Molismostat new crystalline form ii and process for its preparation

Abstract

The application belongs to the field of medicine crystallization, and discloses a new crystal form II of Morlidstat and a preparation method thereof. P The crystal form II of Morlidstat is a triclinic crystal, a with a cell parameter of: b = 6.0316 Å, c = 7.2911 Å, α = 16.1027 Å, β = 101.098°, gamma = 90.447°, = 104.418°. The preparation process of the crystal form II of Morlidstat is simple, stable and highly reproducible. The crystal form II of Morlidstat obtained by the process is stable in crystal form, color and morphology under the condition of 30±5°C and 40±5% RH for 30 days, and the crystal form stability is significantly improved compared with the original crystal form, so that the crystal form II of Morlidstat is suitable for the manufacture and long-term storage of drug preparations. Compared with the Morlidstat sodium salt in the prior art, the crystal form II of Morlidstat has moderate solubility, so that the abnormal bioavailability caused by excessively high solubility can be avoided.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical crystallization technology, and specifically relates to a new crystal form II of moristat and its crystallization preparation method. Background Technology

[0002] Polymorphism, also known as polymorphism or polymorphism, refers to the multiple crystal structures formed by different molecular conformations or arrangements of the same chemical substance. Therefore, although different polymorphs may not differ in chemical properties, they may have significant differences in many physical properties.

[0003] Polymorphism is particularly important in the pharmaceutical industry. It is prevalent in organic drugs and significantly impacts their final efficacy. Firstly, different polymorphs of drugs differ in their physical properties. Stable polymorphs typically have higher melting points and chemical stability, but lower solubility and bioavailability; while unstable and metastable polymorphs have better solubility and bioavailability, but poorer stability. Secondly, differences in polymorphism also affect drug dissolution and solubility, thus influencing the drug's efficacy. Therefore, drugs with different polymorphs have significantly different application value.

[0004]

[0005] Formula I

[0006] 2-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazole-3-one (also known as: molidustat, formula I), with the molecular formula C 13 H 14 N8O2, with a molecular weight of 314.3, is a pale pink or white powder. Moristat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PHI) inhibitor. It works by stabilizing HIF-PHI, inhibiting its degradation, promoting erythropoietin synthesis, and regulating iron metabolism, thereby comprehensively improving renal anemia. Clinical studies have shown that moristat is significantly effective in treating anemia in dialysis- and non-dialysis-dependent chronic kidney disease without increasing the risk of cardiovascular events, potentially providing a more convenient and safer treatment option.

[0007] Currently, the synthesis of molrisstat has been disclosed in Chinese patent CN200780048262.3, but only Chinese patent CN201180055239.3 reports on the pure solid form of molrisstat (crystalline form I), which suffers from severe hygroscopicity. To address the hygroscopicity issue of crystalline form I, patent CN103270031A proposed a technical solution to convert it into a sodium salt to overcome hygroscopicity and handling difficulties, demonstrating that the sodium salt is non-hygroscopic and has excellent stability. However, the sodium salt has significant limitations in practical clinical applications. Its high solubility (2800 mg / 100 mL) leads to rapid dissolution and absorption after oral administration, resulting in a sudden increase in blood drug concentration and an excessively high peak value. Furthermore, its rapid elimination from the body not only causes large fluctuations in bioavailability, making it difficult to maintain a stable effective blood drug concentration, but may also increase the safety risks of clinical use. Therefore, it is essential to further study new crystalline forms of molrisstat to improve both its stability and appropriate solubility. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of the prior art and provide a new crystalline form of molrisstat and its preparation method. The X-ray powder diffraction pattern of the new crystalline form (crystalline form II) is at a diffraction angle of 2°. θ Diffraction peaks are observed at 14.60 ± 2°, 15.26 ± 2°, 15.97 ± 2°, 16.43 ± 2°, 17.84 ± 2°, 18.30 ± 2°, 18.77 ± 2°, 22.08 ± 2°, 25.04 ± 2°, 25.80 ± 2°, and 27.78 ± 2°, among which 2 θ The diffraction peaks at 14.60 ± 2°, 18.30 ± 2°, 22.08 ± 2°, 25.04 ± 2°, and 25.80 ± 2° are the main characteristic peaks. These diffraction peaks are inconsistent with those of moristat crystal form I, confirming the synthesis of the new crystal form.

[0009] Preferably, the new crystal form II of moristat is triclinic. P Space group -1, cell parameters are: a =6.0316 Å, b = 7.2911 Å, c = 16.1027 Å, α = 101.098°, β = 90.447°, γ =104.418°.

[0010] Preferably, the new morphology II crystal product of moristat has a regular rod-shaped or plate-shaped morphology and a relatively large particle size.

[0011] Preferably, TGA / DSC analysis of the new crystalline form II of moristat showed no crystal transformation during heating, indicating good thermal stability. Furthermore, the new crystalline form undergoes thermal decomposition at 235–237 °C. After storage at 30±5 °C and 40±5% RH for 30 days, there was no change in crystalline form, color, or morphology. Moreover, the new crystalline form exhibits moderate solubility (20–23 mg / 100 mL), effectively addressing the problems of bioavailability fluctuations, excessively high peak plasma concentrations, and rapid elimination from the body caused by the excessively high solubility of the sodium salt crystalline form. This is more conducive to the industrial production of solid dosage forms and the stable clinical efficacy.

[0012] The method for preparing the new crystalline form II of morilistat disclosed in this invention is a solution-crystallization method, the specific steps of which include:

[0013] Step 1: Dissolve moristat solid in solvent I, control the stirring speed at 100~800 rpm, and heat to a certain temperature to form a clear solution;

[0014] Step 2: Maintain the clear solution obtained in Step 1 at this temperature, and add a certain amount of solvent II to it at a certain flow rate;

[0015] Step 3: Maintain the temperature from Step 2 and continue crystal growth for a period of time;

[0016] Step 4: Filter and wash the product obtained in Step 3, and dry the resulting crystals; after drying, the new crystal form II of moristat is obtained.

[0017] The moristat used as the initial reactant in this invention is any form of non-salt moristat solid product in the prior art, which can be obtained commercially or by preparation methods disclosed in the prior art. The solute-solvent ratio of the initial reactant in this invention is the mass-volume ratio of moristat solid to solvent in the moristat solution.

[0018] Preferably, the solvent I is one or more of the following: chloroalkane organic solvents (e.g., dichloroethane, chloroform, etc.), ketone organic solvents (e.g., acetone, cyclohexanone, etc.), amide organic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, etc.), ester solvents (e.g., methyl acetate, ethyl acetate, etc.), nitrile compounds (e.g., acetonitrile, etc.), ether compounds (e.g., 1,4-dioxane, isopropyl ether, etc.), and sulfone compounds (e.g., dimethyl sulfoxide, etc.).

[0019] In any of the above-mentioned preferred embodiments, in step 1, the ratio of moristat solid to solvent I is 0.001 g / mL to 0.5 g / mL, that is, the mass-volume ratio of moristat to solvent in the moristat solution obtained in step 1 is 0.001 g:1 mL to 0.5 g:1 mL.

[0020] In any of the above-mentioned preferred embodiments, in step 1, the dissolution temperature of moristat solid in solvent I is 20–80°C.

[0021] In any of the above-mentioned preferred embodiments, in step 2, solvent II is one or more of an alcoholic organic solvent (e.g., ethanol, isopropanol, etc.), an unsaturated alkane (e.g., cyclohexane, toluene, etc.), and water.

[0022] In any of the above-mentioned preferred embodiments, in step 2, the amount of solvent II added is 0.5 to 8 times that of solvent I, and the flow rate of solvent II is 0.1 mL / min to 4.0 mL / min.

[0023] In any of the above-mentioned preferred embodiments, the crystal growth time in step 3 is 0.5 to 4 hours.

[0024] In any of the above-mentioned preferred embodiments, in step 4, the solvent for washing the crystals is one or more of the following: an alcoholic organic solvent (e.g., ethanol, isopropanol, etc.), an unsaturated alkane (e.g., cyclohexane, toluene, etc.), and water.

[0025] In any of the above-mentioned preferred embodiments, in step 4, the crystal drying temperature is 40–80 °C.

[0026] In any of the above-mentioned preferred embodiments, in step 4, the drying method is vacuum drying or forced air drying, and the drying time is 3 to 12 hours.

[0027] Advantages and beneficial effects of the present invention:

[0028] The new crystalline form II of moristat provided by this invention exhibits significantly improved crystal stability compared to the original crystalline form. The product preparation process is simple, stable, and highly reproducible, with a process yield exceeding 80%, making it suitable for pharmaceutical formulation manufacturing and long-term storage. Furthermore, compared to the sodium salt form, the new crystalline form II of moristat provided by this invention has moderate solubility, significantly improving bioavailability and avoiding excessively high peak plasma concentrations and rapid elimination, thus maintaining stable effective plasma drug concentrations and enhancing the efficacy and safety of clinical use. Attached Figure Description

[0029] Figure 1 The image shows the X-ray powder diffraction (PXRD) pattern of the existing molrisstat crystal form I.

[0030] Figure 2 This is the X-ray powder diffraction (PXRD) pattern of the new crystal form II of morilistat in preferred embodiment 1 of the present invention;

[0031] Figure 3 Thermogravimetric analysis and differential scanning calorimetry (TG / DSC) plots of existing molrisstat crystal form I;

[0032] Figure 4 Thermogravimetric analysis and differential scanning calorimetry (TG / DSC) diagrams of the new crystal form II of morilistat in preferred embodiment 1 of the present invention;

[0033] Figure 5 The infrared spectrum of the new crystalline form II of morilistat in preferred embodiment 1 of the present invention;

[0034] Figure 6 This is the Raman spectrum of the new crystal form II of moristat in preferred embodiment 1 of the present invention. Detailed Implementation

[0035] The present invention will be described more clearly and completely through the following embodiments, but the described examples are only a part of the embodiments of the present invention, and not all of them. The embodiments are provided to help understand the present invention and should not be construed as limiting the scope of protection of the present invention.

[0036] Example 1

[0037] A method for preparing a new crystalline form II of morilistat, comprising the following steps:

[0038] 0.1502 g of moristat solid was dissolved in a mixed solution of 1 mL dimethyl sulfoxide and 0.5 mL ethyl acetate at 35 °C. Magnetic stirring was started at 100 rpm to ensure complete dissolution and uniform dispersion of the solid in the solvent. The solution was maintained at 35 °C, and 12 mL of water was added to the clarified solution at a feed rate of 0.1 mL / min. After crystals appeared in the crystallizer, the temperature was maintained for crystal growth for 4 h. After crystal growth, the crystal product was filtered, washed with water, and vacuum filtered to obtain the crystal product. The obtained crystals were placed in a vacuum drying oven at 80 °C and dried for 12 h. After drying, the final new morphology II product of moristat was obtained.

[0039] The product exhibits characteristic peaks at X-ray powder diffraction angles of 14.80±2°, 17.98±2°, 18.40±2°, 21.42±2°, 22.11±2°, 25.23±2°, 26.01±2°, and 27.95±2°. TGA / DSC results indicate a decomposition temperature of 236℃. The product presents as pale yellow, regular rod-shaped crystals with a purity of 99% and a yield of 90%.

[0040] Example 2

[0041] A method for preparing a new crystalline form II of morilistat, comprising the following steps:

[0042] 0.0402 g of moristat solid was dissolved in 40 mL of dichloromethane solution at room temperature. Magnetic stirring was started and the stirring speed was set to 500 rpm to ensure that the solid was completely dissolved and uniformly dispersed in the solvent. The solution was kept at room temperature, and 20 mL of water was added to the clarified solution at a feeding rate of 4 mL / min. After crystals appeared in the crystallizer, the temperature was maintained for crystal growth for 4 h. After crystal growth, the crystal product was filtered, washed with water, and vacuum filtered to obtain the crystal product. The obtained crystals were placed in a vacuum drying oven and dried at 40 °C for 3 h. After drying, the final new crystal form II of moristat was obtained.

[0043] The product exhibits characteristic peaks at X-ray powder diffraction angles of 14.60±2°, 17.85±2°, 18.33±2°, 21.32±2°, 22.19±2°, 25.11±2°, 25.82±2°, and 27.98±2°. TGA / DSC results indicate a decomposition temperature of 237℃. The product presents as pale yellow, regular rod-shaped crystals with a purity of 99% and a yield of 85%.

[0044] Example 3

[0045] A method for preparing a new crystalline form II of morilistat, comprising the following steps:

[0046] 0.1076 g of moristat solid was dissolved in 10 mL of N,N-dimethylacetamide solution at 40 °C. Magnetic stirring was started and the stirring speed was set to 400 rpm to ensure complete dissolution and uniform dispersion of the solid in the solvent. The solution was maintained at 40 °C, and 25 mL of toluene was added to the clarified solution at a feeding rate of 1 mL / min. After crystals appeared in the crystallizer, the temperature was maintained for crystal growth for 3.5 h. After crystal growth, the crystal product was filtered, washed with cyclohexane, and vacuum filtered to obtain the crystal product. The obtained crystals were placed in a vacuum drying oven and dried at 50 °C for 10 h. After drying, the final new crystal form II of moristat was obtained.

[0047] The product exhibits characteristic peaks at X-ray powder diffraction angles of 14.48±2°, 17.95±2°, 18.44±2°, 22.30±2°, 25.21±2°, 25.92±2°, and 28.10±2°. TGA / DSC results show its decomposition temperature is 237℃. The product is a pale yellow, regular rod-shaped crystal with a purity of 99% and a yield of 90%.

[0048] Example 4

[0049] A method for preparing a new crystalline form II of morilistat, comprising the following steps:

[0050] 0.1362 g of moristat solid was dissolved in a mixed solvent of 3 ml cyclohexanone and 2 ml acetonitrile at 80 °C. Magnetic stirring was started and the stirring speed was set to 300 rpm to ensure that the solid was completely dissolved and uniformly dispersed in the solvent. The solution was maintained at 80 °C, and 40 mL of ethanol was added to the clarified solution at a feeding rate of 2 mL / min. After crystals appeared in the crystallizer, the temperature was maintained for crystal growth for 4 h. After crystal growth, the crystal product was filtered, washed with ethanol, and vacuum filtered to obtain the crystal product. The obtained crystals were placed in a forced-air drying oven and dried at 80 °C for 8 h. After drying, the final new crystal form II of moristat was obtained.

[0051] The product exhibits characteristic peaks at X-ray powder diffraction angles of 14.38±2°, 17.75±2°, 18.24±2°, 22.50±2°, 25.11±2°, 25.82±2°, and 27.94±2°. TGA / DSC results indicate a decomposition temperature of 236℃. The product is a pale yellow, regular, plate-like crystal with a purity of 99% and a yield of 96%.

[0052] Example 5

[0053] A method for preparing a new crystalline form II of morilistat, comprising the following steps:

[0054] 0.4998 g of moristat solid was dissolved in 1 ml of isopropyl ether at 20 °C. Magnetic stirring was started and the stirring speed was set to 800 rpm to ensure complete dissolution and uniform dispersion of the solid in the solvent. The solution was maintained at 20 °C, and 8 mL of cyclohexane was added to the clarified solution at a feeding rate of 4 mL / min. After crystals appeared in the crystallizer, the temperature was maintained for crystal growth for 0.5 h. After crystal growth, the crystal product was filtered, washed with cyclohexane, and vacuum filtered to obtain the crystal product. The obtained crystals were placed in a vacuum drying oven and dried at 40 °C for 3 h. After drying, the final new morphology II product of moristat was obtained.

[0055] The product exhibits characteristic peaks at X-ray powder diffraction angles of 14.45±2°, 17.92±2°, 18.41±2°, 22.36±2°, 25.17±2°, 25.85±2°, and 28.02±2°. TGA / DSC results indicate a decomposition temperature of 235℃. The product is a white powdery crystal with a purity of 98% and a yield of 98%.

[0056] The space group and cell parameters of the new crystalline form II of molrisstat and the existing crystalline form I are shown in Table 1. The existing crystalline form I is a hydrate, and water molecules can easily be partially removed between layers, resulting in voids in the lattice. This reveals the fundamental reason for the instability of crystalline form I. In contrast, the new crystalline form II of molrisstat does not contain any solvent within its cell, thus exhibiting higher stability.

[0057] Table 1. Space group and cell parameters of molrisstat crystal form II and crystal form I

[0058]

[0059] The crystal stability of the prepared molrisstat new crystal form II and crystal form I was compared and investigated, and the results are shown in Table 2. During storage at 30±5 ℃ and 40±5% RH for 30 days, crystal form I underwent crystal transformation within 5 days, converting to crystal form II, exhibiting extremely poor crystal stability. In contrast, the molrisstat new crystal form II product disclosed in this invention showed no changes in color, morphology, or crystal form after storage at 30±5 ℃ and 40±5% RH for 30 days, indicating good crystal stability. Further verification showed that its stability is comparable to the sodium salt crystal form disclosed in prior art (CN103270031A), fully meeting the industry requirements for long-term storage of pharmaceutical preparations.

[0060] Table 2. Evaluation of the Crystal Form Stability of Morilista Products

[0061]

[0062] Thermal analysis was performed on crystal forms II and I to investigate their thermal stability. The TG / DSC spectra of crystal form I showed that it lost its water of crystallization at 30–70 °C, underwent crystal transformation at 130–160 °C, and thermally decomposed at 235–237 °C. Therefore, compared to crystal form I, the new crystal form II exhibits good thermal stability without solvent loss or crystal transformation during heating.

[0063] Furthermore, while maintaining excellent stability, the crystal form II of this invention has advantages over sodium salt in terms of powder properties such as dissolution kinetics, oral bioavailability, flowability, and long-lasting sustained release. The relevant performance data are shown in Table 3.

[0064] Table 3 Comparison of solubility, bioavailability and powder properties of crystal form II and sodium salt of the present invention

[0065]

[0066] The novel morpholine form II of moristat and its preparation method disclosed and proposed in this invention can be implemented by those skilled in the art by appropriately modifying the raw materials, process parameters, and other aspects, based on the content of this document. The methods and products of this invention have been described through preferred embodiments. Those skilled in the art can obviously modify or appropriately change and combine the methods and products described herein without departing from the content, spirit, and scope of this invention to achieve the technology of this invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included within the spirit, scope, and content of this invention.

Claims

1. A new crystalline form II of morilistat, characterized in that, The crystal is triclinic. P Space group -1, cell parameters are: a =6.0316 Å, b = 7.2911 Å, c = 16.1027 Å, α = 101.098° β = 90.447°, γ = 104.418°, and its X-ray powder diffraction pattern shows characteristic peaks at 2θ diffraction angles of 14.60±2°, 15.26±2°, 15.97±2°, 16.43±2°, 17.84±2°, 18.30±2°, 18.77±2°, 22.08±2°, 25.04±2°, 25.80±2°, and 27.78±2°.

2. The new morphoform II of moristat according to claim 1, characterized in that, The thermal decomposition temperature of the crystal form is 235~237℃. After being stored at 30±5℃ and 40±5% RH for 30 days, there is no change in crystal form, color, or morphology. The solubility of the new crystal form is 20~23 mg / 100mL.

3. The new morphoform II of moristat according to claim 1, characterized in that, The crystal form has a regular rod-like or plate-like morphology, a crystal purity of ≥98%, and contains no solvent molecules within the unit cell.

4. The method for preparing the new crystalline form II of moristat according to any one of claims 1 to 3, characterized in that, The solution-crystallization method includes the following steps: Step 1: Dissolve solid moristat in solvent I, control the stirring speed at 100~800 rpm, and heat to 20~80℃ to form a clear moristat solution; Step 2: Maintain the clarified moristat solution obtained in Step 1 at this temperature, and add a certain amount of solvent II to it at a certain flow rate; Step 3: Maintain the temperature from Step 2 and continue crystal growth for 0.5–4 hours; Step 4: Filter and wash the product obtained in Step 3, and dry the resulting crystals; after drying, the new crystal form II of moristat is obtained.

5. The preparation method according to claim 4, characterized in that, In step 1, solvent I is one or more of the following: chloroalkane organic solvents, ketone organic solvents, amide organic solvents, ester solvents, nitrile compounds, ether compounds, and sulfone compounds.

6. The preparation method according to claim 4, characterized in that, In step 1, the mass-to-volume ratio of moristat to solvent in the clear moristat solution obtained in step 1 is 0.001 g:1 mL to 0.5 g:1 mL.

7. The preparation method according to claim 4, characterized in that, In step 2, solvent II is one or more of alcoholic organic solvents, unsaturated alkanes, and water.

8. The preparation method according to claim 4, characterized in that, In step 2, the amount of solvent II added is 0.5 to 8 times that of solvent I, and the dropping rate of solvent II is 0.1 mL / min to 4.0 mL / min.

9. The preparation method according to claim 4, characterized in that, In step 4, the solvent for washing the crystals is one or more of the following: alcoholic organic solvents, unsaturated alkanes, and water.

10. The preparation method according to claim 4, characterized in that, In step 4, the crystal drying temperature is 40–80℃; The drying method is vacuum drying or forced air drying, and the drying time is 3 to 12 hours.

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