Meloabalin-fumaric acid crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a miloabalin-fumaric acid crystal form and a preparation method thereof. According to the crystal form, a basic structural unit is composed of one molecule of milobalin and one molecule of fumaric acid, so that the stability of milobalin under damp and hot conditions is improved, the dissolution rate is increased, and the appearance of tablets is improved; meanwhile, the preparation method is simple and easy to operate.

Description

Technical Field

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

[0002] Milobalin was researched and developed by Daiichi Sankyo and was approved for marketing by Japanese regulators on January 8, 2019. Its primary indication is the treatment of peripheral neuropathic pain, covering various types such as diabetic peripheral neuropathy and postherpetic neuralgia. The emergence of this breakthrough drug has brought new hope and treatment options to patients suffering from neuropathic pain. Milobalin's mechanism of action is to precisely bind to the α2δ-1 subunit of the voltage-gated calcium channel, thereby effectively blocking the influx of calcium ions. This inhibitory effect can significantly reduce the release of excitatory neurotransmitters (such as glutamate and substance P) in the central nervous system, thereby playing a key role in the relief of neuropathic pain.

[0003] The currently marketed drug is milopalline besylate, chemically known as [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monomethanesulfonate. This compound is a white to slightly yellowish white powder and is slightly soluble in 1,3-dimethyl-2-imidazolidinone, methanol, ethanol, and water. It is poorly soluble in acetone, nearly insoluble in acetonitrile, and extremely poorly soluble in anisole and methyl tert-butyl ether. It must also be sealed and stored away from moisture.

[0004] Tablets are the most common and convenient oral solid dosage form in the pharmaceutical industry. Tablet quality not only impacts drug efficacy and safety but is also closely linked to patient compliance. The tablet production process typically includes unit operations such as raw material processing, granulation, drying, granulation, blending, tableting, and subsequent coating. However, in actual production, process steps such as granulation and tableting can reduce the stability of the API, thereby compromising the quality of the final product.

[0005] During the production of milobarbitaline besylate tablets, tiny indentations often appear on the tablet surface, typically ranging from 100 to 300 microns in length. While individual indentations appear small from a macroscopic perspective, they are clearly visible under high-power magnification or a microscope, extending across the tablet surface. The causes of these indentations are complex and may be related to a variety of factors, including the structural characteristics of the raw material milobarbitaline besylate, its fluidity and plastic deformation properties during tableting, the strength of the interparticle bonds, the precision of the tablet press punches, and the uniformity of pressure distribution.

[0006] The presence of surface dents on milobarlin besylate tablets affects the drug's appearance quality. The pharmaceutical industry has strict requirements for drug appearance, and consumers often use appearance as an intuitive basis for judging a drug's quality. Tablets covered with tiny dents make the tablets appear less smooth and neat, lacking the desired gloss and aesthetic appeal, easily leaving patients with the impression of poor drug quality. While these cosmetic flaws do not directly equate to inherent quality defects, they can directly reduce patients' confidence in the drug's efficacy and safety, and may even affect their medication compliance. This is particularly important for patients with neuropathic pain who require regular, long-term medication.

[0007] In order to solve the above-mentioned appearance problem, one of the most common methods in the prior art is to use coating means. By uniformly applying one or more layers of film coating on the surface of the tablet core, the indentations on the surface of the tablet core are effectively covered, significantly improving the appearance of the tablet. Another method is to adjust the particle size distribution of the raw material (milopalline besylate) and its excipients. For example, by fine grinding or controlling the crystallization process, more uniform and finer particles are obtained, hoping to form a denser and more uniform tablet core structure during the granulation and tableting process, reducing the occurrence of surface defects. On this basis, film coating is performed to achieve a better appearance effect.

[0008] However, the coating or particle size distribution adjustment methods used in the prior art can make the tablet surface smooth to a certain extent and cover up the original indentations, but do not fundamentally solve the stability problem of milobarlin besylate tablets during long-term storage under special environmental conditions such as high temperature and high humidity.

[0009] Therefore, how to break the limitations of traditional surface treatment or physical modification ideas and fundamentally improve the physical and chemical stability of milobarlin under various environmental conditions, especially high temperature and high humidity conditions, while taking into account or improving the appearance quality of tablets has become a technical problem that needs to be solved urgently by those skilled in the art. Summary of the Invention

[0010] In response to the problems existing in the prior art, the present invention provides a crystalline form of milobalin-fumaric acid, which comprises a basic structural unit consisting of one molecule of milobalin and one molecule of fumaric acid. This crystalline form improves the stability of milobalin under hot and humid conditions, increases its solubility, and enhances the tablet appearance. The present invention also relates to a method for preparing the crystalline form of milobalin-fumaric acid, which is characterized by its simplicity and ease of operation and shows promising prospects for industrial production.

[0011] The technical solutions of the present invention are as follows:

[0012] A milobalin-fumaric acid crystal form comprises a basic structural unit consisting of one milobalin molecule and one fumaric acid molecule. Using Cu-Kα radiation, an X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 5.1±0.2°, 5.3±0.2°, 18.5±0.2°, 21.2±0.2°, 27.0±0.2°, and 28.7±0.2°.

[0013] Preferably, the milopalline-fumaric acid crystalline form uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 5.1±0.2°, 5.3±0.2°, 14.5±0.2°, 15.1±0.2°, 17.7±0.2°, 18.5±0.2°, 21.2±0.2°, 22.8±0.2°, 24.7±0.2°, 27.0±0.2°, and 28.7±0.2°.

[0014] Preferably, the milopalline-fumaric acid crystalline form, using Cu-Kα radiation, has characteristic peaks that meet the following Figure 1 The X-ray powder diffraction pattern is shown.

[0015] Preferably, the milopalline-fumaric acid crystalline form has a molecular formula of C 16 H 23 NO6, crystallographic parameters are: monoclinic system, space group is C2, unit cell parameters are: a=22.5401(7), b=7.9278(2), c=9.7610(3), α=90°, β=101.854(3)°, γ=90°, unit cell volume V=1707.03(9).

[0016] On the other hand, the present invention provides a method for preparing a crystalline form of milopalpine-fumaric acid, comprising the following steps:

[0017] The milobalin and fumaric acid crystal forms are dissolved in an organic solvent, heated and stirred, filtered, cooled for crystallization, grown, filtered and dried to obtain the milobalin-fumaric acid crystal form.

[0018] Preferably, in the preparation method, the molar ratio of milopalline to fumaric acid is 1:1 to 2.5, more preferably 1:1.6.

[0019] Preferably, the mass-to-volume ratio of milopalline to the organic solvent is 15.7:1-3; more preferably 15.7:2, wherein the mass is in mg and the volume is in mL.

[0020] Preferably, in the preparation method, the organic solvent is selected from a mixed solvent of ethanol and ethyl acetate, or a mixed solvent of ethanol and acetonitrile; more preferably, it is a mixed solvent of ethanol and acetonitrile.

[0021] Further preferably, in the preparation method, the volume fraction of ethanol in the mixed solvent is 20 to 50%.

[0022] Further preferably, in the preparation method, the volume ratio of ethanol to ethyl acetate is 1:1-3.

[0023] Further preferably, in the preparation method, the volume ratio of ethanol to acetonitrile is 1:2-4.

[0024] Preferably, in the preparation method, the heating temperature is 40-65°C, preferably 55°C.

[0025] Preferably, in the preparation method, the crystallization by cooling is a gradient crystallization with a cooling amplitude of 3 to 5°C / h, and the temperature is lowered to 10 to 15°C.

[0026] Preferably, in the preparation method, after cooling and crystallization, the crystal is allowed to stand for 10 to 36 hours.

[0027] The drying temperature is 50-60° C., and the drying time is 7-10 hours.

[0028] The raw material milopaline used in the preparation method can be prepared according to any method in the prior art or purchased from a commercial product.

[0029] Confirmation of crystal structure

[0030] The X-ray crystallographic data for the polymorphic test of milopalline-fumaric acid described in the present invention were collected on a Rigaku XtaLABSynergy instrument at a test temperature of 293(2)K using Cu-Ka radiation, and data were collected in an ω scanning mode with Lp correction. The structure was solved by a direct method, and all non-hydrogen atoms were identified by the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by the least squares method.

[0031] The crystallographic data of the crystalline form of milopalline-fumaric acid prepared by the present invention (as shown in Table 1) are: monoclinic crystal system, space group is C2, unit cell parameters are: a=22.5401(7), b=7.9278(2), c=9.7610(3), α=90°, β=101.854(3)°, γ=90°, unit cell volume V=1707.03(9).

[0032] Table 1 Main crystallographic data of Milobarline-fumaric acid crystal form

[0033]

[0034]

[0035] The ORTEP diagram of the milobalin-fumaric acid crystalline form of the present invention shows that the crystalline form contains one molecule of milobalin and one molecule of fumaric acid, as shown in the attached diagram. Figure 2 The hydrogen bond diagram of Milobarline-fumaric 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 Milobarline-fumaric acid crystal form

[0037]

[0038]

[0039] In the specific embodiment of the present invention, the milopalline-fumaric 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 present invention has the following outstanding advantages:

[0041] 1. The milopalline-fumaric acid crystal form obtained by the present invention has high purity and high yield, the preparation method is simple to operate, the crystallization process is easy to control, and the reproducibility is good;

[0042] 2. The crystal form obtained by the present invention improves the stability of milopalline under hot and humid conditions, increases the solubility, and improves the appearance of the tablets;

[0043] 3. The crystal form obtained by the present invention has excellent solubility and is expected to improve the bioavailability of milopalanin BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 .PXRD spectrum of Milobarlin-fumaric acid crystal form.

[0045] Figure 2 .ORTEP diagram of the crystalline form of Milobarline-fumaric acid.

[0046] Figure 3 .Hydrogen bond diagram of milobarlin-fumaric acid crystalline form. 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] 209.3 mg of milopalline and 185.7 mg of fumaric acid were dissolved in a mixed solvent of 9.0 mL of ethanol and 18.0 mL of ethyl acetate, heated in a water bath at 50°C with stirring until completely dissolved, filtered while hot, and crystallized by gradient cooling at a rate of 5°C / h until the temperature was lowered to 10°C. After the crystallization was completed, the crystals were allowed to stand for 24 hours, filtered, and dried at 50°C for 8 hours to obtain milopalline-fumaric acid crystals with a yield of 96.2% and a purity of 99.93%.

[0050] Example 2

[0051] 209.3 mg of milopalline and 116.1 mg of fumaric acid were dissolved in a mixed solvent of 6.5 mL of ethanol and 6.5 mL of ethyl acetate, heated in a water bath at 40°C with stirring until completely dissolved, filtered while hot, and crystallized by gradient cooling at a rate of 5°C / h until the temperature was lowered to 12°C. After the crystallization was completed, the crystals were allowed to stand for 10 hours, filtered, and dried at 50°C for 7 hours to obtain milopalline-fumaric acid crystals with a yield of 95.4% and a purity of 99.94%.

[0052] Example 3

[0053] 209.3 mg of milopalline and 290.2 mg of fumaric acid were dissolved in a mixed solvent of 8.0 mL of ethanol and 32.0 mL of acetonitrile, heated in a water bath at 65°C with stirring until completely dissolved, filtered while hot, and crystallized by gradient cooling at a rate of 5°C / h until the temperature was lowered to 15°C. After the crystallization was completed, the crystals were allowed to stand for 36 hours, filtered, and dried at 60°C for 10 hours to obtain milopalline-fumaric acid crystals with a yield of 97.1% and a purity of 99.91%.

[0054] Example 4

[0055] 209.3 mg of milopalline and 464.3 mg of fumaric acid were dissolved in a mixed solvent of 9.0 mL of ethanol and 18.0 mL of ethyl acetate, heated in a water bath at 50°C with stirring until completely dissolved, filtered while hot, and crystallized by gradient cooling at a rate of 5°C / h. The temperature was lowered to 10°C. After the crystallization was completed, the crystals were allowed to stand for 24 hours, filtered, and dried at 50°C for 8 hours to obtain milopalline-fumaric acid crystals with a yield of 90.3% and a purity of 99.90%.

[0056] Example 5

[0057] 209.3 mg of milopalline and 185.7 mg of fumaric acid were dissolved in a mixed solvent of 9.0 mL of ethanol and 18.0 mL of ethyl acetate, heated in a water bath at 50°C with stirring until completely dissolved, filtered while hot, cooled at 10°C for crystallization, and allowed to stand for 24 hours after crystallization, filtered, and dried at 50°C for 8 hours to obtain milopalline-fumaric acid crystals with a yield of 83.8% and a purity of 99.92%.

[0058] Example 6

[0059] 90.0 g of crystalline cellulose and 10.0 g of dl-α-tocopherol were placed in a granulator and stirred for 25 min to obtain a tocopherol mixed grinding powder; the milobarlin-fumaric acid crystalline form obtained in Example 1 (878.0 g, calculated as milobarlin), 8.21 kg of D-mannitol, 1 kg of carboxymethylcellulose calcium, 150.0 g of citric acid hydrate (unscreened), the tocopherol mixed grinding powder obtained above, and 30.0 g of magnesium metasilicate were placed in a V-type mixer and mixed for 10 min; 150.0 g of magnesium stearate was added and mixing was continued for 7 min; and tablets were pressed, with the tablet mass set to 300 mg.

[0060] Comparative Example 1

[0061] Milopalline (8.0 g) was dissolved in anisole (156 mL), and then the dropping speed was controlled to add benzenesulfonic acid (6.29 g) dissolved in anisole (20 mL) dropwise thereto for 2 h; after the addition was complete, 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 milopalline benzenesulfonate Form I with a yield of 93.7% and a purity of 99.92%.

[0062] Comparative Example 2

[0063] 90.0 g of crystalline cellulose and 10.0 g of dl-α-tocopherol were placed in a granulator and stirred for 25 minutes to obtain a tocopherol mixed ground powder; the milobarlin besylate crystal form I (878.0 g, calculated as milobarlin) obtained in Comparative Example 1, 8.21 kg of D-mannitol, 1 kg of carboxymethylcellulose calcium, 150.0 g of citric acid hydrate (manually sieved through a 200-mesh sieve to obtain a citric acid hydrate sieved powder), the tocopherol mixed ground powder obtained above, and 30.0 g of magnesium metasilicate were placed in a V-type mixer and mixed for 10 minutes. The resultant was sieved using a Comil at 1560 rpm to obtain a sieved powder; 150.0 g of magnesium stearate was added and mixing was continued for 7 minutes; tableting was performed, and the tablet mass was set to 300 mg; OPADRY (R) was dispersed in purified water (12.5 w / w%) to obtain a coating solution, and after coating, coated tablets were obtained.

[0064] Verification Example

[0065] Experimental Example 1 Solubility Investigation

[0066] The solubility of the milopalamine crystals obtained in Example 1 and Comparative Example 1 was measured in different media (water, pH 6.8 phosphate buffer).

[0067] Determination method: 10 mL of medium was measured and placed in a vial. 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 sample was filtered through a 0.45 μm filter membrane. The filtrate was taken and the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The results are shown in Table 1 below:

[0068] Table 1 Solubility of Milobalin crystals in different media

[0069]

[0070] The results show that the milobalin-fumaric acid crystal form prepared by the present invention has high solubility, which helps to improve the bioavailability of milobalin in the body.

[0071] Experimental Example 2 Investigation of Crystal Stability

[0072] The milopalline crystals obtained in Example 1 of the present invention and Comparative Example 1 were placed under high temperature (60° C.), high humidity (25° C., relative humidity 90±5%), and strong light irradiation (illuminance 4500±500 lx) conditions, and left open for 10 days for stability investigation. The specific test results are shown in Table 2.

[0073] Table 2 Stability test results of samples

[0074]

[0075]

[0076] As can be seen from the table, the milopalline-fumaric acid crystalline form prepared by the present invention shows excellent stability. In the accelerated test of high temperature, high humidity and strong light irradiation, the content of related substances is significantly lower than that of the milopalline benzenesulfonate-crystalline form I prepared in Comparative Example 1, showing better long-term storage stability; while the crystalline form obtained in Comparative Example 1 shows obvious instability under the above-mentioned harsh conditions, and the content of related substances increases rapidly.

[0077] Experimental Example 3: Stability Study of the Preparation

[0078] The tablets obtained in Example 6 of the present invention and Comparative Example 2 were placed under different temperature and humidity conditions and left uncovered for 6 months. The contents of related substances were measured. The results are shown in Table 3 below.

[0079] Table 3 Stability test results of samples

[0080]

[0081] As can be seen from the table, the tablets prepared using milopalline besylate-crystalline form I in Comparative Example 2 require strict control of the particle size of citric acid hydrate and require coating to overcome the dents that appear on the tablets during placement; while the tablets prepared using milopalline-fumaric acid crystalline form in Example 6 of the present invention do not require strict control of the particle size of the auxiliary material citric acid hydrate, nor do they require complicated coating steps. The resulting tablets still exhibit a smooth surface when placed under high temperature and high humidity conditions, have a low content of related substances, and are highly stable.

Claims

1. A crystalline form of milopalline-fumaric acid, characterized in that: The molar ratio of milopalline to fumaric acid in the crystal form is 1:

1.

2. 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 5.1±0.2°, 5.3±0.2°, 18.5±0.2°, 21.2±0.2°, 27.0±0.2°, and 28.7±0.2°.

3. The crystal form according to claim 2, wherein The crystal form uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 5.1±0.2°, 5.3±0.2°, 14.5±0.2°, 15.1±0.2°, 17.7±0.2°, 18.5±0.2°, 21.2±0.2°, 22.8±0.2°, 24.7±0.2°, 27.0±0.2°, and 28.7±0.2°.

4. The crystal form according to claim 1, wherein The characteristic peaks of the crystal form conform to the X-ray powder diffraction pattern shown in FIG1 using Cu-Kα radiation.

5. The crystal form according to claim 1, wherein The crystal form, whose molecular formula is C 16 H 23 NO6, crystallographic parameters are: monoclinic system, space group is C2, unit cell parameters are: a=22.5401(7), b=7.9278(2), c=9.7610(3), α=90°, β=101.854(3)°, γ=90°, unit cell volume V=1707.03(9).

6. A method for preparing the crystal form according to claim 1, characterized in that: The method comprises the following steps: dissolving milobalin and fumaric acid crystal form in an organic solvent, heating and stirring, filtering, cooling and crystallizing, growing crystals, filtering and drying to obtain the milobalin-fumaric acid crystal form.

7. The method according to claim 6, wherein In the method, the molar ratio of milopalline to fumaric acid is 1:1 to 2.

5.

8. The method according to claim 6, wherein In the method, the organic solvent is selected from a mixed solvent of ethanol and ethyl acetate, or ethanol and acetonitrile, and the volume fraction of ethanol in the mixed solvent is 20-50%.

9. The method according to claim 6, wherein In the method, the crystallization by cooling is a gradient crystallization with a cooling amplitude of 3 to 5°C / h, and the temperature is lowered to 10 to 15°C.

10. The method according to claim 6, wherein In the method, after cooling and crystallization, the crystal is allowed to stand for 10 to 36 hours.

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