Fnerenone-maleic acid eutectic crystal and preparation method thereof

Abstract

The invention belongs to the field of medicines, and particularly relates to a pharmaceutical co-crystal of fenerenone and maleic acid and a preparation method of the pharmaceutical co-crystal. The pharmaceutical co-crystal of the fenerenone and the maleic acid prepared by the invention has the advantages of high purity, proper solubility, good stability and the like, and is suitable for new drug development and industrial production. The preparation method of the pharmaceutical co-crystal of the fenerenone and the maleic acid, provided by the invention, is simple in process route, low in cost and suitable for industrial production.

Description

Technical Field

[0001] This application belongs to the field of medicine, and specifically relates to a finerenone-maleic acid cocrystal and a preparation method thereof. Background Art

[0002] Finerenone, chemical name: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, is a non-steroidal antagonist (MR) that acts as a mineralocorticoid receptor and was developed by Bayer. Finerenone was approved for marketing in China in June 2022. MR is expressed in the kidneys, heart, and blood vessels. Finerenone tablets can reduce inflammation and fibrosis mediated by overactivation of MR. This drug is suitable for adult patients with chronic kidney disease related to type 2 diabetes and can reduce the risk of continuous decline in eGFR and end-stage kidney disease. While reducing urinary albumin, this product can delay the progression of kidney disease and reduce the cardiovascular risk. The relevant key phase III FIDELIO-DKD study showed that this product can continuously reduce the proteinuria amplitude by 32%, and reduce the risk of cardiovascular composite endpoint events by 14% and the risk of kidney composite endpoint events by 18%.

[0003] Its structural formula is:

[0004] Finerenone is a pH-dependent drug compound with high gastrointestinal permeability. The dissolution of the drug is the rate-limiting process of absorption. It belongs to class II drugs in the biopharmaceutics classification system, with the characteristics of low solubility and high permeability. pH-dependent drug compounds show significant pH-dependent solubility along the gastrointestinal tract. It is expected to dissolve at low gastric pH in the fasting state of healthy subjects, and then in a higher intestinal pH environment, it may precipitate and / or dissolve incompletely. In addition, food intake, other drug treatments, and pathophysiological conditions may increase the gastric pH. Therefore, the drug dissolution may be reduced, and incomplete dissolution may lead to high inter- and intra-patient variability in the bioavailability of pH-dependent drug compounds. Therefore, the dissolution of finerenone in the in vivo physiological environment affects its absorption, and thus affects its bioavailability, severely restricting the production and use of its preparations, and endangering the effectiveness, safety, quality reliability, and consistency of this product. Summary of the Invention

[0005] The inventors of this application tried crystallization in various crystallization methods and various conditions. As a result, considering various aspects such as product purity, solubility, and chemical stability, it was unexpectedly found that the finerenone-maleic acid cocrystal containing equimolar amounts has high purity, excellent solubility, good stability, etc., which are suitable for new drug development and industrial production.

[0006] In addition, the inventors of the present application developed eutectic conditions with good reproducibility and sufficient purity that can be obtained in a short time. It was confirmed that by controlling the crystallization temperature and the composition of the crystallization solvent, problems such as increased impurities and delayed precipitation were solved, and a process with a simple preparation route, few impurities, low cost, and suitable for industrial production was developed.

[0007] During the experimental study of finerenone, the inventors found that no eutectic formation was observed between finerenone and malic acid, fumaric acid, tartaric acid, citric acid, camphorsulfonic acid, etc., but finerenone can form a eutectic with maleic acid, and this eutectic has high purity and good stability; through a large number of experimental studies, a preparation method of finerenone-maleic acid eutectic was determined.

[0008] One of the purposes of the present application is to provide a finerenone-maleic acid eutectic. This eutectic is formed by finerenone and maleic acid combined at a molar ratio of 1:1; the finerenone-maleic acid eutectic has good stability.

[0009] For a finerenone-maleic acid eutectic crystal form provided by the present application, in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, it has at least the main characteristic absorption peaks at the following positions: 6.93±0.2°, 7.18±0.2°, 8.70±0.2°, 17.45±0.2°, 17.62±0.2°, 17.93±0.2°, 20.71±0.2°, 22.33±0.2° and 22.87±0.2°.

[0010] For the finerenone-maleic acid eutectic crystal form provided by one of the embodiments of the present application, in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, as Figure 1 shown.

[0011] For any finerenone-maleic acid eutectic provided by the present application, its DSC curve shows an endothermic peak at 150-175°C, and the peak value of the endothermic peak appears at 161.5°C.

[0012] For any finerenone-maleic acid eutectic provided by the present application, its TGA curve shows that decomposition starts at about 152.8°C.

[0013] For the finerenone-maleic acid eutectic provided by one of the embodiments of the present application, its DSC curve and TGA curve are as Figure 2 and Figure 3 shown.

[0014] For any finerenone-maleic acid eutectic provided by the present application, its TGA curve shows that decomposition starts at about 152.8°C and is basically completely decomposed at 400°C.

[0015] The finerenone-maleic acid cocrystal provided by one embodiment of the present application, 1 The 1H-NMR spectrum is as shown in Figure 4 shown, 1 1H-NMR indicates that this cocrystal is formed by the combination of finerenone and maleic acid in a molar ratio of 1:1.

[0016] 1 1H-NMR (400 MHz, DMSO-d6): δ = 1.044 - 1.067 (t, 3H), δ = 2.129 (s, 3H), δ = 2.182 (s, 3H), δ = 3.820 (s, 3H), δ = 3.983 - 3.995 (m, 2H), δ = 5.379 (s, 1H), δ = 6.260 (d, 2H), δ = 6.692 - 6.795 (d, 2H), δ = 7.148 - 7.161 (d, 1H), δ = 7.275 - 7.290 (d, 1H), δ = 7.374 - 7.372 (s, 1H), δ = 7.566 (s, 1H), δ = 7.745 (s, 1H).

[0017] The second object of the present application is to provide a preparation method for any finerenone-maleic acid cocrystal of the present application; the preparation method of this finerenone-maleic acid cocrystal has a simple process route and low cost, and is suitable for industrial production.

[0018] The present application provides a preparation method for any finerenone-maleic acid cocrystal. Finerenone and maleic acid are heated and dissolved in a crystallization solvent, cooled for crystallization, filtered, and dried under reduced pressure to obtain the product. Specifically, the "heating and dissolving finerenone and maleic acid in a crystallization solvent" means: adding finerenone and maleic acid into a crystallization solvent, heating to 60 - 80 °C, and stirring; wherein, the molar ratio of finerenone and maleic acid in the feed is 1:1 - 1:2, the mass ratio of finerenone to the crystallization solvent is 1:5 - 20, and the crystallization solvent is one or more of acetone, tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, and water.

[0019] The third object of the present application is to provide a pharmaceutical composition containing any finerenone-maleic acid cocrystal of the present application.

[0020] A pharmaceutical composition containing any finerenone-maleic acid cocrystal of the present application contains the finerenone and maleic acid cocrystal in any crystal form shown in the present application and a pharmaceutically acceptable carrier or excipient.

[0021] The finerenone-maleic acid cocrystal of the present application can be used in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier or excipient. When used in the form of a pharmaceutical composition, an effective dose of the finerenone-maleic acid cocrystal of the present application and one or more pharmaceutically acceptable carriers or diluents are usually combined to form an appropriate administration form or dosage form. This procedure includes mixing, granulating, compressing or dissolving the components in a suitable manner.

[0022] The pharmaceutical composition of the present application can be administered in any of the following ways: orally, by spray inhalation, subcutaneously, intravenously, intramuscularly or by infusion, or by means of an implanted reservoir; among them, oral, spray inhalation, intramuscular injection or intravenous administration are preferred.

[0023] The pharmaceutical carriers contained in the pharmaceutical composition of the present application include but are not limited to: ion exchangers, buffering substances, water, salts or electrolytes, etc.; the weight content of the carrier in the pharmaceutical composition can be 1-98%, usually about 80%.

[0024] In the present application, the purity of the crystal form refers to the content of this crystal form after removing, for example, other crystal forms or amorphous forms of the finerenone-maleic acid cocrystal and other impurities, and its measurement method is, for example, by HPLC measurement.

[0025] In the present application, the position of the absorption peak in the X-ray powder diffraction pattern of each crystal form can be within the range of the specific values disclosed above ±0.2°, for example, within the range of ±0.1°, and the melting point determined by differential scanning calorimetry can be within the range of the specific values disclosed above ±3.0°C.

[0026] In the present invention, the so-called "about" a certain value means within the range of 90%-110% around this value, for example, within the range of 95%-105%.

[0027] It should be understood that slightly different melting point readings may be given using different types of equipment or different test conditions. The correct values of the melting points of different crystal forms will be affected by the compound purity, sample weight, heating rate, particle size, and calibration and maintenance of the test equipment. The values provided cannot be used as absolute values.

[0028] It should be understood that slightly different XRPD patterns and peaks may be given using different types of equipment or different test conditions. The patterns, peaks and relative intensities of each diffraction peak of different crystal forms will be affected by the compound purity, pretreatment of the sample, scanning speed, particle size, and calibration and maintenance of the test equipment. The values provided cannot be used as absolute values.

[0029] In this application, crystalline solvents are used to heat-dissolve finerenone and maleic acid, and then crystallization is carried out at 0-20°C to obtain a finerenone-maleic acid co-crystal with a purity of over 99.8% and a single impurity of less than 0.1%, and the yield reaches 90%.

[0030] The finerenone-maleic acid co-crystal prepared in this application has good stability and high purity, and is suitable for new drug development and industrial production.

[0031] The preparation method of the finerenone-maleic acid co-crystal provided in this application has a simple process route and low cost, and is suitable for industrial production. Description of the Drawings

[0032] Figure 1 XRPD pattern of the finerenone-maleic acid co-crystal prepared in Example 1.

[0033] Figure 2 DSC pattern of the finerenone-maleic acid co-crystal prepared in Example 1.

[0034] Figure 3 TGA pattern of the finerenone-maleic acid co-crystal prepared in Example 1.

[0035] Figure 4 1H-NMR pattern of the finerenone-maleic acid co-crystal prepared in Example 1 1 1H-NMR pattern

[0036] Figure 5 1H-NMR pattern of finerenone 1 1H-NMR pattern

[0037] Figure 6 XRPD pattern of finerenone Detailed Description of the Invention

[0038] The following will describe the embodiments of the present invention in detail in conjunction with the examples. However, those skilled in the art should understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. For reagents or instruments not specified for the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0039] In this application: XRPD: x ray powder diffraction, X-ray powder diffraction (also called XRD); TGA: Thermogravimetric Analysis, thermogravimetric analysis; DSC: differential scanning calorimetry, differential scanning calorimetry.

[0040] The XRPD pattern was collected on a PANalytical Empyrean X-ray powder diffractometer. The X-ray powder diffraction test conditions were as follows: Cu Ka radiation, 40 kV, 100 mA. The TGA-DSC curves were collected on a METTLER TOLEDO TGA / DSC 3+ synchronous thermal analyzer. The test conditions for thermogravimetric analysis and differential scanning calorimetry were as follows: the temperature measurement range was 30 - 400 °C; the heating rate was 10 °C / min; the argon atmosphere was 50 ml / min. Example 1

[0041] 100 g of finerenone and 30.6 g of maleic acid were added to 500 g of ethanol / water (2:1). The mixture was stirred and heated to 70 °C until completely dissolved. Heating was stopped, and stirring was continued while cooling for crystallization. The temperature was lowered to 0 - 20 °C, and crystallization was carried out with insulation for 5 h. The mixture was filtered and dried under reduced pressure at 50 °C for 10 h to obtain 119.1 g of the co-crystal. The yield was 91.2%, the purity (determined by HPLC) was 99.8%, and the single impurity was less than 0.1%. XRPD was performed on the obtained refined product, and the obtained XRPD pattern was as Figure 1 shown. The peak information of the pattern is shown in Table 1. The typical TGA curve and DSC curve are shown in Figure 2 and Figure 3 . The obtained refined product is the finerenone-maleic acid co-crystal polymorph of this application.

[0042] Table 1 Data table of powder diffraction of the sample obtained in Example 1 2θ (°) d-value (Å) <![CDATA[I / I 0 (%)]]> 6.9340 12.74828 78.32 7.1826 12.30760 72.27 8.7048 10.15851 58.32 17.4595 5.07951 100.00 17.6205 5.03344 91.55 17.9365 4.94550 57.11 22.6113 3.93250 13.67 20.7150 4.28801 51.48 22.3308 3.98125 93.62 22.8797 3.88697 63.92 Example 2

[0043] 100 g of finerenone and 30.6 g of maleic acid were added to 1000 g of ethanol. The mixture was stirred and heated to 80 °C until completely dissolved. Heating was stopped, and stirring was continued while cooling for crystallization. The temperature was lowered to 0 - 20 °C, and crystallization was carried out with insulation for 6 h. The mixture was filtered and dried under reduced pressure at 50 °C for 10 h to obtain 124.07 g of the finerenone-maleic acid co-crystal. The yield was 95.0%, the purity (determined by HPLC) was 99.8%, and the single impurity was less than 0.1%. XRPD was performed on the obtained refined product, and the obtained refined product is the finerenone-maleic acid co-crystal polymorph of this application.

[0044] Table 2 Data table of powder diffraction of the sample obtained in Example 2 2θ (°) d-value (Å) <![CDATA[I / I 0 (%)]]> 6.9450 12.75012 78.34 7.1837 12.32345 72.29 8.7052 10.15785 58.39 17.4587 5.07858 100.10 17.6224 5.03155 91.65 17.9297 4.95466 57.14 22.6201 3.93244 13.57 20.7220 4.28733 51.49 22.3332 3.98243 93.66 22.8788 3.89546 63.82 Example 3

[0045] 100 g of finerenone and 30.6 g of maleic acid were added to 2000 g of acetone / water (5:1). The mixture was stirred and heated to 75 °C until completely dissolved. Heating was stopped, and stirring was continued while cooling for crystallization. The temperature was lowered to 0 - 20 °C, and crystallization was carried out while maintaining the temperature for 5 h. Then, filtration was performed, and drying under reduced pressure at 50 °C for 10 h yielded 120.6 g of the co-crystal. The yield was 92.4%, the purity (determined by HPLC) was 99.8%, and the single impurity was less than 0.1%. XRPD was performed on the obtained refined product, and the obtained refined product was the finerenone-maleic acid co-crystal form of this application.

[0046] Table 3 Powder diffraction data table of the sample obtained in Example 3 2θ (°) d-value (Å) <![CDATA[I / I 0 (%)]]> 6.9433 12.75244 78.51 7.1856 12.32465 72.35 8.7047 10.15733 58.41 17.4564 5.07567 100.21 17.6225 5.03211 91.45 17.9235 4.95364 57.34 22.6366 3.93264 13.48 20.7215 4.28456 51.50 22.3321 3.98266 93.69 22.8736 3.89432 63.78 Example 4

[0047] 100 g of finerenone and 61.2 g of maleic acid were added to 1000 g of methanol / water (2:1). The mixture was stirred and heated to 60 °C until completely dissolved. Heating was stopped, and stirring was continued while cooling for crystallization. The temperature was lowered to 0 - 20 °C, and crystallization was carried out while maintaining the temperature for 5 h. Then, filtration was performed, and drying under reduced pressure at 50 °C for 10 h yielded 116.8 g of the co-crystal. The yield was 89.5%, the purity (determined by HPLC) was 99.8%, and the single impurity was less than 0.1%. XRPD was performed on the obtained refined product, and the obtained refined product was the finerenone-maleic acid co-crystal form of this application.

[0048] Table 4 Powder diffraction data table of the sample obtained in Example 4 2θ (°) d-value (Å) <![CDATA[I / I 0 (%)]]> 6.9434 12.75467 78.43 7.1843 12.32356 72.67 8.7046 10.15743 58.32 17.4563 5.07567 100.45 17.6245 5.03242 91.64 17.9233 4.95389 57.61 22.6374 3.93290 13.57 20.7235 4.28435 51.57 22.3359 3.98277 93.78 22.8733 3.89489 63.76 Example 5 Preparation of finerenone crystal form I for comparative example

[0049] 10 g of finerenone was added to 150 g of ethanol. The mixture was stirred and heated to 75 °C until completely dissolved. Heating was stopped, and stirring was continued while cooling for crystallization. The temperature was lowered to 0 - 20 °C, and crystallization was carried out while maintaining the temperature for 5 h. Then, filtration was performed, and drying under reduced pressure at 50 °C for 10 h yielded 8.8 g of refined finerenone. The yield was 88%, the purity (determined by HPLC) was 99.8%, and the single impurity was less than 0.1%. XRPD was performed on the obtained refined product, showing finerenone crystal form I, which was different from the finerenone-maleic acid co-crystal form of this application. The 1H NMR spectrum showed that no proton transfer occurred in the co-crystal compared with finerenone, proving that a co-crystal rather than a salt was formed; through 1H NMR spectrum analysis, the molar ratio of finerenone to maleic acid in the co-crystal molecule was calculated to be 1:1. See Attachment Figure 5 and Attachment Figure 6 .

[0050] Table 5 Powder diffraction data table of the sample obtained in Example 5 2θ (°) d-value (Å) <![CDATA[I / I 0 (%)]]> 8.5457 10.34734 38.60 14.0237 6.31531 100.00 17.1388 5.17382 40.91 19.0088 4.66887 93.45 20.4844 4.33574 30.78 22.9242 3.87952 34.42 25.5173 3.49086 43.64 26.4445 3.37052 38.24 Example 6 Determination of saturated solubility

[0051] The conventional saturation solubility measurement method was used to evaluate the saturation solubility of finerenone-maleic acid cocrystal. Referring to the measurement method of USP <1236> Solubility Measurements, the measurement temperature was 25 °C.

[0052] The applicant of the present invention unexpectedly found a significant difference in the solubility of finerenone-maleic acid cocrystal compared with that of finerenone when obtaining the solubility comparison between finerenone-maleic acid cocrystallization and finerenone.

[0053] Table 6 Solubility test results Finerenone-Maleic Acid Cocrystal Finerenone pH 1.0 Buffer Solution (0.1 mol / L Hydrochloric Acid) 68 mg / ml 46 mg / ml pH 4.0 Buffer Solution (Acetate Buffer) 3.10 mg / ml 0.11 mg / ml pH 6.8 Buffer Solution (Phosphate Buffer) 0.36 mg / ml 0.03 mg / ml Example 7 Stability experiment

[0054] A series of stability tests were conducted on the finerenone-maleic acid cocrystals prepared in Examples 1-4, including stress testing and accelerated testing. The test results are shown in Tables 7 and 8.

[0055] Table 7 Stress test results

[0057] Table 8 Accelerated (intermediate condition) test results (Storage condition: temperature 30 °C ± 2 °C, RH 65% ± 5%)

[0058] From the stress test results in Table 7, it can be seen that for each index of the key items for investigating the stability of the finerenone-maleic acid cocrystal of the present application, there is no obvious change compared with the 0 time. The purity is greater than 99.8%, and the single impurity is less than 0.1%, indicating relatively stable. From the accelerated (intermediate condition) test results in Table 8, it can be seen that in the accelerated test, through the investigation of 6 months of acceleration, for each index of the key items for investigating the stability of the finerenone maleic acid cocrystal of the present application, there is no obvious change compared with the 0 time. The purity is greater than 99.8%, and the single impurity is less than 0.1%, indicating relatively stable.

[0059] In the above specific embodiments: In Tables 4-5, "Total impurities" refers to: the total amount of impurities contained in finerenone-maleic acid cocrystal, in mass percentage; "Water content" refers to: the amount of water contained in finerenone-maleic acid cocrystal, in mass percentage; "Content" refers to: the amount of finerenone active ingredient contained in finerenone-maleic acid cocrystal (using the reference standard as a control); in mass fraction; "RH" refers to: relative humidity; Method for water determination: Take 1.0 g of this product and determine according to the water determination method (Method A, General Principles 0832, Volume IV, Chinese Pharmacopoeia 2015 Edition). Methods for determination of single impurity, total impurities and content: Determine according to the high performance liquid chromatography method (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2015 Edition).

Claims

1. A drug co-crystal of finerenone and maleic acid, characterized in that, the molar ratio of finerenone to maleic acid is 1:

1.

2. The finerenone-maleic acid co-crystal according to claim 1, characterized in that, using Cu-Kα radiation, in the X-ray powder diffraction pattern expressed in 2θ angle, there are at least main characteristic absorption peaks at the following positions: 6.93±0.2°, 7.18±0.2°, 8.70±0.2°, 17.45±0.2°, 17.62±0.2°, 17.93±0.2°, 20.71±0.2°, 22.33±0.2° and 22.87±0.2°.

3. The finerenone-maleic acid co-crystal according to claim 1, characterized in that, its DSC chart shows an endothermic peak at 150-175°C, and the peak value of the endothermic peak appears at 161.5°C.

4. The finerenone-maleic acid co-crystal according to claim 1, characterized in that, its TGA chart shows that decomposition starts at about 152.8°C.

5. The finerenone-maleic acid co-crystal according to claim 3 or 4, characterized in that, it has a DSC chart and a TGA chart substantially as shown in Figures 2 and 3.

6. A preparation method of a finerenone-maleic acid co-crystal, characterized in that, finerenone and maleic acid are heated and dissolved with a crystallization solvent, cooled for crystallization, filtered, and dried under reduced pressure to obtain the product.

7. The preparation method of the finerenone-maleic acid co-crystal according to claim 6, characterized in that, the crystallization solvent is selected from one or more of acetone, tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol and water.

8. The preparation method of the finerenone-maleic acid co-crystal according to claim 6, characterized in that, the mass ratio of finerenone to the crystallization solvent is 1:5-20.

9. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises the finerenone-maleic acid co-crystal shown in any one of claims 1-5 and a pharmaceutically acceptable carrier or excipient.

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