Melogabalin-oxalic acid crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a melogabalin-oxalic acid crystal form and a preparation method thereof. According to the crystal form, two molecules of melogabalin and one molecule of oxalic acid form a basic structural unit, so that the stability and solubility of melogabalin are improved; the preparation method is simple and easy to operate, and is expected to realize industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a melogabalin-oxalic acid crystal form and a preparation method thereof. Background Art

[0002] Melegabalin is a novel analgesic that selectively binds to the α2δ-1 subunit of voltage-gated calcium channels, inhibiting calcium influx and reducing the release of excitatory neurotransmitters in the central nervous system, such as glutamate and substance P, thereby relieving neuropathic pain. Melegabalin, developed by Daiichi Sankyo, was approved in Japan on January 8, 2019, for the treatment of peripheral neuropathy pain, including diabetic peripheral neuropathy and postherpetic neuralgia.

[0003] The melogabalin in the marketed dosage form is melogabalin besylate, with CAS number 1138245-21-2. It is a white to slightly yellowish white powder, slightly soluble in 1,3-dimethyl-2-imidazolidinone, methanol, ethanol and water, poorly soluble in acetone, almost insoluble in acetonitrile, and extremely poorly soluble in anisole and methyl tert-butyl ether; it has poor stability and needs to be stored below 30°C and away from light.

[0004] CN201480001374.3 discloses a solid composition of an aminocarboxylate. Due to stability issues during the preparation and storage of melogabalin besylate, it produces related substances under various conditions, affecting the therapeutic effect. This patent utilizes a pharmaceutical solid composition consisting of Compound (I) with D-mannitol, carboxymethylcellulose calcium, and magnesium stearate, and produces stabilized tablets via direct extrusion, ensuring that the amount of related substances is 3% or less under specific conditions.

[0005] CN201680016043.6 discloses a solid preparation of melogabalin besylate containing a colorant, which is obtained by using a combination of titanium dioxide and one or two or more other colorants, adding the colorant to a coating agent, and then coating.

[0006] CN201680016044.0 discloses a stable pharmaceutical solid preparation of melogabalin besylate, comprising melogabalin besylate, an excipient, a disintegrant and a specific antioxidant. The stability of melogabalin besylate is improved by screening a specific oxidant.

[0007] CN201980023976.1 discloses a solid pharmaceutical preparation of melogabalin besylate containing a stabilizer, which improves the stability of melogabalin besylate by adding a combination of citric anhydride or citric acid hydrate and α-tocopherol as a stabilizer to the prescription.

[0008] The stability of active pharmaceutical ingredients is crucial to the efficacy and safety of drugs. The stability of melogabalin besylate in formulations has always been a widespread concern. Although existing formulation technologies can improve the stability of melogabalin besylate to a certain extent, such as by adjusting the formulation formula and optimizing process parameters, these methods often require complex process flows and high production costs, and may have adverse effects on the bioavailability of the drug and patient compliance. In addition, formulation technology cannot fundamentally improve the structural stability of the raw materials themselves, and therefore cannot completely solve the stability problem of the API.

[0009] How to fundamentally solve the stability problem of melogabalin besylate, how to explore new synthesis methods or structural modification strategies, improve the quality and efficacy of melogabalin drugs, reduce production costs, and provide patients with safer and more effective treatment options have become technical problems that need to be solved urgently. Summary of the Invention

[0010] In view of the shortcomings of the existing technology, the present invention provides a melogabalin-oxalic acid crystalline form, which comprises two melogabalin molecules and one oxalic acid molecule as its basic structural unit. The present invention improves the stability and solubility of melogabalin. The present invention also provides a method for preparing the melogabalin-oxalic acid crystalline form, which is simple, easy to operate, and has the potential to be industrialized.

[0011] The technical solution of the present invention is: a melogabalin-oxalic acid crystal form, wherein the crystal form is composed of two melogabalin molecules and one oxalic acid molecule as a basic structural unit, and uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 7.5±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 24.6±0.2°, and 28.8±0.2°.

[0012] Preferably, the melogabalin-oxalic acid crystalline form uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 7.5±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 22.7±0.2°, 24.0±0.2°, 24.6±0.2°, 25.8±0.2°, 28.8±0.2°, and 31.0±0.2°.

[0013] Preferably, the characteristic peaks of the melogabalin-oxalic acid crystal form using Cu-Kα radiation conform to the following Figure 1 The X-ray powder diffraction pattern is shown.

[0014] Preferably, the melogabalin-oxalic acid crystal form has a molecular formula of C26 H 40 N2O8, crystallographic parameters are: monoclinic system, space group is P21, unit cell parameters are: a=6.3700(3), b=22.3389(11), c=9.7567(4), α=90°, β=98.869(4)°, γ=90°, unit cell volume V=1371.77(11).

[0015] In another aspect, the present invention provides a method for preparing a melogabalin-oxalic acid crystalline form, comprising the following steps:

[0016] Melogabalin and oxalic acid are dissolved in a mixed solvent, heated and stirred, filtered, cooled and crystallized, filtered and dried to obtain a melogabalin-oxalic acid crystal form.

[0017] Preferably, in the preparation method, the molar ratio of melogabalin to oxalic acid is 2:0.9-2.3; more preferably 2:1.2.

[0018] Preferably, in the preparation method, the mass-to-volume ratio of melogabalin to the mixed solvent is 14:1-3; more preferably 14:1.5, wherein the mass is in mg and the volume is in mL.

[0019] Preferably, in the preparation method, the mixed solvent is selected from a mixed solvent of ethanol and other solvents, and the other solvent is selected from one of acetone, water or trifluoroethanol.

[0020] Further preferably, in the preparation method, the mixed solvent is a mixed solvent of ethanol and acetone.

[0021] Further preferably, in the preparation method, the volume ratio of ethanol to other solvents in the mixed solvent is 2 to 3:1.

[0022] Preferably, in the preparation method, the heating temperature is 40-50°C, preferably 45°C.

[0023] In the preparation method, the cooling and crystallization temperature is 0-30°C, preferably, the cooling and crystallization temperature is 10-15°C.

[0024] In the preparation method, the crystallization time is 8 to 72 hours.

[0025] In the preparation method, the drying temperature is 45 to 65° C., and the drying time is 8 to 12 hours.

[0026] In the preparation method, the raw material melogabalin can be prepared according to any method in the prior art or purchased as a commercial product.

[0027] In a third aspect, the present invention provides a pharmaceutical composition comprising the melogabalin-oxalic acid crystalline form of the present invention and other pharmaceutically feasible components.

[0028] Preferably, the other pharmaceutically acceptable components may be active pharmaceutical ingredients that can be used in combination and / or pharmaceutically acceptable auxiliary ingredients.

[0029] Confirmation of crystal structure

[0030] X-ray crystallographic data for the melogabalin-oxalic acid crystal form described in the present invention were collected on a Rigaku XtaL ABSynergy instrument at a temperature of 293(2)K using Cu-Ka radiation, with data collected in an ω scan mode and Lp correction performed. The structure was solved using a direct method, with the difference Fourier transform method identifying all non-hydrogen atoms. All hydrogen atoms on carbon and nitrogen were obtained using theoretical hydrogenation, and the structure was refined using the least squares method.

[0031] The crystallographic data of the melogabalin-oxalic acid crystal form prepared by the present invention (as shown in Table 1) are: monoclinic crystal system, space group is P21, unit cell parameters are: a=6.3700(3), b=22.3389(11), c=9.7567(4), α=90°, β=98.869(4)°, γ=90°, unit cell volume V=1371.77(11).

[0032] Table 1 Main crystallographic data of melogabalin-oxalic acid crystal form

[0033]

[0034]

[0035] The ORTEP diagram of the melogabalin-oxalic acid crystal form of the present invention shows that the crystalline form contains two molecules of melogabalin and one molecule of oxalic acid, as shown in the attached figure. Figure 2 The hydrogen bond diagram of melogabalin-oxalic acid of the present invention is shown in the attached figure. Figure 3 According to the above crystallographic data, the corresponding characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) are shown in the attached Figure 1 And Table 2.

[0036] Table 2 PXRD peaks of melogabalin-oxalic acid crystal form

[0037]

[0038]

[0039] In the specific embodiment of the present invention, the melogabalin-oxalic acid crystal samples prepared in Examples 1 to 5 all have the same crystallographic parameters and X-ray powder diffraction spectra as mentioned above.

[0040] Compared with the prior art, the technical effects achieved by the present invention are:

[0041] (1) The melogabalin-oxalic acid crystal form provided by the present invention has a simple preparation method, easy control of the crystallization process, good reproducibility, high purity and high yield;

[0042] (2) The crystal form prepared by the present invention utilizes the amino group in melogabalin and the reducing oxalic acid to form a new crystal form, thereby improving the stability and antioxidant properties of melogabalin;

[0043] (3) The crystalline form prepared by the present invention has good solubility and can effectively improve the bioavailability of melogabalin. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 .PXRD spectrum of the melogabalin-oxalic acid crystal form obtained in Example 1.

[0045] Figure 2 . ORTEP diagram of the melogabalin-oxalic acid crystal form obtained in Example 1.

[0046] Figure 3 .Hydrogen bond diagram of the melogabalin-oxalic acid crystal form obtained in Example 1. DETAILED DESCRIPTION

[0047] The following specific embodiments are listed to further illustrate the present invention, but do not limit the scope of the present invention in any way. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0048] Example 1

[0049] 418.6 mg of melogabalin (C 12 H 19 NO2) and 108.0 mg of oxalic acid were dissolved in a mixed solvent of 15.0 mL of acetone and 30.0 mL of ethanol, heated in a water bath at 45°C with stirring until completely dissolved, filtered while hot, cooled to 15°C for crystallization for 50 h, filtered, and dried at 50°C for 10 h to obtain melogabalin-oxalic acid crystalline form with a yield of 96.2% and a purity of 99.95%.

[0050] Example 2

[0051] 418.6 mg of melogabalin and 81.0 mg of oxalic acid were dissolved in a mixed solvent of 10.0 mL of water and 20.0 mL of ethanol, heated in a water bath at 40°C with stirring until completely dissolved, filtered while hot, cooled and crystallized at 0°C for 8 hours, filtered, and dried at 45°C for 12 hours to obtain melogabalin-oxalic acid crystalline form with a yield of 95.9% and a purity of 99.97%.

[0052] Example 3

[0053] 418.6 mg of melogabalin and 207.1 mg of oxalic acid were dissolved in a mixed solvent of 22.5 mL of trifluoroethanol and 67.5 mL of ethanol, heated in a water bath at 50°C with stirring until completely dissolved, filtered while hot, cooled to 30°C for crystallization for 72 h, filtered, and dried at 65°C for 8 h to obtain melogabalin-oxalic acid crystalline form with a yield of 97.3% and a purity of 99.93%.

[0054] Example 4

[0055] 418.6 mg of melogabalin (C 12 H 19 NO2) and 324.0 mg of oxalic acid were dissolved in a mixed solvent of 15.0 mL of acetone and 30.0 mL of ethanol, heated in a water bath at 45°C with stirring until completely dissolved, filtered while hot, cooled to 15°C for crystallization for 50 h, filtered, and dried at 50°C for 10 h to obtain melogabalin-oxalic acid crystalline form with a yield of 85.2% and a purity of 99.90%.

[0056] Example 5

[0057] 418.6 mg of melogabalin (C 12 H 19 NO2) and 108.0 mg of oxalic acid were dissolved in a mixed solvent of 60.0 mL of acetone and 120.0 mL of ethanol, heated in a water bath at 45°C with stirring until completely dissolved, filtered while hot, cooled to 15°C for crystallization for 50 h, filtered, and dried at 50°C for 10 h to obtain melogabalin-oxalic acid crystalline form with a yield of 89.7% and a purity of 99.91%.

[0058] Example 6

[0059] The melogabalin-oxalic acid crystalline form (439.0 g, calculated as melogabalin) obtained in Example 1, 8.35 kg of D-mannitol, and 1 kg of carboxymethylcellulose calcium were placed in a V-type mixer and stirred for 5 minutes. 200.0 g of magnesium stearate was added and mixing was continued for 3 minutes. The tablets were compressed to a tablet weight of 100 mg. The tablets were coated with OPADRY coating solution (the coating solution was composed of 488 g of OPADRY, 360 g of hypromellose, 58 g of titanium dioxide, and 70 g of talc, which were dispersed in purified water to obtain a coating solution). After coating, coated tablets were obtained.

[0060] Comparative Example 1

[0061] Melegabalin (8.0 g) was dissolved in anisole (156 mL), and then benzenesulfonic acid (6.29 g) dissolved in anisole (20 mL) was added dropwise thereto under controlled dropping speed for 2 h. After the addition, anisole (8 mL) was added to the suspension, and the mixture was stirred at room temperature for 1.5 h. Acetone (40 mL) was then added, and the mixture was further stirred for 1.5 h, and then cooled to 2° C. The suspension was filtered, and the separated solid was washed with cooled acetone (28 mL) and dried under reduced pressure to obtain the desired melogababalin benzenesulfonate Form I with a yield of 93.7% and a purity of 99.92%.

[0062] Comparative Example 2

[0063] The melogabalin besylate - Form I (439.0 g, calculated as melogabalin) obtained in Comparative Example 1, 8.35 kg of D-mannitol, 1 kg of carboxymethylcellulose calcium, and 100.0 g of butylated hydroxytoluene were placed in a V-type mixer and stirred for 5 minutes. 200.0 g of magnesium stearate was added and mixing was continued for 3 minutes. The tablets were compressed to a tablet weight of 100 mg. The tablets were coated with OPADRY coating solution (the coating solution was composed of 488 g of OPADRY, 360 g of hypromellose, 58 g of titanium dioxide, and 70 g of talc, which were dispersed in purified water to obtain a coating solution) to obtain coated tablets.

[0064] Comparative Example 3

[0065] The melogabalin besylate - Form I (439.0 g, calculated as melogabalin) obtained in Comparative Example 1, 8.35 kg of D-mannitol, and 1 kg of carboxymethylcellulose calcium were placed in a V-type mixer and stirred for 5 minutes. 200.0 g of magnesium stearate was added and mixing was continued for 3 minutes. The tablets were compressed to a tablet weight of 100 mg. The tablets were coated with OPADRY coating solution (wherein the coating solution comprises 488 g of OPADRY, 360 g of hypromellose, 58 g of titanium dioxide, and 70 g of talc, which are dispersed in purified water to obtain a coating solution) to obtain coated tablets.

[0066] Verification Example

[0067] Experimental Example 1 Solubility Investigation

[0068] The solubility of the melogabalin crystals obtained in Example 1 and Comparative Example 1 in different media (water, pH 6.8 phosphate buffer) was determined. Determination method: 10 mL of the medium was measured and placed in a vial, and an excess of the sample to be tested was added. The vial was sealed and placed in a 25°C constant temperature water bath with stirring for 24 hours. The solution was filtered through a 0.45 μm filter membrane, and the filtrate was used to determine the sample content in the saturated solution by high performance liquid chromatography (HPLC). The results are shown in Table 1 below:

[0069] Table 1 Solubility of melogabalin crystals in different media

[0070]

[0071] The results show that the melogabalin-oxalic acid crystal form prepared by the present invention has good solubility, which helps to improve the bioavailability of melogabalin.

[0072] Experimental Example 2 Investigation of Crystal Stability

[0073] The melogabalin crystals obtained in Example 1 of the present invention and Comparative Example 1 were tested under high temperature (60° C.), high humidity (25° C., relative humidity 90±5%), and strong light irradiation (illuminance 4500±500 lx) and left open for 10 days. The specific test results are shown in Table 2.

[0074] Table 2 Stability test results of samples

[0075]

[0076]

[0077] The results show that the melogabalin oxalic acid crystal prepared by the present invention has a low content of related substances and good stability in high temperature, high humidity and strong light irradiation experiments; while the melogabalin benzenesulfonate crystal form I obtained in the comparative example has poor stability.

[0078] Experimental Example 3: Stability Study of the Preparation

[0079] The tablets obtained in Example 6 of the present invention and Comparative Examples 2-3 were placed under different temperature and humidity conditions and left open for 3 months. The contents of related substances were measured. The results are shown in Table 3 below.

[0080] Table 3 Stability test results of the preparations

[0081]

[0082] The results show that the stability of Comparative Example 2, which adds the antioxidant butylated hydroxytoluene, is higher than that of Comparative Example 3, which does not add the antioxidant. However, the present invention uses tablets containing melogabalin-oxalic acid crystals and does not add an antioxidant in the formulation, but still has high stability.

Claims

1. A melogabalin-oxalic acid crystal form, characterized in that: The crystal form comprises two molecules of melogabalin and one molecule of oxalic acid as basic structural units.

2. The crystal form according to claim 1, wherein The crystal form uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at at least 7.5±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 24.6±0.2°, and 28.8±0.2°.

3. The crystal form according to claim 1, wherein The crystal form uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 7.5±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 22.7±0.2°, 24.0±0.2°, 24.6±0.2°, 25.8±0.2°, 28.8±0.2°, and 31.0±0.2°.

4. The crystal form according to claim 1, wherein The crystal form uses Cu-Kα radiation, and its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 1.

5. The crystal form according to claim 1, wherein The crystal form has the molecular formula C 26 H 40 N2O8, crystallographic parameters are: monoclinic system, space group is P21, unit cell parameters are: a=6.3700(3), b=22.3389(11), c=9.7567(4), α=90°, β=98.869(4)°, γ=90°, unit cell volume V=1371.77(11).

6. A method for preparing the crystal form according to claim 1, characterized in that: The method comprises the following steps: dissolving melogabalin and oxalic acid in a mixed solvent, heating and stirring, filtering, cooling and crystallizing, filtering and drying to obtain a melogabalin-oxalic acid crystal form.

7. The method according to claim 6, wherein In the method, the molar ratio of melogabalin to oxalic acid is 2:0.9-2.

3.

8. The method according to claim 6, wherein In the method, the mixed solvent is selected from a mixed solvent of ethanol and other solvents, and the other solvent is selected from one of acetone, water or trifluoroethanol.

9. The method according to claim 6, wherein In the method, the mass volume ratio of melogabalin to the mixed solvent is 14:1-3.

10. The method according to claim 6, wherein In the method, the volume ratio of ethanol to other solvents in the mixed solvent is 2 to 3:1.

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