Method for determining particle size of levosalbutamol tartrate bulk drug

Abstract

The invention belongs to the field of detection of pharmaceutical preparations, and provides a method for determining the particle size of a levosalbutamol tartrate bulk drug, which adopts a saturated solution of levosalbutamol tartrate in acetone as a dispersion medium, so that levosalbutamol tartrate can be well dispersed and can be stably dispersed within 20 minutes, and the particle size of the levosalbutamol tartrate can be accurately measured. Meanwhile, the solubility of the levosalbutamol tartrate is not increased, and the dispersion medium is more suitable for being used as a dispersion medium for determining the particle size distribution of the levosalbutamol tartrate. The measuring method is good in repeatability, high in accuracy and good in durability, a new method is provided for measuring the particle size distribution of the levosalbutamol tartrate, and the quality of the levosalbutamol tartrate can be better controlled.

Description

Technical Field

[0001] The invention belongs to the field of drug preparation detection and relates to a method for determining the particle size of levsalbutamol tartrate. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Levosalbutamol is an adrenergic β2 receptor agonist with significant bronchodilator effect. It is the first choice for the clinical treatment of bronchospasm and acute exacerbation of bronchial asthma, asthmatic bronchitis, emphysema, acute exacerbation of chronic obstructive pulmonary disease and other airway spasms. Levosalbutamol is a single enantiomer separated and purified from racemic salbutamol, which removes the dextrorotatory isomer and is the main active ingredient of racemic salbutamol.

[0004] The main preparation of levosalbuterol tartrate is levosalbuterol tartrate inhalation aerosol. For suspension, the particle size and particle size distribution of levosalbuterol tartrate are key evaluation indicators. The difference in particle size may affect the release effect and clinical efficacy of the drug, and strict quality control of the particle size of levosalbuterol tartrate suspension is required. Therefore, it is of great significance to develop a method that can accurately measure the particle size of levosalbuterol tartrate in levosalbuterol tartrate inhalation aerosol. Summary of the invention

[0005] In order to solve the above problems, the present invention provides a method for measuring the particle size of levosalbuterol tartrate with a simple and convenient measuring process, so as to be used for particle size testing during the production and use of levosalbuterol tartrate inhalation aerosol, thereby providing a technical means for product quality control thereof.

[0006] In order to achieve the above object, the present invention adopts the following technical solution:

[0007] The first aspect of the present invention provides a method for determining the particle size of salbutamol tartrate raw material drug, comprising:

[0008] Acetone is used as a solvent to prepare a saturated solution of levosalbutamol tartrate, and then ultrasonically treated, allowed to stand, and filtered to obtain a dispersion medium;

[0009] The salbutamol tartrate raw material to be tested is mixed evenly with the dispersion medium to obtain a test solution;

[0010] The particle size of the test solution is measured by a laser particle size analyzer.

[0011] In some embodiments, the mass ratio of the drug substance to the dispersion medium is 1:3.5-4.5, preferably 1:4.

[0012] In some embodiments, the ultrasound duration is 10-15 min.

[0013] In some embodiments, the filtration is performed using a 0.22 μm filter membrane.

[0014] In some embodiments, the shading degree of the test solution is 15% to 22%, preferably 20%.

[0015] In some embodiments, the salbutamol tartrate drug substance to be tested is mixed with the dispersion medium and then ultrasonically treated for 5 to 15 minutes, preferably 10 minutes.

[0016] In some embodiments, the speed of the injector is 1000 r / min to 1500 r / min, preferably, 1100 r / min to 1300 r / min, and more preferably, 1200 r / min.

[0017] The second aspect of the present invention provides a dispersion medium for levsalbutamol tartrate particles, wherein the dispersion medium is a saturated solution of levsalbutamol tartrate, and the solvent of the saturated solution is acetone.

[0018] In some embodiments, the saturated solution of salbutamol tartrate is treated with ultrasound and allowed to stand overnight.

[0019] In some embodiments, the saturated solution is allowed to stand overnight and then filtered through a 0.22 μm filter membrane.

[0020] Beneficial effects of the present invention

[0021] (1) After long-term research and experimental exploration, the present invention found that: using a saturated solution of tartaric acid salbutamol in acetone as a dispersion medium can make tartaric acid salbutamol dispersed better, and it can be stably dispersed within 60 minutes, and at the same time will not increase the solubility of tartaric acid salbutamol, and is more suitable for use as a dispersion medium for measuring the particle size distribution of tartaric acid salbutamol.

[0022] (2) The determination method of the present invention has good repeatability, high accuracy and good durability, and provides a new method for the particle size determination of salbutamol tartrate, which can better control the quality of salbutamol tartrate and can also be used for the particle size determination of the same type of water-soluble drugs.

[0023] (3) The preparation method of the present invention is simple, practical and easy to promote. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention, and the exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute improper limitations on the present invention.

[0025] Figure 1 This is a diagram of the dispersion of levosalbuterol tartrate in acetonitrile, acetone, and n-heptane, wherein, from left to right, it shows the dispersion of excess levosalbuterol tartrate in acetonitrile, acetone, and n-heptane. DETAILED DESCRIPTION

[0026] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0027] The present invention will be further described in detail below in conjunction with specific embodiments. It should be noted that the specific embodiments are intended to explain the present invention rather than to limit it.

[0028] The levosalbuterol tartrate used in the embodiment of the present invention is a factory-produced product.

[0029] Example 1 Screening of dispersion medium

[0030] 1. Ethanol

[0031] Levosalbutamol tartrate is slightly soluble in ethanol, which affects the determination of the particle size distribution of levosalbutamol tartrate in the preparation.

[0032] 2. n-Heptane

[0033] The saturated solution of n-heptane was directly used as the dispersion medium. When preparing the sample, it was found that the dispersion effect of levosalbutamol tartrate in the saturated solution of n-heptane was poor (see Figure 1 ), uneven distribution, obvious agglomeration visible to the naked eye, and partial dissolution, which will affect the accuracy of the particle size distribution measurement of levsalbutamol tartrate.

[0034] 3. Acetonitrile

[0035] The saturated solution of acetonitrile was directly used as the dispersion medium. It was found that although the dispersion effect of tartaric acid salbutamol in acetonitrile was improved to a certain extent, more tartaric acid salbutamol was dissolved with the increase of stirring time. The changes in the particle size distribution of tartaric acid salbutamol are shown in Table 1.

[0036] Table 1

[0037]

[0038] As can be seen from Table 1, when the saturated solution of acetonitrile is directly used as the dispersion medium, the particle size distribution and optical concentration of tartrate salbutamol fluctuate to a certain extent with the increase of stirring time, indicating that part of tartrate salbutamol is dissolved during the sample preparation process, which will inevitably affect the accuracy of the test results.

[0039] 4. Acetone

[0040] The saturated solution of acetone was directly used as the dispersion medium. It was found that the dispersion effect of tartaric acid salbutamol in acetone was good. With the increase of stirring time, the particle size distribution and optical concentration of tartaric acid salbutamol were relatively stable. The changes in the particle size distribution of tartaric acid salbutamol are shown in Table 2.

[0041] Table 2

[0042]

[0043] As can be seen from Table 2, when the saturated solution of acetone is directly used as the dispersion medium, with the increase of stirring time, there is no obvious difference in the particle size distribution and optical concentration of tartrate salbutamol. The system of tartrate salbutamol is uniform in the saturated solution of acetone, there is no aggregation, and the dispersion effect is good. Finally, the saturated solution of acetone is selected as the dispersion medium for the particle size determination of tartrate salbutamol.

[0044] Example 2 Determination of particle size of levosalbuterol tartrate

[0045] 1. Solution Preparation

[0046] Dispersion medium: saturated solution of tartaric acid salbutamol in acetone: Take 100 mg of tartaric acid salbutamol, add 500 ml of acetone to dissolve, add tartaric acid salbutamol while stirring to make a saturated solution, ultrasonicate for 10 minutes, let stand overnight, and filter with a 0.22 μm filter membrane.

[0047] Preparation of test solution: Take a small amount of salbutamol tartrate API and add it to the dispersion medium (the mass ratio of API to dispersion medium is about 1:4), shake well, transfer to a suitable glass bottle, and ultrasonicate for 10 minutes.

[0048] 2. Detection process

[0049] Adjust the speed of the sampler to 1200r / min and measure the background. Add the test solution into the sampler to make the shading degree in the range of 15%-25%. When the shading degree is stable, stir for 1 minute and measure.

[0050] 3. Test results

[0051] The method was validated by precision (repeatability and intermediate precision), solution stability (solution stability in the injector), and durability (ultrasonic time and optical concentration). The results showed that the method had good data repeatability, method repeatability, and high durability for the determination of particle size distribution of levsalbutamol tartrate.

[0052] 3.1 Precision

[0053] Table 3

[0054]

[0055]

[0056] According to the results in Table 3, the relative standard deviations of the results D(10), D(50), and D(90) of the 6 samples measured by the first person were 0.76%, 0.92%, and 1.10%, respectively. All of them were less than 5.0%; the relative standard deviations of the results D(10), D(50), and D(90) of the 6 samples measured by the second person were 0.76%, 1.13%, and 1.12%, respectively. All of them were less than 5.0%; the relative standard deviations of the results D(10), D(50), and D(90) of the 12 samples were 0.72%, 1.30%, and 1.12%, respectively, all of them were less than 5.0%. The precision of the determination method of the present invention is good.

[0057] 3.2 Solution stability

[0058] Table 4

[0059]

[0060] According to the results in Table 4, the relative standard deviations of D(10), D(50), and D(90) measured at different times in the sample injector are 1.14%, 0.75%, and 0.35%, respectively, all less than 5.0%, and the sample solution in the injector is stable within 20 minutes. It can be seen that the present invention uses a saturated solution of acetone as a dispersion medium, has a good dispersion effect, and can be stably dispersed within 20 minutes.

[0061] Example 3 Ultrasonic time screening of levosalbuterol tartrate test solution

[0062] Table 5

[0063]

[0064]

[0065] According to the results in Table 5, after the test solution was ultrasonicated for 5 minutes, the relative standard deviations of D(10), D(50), and D(90) measured at different times were 0.75%, 0.97%, and 0.83%, respectively; after the test solution was ultrasonicated for 10 minutes, the relative standard deviations of D(10), D(50), and D(90) measured at different times were 1.14%, 0.75%, and 0.35%, respectively. It can be seen that after the test solution was ultrasonicated for 5 minutes and 10 minutes, the dispersion effect was good and all could be stably dispersed within 20 minutes. The dispersion of the test solution was more stable after ultrasonication for 10 minutes.

[0066] Example 4 Particle size determination and optical concentration screening of levosalbuterol tartrate

[0067] Table 6

[0068] Optical Concentration <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> 15.49％ 0.75 2.05 5.93 18.49％ 0.72 2.03 5.97 20.67％ 0.72 2.04 6.05 22.30％ 0.73 2.07 6.07 25.19％ 0.74 2.17 6.55

[0069] According to the results in Table 6, the measured particle size will increase when the optical concentration is 25%, so the optical concentration needs to be controlled between 15% and 22% when measuring the particle size.

[0070] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for determining the particle size of salbutamol tartrate bulk drug, characterized in that: include: Acetone is used as a solvent to prepare a saturated solution of levosalbutamol tartrate, and then ultrasonically treated, allowed to stand, and filtered to obtain a dispersion medium; The salbutamol tartrate raw material to be tested is mixed evenly with the dispersion medium to obtain a test solution; The particle size of the test solution is measured by a laser particle size analyzer.

2. The method for measuring the particle size of the salbutamol tartrate bulk drug according to claim 1, wherein: The mass ratio of the raw material to the dispersion medium is 1:3.5-4.5, or 1:

4.

3. The method for measuring the particle size of the salbutamol tartrate bulk drug according to claim 1, wherein: The ultrasonic time is 10-15 minutes.

4. The method for measuring the particle size of the salbutamol tartrate bulk drug according to claim 1, wherein: The filtration is carried out by using a 0.22 μm filter membrane.

5. The method for measuring the particle size of the salbutamol tartrate bulk drug according to claim 1, wherein: The shading degree of the test solution is 15% to 22% or 20%.

6. The method for measuring the particle size of the salbutamol tartrate bulk drug according to claim 1, wherein: The levosalbuterol tartrate raw material to be tested is mixed with the dispersion medium and then ultrasonically treated for 5 to 15 minutes, or 10 minutes.

7. The method for measuring the particle size of the salbutamol tartrate bulk drug according to claim 1, wherein: The speed of the injector is 1000r / min~1500r / min, or 1100r / min~1300r / min, or 1200r / min.

8. A dispersion medium for levosalbuterol tartrate particles, characterized in that: The dispersion medium is a saturated solution of levsalbutamol tartrate, and the solvent of the saturated solution is acetone.

9. The dispersion medium of the levosalbuterol tartrate particles according to claim 8, characterized in that: The saturated solution of levosalbutamol tartrate is subjected to ultrasonic treatment and allowed to stand overnight.

10. The dispersion medium of the levosalbuterol tartrate particles according to claim 8, characterized in that: The saturated solution was allowed to stand overnight and then filtered through a 0.22 μm filter membrane.

Images