Dissolution detection method and quality control method of balmacate oral solid preparation

Abstract

The invention relates to the technical field of pharmaceutical analysis, in particular to a dissolution detection method and a quality control method of a palmitate oral solid preparation. According to the method, the test sample solution is determined by adopting specific high-speed line chromatography detection conditions, the dissolution rate of the test sample at different sampling time points can be effectively and rapidly detected, and the method has the characteristics of strong specificity, rapidness, accuracy, good reproducibility and high sensitivity, can be widely applied to quality monitoring of preparations, and has wide application prospects. Reliable reference basis can be provided for development of a prescription process of a preparation, and is closely related to the in-vivo bioavailability, so that the research risk of the in-vivo bioavailability and bioequivalence can be greatly reduced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical analysis technology, and in particular to a dissolution detection method and quality control method for pemafibrate oral solid dosage form. Background Technology

[0002] Pemafibrate (CAS: 848259-27-8, molecular formula: C) 28 H 30 N2O6 (molecular weight: 490.55) belongs to the BCS II class of low-solubility, high-permeability drugs. Pemafibrate, as a novel fibrate lipid-lowering drug, works by selectively acting on PPARα receptors, causing conformational changes that lower triglycerides (TG), increase HDL-C levels, and comprehensively promote lipid metabolism. Currently, it is mainly used clinically to treat hyperlipidemia, including familial hyperlipidemia. Clinical guidelines recommend it as the first-line treatment for patients with severe hypertriglyceridemia (TG), and for treating mild to moderate hypertriglyceridemia when statin therapy is ineffective. In recent years, with the improvement of national living standards, the number of patients with hyperlipidemia has been increasing year by year, and there is a trend towards younger patients. Conventional lipid-lowering drugs, such as statins, only lower cholesterol and have little effect on triglycerides. Pemafibrate tablets, as a new generation of fibrates, not only have the traditional effect of lowering triglycerides, but also have the advantages of higher activity, stronger efficacy, and fewer side effects compared to previous generation drugs such as fenofibrate.

[0003] The original drug for pemafibrate tablets was developed by Kowa Co., Ltd. of Japan and launched in China in April 2025. The original drug for pemafibrate extended-release tablets was launched in Japan in June 2023. Neither of them is currently included in any pharmacopoeia. A review of domestic and foreign literature has not yet yielded any testing methods or reference materials that can be directly used for reference.

[0004] The physicochemical properties of pemafibrate show that it is almost insoluble in water, and its Biopharmaceutical Classification (BCS) has not yet been found. Preliminary experiments have shown that pemafibrate belongs to BCS Class II, meaning it has low solubility and high permeability. In conducting formulation and dissolution studies, selecting appropriate solubility and dissolution methods for pemafibrate is crucial to achieving certain in vitro leakage conditions and is key to developing in vitro dissolution testing methods.

[0005] In addition, pemafibrate is a highly active raw material, and the formulation is a very small-volume formulation, so the accuracy, sensitivity and specificity of the detection method are very important. Summary of the Invention

[0006] In view of this, the present invention provides a method for dissolution detection and quality control of pemafibrate oral solid dosage forms. This method is characterized by high specificity, speed, accuracy, good reproducibility, and high sensitivity.

[0007] A method for detecting the dissolution of pemafibrate oral solid dosage form, comprising the following steps:

[0008] S1. Dissolution sampling of the oral solid dosage form of pemafibrate to be tested was performed to obtain the test solution at different time points;

[0009] S2. The test solution is subjected to high performance liquid chromatography for detection, and the content of pemafibrate in the test solution is calculated by external standard method, and the solubility of pemafibrate preparation at different time points is obtained.

[0010] The conditions for the high-performance liquid chromatography detection include:

[0011] The mobile phase is a mixed solution of acetonitrile, trifluoroacetic acid and 0.01 mol / L potassium dihydrogen phosphate aqueous solution.

[0012] In this invention, the volume ratio of the 0.01 mol / L potassium dihydrogen phosphate aqueous solution, acetonitrile and trifluoroacetic acid is (38-50):(50-62):0.1, specifically 40:60:0.1 or 38:62:0.1.

[0013] In the high-performance liquid chromatography (HPLC) detection described in this invention, the column packing material is octadecylsilane-bonded silica gel. Further, the particle size of the packing material does not exceed 5.0 μm. In some specific embodiments, the column is any one of Agilent ZORBAX SB C18, Agilent Eclipse XDB-C18, and Thermo Fisher Acclaim C18. In this invention, the column size is preferably 4.6 * 50 mm. In this invention, the sample injection volume is 100 μl.

[0014] In the high-performance liquid chromatography detection described in this invention, the detection wavelength is 275–285 nm. The detector is preferably an ultraviolet or diode array detector.

[0015] In the high-performance liquid chromatography detection described in this invention, the column temperature is 25-35℃, specifically 25℃, 30℃ or 35℃.

[0016] In the high-performance liquid chromatography detection described in this invention, the flow rate is 1.0 to 2.0 ml / min, specifically 1.0 ml / min, 1.5 ml / min, or 2 ml / min.

[0017] Dissolution medium is a key factor affecting formulation dissolution. The selection of the medium must simultaneously consider both "simulating the in vivo dissolution environment" and "compliance with HPLC detection requirements" to accurately reflect the formulation's dissolution behavior in vivo and avoid introducing interfering components that affect chromatographic separation and detector response, thus ensuring the accuracy of the final HPLC detection results. This invention explored different media and found that a sodium chloride-containing hydrochloric acid solution with a pH of 1.2 exhibited good separation performance for pemafibrate (see...). Figure 5 This invention provides a highly effective differentiation between different processes and can achieve the final dissolution rate of the drug. Traditional media (such as pH 6.8 phosphate buffer) cannot effectively differentiate formulations from different processes. Conventionally, media with pH values ​​near the lowest solubility of the active pharmaceutical ingredient (API), such as a pH 3.0 disodium hydrogen phosphate-citric acid solution, cannot achieve the final dissolution rate of the drug within two hours, thus affecting the assessment of formulation quality. Furthermore, this invention uses the aforementioned medium to dissolve the formulation and prepare a test solution, which is then analyzed under specific high-resolution chromatography conditions, ultimately significantly improving the accuracy, reproducibility, and sensitivity of the detection results. In this invention, the preferred dissolution medium is a hydrochloric acid solution with pH 1.2 containing 2.0 g / L sodium chloride; that is, the medium is a mixed solution containing hydrochloric acid and 2.0 g / L sodium chloride at pH 1.2.

[0018] In this invention, step S1 includes: dissolving pemafibrate oral solid dosage form in a dissolution medium, conducting a dissolution test using a closed-loop flow cell method, setting sampling time points, and obtaining test solutions at different time points.

[0019] In this invention, the sampling time points are 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, and 120 min.

[0020] In this invention, the concentration of pemafibrate in the test solution at different time points is 0–0.2 μg / ml.

[0021] In this invention, a closed-loop flow cell method is used for dissolution testing. The flow cell selected for this method is a large-cup flow cell. In some specific embodiments, the diameter of the large-cup flow cell is 22.6 ml, and its volume is 14 ml. In this invention, the volume of the dissolution medium is 500–1000 ml. The flow rate of the flow cell also affects the dissolution discrimination power. In this invention, the flow rate of the flow cell is 6–8 ml / min, preferably 8 ml / min.

[0022] In this invention, the filter membrane used for filtering the test solution or reference solution in the dissolution determination at each time point comprises one layer of WhatMan GF / D and two layers of Jinteng MCE, i.e., three layers stacked together. In some specific embodiments, the filter membrane comprises one layer of WhatMan GF / D (25 mm 2.7 μm) and two layers of Jinteng MCE (25 mm 0.8 μm).

[0023] The dissolution detection method of the present invention further includes the steps of preparing a reference solution and performing high-performance liquid chromatography (HPLC) detection on the reference solution. The HPLC detection conditions are as described above.

[0024] Specifically, the preparation method of the reference solution includes: taking pemafibrate reference standard, dissolving it in acetonitrile, and diluting it with a dissolution medium to obtain the reference solution. In this invention, the concentration of the pemafibrate reference solution is 0.2 μg / ml.

[0025] This invention also provides a quality control method for pemarix oral solid dosage forms, comprising:

[0026] Perform in vitro dissolution testing on the test pedmafibrate oral solid dosage form and the reference dosage form as described above; obtain the cumulative dissolution amount of the test pedmafibrate oral solid dosage form and the reference dosage form at different time points;

[0027] Plot dissolution curves with sampling time points on the x-axis and cumulative dissolution amount on the y-axis, and compare the similarity factor f2 between the reference formulation and the self-made formulation.

[0028] When f2 ≥ 50, the dissolution curves of the test formulation and the reference formulation are considered similar; when f2 < 50, the dissolution curves of the test formulation and the reference formulation are considered dissimilar.

[0029] In this invention, the oral solid dosage form of Pemafibrate is specifically a tablet, capsule, oral liquid, or granule, etc.

[0030] This invention also provides the application of the dissolution detection method and the quality control method in the consistency evaluation of pemafibrate reference formulation and generic formulation.

[0031] This invention overcomes the shortcomings of existing technologies and provides a discriminative in vitro dissolution detection method for pemafibrate oral solid dosage forms, comprising: S1, sampling the pemafibrate oral solid dosage form to be tested for dissolution, obtaining test solutions at different time points; S2, performing high-performance liquid chromatography (HPLC) on the test solutions, calculating the pemafibrate content in the test solutions using the external standard method, and obtaining the solubility of the pemafibrate formulation at different time points; the HPLC detection conditions include: a mobile phase consisting of a mixed solution of acetonitrile, trifluoroacetic acid, and 0.01 mol / L potassium dihydrogen phosphate aqueous solution. This detection method combines a flow-through cell method with a specific medium and a specific HPLC detection system, enabling rapid and efficient acquisition of discriminative dissolution curves for pemafibrate. The method is simple, rapid, stable, accurate, and highly efficient. It facilitates accurate evaluation of the quality of pemafibrate oral solid dosage forms, guiding formulation development, providing reliable reference for formulation process development, and guiding the preparation of pemafibrate formulations that are of qualified quality, stable performance, and consistent with the original formulation. It also provides key technical support for the consistency evaluation of generic drugs and the equivalence of clinical use, ensuring that generic drugs are consistent with the original drugs in terms of quality and clinical efficacy, greatly reducing the risk of failure in bioequivalence experiments of pemafibrate preparations, and saving time and R&D costs. Attached Figure Description

[0032] Figure 1 This is the dissolution curve of the pemafibrate tablets in Example 1;

[0033] Figure 2 The results show the comparison of melting and curing at different granulation times;

[0034] Figure 3 The results show the comparison of different flow rates in the flow-through cell;

[0035] Figure 4 For samples of different particle sizes, the melting process was carried out.

[0036] Figure 5 The chromatogram is for the blank solvent;

[0037] Figure 6 Chromatogram of the reference solution used for dissolution curve determination of pemafibrate tablets;

[0038] Figure 7 Chromatogram of the test solution used for dissolution curve determination of pemafibrate tablets;

[0039] Figure 8 The sample chromatogram is shown at a detection wavelength of 245 nm.

[0040] Figure 9 The sample chromatogram is shown at a detection wavelength of 210 nm.

[0041] Figure 10 The sample chromatogram is shown at a detection wavelength of 280 nm.

[0042] Figure 11 The peak position diagram of Pembavertine in Example 8 is shown in the medium with pH 3.0 and the mobile phase being potassium dihydrogen phosphate aqueous solution-acetonitrile-trifluoroacetic acid (ratio 50:50:0.1).

[0043] Figure 12 The peak position diagram of Pembavertine in Example 8 is shown in the medium with pH 3.0 and the mobile phase being potassium dihydrogen phosphate aqueous solution-acetonitrile-trifluoroacetic acid (ratio 30:70:0.1).

[0044] Figure 13 The peak position diagram of Pembavertine in Example 8 is shown in the medium with pH 3.0 and the mobile phase being potassium dihydrogen phosphate aqueous solution-acetonitrile-trifluoroacetic acid (ratio 40:60:0.1).

[0045] Figure 14 The dissolution curve of Pemafibrate tablets in Example 8 is shown in the medium with pH 3.0 and the mobile phase being potassium dihydrogen phosphate aqueous solution-acetonitrile-trifluoroacetic acid (ratio 40:60:0.1).

[0046] Figure 15 The dissolution curves are for the two self-made formulations and the reference formulation in Example 9. Detailed Implementation

[0047] This invention provides a method for dissolution detection and quality control of pemafibrate oral solid dosage forms. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired results. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments, and those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to implement and apply the technology of this invention.

[0048] The test materials used in this invention are all common commercial products and can be purchased on the market.

[0049] An embodiment of a quality control method for a pemafibrate formulation provided by the present invention includes:

[0050] Provide test solutions for dissolution testing of pemaribate formulations at various time points;

[0051] Using octadecylsilane-bonded silica gel as the packing material and a mixed solution of 0.01 mol / L potassium dihydrogen phosphate aqueous solution-acetonitrile-trifluoroacetic acid as the mobile phase, the test solution was detected in a high-performance liquid chromatograph. The dissolution rate of the pemafibrate preparation at each time point was obtained by external standard method, and dissolution curves were plotted.

[0052] The test solutions for each time point of the pemafibrate preparation described in this invention refer to the test solutions obtained at each time point by placing the pemafibrate preparation into a flow cell containing 500 ml of pH 1.2 medium and conducting experiments according to set parameters. The dissolution medium is pH 1.2 solution, pH 4.5 solution, pH 6.8 solution, and pure water, more preferably pH 1.2 solution; the flow rate is 6.0 ml / min to 8.0 ml / min, more preferably 8.0 ml / min; the concentration of the reference solution is preferably 0.02 to 0.22 μg / mL, more preferably 0.2 μg / mL.

[0053] According to the present invention, the test solution is detected in liquid chromatography using octadecylsilane-bonded silica gel as the packing material and a mixed solution of 0.01 mol / L potassium dihydrogen phosphate aqueous solution, acetonitrile, and trifluoroacetic acid as the mobile phase. In the mixed solution of 0.01 mol / L potassium dihydrogen phosphate aqueous solution, acetonitrile, and trifluoroacetic acid, the preferred volume ratio is (38–50):(50–62):0.1, more preferably 40:60:0.1 or 38:62:0.1.

[0054] The detection wavelength used in the liquid chromatograph to detect the test solution is preferably 275-285 nm, more preferably 280 nm.

[0055] According to the present invention, preferably, a pemafibrate reference solution is injected into the liquid chromatograph for detection, and then the dissolution rate of pemafibrate in each test solution is calculated by the external standard method based on the peak area, and a dissolution curve is plotted.

[0056] To further understand the present invention, the quality inspection method for pemafibrate raw materials and their preparations provided by the present invention is described below with reference to embodiments.

[0057] The following are test samples of the pemafibrate preparation provided by Yunnan Longjin Kangyou Biomedical Co., Ltd., used in the embodiments of the present invention.

[0058] The following embodiments are further illustrative examples of the present invention, and not limitation thereof.

[0059] Example 1

[0060] The dissolution apparatus used was a SOTAX CE7 SMART. The closed-loop method was employed, and the pemafibrate formulation test samples were subjected to dissolution experiments according to the parameters in Table 1 below to obtain the dissolution test solution at each time point.

[0061] Table 1. Experimental parameters for dissolution using the closed-loop method in a flow-through cell.

[0062]

[0063]

[0064] Reference solution: Take pemafibrate reference standard (content is 100.00%), add an appropriate amount of acetonitrile to dissolve it, and then dilute it with pH 1.2 dissolution medium to obtain a solution with a concentration of about 0.2 μg / ml, which is used as the reference solution.

[0065] The detection instrument used was an Agilent 1260Ⅱ high performance liquid chromatograph, including a DEAE210761 quaternary gradient pump, a DEAEQ47248 autosampler, a DEACX26246 UV detector, a DEAED29390 column oven, and an Agilent ZORBAX SB-C18 column, 4.6 mm × 50 mm, 5 μm.

[0066] The column was filled with octadecylsilane-bonded silica gel, and the mobile phase was a mixed solution of 0.01 mol / L potassium dihydrogen phosphate aqueous solution, acetonitrile, and trifluoroacetic acid, with a volume ratio of 40:60:0.1. The detection wavelength was 280 nm, the column temperature was 30 °C, and the flow rate was 1.5 ml / min.

[0067] Measure 100 μl of each of the reference solution and the test solution and inject them into the liquid chromatograph, and record the chromatograms.

[0068] Content was calculated using the external standard method: the dissolution rate of the test solution at different time points was obtained by measuring the peak areas of the test solution and the reference solution. The results are shown in Table 2 below. Figure 1 .

[0069] Table 2. Chromatographic analysis results of the dissolution curves of pemafid tablets in Example 1.

[0070]

[0071]

[0072] Example 2

[0073] Following the flow cell experimental parameters and high-performance liquid chromatography (HPLC) parameters described in Example 1, the dissolution curves of the test samples with different granulation times in the formulation process were determined. The results are shown below. Figure 2 (Comparison of different granulation times for melting and curing)

[0074] Depend on Figure 2 The results show that the dissolution curves exhibit different results when the granulation time is different, indicating the high discriminative power of the dissolution conditions.

[0075] Example 3

[0076] Following the flow cell experimental parameters (except flow rate) in Example 1 and the high-performance liquid chromatography (HPLC) parameter determination conditions in Example 1, dissolution curves of the same batch of self-made samples were measured at different flow rates in the flow cell. The results are shown below. Figure 3 (Comparison of long-term melting at different flow rates in a flow-through cell)

[0077] Depend on Figure 3 The results show that, with all other conditions in the flow cell being the same, the dissolution curves exhibited different trends under different flow rates. At a flow rate of 4 ml / min, the dissolution rate was too slow, with only 65% ​​dissolved after 120 minutes, far from the endpoint, indicating that this flow rate setting was unreasonable. At a flow rate of 12 ml / min, the dissolution rate was too fast, reaching over 85% at 15 minutes, which lacked discriminative power, making this flow rate also undesirable. At a flow rate of 8 ml / min, the dissolution curve showed a smoother trend, with significant changes in dissolution rate in the first 30 minutes. Dissolution essentially plateaued at 60 minutes, and the endpoint dissolution was reached within the 120-minute experimental timeframe. Therefore, a flow rate of 8 ml / min was chosen as the optimal solution.

[0078] Example 4

[0079] Following the flow-through cell experimental parameters and high-performance liquid chromatography (HPLC) measurement conditions described in Example 1, dissolution profiles were determined for three batches of samples prepared using active pharmaceutical ingredients (APIs) of different particle sizes according to the same formulation process parameters. The results are shown below. Figure 4 (Dissolution of samples with different particle sizes).

[0080] Depend on Figure 4 The results show that samples prepared from APIs of different particle sizes under the same formulation process conditions exhibit different dissolution curve morphologies. The dissolution curve trend of the sample prepared from API with particle size c is most similar to that of the reference formulation. This is of great significance for us to select a suitable API particle size so as to prepare a product with the same quality as the original drug. It also demonstrates once again that the dissolution detection method of the present invention has good discriminative power.

[0081] Example 5

[0082] The instrument used was an Agilent 1260Ⅱ high performance liquid chromatograph, including a DEAE210772 quaternary gradient pump, a vacuum degasser, a DEAEQ47236 autosampler, a DEAC6172786 diode array detector, a DEAED29383 column oven, and an Agilent ZORBAX Eclipse-C18 column, 4.6 mm × 50 mm, 5 μm.

[0083] Take pemafibrate reference standard (content is 100.00%), add an appropriate amount of acetonitrile to dissolve it, and then dilute it with pH 1.2 dissolution medium to obtain a solution with a concentration of about 0.2 μg / ml, which is used as the reference solution.

[0084] The column was filled with octadecylsilane-bonded silica gel, and the mobile phase was a 0.01 mol / L potassium dihydrogen phosphate aqueous solution-acetonitrile-trifluoroacetic acid mixed solution. The volume ratio of the 0.01 mol / L potassium dihydrogen phosphate aqueous solution-acetonitrile-trifluoroacetic acid was 380:620:1 (i.e., 38:62:0.1). The detection wavelength was 275 nm, the column temperature was 35 °C, and the flow rate was 1.6 ml / min.

[0085] Measure 100 μl of each of the reference solution and the test solution and inject them into the liquid chromatograph, and record the chromatograms.

[0086] The content was calculated using the external standard method: the dissolution rate of the test solution was obtained by calculating the ratio of the peak areas of the test solution and the reference solution. The results are shown in Table 3 and... Figures 5-7 .

[0087] Table 3. Chromatographic analysis results of the dissolution rate of pemafid tablets in Example 4.

[0088]

[0089] Example 6

[0090] The self-made pemafibrate tablets (particle size c of Example 4) that are highly similar to the original drug were screened using the in vitro flow cell method with high discrimination determined by this invention and HPLC method, and a reference drug purchased from the original drug manufacturer, Kowa Co., Ltd. of Japan. A third-party company with legal qualifications was commissioned to conduct a pre-BE experiment using the double-period (pre-meal + post-meal) method to examine the quality consistency between the self-developed product and the original drug. The results are shown in Tables 4 and 5 below.

[0091] Table 4. Results of fasting equivalence analysis of Pemabet tablets.

[0092]

[0093] Table 5. Results of postprandial equivalence analysis of Pemabet tablets.

[0094]

[0095] As shown in Tables 4 and 5 above, the pre-BE results indicate that the in vivo changes of the self-made pemafibrate tablets of this invention are highly consistent with those of the original formulation. This further demonstrates that the in vitro dissolution method used in this invention has high discriminative power and provides an important reference for the study of formulation processes. Through the evaluation system of in vitro dissolution experiments, generic drugs with in vivo processes highly similar to those of the original formulation can be prepared.

[0096] Example 7 investigated the effect of different detection wavelengths on the method.

[0097] The effects of different wavelengths (210 nm, 245 nm, 280 nm) on the detection results of pemafibrate tablets (pemafibrate tablets with particle size c from Example 4) were investigated. Other conditions were performed according to the method in Example 5. The results are shown in [Figure 5]. Figures 8-10 .

[0098] The results showed that at detection wavelengths of 210 nm and 245 nm, there were many spurious peaks, which interfered with the detection results. At a detection wavelength of 280 nm, the baseline was basically flat and the spurious peaks were significantly reduced, making it the better choice.

[0099] Example 8 investigated the detection results under different mobile phase systems.

[0100] The ratio of mobile phase 1 to mobile phase 1 (0.01 mol / L potassium dihydrogen phosphate aqueous solution, acetonitrile, and trifluoroacetic acid) is 50:50:0.1.

[0101] Mobile phase 2: The ratio of 0.01 mol / L potassium dihydrogen phosphate aqueous solution, acetonitrile, and trifluoroacetic acid is 30:70:0.1.

[0102] The ratio of mobile phase 3 (0.01 mol / L potassium dihydrogen phosphate aqueous solution, acetonitrile, and trifluoroacetic acid) is 40:60:0.1.

[0103] The effects of the three different mobile phases on the detection results were investigated in a medium (containing disodium hydrogen phosphate-citric acid solution) at pH 3.0. Other detection conditions and detection reagents were the same as in Example 5. The results of mobile phases 1-3 are shown in the table below. Figures 11-13 The dissolution results of mobile phase 3 are shown in Table 6 and Figure 14 .

[0104] Table 6

[0105]

[0106] Depend on Figure 11It is known that the chromatographic peak of pemafibrate appears at about 4 to 5 minutes. For multiple time points of the dissolution curve and a sample volume of at least 12 cups, this peak elution time is significantly longer, which will lead to a longer detection time. It will take at least 3 days to complete the detection of a batch of products.

[0107] Depend on Figure 12 It can be seen that the chromatographic peak of pemafibrate appears within 1 minute, but it obviously overlaps with the solvent peak, resulting in poor separation and potentially interfering with the accuracy of the detection.

[0108] Depend on Figure 13 It is known that the chromatographic peak of pemafibrate appears at 1-2 minutes, which not only shortens the detection time, but also maintains a good separation effect with solvent peaks, etc., making it a more ideal method for dissolution curve detection. The mobile phase 3 system is preferred.

[0109] Depend on Figure 14 It can be seen that although the detection conditions of pH 3.0 and mobile phase of potassium dihydrogen phosphate aqueous solution-acetonitrile-trifluoroacetic acid (ratio 40:60:0.1) maintained a good separation effect with solvent peaks, the cumulative dissolution rate was poor and could not meet the final dissolution amount of the formulation, thus affecting the accurate judgment of direct quality.

[0110] Example 9: The Influence of Traditional Dissolution Media and Methods on Detection Results

[0111] In this embodiment, dissolution tests were conducted on the reference formulation and two self-made formulations using a conventional dissolution medium. The dissolution medium was pH 6.8 phosphate buffer, and the dissolution was performed using the standard slurry method. Other detection steps and parameters were the same as in Example 5. The results are shown in Table 7 and... Figure 15 .

[0112] Table 7 Dissolution curves of the self-made formulation and reference formulation in pH 6.8 medium.

[0113]

[0114] The results showed that, under traditional dissolution media and detection methods, the dissolution curves of the two self-prepared pemafibrate formulations were highly similar: at four key time points within the first 20 minutes, the slopes of the two curves were completely identical, and the overall curves almost overlapped. This indicates that traditional dissolution media and methods have low distinguishing ability for pemafibrate formulations and are difficult to effectively identify formulations prepared by different formulation processes.

[0115] The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for detecting the dissolution of pemarixate oral solid dosage form, characterized in that, Includes the following steps: S1. Dissolution sampling of the oral solid dosage form of pemafibrate to be tested was performed to obtain the test solution at different time points; S2. The test solution is subjected to high performance liquid chromatography for detection, and the content of pemafibrate in the test solution is calculated by external standard method to obtain the cumulative dissolution amount of pemafibrate preparation at different time points; The conditions for the high-performance liquid chromatography detection include: The mobile phase is a mixed solution of acetonitrile, trifluoroacetic acid and 0.01 mol / L potassium dihydrogen phosphate aqueous solution.

2. The dissolution detection method according to claim 1, characterized in that, The volume ratio of the 0.01 mol / L potassium dihydrogen phosphate aqueous solution, acetonitrile, and trifluoroacetic acid is (38-50):(50-62):0.

1.

3. The dissolution detection method according to claim 1 or 2, characterized in that, The volume ratio of the 0.01 mol / L potassium dihydrogen phosphate aqueous solution, acetonitrile, and trifluoroacetic acid is 40:60:0.1 or 38: 62：0.1。 4. The dissolution detection method according to claim 1, characterized in that, The conditions for the high-performance liquid chromatography detection also include any of the following: The column packing material is octadecylsilane-bonded silica gel; The chromatographic column is any one of Agilent ZORBAX SB C18, Agilent Eclipse XDB-C18, or ThermoFisher Acclaim C18; The particle size of the filler does not exceed 5.0 μm; The detection wavelength range is 275–285 nm; The column temperature is 25–35℃; The flow rate is 1.0–2.0 ml / min.

5. The dissolution detection method according to claim 1, characterized in that, The leaching medium is a hydrochloric acid solution with pH 1.2 containing 2.0 g / L sodium chloride.

6. The dissolution detection method according to claim 1, characterized in that, Step S1 includes: performing a dissolution test on the oral solid dosage form of pemafibrate to be tested using the closed-loop flow cell method, taking samples at different sampling time points to obtain test solutions at different time points.

7. The dissolution detection method according to claim 6, characterized in that, The sampling time points are 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min.

8. The dissolution detection method according to any one of claims 1 to 7, characterized in that, It also includes the steps of preparing a reference solution and performing high-performance liquid chromatography (HPLC) detection on the reference solution; The method for preparing the reference solution includes: taking pemafibrate reference standard, dissolving it in acetonitrile, and diluting it with a dissolution medium to a pemafibrate concentration of 0.2 μg / ml to obtain the reference solution.

9. The dissolution detection method according to any one of claims 1 to 8, characterized in that, The oral solid dosage form of pemafibrate includes pemafibrate tablets, pemafibrate capsules, pemafibrate extended-release tablets, or pemafibrate granules.

10. A quality control method for pemarix oral solid dosage form, characterized in that, include: The dissolution detection method according to any one of claims 1 to 9 is used to perform in vitro dissolution detection on the test pedmafibrate oral solid dosage form and the reference dosage form; the cumulative dissolution amount of the test pedmafibrate oral solid dosage form and the reference dosage form at different time points is obtained; Plot dissolution curves with sampling time points on the x-axis and cumulative dissolution amount on the y-axis, and compare the similarity factor f2 between the reference formulation and the self-made formulation.

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