Melogabalin-malic acid crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel melogabalin crystal form and a preparation method thereof. The novel crystal form provided by the invention is a melogabalin-malic acid eutectic crystal, contains one molecule of melogabalin, one molecule of malic acid and a basic unit of a crystal form, has beneficial effects in the aspects of stability, solubility, permeability and the like, and has relatively remarkable progress in comprehensive performance compared with a melogabalin crystal form reported in the prior art; the composition is more suitable for pharmaceutical preparations.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and relates to a new crystal form of mirogabalin, in particular, mirogabalin malate and a preparation method and application thereof. BACKGROUND

[0002] Mirogabalin, with a chemical name of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid, English name: Mirogabalin, and a structural formula as follows:

[0003]

[0004] Mirogabalin is created by the Japanese pharmaceutical company DAIICHI SANKYO COMPANY, LTD., and is an alpha2delta-1 ligand for the treatment of peripheral neuropathic pain (PNP), which can be preferentially and selectively combined with the alpha2delta-1 subunit of voltage-dependent calcium channels (1 and 2), has unique binding properties and long-acting effects. DPNP is a disease that can cause peripheral neuropathy and numbness, and is one of the three most common long-term complications of diabetes, and its symptoms include severe pain, hyperalgesia, numbness, impaired balance and muscle movement, burning and stabbing pain, and the pain often worsens at night and can cause sleep disorders.

[0005] At present, mirogabalin is mainly mirogabalin benzenesulfonate, and has good clinical effects, but also has application defects. When used at a normal therapeutic dose, a series of adverse reactions such as digestive system reactions such as nausea, vomiting, and diarrhea, and allergic reactions occur. In order to add more salt crystal forms and change the related side effects of mirogabalin, it is important to adjust the solubility and dissolution rate for different administration routes. SUMMARY

[0006] The purpose of the present application is to provide a mirogabalin pharmaceutical co-crystal and a preparation method thereof to solve the problems in the above background art in view of the defects of the prior art. The present application aims to provide a new crystal form of mirogabalin with low hygroscopicity, i.e., a mirogabalin-malate crystal form. In addition, the present application provides a method for preparing the mirogabalin-malate crystal form, which is simple, convenient and suitable for industrial production.

[0007] The specific technical content of the present application is as follows:

[0008] In one aspect, the present application provides a mirogabalin-malate crystal form, characterized in that the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation has characteristic peaks at least at 6.7±0.2°, 13.1±0.2°, 19.6±0.2°, 19.9±0.2°, 20.3±0.2°, and 21.1±0.2°.

[0009] Preferably, the X-ray diffraction spectrum of the meloxicam-malic acid crystal form, using Cu-Ka radiation, has characteristic peaks at at least 6.7±0.2°, 13.1±0.2°, 14.6±0.2°, 15.7±0.2°, 17.3±0.2°, 17.8±0.2°, 18.6±0.2°, 19.6±0.2°, 19.9±0.2°, 20.3±0.2°, 21.1±0.2°, 23.0±0.2°, 23.6±0.2°, 24.1.5±0.2°, 26.6±0.2°, 28.9±0.2°, 35.9±0.2°, 37.6±0.2°.

[0010] Preferably, the X-ray diffraction spectrum of the meloxicam-malic acid crystal form, using Cu-Ka radiation, has characteristic peaks at at least 6.7±0.2°, 13.1±0.2°, 14.6±0.2°, 15.7±0.2°, 17.3±0.2°, 17.8±0.2°, 18.6±0.2°, 19.6±0.2°, 19.9±0.2°, 20.3±0.2°, 21.1±0.2°, 23.0±0.2°, 23.6±0.2°, 24.1.5±0.2°, 26.6±0.2°, 28.9±0.2°, 35.9±0.2°, 37.6±0.2°. Figure 1

[0011] Preferably, the meloxicam-malic acid crystal form has the molecular formula of C 32 H 50 N2O 14 , and the crystallographic parameters are: triclinic crystal system, space group P1, cell parameters: a=7.5300(5), b=9.6706(11), c=13.5207(10), α=94.856(8)°, β=91.500(6)°, γ=108.755(8)°, cell volume V=927.406(15).

[0012] In another aspect, the present application provides a method for preparing the meloxicam-malic acid crystal form, comprising the following steps:

[0013] The meloxicam and the malic acid crystal form are dissolved in a mixed solvent, heated and stirred, filtered, cooled and placed to volatilize and crystallize, filtered and dried to obtain the meloxicam-malic acid crystal form.

[0014] Preferably, the solvent is selected from the mixed solvent of acetonitrile and methanol, ethanol, water, acetone and trifluoroethanol, and particularly preferably the mixed solvent of acetonitrile and methanol.

[0015] Preferably, the mass-volume ratio of the meloxicam and the organic solvent is 11:0.8-3.0, in mg / mL; preferably 11:0.8-1.5, in mg / mL.

[0016] Preferably, the molar ratio of the meloxicam and the malic acid is 1:0.9-3.0, preferably 1:0.9-2.0.

[0017] Preferably, the heating temperature is 40-70°C, preferably 45°C. ​

[0018] The temperature for the temperature reduction crystallization is 0-30°C, preferably, the temperature for the temperature reduction crystallization is 10-15°C.

[0019] The drying temperature is 45-65°C, and the drying time is 8-12 hours.

[0020] The raw material meloxicam used in the preparation method can be prepared according to any method in the prior art or purchased from a commercially available product.

[0021] Finally, the present application provides a pharmaceutical composition containing the meloxicam-malic acid crystal form of the present application and other pharmaceutically acceptable components.

[0022] Preferably, the other pharmaceutically acceptable components can be a combination of a pharmaceutically active ingredient and / or a pharmaceutically acceptable excipient.

[0023] Confirmation of crystal structure

[0024] The X-ray crystal data of the meloxicam-malic acid crystal form of the present application in the test is collected on a Japan Rigaku XtaLAB Synergy model instrument, the test temperature is 293(2) K, Cu-Ka radiation is used, the data is collected in an omega scanning mode and Lp correction is performed. The structure is solved by a direct method, all non-hydrogen atoms are found by a difference Fourier method, all hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the structure is refined by a least squares method.

[0025] The crystallographic data of the meloxicam-malic acid crystal form of the present application prepared in the test and analysis (as shown in Table 1) is: triclinic crystal system, space group P1, cell parameters: a = 7.5300(5), b = 9.6706(11), c = 13.5207(10), α = 94.856(8) °, β = 91.500(6) °, γ = 108.755(8) °, cell volume V = 927.406(15).

[0026] Table 1 Main crystallographic data of meloxicam-malic acid crystal form

[0027]

[0028] The ORTEP diagram of the meloxicam-malic acid crystal form of the present application shows that the crystal form contains one molecule of meloxicam and one molecule of malic acid, as shown in the attached Figure 2 The hydrogen bond diagram of the meloxicam-malic acid of the present application is shown in the attached Figure 3 According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in the attached Figure 1 and Table 2.

[0029] Table 2 PXRD peaks of meloxicam-malic acid crystal form

[0030]

[0031]

[0032] Compared with the prior art, the present application has the following technical effects:

[0033] The present application provides a meloxicam-malic acid crystal form for the first time, which has simple operation, easy control of crystallization process and good reproducibility. The solubility of meloxicam can be significantly enhanced after the formation of the co-crystal, and the meloxicam-malic acid crystal form has strong drug value. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 . PXRD spectrum of meloxicam-malic acid crystal form.

[0035] Figure 2 . ORTEP diagram of meloxicam-malic acid crystal form.

[0036] Figure 3 . Hydrogen bond diagram of meloxicam-malic acid crystal form. DETAILED DESCRIPTION

[0037] The present application will be further described below by examples. It should be understood that the examples of the present application are only used to illustrate the present application, but not to limit the present application, so that simple improvements of the present application under the premise of the method of the present application are within the scope of the present application.

[0038] Example 1

[0039] Meloxicam (31.6 mg, 0.15 mmol) and malic acid (30.0 mg, 0.22 mmol) were dissolved in a mixed solvent of 10 mL of acetonitrile and 20 mL of methanol, and were heated in a water bath at 45°C and stirred by ultrasonic waves until completely dissolved. Filtration was performed, and the crystals were precipitated by volatilization at room temperature to obtain meloxicam-malic acid, with a yield of 97.2% and a purity of 99.96%.

[0040] Example 2

[0041] Meloxicam (31.6 mg, 0.15 mmol) and malic acid (18.8 mg, 0.14 mmol) were dissolved in a mixed solvent of 10 mL of acetonitrile and 13 mL of ethanol, and were heated in a water bath at 40°C and stirred by ultrasonic waves until completely dissolved. Filtration was performed, and the crystals were precipitated by volatilization at room temperature to obtain meloxicam-malic acid, with a yield of 94.3% and a purity of 99.60%.

[0042] Example 3

[0043] Meloxicam (31.6 mg, 0.15 mmol) and malic acid (60.3 mg, 0.45 mmol) were dissolved in 33 mL of acetonitrile and 55 mL of water mixed solvent, heated with ultrasonic stirring in 70 °C water bath until completely dissolved, filtered, and left to stand at room temperature to volatilize crystallization to obtain meloxicam-malic acid, yield: 95.2%, purity: 99.51%.

[0044] Example 4

[0045] Meloxicam (31.6 mg, 0.15 mmol) and malic acid (16.1 mg, 0.12 mmol) were dissolved in 8 mL of acetonitrile and 15 mL of acetone mixed solvent, heated with ultrasonic stirring in 38 °C water bath until completely dissolved, filtered, and left to stand at room temperature to volatilize crystallization to obtain meloxicam-malic acid, yield: 85.6%, purity: 98.56%.

[0046] Example 5

[0047] Meloxicam (31.6 mg, 0.15 mmol) and malic acid (64.3 mg, 0.48 mmol) were dissolved in 40 mL of acetonitrile and 60 mL of trifluoroethanol mixed solvent, heated with ultrasonic stirring in 75 °C water bath until completely dissolved, filtered, and left to stand at room temperature to volatilize crystallization to obtain meloxicam-malic acid, yield: 88.3%, purity: 98.02%.

[0048] Example 6

[0049] Meloxicam-malic acid crystal form obtained in Example 1 (439.0 g, calculated as meloxicam), 8.35 Kg of D-mannitol, and 1 Kg of carboxymethylcellulose calcium were placed in a V-type mixer, stirred and mixed for 5 min, 200.0 g of magnesium stearate was added, and the mixing was continued for 3 min; tabletting was performed, and the tablet mass was set to 100 mg; after coating with OPADRY coating liquid (wherein the components of the coating liquid are OPADRY 488 g, hydroxypropyl methylcellulose 360 g, titanium dioxide 58 g, talc 70 g, dispersed in purified water to obtain the coating liquid), coated tablets were obtained.

[0050] Comparative Example 1

[0051] Meloxicam (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 at a controlled dropping rate, the dropping time being 2 h; after the addition was completed, anisole (8 mL) was added to the suspension and the mixture was stirred at room temperature for 1.5 h; further, acetone (40 mL) was added and the mixture was stirred for 1.5 h and then cooled to 2°C; the suspension was filtered and the isolated solid was washed with cooled acetone (28 mL) and dried under reduced pressure to give the desired benzenesulfonic acid meloxicam Form I, in a yield of 93.7% and a purity of 99.92%.

[0052] Comparative Example 2

[0053] Benzenesulfonic acid meloxicam Form I (439.0 g, based on meloxicam) obtained in Comparative Example 1, 8.35 Kg D-mannitol, 1 Kg carboxymethylcellulose calcium, 100.0 g of dibutylhydroxytoluene were placed in a V-type mixer, mixed by stirring for 5 min, 200.0 g of magnesium stearate was added and mixing was continued for 3 min; the tablets were compressed, the tablet mass being set to 100 mg; after coating with OPADRY coating liquid (wherein the components of the coating liquid are OPADRY 488 g, hydroxypropylmethylcellulose 360 g, titanium dioxide 58 g, talc 70 g, dispersed in purified water to obtain the coating liquid), coated tablets were obtained.

[0054] Comparative Example 3

[0055] Benzenesulfonic acid meloxicam Form I (439.0 g, based on meloxicam) obtained in Comparative Example 1, 8.35 Kg D-mannitol, 1 Kg carboxymethylcellulose calcium were placed in a V-type mixer, mixed by stirring for 5 min, 200.0 g of magnesium stearate was added and mixing was continued for 3 min; the tablets were compressed, the tablet mass being set to 100 mg; after coating with OPADRY coating liquid (wherein the components of the coating liquid are OPADRY 488 g, hydroxypropylmethylcellulose 360 g, titanium dioxide 58 g, talc 70 g, dispersed in purified water to obtain the coating liquid), coated tablets were obtained.

[0056] Validation Example

[0057] 1.1 Stability Test

[0058] Test method: The test was carried out according to the method of <9001 Raw materials and preparation stability test guidelines> in Appendix IV of Chinese Pharmacopoeia (2020 edition). The meloxicam crystal forms obtained in Example 1 and Comparative Example 1 were evenly distributed in an open petri dish with a thickness of ≤5 mm, and the distance was adjusted to make the light intensity 4500±500Lx; the meloxicam crystal forms obtained in Example 1 and Comparative Example 1 were placed in a sealed clean glass bottle and placed in a 60℃ constant temperature drying oven; the meloxicam crystal forms obtained in Example 1 and Comparative Example 1 were evenly distributed in an open petri dish with a thickness of ≤5 mm and placed in a constant temperature and humidity incubator at room temperature (about 25℃) with a relative humidity of 92±5%. The sample was taken out for detection after 10 days, and the results are shown in Table 1.

[0059] Table 1: Results of light stability test of meloxicam crystal form

[0060] Placement conditions Placement time (days) Example 1 Comparative Example 1 Sample before placement 0 99.96％ 99.92％ High temperature test 10 99.92％ 99.82％ High humidity test 10 99.93％ 99.87％ Strong light irradiation test 10 99.92％ 99.75％

[0061] 1.2 Accelerated stability test

[0062] The meloxicam crystal forms obtained in Example 1 and Comparative Example 1 were sealed and packaged in polyethylene film plastic bags and placed in a constant temperature and humidity incubator at 40±2℃ and a relative humidity of 75±5%, and were placed for six months. The sample was taken out for detection at the end of 1, 2, 3 and 6 months, and the results are shown in Table 2.

[0063] Table 2: Results of accelerated stability test of meloxicam crystal form

[0064]

[0065] Through experiments, the meloxicam-malic acid crystal forms (Examples 1-5) prepared by the present application did not have a significant change in purity and appearance under the conditions of light, high temperature and high humidity, while the purity of the meloxicam crystal form-oxalate crystal form was greatly reduced under the same experimental conditions, and the impurity content was significantly increased. It can be seen that the crystal form prepared by the present application has good chemical stability.

[0066] 2. Solubility test

[0067] 10ml of medium (water and pH 6.8 phosphate buffer) was taken in a shirn bottle, and an excess of the sample to be tested was added. The shirn bottle was sealed and placed in a 25℃ constant temperature water bath for stirring for 30min. The water phase was filtered with a microporous filter membrane, and the filtrate was determined by high performance liquid chromatography to obtain the concentration of meloxicam in the solution, and the solubility was obtained. The results are shown in Table 3.

[0068] Table 3: Solubility of meloxicam crystal form in different media

[0069]

[0070] 3. Stability of the preparation

[0071] The tablets obtained in Example 6 and Comparative Examples 2-3 were placed in different temperature and humidity conditions, and left open for 3 months. The content of the related substances was determined, and the results are shown in Table 3.

[0072] Table 5 Stability test of the preparation

[0073]

[0074] It can be seen that the stability of Comparative Example 2, which contains the antioxidant dibutylhydroxytoluene, is higher than that of Comparative Example 3, which does not contain the antioxidant. The tablets of the present application contain the meloxicam-malic acid crystal form, and the formulation does not contain the antioxidant, and the stability is still high.

Claims

1. A crystalline form of meloxicam-malic acid characterized in that, The molar ratio of meloxicam and malic acid in the crystal unit structure is 1:

1.

2. The meloxicam-malic acid crystalline form according to claim 1, characterized in that, Cu-K α radiation, expressed in 2 θ X-ray powder diffraction expressed in 2Θ has characteristic diffraction peaks at 6.7 ± 0.2°, 13.1 ± 0.2°, 19.5 ± 0.2°, 19.9 ± 0.2°, 20.2 ± 0.2°, 21.1 ± 0.2°.

3. The meloxicam-malic acid crystalline form of claim 1, characterized in that, Cu-K α radiation, expressed in 2 θ X-ray powder diffraction expressed in 2Θ has diffraction peaks at 6.7 ± 0.2, 13.1 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 17.3 ± 0.2, 17.8 ± 0.2, 18.6 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.3 ± 0.2, 21.1 ± 0.2, 23.0 ± 0.2, 23.6 ± 0.2, 24.1.5 ± 0.2, 26.6 ± 0.2, 28.9 ± 0.2, 35.9 ± 0.2, 37.6 ± 0.2°.

4. The meloxicam-malic acid crystalline form of claim 1, characterized in that, The crystal form has an X-ray powder diffraction pattern as shown in Figure 1.

5. The meloxicam-malic acid crystalline form of claim 1, characterized in that, The crystallographic parameters are: triclinic crystal system, space group P1, cell parameters: a = 7.5300(5), b = 9.6706(11), c = 13.5207(10), alpha = 94.856(8) degrees, beta = 91.500(6) degrees, gamma = 108.755(8) degrees, and cell volume V = 927.406(15).

6. A process for the preparation of the crystalline form of the meloxicam-malic acid of any one of claims 1 to 5, characterized in that, The preparation method comprises the following steps: dissolving meloxicam and malic acid crystal form in a mixed solvent, heating and stirring, filtering, cooling and standing to volatilize and crystallize, filtering and drying to obtain meloxicam-malic acid crystal form.

7. The process for the preparation of the crystalline form of meloxicam-malic acid according to claim 6, characterized in that, The solvent is selected from the group consisting of acetonitrile and mixed solvents of methanol, ethanol, water, acetone and trifluoroethanol.

8. The process for the preparation of a crystalline form of meloxicam-malic acid according to claim 6, characterized in that, The mass-volume ratio of meloxicam and organic solvent is 11:0.8-3.0, in mg / mL.

9. The process for the preparation of a crystalline form of meloxicam-malic acid according to claim 6, characterized in that, The molar ratio of meloxicam and malic acid is 1:0.9-3.

0.

10. The process for the preparation of a crystalline form of meloxicam-malic acid according to claim 6, characterized in that, The heating temperature is 40-70 DEG C; and the cooling and crystallization temperature is 0-30 DEG C.

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