Novel tizanidine salt and preparation method thereof

Abstract

The invention relates to a novel tizanidine salt and a preparation method thereof, and belongs to the technical field of pharmaceutical chemicals. The novel tizanidine salt is obtained by selecting low-corrosivity and weak-acidity organic carboxylic acid as a ligand through a cooling crystallization or solvent evaporation crystallization mode. Wherein the organic carboxylic acid is selected from salicylic acid, p-hydroxybenzoic acid, maleic acid and pimelic acid. The formed tizanidine salicylate is in a P21 / n space group of a monoclinic system; the tizanidine p-hydroxybenzoate is an orthorhombic crystal system and has a Pbcn space group; the alpha crystal form of the tizanidine maleate is a P21 / c space group of a monoclinic system; the beta crystal form of the tizanidine maleate is a P21 / c space group of a monoclinic system; the tizanidine pimelate is an orthorhombic crystal system and has a Pna21 space group. The dissolution rate and the inherent dissolution rate of the tizanidine are improved in a mode of forming salt through crystal engineering, the obtained novel tizanidine salt has good stability, the bioavailability of the tizanidine is improved so that the tizanidine salt can give full play to the curative effect, the preparation condition is mild, the reproducibility is good, and large-scale production is easy to realize.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, specifically relating to a novel tizanidine salt and its preparation method. Background Technology

[0002] Tizanidine is a centrally acting muscle relaxant that selectively inhibits multisynaptic mechanisms associated with muscle hyperexcitability, reducing the release of excitatory amino acids from interneurons. Originally developed by Novartis in Switzerland, it was first marketed in Denmark and Switzerland in 1988, and subsequently granted marketing authorization in more than 20 countries including Europe, the United States, and Japan. Tizanidine does not affect neuromuscular transmission, is well-tolerated, and reduces resistance to passive movement, alleviating spasms and clonus, and enhancing the intensity of voluntary movements. It is effective for acute painful muscle spasms and chronic rigidity originating from the spinal cord and brain. Tizanidine can also enhance the anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and prevent NSAID-induced gastric mucosal damage. It can also be used as an adjunct to general or regional anesthesia, a preoperative and postoperative sedative, and a postoperative analgesic.

[0003] In the context of crystal engineering, the design of multicomponent crystals offers a method to improve the physicochemical properties of crystals without altering the chemical properties of the target molecules. Multicomponent crystals can be categorized into solvates, salts, and cocrystals. Solvates are not very effective in improving the physicochemical properties of drugs and pose potential toxicity; therefore, research on multicomponent drugs mainly focuses on salts and cocrystals. The formation of salts or cocrystals has significant advantages in improving the physicochemical properties of active pharmaceutical ingredients, such as solubility, hygroscopicity, stability, permeability, and tableting performance.

[0004] Currently reported tizanidine crystal forms have poor water solubility, resulting in low bioavailability. The main commercially available form is tizanidine hydrochloride, and research on tizanidine primarily focuses on its salt forms. For example, US3843668A, AU505664B2, EP0644192B1, and CN102140095 report methods for preparing tizanidine hydrochloride, and patent CN105566314A discloses the crystal forms of tizanidine hydrochloride. Patents CN109535149B, CN109535150B, CN109535151B, and CN109535152B disclose the crystal forms of tizanidine mesylate, tizanidine phenylacetate, tizanidine p-toluenesulfonic acid, and tizanidine nitrate, respectively. However, the ligands selected for tizanidine salt formulations currently reported are all highly acidic or corrosive substances, with phenylacetic acid even listed as a Category II controlled chemical. This significantly increases the complexity of the tizanidine salt production process, leading to more environmental pollution, and the impact on drug safety and toxicology is incalculable. Therefore, selecting milder and more environmentally friendly ligands could play a more positive role in industrial production and clinical use.

[0005] Tizanidine (C9H8ClN5S, molecular weight 253.7, CAS number 51322-75-9, structure as shown in Formula 1) has poor water solubility, with a solubility of only 0.0355 g / L in water at 25°C. This greatly limits its clinical application. Research has revealed that the tizanidine molecule contains multiple hydrogen bond donors and acceptors, laying the foundation for forming multi-component crystals with other molecules through crystal engineering, thus revealing its physicochemical properties.

[0006]

[0007] Formula 1. Chemical structural formula of tizanidine. Summary of the Invention

[0008] The purpose of this invention is to overcome the problem of low bioavailability of tizanidine due to its low water solubility in existing technologies. Currently available salt forms of tizanidine use ligands that are all strong acids or highly corrosive acids, greatly increasing the complexity of the production process and causing more environmental pollution. Furthermore, the impact on drug safety and toxicology is incalculable. The technical solution of this invention develops five new salts of tizanidine with less corrosive and acidic organic carboxylic acids, improving the dissolution rate and intrinsic dissolution rate of tizanidine, exhibiting good stability, and enhancing its bioavailability to maximize its therapeutic effect. The preparation conditions are mild and reproducible, facilitating large-scale production.

[0009] To achieve the above objectives, the present invention is specifically implemented through the following technical solutions:

[0010] The novel tizanidine salt is a carboxylate salt of tizanidine with tizanidine as the active drug molecule and an organic carboxylic acid as the ligand constituting the basic structural unit. The organic carboxylic acid is selected from salicylic acid, p-hydroxybenzoic acid, maleic acid and pimelic acid.

[0011] The formed tizanidine salicylate is a monoclinic crystal with space group P21 / n. The asymmetric unit cell consists of one tizanidine molecule and one maleic acid molecule, and the unit cell parameters are as follows: α / °=90, β / °=95.548(6), γ / °=90;

[0012] The formed tizanidine p-hydroxybenzoate is orthorhombic, space group Pbcn, with an asymmetric unit consisting of one tizanidine molecule and one p-hydroxybenzoic acid molecule, and the unit cell parameters are as follows. α / °=90, β / °=90, γ / °=90;

[0013] The resulting tizanidine maleate has an α-crystal form that is monoclinic, space group P21 / c, with an asymmetric unit consisting of one tizanidine molecule and one maleate molecule, and a unit cell parameter of [missing information]. α / °=90, β / °=93.978(2), γ / °=90;

[0014] The resulting tizanidine maleate has a monoclinic crystal system, space group P21 / c, and its asymmetric unit comprises one tizanidine molecule and one maleate molecule. Its unit cell parameters are as follows: α / °=90, β / °=97.647(1), γ / °=90;

[0015] The formed tizanidine pimerate is an orthorhombic crystal system, space group Pna21. The asymmetric unit comprises one tizanidine molecule and one pimerate molecule, with the following cell parameters: α / °=90, β / °=90, γ / °=90; its single-crystal structure asymmetric unit is shown in the attached figure. Figure 1-5 As shown.

[0016] A novel tizanidine salt, wherein the X-ray powder diffraction pattern of the tizanidine salicylate is at 9.0±0.2°, 9.9±0.2°, 12.3±0.2°, 12.6±0.2°, 13.9±0.2°, 14.2±0.2°, 15.0±0.2°, 16.3±0.2°, 16.7±0.2°, 17.3±0.2°, 18.1±0.2°, 18.7±0.2°, 19.8±0.2°, and 20.4±0.2°. The following values ​​have characteristic peaks: °, 21.3±0.2°, 22.2±0.2°, 22.7±0.2°, 23.2±0.2°, 23.4±0.2°, 23.8±0.2°, 24.4±0.2°, 24.9±0.2°, 25.1±0.2°, 26.1±0.2°, 26.6±0.2°, 27.2±0.2°, 28.3±0.2°, 28.6±0.2°, 29.3±0.2°, and 30.0±0.2°.

[0017] The X-ray powder diffraction pattern of tizanidine p-hydroxybenzoate is at 9.5±0.2°, 11.7±0.2°, 13.0±0.2°, 13.3±0.2°, 13.7±0.2°, 14.1±0.2°, 15.2±0.2°, 17.0±0.2°, 17.4±0.2°, 17.8±0.2°, 18.9±0.2°, 19.0±0.2°, 19.3±0.2°, and 20.1±0.2°. Characteristic peaks are observed at 21.6±0.2°, 22.5±0.2°, 22.7±0.2°, 23.0±0.2°, 24.6±0.2°, 25.1±0.2°, 25.4±0.2°, 26.0±0.2°, 26.9±0.2°, 27.2±0.2°, 27.8±0.2°, 28.1±0.2°, 28.4±0.2°, 28.6±0.2°, 29.1±0.2°, and 29.4±0.2°.

[0018] The α-crystal X-ray powder diffraction pattern of the tizanidine citrate is at 9.6±0.2°, 10.7±0.2°, 10.8±0.2°, 13.4±0.2°, 14.0±0.2°, 15.2±0.2°, 15.9±0.2°, 16.8±0.2°, 17.5±0.2°, 18.1±0.2°, 18.5±0.2°, 19.3±0.2°, 19.8±0.2°, 20.5±0.2°, 20. Characteristic peaks are observed at 8±0.2°, 21.4±0.2°, 22.1±0.2°, 22.8±0.2°, 23.2±0.2°, 24.1±0.2°, 24.3±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, 27.0±0.2°, 27.8±0.2°, 28.2±0.2°, 28.5±0.2°, 29.1±0.2°, 29.4±0.2°, and 29.8±0.2°.

[0019] The β-crystal X-ray powder diffraction pattern of the tizanidine citrate was observed at 9.2±0.2°, 9.5±0.2°, 10.3±0.2°, 13.1±0.2°, 14.9±0.2°, 15.4±0.2°, 16.7±0.2°, 18.6±0.2°, 19.1±0.2°, 19.7±0.2°, 20.2±0.2°, 20.7±0.2°, 21.2±0.2°, and 21.8°. Characteristic peaks are observed at ±0.2°, 22.1±0.2°, 22.8±0.2°, 23.2±0.2°, 23.6±0.2°, 23.9±0.2°, 24.1±0.2°, 25.0±0.2°, 26.1±0.2°, 26.3±0.2°, 27.2±0.2°, 27.4±0.2°, 28.5±0.2°, 29.2±0.2°, 29.5±0.2°, and 29.9±0.2°.

[0020] The X-ray powder diffraction pattern of the tizanidine heptanoate was observed at 7.7±0.2°, 9.5±0.2°, 11.6±0.2°, 13.8±0.2°, 14.4±0.2°, 15.0±0.2°, 16.3±0.2°, 17.4±0.2°, 17.8±0.2°, 18.5±0.2°, 19.1±0.2°, 19.3±0.2°, 21.0±0.2°, and 22°. Characteristic peaks are observed at 0.3±0.2°, 23.0±0.2°, 23.4±0.2°, 24.0±0.2°, 24.3±0.2°, 25.0±0.2°, 25.9±0.2°, 26.1±0.2°, 26.5±0.2°, 27.3±0.2°, 27.9±0.2°, 28.7±0.2°, 29.0±0.2°, 29.2±0.2°, and 29.8±0.2°. The X-ray powder diffraction pattern of the novel salt is shown below. Figure 6-10 As shown.

[0021] The differential scanning calorimetry (DSC) spectra of the tizanidine salicylate show characteristic melting peaks at 196℃–200℃; the tizanidine p-hydroxybenzoate shows characteristic melting peaks at 223℃–227℃; the α-crystal form of the tizanidine maleate shows characteristic melting peaks at 162℃–166℃; the β-crystal form of the tizanidine maleate shows characteristic melting peaks at 147℃–151℃; and the tizanidine hemianate shows characteristic melting peaks at 153℃–157℃. The DSC spectra of the novel salts are shown below. Figure 11-15 As shown.

[0022] According to another aspect of the present invention, a method for preparing a novel tizanidine salt is provided, wherein tizanidine and an organic carboxylic acid ligand are dissolved in a solvent, and the novel tizanidine salt is obtained by cooling crystallization or solvent evaporation crystallization and drying.

[0023] The method for preparing the novel tizanidine salt, wherein the cooling crystallization method involves completely dissolving tizanidine and an organic carboxylic acid ligand in a solvent at a high temperature, cooling to a low temperature at a certain cooling rate, filtering, and drying; wherein the organic carboxylic acid is selected from salicylic acid, p-hydroxybenzoic acid, maleic acid, and pimelic acid; the stoichiometric ratio of tizanidine to the organic carboxylic acid ligand is 1:3-3:1; the high temperature is 30-50℃; the solid-to-solvent ratio is 4.138-41.385 g / L; the cooling rate is 0.1-1℃ / min; and the low temperature is 0-5℃.

[0024] The method for preparing the novel tizanidine salt, wherein the solvent evaporation crystallization method involves completely dissolving tizanidine and the organic carboxylic acid ligand in a solvent, and evaporating the solvent until crystals precipitate; wherein the volume of the added solvent should be sufficient to completely dissolve tizanidine, and the solvent evaporation time is determined by the precipitation of crystals.

[0025] The method for preparing the novel tizanidine salt, wherein the solvent is selected from one or more combinations of methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, butanone, benzene, and diethyl ether. The method for preparing the novel tizanidine salt, wherein the solvent is selected from one of acetone, butanone, benzene, and diethyl ether.

[0026] The method for preparing the novel tizanidin salt, wherein the drying conditions are: forced air drying at a temperature of 40-60℃ for 8-12 hours.

[0027] The method for preparing tizanidine salt described in this invention has a yield of over 40%.

[0028] Accelerated stability testing showed that the five novel tizanidine salts exhibited good stability. Equilibrium solubility and in vitro dissolution rate measurements revealed that the five novel tizanidine salts had higher water solubility and faster dissolution rates than tizanidine alone. The preparation method of the novel tizanidine salts described in this invention is simple, the crystallization process is easy to control, and it is suitable for industrial production, showing promising prospects for industrial application.

[0029] Accelerated stability tests were conducted on the novel tizanidine salt of this invention using a constant temperature and humidity chamber. 3.0 g of powder of the novel tizanidine salt, with a particle size between 50-100 μm, was stored for 60 days at 50°C and 75±5% relative humidity. Powder X-ray diffraction experiments were performed at 0, 14, 30, and 60 days to monitor the phase transition of the novel tizanidine salt under humid and hot conditions. The powder X-ray diffraction pattern remained unchanged throughout the test, as shown in the attached figure. Figure 1-5 As shown in the figure. This result demonstrates that the novel tizanidine salt obtained in this invention exhibits good stability under high temperature and high humidity conditions.

[0030] The solubility of novel tizanidine salts in pure water was determined using a static method. At 37°C, the water solubility of tizanidine salicylate was 1.7286 g / L, tizanidine p-hydroxybenzoate was 2.5635 g / L, the α-crystal form of tizanidine maleate was 13.3625 g / L, the β-crystal form of tizanidine maleate was 15.4816 g / L, and the water solubility of tizanidine pimelic acid was 5.5605 g / L. Compared to the water solubility of α-crystal form of tizanidine before salt formation (0.1304 g / L) and β-crystal form (0.2149 g / L), these figures are significantly lower.

[0031] The dissolution rates of tizanidine and novel tizanidine salts in phosphate buffer at 37°C and pH 6.8 were determined by in vitro dissolution experiments. The dissolution rates of all five novel salts were significantly better than those of tizanidine. The results are shown in the attached figure. Figure 16 As shown.

[0032] In summary, the novel tizanidine salt disclosed in this invention has higher water solubility and dissolution rate than tizanidine, and good stability, which can improve the bioavailability of tizanidine, and therefore has great potential for clinical application.

[0033] The advantages of this invention are that the product is green, the process is simple, it is easy to operate, the equipment requirements are low, the production cycle is short, and it is suitable for industrial production. Attached Figure Description

[0034] Figure 1 The crystal structure of tizanidine salicylate obtained in Example 1 was determined by single-crystal X-ray diffraction.

[0035] Figure 2 The crystal structure of tizanidine p-hydroxybenzoate obtained in Example 2 was determined by single-crystal X-ray diffraction.

[0036] Figure 3 The crystal structure of tizanidine citrate α obtained in Example 3 was determined by single-crystal X-ray diffraction.

[0037] Figure 4 The crystal structure of tizanidin cistanediol β obtained in Example 4 was determined by single-crystal X-ray diffraction.

[0038] Figure 5 The crystal structure of tizanidin heptanoate obtained in Example 5 was determined by single-crystal X-ray diffraction.

[0039] Figure 6 The PXRD pattern of tizanidin salicylate obtained in Example 6 is shown. The vertical axis represents diffraction intensity in counts, and the horizontal axis represents diffraction angle 2θ in degrees (°).

[0040] Figure 7 The PXRD pattern of tizanidine p-hydroxybenzoate obtained in Example 7 is shown. The vertical axis represents diffraction intensity in counts, and the horizontal axis represents diffraction angle 2θ in degrees (°).

[0041] Figure 8 The PXRD pattern of tizanidine cisbutenedioate crystal form α obtained in Example 8 is shown. The vertical axis represents diffraction intensity in counts, and the horizontal axis represents diffraction angle 2θ in degrees (°).

[0042] Figure 9The PXRD pattern of tizanidin cis-butenedioate crystal form β obtained in Example 9 is shown. The vertical axis represents diffraction intensity in counts, and the horizontal axis represents diffraction angle 2θ in degrees (°).

[0043] Figure 10 The PXRD pattern of tizanidin hemprate obtained in Example 10 is shown. The vertical axis represents diffraction intensity in counts, and the horizontal axis represents diffraction angle 2θ in degrees (°).

[0044] Figure 11 The image shows the DSC spectrum of tizanidine salicylate obtained in Example 6. The vertical axis represents the heat flux released per unit mass of the substance, in W / g, with exothermic values ​​at the top; the horizontal axis represents the temperature, in degrees Celsius (°C).

[0045] Figure 12 The image shows the DSC spectrum of tizanidine p-hydroxybenzoate obtained in Example 7. The vertical axis represents the heat flux released per unit mass of the substance, in W / g, with exothermic values ​​at the top; the horizontal axis represents the temperature, in degrees Celsius (°C).

[0046] Figure 13 The image shows the DSC spectrum of tizanidine cisbutenedioate crystal form α obtained in Example 8. The vertical axis represents the heat flux released per unit mass of the substance, in W / g, with the upward axis representing exothermic reactions. The horizontal axis represents the temperature, in degrees Celsius (°C).

[0047] Figure 14 The image shows the DSC spectrum of tizanidine cisbutenedioate crystal form β obtained in Example 9. The vertical axis represents the heat flux released per unit mass of the substance, in W / g, with the upward axis representing exothermic activity; the horizontal axis represents the temperature, in degrees Celsius (°C).

[0048] Figure 15 The image shows the DSC spectrum of tizanidin hemprate obtained in Example 10. The vertical axis represents the heat flux released per unit mass of the substance, in W / g, with exothermic values ​​at the top; the horizontal axis represents the temperature, in degrees Celsius (°C).

[0049] Figure 16 The figures show the dissolution curves of the novel tizanidine salts obtained in Examples 6-10. The vertical axis represents the concentration of tizanidine in g / L, and the horizontal axis represents time in minutes. Detailed Implementation

[0050] To enhance understanding of the present invention, the invention will be further described in detail below with reference to embodiments and accompanying drawings. These embodiments are only for explaining the invention and do not constitute a limitation on the scope of protection of the invention.

[0051] Testing instruments and methods:

[0052] Single-crystal X-ray diffraction measurements were performed using a Rigaku X-ray surface detector diffractometer (Rapid-RigakuП) from Rigaku Corporation, Japan, with a MoKα target wavelength of 7.103 × 10⁻⁶. -10 m was scanned. The SAINT program was used to integrate and scale the intensity data. The structure was resolved using a direct method with SHELXS-XT. Refinement was performed using full-matrix least squares with SHELXL-XL; the hydrogen atom refinement process was obtained through isotropic calculations.

[0053] Powder X-ray diffraction was performed using a Rigaku D / max-2500 X-ray diffractometer (Japan), with a Cu / Kα1 X-ray source. The scanning range is 2-35° (2θ), the scanning step size is 0.02°, and the scanning speed is 8° / min. The power supply is set to 40kV, 100mA.

[0054] DSC was performed using a Mettler DSC 1 system (STARe, Mettler, Switzerland). Samples weighing 3–5 mg were heated in a standard aluminum dish at a heating rate of 10 °C / min under a nitrogen flow of 50 mL / min.

[0055] Dissolution testing was conducted using a dissolution analyzer (RC-6, Tianguo Optical Instruments Co., Ltd., Tianjin, China), with a blade rotation speed of 100 rpm and a temperature of 37.0 ± 0.1℃. To mitigate the size effect, the samples were initially sieved, selecting particles in the 100-150 mesh range. Dissolution was evaluated after tableting.

[0056] Example 1:

[0057] Weigh 0.5074 g of tizanidine and 0.1381 g of salicylic acid, add 80 mL of methanol to dissolve them. After dissolution, allow the solvent to slowly evaporate at room temperature until crystals precipitate. Filter the solution and dry it in a forced-air drying oven at 40°C for 8 hours to obtain tizanidine maleate, with a yield of 41.5%. The crystal structure diagram resolved by single-crystal X-ray diffraction is shown below. Figure 1 As shown, this is a monoclinic crystal system, space group P21 / n. The asymmetric unit cell consists of one tizanidine molecule and one maleic acid molecule. The unit cell parameters are... α / °=90, β / °=95.548(6), γ / °=90; the PXRD pattern of the product is shown below. Figure 6As shown, the characteristic peaks (2θ, ±0.2°) are: 9.0±0.2°, 9.9±0.2°, 12.3±0.2°, 12.6±0.2°, 13.9±0.2°, 14.2±0.2°, 15.0±0.2°, 16.3±0.2°, 16.7±0.2°, 17.3±0.2°, 18.1±0.2°, 18.7±0.2°, 19.8±0.2°, 20.4±0.2°, 21.3± 0.2°, 22.2±0.2°, 22.7±0.2°, 23.2±0.2°, 23.4±0.2°, 23.8±0.2°, 24.4±0.2°, 24.9±0.2°, 25.1±0.2°, 26.1±0.2°, 26.6±0.2°, 27.2±0.2°, 28.3±0.2°, 28.6±0.2°, 29.3±0.2°, 30.0±0.2°; its DSC spectrum is as follows Figure 11 As shown, the characteristic values ​​are: melting point 198.0℃; solubility in water at 37℃ is 1.7286 g / L. After 60 days of accelerated stability testing in a constant temperature and humidity chamber, the PXRD pattern showed no change, consistent with the attached... Figure 6 Consistent; its dissolution rate curve is consistent with the attached Figure 16 Consistent.

[0058] Example 2:

[0059] Weigh 0.2537 g of tizanidine and 0.1381 g of p-hydroxybenzoic acid, add 60 mL of ethanol to dissolve them. After dissolution, allow the solvent to slowly evaporate at room temperature until crystals precipitate. Filter the solution and dry it in a forced-air drying oven at 50 °C for 10 hours to obtain tizanidine p-hydroxybenzoate, with a yield of 42.3%. The crystal structure diagram resolved by single-crystal X-ray diffraction is shown below. Figure 2 As shown, this is an orthorhombic crystal system, space group Pbcn. The asymmetric unit cell consists of one tizanidine molecule and one p-hydroxybenzoic acid molecule. The unit cell parameters are... α / ° = 90, β / ° = 90, γ / ° = 90; the PXRD pattern of the product is shown below. Figure 7As shown, the characteristic peaks (2θ, ±0.2°) are: 9.5±0.2°, 11.7±0.2°, 13.0±0.2°, 13.3±0.2°, 13.7±0.2°, 14.1±0.2°, 15.2±0.2°, 17.0±0.2°, 17.4±0.2°, 17.8±0.2°, 18.9±0.2°, 19.0±0.2°, 19.3±0.2°, 20.1±0.2°, 21.6 ±0.2°, 22.5±0.2°, 22.7±0.2°, 23.0±0.2°, 24.6±0.2°, 25.1±0.2°, 25.4±0.2°, 26.0±0.2°, 26.9±0.2°, 27.2±0.2°, 27.8±0.2°, 28.1±0.2°, 28.4±0.2°, 28.6±0.2°, 29.1±0.2°, 29.4±0.2°; its DSC spectrum is as follows Figure 12 As shown, the characteristic values ​​are: melting point 225.2℃; solubility in water at 37℃ is 2.5635 g / L. After 60 days of accelerated stability testing in a constant temperature and humidity chamber, the PXRD pattern showed no change, consistent with the attached... Figure 7 Consistent; its dissolution rate curve is consistent with the attached Figure 16 Consistent.

[0060] Example 3:

[0061] Weigh 0.2537 g of tizanidine and 0.3480 g of maleic acid, add 30 mL of n-propanol to dissolve them. After dissolution, allow the solvent to slowly evaporate at room temperature until crystals precipitate. Filter and dry in a forced-air drying oven at 60 °C for 12 hours to obtain tizanidine maleate crystal form α, with a yield of 52.5%. The crystal structure diagram resolved by single-crystal X-ray diffraction is shown below. Figure 3 As shown, this is a monoclinic crystal system, space group P21 / c. The asymmetric unit cell consists of one tizanidine molecule and one maleic acid molecule. The cell parameters are... α / °=90, β / °=93.978(2), γ / °=90; the PXRD pattern of the product is as follows. Figure 7As shown, the characteristic peaks (2θ, ±0.2°) are: 9.6±0.2°, 10.7±0.2°, 10.8±0.2°, 13.4±0.2°, 14.0±0.2°, 15.2±0.2°, 15.9±0.2°, 16.8±0.2°, 17.5±0.2°, 18.1±0.2°, 18.5±0.2°, 19.3±0.2°, 19.8±0.2°, 20.5±0.2°, 20.8±0.2° , 21.4±0.2°, 22.1±0.2°, 22.8±0.2°, 23.2±0.2°, 24.1±0.2°, 24.3±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, 27.0±0.2°, 27.8±0.2°, 28.2±0.2°, 28.5±0.2°, 29.1±0.2°, 29.4±0.2°, 29.8±0.2°; its DSC spectrum is as follows Figure 13 As shown, the characteristic values ​​are: melting point 164.4℃; solubility in water at 37℃ is 13.3625 g / L. After 60 days of accelerated stability testing in a constant temperature and humidity chamber, the PXRD pattern showed no change, consistent with the attached... Figure 7 Consistent; its dissolution rate curve is consistent with the attached Figure 16 Consistent.

[0062] Example 4:

[0063] Weigh 0.2537 g of tizanidine and 0.3480 g of salicylic acid, add 40 mL of acetone to dissolve them. After dissolving completely, allow the solvent to slowly evaporate at room temperature until crystals precipitate. Filter the solution and dry it in a forced-air drying oven at 50 °C for 8 hours to obtain tizanidine maleate crystal form β, with a yield of 46.5%. The crystal structure diagram resolved by single-crystal X-ray diffraction is shown below. Figure 4 As shown, this is a monoclinic crystal system, space group P21 / c. The asymmetric unit cell consists of one tizanidine molecule and one maleic acid molecule. The cell parameters are... α / °=90, β / °=97.647(1), γ / °=90; the PXRD pattern of the product is shown below. Figure 6As shown, the characteristic peaks (2θ, ±0.2°) are: 9.2±0.2°, 9.5±0.2°, 10.3±0.2°, 13.1±0.2°, 14.9±0.2°, 15.4±0.2°, 16.7±0.2°, 18.6±0.2°, 19.1±0.2°, 19.7±0.2°, 20.2±0.2°, 20.7±0.2°, 21.2±0.2°, 21.8±0.2°. 22.1±0.2°, 22.8±0.2°, 23.2±0.2°, 23.6±0.2°, 23.9±0.2°, 24.1±0.2°, 25.0±0.2°, 26.1±0.2°, 26.3±0.2°, 27.2±0.2°, 27.4±0.2°, 28.5±0.2°, 29.2±0.2°, 29.5±0.2°, 29.9±0.2°; their DSC spectra are as follows Figure 14 As shown, the characteristic values ​​are: melting point 149.5℃; solubility in water at 37℃ is 15.4816 g / L. After 60 days of accelerated stability testing in a constant temperature and humidity chamber, the PXRD pattern showed no change, consistent with the attached... Figure 9 Consistent; its dissolution rate curve is consistent with the attached Figure 16 Consistent.

[0064] Example 5:

[0065] Weigh 0.2537 g of tizanidine and 0.1601 g of pimelic acid, add 100 mL of acetonitrile to dissolve them. After dissolving completely, allow the solvent to slowly evaporate at room temperature until crystals precipitate. Filter the solution and dry it in a forced-air drying oven at 60 °C for 10 hours to obtain tizanidine pimelic acid salt, with a yield of 49.5%. The crystal structure diagram resolved by single-crystal X-ray diffraction is shown below. Figure 5 As shown, this is an orthorhombic crystal system, space group Pna21. The asymmetric unit cell consists of one tizanidine molecule and one pimelic acid molecule. The unit cell parameters are... α / ° = 90, β / ° = 90, γ / ° = 90; the PXRD pattern of the product is shown below. Figure 10As shown, the characteristic peaks (2θ, ±0.2°) are: 7.7±0.2°, 9.5±0.2°, 11.6±0.2°, 13.8±0.2°, 14.4±0.2°, 15.0±0.2°, 16.3±0.2°, 17.4±0.2°, 17.8±0.2°, 18.5±0.2°, 19.1±0.2°, 19.3±0.2°, 21.0±0.2°, 22.3± 0.2°, 23.0±0.2°, 23.4±0.2°, 24.0±0.2°, 24.3±0.2°, 25.0±0.2°, 25.9±0.2°, 26.1±0.2°, 26.5±0.2°, 27.3±0.2°, 27.9±0.2°, 28.7±0.2°, 29.0±0.2°, 29.2±0.2°, 29.8±0.2°; its DSC spectrum is as follows Figure 15 As shown, the characteristic values ​​are: melting point 198.0℃; solubility in water at 37℃ is 5.5605 g / L. After 60 days of accelerated stability testing in a constant temperature and humidity chamber, the PXRD pattern showed no change, consistent with the attached... Figure 10 Consistent; its dissolution rate curve is consistent with the attached Figure 16 Consistent.

[0066] Example 6:

[0067] Weigh 0.5074 g of tizanidine and 0.2762 g of salicylic acid, add 50 ml of isopropanol, and dissolve completely at 60 °C. Then, cool to 0 °C at a rate of 0.1 °C / min, filter, and dry in a forced-air drying oven at 40 °C for 8 hours to obtain tizanidine salicylate, with a yield of 41.2%. The PXRD pattern, DSC pattern, accelerated stability test results, and dissolution rate determination results of this product are similar to those of Example 1. The solubility in water at 37 °C is 1.7286 g / L.

[0068] Example 7:

[0069] Weigh 0.5074 g of tizanidine and 0.2762 g of p-hydroxybenzoic acid, add 90 ml of butanone, and dissolve completely at 50 °C. Then, cool to 0 °C at a rate of 0.5 °C / min, filter, and dry in a forced-air drying oven at 50 °C for 10 hours to obtain tizanidine p-hydroxybenzoate, with a yield of 43.2%. The PXRD pattern, DSC pattern, accelerated stability test results, and dissolution rate determination results of this product are similar to those of Example 2. The solubility in water at 37 °C is 2.5635 g / L.

[0070] Example 8:

[0071] Weigh 0.5074 g of tizanidine and 0.3483 g of maleic acid, add 40 ml of benzene, and dissolve completely at 30 °C. Then, cool to 0 °C at a rate of 1 °C / min, filter, and dry in a forced-air drying oven at 50 °C for 8 hours to obtain the α-crystal form of tizanidine maleate, with a yield of 40.4%. The PXRD pattern, DSC pattern, accelerated stability test results, and dissolution rate determination results of this product are similar to those of Example 3. The solubility in water at 37 °C is 13.3625 g / L.

[0072] Example 9:

[0073] Weigh 0.5074 g of tizanidine and 0.3483 g of maleic acid, add 50 ml of diethyl ether, and dissolve completely at 50 °C. Then, cool to 0 °C at a rate of 0.5 °C / min, filter, and dry in a forced-air drying oven at 40 °C for 8 hours to obtain the β-crystal form of tizanidine maleate, with a yield of 43.5%. The PXRD pattern, DSC pattern, accelerated stability test results, and dissolution rate determination results of this product are similar to those of Example 4. The solubility in water at 37 °C is 15.4816 g / L.

[0074] Example 10:

[0075] Weigh 0.5074 g of tizanidine and 0.3203 g of pimelic acid, add 20 ml of methanol, and dissolve completely at 50 °C. Then, cool to 0 °C at a rate of 0.5 °C / min, filter, and dry in a forced-air drying oven at 50 °C for 8 hours to obtain tizanidine pimelic acid salt, with a yield of 44.5%. The PXRD pattern, DSC pattern, accelerated stability test results, and dissolution rate determination results of this product are similar to those of Example 5. The solubility in water at 37 °C is 5.5605 g / L.

[0076] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these examples without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A novel tizanidine salt, wherein tizanidine is the active drug molecule, characterized in that, The novel tizanidine salt is a carboxylate salt of tizanidine with organic carboxylic acids as ligands forming the basic structural units. The organic carboxylic acids are selected from salicylic acid, p-hydroxybenzoic acid, maleic acid and pimelic acid. The formed tizanidine salicylate is a monoclinic crystal with space group P21 / n. The asymmetric unit cell consists of one tizanidine molecule and one maleic acid molecule, and the unit cell parameters are as follows: α / °=90, β / °=95.548(6), γ / °=90; The formed tizanidine p-hydroxybenzoate is orthorhombic, space group Pbcn, with an asymmetric unit consisting of one tizanidine molecule and one p-hydroxybenzoic acid molecule, and the unit cell parameters are as follows. α / °=90, β / °=90, γ / °=90; The resulting tizanidine maleate has an α-crystal form that is monoclinic, space group P21 / c, with an asymmetric unit consisting of one tizanidine molecule and one maleate molecule, and a unit cell parameter of [missing information]. α / °=90, β / °=93.978(2), γ / °=90; The resulting tizanidine maleate has a monoclinic crystal system, space group P21 / c, and its asymmetric unit comprises one tizanidine molecule and one maleate molecule. Its unit cell parameters are as follows: α / °=90, β / °=97.647(1), γ / °=90; The formed tizanidine pimerate is an orthorhombic crystal system, space group Pna21. The asymmetric unit comprises one tizanidine molecule and one pimerate molecule, with the following cell parameters: α / °=90, β / °=90, γ / °=90.

2. The novel tizanidine salt according to claim 1, characterized in that, The X-ray powder diffraction pattern of the tizanidine salicylate was observed at 9.0±0.2°, 9.9±0.2°, 12.3±0.2°, 12.6±0.2°, 13.9±0.2°, 14.2±0.2°, 15.0±0.2°, 16.3±0.2°, 16.7±0.2°, 17.3±0.2°, 18.1±0.2°, 18.7±0.2°, 19.8±0.2°, 20.4±0.2°, and 21. Characteristic peaks are observed at 0.3±0.2°, 22.2±0.2°, 22.7±0.2°, 23.2±0.2°, 23.4±0.2°, 23.8±0.2°, 24.4±0.2°, 24.9±0.2°, 25.1±0.2°, 26.1±0.2°, 26.6±0.2°, 27.2±0.2°, 28.3±0.2°, 28.6±0.2°, 29.3±0.2°, and 30.0±0.2°. The X-ray powder diffraction pattern of tizanidine p-hydroxybenzoate is as follows: 9.5±0.2°, 11.7±0.2°, 13.0±0.2°, 13.3±0.2°, 13.7±0.2°, 14.1±0.2°, 15.2±0.2°, 17.0±0.2°, 17.4±0.2°, 17.8±0.2°, 18.9±0.2°, 19.0±0.2°, 19.3±0.2°, 20.1±0.2°. Characteristic peaks are observed at 21.6±0.2°, 22.5±0.2°, 22.7±0.2°, 23.0±0.2°, 24.6±0.2°, 25.1±0.2°, 25.4±0.2°, 26.0±0.2°, 26.9±0.2°, 27.2±0.2°, 27.8±0.2°, 28.1±0.2°, 28.4±0.2°, 28.6±0.2°, 29.1±0.2°, and 29.4±0.2°. The α-crystal X-ray powder diffraction pattern of the tizanidine citrate is as follows: 9.6±0.2°, 10.7±0.2°, 10.8±0.2°, 13.4±0.2°, 14.0±0.2°, 15.2±0.2°, 15.9±0.2°, 16.8±0.2°, 17.5±0.2°, 18.1±0.2°, 18.5±0.2°, 19.3±0.2°, 19.8±0.2°, 20.5±0.2°, 20.8 Characteristic peaks are observed at ±0.2°, 21.4±0.2°, 22.1±0.2°, 22.8±0.2°, 23.2±0.2°, 24.1±0.2°, 24.3±0.2°, 24.8±0.2°, 25.4±0.2°, 26.1±0.2°, 27.0±0.2°, 27.8±0.2°, 28.2±0.2°, 28.5±0.2°, 29.1±0.2°, 29.4±0.2°, and 29.8±0.2°. The β-crystal X-ray powder diffraction pattern of the tizanidine citrate was observed at 9.2±0.2°, 9.5±0.2°, 10.3±0.2°, 13.1±0.2°, 14.9±0.2°, 15.4±0.2°, 16.7±0.2°, 18.6±0.2°, 19.1±0.2°, 19.7±0.2°, 20.2±0.2°, 20.7±0.2°, 21.2±0.2°, and 21.8°. Characteristic peaks are observed at ±0.2°, 22.1±0.2°, 22.8±0.2°, 23.2±0.2°, 23.6±0.2°, 23.9±0.2°, 24.1±0.2°, 25.0±0.2°, 26.1±0.2°, 26.3±0.2°, 27.2±0.2°, 27.4±0.2°, 28.5±0.2°, 29.2±0.2°, 29.5±0.2°, and 29.9±0.2°. The X-ray powder diffraction pattern of the tizanidine heptanoate was observed at 7.7±0.2°, 9.5±0.2°, 11.6±0.2°, 13.8±0.2°, 14.4±0.2°, 15.0±0.2°, 16.3±0.2°, 17.4±0.2°, 17.8±0.2°, 18.5±0.2°, 19.1±0.2°, 19.3±0.2°, 21.0±0.2°, and 22°. Characteristic peaks are observed at 0.3±0.2°, 23.0±0.2°, 23.4±0.2°, 24.0±0.2°, 24.3±0.2°, 25.0±0.2°, 25.9±0.2°, 26.1±0.2°, 26.5±0.2°, 27.3±0.2°, 27.9±0.2°, 28.7±0.2°, 29.0±0.2°, 29.2±0.2°, and 29.8±0.2°.

3. The novel tizanidin salt according to claim 1, characterized in that, The differential scanning calorimetry (DSC) spectrum of tizanidine salicylate has a characteristic melting peak at 196℃ to 200℃; the DSC spectrum of tizanidine p-hydroxybenzoate has a characteristic melting peak at 223℃ to 227℃; the DSC spectrum of tizanidine maleate (α-crystal form) has a characteristic melting peak at 162℃ to 166℃; the DSC spectrum of tizanidine maleate (β-crystal form) has a characteristic melting peak at 147℃ to 151℃; and the DSC spectrum of tizanidine heptanate has a characteristic melting peak at 153℃ to 157℃.

4. The method for preparing the novel tizanidine salt according to any one of claims 1-3, characterized in that, After dissolving tizanidine and an organic carboxylic acid ligand in a solvent, the novel tizanidine salt was obtained by cooling crystallization or solvent evaporation crystallization and drying.

5. The preparation method according to claim 4, characterized in that, The solvent is selected from one of methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, butanone, benzene, and diethyl ether.

6. The preparation method according to claim 4, characterized in that, The cooling crystallization method involves completely dissolving tizanidine and the organic carboxylic acid ligand in a solvent at a high temperature, cooling to a low temperature at a certain cooling rate, filtering, and drying. The organic carboxylic acid is selected from salicylic acid, p-hydroxybenzoic acid, maleic acid, and pimelic acid. The stoichiometric ratio of tizanidine to the organic carboxylic acid ligand is 1:3-2:

1. The high temperature is 30-50℃, the solid-to-solvent ratio is 4.138-41.385 g / L, the cooling rate is 0.1-1℃ / min, and the low temperature is 0-5℃.

7. The preparation method according to claim 4, characterized in that, The method for solvent evaporation and crystallization is to completely dissolve tizanidine and the organic carboxylic acid ligand in the solvent, and then evaporate the solvent until crystals precipitate. The volume of solvent added should be sufficient to completely dissolve tizanidine, and the solvent evaporation time should be determined by the precipitation of crystals.

8. The preparation method according to claim 4, characterized in that, The drying conditions are: forced air drying, temperature 40-60℃, time 8-12 hours.

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