Rapid detection method for particle size in solid preparation

Abstract

The invention relates to a method for rapidly detecting the particle size in a solid preparation, which is simple to operate, does not need to prepare raw material medicines with different particle sizes into finished products for research and development small tests, and can roughly determine the particle size range of the raw material medicines in a reference preparation by directly comparing dissolution curves of the raw material medicines with different particle sizes with the dissolution curves of the reference preparation. And a novel detection method is provided for researching the particle size range of the raw material medicines in the reference preparation.

Description

Technical Field

[0001] This invention belongs to the field of particle size detection technology, specifically relating to a rapid method for detecting particle size in solid dosage forms. Background Technology

[0002] my country is a major producer of generic drugs, but the quality of these drugs varies greatly. To control the quality of generic drugs from the source and effectively improve their quality level, the country has comprehensively promoted the consistency evaluation of generic drugs. Generally, the development of generic drug products begins with the characterization of the original drug or reference preparation. During the consistency evaluation process, pharmaceutical manufacturers must conduct comprehensive and in-depth comparative studies using the reference preparation as a control. These studies include comparative studies of major pharmaceutical indicators such as formulation, quality standards, crystal form, particle size, and impurities, as well as comparative studies of dissolution curves of solid dosage forms. This aims to improve the success rate of in vivo bioequivalence tests and provide a basis for including characteristic dissolution curves of drugs in the corresponding quality standards.

[0003] The size of particles is called particle size, which is generally expressed as diameter, hence also called particle size. Particle size and distribution are important indicators of formulation quality and are "internal control indicators" for original drug manufacturers. APIs with different particle sizes have completely different release and absorption rates and degrees in vivo, which determines the drug's dissolution rate and bioavailability. Generally speaking, the smaller the particle size, the larger the specific surface area, the larger the area in contact with the surrounding medium, and the greater the dissolution rate.

[0004] The CFDA's Technical Guidelines for Generic Drug Consistency Evaluation clearly state that particle size and particle size distribution are key physicochemical properties of active pharmaceutical ingredients (APIs) and must be analyzed and tested during pharmaceutical evaluation. Studying particle size aims to control particle size distribution in subsequent production to achieve batch-to-batch consistency. This requires identifying the impact of different API particle size distributions on dissolution and determining a particle size range during R&D. In in vitro studies of generic drugs, the solubility of APIs with different particle sizes needs to be measured to examine the effect of particle size on dissolution rate and dissolution rate, identifying different particle size ranges that can distinguish dissolution curves. Therefore, to improve the quality of generic drugs and ensure drug safety and efficacy, achieving particle size consistency with the original drug requires first defining the target particle size, i.e., the particle size of the reference formulation. A direct method is to accurately measure the particle size of the API in the original drug. However, during generic drug development, original drug manufacturers often do not fully disclose information about the reference formulation to protect their formulation, making it difficult to directly measure the API particle size in the original drug.

[0005] Traditional particle size analysis methods require pretreatment of the components in solid dosage forms to separate the active pharmaceutical ingredient (API) particles before analysis. However, the degree of pretreatment is difficult to control; insufficient separation can result in overly large particles, while excessive separation can damage the particle morphology. How to perform non-destructive and rapid in-situ particle size analysis of reference formulations is currently a research challenge in drug reverse engineering.

[0006] The commonly used method involves preparing finished formulations from active pharmaceutical ingredients (APIs) of different particle sizes, then comparing the dissolution curves of the finished formulations with those of a reference formulation. Other methods, such as fitting the dissolution curves of the finished and reference formulations, are then used to screen the particle size distribution range of the API. This method requires preparing finished formulations from APIs of different particle sizes, adding a step to small-scale studies, and is time-consuming and labor-intensive. Summary of the Invention

[0007] This invention provides a rapid method for detecting particle size in solid dosage forms. It addresses the challenge of directly determining the particle size of APIs in reference formulations during research and development. This method is simple to operate, eliminating the need to prepare APIs of different particle sizes into finished products for small-scale research trials. Instead, it directly compares the dissolution curves of APIs of different particle sizes with those of the reference formulation, allowing for a rough determination of the particle size range of the API in the reference formulation. This reduces the steps required for small-scale research, saving time and effort, and providing a new detection method for studying the particle size range of APIs in reference formulations.

[0008] To achieve the above objectives, the present invention provides the following technical solution: A rapid method for detecting particle size in solid dosage forms, the method comprising the following steps: (1) Take an appropriate amount of solid preparation with unknown particle size and grind it into powder; (2) Determine the dissolution curve of the solid dosage form in step (1) according to the dissolution test method; (3) Provide an active pharmaceutical ingredient with the same active ingredient as the solid dosage form of step (1), wherein the particle size of the active pharmaceutical ingredient is known, and determine the dissolution profiles of at least two batches of the active pharmaceutical ingredient with different particle sizes; (4) Compare the dissolution curve of the solid dosage form determined in step (2) with the dissolution curve of the active pharmaceutical ingredient with known particle size determined in step (3). If the dissolution curve of the solid dosage form is close to the dissolution curve of the active pharmaceutical ingredient with known particle size, then the particle size of the solid dosage form is close to the particle size of the active pharmaceutical ingredient with known particle size.

[0009] Furthermore, the solid dosage form with unknown particle size in step (1) is a reference dosage form.

[0010] Furthermore, the reference formulation with unknown particle size in step (1) is any one of mesalazine enteric-coated tablets, valsartan tablets, empagliflozin tablets, and apaxaban tablets.

[0011] Furthermore, the dissolution medium used in the dissolution determination method in step (2) is either water or a phosphate buffer solution with pH 6.8.

[0012] A rapid method for detecting the particle size of the active pharmaceutical ingredient (API) in mesalazine enteric-coated tablets, the method comprising the following steps: (1) Take an appropriate amount of mesalazine enteric-coated tablets reference preparation and crush it; (2) The dissolution curve of the crushed mesalazine enteric-coated tablets reference preparation was determined by the dissolution test method; (3) Take at least two batches of mesalazine raw materials with known different particle sizes and determine the dissolution curves according to the dissolution test method; (4) Compare the dissolution curves of the active pharmaceutical ingredients with different particle sizes in step (3) with the dissolution curve of the reference formulation of mesalazine enteric-coated tablets determined in step (2).

[0013] Furthermore, the dissolution determination method in steps (2) and (3) includes a phosphate buffer solution with pH 6.8 as the dissolution medium, a rotation speed of 50 rpm, and determination time points of 2 min, 5 min, 8 min, 10 min, and 15 min.

[0014] Furthermore, in step (3), the particle sizes of the mesalazine raw material are D90: 9μm, D90: 30μm and D90: 48μm, respectively.

[0015] Furthermore, in step (4), the dissolution data of the reference formulation of mesalazine enteric-coated tablets measured at 2 min, 5 min, 8 min, 10 min, and 15 min are compared one-to-one with the dissolution data of mesalazine raw materials with particle sizes of D90: 9 μm, D90: 30 μm, and D90: 48 μm measured at 2 min, 5 min, 8 min, 10 min, and 15 min. The one with the closest dissolution curve data is determined to be the particle size closest to the reference formulation of mesalazine enteric-coated tablets.

[0016] Traditional particle size analysis methods require pretreatment of the components in solid dosage forms to separate the active pharmaceutical ingredient (API) particles before analysis. However, the degree of pretreatment is difficult to control. Insufficient separation can result in oversized particles, while excessive separation can damage the particle morphology. How to perform in-situ particle size analysis of reference formulations in a non-destructive and rapid manner is a current research challenge in drug reverse engineering.

[0017] Current technology involves preparing finished formulations from active pharmaceutical ingredients (APIs) of different particle sizes, then comparing the dissolution curves of the finished formulations with those of a reference formulation, and using other methods such as fitting the dissolution curves of the finished and reference formulations to screen the particle size distribution range of the API. This method requires preparing finished formulations from APIs of different particle sizes before testing, adding a step to small-scale studies, which is time-consuming and labor-intensive.

[0018] The particle size detection method described in this application eliminates the need to prepare finished formulations from multiple batches of unknown active pharmaceutical ingredients (APIs) with different particle sizes. Instead of comparing the dissolution curves of the finished formulations with those of a reference formulation to screen for the particle size distribution range of the API, this method only requires measuring the dissolution curves of at least two batches of APIs with known particle sizes and the dissolution curves of the reference formulation. By comparing the data of the dissolution curves of the APIs with those of the reference formulation, it can be determined which batch of APIs with known particle sizes the dissolution curve of the reference formulation is closest to. If the data of the dissolution curve of the reference formulation is close to the data of the dissolution curve of the API with known particle sizes, then the particle size of the reference formulation is close to that of the API. This rapid screening method can quickly determine the particle size range of the reference formulation, thereby reducing the steps of small-scale research, effectively saving R&D time and effort.

[0019] This invention provides a convenient and efficient detection method to solve the problem of particle size detection of reference preparations. It can be used to determine the particle size range of reference preparations, thereby effectively saving research and development time and effort. Detailed Implementation

[0020] The present invention is further illustrated by the following examples, but these are not intended to limit the invention. Example 1

[0021] (1) Take several mesalazine enteric-coated tablets of the reference preparation, wrap them in kraft paper, and crush them. Try to avoid losing tablets during this process.

[0022] (2) The dissolution curve of the reference preparation of mesalazine enteric-coated tablets after crushing was determined at 50 rpm using the dissolution medium of phosphate buffer solution with pH 6.8, according to the dissolution test method (Chinese Pharmacopoeia 2025 edition, Part IV, General Chapter 0931, Method II).

[0023] (3) Take mesalazine raw materials with D90: 9μm, D90: 30μm and D90: 48μm and determine the dissolution curves.

[0024] (4) Compare the dissolution curves of the three batches of raw materials with different particle sizes in step (3) with the dissolution curve of the reference preparation of crushed mesalazine enteric-coated tablets. The data are shown in Table 1.

[0025]

[0026] The smaller the particle size, the larger the specific surface area, the larger the area in contact with the surrounding medium, and the greater the dissolution rate. By observing and comparing the dissolution curve data, it can be preliminarily determined that the particle size D90 of the active pharmaceutical ingredient in the reference formulation of mesalazine enteric-coated tablets is above 30 μm. During the research process, the particle size can be controlled within 30 μm ≤ D90 ≤ 50 μm.

[0027] To verify the particle size range of the reference formulation of mesalazine enteric-coated tablets, the dissolution curves of the finished mesalazine enteric-coated tablets (sample 1, sample 2, and sample 3) prepared from active pharmaceutical ingredients 1, 2, and 3 were compared with those of the reference formulation in different media. The results are as follows.

[0028]

[0029]

[0030]

[0031] As shown in Table 2-4, the dissolution curve of sample 3 is closest to that of the reference formulation, indicating that the particle size D90 of the active pharmaceutical ingredient of the mesalazine enteric-coated tablet reference formulation is close to 48 μm, and it has the highest similarity to the reference formulation in various media.

[0032] Example 2 (1) Take several valsartan tablets as a reference preparation, wrap them in kraft paper, and crush them. Try to avoid losing tablets during this process.

[0033] (2) The dissolution curve of the reference preparation of crushed valsartan tablets was determined at 50 rpm using the dissolution medium of phosphate buffer solution with pH 6.8, according to the dissolution test method (Chinese Pharmacopoeia 2025 edition, Part IV, General Chapter 0931, Method II).

[0034] (3) Take valsartan raw materials with D90: 66μm, D90: 125μm and D90: 178μm and determine the dissolution curves.

[0035] (4) Compare the dissolution curves of the three batches of raw materials with different particle sizes in step (3) with the dissolution curve of the crushed valsartan tablet reference preparation. The data are shown in Table 5.

[0036]

[0037] The smaller the particle size, the larger the specific surface area, the larger the area in contact with the surrounding medium, and the greater the dissolution rate. By observing and comparing the dissolution curve data, it can be preliminarily determined that the particle size D90 of the active pharmaceutical ingredient in the reference formulation of valsartan tablets is above 100 μm. During the research process, the particle size can be controlled within 120 μm ≤ D90 ≤ 180 μm.

[0038] To verify the particle size range of the reference formulation of valsartan tablets, valsartan tablets (specification: 80mg) were prepared using active pharmaceutical ingredients 1, 2, and 3 (samples 1, 2, and 3, respectively), and their dissolution curves in different media were compared with those of the reference formulation. The results are as follows.

[0039]

[0040]

[0041]

[0042] As shown in Table 6-8, the dissolution curve of sample 3 is closest to that of the reference formulation, indicating that the particle size D90 of the active pharmaceutical ingredient of the reference formulation of valsartan tablets is close to 178 μm, and it has the highest similarity to the reference formulation in various media.

[0043] Example 3 (1) Take several empagliflozin tablets, wrap them in kraft paper, and crush them. Try to avoid losing tablets during this process.

[0044] (2) The dissolution curve of the reference preparation of crushed empagliflozin tablets was determined according to the dissolution test method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method II) with the dissolution medium being an aqueous solution.

[0045] (3) Take empagliflozin raw materials with D90: 25μm, D90: 45μm and D90: 78μm and determine the dissolution curves.

[0046] (4) Compare the dissolution curves of the three batches of raw materials with different particle sizes in step (3) with the dissolution curve of the crushed empagliflozin reference preparation. The data are shown in Table 9.

[0047]

[0048] The smaller the particle size, the larger the specific surface area, the larger the area in contact with the surrounding medium, and the greater the dissolution rate. By observing and comparing the dissolution curve data, it can be preliminarily determined that the particle size D90 of the active pharmaceutical ingredient in the reference formulation of empagliflozin tablets is below 45 μm. During the research process, the particle size can be controlled to D90≤45 μm.

[0049] To verify the particle size range of the reference formulation of empagliflozin, empagliflozin (specification: 25mg) was prepared using active pharmaceutical ingredients 1, 2, and 3 (samples 1, 2, and 3, respectively), and the dissolution curves of the finished products were compared with those of the reference formulation in different media. The results are as follows.

[0050]

[0051]

[0052]

[0053] Based on the data in Table 10-12, the dissolution curve of sample 2 is closest to that of the reference formulation, indicating that the particle size D90 of the active pharmaceutical ingredient of the reference formulation of empagliflozin tablets is close to 45 μm, and it has the highest similarity to the reference formulation in various media.

[0054] Example 4 To verify the accuracy of this application, experiments were conducted using apixaban tablets with a reference formulation active pharmaceutical ingredient particle size disclosed in the published literature. In the published literature, the particle size D90 of the reference formulation apixaban tablets active pharmaceutical ingredient is ≤89μm.

[0055] (1) Take several apixaban tablets (5mg) reference preparation, wrap them in kraft paper and crush them. Try to avoid losing tablets during this process.

[0056] (2) The dissolution curve of the reference preparation of crushed apixaban tablets was determined by the dissolution test method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method II) with the dissolution medium being pH 6.8 sodium phosphate buffer (containing 0.05% SDS) at 75 rpm.

[0057] (3) Take apixaban raw materials with D90: 117μm, D90: 85μm and D90: 18μm and determine the dissolution curves.

[0058] (4) Compare the dissolution curves of the three batches of raw materials with different particle sizes in step (3) with the dissolution curve of the crushed apixaban tablet reference preparation. The data are shown in Table 13.

[0059]

[0060] The smaller the particle size, the larger the specific surface area, the larger the area in contact with the surrounding medium, and the greater the dissolution rate. By observing and comparing the dissolution curve data, it can be preliminarily determined that the particle size D90 of the active pharmaceutical ingredient in the reference formulation of apixaban tablets is below 85μm. During the research process, the particle size can be controlled to D90≤85μm.

[0061] To verify the particle size range of the reference formulation of apixaban tablets, apixaban (specification: 5mg) finished products (sample 1, sample 2, and sample 3) were prepared using active pharmaceutical ingredients 1, 2, and 3, respectively, and their dissolution curves in different media were compared with those of the reference formulation. The results are as follows.

[0062]

[0063]

[0064] Based on the data in Tables 14 and 15, the dissolution curves of samples 2 and 3 are similar to those of the reference formulation, indicating that the particle size D90 of the active pharmaceutical ingredient of the reference formulation of apixaban tablets is close to 85 μm, and it has the highest similarity to the reference formulation in various media.

[0065] The experiment in Example 4 verifies that the particle size of the active pharmaceutical ingredient (API) of the reference formulation of apixaban tablets can be quickly determined to be close to 85 μm using the method of this application. This is very close to the particle size D90≤89 μm of the reference formulation of apixaban tablets disclosed in the literature, indicating that the particle size range of the reference formulation of apixaban tablets can be quickly determined using the method of this application.

[0066] As can be seen from the above embodiments, the method of this application can quickly and roughly determine the particle size range of the active pharmaceutical ingredient (API) in the reference formulation. It eliminates the need to prepare finished formulations from APIs of different particle sizes, compare the dissolution curves of the finished formulations with those of the reference formulation, and use other methods such as fitting the dissolution curves of the finished formulations and the reference formulation to screen the particle size distribution range of the API. This process increases the steps of small-scale research, which is time-consuming and labor-intensive. This application can reduce the steps of small-scale research, saving time and effort, and provides a new detection method for studying the particle size range of APIs in reference formulations.

Claims

1. A rapid method for detecting particle size in solid dosage forms, characterized in that, The detection method includes the following steps: (1) Take an appropriate amount of solid preparation with unknown particle size and grind it into powder; (2) Determine the dissolution curve of the solid dosage form in step (1) according to the dissolution test method; (3) Provide an active pharmaceutical ingredient with the same active ingredient as the solid dosage form of step (1), wherein the particle size of the active pharmaceutical ingredient is known, and determine the dissolution profiles of at least two batches of the active pharmaceutical ingredient with different particle sizes; (4) Compare the dissolution curve of the solid dosage form determined in step (2) with the dissolution curve of the active pharmaceutical ingredient with known particle size determined in step (3). If the dissolution curve of the solid dosage form is close to the dissolution curve of the active pharmaceutical ingredient with known particle size, then the particle size of the solid dosage form is close to the particle size of the active pharmaceutical ingredient with known particle size.

2. The rapid detection method according to claim 1, characterized in that, The solid dosage form with unknown particle size in step (1) is a reference dosage form.

3. The rapid detection method according to claim 2, characterized in that, The reference formulation for the unknown particle size in step (1) is any one of mesalazine enteric-coated tablets, valsartan tablets, empagliflozin tablets, and apaxaban tablets.

4. The rapid detection method according to claim 3, characterized in that, The dissolution medium used in the dissolution determination method in step (2) is either water or phosphate buffer solution with pH 6.

8.

5. A rapid method for detecting the particle size of the active pharmaceutical ingredient in mesalazine enteric-coated tablets, characterized in that, The detection method includes the following steps: (1) Take an appropriate amount of mesalazine enteric-coated tablets reference preparation and crush it; (2) The dissolution curve of the crushed mesalazine enteric-coated tablets reference preparation was determined by the dissolution test method; (3) Take at least two batches of mesalazine raw materials with known different particle sizes and determine the dissolution curves according to the dissolution test method; (4) Compare the dissolution curves of the active pharmaceutical ingredients with different particle sizes in step (3) with the dissolution curve of the reference formulation of mesalazine enteric-coated tablets determined in step (2).

6. The rapid detection method according to claim 5, characterized in that, The dissolution determination method in steps (2) and (3) includes a phosphate buffer solution with pH 6.8 as the dissolution medium, a rotation speed of 50 rpm, and measurement time points of 2 min, 5 min, 8 min, 10 min, and 15 min.

7. The rapid detection method according to claim 6, characterized in that, In step (3), the particle sizes of the mesalazine raw material are D90: 9μm, D90: 30μm and D90: 48μm, respectively.

8. The rapid detection method according to claim 7, characterized in that, In step (4), the dissolution data of the reference formulation of mesalazine enteric-coated tablets measured at 2 min, 5 min, 8 min, 10 min, and 15 min are compared one-to-one with the dissolution data of mesalazine raw materials with particle sizes of D90: 9 μm, D90: 30 μm, and D90: 48 μm measured at 2 min, 5 min, 8 min, 10 min, and 15 min. The one with the closest dissolution curve data is determined to be the particle size closest to the reference formulation of mesalazine enteric-coated tablets.

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