Finerenone-maleic acid cocrystal and preparation method therefor

Abstract

The present application belongs to the field of medicines, and particularly relates to a pharmaceutical cocrystal of finerenone and maleic acid, and a preparation method therefor. The pharmaceutical cocrystal of finerenone and maleic acid prepared in the present application has the advantages of high purity, suitable solubility, good stability, etc. and is suitable for new drug development and industrial production. The method for preparing the pharmaceutical cocrystal of finerenone and maleic acid provided in the present application has the advantages of simple process route and low cost, and is suitable for industrial production.

Description

A finerenone-maleic acid cocrystal and preparation method thereof Technical Field

[0001] The present 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) of the mineralocorticoid receptor 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 excessive MR activation. This drug is suitable for adult patients with chronic kidney disease associated with type 2 diabetes and can reduce the risk of sustained decline in eGFR and end-stage renal disease. While reducing urinary albumin, this product can delay the progression of kidney disease and reduce cardiovascular risk. The related key Phase III FIDELIO-DKD study showed that this product can continuously reduce proteinuria by 32%, and reduce the risk of cardiovascular composite endpoint events by 14% and the risk of renal composite endpoint events by 18%.

[0003] Its structural formula is:

[0004]

[0005] Finerenone is a pH-dependent drug compound with high gastrointestinal permeability. Drug dissolution is the rate-limiting process for absorption. It is a BCS Class II drug, characterized by low solubility and high permeability. pH-dependent drug compounds exhibit pronounced pH-dependent solubility along the gastrointestinal tract. Dissolution occurs at the expected low gastric pH in healthy subjects in the fasting state, but may precipitate and / or dissolve incompletely at the higher intestinal pH. Furthermore, food intake, other medications, and pathophysiological conditions can increase gastric pH, thereby reducing drug dissolution. Incomplete dissolution can lead to high inter- and intra-patient variability in bioavailability for pH-dependent drug compounds. Therefore, the dissolution of finerenone under physiological conditions in vivo affects its absorption and, consequently, its bioavailability, severely restricting the production and use of its formulations and jeopardizing the efficacy, safety, quality assurance, and consistency of the product. Summary of the Invention

[0006] The inventors of the present application attempted crystallization using various crystallization methods and conditions. As a result, they unexpectedly discovered that, considering various aspects such as product purity, solubility, and chemical stability, a finerenone-maleic acid cocrystal containing equimolar amounts exhibited high purity, excellent solubility, and good stability, making it suitable for new drug development and industrial production.

[0007] Furthermore, the inventors of this application have developed conditions for obtaining cocrystals of sufficient purity in a short time with good reproducibility. They have confirmed that the crystallization temperature and the composition of the crystallization solvent can resolve the problems of increased impurities and delayed precipitation, thus developing a simple preparation process with low impurities, low cost, and suitability for industrial production.

[0008] During experimental research on finerenone, the inventors discovered that no cocrystals were observed with finerenone using malic acid, fumaric acid, tartaric acid, citric acid, camphorsulfonic acid, etc. However, finerenone could form cocrystals with maleic acid, and the cocrystals were high in purity and good in stability. Through extensive experimental research, the inventors determined a method for preparing finerenone-maleic acid cocrystals.

[0009] One of the purposes of the present application is to provide a finerenone-maleic acid cocrystal. The cocrystal comprises finerenone and maleic acid in a molar ratio of 1:1 and has good stability.

[0010] The present application provides a co-crystal form of finerenone and maleic acid, which has at least the following main characteristic absorption peaks at the following positions in an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Ka radiation: 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°.

[0011] The X-ray powder diffraction pattern of the finerenone-maleic acid cocrystal provided in one embodiment of the present application using Cu-Ka radiation and expressed in 2θ angles is shown in FIG1 .

[0012] Any finerenone-maleic acid co-crystal provided in the present application has an endothermic peak in the DSC graph at 150-175° C., and the peak value of the endothermic peak appears at 161.5° C.

[0013] The TGA chart of any finerenone-maleic acid cocrystal provided in the present application shows that decomposition begins at about 152.8°C.

[0014] The DSC and TGA diagrams of the finerenone-maleic acid co-crystal provided in one of the examples of the present application are shown in Figures 2 and 3 .

[0015] The TGA chart of any finerenone-maleic acid cocrystal provided in the present application shows that it begins to decompose at about 152.8°C and is substantially completely decomposed at 400°C.

[0016] One of the embodiments of the present application provides a finerenone-maleic acid cocrystal, 1 The H-NMR diagram is shown in Figure 4. 1 H-NMR showed that the cocrystal was composed of finerenone and maleic acid in a molar ratio of 1:1.

[0017] 1 H-NMR (400MHz, 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).

[0018] The second object of the present application is to provide a method for preparing any finerenone-maleic acid cocrystal of the present application; the method for preparing the finerenone-maleic acid cocrystal has a simple process route, low cost, and is suitable for industrial production.

[0019] The present application provides a method for preparing any one of finerenone-maleic acid cocrystals, comprising dissolving finerenone and maleic acid in a crystallization solvent by heating, cooling, crystallizing, filtering, and drying under reduced pressure to obtain the product. Specifically, "dissolving finerenone and maleic acid in a crystallization solvent by heating" refers to adding finerenone and maleic acid to a crystallization solvent, heating to 60-80°C, and stirring; wherein the molar ratio of finerenone to maleic acid is 1:1-1:2, the mass ratio of finerenone to crystallization solvent is 1:5-20, and the crystallization solvent is one or more of acetone, tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, and water.

[0020] The third object of the present application is to provide a pharmaceutical composition containing any one of the finerenone-maleic acid cocrystals of the present application.

[0021] A pharmaceutical composition containing any finerenone-maleic acid cocrystal of the present application, comprising finerenone and maleic acid cocrystal in any crystalline form shown in the present application and a pharmaceutically acceptable carrier or excipient.

[0022] The finerenone-maleic acid cocrystal of the present application can be used together with a pharmaceutically acceptable carrier or excipient in the form of a pharmaceutical composition. 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 a suitable administration form or dosage form. This procedure includes mixing, granulating, compressing or dissolving the components by appropriate means.

[0023] The pharmaceutical composition of the present application can be administered in any of the following ways: oral administration, spray inhalation, subcutaneous, intravenous, intramuscular injection or infusion, or administration via an explanted reservoir; among which oral administration, spray inhalation, intramuscular injection or intravenous administration is preferred.

[0024] The pharmaceutical composition of the present application contains pharmaceutical carriers including but not limited to: ion exchangers, buffer substances, water, salts or electrolytes, etc.; the weight content of the carrier in the pharmaceutical composition can be 1-98%, usually about 80%.

[0025] In the present application, the purity of the crystal form refers to the content of the crystal form after removing, for example, other crystal forms or amorphous form of finerenone-maleic acid cocrystal and other impurities, and the measurement method thereof is, for example, measured by HPLC.

[0026] 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 ±0.2° of the specific value disclosed above, for example, within the range of ±0.1°, and the melting point determined by differential scanning calorimetry can be within the range of ±3.0°C of the specific value disclosed above.

[0027] In the present invention, the "about" numerical value refers to the range of 90%-110% around the numerical value, such as the range of 95%-105%.

[0028] It should be understood that using different types of equipment or using different test conditions may give slightly different melting point readings. The exact value of the melting point of different crystalline forms will be affected by compound purity, sample weight, heating rate, particle size, and calibration and maintenance of the test equipment. The values ​​provided should not be regarded as absolute values.

[0029] It should be understood that different types of equipment or testing conditions may produce slightly different XRPD patterns and peaks. The patterns, peaks, and relative intensities of the diffraction peaks of different crystalline forms will be affected by compound purity, sample preparation, scanning speed, particle size, and calibration and maintenance of the testing equipment. The values ​​provided should not be regarded as absolute values.

[0030] The present application uses a crystallization solvent to heat and dissolve finerenone and maleic acid, and then crystallizes at 0-20°C to obtain a finerenone-maleic acid cocrystal with a purity of more than 99.8% and a single impurity content of less than 0.1%, with a yield of 90%.

[0031] The phenelenone-maleic acid cocrystal prepared in the present application has good stability and high purity, and is suitable for new drug development and industrial production.

[0032] The preparation method of finerenone-maleic acid cocrystal provided in the present application has a simple process route, low cost, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG1 is an XRPD pattern of phenerenone-maleic acid cocrystal prepared in Example 1.

[0034] FIG2 is a DSC graph of the phenerenone-maleic acid cocrystal prepared in Example 1.

[0035] FIG3 is a TGA graph of the phenerenone-maleic acid cocrystal prepared in Example 1.

[0036] Figure 4 is a phenaretin-maleic acid cocrystal prepared in Example 1 1 H-NMR spectrum.

[0037] Figure 5 shows the 1 H-NMR spectrum.

[0038] FIG6 is an XRPD pattern of finerenone. DETAILED DESCRIPTION

[0039] The embodiments of the present invention will be described in detail below with reference to the examples, but it should be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0040] In this application:

[0041] XRPD: x ray powder diffraction, x-ray powder diffraction (also called XRD);

[0042] TGA: Thermogravimetric Analysis, thermogravimetric analysis;

[0043] DSC: differential scanning calorimetry, differential scanning calorimetry.

[0044] XRPD patterns were collected on a PANalytical Empyrean X-ray powder diffraction analyzer. X-ray powder diffraction test conditions were: Cu Ka radiation, 40 kV, 100 mA;

[0045] TGA-DSC patterns were collected on a METTLER TOLEDO TGA / DSC 3+ simultaneous thermal analyzer. Thermogravimetric analysis and differential scanning calorimetry test conditions were as follows: measurement temperature range 30-400°C; heating rate 10°C / min; argon atmosphere, 50 ml / min. Example 1

[0046] 100g of finerenone and 30.6g of maleic acid were added to 500g of ethanol / water (2:1), stirred and heated to 70°C until complete dissolution. Heating was stopped, and the mixture was cooled and crystallized while stirring. The temperature was then lowered to 0-20°C and held for 5 hours to allow crystallization. The mixture was filtered and dried under reduced pressure at 50°C for 10 hours to obtain 119.1g of cocrystals with a yield of 91.2% and a purity (HPLC determination) of 99.8%, with each impurity less than 0.1%. The resulting refined product was subjected to XRPD analysis, and the resulting XRPD pattern is shown in Figure 1. Its peak information is shown in Table 1. Typical TGA and DSC patterns are shown in Figures 2 and 3. The resulting refined product is the finerenone-maleic acid cocrystal form of the present application.

[0047] Table 1 Powder diffraction data of the sample obtained in Example 1

[0048] 2θ (°) d-value (Å) I / I0 (%) 6.934012.7482878.327.182612.3076072.278.704810.1585158.3217.45955.07951100.0017.6205 5.0334491.5517.93654.9455057.1122.61133.9325013.6720.71504.2880151.4822.33083.9812593.6222.87973.8869763.92 Example 2

[0049] 100 g of finerenone and 30.6 g of maleic acid were added to 1000 g of ethanol, stirred and heated to 80° C. until completely dissolved. Heating was stopped, and the mixture was cooled and crystallized while stirring. The temperature was then lowered to 0-20° C. and kept for 6 hours to crystallize. The mixture was filtered and dried under reduced pressure at 50° C. for 10 hours to obtain 124.07 g of finerenone and maleic acid cocrystals. The yield was 95.0%, the purity (HPLC determination) was 99.8%, and the impurity content was less than 0.1%. XRPD analysis of the resulting refined product revealed that the refined product was the finerenone-maleic acid cocrystal of the present application.

[0050] Table 2 Powder diffraction data of the sample obtained in Example 2

[0051] 2θ (°) d-value (Å) I / I0 (%) 6.945012.7501278.347.183712.3234572.298.705210.1578558.3917.45875.07858100.1017.6224 5.0315591.6517.92974.9546657.1422.62013.9324413.5720.72204.2873351.4922.33323.9824393.6622.87883.8954663.82 Example 3

[0052] 100g of finerenone and 30.6g of maleic acid were added to 2000g of acetone / water (5:1), stirred, and heated to 75°C until complete dissolution. Heating was stopped, and the mixture was cooled with continued stirring to allow crystallization. The temperature was then lowered to 0-20°C, incubated for 5 hours, and filtered. The mixture was then dried under reduced pressure at 50°C for 10 hours to obtain 120.6g of cocrystals with a yield of 92.4% and a purity (HPLC determination) of 99.8%, with each impurity less than 0.1%. XRPD analysis of the resulting refined product revealed the finerenone-maleic acid cocrystal form of the present application.

[0053] Table 3 Powder diffraction data of the sample obtained in Example 3

[0054] 2θ (°) d-value (Å) I / I0 (%) 6.943312.7524478.517.185612.3246572.358.704710.1573358.4117.45645.07567100.2117.6225 5.0321191.4517.92354.9536457.3422.63663.9326413.4820.72154.2845651.5022.33213.9826693.6922.87363.8943263.78 Example 4

[0055] 100g of finerenone and 61.2g of maleic acid were added to 1000g of methanol / water (2:1), stirred and heated to 60°C until complete dissolution. Heating was stopped, and the mixture was cooled and crystallized while stirring. The temperature was then lowered to 0-20°C and held for 5 hours to allow crystallization. The mixture was filtered and dried under reduced pressure at 50°C for 10 hours to obtain 116.8g of cocrystals with a yield of 89.5% and a purity (HPLC determination) of 99.8%, with each impurity less than 0.1%. XRPD analysis of the resulting refined product revealed the finerenone-maleic acid cocrystal form of the present application.

[0056] Table 4 Powder diffraction data of the sample obtained in Example 4

[0057] 2θ (°) d-value (Å) I / I0 (%) 6.943412.7546778.437.184312.3235672.678.704610.1574358.3217.45635.07567100.4517.6245 5.0324291.6417.92334.9538957.6122.63743.9329013.5720.72354.2843551.5722.33593.9827793.7822.87333.8948963.76 Example 5 Comparative Example Preparation of Finerenone Crystal Form I

[0058] 10g of finerenone was added to 150g of ethanol and heated to 75°C with stirring until complete dissolution. Heating was stopped, and the mixture was cooled with continued stirring to crystallize. The mixture was then cooled to 0-20°C and held for 5 hours to crystallize. The mixture was filtered and dried under reduced pressure at 50°C for 10 hours to yield 8.8g of refined finerenone with an 88% yield and 99.8% purity (HPLC determination), with each impurity less than 0.1%. XRPD analysis of the refined product revealed finerenone Form I, which differs from the finerenone-maleic acid cocrystal of the present application. H NMR spectroscopy revealed that the cocrystal exhibited no proton transfer compared to finerenone, confirming the formation of a cocrystal rather than a salt. H NMR analysis determined that the molar ratio of finerenone to maleic acid in the cocrystal was 1:1. See Figures 5 and 6.

[0059] Table 5 Powder diffraction data of the sample obtained in Example 5

[0060] 2θ (°) d-value (Å) I / I0 (%) 8.545710.3473438.6014.02376.31531100.0017.13885.1738240.9119.0088 4.6688793.4520.48444.3357430.7822.92423.8795234.4225.51733.4908643.6426.44453.3705238.24 Example 6 Saturation Solubility Determination

[0061] The saturation solubility of finerenone-maleic acid cocrystal was evaluated using a conventional saturation solubility determination method. <1236> Solubility Measurements: The measurement temperature is 25°C.

[0062] The applicant of the present invention compared the solubility of finerenone-maleic acid cocrystallization with that of finerenone and unexpectedly found that the solubility of finerenone cocrystallization with maleic acid was significantly different from that of finerenone.

[0063] Table 6 Solubility test results

[0064] Finerenone and maleic acid cocrystal Finerenone pH 1.0 buffer solution (0.1mol / L hydrochloric acid) 68mg / ml 46mg / ml pH 4.0 buffer solution (acetate buffer) 3.10mg / ml 0.11mg / ml pH 6.8 buffer solution (phosphate buffer) 0.36mg / ml 0.03mg / ml Example 7 Stability Test

[0065] A series of stability tests were conducted on the eutectic of finerenone and maleic acid prepared in Examples 1-4, including influencing factors and accelerated tests. The test results are shown in Tables 7 and 8.

[0066] Table 7 Test results of influencing factors

[0067]

[0068] Table 8 Accelerated (intermediate conditions) test results (storage conditions: temperature 30℃±2℃, RH 65%±5%)

[0069]

[0070] As shown in the influencing factor test results in Table 7, the key stability indicators of the finerenone-maleic acid cocrystal of the present application showed no significant changes compared to the zero time, the purity was greater than 99.8%, and the single impurity content was less than 0.1%, indicating that the cocrystal was relatively stable. As shown in the accelerated (intermediate conditions) test results in Table 8, in the accelerated test, after 6 months of accelerated testing, the key stability indicators of the finerenone maleic acid cocrystal of the present application showed no significant changes compared to the zero time, the purity was greater than 99.8%, and the single impurity content was less than 0.1%, indicating that the cocrystal was relatively stable.

[0071] In the above specific implementation manner:

[0072] In Table 4-5,

[0073] "Total impurities" refers to the total amount of impurities contained in the finerenone and maleic acid cocrystal, in mass percentage;

[0074] "Water" refers to: the amount of water contained in the finerenone and maleic acid cocrystal, in mass percentage;

[0075] "Content" refers to: the amount of the active ingredient of finerenone in the cocrystal of finerenone and maleic acid (compared with the standard); mass fraction;

[0076] “RH” means: relative humidity;

[0077] Moisture determination method: Take 1.0g of this product and determine the moisture content according to the method for determination of moisture (Chinese Pharmacopoeia 2015 edition, Part IV, General Rules 0832, Method 1 A);

[0078] Determination of single impurities and total impurities content: Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition Part IV General Chapter 0512).

Claims

1. A pharmaceutical 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 cocrystal according to claim 1, characterized in that Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has 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 cocrystal according to claim 1, characterized in that Its DSC graph showed an endothermic peak at 150-175°C, and the peak value of the endothermic peak appeared at 161.5°C.

4. The finerenone-maleic acid cocrystal according to claim 1, characterized in that Its TGA graph showed that it started to decompose at about 152.8°C.

5. The finerenone-maleic acid cocrystal according to claim 3 or 4, characterized in that It has a DSC graph and a TGA graph substantially as shown in FIG. 2 and FIG. 3 .

6. A method for preparing finerenone-maleic acid cocrystal, characterized in that: Finerenone and maleic acid are dissolved by heating with a crystallization solvent, cooled for crystallization, filtered, and dried under reduced pressure to obtain the product.

7. The method for preparing finerenone-maleic acid cocrystal 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 method for preparing finerenone-maleic acid cocrystal 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 cocrystal as claimed in any one of claims 1 to 5 and a pharmaceutically acceptable carrier or excipient.

Images