Felnerenone acetic acid solvate, preparation method and application

Abstract

The invention relates to the field of medicine crystal forms, in particular to a new crystal form of a fenerenone acetic acid solvate. The novel crystal form prepared by the invention has the characteristics of higher solubility, better flowability, safety and medicinal property. Meanwhile, the preparation method is stable, good in reproducibility and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical crystal forms, specifically relating to a phenelzine acetic acid solvate, its preparation method, and its application. Background Technology

[0002] Finerenone (Formula II), chemical name: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, is a novel nonsteroidal selective mineralocorticoid receptor (MR) antagonist that has shown significant renal protection and cardiovascular benefits in clinical practice, especially suitable for type 2 diabetic patients with heart failure or chronic kidney injury.

[0003]

[0004] The marketed drug uses phenelzine crystal form I as the active pharmaceutical ingredient. This crystal form has thermodynamic stability and is a commonly used crystal form in drug development. However, crystal form I has low solubility, which limits its bioavailability to some extent. Further research revealed that crystal form I has poor flowability. Patent CN112237573A describes a wet granulation process to ensure uniformity of phenelzine tablet content, disintegration time, and dissolution rate, requiring sieving through a 60-mesh sieve to control particle size and obtain uniform and fine particles for subsequent tableting. However, the poor flowability of crystal form I may lead to uneven particle distribution, affecting granulation efficiency and final tablet quality. Therefore, it is necessary to develop a new solid form of phenelzine with better solubility, better flowability, stable preparation method, and suitability for industrial production. One approach is to improve solubility by developing new crystal forms or amorphous forms. Patent CN118908956A discloses a co-amorphous system of phenelzine with malic acid, tartaric acid, etc., which significantly improves solubility compared to crystal form I. Patent CN117618368A demonstrates that preparing phenelzine as a solid dispersion can effectively accelerate drug dissolution. On the other hand, constructing new salts or cocrystal forms can also achieve solubilization goals. Patent CN118834205A discloses that the salts formed by the reaction of phenelzine with hydrochloric acid, hydrobromic acid, etc., exhibit significantly improved solubility compared to the active pharmaceutical ingredient. Patent CN120081840A reports a phenelzine cocrystal with maleic acid, which demonstrates superior solubility and stability compared to crystal form I.

[0005] Among the diverse solid states, solvates are also one of the possible crystalline forms to be developed. However, due to the toxicological risks of most organic solvents, the development of pharmaceutical solvates requires careful solvent selection. Acetic acid, as a food source, has a good safety profile, and many acetate drugs are already on the market. There are also marketed drugs based on acetic acid solvates, such as Zinforo, a cephalosporin antibiotic marketed as an acetic acid solvate monohydrate. This drug was approved by the EU in 2012 and is marketed in several countries.

[0006] Against this backdrop, developing a phenelzine solid form with superior solubility, better flowability, and pharmaceutical acceptability is of clear practical significance. The phenelzine acetate solvate (named phenelzine crystalline form SAA) involved in this invention is designed precisely to meet this need. Its preparation method is stable, reproducible, and suitable for industrial production, and its solubility and flowability are significantly better than crystalline form I, demonstrating broad application prospects. Summary of the Invention

[0007] This invention aims to provide a non-nelinerone crystalline form of SAA. This crystalline SAA not only improves solubility but also exhibits better flowability, thus overcoming the shortcomings of non-nelinerone crystalline form I and possessing significant application value. Furthermore, the preparation method of the crystalline SAA is stable, reproducible, and suitable for industrial production.

[0008] The present invention provides a phenelzine crystalline form SAA, wherein the molar ratio of phenelzine molecules to acetic acid molecules in the crystalline structure is 1:2, and the structure is shown in formula (I).

[0009]

[0010] Furthermore, the non-nelitone crystalline form SAA described in this invention has characteristic peaks in its powder X-ray diffraction pattern at 2θ angles of 11.3±0.2°, 14.9±0.2°, 23.1±0.2°, 23.5±0.2° and 26.2±0.2°.

[0011] Furthermore, the powder X-ray diffraction pattern of the non-nelitone crystalline form SAA has characteristic peaks at 2θ angles of 11.3±0.2°, 14.9±0.2°, 16.5±0.2°, 20.9±0.2°, 23.1±0.2°, 23.5±0.2°, 24.2±0.2°, 24.8±0.2°, 25.1±0.2°, and 26.2±0.2°.

[0012] Furthermore, the non-nelitone crystalline form SAA, when tested at 100K, has the following unit cell parameters: α = 90°, β = 90°, γ = 90°, space group is P212121.

[0013] Furthermore, the differential scanning calorimetry (DSC) curves of the non-nelitone crystalline form SAA show endothermic peaks at 101.0±5℃, 108.1±5℃, and 240.6±5℃.

[0014] This invention also relates to a method for preparing phenelzine crystalline form SAA, specifically: phenelzine is placed in a certain volume of acetic acid solvent or a solvent containing acetic acid to dissolve it, then a poor solvent is added, and the mixture is stirred and crystallized at low temperature. After filtration and drying, the resulting solid is phenelzine crystalline form SAA.

[0015] Furthermore, the mass-to-volume ratio of phenelzine to acetic acid is 200–250 mg:mL.

[0016] Furthermore, the antisolvent includes any one of toluene, cyclohexane, n-heptane, and 2-methyltetrahydrofuran.

[0017] Furthermore, the low temperature is 0–5°C; the drying method is vacuum drying; and the drying temperature is 25–40°C.

[0018] This invention relates to the use of the aforementioned fenelone crystalline form SAA in the preparation of products for treating diabetic chronic kidney disease.

[0019] The beneficial effects of this invention are as follows:

[0020] 1. Compared with commercially available phenelzine crystal form I, the crystal form SAA prepared in this invention has higher solubility, which is beneficial to improving bioavailability.

[0021] 2. Compared with commercially available phenelzine crystal form I, the crystal form SAA prepared by this invention has significantly improved powder flowability, which facilitates processing.

[0022] 3. The non-nelitone crystalline SAA preparation method provided by the present invention is stable, has good reproducibility, and is suitable for industrial production. Attached Figure Description

[0023] Figure 1 The image shows the powder X-ray diffraction pattern of the non-nelitone crystalline form SAA obtained in Example 1.

[0024] Figure 2 Differential scanning calorimetry (DSC) of non-nelitone crystalline form SAA obtained in Example 1.

[0025] Figure 3 This is a single crystal morphology diagram of the non-nelitone crystalline form SAA obtained in Example 4.

[0026] Figure 4 This is an asymmetric unit diagram of the single crystal structure of the non-nelitone crystalline form SAA obtained in Example 4. Detailed Implementation

[0027] The following detailed description of the present application is provided in conjunction with embodiments, but is not intended to limit the present application. Any equivalent substitutions made in the art based on the disclosure of the present application shall fall within the protection scope of the present application.

[0028] The abbreviations used in this application are explained as follows:

[0029] XRD: X-ray diffraction

[0030] Powder X-ray diffraction: Approximately 20 mg of the ground sample was used for diffraction data collection at room temperature using a powder X-ray diffractometer (Bruker D8 Advance) with Cu-Kα rays as the light source. The scanning step size is 0.02°, the scanning voltage is set to 40kV, the current to 40mA, the step size to 0.02°, the dwell time to 0.1s, and the scanning range 2θ to 5~40°.

[0031] Single-crystal X-ray diffraction method for determining crystal structure: A high-quality single crystal of phenelzine ether (SAA) was used, and its structure was determined by X-ray diffraction at 100K using a Rigaku Synergy Custom FR-X hybrid pixel array detector single-crystal diffractometer (light source wavelength). The sample was tested, diffraction data was collected, and the data was refined using the least squares method. All non-hydrogen atoms were refined using anisotropy.

[0032] DSC: Differential Scan Calorimetry

[0033] The DSC test described in this application was performed using a DSC 3 (METTLER TOLEDO, Switzerland) differential scanning calorimeter for data collection. Approximately 5 mg of sample was placed in a perforated aluminum crucible for heating analysis. The heating temperature was set from room temperature to 300 °C, the heating rate was 10 °C / min, and the purge carrier gas was nitrogen at a purge rate of 50 mL / min.

[0034] Example 1: Preparation of phenelzine crystalline form SAA

[0035] 200 mg of fenelazol was weighed and placed in 1 mL of acetic acid. The suspension was ultrasonically cleaned for 5 min to obtain a clear solution. 10 mL of toluene was slowly added dropwise to the clear solution. After stirring at 5 °C for a period of time, a solid precipitated. The system was filtered, and the resulting powder was placed in a vacuum drying oven at 25 °C for 16 h. The powder was then passed through a 60-mesh sieve (approximately 250 μm aperture) to control the particle size. The bulk density of the sieved powder was 0.355 g / mL, and the tap density was 0.469 g / mL. The obtained sample was subjected to powder XRD using Cu-Kα rays. The diffraction angles and relative intensities of the spectra are shown in Table 1. The sample powder XRD patterns and differential scanning calorimetry (DSC) are shown below. Figure 1 and Figure 2 As shown.

[0036] Table 1. Diffraction angles and relative intensities of phenelzine crystalline form SAA

[0037]

[0038]

[0039]

[0040] Example 2: Preparation of phenelzine crystalline form SAA

[0041] 200 mg of fenelazol was weighed and placed in 1 mL of acetic acid. The suspension was ultrasonically cleaned for 5 min to obtain a clear solution. 10 mL of cyclohexane was slowly added dropwise to the clear solution. After stirring at 5 °C for a period of time, a solid precipitated. The system was filtered, and the obtained powder was placed in a vacuum drying oven at 25 °C for 16 h. The obtained powder was passed through a 60-mesh sieve to control the particle size. The bulk density of the powder after sieving was 0.361 g / mL, and the tap density was 0.483 g / mL. The obtained sample was subjected to powder XRD using Cu-Ka rays, and its powder XRD pattern was basically consistent with that of Example 1.

[0042] Example 3: Preparation of phenelzine crystalline form SAA

[0043] 200 mg of fenelazol was weighed and placed in 1 mL of acetic acid. The suspension was ultrasonically cleaned for 5 min to obtain a clear solution. 10 mL of 2-methyltetrahydrofuran was slowly added dropwise to the clear solution. After stirring at 5°C for a period of time, a solid precipitated. The system was filtered, and the resulting powder was placed in a vacuum drying oven at 25°C for 16 h. The obtained powder was passed through a 60-mesh sieve to control the particle size. The bulk density of the sieved powder was 0.351 g / mL, and the tap density was 0.467 g / mL. Powder XRD analysis of the obtained sample was performed using Cu-Ka rays, and the powder XRD pattern was basically consistent with that of Example 1.

[0044] Example 4: Preparation of single crystals of non-nelitone crystalline SAA

[0045] 100 mg of fenelazol was placed in 0.5 mL of acetic acid. The suspension was ultrasonicated for 10 min to obtain a clear solution. 5 mL of toluene was slowly added dropwise to the clear solution. The solution was filtered through a 0.22 μm PTFE membrane and then slowly evaporated at room temperature. After 20 days, colorless rod-shaped crystals were harvested. Figure 3 As shown. The asymmetric unit cell diagram of the crystal structure is as follows. Figure 4 As shown, its crystallographic data and structural refinement parameters are summarized in Table 2.

[0046] Table 2 Crystallographic data and structural refinement parameters of phenelzine crystalline form SAA

[0047]

[0048]

[0049] Experimental Example 1: Powder Flowability Test

[0050] Bulk density and tap density are quantities related to the flow properties of powder. Generally, high bulk density and tap density values ​​are desirable. Bulk density indicates the weight of one unit volume of powder under predetermined conditions, expressed as weight per unit volume, usually in g / mL. Tap density also indicates the weight of one unit volume of powder subjected to tapping or vibration under predetermined conditions in a container. Tap density is also expressed as weight per unit volume, usually in g / mL. Therefore, powders with high bulk density and tap density tend to have a higher specific gravity, reflecting a thicker, more substantial crystalline product with relatively better stability. From another perspective, products with high bulk density generally have better particle flowability, making them easier to store and transport.

[0051] Specifically, approximately 200 mg of powder was gently placed into a 5 mL graduated cylinder to measure its volume. The powder was then tapped 1300 times to achieve its most compacted state. The volume after tapping was measured, and the bulk density, tapped density, and Hausner ratio (HR, the ratio of tapped density to bulk density; a higher HR indicates poorer flowability) were calculated. The density evaluation results for phenelzine crystal form I and crystal form SAA are shown in Table 3.

[0052] Table 3 Density test results of phenelzine crystal form I and SAA

[0053]

[0054] Referring to Table 9-4 on page 246 of the book "Theory and Application of Crystalline Drug Development" (Chemical Industry Press, 2019), the following relationship exists between Hausnerby Point (HR) and powder flowability: when HR is between 1.26 and 1.34, the powder has normal flowability; when HR > 1.6, the powder has extremely poor flowability. Based on the test results in Table 3, the HRs of phenelzine crystalline SAA (Example 1), crystalline SAA (Example 2), and crystalline SAA (Example 3) are 1.321, 1.338, and 1.330, respectively. Therefore, crystalline SAA is judged to have normal flowability, while crystalline I has an HR of 2.542, representing extremely poor flowability.

[0055] Experimental Example 2: Powder Dissolution Experiment

[0056] In the powder dissolution experiment, 50 mg of phenelzine I and 65 mg of phenelzine SAA powder were added to 250 mL of phosphate buffer (pH 6.8), respectively. The temperature was controlled at 37 ± 0.2 °C, and the magnetic stirring speed was 100 rpm. Samples were taken at regular intervals to determine the concentration, and an equal volume of medium was added simultaneously. The experiment lasted for 24 h. The concentration of phenelzine was determined using high-performance liquid chromatography (HPLC). The experiment was performed in triplicate. Table 4 shows the data on the dissolution of phenelzine I and phenelzine SAA powders over time, as shown below:

[0057] Table 4. Powder dissolution test results of phenelzine crystal form I and SAA

[0058]

[0059] The results showed that the solubility of phenelzine crystalline form SAA was 0.0019 mg / mL (t = 24 h) at the experimental sampling interval, which was 5.76 times that of phenelzine crystalline form I (t = 24 h). This improved solubility is beneficial for increasing bioavailability.

[0060] In summary, the phenelzine crystalline SAA prepared by this invention has high solubility, which is beneficial to improving bioavailability. At the same time, the crystalline SAA has good flowability, which is convenient for processing. Furthermore, its preparation method is stable, reproducible, and suitable for industrial production.

[0061] It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds and their preparation methods without departing from the spirit or scope of the invention. Therefore, the scope of protection of the present invention covers various modifications and variations made to this application, as long as the modifications or variations are within the scope of the claims and their equivalent embodiments.

Claims

1. A crystalline form of SAA of nonalineone having the structure of formula (I), characterized in that, The molar ratio of non-nelitone molecule to acetic acid molecule in the crystalline SAA is 1:

2.

2. The crystalline Form SAA of Finaflumine according to claim 1, characterized in that, The powder X-ray diffraction pattern of the crystalline SAA was determined using Cu-Ka rays, and characteristic peaks were observed at 2θ angles of 11.3±0.2°, 14.9±0.2°, 23.1±0.2°, 23.5±0.2°, and 26.2±0.2°.

3. The crystalline Form SAA of Finaflumine according to claim 1, characterized in that, The powder X-ray diffraction pattern of the crystalline SAA was determined using Cu-Ka rays, and characteristic peaks were observed at 2θ angles of 11.3±0.2°, 14.9±0.2°, 16.5±0.2°, 20.9±0.2°, 23.1±0.2°, 23.5±0.2°, 24.2±0.2°, 24.8±0.2°, 25.1±0.2°, and 26.2±0.2°.

4. The non-nelitone crystalline form SAA as described in claim 1, characterized in that, The single crystal structure thereof is tested at 100K, and the cell parameters are α = 90°, β = 90°, γ = 90°, and the space group is P212121.

5. The crystalline Form SAA of Finaflumine according to claim 1, characterized in that, The differential scanning calorimetry curves show endothermic peaks at 101.0±5℃, 108.1±5℃ and 240.6±5℃.

6. The method of preparing crystalline Form SAA of finerenone according to any one of claims 1 to 5, wherein, Finelone is placed in a certain volume of acetic acid solvent or a solvent containing acetic acid to dissolve it. Then, a poor solvent is added, and the mixture is stirred at low temperature to crystallize. After filtration and drying, the resulting solid is finelone crystal form SAA.

7. The method of preparing crystalline Form SAA of fnonareniketone according to claim 6, wherein The undesirable solvents include any one of toluene, cyclohexane, n-heptane, and 2-methyltetrahydrofuran.

8. The use of fenelone crystalline form SAA according to any one of claims 1-7 in the preparation of a product for treating diabetic chronic kidney disease.

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