Impurity analysis method for budesonide inhalation solution

Abstract

The invention discloses an impurity analysis method for a budesonide inhalation solution, and relates to the technical field of budesonide impurity analysis, and the method comprises the following steps: weighing 50mg of a budesonide inhalation solution sample, placing the budesonide inhalation solution sample in a 10mL volumetric flask, adding a diluent (such as acetonitrile and methanol) to a scale line, and fully shaking to dissolve the diluent to prepare a 5mg / mL sample solution; and filtering the diluted sample by using a filter so as to remove insoluble impurities. According to the budesonide inhalation solution impurity analysis technology, the product quality, the market competitiveness and the research and development capability of enterprises can be remarkably improved, meanwhile, the requirements of laws and regulations are met, and time and cost are saved; by analyzing the impurities, the product quality and safety can be improved, and by accurately analyzing and controlling the impurity content in the medicine, the purity and quality of the product can be remarkably improved, so that the risk of adverse reaction and side effect can be reduced, and the medication safety of a patient is improved.

Description

Technical Field

[0001] The invention relates to the technical field of budesonide impurity analysis, in particular to an impurity analysis method for a budesonide inhalation solution. Background Art

[0002] The impurity analysis method of budesonide inhalation solution usually involves high performance liquid chromatography (HPLC), which is a technology widely used in drug impurity analysis. High performance liquid chromatography separates different components in a sample through a chromatographic column and uses a detector to detect and quantify the separated components. In the impurity analysis of budesonide inhalation solution, HPLC can accurately identify and determine the impurity components and their contents in the solution.

[0003] In the complex journey of drug research and development, impurity analysis is not only a key to exploring the essence of drugs, but also an important barrier to ensure the safety and effectiveness of drugs. If the in-depth analysis of impurities is neglected, companies will face a series of severe challenges. First of all, impurities are unexpected components in drugs, and their existence is often directly related to the purity of the drugs, which in turn affects the overall quality and therapeutic effect of the drugs. Failure to conduct a systematic analysis of impurities is like sailing in unknown waters. It is difficult to accurately control the course, which increases the risk of adverse reactions or side effects that may be caused by drugs during use. This not only threatens the life safety of patients, but also damages the company's reputation and social responsibility.

[0004] Secondly, impurity analysis plays an indispensable role in optimizing the production process. The types, sources and content changes of impurities can often reflect the subtle differences and potential problems in the production process. Without impurity analysis technology, companies are like blind men touching an elephant, and it is difficult to capture the key factors that affect product stability and consistency in the production process. This not only limits the improvement of production efficiency, but may also lead to large fluctuations in product quality between batches, making it difficult to meet the market's growing demand for high-quality drugs.

[0005] Furthermore, from the perspective of regulatory compliance, strict supervision of impurity content by drug regulatory authorities is an important measure to ensure the safety of public drug use. Without the support of impurity analysis technology, companies will find it difficult to ensure that their products comply with regulatory requirements, and may face severe regulatory penalties and market access barriers, which will not only disrupt the company's production plans and market layout, but may also cause significant economic losses and damage to its brand image.

[0006] In addition, in the fiercely competitive pharmaceutical market, high-quality, low-impurity drugs are the key to winning consumer trust and market share. Without impurity analysis technology, it is difficult for companies to make breakthroughs in product quality and produce high-quality drugs with differentiated competitive advantages, which will put companies at a disadvantage in market competition and may even be eliminated by the market.

[0007] Finally, from a cost-effectiveness perspective, without efficient impurity analysis technology, companies will have to rely on traditional, cumbersome and time-consuming analytical methods, which are not only inefficient but may not accurately detect all types of impurities, leading to deviations and misleading analytical results. This will not only increase the company's analytical and time costs, but may also delay the product's time to market and miss market opportunities.

[0008] In view of the above problems, the present invention provides an impurity analysis method for budesonide inhalation solution. Summary of the invention

[0009] The purpose of the present invention is to provide an impurity analysis method for a budesonide inhalation solution. Having the impurity analysis technology for a budesonide inhalation solution can significantly improve the product quality, market competitiveness and research and development capabilities of an enterprise, while meeting regulatory requirements and saving time and costs; by analyzing impurities, it is beneficial to improve product quality and safety, and by accurately analyzing and controlling the impurity content in a drug, the purity and quality of the product can be significantly improved, which helps to reduce the risk of adverse reactions and side effects, thereby improving the drug safety of patients.

[0010] Secondly, by analyzing the types and contents of impurities in different batches of products, data support can be provided for the optimization of production processes. Enterprises can adjust production process parameters based on the analysis results, reduce the generation of impurities, and improve product stability and consistency.

[0011] Furthermore, drug regulatory authorities have strict regulations on the impurity content in drugs. Possessing this technology can ensure that the budesonide inhalation solution produced by the company complies with relevant regulatory requirements and successfully passes the approval and inspection of regulatory authorities.

[0012] Furthermore, high-quality, low-impurity drugs are more likely to gain market recognition and trust. Companies with the above technologies can produce better-quality drugs and enhance their brand image and market competitiveness.

[0013] Finally, impurity analysis is an indispensable part of the drug research and development process. Analysis of impurities can provide researchers with accurate impurity information, helping them to better understand the properties and behaviors of drugs, thereby accelerating the drug development process. Compared with traditional impurity analysis methods, this technology has higher analysis efficiency and lower cost. It can quickly and accurately detect impurities in drugs, avoiding tedious sample pretreatment and lengthy analysis time, thereby saving companies time and costs, thereby solving problems in background technology.

[0014] To achieve the above object, the present invention provides the following technical solution: a method for analyzing impurities of budesonide inhalation solution, the method comprising the following steps:

[0015] S1: Weigh 50 mg of budesonide inhalation solution sample, place in a 10 mL volumetric flask, add diluent (such as acetonitrile, methanol) to the scale line, shake thoroughly to dissolve, and prepare a 5 mg / mL sample solution.

[0016] S2: Filter the diluted sample using a filter to remove insoluble impurities, select a C18 chromatographic column, and set the mobile phase and chromatographic parameters.

[0017] S3: Take 20 μL each of the diluted sample solution, each known impurity reference solution and blank excipient solution, record the chromatogram within 30 minutes, and use the chromatography data system to automatically identify and integrate the peak area.

[0018] S4: Use chromatographic software to automatically identify impurity peaks and compare them with the standard chromatogram to effectively distinguish the target substance from the impurity components. Use the external standard method, an impurity control solution of known concentration, and test under the same chromatographic conditions, record the peak area at each concentration. Based on these data, establish the relationship between impurity concentration and peak area to ensure the accuracy of quantitative analysis, and establish an impurity library for budesonide inhalation solution, including the retention time and peak shape characteristics of each impurity, to facilitate the rapid identification of subsequent batches of products.

[0019] S5: Set a linear gradient elution program, starting from an initial mobile phase ratio of 0% B and gradually increasing to 100% B, with a total duration of 30 minutes, to achieve optimal separation of different impurities, ensuring that the separation between each impurity peak is greater than 1.5, and that the signal-to-noise ratio of the two peaks of budesonide diastereomers is greater than 10, take blank excipient solutions, inject them into the liquid chromatograph respectively, record and compare the chromatograms of each solution, and analyze whether the impurity content meets the quality standard requirements.

[0020] Furthermore, in step S1, all excipients except budesonide are weighed according to the prescription ratio, and a blank excipient solution is prepared in the same manner as the sample solution.

[0021] Furthermore, in step S1, known impurity reference substances (such as budesonide isomers, degradation products) are weighed respectively and prepared into a series of standard solutions of 0.1 μg / mL, 0.5 μg / mL, 1 μg / mL, 5 μg / mL and 10 μg / mL with a diluent.

[0022] Furthermore, in step S2, the filter may be a filter membrane made of 0.45 μm nylon or PTFE.

[0023] Furthermore, in step S2, the specification of the C18 chromatographic column is 4.6 mm*250 mm, with a particle size of 5 μm, to ensure separation efficiency and durability.

[0024] Furthermore, in step S3, ensure that the test meets the following requirements:

[0025] The resolution of budesonide isomer peaks was >1.5;

[0026] The theoretical plate number of the main budesonide peak is >5000;

[0027] The tailing factor of the main budesonide peak was <1.5;

[0028] The relative standard deviation (RSD) of replicate injections was <2.0%.

[0029] Furthermore, in step S4, the standard curve is established using the external standard method, and the linear range is: 0.1 μg / mL-10 μg / mL, ensuring the correlation coefficient R 2 >0.999.

[0030] Furthermore, in step S5, it is ensured that the separation between the impurity peaks is greater than 1.5, and the signal-to-noise ratio of the two peaks of budesonide diastereomers is greater than 10.

[0031] Furthermore, in step S5, the impurity content is calculated using the formula: impurity content (%) = (impurity peak area / budesonide main peak area) × (budesonide concentration / impurity concentration) × 100%.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The impurity analysis method of a budesonide inhalation solution provided by the present invention has the impurity analysis technology of the budesonide inhalation solution, which can significantly improve the product quality, market competitiveness and research and development capabilities of an enterprise, while meeting regulatory requirements and saving time and costs; by analyzing the impurities, it is beneficial to improve the quality and safety of the product, and by accurately analyzing and controlling the impurity content in the drug, the purity and quality of the product can be significantly improved, which helps to reduce the risk of adverse reactions and side effects, thereby improving the safety of medication for patients.

[0034] Secondly, by analyzing the types and contents of impurities in different batches of products, data support can be provided for the optimization of production processes. Enterprises can adjust production process parameters based on the analysis results, reduce the generation of impurities, and improve product stability and consistency.

[0035] Furthermore, drug regulatory authorities have strict regulations on the impurity content in drugs. Possessing this technology can ensure that the budesonide inhalation solution produced by the company complies with relevant regulatory requirements and successfully passes the approval and inspection of regulatory authorities.

[0036] Furthermore, high-quality, low-impurity drugs are more likely to gain market recognition and trust. Companies with the above technologies can produce better-quality drugs and enhance their brand image and market competitiveness.

[0037] Finally, impurity analysis is an indispensable part of the drug development process. Analysis of impurities can provide researchers with accurate impurity information, helping them better understand the properties and behaviors of drugs, thereby accelerating the drug development process. Compared with traditional impurity analysis methods, this technology has higher analysis efficiency and lower cost. It can quickly and accurately detect impurities in drugs, avoiding tedious sample pretreatment and lengthy analysis time, thereby saving companies time and costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is a flowchart of the gradient elution process of the present invention;

[0039] Figure 2 This is a schematic diagram of the impurity analysis results of typical samples of the present invention;

[0040] Figure 3 This is an example diagram of the standard curve of the present invention;

[0041] Figure 4 It is a specific data frame diagram corresponding to the standard curve of the present invention. DETAILED DESCRIPTION

[0042] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0043] To solve technical problems, such as Figure 1-4 As shown, the following preferred technical solutions are provided:

[0044] A method for analyzing impurities of a budesonide inhalation solution, comprising the following steps:

[0045] S1: Weigh 50 mg of budesonide inhalation solution sample, place in a 10 mL volumetric flask, add diluent acetonitrile: water = 70:30, v / v to the scale line, and ultrasonically oscillate for 10 minutes to dissolve, to prepare a 5 mg / mL sample solution.

[0046] Specifically, in the above step S1, all excipients except budesonide are weighed according to the prescription ratio, and a blank excipient solution is prepared in the same manner as the sample solution.

[0047] Furthermore, in the above step S1, known impurity reference substances such as budesonide isomers and degradation products are weighed respectively, and a series of standard solutions of 0.1 μg / mL, 0.5 μg / mL, 1 μg / mL, 5 μg / mL and 10 μg / mL are prepared with a diluent.

[0048] S2: Filter the diluted sample using a filter to remove insoluble impurities, select a C18 chromatographic column, and set the mobile phase and chromatographic parameters, where:

[0049] Mobile phase A: phosphate buffer pH 3.2, a mixture of potassium dihydrogen phosphate and phosphoric acid adjusted with acetonitrile, the volume ratio is 2:32:68, that is, potassium dihydrogen phosphate-phosphate buffer accounts for 2%, acetonitrile accounts for 68%, and the rest is water, to adjust the total volume to 100%;

[0050] Mobile phase B: a mixture of anhydrous ethanol and acetonitrile, with a volume ratio of 35:65 (v / v);

[0051] Column temperature: set to 35℃±0.5℃ to maintain the stability and separation efficiency of the chromatographic column;

[0052] Flow rate: 1.0 mL / min, to ensure proper analysis time and peak shape;

[0053] Detection wavelength: set at 240nm, the characteristic absorption wavelength of budesonide, which can be adjusted appropriately according to the characteristics of impurities;

[0054] Sampling volume: usually 10μL to 20μL.

[0055] Specifically, in the above step S2, the filter can be a filter membrane made of 0.45 μm nylon or PTFE.

[0056] Furthermore, in the above step S2, the specification of the C18 chromatographic column is 4.6 mm*250 mm, with a particle size of 5 μm, to ensure separation efficiency and durability.

[0057] S3: Take 20 μL each of the diluted sample solution, each known impurity reference solution and blank excipient solution, record the chromatogram within 30 minutes, and use the chromatography data system to automatically identify and integrate the peak area.

[0058] Specifically, in the above step S3, ensure that the test meets the following requirements:

[0059] The resolution of budesonide isomer peaks was >1.5;

[0060] The theoretical plate number of the main budesonide peak is >5000;

[0061] The tailing factor of the main budesonide peak was <1.5;

[0062] The relative standard deviation (RSD) of replicate injections was <2.0%.

[0063] S4: Use chromatographic software to automatically identify impurity peaks and compare them with the standard chromatogram to effectively distinguish the target substance from the impurity components. Use the external standard method, an impurity control solution of known concentration, and test under the same chromatographic conditions, record the peak area at each concentration. Based on these data, establish the relationship between impurity concentration and peak area to ensure the accuracy of quantitative analysis, and establish an impurity library for budesonide inhalation solution, including the retention time and peak shape characteristics of each impurity, to facilitate the rapid identification of subsequent batches of products.

[0064] Specifically, in step S4, the standard curve was established using the external standard method, with a linear range of 0.1 μg / mL-10 μg / mL, ensuring the correlation coefficient R 2 >0.999.

[0065] S5: Set a linear gradient elution program, starting from an initial mobile phase ratio of 0% B and gradually increasing to 100% B, with a total duration of 30 minutes, to achieve optimal separation of different impurities, ensuring that the separation between each impurity peak is greater than 1.5, and that the signal-to-noise ratio of the two peaks of budesonide diastereomers is greater than 10, take blank excipient solutions, inject them into the liquid chromatograph respectively, record and compare the chromatograms of each solution, and analyze whether the impurity content meets the quality standard requirements.

[0066] Specifically, in the above step S5, it is ensured that the separation between the impurity peaks is greater than 1.5, and the signal-to-noise ratio of the two peaks of budesonide diastereomers is greater than 10.

[0067] Furthermore, in the above step S5, the impurity content is calculated by the formula: impurity content (%) = (impurity peak area / budesonide main peak area) × (budesonide concentration / impurity concentration) × 100%.

[0068] In summary, method validation includes:

[0069] Specificity: confirmed by comparing blank, standard and sample chromatograms;

[0070] Linearity: R in the range of 0.1-10μg / mL 2 >0.999;

[0071] Precision: 6 repeated measurements RSD < 2.0%;

[0072] Accuracy: The recovery rate of known amount of impurities is between 98-102%;

[0073] Limit of detection (LOD): S / N>3;

[0074] Limit of quantitation (LOQ): S / N>10, confirmed by comparing blank, standard and sample chromatograms.

[0075] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0076] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for analyzing impurities of budesonide inhalation solution, characterized in that: The method comprises the following steps: S1: Weigh 50 mg of budesonide inhalation solution sample, place in a 10 mL volumetric flask, add diluent (such as acetonitrile, methanol) to the scale line, shake thoroughly to dissolve, and prepare a 5 mg / mL sample solution; S2: Filter the diluted sample using a filter to remove insoluble impurities, select a C18 chromatographic column, and set the mobile phase and chromatographic parameters; S3: Take 20 μL of the diluted sample solution, each known impurity reference solution and blank excipient solution, record the chromatogram within 30 minutes, and use the chromatography data system to automatically identify and integrate the peak area; S4: Use chromatographic software to automatically identify impurity peaks and compare them with the standard chromatogram to effectively distinguish the target substance from the impurity components. Use the external standard method, an impurity control solution with a known concentration, and test under the same chromatographic conditions to record the peak area at each concentration. Based on these data, establish the relationship between impurity concentration and peak area to ensure the accuracy of quantitative analysis. Establish an impurity library for budesonide inhalation solution, including the retention time and peak shape characteristics of each impurity, to facilitate rapid identification of subsequent batches of products; S5: Set a linear gradient elution program, starting from an initial mobile phase ratio of 0% B and gradually increasing to 100% B, with a total duration of 30 minutes, to achieve optimal separation of different impurities, ensuring that the separation between each impurity peak is greater than 1.5, and that the signal-to-noise ratio of the two peaks of budesonide diastereomers is greater than 10, take blank excipient solutions, inject them into the liquid chromatograph respectively, record and compare the chromatograms of each solution, and analyze whether the impurity content meets the quality standard requirements.

2. The impurity analysis method of a budesonide inhalation solution according to claim 1, characterized in that: In the step S1, all excipients except budesonide are weighed according to the prescription ratio, and a blank excipient solution is prepared in the same manner as the sample solution.

3. The impurity analysis method of a budesonide inhalation solution according to claim 1, characterized in that: In step S1, known impurity reference substances (such as budesonide isomers and degradation products) are weighed respectively, and a series of standard solutions of 0.1 μg / mL, 0.5 μg / mL, 1 μg / mL, 5 μg / mL and 10 μg / mL are prepared with a diluent.

4. The impurity analysis method of a budesonide inhalation solution according to claim 1, characterized in that: In step S2, the filter may be a filter membrane made of 0.45 μm nylon or PTFE.

5. The impurity analysis method of a budesonide inhalation solution according to claim 1, characterized in that: In step S2, the specification of the C18 chromatographic column is 4.6 mm*250 mm and the particle size is 5 μm to ensure separation efficiency and durability.

6. The impurity analysis method of a budesonide inhalation solution according to claim 1, characterized in that: In step S3, ensure that the test meets the following requirements: The resolution of budesonide isomer peaks was >1.5; The theoretical plate number of the main budesonide peak is >5000; The tailing factor of the main budesonide peak was <1.5; The relative standard deviation (RSD) of replicate injections was <2.0%.

7. The impurity analysis method of a budesonide inhalation solution according to claim 1, characterized in that: In step S4, the standard curve was established using the external standard method, with a linear range of 0.1 μg / mL-10 μg / mL, ensuring the correlation coefficient R 2 >0.

999.

8. The impurity analysis method of a budesonide inhalation solution according to claim 1, characterized in that: In step S5, it is ensured that the separation between the impurity peaks is greater than 1.5, and the signal-to-noise ratio of the two peaks of the budesonide diastereomers is greater than 10.

9. The impurity analysis method of a budesonide inhalation solution according to claim 1, characterized in that: In step S5, the impurity content is calculated using the formula: impurity content (%) = (impurity peak area / budesonide main peak area) × (budesonide concentration / impurity concentration) × 100%.

Images