatide has the chemical name of L-seryl-L-valyl-L-seryl-L-alpha-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparaginyl-L-leucyl-glycyl-L-lysyl-L-histidyl-L-leucyl-L-asparaginyl-L-seryl-L-methionyl-L-alpha-glutamyl-L-arginyl-L-valyl-L-alpha-glutamyl-L-tryptophanyl-L-leucyl-L-arginyl-L-lysyl-L-leucyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidyl-L-asparaginyl-L-phenylalaninyl-L-phenylalanine, is white or white powder, and has the molecular formula of C 181 H 291 N 55 O 51 S 2 And the molecular weight is 4117.8. The product is suitable for treating osteoporosis of postmenopausal women with high fracture risk, can obviously reduce the fracture risk of vertebra and non-vertebra of postmenopausal women, but has no proved effect on reducing the fracture risk of hip bone; foreign application for treating bone injury; osteoporosis; male osteoporosis; postmenopausal osteoporosis.
Teriparatide is a human parathyroid hormone analogue, has the same structure with 34N-terminal amino acid sequences of natural parathyroid hormone (PTH), can be combined with a PTH-1 receptor to play the physiological role of PTH on bones and kidneys, and does not have the adverse effect of C-terminal peptide on bone metabolism. Research shows that the medicine can effectively increase the number and activity of osteoblasts, thereby promoting the production of new bones, increasing bone density, reducing fracture risk, and enhancing curative effect by being combined with other medicines for treating osteoporosis.
Related substance impurities contained in teriparatide generally consist of impurities introduced in the starting material, by-products of chemical synthesis reactions and degradation products during storage. The related substances can reduce the proportion of teriparatide in a molecular state, so that the drug effect is reduced, the side effect of the drug is increased, and the potential safety hazard is brought to patients. Therefore, the detection and control of related substances in teriparatide become a non-negligible aspect of the drug preparation process.
Teriparatide is a peptide compound prepared by solid-phase synthesis of protected amino acid, the structure of the teriparatide contains 2 molecules of methionine, and the methionine is easy to oxidize, so that the teriparatide is easy to generate 3 oxidation impurities; the teriparatide structure contains leucine and isoleucine which are isomers, and starting materials of the teriparatide structure are impurities to form isomeric impurities of the teriparatide; starting materials and impurity peptides which can generate racemic amino acid in the synthesis process; the teriparatide consists of 34 amino acids, and insertion peptides and deletion peptides are easy to form in the synthesis process.
In the existing detection methods, USP40, EP 9.0 and JS20160050 all include a method for detecting related substances of teriparatide, JS20160050 and JS20100009 include a method for detecting related substances of teriparatide injection, wherein 3 standard raw materials have the same detection method, and 2 preparations have the same detection method. However, the detection standard is easy to oxidize teriparatide in the detection process, so that the detected oxidized impurity level is higher than the true value, and the detection capability on part of inserted peptide impurities and part of isomeric impurities is unavailable.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for detecting impurities contained in teriparatide.
The technical scheme of the invention is as follows:
the invention aims to provide a method for detecting impurities contained in teriparatide, which is characterized in that the teriparatide is analyzed by adopting a liquid chromatography, wherein a mobile phase A is formed by mixing 0.05mol/L sodium salt solution and acetonitrile according to a volume ratio of 90; the preparation process of the sodium salt solution comprises the following steps: 28.8g of sodium lauryl sulfate and 0.05g of phenol were dissolved in 1800mL of water, and the pH was adjusted to 2.3 using 85% phosphoric acid solution to a constant volume of 2000mL.
The column is further defined as a ZORBAX 300SB-C18 column, 150X 4.6mm,3.5 μm, 300A.
Further defined, the detection wavelength is 214nm.
Further defined, the flow rate was 1.0ml/min.
Further defined, the column temperature was 40 ℃.
Further defined, the injection volume was 20. Mu.l.
Further defined, the gradient elution conditions are: 0min, the mobile phase A is 100%, and the mobile phase B is 0%;5min, the mobile phase A is 69%, and the mobile phase B is 31%;47min, mobile phase A is 60%, and mobile phase B is 40%;57min, wherein the mobile phase A is 40% and the mobile phase B is 60%;62min, the mobile phase A is 0%, and the mobile phase B is 100%;67min, mobile phase A is 100%, and mobile phase B is 0%;75min, 100% of mobile phase A and 0% of mobile phase B.
Further limiting, the preparation process of the solution with system applicability is as follows: the teriparatide control and various impurities were added to mobile phase a to prepare a system-compatible solution containing 0.8mg teriparatide per 1mL of the solution and 4 μ g of each impurity.
More particularly, the impurity is [ Met ] 18 (O)]Teriparatide, [ Met 8 (O)]Teriparatide, [ Met 8 (O)，Met 18 (O)]Teriparata, [ rhPTH (1-30)]Teriparatide, val-Arg-rhPTH (1-34) teriparatide and [ des + Ser 1 ]Teriparatide.
Further limiting, the impurities are from degradation products and/or oxides during storage and byproducts during synthesis.
Compared with the prior art, the method has the following beneficial effects:
(1) The invention utilizes the characteristic that polypeptide is an amphoteric compound, the surface of the molecule of the amphoteric compound has positive and negative charges simultaneously, and uses an anionic active agent sodium dodecyl sulfate as a mobile phase, the negative charges of the amphoteric compound can be combined with the positive charges on the surface of the polypeptide, so that the elution capacity of the polypeptide relative to the mobile phase is enhanced, and the elution time of the mobile phase is different due to different charges of different teriparatide impurities and teriparatide, thereby enhancing the separation capacity of the impurities and the teriparatide, particularly the inserted peptide impurities.
(2) The invention also adds antioxidant phenol in the mobile phase, thereby ensuring that teriparatide is not oxidized in the detection process and ensuring the accuracy of detection of oxidized impurities.
(3) The method reasonably regulates and controls the selection of the chromatographic column, the selection of the mobile phase, the limitations of an elution mode, system applicability and the like in the high performance liquid chromatography detection process, effectively and effectively separates teriparatide from oxidation impurities, racemate impurities, isomeric impurities, insertion peptide impurities, deletion peptide impurities and hydrolysis impurities, and ensures the accuracy of the detection result of related substances of the teriparatide.
(4) The method provided by the invention only needs to prepare the reference solution and the sample solution according to requirements, and then the reference solution and the sample solution pass through the same chromatographic column respectively, so that the content of related substances can be calculated through the peak appearance time, the peak area and the like, and the detection method is simple and strong in operability.
Drawings
FIG. 1 is a chromatogram for detecting teriparatide by a raw material method;
FIG. 2 is a chromatogram for detecting teriparatide by a preparation method;
FIG. 3 is a mixed detection spectrum of related substances obtained in example 1;
FIG. 4 is an HPLC chromatogram of the test sample solution of example 1;
FIG. 5 is an HPLC chromatogram of a control solution of example 1;
FIG. 6 is an HPLC profile of a suitability solution for the system of example 1;
FIG. 7 is an HPLC chromatogram of mobile phase A containing phenol of comparative example 1;
FIG. 8 is an HPLC chromatogram of mobile phase A of comparative example 1 without phenol;
FIG. 9 is an HPLC profile of a suitability solution for the system of example 2;
FIG. 10 is the HPLC profile front portion of the test sample solution of example 2;
FIG. 11 is a back portion of an HPLC profile of a test sample solution of example 2;
FIG. 12 is an enlarged view of a portion of FIG. 10;
FIG. 13 is an HPLC chromatogram of the mobile phase of comparative example 2;
FIG. 14 is an HPLC chromatogram of the mobile phase of comparative example 3.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The experimental procedures used in the following examples are conventional unless otherwise specified. The materials, reagents, methods and apparatus used, unless otherwise specified, are conventional in the art and are commercially available to those skilled in the art.
Embodiment mode 1:
(1) Typical relevant substances contained in the synthetic teriparatide are shown in table 1 below:
TABLE 1
The detection results of related substances contained in teriparatide by the conventional raw material method and preparation method are shown in fig. 1 and fig. 2, and are specifically shown in tables 2 and 3, wherein table 2 is the detection result of related substances by the preparation method by mass spectrometry, and table 3 is the detection result of related substances by the raw material method.
TABLE 2
TABLE 3
As can be seen from tables 1 to 3 above, the impurities that cannot be detected by the existing raw materials and preparation methods are: impurity 5, impurity 7, impurity 9, impurity 16, impurity 19 and impurity 22, and therefore the substance-related methods of USP40, EP 9.0, JS20160050, JS20100009 do not have the ability to detect the inserted peptide (impurity 5, impurity 7, impurity 9, impurity 22) and the leucine isomeric impurities (impurity 16, impurity 19).
Example 1:
(1) Preparation of sodium salt solution:
28.8g of sodium lauryl sulfate and 0.05g of phenol were dissolved in 1800mL of water, and the pH was adjusted to 2.3 using 85% phosphoric acid solution, and the volume was adjusted to 2000mL to obtain a sodium salt solution.
(2) Preparation of test sample solution:
teriparatide (bulk drug, lot: CP-013-20200901) was dissolved by adding to mobile phase a and diluted to a test sample solution containing 0.8mg per 1 ml. Wherein the mobile phase A is formed by mixing 0.2mol/L sodium salt solution and acetonitrile according to the volume ratio of 90.
The HPLC profile of the test sample solution obtained is shown in fig. 4.
(3) Preparation of control solution:
1mL of the sample solution is put into a 100mL measuring flask, and mobile phase A is added to dilute to the scale, and the mixture is shaken uniformly.
The HPLC profile of the obtained control solution is shown in FIG. 5.
(4) Preparation of system suitability solution:
the teriparatide control and impurities 1, 2, 3, 6, 17 and 32 were added to mobile phase a to dissolve and dilute it, making a system-compatible solution containing 0.8mg teriparatide per 1mL of solution and 4 μ g of each impurity.
The HPLC profile of the obtained system suitability solution is shown in FIG. 6.
(5) And (3) chromatographic detection:
detection conditions are as follows:
using octadecylsilane chemically bonded silica as a filler, carrying out gradient elution on a chromatographic column of ZORBAX 300SB-C18, 150X 4.6mm,3.5 mu m and 300A by using a mobile phase A and a mobile phase B according to gradient elution conditions shown in the following table 4, wherein the detection wavelength is 214nm; the column temperature was 40 ℃; the flow rate was 1.0ml per minute; the injection volume was 20. Mu.l.
TABLE 4
System applicability requirements:
in the system applicability solution chromatogram, the appearance sequence is impurity 3, impurity 2 (detected in a double-peak form), impurity 6, impurity 1 (if impurity 6 and impurity 1 are superposed, the proportion of a mobile phase can be properly adjusted), impurity 32, impurity 17 and teriparatide, the separation degree between the teriparatide peak and the impurity 17 peak is not less than 1.5, and the theoretical plate number is not less than 2000 calculated according to the teriparatide peak.
The determination method comprises the following steps:
the control solution and the test solution were injected into a liquid chromatograph, respectively, and chromatograms were recorded, as shown in fig. 3, and the detection results are shown in table 5 below.
TABLE 5
As shown in table 5 above, in the present embodiment, impurities 5, 7, 9, 16, 19, and 22 are successfully detected, and since impurities 5, 7, 9, 16, 19, and 22 are process impurities, when the detection method provided in the present embodiment is used to detect the impurities, the process impurities can be removed in a purification process during teriparatide production, and the impurities are non-degradable impurities, so that the present embodiment does not analyze the detected content of the impurities.
The specific detection results of teriparatide related substances are shown in the following table 6:
TABLE 6
Comparative example 1:
the comparative example differs from example 1 in that: the mobile phase A contained no phenol, and the batch number of teriparatide was CP-013-20201002, and the rest of the procedures and parameter settings were the same as those in example 1.
The HPLC profile of mobile phase A without phenol in this comparative example is shown in FIG. 8.
In order to better reflect the effect of phenol, the comparative example also uses the same batch of teriparatide bulk drug to perform a test that mobile phase a contains phenol, which is different from example 1 in that: the batch number of teriparatide was CP-013-20201002, and the rest of the procedures and parameter settings were the same as in example 1.
The HPLC profile of the phenol-containing mobile phase A of this comparative example is shown in FIG. 7.
For the comparison of the results of the detection of the relevant substances in the mobile phase A containing phenol and not containing phenol in this comparative example, the following Table 7 shows:
TABLE 7
As can be seen from table 7, the antioxidant phenol is added to the mobile phase, so that the teriparatide is not oxidized in the detection process, and the accuracy of detecting oxidized impurities is ensured.
Comparative example 2:
the comparative example differs from example 1 in that: the procedure of example 1 was repeated except that 28.8g of sodium lauryl sulfate in the mobile phase a was replaced with 56.8g of anhydrous sodium sulfate, and the teriparatide raw material solution was replaced with the teriparatide single-step purified solution (the teriparatide raw material solution contained no insertion-peptide-specific impurities, and thus the teriparatide single-step purified solution containing such impurities was used instead).
The HPLC profile of the mobile phase in this comparative example is shown in FIG. 13.
Comparative example 3:
the comparative example differs from example 1 in that: the teriparatide raw material solution was replaced with the teriparatide one-step purified solution, and the rest of the operation and parameter settings were the same as those in example 1.
The HPLC profile of the mobile phase in this comparative example is shown in FIG. 14.
The results of the tests of comparative example 2 and comparative example 3 were compared and are shown in table 8 below:
TABLE 8
And (4) comparing the results: the retention time of the impurity 12, the impurity 15 and the impurity 16 is consistent, so the detected impurity is the sum of 3 impurities, the conventional mobile phase impurity 16 is coincided with the main peak of teriparatide and cannot be detected, and the sum of 3 impurities detected by adopting sodium dodecyl sulfate as a mobile phase system is obviously larger than the sum of impurities detected by adopting an anhydrous sodium sulfate system; the total impurities detected by adopting the sodium dodecyl sulfate as a mobile phase system are obviously higher than those detected by adopting an anhydrous sodium sulfate system, and the main total impurities are concentrated in front of and behind a main peak of teriparatide, which shows that the total impurities with similar polarity to that of teriparatide can be effectively separated by adopting the sodium dodecyl sulfate as the mobile phase system, and the impurity separation efficiency of reversed phase chromatography is effectively improved.
Example 2:
the difference between this example and example 1 is: the test sample solution was a stock teriparatide injection solution (gift, lot C969753H), and the rest of the procedure and parameter settings were the same as in example 1.
The HPLC profile of the system suitability solution in this example is shown in FIG. 9, and the HPLC profile of the test sample solution is shown in FIGS. 10, 11 and 12.
The detection results of the substances of the teriparatide injection stock solution of the embodiment are shown in the following table 9:
TABLE 9
Example 3:
this example is a methodological validation of the materials, and the results are shown in table 10 below:
TABLE 10
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (3)
1. A method for detecting teriparatide related substances is characterized in that liquid chromatography is adopted to analyze teriparatide, wherein a mobile phase A is formed by mixing 0.05mol/L sodium salt solution and acetonitrile according to a volume ratio of 90;
the preparation process of the sodium salt solution comprises the following steps: 28.8g of sodium dodecyl sulfate and 0.05g of phenol are dissolved in 1800mL of water, the pH value is adjusted to 2.3 by using a phosphoric acid solution with the concentration of 85%, and the volume is adjusted to 2000mL;
the chromatographic detection conditions are as follows: octadecylsilane chemically bonded silica is used as a filler, and a chromatographic column is ZORBAX 300SB-C18;
the gradient elution conditions were: 0min, the mobile phase A is 100%, and the mobile phase B is 0%;5min, wherein the mobile phase A is 69 percent, and the mobile phase B is 31 percent; 47min, mobile phase A is 60%, and mobile phase B is 40%;57min, wherein the mobile phase A is 40% and the mobile phase B is 60%;62min, the mobile phase A is 0%, and the mobile phase B is 100%;67min, mobile phase A is 100%, and mobile phase B is 0%;75min, the mobile phase A is 100%, and the mobile phase B is 0%;
the detection wavelength is 214nm; the flow rate is 1.0ml/min; the column temperature is 40 ℃; the injection volume is 20 mul;
the impurity is [ Met 18 (O)]Teriparatide, [ Met 8 (O)]Teriparatide, [ Met 8 (O)，Met 18 (O)]Teriparata, [ rhPTH (1-30)]Teriparatide, val-Arg-rhPTH (1-34) teriparatide and [ des+Ser 1 ]Teriparatide;
the impurities come from degradation products and/or oxides in the storage process and byproducts in the synthesis process.
2. The method for detecting a teriparatide-related substance according to claim 1, wherein the column is a ZORBAX 300SB-C18 column, 150 x 4.6mm,3.5 μm, 300A.
3. The method for detecting teriparatide-related substances according to claim 1, wherein the preparation process of the system suitability solution is as follows: the teriparatide control and various impurities were added to mobile phase a to prepare a system-compatible solution containing 0.8mg teriparatide per 1mL of the solution and 4 μ g of each impurity.
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