A crystalline form of cinoxamate and a method of preparing the same

Abstract

The present application relates to a crystal form of cinoxamate and a preparation method thereof. The cinoxamate crystal form prepared by the present application has good stability, small hygroscopicity and high solubility, is convenient for long-term storage of drugs, is simple to produce and operation, and meets the needs of industrial mass production.

Description

TECHNICAL FIELD

[0001] The present application relates to a crystal form of Cenobamate and a preparation method thereof. BACKGROUND

[0002] Cenobamate is a sodium channel blocker developed and marketed by SK Biopharmaceuticals, a Korean company, and its US subsidiary, SK Life Sciences. It is a positive allosteric modulator of the gamma-aminobutyric acid (GABAA) ion channel and a presynaptic GABA release enhancer. It was approved by the FDA in 2019 for the treatment of partial-onset seizures in adult patients.

[0003]

[0004] The compound patent US7598279 of SK Biopharmaceuticals discloses a synthetic route of Cenobamate, and the synthetic product is recrystallized with dichloromethane and diethyl ether (1:1), but the patent document does not disclose the crystal form information of Cenobamate, nor does it disclose any characterization data, stability, and drugability information of the obtained crystal. The present application provides a crystal form of Cenobamate, which has good stability, high solubility, and low hygroscopicity, is suitable for industrial production, and has more market value and far-reaching practical significance. SUMMARY

[0005] The present application aims to overcome the shortcomings of the prior art and provide a crystal form of Cenobamate with good stability, high solubility, and low hygroscopicity.

[0006] The technical solution adopted by the present application to solve its technical problems is as follows:

[0007] In one aspect, the present application provides a crystal form of Cenobamate, which has characteristic peaks at diffraction angles (2θ) of 14.97±0.2°, 19.47±0.2°, 22.20±0.2°, 25.13±0.2°, and 25.78±0.2° in the X-ray powder diffraction pattern.

[0008] Preferably, the crystal form of Cenobamate has characteristic peaks at diffraction angles (2θ) of 12.51±0.2°, 14.97±0.2°, 19.47±0.2°, 22.20±0.2°, 25.13±0.2°, 25.78±0.2°, 26.00±0.2°, 28.62±0.2°, and 28.82±0.2° in the X-ray powder diffraction pattern.

[0009] More preferably, the crystalline cinoxamate of the present application has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2 theta) substantially the same as those shown in Figure 1.

[0010] The crystalline cinoxamate of the present application has an XRPD pattern comprising peaks at diffraction angles (2 theta) substantially the same as those shown in Figure 1. Figure 1 Preferably, the XRPD pattern of the crystalline cinoxamate is as shown in Figure 1. Figure 1

[0011] The crystalline cinoxamate of the present application has a DSC pattern comprising a characteristic peak at about 85 ± 5 °C (onset temperature).

[0012] Preferably, the DSC pattern of the crystalline cinoxamate further comprises a characteristic peak at about 203 ± 5 °C (onset temperature).

[0013] Further preferably, the DSC pattern of the crystalline cinoxamate comprises characteristic peaks at substantially the same temperatures as those shown in Figure 2. Figure 2 More preferably, the DSC pattern of the crystalline cinoxamate is as shown in Figure 2. Figure 2

[0014] Another aspect of the present application provides a method for preparing the crystalline cinoxamate, which is characterized in that it comprises the step of crystallizing cinoxamate in a mixed system of one or more solvents.

[0015] Preferably, the crystallization method comprises suspension stirring, heating and cooling, evaporation or anti-solvent addition.

[0016] Preferably, the solvent comprises a single or mixed system of alcohols, ethers, ketones, esters, aromatic hydrocarbons, halogenated hydrocarbons, nitrile, nitroalkanes, aliphatic hydrocarbons.

[0017] More preferably, the solvent is one or a mixture of dichloromethane, chloroform, ethyl acetate, acetonitrile, n-propanol, isopropanol, heptane, isopropyl ether, diethyl ether, methyl tert-butyl ether. DETAILED DESCRIPTION

[0019] ​​In the specification and claims of the present application, unless otherwise indicated, the scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. However, for better understanding of the present application, the definitions and explanations of some relevant terms are provided below. In addition, when the definitions and explanations of the terms provided in the present application are inconsistent with the meanings commonly understood by one of ordinary skill in the art, the definitions and explanations of the terms provided in the present application shall prevail.

[0020] The "X-ray powder diffraction pattern or XRPD" described in the present application refers to a set of X-ray powder diffraction patterns that can be measured when X-rays are incident on a certain atomic plane of a crystal or part of a crystal sample with a d interplanar spacing at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle), which satisfies the Bragg equation 2d sinθ = nλ (where λ is the wavelength of X-rays, and the order of diffraction n is any positive integer, generally taking the first order diffraction peak, n = 1).

[0021] The "differential scanning calorimetry or DSC" described in the present application refers to measuring the temperature difference and heat flow difference between the sample and the reference during the heating or constant temperature process of the sample, to characterize all physical and chemical changes related to thermal effects, and to obtain the phase transition information of the sample.

[0022] The "2θ or 2θ angle" described in the present application refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, the error range of 2θ is ± 0.1 ~ ± 0.5, preferably ± 0.1 ~ ± 0.3, more preferably ± 0.2.

[0023] Through the above technical scheme, compared with the prior art, the present application has the following beneficial effects:

[0024] The crystal form provided by the present application has good stability, solubility and low hygroscopicity;

[0025] The preparation method of the crystal form provided by the present application is simple and has good repeatability, the solvent is not easy to remain, and the process is controllable, which is suitable for direct industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 is the XRPD pattern of the crystalline cinnoxicam described in the present application;

[0027] Figure 2 is the DSC pattern of the crystalline cinnoxicam described in the present application. DETAILED DESCRIPTION

[0028] The present application will be explained in more detail below with examples, which are only used to illustrate the technical solutions of the present application, and do not limit the essence and scope of the present application.

[0029] ​In the following examples, the experimental methods were generally performed according to the conventional conditions or the conditions recommended by the manufacturers; the cinnoxicam was prepared by the method of patent US7598279.

[0030] Test instruments used in the experiments:

[0031] 1. Differential Scanning Calorimeter (DSC)

[0032] Instrument model: Mettler Toledo DSC 3+ STARe System

[0033] Purging gas: nitrogen

[0034] Temperature rate: 10.0°C / min

[0035] Temperature range: 25-350

[0036] 2. X-ray Powder Diffraction (XRPD)

[0037] Instrument model: Bruker D8 Discover A25 X-ray powder diffractometer

[0038] Ray: monochromatic Cu-Ka ray (λ = 1.5406)

[0039] Scanning mode: θ / 2θ, scanning range: 10-48°

[0040] Voltage: 40KV, current: 40mA

[0041] Example 1: Take 10g of cinnoxicam and add it to a 100ml flask, add 50ml of acetonitrile, heat, reflux, filter, cool the filtrate, filter, wash the filter cake, and dry under reduced pressure to obtain 8.8g of solid. The solid was subjected to XRPD detection, and the obtained XRPD spectrum is shown in Figure 1 The solid was subjected to DSC detection, and the obtained DSC spectrum is shown in Figure 2 The test showed that its DSC spectrum contains a characteristic peak at 85±5°C (starting temperature).

[0042] Example 2: Take 10g of cinnoxicam and add it to a 100ml flask, add 30ml of ethyl acetate, heat, reflux, filter, cool the filtrate, filter, wash the filter cake, and dry under reduced pressure to obtain 8.9g of solid. The solid was subjected to XRPD detection, and the obtained XRPD spectrum is basically the same as Figure 1

[0043] ​Example 3: Cinoxamate 10 g was added into a 100 ml flask, 10 ml of isopropyl alcohol was added, heated, refluxed, filtered, the filtrate was cooled, filtered, the filter cake was washed, and dried under reduced pressure to obtain 7.9 g of solid. The solid was subjected to XRPD detection, and the obtained XRPD spectrum was substantially the same as that of the crystal form of cinoxamate prepared in Example 1. Figure 1 Example 2.

[0044] Example 4: Cinoxamate 10 g was added into a 100 ml flask, 10 ml of isopropyl alcohol and 20 ml of heptane were added, heated, refluxed, filtered, the filtrate was cooled, filtered, the filter cake was washed, and dried under reduced pressure to obtain 9.5 g of solid. The solid was subjected to XRPD detection, and the obtained XRPD spectrum was substantially the same as that of the crystal form of cinoxamate prepared in Example 1. Figure 1 Example 2.

[0045] Example 5: Cinoxamate 10 g was added into a 100 ml flask, 20 ml of chloroform was added, heated, refluxed, filtered, the filtrate was cooled, filtered, the filter cake was washed, and dried under reduced pressure to obtain 9.2 g of solid. The solid was subjected to XRPD detection, and the obtained XRPD spectrum was substantially the same as that of the crystal form of cinoxamate prepared in Example 1. Figure 1 Example 2.

[0046] Example 6: Water solubility determination

[0047] Water solubility (according to the requirements of the Chinese Pharmacopoeia), specific operation: the test sample ground into fine powder was placed in a solvent of a certain volume at 25°C, and was shaken vigorously for 30 s every 5 min, and the dissolution was observed within 30 min. If no visible solute particles were observed, it was considered to be completely dissolved. The measurement results are shown in Table 1.

[0048] Table 1: Solubility of cinoxamate crystal

[0049]

[0050] The solubility test showed that the solubility of the cinoxamate crystal of the present application in water was significantly improved compared with the crystal form prepared in patent US7598279.

[0051] Example 7: Hygroscopicity investigation test

[0052] The test product was placed in a clean crucible and laid flat in an open state, and the mass increase percentage was checked under the condition of 25°C and 20% relative humidity. If the weight gain was less than 0.01% within 15 min, the humidity was increased by 10% successively, and the highest humidity was 80%. If the weight gain was greater than 0.01% within 15 min successively, the humidity was maintained for 90 min. The measurement results are shown in Table 2.

[0053] Table 2: Hygroscopicity of cinoxamate crystal

[0054]

[0055] The results show that the hygroscopicity of the crystalline form of the present application is significantly less than that of the crystalline form prepared in patent US7598279. Therefore, the crystalline form of the present application has significant progress.

[0056] Example 8 Stability of the crystalline form

[0057] The crystalline form prepared in each example of the present application was placed in room temperature dry and room temperature high humidity (70% relative humidity) conditions for 14 days, and samples were taken at 1 day, 7 days, and 14 days for detection of the crystalline form, and the detection results are shown in Table 3.

[0058] Table 3 Stability of the crystalline form of PF-06651600 salt

[0059]

[0060] The results show that under room temperature high humidity (70% relative humidity) conditions for 14 days, the crystallinity of the crystalline form of the present application does not change, and the crystalline form prepared in patent US7598279 is reduced.

[0061] Those skilled in the art can understand that, unless otherwise defined, all terms (including technical terms and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It should also be understood that terms such as those defined in a general dictionary should be understood to have meanings consistent with meanings in the context of the present technology, and should not be interpreted with idealized or overly formal meanings unless otherwise defined as such.

[0062] The meaning of "and / or" described in the present application means that each individual existence or both existences are included.

[0063] Based on the above ideal embodiments according to the present application, through the above description, relevant personnel can make various changes and modifications without deviating from the technical idea of the present application. The technical scope of the present application is not limited to the contents of the specification, and the technical scope must be determined according to the scope of the claims.

Claims

1. A crystalline form of cinuoamine, wherein the crystalline form of cinuoamine exhibits characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 12.51±0.2°, 14.97±0.2°, 19.47±0.2°, 22.20±0.2°, 25.13±0.2°, 25.78±0.2°, 26.00±0.2°, 28.62±0.2°, and 28.82±0.2°.

2. The crystalline form of cinnoamino ester as described in claim 1, characterized in that, The crystalline form of the cinnouryl ester exhibits characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 12.51±0.2°, 13.78±0.2°, 14.97±0.2°, 16.42±0.2°, 17.13±0.2°, 18.47±0.2°, 19.47±0.2°, 21.10±0.2°, 22.20±0.2°, 25.13±0.2°, 25.78±0.2°, 26.00±0.2°, 28.62±0.2°, and 28.82±0.2°.

3. The cinnoamino ester crystal as described in claim 1, characterized in that, The XRPD pattern of the crystal includes a peak at a diffraction angle of 2θ that is substantially the same as that shown in Figure 1.

4. The cinnoamino ester crystal as described in claim 1, characterized in that, The XRPD pattern of the crystal is shown in Figure 1.

5. The crystal of cinuoamine as described in any one of claims 1 to 4, wherein the DSC spectrum of the crystal includes a characteristic peak at a starting temperature of 85 ± 5 °C.

6. The crystal of cinuoamine as described in claim 5, wherein the DSC spectrum of the crystal further includes a characteristic peak at a starting temperature of 203±5℃.

7. The crystal of cinuoamine as described in claim 6, wherein the DSC spectrum of the crystal includes characteristic peaks at substantially the same temperatures as shown in Figure 2.

8. The crystal of cinuoamine as described in claim 7, wherein the DSC spectrum of the crystal of the compound is shown in Figure 2.

9. The method for preparing cinnoamino ester crystals according to any one of claims 1 to 8, characterized in that, The method includes crystallizing cinnoamino ester in a mixture of one or more solvents, wherein the crystallization method includes suspension stirring, heating and cooling, evaporation or anti-solvent addition, and the solvent is one or a mixture of several solvents such as dichloromethane, chloroform, ethyl acetate, acetonitrile, n-propanol, isopropanol, heptane, isopropyl ether, diethyl ether, and methyl tert-butyl ether.

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