New crystal form of perampanel as well as preparation method and application thereof

Abstract

The invention aims to provide a novel crystal form of perampanel, a preparation method, a pharmaceutical composition and application of perampanel in preparation of drugs for treating nervous system diseases. Compared with the prior art, the crystal form provided by the invention has one or more improved properties, and is of great significance to further development of the medicine.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and in particular to a new crystal form of perampanel and a preparation method and application thereof. Background Art

[0002] Perampanel (Fycompa) is a non-competitive AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist developed by Eisai (Japan), which selectively inhibits postsynaptic AMPA glutamate receptors. It was approved for marketing by the FDA and EMA in 2012 and approved for marketing in China in 2019. It is suitable for the adjunctive treatment of partial epileptic seizures in adults and children aged 12 years and above (with or without secondary generalized epileptic seizures). The chemical name of Perampanel is: 3-(2-cyanophenyl-5-(2-pyridinyl)-1-phenyl-1,2-dihydropyridin-2-one, and the structural formula is as follows:

[0003]

[0004] Drug polymorphism refers to the different lattice arrangements formed by the orderly arrangement of chemical drug molecules in the microstructure, which is generally manifested as different forms of drug raw materials in the solid state. A drug can exist in multiple crystal forms. Different crystal forms of the same drug may show different physical or chemical properties. The study of drug polymorphism can discover the drug's dominant crystal form that is conducive to the drug's effect.

[0005] WO2006004100A discloses hydrated crystal forms and anhydrous crystal forms I, II, III and V of perampanel. The hydrated crystal form is selected as the crystal form of perampanel for marketed drugs due to its good stability. For polymorphic drugs, there is still a need to develop a more suitable crystal form for pharmaceutical use. Summary of the invention

[0006] One object of the present invention is to provide a new crystalline form of perampanel, named Form Z.

[0007] In some embodiments, the crystal form Z provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.1°±0.2°, 8.9°±0.2°, 16.8°±0.2°, 22.9°±0.2°, and 24.6°±0.2°.

[0008] In some embodiments, the crystal form Z provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.1°±0.2°, 8.9°±0.2°, 9.7°±0.2°, 15.6°±0.2°, 16.8°±0.2°, 22.9°±0.2°, 24.6°±0.2°, and 28.3°±0.2°.

[0009] In some embodiments, the present invention provides a crystalline form Z, characterized in that its X-ray powder diffraction pattern is as follows Figure 1 shown.

[0010] In some embodiments, the present invention provides a method for preparing the crystal form Z, which is characterized by comprising: dissolving the perampanel compound in an organic solvent, crystallizing after the solution is clear, and drying to obtain the crystal form Z.

[0011] In some preferred embodiments, in the preparation method, the organic solvent is acetone, butanone, dichloromethane, or N,N-dimethylformamide.

[0012] In some preferred embodiments, in the preparation method, the dissolving is performed by heating, and the crystallization is performed by cooling.

[0013] In other preferred embodiments, the preparation method further comprises the step of adding seed crystals after dissolving.

[0014] In some embodiments, the present invention provides a pharmaceutical composition comprising the perampanel crystalline form Z described in the present invention, and a pharmaceutically acceptable excipient.

[0015] In some embodiments, the present invention provides use of the perampanel crystal form Z of the present invention in the preparation of a medicament for a nervous system disease. Preferably, the disease is Parkinson's disease, multiple sclerosis or epilepsy.

[0016] In some embodiments, the present invention provides use of the perampanel crystal form Z prepared by the preparation method of the present invention in preparing drugs for nervous system diseases. Preferably, the disease is Parkinson's disease, multiple sclerosis or epilepsy.

[0017] In some embodiments, the present invention provides use of the pharmaceutical composition comprising perampanel form Z and a pharmaceutically acceptable excipient according to the present invention in the preparation of a medicament for a nervous system disease. Preferably, the disease is Parkinson's disease, multiple sclerosis or epilepsy. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is the X-ray powder diffraction pattern of the crystal form Z according to Example 1 of the present invention;

[0019] Figure 2 is a DSC graph of the crystal form Z according to Example 1 of the present invention;

[0020] Figure 3 is a TGA graph of the crystal form Z according to Example 1 of the present invention;

[0021] Figure 4 The high temperature (GW), high humidity (GS), and light irradiation (GZ) X-ray powder diffraction patterns according to Example 8 of the present invention;

[0022] Figure 5 This is the X-ray powder diffraction pattern after grinding (YM) according to Example 8 of the present invention.

[0023] Figure 6 It is the X-ray powder diffraction pattern of the crystal form of Comparative Example 1, Comparative Example 3 and Comparative Example 5 according to the present invention.

[0024] Figure 7 : This is the X-ray powder diffraction pattern of Form V according to Comparative Example 2 of the present invention.

[0025] Figure 8 It is the DSC graph of Form V according to Comparative Example 2 of the present invention.

[0026] Fig. 9 This is a TGA graph of Form V according to Comparative Example 2 of the present invention.

[0027] Fig.10 It is the X-ray powder diffraction pattern of Form VI according to Comparative Example 4 of the present invention.

[0028] Fig.11 This is the DSC graph of Form VI according to Comparative Example 4 of the present invention.

[0029] Fig.12 The TGA diagram of Form VI according to Comparative Example 4 of the present invention is

[0030] Fig.13 1 is the X-ray powder diffraction pattern of the crystal form Z before and after the solvent stability test according to Example 10 of the present invention.

[0031] Fig.14 1 is the X-ray powder diffraction pattern of Form V before and after the solvent stability test according to Example 10 of the present invention.

[0032] Fig.15 1 is the X-ray powder diffraction pattern of Form VI before and after the solvent stability test according to Example 10 of the present invention. DETAILED DESCRIPTION

[0033] The present invention is further described in detail by the following examples, which are not intended to limit the protection scope of the present invention.

[0034] Testing instruments and methods:

[0035] X-ray powder diffraction (XRPD) test method: instrument model: Empyrean, diffraction line: CuK (45KV, 50mA), scanning time: 30s, scanning range: 3°-30° (2θ), Soller slit: 0.04rad.

[0036] Differential Scanning Calorimetry (DSC) test method: Instrument model: DSC 214 Nevio; Heating rate: 10°C / min, Temperature range: 40°C-400°C, Atmosphere: N 2 .

[0037] Thermogravimetric analyzer (TGA) test method: Instrument model: Mettler TGA2; Heating rate: 10℃ / min, Temperature range: 30℃-500℃, Atmosphere: N 2 .

[0038] The perampanel compound can be obtained by commercial purchase or self-production. For example, it can be prepared by referring to the method described in the prior art patent CN01811052.5. The crystalline forms prepared in the embodiments and comparative examples of the present invention are all prepared using perampanel (Vphm0081222) purchased from MSN Company of India as raw materials, with a purity of 99.90%, a total impurity of 0.10%, and 6 impurities.

[0039] Example 1 Preparation of Form Z

[0040] Take 200 mg of the perampanel compound sample, add 4 mL of acetone thereto, dissolve at 55° C., cool down to crystallize, and dry naturally to obtain the compound.

[0041] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Figure 1 , 2 , 3. The DSC spectrum shows that the crystal form Z has an endothermic peak when heated to about 186.7°C. The TGA spectrum shows that the crystal form Z has no obvious weight loss at 30°C-200°C. The XRPD data are shown in Table 1.

[0042] Table 1

[0043]

[0044]

[0045] Comparative Example 1 Preparation of Hydrate Crystalline Form

[0046] According to the method described in Example B1 of patent CN1942443A (i.e., CN200580011565.9), hydrate crystals were prepared, and their XRPD powder diffraction pattern is shown in Figure 6 .

[0047] Comparative Example 2 Preparation of Type V Crystals

[0048] According to the method described in Example C1 of patent CN1942443A (i.e., CN200580011565.9), V-type crystals were prepared, and their XRPD powder diffraction pattern, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) were as follows: Figure 7 , 8 , 9. The DSC test spectrum shows an endothermic peak near 187.7°C. The TGA test spectrum shows no obvious weight loss at 30°C-200°C.

[0049] Comparative Example 3 Preparation of Type IV Crystals

[0050] Type IV crystals were prepared according to the method described in Example 1 of patent WO2007072868A1, and their XRPD powder diffraction pattern is shown in Figure 6 , after comparison, it is consistent with the XRPD powder diffraction pattern of the hydrate crystal form obtained in Comparative Example 1.

[0051] Comparative Example 4 Preparation of Type VI Crystals

[0052] According to the method described in Example 1 of patent WO2016172333A1, type VI crystals were prepared, and their XRPD powder diffraction spectrum, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) were as follows: Fig.10 , 11 , 12. The DSC test spectrum shows an endothermic peak near 178.8°C. The TGA test spectrum shows no obvious weight loss at 30°C-200°C.

[0053] Comparative Example 5 Preparation of Crystal 1 and Crystal 2

[0054] Crystal 1 and Crystal 2 were prepared according to the method described in Example 1 and Example 2 of Patent CN105566210A, and their XRPD powder diffraction patterns were shown in Figures 1 and 2. Figure 6 Crystal 1 and Crystal 2 in the above-mentioned embodiment are compared and their XRPD powder diffraction patterns are consistent with those of the hydrate crystal form obtained in Comparative Example 1.

[0055] Example 2 Preparation of Form Z

[0056] Take 200 mg of the perampanel compound sample, add 1 mL of N,N-dimethylformamide thereto, dissolve at room temperature, stand to precipitate solids, and dry naturally to obtain the compound. Its XRPD, DSC, and TGA spectra are basically the same as those in Example 1.

[0057] Example 3 Preparation of Form Z

[0058] Take 200 mg of the perampanel compound sample, add 1 mL of dichloromethane thereto, dissolve at room temperature, stand to precipitate solids, and dry naturally to obtain the compound. Its XRPD, DSC, and TGA spectra are basically the same as those in Example 1.

[0059] Example 4 Preparation of Form Z

[0060] Take 200 mg of the perampanel compound sample, add 4 mL of butanone thereto, dissolve at 78°C, cool to crystallize, and dry naturally to obtain the compound. Its XRPD, DSC, and TGA spectra are basically the same as those in Example 1.

[0061] Example 5 Preparation of Form Z

[0062] 2.00 g of the perampanel compound sample was placed in a 100 mL single-mouth bottle, 76 mL of acetone was added, the temperature was raised to reflux to dissolve, and when the temperature was lowered to 50° C., a crystal seed of Form Z was added, the mixture was stirred for 3 h, filtered, and dried naturally to obtain the compound. Its XRPD, DSC, and TGA spectra were basically the same as those in Example 1.

[0063] Example 6: Hygroscopicity Test

[0064] The hygroscopicity of the perampanel crystal form Z prepared by the present invention and the hydrate crystal form prepared according to CN200580011565.9 was investigated by a dynamic vapor sorption instrument (DVS), and the results are shown in Table 2. The results show that the crystal form Z has no hygroscopicity, and the hydrate crystal form has a certain hygroscopicity. The crystal form Z has lower hygroscopicity than the hydrate crystal form.

[0065] Table 2

[0066] Crystal form New crystal form Z Hydrate Moisture-induced weight gain 0.1851％ 0.4089％ Judgment result No hygroscopicity Slightly hygroscopic

[0067] Example 7 Solubility Experiment

[0068] The solubility of the perampanel crystal form Z prepared by the present invention, the hydrate crystal form prepared in Comparative Example 1, the V-type crystal prepared in Comparative Example 2, and the VI-type crystal prepared in Comparative Example 4 was investigated in water and different pH buffers (dissolution media are shown in Table 3), and the results are shown in Tables 4-5. The results show that the solubility of the crystal form Z is better than that of the hydrate crystal form, and is also better than that of the V-type anhydrate crystal and the VI-type crystal.

[0069] Table 3 Dissolution media

[0070] pH Dissolution medium 1.0 Hydrochloric acid solution 4.5 Acetate buffer 6.8 Phosphate buffered saline

[0071] Table 4

[0072]

[0073] Table 5

[0074]

[0075] Example 8 Stability Study

[0076] Investigation of influencing factors. The perampanel crystal form Z prepared by the present invention was placed under high temperature, high humidity and light conditions for 0, 5, 10 and 30 days, and whether crystal transformation occurred was investigated by XPRD. The results are as follows: Figure 4 And Table 6.

[0077] Table 6

[0078]

[0079] Grinding stability investigation. The perampanel crystal form Z prepared by the present invention was ground in an agate mortar at room temperature for 1 min, 3 min, 5 min, and 10 min, and XPRD detection was performed to investigate whether crystal transformation occurred. The results are as follows: Figure 5 And Table 7.

[0080] Table 7

[0081] Grinding time Crystal form 0min Crystal form Z 1min Crystal form Z 3min Crystal form Z 5min Crystal form Z 10min Crystal form Z

[0082] Example 9 Impurity Detection

[0083] The crystal forms prepared in the embodiments of the present invention and the comparative examples are all prepared using perampanel (Vphm0081222) purchased from MSN Company, India as a raw material, with a purity of 99.90%, a total impurity of 0.10%, and an impurity number of 6. The perampanel crystal form Z prepared by the present invention, the V-type crystal prepared in comparative example 2, and the VI-type crystal prepared in comparative example 4 were tested for impurities and compared with the perampanel starting raw materials used to prepare the above crystal forms. The results are shown in Table 8.

[0084] Table 8

[0085] Crystal form Total impurities content Number of impurities Perampanel Raw Materials 0.10％ 6 Crystal form Z 0.03％ 3 Crystalline Form V 0.04％ 4 Form VI 0.07％ 5

[0086] Example 10 Solvent Stability

[0087] The perampanel crystal form Z prepared by the present invention, the V-type crystal prepared by comparative example 2, and the VI-type crystal prepared by comparative example 4 were suspended and slurried in water and ethanol-water (1:1 v / v) at 60° C. for 3 hours, then filtered and evaporated, and the crystal form changes were detected by X-ray powder diffraction test. The results are as follows: Figure 13-15 and Table 9.

[0088] Table 9

[0089] Crystal form water Water-Ethanol Crystal form Z Untransformed Untransformed Crystalline Form V Transcrystal transformation occurs, transforming into hydrate crystal form Transcrystal transformation occurs, transforming into hydrate crystal form Form VI Untransformed Transcrystal transformation occurs, transforming into hydrate crystal form

Claims

1. A crystal form Z of perampanel, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.1°±0.2°, 8.9°±0.2°, 16.8°±0.2°, 22.9°±0.2°, and 24.6°±0.2°.

2. The crystal form Z according to claim 1, characterized in that Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.1°±0.2°, 8.9°±0.2°, 9.7°±0.2°, 15.6°±0.2°, 16.8°±0.2°, 22.9°±0.2°, 24.6°±0.2°, and 28.3°±0.2°.

3. The crystal form Z according to claim 1, characterized in that: Its X-ray powder diffraction pattern is basically consistent with that in FIG1 .

4. A method for preparing the crystal form Z according to any one of claims 1 to 3, characterized in that The method comprises dissolving the perampanel compound in an organic solvent, crystallizing after the solution is clear, and drying to obtain the product.

5. The preparation method according to claim 4, characterized in that: The organic solvent is selected from acetone, butanone, dichloromethane and N,N-dimethylformamide.

6. The preparation method according to claim 4, characterized in that: The dissolution is performed by heating, and the crystallization is performed by cooling.

7. The preparation method according to any one of claims 4 to 6, characterized in that: The method also includes the step of adding seed crystals after dissolving.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the crystal form according to any one of claims 1 to 3, and a pharmaceutically acceptable excipient.

9. Use of the crystal form according to any one of claims 1 to 3, the crystal form obtained by the preparation method according to any one of claims 4 to 7, and the pharmaceutical composition according to claim 8 in the preparation of drugs for nervous system diseases.

10. The use according to claim 9, characterized in that The disease is Parkinson's disease, multiple sclerosis or epilepsy.

Images