CN110632205A - Method for detecting salbutamol sulfate solution related substances for inhalation - Google Patents
Method for detecting salbutamol sulfate solution related substances for inhalation Download PDFInfo
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- CN110632205A CN110632205A CN201910950434.0A CN201910950434A CN110632205A CN 110632205 A CN110632205 A CN 110632205A CN 201910950434 A CN201910950434 A CN 201910950434A CN 110632205 A CN110632205 A CN 110632205A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
Abstract
The invention discloses a method for detecting related substances of salbutamol sulfate solution for inhalation, which adopts a high performance liquid chromatography method to carry out qualitative or/and quantitative detection on related substances of salbutamol sulfate solution for inhalation, wherein the detection conditions of the liquid chromatography comprise: the chromatographic column is a C8 chromatographic column, and the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is a phosphate buffer solution; the mobile phase B is acetonitrile: the volume ratio of methanol is (40-65): (60-35) of a mixed solution; the mobile phase adopts a gradient elution method. The method can effectively detect the main drug and other related impurities in the salbutamol sulfate solution for inhalation, has specificity and stability indicating capability, and can detect new impurity 5-hydroxy salbutamol.
Description
Technical Field
The invention relates to the field of detection methods, in particular to a detection method of substances related to salbutamol sulfate solution for inhalation.
Background
Salbutamol sulfate is a selective beta2Adrenergic receptor agonists, bronchodilators with rapid onset (within 5 minutes), short-acting (4 to 6 hours) on reversible airway obstruction. At therapeutic doses, act on beta located on bronchial smooth muscle2The adrenergic receptor, because of its rapid onset of action, is particularly well suited for use in the treatment and prevention of asthma exacerbations.
The aerosol therapeutic medicine can reach the affected part directly, so the aerosol inhalation is widely applied in the department of respiration, and the aerosol inhalation is mostly adopted in the using mode of salbutamol sulfate at present, so that the patient mostly uses the salbutamol sulfate solution preparation for inhalation, compared with other therapeutic modes, the aerosol inhalation therapeutic medicine is more convenient to use and faster in effect, and the market demand of the salbutamol sulfate solution for inhalation is growing quietly.
However, in the pharmacopoeias of many countries, such as EP9.8, USP42, and ChP2015, there is no record of salbutamol sulfate for inhalation; in BP2019, "salbutamol sulfate solution for inhalation" was recorded, but the impurities were less detectable.
Therefore, the quality control method of salbutamol sulfate solution for inhalation needs to be further developed, improved and perfected.
Disclosure of Invention
The invention aims to provide a detection method of salbutamol sulfate solution related substances for inhalation, which can better control the quality of the salbutamol sulfate solution for inhalation.
At present, the quality detection method of salbutamol sulfate solution for inhalation is less, but the method has the problems of incomplete controlled impurity types and the like.
The impurity J in the invention is salbutamol, which is a known impurity in salbutamol sulfate solution for inhalation. For salbutamol sulfate solution for inhalation, China has import registration standard JX20160145 with strong credibility and authority for the drug, and detection methods for analyzing related substances in the salbutamol sulfate solution for inhalation are recorded in the standard.
Surprisingly, however, the inventors have found that by repeated experiments, it is indeed impossible to completely separate the major peak from impurity J in the solution of albuterol sulphate by inhalation using the method described in the imported registered standard JX 20160145.
In the invention, the inventor develops a new method, which can effectively separate the impurity J from the main drug, and further carry out good quality control on the impurity J.
The invention provides a method for detecting related substances of salbutamol sulfate, which adopts high performance liquid chromatography to qualitatively or/and quantitatively detect related impurities of salbutamol sulfate, and the detection conditions of the liquid chromatography comprise:
a chromatographic column: octane silane bonding silica gel column or equivalent chromatographic column;
mobile phase: mobile phase A and mobile phase B;
wherein, the mobile phase A is phosphate buffer solution; the mobile phase B is a mixed solution of acetonitrile and/or methanol; the mobile phase was subjected to the following gradient elution procedure:
| time (min) | Mobile phase a (vol.%) | Mobile phase B (vol.%) |
| 0 | 90～99 | 1～10 |
| 5～20 | 90～99 | 1～10 |
| 20～40 | 60～80 | 20～40 |
。
In addition, the inventors have found that 5-hydroxysalbutamol as an impurity is contained in a salbutamol sulfate solution for inhalation in the study of the above impurity J. However, surprisingly, the inventors also tested salbutamol sulphate drug substance before the impurity was found in the solution for inhalation, and no 5-hydroxysalbutamol was found in the drug substance, as shown in figure 6. It is seen that the impurities present in the drug substance and the pharmaceutical preparation are not completely the same, and the type of impurity in one cannot be predicted from the impurity in the other. There have been no reports on the inclusion of 5-hydroxysalbutamol as an impurity in salbutamol sulfate solution for inhalation.
Further, the mobile phase B is acetonitrile: the volume ratio of methanol is (20-80): (80-20) mixing the solution; the mobile phase was subjected to the following gradient elution procedure:
| time (min) | Mobile phase a (vol.%) | Mobile phase B (vol.%) |
| 0 | 95～99 | 1～5 |
| 10～15 | 95～99 | 1～5 |
| 30～35 | 65～75 | 25～35 |
；
Further, mobile phase B was acetonitrile: the volume ratio of methanol is (40-65): (60-35) of a mixed solution;
further, the mobile phase was subjected to the following gradient elution procedure:
| time (min) | Mobile phase a (vol.%) | Mobile phase B (vol.%) |
| 0 | 97 | 3 |
| 10～15 | 97 | 3 |
| 30～35 | 70 | 30 |
。
In the gradient elution procedure of the mobile phase, the time is limited to 35min, and does not mean that the gradient elution procedure only comprises 0-35 min, the limitation of the gradient elution procedure is considered as an open limitation, and the gradient elution procedure can also comprise other elution procedures after 35 min.
The impurities are introduced in the technological processes of synthesis and the like, and comprise reactants, intermediates, byproducts, reagents, catalysts and the like.
Further, the impurities comprise at least the impurity J and/or 5-hydroxysalbutamol.
The phosphate buffer mainly comprises phosphate buffer prepared by using phosphate or/and hydrogen phosphate or/and dihydrogen phosphate or/and acid or/and alkali or/and other salts.
Further, the phosphate buffer solution contains hydrogen phosphate ions, dihydrogen phosphate ions, phosphate ions and alkali metal ions; further, the alkali metal ions are selected from one or two of potassium ions and sodium ions. For example, a solution containing hydrogen phosphate ions, dihydrogen phosphate ions, and potassium ions, a solution containing hydrogen phosphate ions, dihydrogen phosphate ions, and sodium ions, or a solution containing hydrogen phosphate ions, dihydrogen phosphate ions, potassium ions, and sodium ions may be mentioned.
In a specific embodiment of the present invention, the phosphate buffer is a phosphate-phosphate buffer; further, the phosphate buffer solution is a sodium dihydrogen phosphate solution with the concentration of 0.025 +/-0.002 mmol/L, and also comprises triethylamine, and the pH value of the phosphate buffer solution is adjusted to 2.0-4.0 by using phosphoric acid to obtain the phosphate buffer solution; wherein the volume concentration of the triethylamine is 0.03-0.07%.
Further, the phosphate buffer was adjusted to pH 3 with phosphoric acid and the triethylamine volume concentration was 0.05%.
In a particular embodiment of the invention, the organic phase is selected from acetonitrile: the volume ratio of methanol is 40: 60 of a mixed solution; the mobile phase was eluted after 35min using the following gradient elution procedure:
| time (min) | Mobile phase a (vol.%) | Mobile phase B (vol.%) |
| 37 | 70 | 30 |
| 37.01 | 10 | 90 |
。
In a preferred embodiment of the invention, the organic phase is selected from acetonitrile: the volume ratio of methanol is 40: 60 of a mixed solution; the mobile phase was subjected to the following gradient elution procedure:
| time (min) | Mobile phase a (vol.%) | Mobile phase B (vol.%) |
| 0 | 97 | 3 |
| 15 | 97 | 3 |
| 35 | 70 | 30 |
| 37 | 70 | 30 |
| 37.01 | 10 | 90 |
。
Through the gradient elution procedure, the impurity J, the 5-hydroxyl salbutamol and the main peak can be well separated, and the peak shape is good.
Further, the liquid chromatography detection conditions further comprise one or more of the following i to iv:
i specification of chromatographic column: 4.6 is multiplied by 250mm, 3-5 μm;
ii column temperature: 28-32 ℃;
iii flow rate: 0.9-1.1 ml/min;
iv detection wavelength: 273. + -. 2 nm.
Further, the liquid chromatography detection conditions further comprise one or more of the following i to iv:
i specification of chromatographic column: 4.6X 250mm, 5 μm;
ii column temperature: 30 ℃;
iii flow rate: 1.0 ml/min;
iv detection wavelength: 273 nm.
The chromatographic columns used in the embodiments of the present invention are commercially available as Hypersil BDS C8 and COSMOSIL C8-MS, and are not limited to the above commercial products as long as the chromatographic columns satisfying the above description can be used in the detection method of the present invention.
Further, the detection method further comprises the following steps of preparing a test solution or/and a reference solution: and (3) dissolving the sample by using a diluent and diluting the sample to a specified concentration, wherein the diluent is a mobile phase A.
Further, the detection method further comprises the following steps:
(1) injecting a control solution for detection;
(2) and (5) injecting a sample solution for detection.
The detection method can analyze and calculate the detection result by using methods such as an area normalization method, a self-comparison method, an internal standard method, an external standard method and the like.
In a specific embodiment of the present invention, the impurity content is calculated using an area normalization method.
Furthermore, the sample amount is 20 to 100. mu.l, preferably 50. mu.l.
The invention also provides a salbutamol sulfate solution for inhalation, which comprises salbutamol sulfate, salbutamol ketone and 5-hydroxy salbutamol, wherein the content of the salbutamol ketone is not more than 0.3 percent, and the content of the 5-hydroxy salbutamol is not more than 0.3 percent.
The invention has the beneficial effects that:
(1) the detection method of the invention is adopted to carry out quality control on the salbutamol sulfate solution for inhalation, can detect the 5-hydroxy salbutamol which is not detected before, and can better carry out quality control on the salbutamol sulfate solution for inhalation.
(2) The detection method can simultaneously control the quality of the impurity J and the 5-hydroxyl salbutamol of the salbutamol sulfate, can realize effective separation between the impurities and a main peak, and has better peak shape than the prior art, thus being more suitable for the quality control of the salbutamol sulfate solution for inhalation.
Drawings
FIG. 1 is a detection spectrum of condition 1;
FIG. 2 is a detection spectrum of condition 2;
FIG. 3 is a detection spectrum of condition 3;
FIG. 4 is a detection spectrum of condition 4;
FIG. 5 is a detection spectrum of condition 5;
FIG. 6 is a spectrum of salbutamol sulfate drug substance.
Detailed description of the invention
The detection method of the present invention is further described below by way of specific embodiments and experiments.
Example 1
Solution preparation:
diluent agent: mobile phase a.
Test solution: taking 1 piece of the product, precisely measuring 1ml, placing into a 10ml measuring flask, diluting with diluent to scale, and shaking.
System applicability solution: accurately weighing appropriate amount of 5-hydroxy salbutamol, impurity J and salbutamol sulfate reference substance, dissolving with diluent, and diluting to obtain mixed solution containing salbutamol 0.2mg and impurity (including 5-hydroxy salbutamol) 0.4 μ g each per 1ml, and using as system applicability solution.
(1) Condition 1: chromatographic method for performing import registration standard JX20160145
The method is confirmed, the chromatographic conditions are shown in Table 1, and the detection results are shown in FIG. 1.
TABLE 1 confirmation of chromatographic conditions by method JX20160145
The result of the confirmation of the chromatographic method of JX20160145 shows that under the chromatographic condition, the impurity J and the salbutamol sulfate peak partially coincide and cannot be separated, so that the method is not suitable for detecting substances related to the salbutamol sulfate solution for inhalation, and a method for detecting substances related to the salbutamol sulfate solution for inhalation needs to be further developed.
(2) Condition 2
The gradient was further optimized on the basis of condition 1 in an attempt to obtain good separation and peak shape. The chromatographic conditions are shown in Table 2, and the results are shown in FIG. 2.
TABLE 2 chromatographic conditions 2
The result shows that the impurity J and the main peak achieve baseline separation, and the 5-hydroxyl salbutamol can be well separated from the impurity J and the main peak.
(3) Condition 3
The composition of mobile phase B was further optimized on the basis of condition 2, the chromatographic conditions are shown in table 3, and the results are shown in fig. 3.
TABLE 3 chromatographic conditions 3
The results show that under the chromatographic conditions, baseline separation is achieved among 5-hydroxysalbutamol, impurity J and the main peak.
(4) Condition 4
The composition of mobile phase B was further optimized on the basis of condition 3, the chromatographic conditions are shown in table 4, and the results are shown in fig. 4.
TABLE 4 chromatographic conditions 4
The result shows that under the chromatographic condition, the 5-hydroxyl salbutamol, the impurity J and the main peak all meet the requirement of baseline separation.
(5) Condition 5
The chromatographic column is replaced on the basis of the condition 4, the equilibrium time of the chromatographic column at the tail end of the gradient is prolonged, the chromatographic conditions are shown in a table 5, and the result is shown in a table 5.
TABLE 5 chromatographic conditions 5
The result shows that under the chromatographic condition, the 5-hydroxy salbutamol, the impurity J, the main peak and other impurities can be well separated from the impurities and from the main peak, and a good peak shape can be obtained, so that the detection requirement of related substances of the salbutamol sulfate solution for inhalation can be met. Meanwhile, the content of 5-hydroxysalbutamol was measured to be 0.14%, and the content of impurity J was measured to be 0.11%.
The content of impurities can be calculated by the following formula:
in the formula: a. thesam-impurity peak area in the test sample solution;
Am-peak area of salbutamol in the test solution.
Example 2 detection of drug substances
The chromatographic conditions in table 6 were used:
TABLE 6
Fig. 6 is a detection spectrogram of the raw material drug, and it can be seen that the raw material drug has high purity and hardly contains any impurities.
Methodology validation report:
TABLE 7 verification project and results Profile
The analysis method verifies that the method has good specificity, the blank auxiliary materials do not interfere impurity detection, each impurity is well separated from the main peak, the detection limit and the quantitative limit of each impurity meet the determination requirement, and the linearity of each impurity is good; the method is proved to have better durability by fine adjustment of chromatographic conditions.
In conclusion, the detection method is superior to the existing chromatographic conditions in the import registration standard, can be used for qualitatively/quantitatively controlling the impurity J and the 5-hydroxysalbutamol in the salbutamol sulfate, can realize effective separation among the 5-hydroxysalbutamol, the impurity J and the main peak, can obtain good peak shape and separation, and is efficient and rapid.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present specification and drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (10)
1. A detection method of salbutamol sulfate related substances is characterized in that high performance liquid chromatography is adopted for qualitative or/and quantitative detection of salbutamol sulfate related impurities, and the detection conditions of the liquid chromatography comprise:
a chromatographic column: octane silane bonding silica gel column or equivalent chromatographic column;
mobile phase: mobile phase A and mobile phase B;
wherein, the mobile phase A is phosphate buffer solution; the mobile phase B is a mixed solution of acetonitrile and/or methanol; the mobile phase was subjected to the following gradient elution procedure:
。
2. The detection method according to claim 1, wherein the mobile phase B is acetonitrile: the volume ratio of methanol is (20-80): (80-20) mixing the solution; the mobile phase was subjected to the following gradient elution procedure:
；
Further, mobile phase B was acetonitrile: the volume ratio of methanol is (40-65): (60-35) of a mixed solution;
further, the mobile phase was subjected to the following gradient elution procedure:
。
3. The detection method according to claim 1, wherein the impurity at least includes impurity J and/or 5-hydroxysalbutamol.
4. The method according to claim 1, wherein the phosphate buffer solution contains hydrogen phosphate ions, dihydrogen phosphate ions, and alkali metal ions; further, the alkali metal ions are selected from one or two of potassium ions and sodium ions.
5. The method of detecting according to claim 4, wherein the phosphate buffer is a phosphate-phosphate buffer; further, the phosphate buffer solution is a sodium dihydrogen phosphate solution with the concentration of 0.025 +/-0.002 mmol/L, and also comprises triethylamine, and the pH value of the phosphate buffer solution is adjusted to 2.0-4.0 by using phosphoric acid to obtain the phosphate buffer solution; wherein the volume concentration of the triethylamine is 0.03-0.07%.
6. The detection method according to claim 5, wherein the phosphate buffer is adjusted to pH 3 with phosphoric acid and the triethylamine is present at a concentration of 0.05% by volume.
7. The detection method according to claim 6, wherein the organic phase is selected from the group consisting of acetonitrile: the volume ratio of methanol is 40: 60 of a mixed solution; the mobile phase was eluted after 35min using the following gradient elution procedure:
。
8. The detection method according to any one of claims 1 to 7, wherein the liquid chromatography detection conditions further include one or more of the following i to iv:
i specification of chromatographic column: 4.6 is multiplied by 250mm, 3-5 μm;
ii column temperature: 28-32 ℃;
iii flow rate: 0.8-1.2 ml/min;
iv detection wavelength: 273. + -. 2 nm.
Further, the liquid chromatography detection conditions further comprise one or more of the following i to iv:
i specification of chromatographic column: 4.6X 250mm, 5 μm;
ii column temperature: 30 ℃;
iii flow rate: 1.0 ml/min;
iv detection wavelength: 273 nm;
furthermore, the amount of sample is 20 to 100. mu.l, preferably 50. mu.l.
9. The detection method according to any one of claims 1 to 7, further comprising preparing a test solution or/and a control solution: and (3) dissolving the sample by using a diluent and diluting the sample to a specified concentration, wherein the diluent is a mobile phase A.
10. An albuterol sulfate solution for inhalation, comprising albuterol sulfate, salbutamol ketone and 5-hydroxysalbutamol, wherein the content of the albuterol ketone is not more than 0.3%, and the content of the 5-hydroxysalbutamol is not more than 0.3%.
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| CN114034782A (en) * | 2021-09-23 | 2022-02-11 | 北京四环科宝制药有限公司 | Method for detecting salbutamol sulfate related substances |
| CN115248273A (en) * | 2022-06-21 | 2022-10-28 | 浙江福瑞喜药业有限公司 | Method for detecting related substances of salbutamol sulfate solution for inhalation |
| CN115463117A (en) * | 2022-09-14 | 2022-12-13 | 四川普锐特药业有限公司 | Budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114034782A (en) * | 2021-09-23 | 2022-02-11 | 北京四环科宝制药有限公司 | Method for detecting salbutamol sulfate related substances |
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| CN115248273B (en) * | 2022-06-21 | 2023-10-13 | 浙江福瑞喜药业有限公司 | Method for detecting related substances of salbutamol sulfate solution for inhalation |
| CN115463117A (en) * | 2022-09-14 | 2022-12-13 | 四川普锐特药业有限公司 | Budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency and preparation method thereof |
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