Crystal form detection method for Pinefibrate in Pinefibrate tablet

Abstract

The invention relates to the technical field of pharmaceutical analysis, in particular to a crystal form detection method for Pinefibrate in Pinefibrate tablets, which comprises the following steps: acquiring a sample to be detected from the Pinefibrate tablets; detecting the sample to be detected by using a chemical imaging method based on a vibration spectrum to obtain spectral data; and comparing the spectral data with the spectral data of the known crystal form of Pinefibrate, and identifying the crystal form of Pinefibrate. The method for detecting the crystal form of the pterofibrate in the pterofibrate tablet has the beneficial effects that a Raman spectrometer is used for qualitatively testing the crystal form of a pterofibrate bulk drug in a preparation, complicated pretreatment on a sample is not needed, the risk of crystal transformation possibly caused by pretreatment is avoided, and the sample loading process of the sample is simplified. Meanwhile, the sample is directly scanned and imaged, the position of the pterofibrate bulk drug is accurately positioned, the interference of auxiliary materials is reduced, and the crystal form of pterofibrate in the preparation is rapidly measured.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical analysis, and in particular to a crystal form detection method for pemafibrate in pemafibrate tablets. BACKGROUND

[0002] Pemafibrate, with the English name Pemafibrate, was developed by Japan's Sankyo Group and approved in Japan on July 3, 2017 for the treatment of hyperlipidemia. It is the first highly selective peroxisome proliferator-activated receptor alpha (PPARa) developed based on a new concept. The lipid-lowering effect of low-dose pemafibrate is greater than 200 times that of high-dose fenofibrate. Pemafibrate is mainly metabolized by the liver and not excreted by the kidneys, so it can be used in CKD patients. Pemafibrate has no drug interactions with statins, and it is safe to administer any statin. For patients with limited efficacy of existing betaine drugs (including patients taking statins and patients with impaired renal function or liver steatosis), pemafibrate may have a better risk-benefit balance than existing betaine drugs and is considered a safer drug.

[0003] It is an industry consensus that pharmaceutical molecules have polymorphism. Different crystal forms of drugs have significant differences in physical properties and crystal structures. The differences in physical properties are reflected in melting point, powder diffraction, infrared spectrum, Raman spectrum, solubility, etc., which in turn affect the stability, release, and bioavailability of drug preparations. Therefore, controlling the crystal form is of great significance to the drug activity of pemafibrate. There are currently several reported crystal forms of pemafibrate raw materials, such as WO2019133462, which reports crystal form A, crystal form B, crystal form C, crystal form D, and amorphous of pemafibrate. Patent IN202041005093 reports crystal form S of pemafibrate, which has a melting point of about 90°C. Non-patent literature 1 (Long Li (DOI: 10.1021 / acsomega.0c04005) reports crystal form II of pemafibrate. In addition, non-patent literature 2 (Yukiyoshi Yamazaki, et al, Synthesis, 2008 (7), 10171022) reports crystal form I of pemafibrate. The differences between different crystal forms are large, so a method for accurately measuring the crystal form is crucial for drug research.

[0004] Currently, the methods for measuring pemafibrate crystal alone include X-ray diffraction, infrared absorption spectroscopy, melting point method, and microscopy, thermal analysis. These methods can only directly measure high-purity raw materials.

[0005] Unlike the measurement of pemafibrate crystal alone, pemafibrate tablets have a low content of pemafibrate (<0.1%) and contain various excipients. Currently, there is no literature reporting specific detection methods.

[0006] X-ray diffraction method, infrared absorption spectroscopy, melting point method and microscope method, thermal analysis method can measure the crystal form of pemafibrate in the bulk drug, but in the pemafibrate tablets, because there are many auxiliary materials, and the content of the main component is low, when using the above methods to detect the crystal form, the main component will be interfered by the auxiliary materials, and the true crystal form cannot be measured, which affects the detection result. When measuring the crystal form by infrared absorption spectroscopy, melting point method and microscope method, thermal analysis method, the sample will be destroyed, and the interference of the auxiliary materials is strong.

[0007] In summary, the prior art has deficiencies in identifying the crystal form of the active ingredient in pemafibrate tablets, and there is an urgent need to develop a high-sensitivity, rapid, efficient, stable and direct method to identify the crystal form of the active ingredient in pemafibrate tablets. SUMMARY

[0008] In order to solve the above technical problems, the present application provides a crystal form detection method for pemafibrate in pemafibrate tablets, which can directly, quickly and accurately identify the crystal form in the tablets, and overcome the problem of auxiliary material interference.

[0009] In order to solve the above technical problems, the technical scheme adopted by the present application is as follows: a crystal form detection method for pemafibrate in pemafibrate tablets, comprising the following steps: Obtaining Raman spectrum of different crystal forms of pemafibrate; Using vibration spectrum-based chemical imaging method to detect the sample to be tested, and obtaining spectrum data; Comparing the spectrum data with the spectrum data of known crystal form of pemafibrate to identify the crystal form of pemafibrate.

[0010] Further, in the crystal form detection method described above, the step of obtaining the sample to be tested from the pemafibrate tablets comprises: Removing the coating of the pemafibrate tablets and taking the core part for analysis.

[0011] Further, in the crystal form detection method described above, the vibration spectrum is Raman spectrum, infrared spectrum or terahertz spectrum.

[0012] Further, in the crystal form detection method described above, the step of using Raman spectrum-based chemical imaging method to detect the sample to be tested and obtaining spectrum data specifically comprises: Using Raman spectrometer to perform Raman spectrum scanning on the sample to be tested, and using least square method to perform component analysis and imaging analysis on the Raman spectrum data set obtained by Raman spectrum scanning to obtain an imaging graph; Taking the Raman spectrum graph at the position with strong pemafibrate spectrum signal in the imaging graph as the Raman spectrum graph of pemafibrate in the pemafibrate tablets.

[0013] Further, in the crystal form detection method described above, the comparison of the spectrum data with the spectrum data of the known crystal form of pemafibrate is specifically: analyzing the consistency of the main characteristic peaks of the Raman spectrum to identify the crystal form of pemafibrate.

[0014] Further, in the crystal form detection method described above, the test light source of the Raman imaging is 530nm~1064nm.

[0015] Further, in the crystal form detection method described above, the test area of the Raman imaging is 100μm 2 ~50mm 2 .

[0016] Further, in the crystal form detection method described above, the test conditions of the Raman imaging are: detection wavelength 785nm, laser power 100%, exposure time 2s, and scanning step 10μm.

[0017] The present application has the following beneficial effects: There are more auxiliary materials in the pemafibrate tablets, and the auxiliary materials and the pemafibrate raw materials are mixed together, so that the crystal form of pemafibrate in the pemafibrate tablets cannot be directly and truly measured by the conventional analysis method. The chemical imaging can obtain tens of thousands to hundreds of thousands of spectra by scanning the selected area, and the imaging diagram obtained by analyzing the spectrum data set can accurately locate the position of the raw materials in the preparation, greatly reducing or even completely eliminating the interference of the auxiliary materials.

[0018] The crystal form detection method of pemafibrate in the pemafibrate tablets of the present application uses the chemical imaging method to qualitatively test the crystal form of pemafibrate raw materials in the preparation, without the need for complex pretreatment of the sample, thereby avoiding the risk of crystal transformation caused by pretreatment and simplifying the sample loading process. At the same time, the sample to be analyzed is directly scanned and imaged, the position of the pemafibrate raw materials is accurately located, the interference of the auxiliary materials is reduced, and the difficulty in analyzing the crystal form of pemafibrate in the pemafibrate tablets is overcome. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 Raman spectra of different crystal forms of pemafibrate; Figure 2 Raman imaging diagram of the pemafibrate tablets of Example 1 of the specific embodiment of the present application (red for pemafibrate and blue for microcrystalline cellulose); Figure 3 Comparison diagram of the Raman spectrum of pemafibrate in the pemafibrate tablets and the Raman spectrum of different crystal forms of pemafibrate obtained in Example 1 of the specific embodiment of the present application; Figure 4 Raman imaging diagram of the pemafibrate tablets of Example 2 of the specific embodiment of the present application (red for pemafibrate and blue for microcrystalline cellulose); Figure 5Figure 1 is a comparison chart of the Raman spectrum of the pemafibrate tablet obtained in Example 2 of the specific embodiment of the present application and the Raman spectra of different crystal forms of pemafibrate. DETAILED DESCRIPTION

[0020] To illustrate the technical content, purposes and effects of the present application, the following will be described in conjunction with the embodiments and the accompanying drawings.

[0021] In the following examples, the detection instruments and methods are as follows: Raman spectrum and Raman imaging method: Renishaw R802 Raman spectrometer, the sample is fixed on a glass slide, focused observation, and Raman imaging test detection conditions are as follows: detection wavelength 785 nm, laser power 100%, scanning area 4 mm 2 (2000 μm x 2000 μm), exposure time 2 s, scanning step 10 μm.

[0022] Example 1 Please refer to Figure 1 , Figure 2 and Figure 3 , a crystal form detection method of pemafibrate in pemafibrate tablets, comprising the following steps: Step 1: Raman spectra of different crystal forms of pemafibrate Take different crystal forms of pemafibrate samples, fix them on a glass slide, and place them on the Raman spectrometer analysis platform for Raman spectrum determination, and obtain the Raman spectra of different crystal forms of pemafibrate as shown in Figure 1 .

[0023] Step 2: Sample preparation Take pemafibrate tablets, remove the coating, and fix them on a glass slide, and place them on the Raman spectrometer analysis platform.

[0024] Step 3: Spectrum acquisition The micro-Raman spectrometer is used to collect the spectrum of the sample to be tested. The test parameters are: detection wavelength 785 nm, laser power 100%, exposure time 2 s, scanning step 10 μm.

[0025] Step 4 chemical imaging The spectrum data set obtained in step 3 is analyzed by imaging to obtain an imaging graph Figure 2 . The red position in the graph is the pemafibrate drug substance in the preparation, and the blue position is the auxiliary material microcrystalline cellulose. The Raman spectrum of the red position with strong signal is the Raman spectrum data of pemafibrate in the preparation.

[0026] Step 5 spectrum analysis Take the Raman spectrum of pemafibrate in the preparation obtained in step 4 and Figure 1The Raman spectra of different crystal forms of pemafibrate were compared, and the consistency of the main characteristic peaks of the Raman spectrum was analyzed. The Raman spectrum of pemafibrate in the preparation was taken Figure 1 , and compared with the Raman spectra of different crystal forms of pemafibrate. The comparison chart is shown in Figure 3 , and the consistency of the main characteristic peaks of the Raman spectrum was analyzed. It can be seen that the pemafibrate in the preparation is consistent with crystal form III (±2cm- 1 ) at 255cm -1 , 748cm -1 , 996cm -1 , 1245ccm -1 , 1464cm -1 , 1584cm -1 , and 1630cm -1 , indicating that the crystal form of pemafibrate in the preparation is consistent with crystal form III.

[0027] Example 2 Please refer to Figure 1 , Figure 4 and Figure 5 , a method for detecting the crystal form of pemafibrate in a pemafibrate tablet, comprising the following steps: Step 1: Raman spectra of different crystal forms of pemafibrate Take different crystal forms of pemafibrate samples, fix them on a glass slide, and place them on the analysis platform of the Raman spectrometer for Raman spectrum determination. The Raman spectra of different crystal forms of pemafibrate are shown in Figure 1 .

[0028] Step 2: Sample preparation Take pemafibrate tablets, remove the coating, and fix them on a glass slide on the analysis platform of the Raman spectrometer.

[0029] Step 3: Spectrum acquisition Use a micro-Raman spectrometer to collect the spectrum of the sample to be tested. The test parameters are: detection wavelength 785nm, laser power 100%, exposure time 5s, and scanning step 30μm.

[0030] Step 4: Raman imaging chart processing Perform imaging analysis on the spectrum data set obtained in step 3 to obtain an imaging chart ( Figure 4 ). The red position in the chart is the pemafibrate in the preparation, and the blue position is the auxiliary material microcrystalline cellulose. Take the Raman spectrum of the red position with strong signal as the Raman spectrum data of pemafibrate in the preparation.

[0031] Step 5: Spectrum analysis Take the Raman spectrum of pemafibrate in the preparation obtained in step 4 and Figure 1The Raman spectra of different crystal forms of pemafibrate were compared, and the comparison chart is shown in Figure 5 The consistency of the main characteristic peaks of the Raman spectrum was analyzed, and it was found that the pemafibrate in the preparation was consistent with crystal form III (±2cm -1 , 748cm -1 , 997cm -1 , 1244cm -1 , 1464cm -1 , 1585cm -1 , 1632cm -1 ) at 253cm -1 , which indicated that the crystal form of pemafibrate in the preparation was consistent with crystal form III.

[0032] The above is only an embodiment of the present application, and does not limit the patent scope of the present application, and any equivalent transformation, direct or indirect application in related technical fields using the content of the specification and drawings of the present application are also included in the patent protection scope of the present application.

Claims

1. A method for detecting a crystal form of pemafibrate in a pemafibrate tablet, characterized by, The method comprises the following steps: obtaining a test sample from a pemafibrate tablet; detecting the test sample by using a vibration spectrum-based chemical imaging method to obtain spectral data; comparing the spectral data with spectral data of known crystal forms of pemafibrate to identify the crystal form of pemafibrate.

2. The method according to claim 1, wherein the crystal form of pemafibrate is detected in the pemafibrate tablet. The step of obtaining a test sample from a pemafibrate tablet comprises the following steps: removing the coating of the pemafibrate tablet and scraping the powder to obtain the test sample.

3. The method of claim 1, wherein the crystal form of pemafibrate is detected by X-ray powder diffraction. The vibration spectrum is Raman spectrum, infrared spectrum or terahertz spectrum.

4. The method of claim 1, wherein the crystal form of pemafibrate is detected by X-ray powder diffraction. The step of detecting the test sample by using a vibration spectrum-based chemical imaging method to obtain spectral data specifically comprises the following steps: performing chemical imaging on the test sample by using a Raman spectrometer, performing component analysis and imaging analysis on a Raman spectral data set obtained by chemical imaging by using a least square method to obtain an imaging graph; obtaining a Raman spectrum graph of a position with a stronger spectral signal of pemafibrate in the imaging graph as a Raman spectrum graph of pemafibrate drug substance in the pemafibrate tablet.

5. The method for detecting the crystal form of pemafibet in pemafibet slices according to claim 4, characterized in that, The step of comparing the spectral data with spectral data of known crystal forms of pemafibrate specifically comprises the following step: analyzing the consistency of main characteristic peaks of the Raman spectrum graph to identify the crystal form of pemafibrate.

6. The method of claim 4, wherein the crystal form of pemafibrate is detected by X-ray powder diffraction. The test light source of the Raman imaging is 532 nm-1064 nm.

7. The method according to claim 4, wherein the crystal form of pemafibrate is detected by X-ray powder diffraction using Cu-Kα radiation (λ = 1.5418 A) at a voltage of 40 kV and a current of 30 mA. The Raman imaging test area is 100 μm 2 ~ 50 mm 2 .

8. The method of claim 4, wherein the crystal form of pemafibrate is detected by X-ray powder diffraction. The test condition of the Raman imaging is as follows: detection wavelength 785 nm, laser power 100%, exposure time 2 s and scanning step 10 μm.

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