Procaterol hydrochloride inhalation solution related substance detection method

Abstract

The invention relates to the technical field of substance impurity detection methods, in particular to a procaterol hydrochloride inhalation solution related substance detection method which adopts high performance liquid chromatography for detection, and chromatographic conditions are as follows: mobile phases include a mobile phase A and a mobile phase B; the mobile phase A is a phosphate buffer solution, and the mobile phase B is methanol. The method can effectively detect the related substances in the procaterol hydrochloride inhalation solution, has the advantages of strong specificity, high sensitivity and comprehensive impurity control, and can better control the quality of a preparation.

Description

Technical Field

[0001] This invention relates to the field of methods for detecting substance impurities, and more specifically, to a method for detecting related substances in a procaterol hydrochloride inhalation solution. Background Technology

[0002] Procaterol hydrochloride is a β2 receptor agonist that can specifically activate β2 receptors in respiratory smooth muscle, thereby dilating the bronchi. It can also enhance the activity of adenylate cyclase, thereby inhibiting the release of inflammatory mediators and exerting an anti-allergic effect. Procaterol hydrochloride can also relieve cough and expectoration by promoting the movement of respiratory cilia.

[0003] Procaterol hydrochloride is listed in the pharmacopoeias of many countries, such as JP18, KP10, and ChP2020. However, procaterol hydrochloride inhalation solution is not currently included in the pharmacopoeias of many countries, such as JP18, EP10.0, USP42, and ChP2020. Therefore, the detection method for procaterol hydrochloride inhalation solution needs further development and establishment. Summary of the Invention

[0004] In order to achieve better quality control of procaterol hydrochloride inhalation solution and solve the problems mentioned in the background art, this application provides a method for detecting related substances in procaterol hydrochloride inhalation solution.

[0005] To achieve the above objectives, the present invention provides the following technical solution: A method for detecting related substances in procaterol hydrochloride inhalation solution, the method comprising using high performance liquid chromatography (HPLC) to detect the related substances, wherein the chromatographic conditions are as follows: Mobile phases: Mobile phase A, Mobile phase B; The mobile phase A is a phosphate buffer solution, and the mobile phase B is methanol; The phosphate buffer solution is prepared as follows: take 10.94g-11.14g of sodium dihydrogen phosphate dihydrate, add water to 1000ml to dissolve it, and adjust the pH value to 3.0-3.2 with phosphoric acid; The chromatographic column was a Welch Ultimate AQ-C18, 4.6 × 150 mm, 5 μm, with a detection wavelength of 257 nm. 261 nm, column temperature 25 °C 35℃, flow rate 1.0 mL / min; The mobile phase is subjected to gradient elution in the following manner: Initial equilibrium was established at 0 min, with mobile phase A at 95 vol.% and mobile phase B at 5 vol.%. The linear gradient elution phase lasted from 0 min to 30 min, with mobile phase A decreasing from 95 vol.% to 70 vol.% and mobile phase B increasing from 5 vol.% to 30 vol.%. The isocratic elution phase was carried out for 30-35 minutes, with mobile phase A kept at 70 vol.% and mobile phase B kept at 30 vol.%. During the rapid reset phase at 35-36 minutes, mobile phase A was rapidly switched from 70 vol.% to 95 vol.%, and mobile phase B was rapidly switched from 25 vol.% to 5 vol.%. The column equilibration phase was carried out for 36-45 minutes, with mobile phase A kept at 95 vol.% and mobile phase B kept at 5 vol.%.

[0006] Preferably, the related substances include: Impurity I, Impurity II, and Impurity III; The molecular structures of impurity I, impurity II, and impurity III are shown below: Impurity I: C 16 H 33 N2O3 290.36 Soviet-style procarbazol; Impurity II: C9H7NO2161.16 8-Hydroxyquinolones; Impurity III: C 10 H7NO3189.17 5-Aldehyde-8-hydroxyquinolone.

[0007] Preferably, the phosphate buffer solution is prepared using the following method: Dissolve and dilute sodium dihydrogen phosphate dihydrate in water, and adjust the pH to 3.1 with phosphoric acid solution.

[0008] Preferably, the mass ratio of the sodium dihydrogen phosphate dihydrate to the volume ratio of the diluted and dissolved solution is 11.04 g: 1000 ml.

[0009] Preferably, the column temperature of the chromatographic column is 30°C.

[0010] Preferably, the detection wavelength is 259 nm.

[0011] Preferably, the chromatographic conditions further include: The injection volume is 45-55 μl.

[0012] Preferably, the correction factor for impurity I and impurity II is 1.0; The correction factor for impurity III is 0.7.

[0013] Compared with the prior art, the beneficial effects of the present invention are: By employing the above-mentioned technical solution, this invention enables the detection of all known impurities in the related substances method, with a resolution of not less than 1.5 between each peak, thus accurately detecting related substances in procaterol hydrochloride inhalation solution.

[0014] The method described in this application can effectively detect related substances in procaterol hydrochloride inhalation solution. It has the advantages of high specificity and high sensitivity, and can better control the quality of the formulation. Attached Figure Description

[0015] Figure 1 This is a typical system applicability diagram of Embodiment 1 of the present invention; Figure 2 The typical chromatograms for the system suitability of the related substances method in the 2020 edition of the Chinese Pharmacopoeia are shown in Comparative Example 1. Figure 3 This is a typical chromatogram of the systematic applicability of the JP18 related matter method in Comparative Example 2. Detailed Implementation

[0016] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0017] Please see Figures 1-3 The present invention provides a technical solution: A method for detecting related substances in procaterol hydrochloride inhalation solution, using high-performance liquid chromatography (HPLC), with the following chromatographic conditions: Mobile phases: Mobile phase A, Mobile phase B; The mobile phase A is phosphate buffer, and the mobile phase B is acetonitrile; The chromatographic column was a Welch Ultimate AQ-C18, 4.6 × 150 mm, 5 μm, with a detection wavelength of 257 nm. 261 nm, column temperature 25 °C 35℃, flow rate 1.0 mL / min; The mobile phase employs the following gradient elution:

[0018] The phosphate buffer solution is prepared by the following method: take 10.94g, 11.04g, or 11.14g of sodium dihydrogen phosphate dihydrate, dissolve it in water according to the mass-volume ratio, and dilute it to 1000ml. Adjust the pH value to 3.0, 3.1, or 3.2 with phosphate solution.

[0019] In this embodiment, the optimal technical solution is that the mobile phase A is prepared by the following method: take 11.04 g of sodium dihydrogen phosphate dihydrate, dissolve it in water and dilute it to 1000 ml, and adjust the pH value to 3.1 with phosphoric acid solution.

[0020] Example 1 A method for detecting related substances in procaterol hydrochloride inhalation solution, the chromatographic conditions of which are shown in Table 1:

[0021] Table 2: System Suitability Test Results (Example 1)

[0022] according to Figure 1 As shown in Table 2, using the method of Example 1, all known impurities were detected in the related substances method. The resolution between the main peak and adjacent impurity peaks was not less than 1.5, and the resolution of each impurity peak was not less than 1.5. The peak shapes of each peak were good. Therefore, the method of this application has the advantages of good specificity, high sensitivity, and comprehensive impurity control, and can achieve good quality control of procaterol hydrochloride inhalation solution.

[0023] Comparative Example 1 According to the detection method for related substances of procaterol hydrochloride in the 2020 edition of the Chinese Pharmacopoeia, the chromatographic conditions are shown in Table 3: Table 3

[0024] Table 4: Results of System Suitability Tests (Related Substances Methods, Chinese Pharmacopoeia 2020 Edition)

[0025] according to Figure 2 As shown in Table 4, using the method of Comparative Example 1, all known impurities were detected in the related substances method. The resolution between the main peak and the adjacent impurity peak was not less than 1.5, the resolution of each impurity peak was not less than 1.5, and the peak shape of each peak was good. However, the elution efficiency of the isocratic elution program was poor.

[0026] Comparative Example 2 According to the detection method for related substances of procaterol hydrochloride in JP18, the chromatographic conditions are shown in Table 5: Table 5

[0027] Table 6: System Suitability Test Results (JP18 Related Substances Method)

[0028] according to Figure 3 As shown in Table 6, using the method of Comparative Example 2, the peaks of impurity I and impurity III overlapped, and impurity I and impurity III could not be separated.

[0029] The methodology verification report for Example 1 of this application, including the verification items and results, is shown in Table 7: Table 7

[0030] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for detecting related substances in procaterol hydrochloride inhalation solution, characterized in that: The detection method includes detecting related substances using high-performance liquid chromatography (HPLC), with the following chromatographic conditions: Mobile phases: Mobile phase A, Mobile phase B; The mobile phase A is phosphate buffer, and the mobile phase B is methanol; The phosphate buffer solution is prepared as follows: take 10.94g-11.14g of sodium dihydrogen phosphate dihydrate, add water to 1000ml to dissolve it, and adjust the pH value to 3.0-3.2 with phosphoric acid; The chromatographic column was a Welch Ultimate AQ-C18, 4.6 × 150 mm, 5 μm, with a detection wavelength of 257 nm. 261 nm, column temperature 25 °C 35℃, flow rate 1.0 mL / min; The mobile phase is subjected to gradient elution in the following manner: Initial equilibrium was established at 0 min, with mobile phase A at 95 vol.% and mobile phase B at 5 vol.%. The linear gradient elution phase lasted from 0 min to 30 min, with mobile phase A decreasing from 95 vol.% to 70 vol.% and mobile phase B increasing from 5 vol.% to 30 vol.%. The isocratic elution phase was carried out for 30-35 minutes, with mobile phase A kept at 70 vol.% and mobile phase B kept at 30 vol.%. During the rapid reset phase at 35-36 minutes, mobile phase A was rapidly switched from 70 vol.% to 95 vol.%, and mobile phase B was rapidly switched from 25 vol.% to 5 vol.%. The column equilibration phase was carried out for 36-45 minutes, with mobile phase A kept at 95 vol.% and mobile phase B kept at 5 vol.%.

2. The method for detecting related substances in a procaterol hydrochloride inhalation solution according to claim 1, characterized in that, The relevant substances include: Impurity I, Impurity II, and Impurity III; The molecular structures of impurity I, impurity II, and impurity III are shown below: Impurity I: C 16 H 33 N2O3 290.36 Soviet-style procarbazol; Impurity II: C9H7NO2 161.16 8-Hydroxyquinolones; Impurity III: C 10 H7NO3 189.17 5-Aldehyde-8-hydroxyquinolone.

3. The method for detecting related substances in a procaterol hydrochloride inhalation solution according to claim 1, characterized in that, The phosphate buffer solution was prepared using the following method: Dissolve and dilute sodium dihydrogen phosphate dihydrate in water, and adjust the pH to 3.1 with phosphoric acid solution.

4. The method for detecting related substances in a procaterol hydrochloride inhalation solution according to claim 3, characterized in that, The mass ratio of the sodium dihydrogen phosphate dihydrate to the volume ratio of the diluted and dissolved solution is 11.04 g: 1000 ml.

5. The method for detecting related substances in a procaterol hydrochloride inhalation solution according to claim 1, characterized in that, The column temperature of the chromatographic column is 30℃.

6. The method for detecting related substances in a procaterol hydrochloride inhalation solution according to claim 1, characterized in that, The detection wavelength is 259 nm.

7. The method for detecting related substances in a procaterol hydrochloride inhalation solution according to claim 1, characterized in that, The chromatographic conditions also include: The injection volume is 45-55 μl.

8. The method for detecting related substances in a procaterol hydrochloride inhalation solution according to claim 1, characterized in that: The correction factors for impurities I and II are 1.0; The correction factor for impurity III is 0.7.

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