Tizanidine crystal form and preparation method thereof

Abstract

The invention relates to a tizanidine crystal form, and belongs to the technical field of pharmaceutical chemicals. The X-ray diffraction pattern of the tizanidine crystal form has characteristic peaks at 7.0 + / -0.2 degrees, 9.8 + / -0.2 degrees, 14.1 + / -0.2 degrees, 15.7 + / -0.2 degrees, 17.9 + / -0.2 degrees, 20.0 + / -0.2 degrees, 21.4 + / -0.2 degrees, 23.6 + / -0.2 degrees, 24.7 + / -0.2 degrees, 25.4 + / -0.2 degrees, 26.5 + / -0.2 degrees, 27.4 + / -0.2 degrees, 28.6 + / -0.2 degrees, 29.3 + / -0.2 degrees and 30.0 + / -0.2 degrees; the invention also provides a related preparation method. The tizanidine crystal form disclosed by the invention is relatively good in stability and relatively high in water solubility, the bioavailability can be increased and the drug effect can be improved by utilizing the tizanidine crystal form to prepare drugs, and the tizanidine crystal form is simple in production operation and easy to commercialize.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine and chemical industry, and particularly relates to a crystalline form of tizanidine and a preparation method thereof. BACKGROUND

[0002] Tizanidine is a central muscle relaxant that selectively inhibits the polysynaptic mechanism associated with muscle hyperactivity and reduces the release of excitatory amino acids from interneurons. It was first developed by Novartis in Switzerland and was first marketed in Denmark and Switzerland in 1988, and then successively obtained marketing licenses in more than 20 countries such as Europe, the United States, and Japan. Tizanidine does not affect the transmission of nerves and muscles, and has good tolerance, and can reduce the resistance of passive movement, relieve spasm and clonus, and enhance the strength of voluntary movement. It is effective for acute painful muscle spasm and chronic rigidity originating from the spinal cord and brain. Tizanidine can also increase the anti-inflammatory effect of non-steroidal anti-inflammatory drugs (NSAIDs) and prevent NSAID-induced gastric mucosal damage. It can also be used as an anesthetic or regional anesthetic adjuvant, a preoperative and postoperative sedative, and a postoperative analgesic.

[0003] Polymorphism is common in drugs. With the change of the crystal form, the physicochemical properties of different crystal forms of the drug will change. The crystal form can significantly affect the solubility, dissolution rate, stability, and bioavailability of the drug. The change of the crystal form will affect the crystallization process, efficacy, and quality safety of the drug. Systematic research on the crystal form of the drug is of great significance to the development of the crystallization process of the drug, the quality control of the drug, and the safety evaluation of the drug.

[0004] The currently reported crystal forms of tizanidine have poor water solubility and thus low bioavailability. The main product on the market is tizanidine hydrochloride, and the research on tizanidine is mainly focused on the salt form of tizanidine. For example, US3843668A, AU505664B2, EP0644192B1, CN102140095, and the like report the preparation method of tizanidine hydrochloride. Patent CN105566314A discloses the crystal form of tizanidine hydrochloride. Patents CN109535149B, CN109535150B, CN109535151B, and CN109535152B disclose the crystal forms of tizanidine mesylate, tizanidine phenylacetate, tizanidine p-toluenesulfonate, and tizanidine nitrate, respectively. Although the salt formation of the drug can improve the water solubility, the introduction of other molecules cannot be estimated in terms of the safety and toxicology of the drug. Therefore, the exploration and research on the crystal form of the drug can play a more positive role in clinical medication.

[0005] Tizanidine (C9H8ClN5S, molecular weight 253.7, CAS No. 51322-75-9, structure as shown in formula 1) has only one reported crystal form, which has poor water solubility, only 0.0355 g / L in water at 25℃. It greatly limits its clinical application. It has been found that tizanidine molecule contains multiple hydrogen bond donors and acceptors, so it is expected to form various types of molecular arrangement by hydrogen bonding. At the same time, tizanidine molecule is a flexible molecule containing two rotatable chemical bonds. This lays the foundation for the development of tizanidine polymorphs.

[0006]

[0007] Formula 1. Chemical structure of tizanidine. SUMMARY

[0008] The purpose of the present application is to overcome the problem of low bioavailability of the drug due to the low water solubility of tizanidine in the prior art. The commonly used method to improve its properties is to develop a salt form of tizanidine, which not only has high cost, but also makes the pharmacological action more complex due to the addition of a new substance. The technical solution of the present application develops a new crystal form of tizanidine, which has higher water solubility than the existing crystal form and can remain stable for a long time. At the same time, the method is simple, the production cost is low, and the production cycle is short.

[0009] To achieve the above-mentioned purpose, the present application specifically realizes the following technical solutions:

[0010] A crystal form of tizanidine, characterized in that the X-ray powder diffraction pattern has characteristic peaks at 7.0±0.2°, 9.8±0.2°, 14.1±0.2°, 15.7±0.2°, 17.9±0.2°, 20.0±0.2°, 21.4±0.2°, 23.6±0.2°, 24.7±0.2°, 25.4±0.2°, 26.5±0.2°, 27.4±0.2°, 28.6±0.2°, 29.3±0.2°, 30.0±0.2°. The powder X-ray diffraction pattern is shown in Figure 1. Figure 1

[0011] The crystal system of the tizanidine crystal form is an orthorhombic system, the space group is Pbca, and the unit cell parameters are a=9. 0±0.1 Å, b= 15. 0±0.1 Å, c= 21. 0±0.1 Å. The axis angle is α=90°, β=90°, γ=90°, and the structure is shown in Figure 2. Figure 2

[0012] The differential scanning calorimetry spectrum of the tizanidine crystal form has a characteristic melting peak at 222℃-226℃, as shown in Figure 3. Figure 3

[0013] ​​​The infrared spectrum of the tizanidine crystal form has characteristic peaks at 3397±1 cm -1 , 3150±1 cm -1 , 2865±1 cm -1 , 1645±1 cm -1 , 1513±1 cm -1 , 1455±1 cm -1 , 1387±1 cm -1 , 1278±1 cm -1 , 1193±1 cm -1 , 1111±1 cm -1 , 938±1 cm -1 , 839±1 cm -1 , 804±1 cm -1 , 692±1 cm -1 , as shown in the accompanying Figure 4 .

[0014] According to another aspect of the present application, there is provided a method for preparing the tizanidine crystal form, which comprises dissolving tizanidine solid in a solvent, and then using cooling crystallization or suspension crystallization or solvent evaporation crystallization, and drying to obtain the tizanidine crystal form.

[0015] The method for preparing the tizanidine crystal form, wherein the cooling crystallization method comprises completely dissolving tizanidine in a solvent at a high temperature end, cooling to a low temperature end at a certain cooling rate, filtering, and drying; wherein the high temperature end is 40-50℃, the ratio of the solid to the solvent is 3.62-6.34g / L, the cooling rate is 0.1-1℃ / min, and the low temperature end is 0-5℃.

[0016] The method for preparing the tizanidine crystal form, wherein the suspension crystallization method comprises suspending tizanidine in a solvent, filtering, and drying; wherein the ratio of tizanidine to the solvent is 0.05-0.10g / mL, and the suspension time is 12-24h.

[0017] The method for preparing the tizanidine crystal form, wherein the solvent evaporation crystallization method comprises completely dissolving tizanidine in a solvent, and evaporating until crystals are precipitated; the volume of the solvent added should be enough to completely dissolve tizanidine, and the evaporation time of the solvent is determined according to the precipitation of crystals.

[0018] The method for preparing the tizanidine crystal form, wherein the solvent is selected from one of acetone, butanone, benzene, and diethyl ether.

[0019] The method for preparing the tizanidine crystal form, wherein the drying condition is: air drying, the temperature is 40-60℃, and the time is 8-12h.

[0020] The method for preparing the tizanidine crystal form has a yield of more than 40% and up to more than 96.0%.

[0021] The tizanidine crystal form has good stability through accelerated stability testing, has excellent hygroscopic stability through dynamic water vapor adsorption testing, and has higher water solubility than the existing tizanidine crystal form through dynamic equilibrium water solubility testing.

[0022] The solubility of the tizanidine crystal form in pure water is detected by a dynamic method. At 25 DEG C and 37 DEG C, tizanidine solids are gradually added to 500 mL of water, and stirring is continuously performed until the solids are no longer dissolved. The solubility of the tizanidine crystal form in water at 25 DEG C is 0.0570 g / L, the solubility of the existing tizanidine crystal form is 0.0355 g / L, the solubility of the tizanidine crystal form in water at 37 DEG C is 0.2149 g / L, and the solubility of the existing tizanidine crystal form is 0.1304 g / L.

[0023] The hygroscopic stability of the obtained tizanidine crystal form product is detected by a dynamic water vapor adsorption instrument. At 25 DEG C, a cycle of 0%-95%-5% relative humidity (RH) is set. The obtained isothermal adsorption / desorption curve is shown in FIG. 2. Figure 5 As the humidity increases, the adsorption curve of the tizanidine crystal form increases at a smaller rate, and the desorption curve almost does not have a stagnation phenomenon. After the dynamic adsorption experiment, the powder X-ray diffraction pattern of the tizanidine crystal form is consistent with FIG. 3, and compared with before the dynamic adsorption experiment, the characteristic peaks do not change. The results show that the tizanidine crystal form can remain stable in a high-humidity environment. Figure 1

[0024] The tizanidine crystal form product of the application is subjected to accelerated stability testing by using a constant-temperature and constant-humidity box. Three grams of the tizanidine crystal form powder having a particle size of 50-100 μm is stored at a temperature of 50 DEG C and a relative humidity of 75 DEG C±5% for 60 days, and samples are taken at 0 days, 14 days, 30 days and 60 days for powder X-ray diffraction experiments to monitor the phase change of the tizanidine crystal form in a humid heat environment. The powder X-ray diffraction pattern does not change, as shown in FIG. 4. Figure 1 The results show that the obtained tizanidine crystal form has good stability in a high-temperature and high-humidity environment.

[0025] In summary, the tizanidine crystal form disclosed in the application has higher water solubility than the existing crystal form, and has good stability and hygroscopic stability. The bioavailability of tizanidine is improved, and thus the tizanidine crystal form has great clinical application prospects.​

[0026] The present application has the advantages of simple process, strong operability, low equipment requirement, short production cycle, suitability for industrial production, and preparation of tizanidine crystal forms for industrial production according to needs. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 The PXRD pattern of the tizanidine crystal form obtained in Example 1, with the vertical coordinate being diffraction intensity in counts and the horizontal coordinate being diffraction angle 2θ in degrees;

[0028] Figure 2 The crystal structure of the tizanidine crystal form obtained in Example 1 analyzed by single crystal X-ray diffraction;

[0029] Figure 3 The DSC pattern of the tizanidine crystal form obtained in Example 1, with the vertical coordinate being heat flow per unit mass of substance in W / g, upward being exothermic, and the horizontal coordinate being temperature in degrees Celsius (℃);

[0030] Figure 4 The infrared spectrum of the tizanidine crystal form obtained in Example 1, with the vertical coordinate being transmittance in % and the horizontal coordinate being wave number in cm -1 -1.

[0031] Figure 5 The dynamic water vapor adsorption and desorption curve of the tizanidine crystal form obtained in Example 1 at 25℃, with the horizontal coordinate being humidity (%) and the vertical coordinate being weight (mg). DETAILED DESCRIPTION

[0032] In order to deepen the understanding of the present application, the present application is further described in detail below in combination with the embodiments and the drawings, which are only used to explain the present application and do not constitute a limitation on the protection scope of the present application.

[0033] Detection instrument and method:

[0034] Single crystal X-ray diffraction measurement is performed by scanning with a Japan Rigaku X-ray area detection diffractometer Rapid-RigakuП, MoKα target ray wavelength 7.103 x 10 -10 The SAINT program is used to complete the integration and scaling of intensity data. The structure is resolved by a direct method using SHELXS-XT. The refinement is performed by full matrix least squares method using SHELXL-XL, and the hydrogen atom refinement process is obtained by isotropic calculation.

[0035] Powder X-ray diffraction is performed by using a Japan Rigaku D / max-2500 type X-ray diffractometer, with a Cu target ray source The scan range was 2-35° (2 theta) with a scan step of 0.02° and a rate of 8° / min. The power supply was set at 40 kV, 100 mA.

[0036] DSC was performed in a Mettler DSC 1 system (STARe, Mettler, Switzerland). The sample with a weight of 3-5 mg was heated in a standard aluminum pan at a heating rate of 10 °C / min under a nitrogen flow of 50 mL / min.

[0037] Infrared spectra were collected on an ALPHA II infrared instrument (Bruker, Germany). Each sample was scanned over a spectral range of 4000-400 cm -1 at a resolution of 4 cm -1 -1 with at least 16 scans collected and averaged.

[0038] Dynamic vapor sorption experiments were performed using a VTI-SA+ vapor sorption analyzer (TA Instruments) to measure samples at 25 °C over a humidity range of 0% to 95% relative humidity (RH) with a 5% step. If less than 0.02% weight change occurred within 5 minutes, the next humidity point was performed with a maximum hold time of 30 minutes.

[0039] Example 1:

[0040] Tizanidine 0.2537 g was weighed and dissolved in acetone 80 mL, after the solution was clear, the solvent was slowly evaporated at room temperature until crystals precipitated, filtered, and placed in a blast drying oven, the temperature was 40 °C, the time was 8 hours, to obtain the tizanidine crystal form, the yield was 53.5%. The PXRD pattern of the product is shown in Figure 1 , the characteristic peak values (2 theta, ±0.2°) are: 7.0±0.2°, 9.8±0.2°, 14.1±0.2°, 15.7±0.2°, 17.9±0.2°, 20.0±0.2°, 21.4±0.2°, 23.6±0.2°, 24.7±0.2°, 25.4±0.2°, 26.5±0.2°, 27.4±0.2°, 28.6±0.2°, 29.3±0.2°, 30.0±0.2°; the crystal structure analyzed by single crystal X-ray diffraction experiment is shown in Figure 2 , the crystal system is orthorhombic, the space group is Pbca, and the unit cell parameters are the axial angle is a = 90°, b = 90°, g = 90°; the DSC pattern is shown in Figure 3 , the characteristic values are: the melting point is 224.3 °C; the infrared spectrum is shown in Figure 4 , 3397±1 cm -1 , 3150±1 cm -1、2865±1cm -1 、1645±1cm -1 、1513±1cm -1 、1455±1cm -1 、1387±1cm -1 、1278±1cm -1 、1193±1cm -1 、1111±1cm -1 、938±1cm -1 、839±1cm -1 、804±1cm -1 、692±1cm -1 There is a characteristic peak at ; in 25℃ water, the solubility is 0.0570g / L, in 37℃ water, the solubility is 0.2149g / L. The isothermal adsorption / desorption curve measured by dynamic water vapor adsorption instrument is as follows Figure 5 As shown in the figure, there is almost no stagnation phenomenon, and the PXRD pattern after the isothermal adsorption / desorption experiment is consistent with the Figure 1 After 60 days of accelerated stability test in a constant temperature and humidity chamber, the PXRD pattern did not change, which was consistent with the attached Figure 1 consistent.

[0041] Example 2:

[0042] Take tizanidine 0.2537g, add butanone 100mL and dissolve it, molten clear rear in room temperature, slowly evaporate solvent to having crystal to separate out, filter, be placed in air drying oven dry, temperature is 40 ℃, and the time is 10 hours, obtains this tizanidine crystal formation, yield 50.5%.The crystalline structure of this product through single crystal X-ray diffraction experiment analysis, PXRD pattern, DSC pattern, infrared spectrum, isothermal adsorption / desorption curve, accelerated stability test result are similar to Example 1, and in 25 ℃ of water, solubility is 0.0570g / L, and in 37 ℃ water, solubility is 0.2149g / L.

[0043] Example 3:

[0044] Take tizanidine 0.2537g, add 60mL butanone, it is dissolved completely at 50 ℃, then be cooled to 0 ℃ with the temperature falling rate of 0.1 ℃ / min, filter, be placed in air drying oven and dry, temperature is 40 ℃, and the time is 8 hours, obtains this tizanidine crystal formation, and yield is 41.2%.PXRD pattern, DSC pattern, infrared spectrum, isothermal adsorption / desorption curve, accelerated stability test result of this product are similar to Example 1, and in 25 ℃ of water, solubility is 0.0570g / L, and in 37 ℃ water, solubility is 0.2149g / L.

[0045] Example 4:

[0046] Tizanidine 0.2537 g was weighed, 40 mL of benzene was added, it was completely dissolved at 45 °C, then it was cooled to 2 °C at a cooling rate of 0.5 °C / min, filtered, and dried in a blast drying oven at a temperature of 50 °C for 10 h to obtain the tizanidine crystalline form with a yield of 43.2%. The PXRD pattern, DSC pattern, IR pattern, isothermic adsorption / desorption curve, and accelerated stability test results of the product were similar to those of Example 1, and the solubility in water at 25 °C was 0.0570 g / L, and the solubility in water at 37 °C was 0.2149 g / L.

[0047] Example 5:

[0048] Tizanidine 0.2537 g was weighed, 70 mL of ether was added, it was completely dissolved at 40 °C, then it was cooled to 5 °C at a cooling rate of 1 °C / min, filtered, and dried in a blast drying oven at a temperature of 45 °C for 12 h to obtain the tizanidine crystalline form with a yield of 40.2%. The PXRD pattern, DSC pattern, IR pattern, isothermic adsorption / desorption curve, and accelerated stability test results of the product were similar to those of Example 1, and the solubility in water at 25 °C was 0.0570 g / L, and the solubility in water at 37 °C was 0.2149 g / L.

[0049] Example 6:

[0050] Tizanidine 0.5074 g was weighed, 5 mL of acetone was added, it was stirred at room temperature for 12 h, filtered, and dried in a blast drying oven at a temperature of 60 °C for 8 h to obtain the tizanidine crystalline form with a yield of 96.2%. The PXRD pattern, DSC pattern, IR pattern, isothermic adsorption / desorption curve, and accelerated stability test results of the product were similar to those of Example 1, and the solubility in water at 25 °C was 0.0570 g / L, and the solubility in water at 37 °C was 0.2149 g / L.

[0051] Example 7:

[0052] Tizanidine 0.5074 g was weighed, 8 mL of butanone was added, it was stirred at room temperature for 16 h, filtered, and dried in a blast drying oven at a temperature of 50 °C for 10 h to obtain the tizanidine crystalline form with a yield of 94.8%. The PXRD pattern, DSC pattern, IR pattern, isothermic adsorption / desorption curve, and accelerated stability test results of the product were similar to those of Example 1, and the solubility in water at 25 °C was 0.0570 g / L, and the solubility in water at 37 °C was 0.2149 g / L.

[0053] Example 8:

[0054] Tizanidine 0.5074 g was weighed into 10 ml of benzene and stirred at room temperature for 24 h, filtered and dried in a forced air oven at 40 °C for 12 h to obtain the tizanidine crystalline form in 93.2% yield. The PXRD pattern, DSC pattern, IR pattern, isothermal adsorption / desorption curve, and accelerated stability test results of the product were similar to those of Example 1, and the solubility in water at 25 °C was 0.0570 g / L and in water at 37 °C was 0.2149 g / L.

[0055] While embodiments of the application have been shown and described, it is to be understood that the embodiments described are merely exemplary of the principles and application of the present application. Numerous modifications, changes, omissions, substitutions and alterations can be made by one having ordinary skill in the art without departing from the application, which is intended to be defined by the following claims, along with their equivalents.

Claims

1. A crystalline form of tizanidine characterized by, The X-ray powder diffraction pattern has characteristic peaks at 7.0±0.2°, 9.8±0.2°, 14.1±0.2°, 15.7±0.2°, 17.9±0.2°, 20.0±0.2°, 21.4±0.2°, 23.6±0.2°, 24.7±0.2°, 25.4±0.2°, 26.5±0.2°, 27.4±0.2°, 28.6±0.2°, 29.3±0.2°, 30.0±0.2°.

2. The crystalline form of tizanidine of claim 1, characterized in that, The crystal form of the tizanidine has an orthorhombic crystal system, a space group of Pbca, and a unit cell parameter of a = 8. 1 A, b = 10. 1 A, c = 21. 6 A The axis angles are a = 90°, β = 90°, γ = 90°.

3. The crystalline form of tizanidine of claim 1, characterized in that, The differential scanning calorimetry analysis spectrum of the crystal form has a characteristic melting peak at 222℃-226℃.

4. tizanidine crystal form according to claim 1, is characterized in that, This crystalline form has characteristic peaks in the infrared spectrum at 3397 ± 1 cm -1 -1, 3150 ± 1 cm -1 -1, 2865 ± 1 cm -1 -1, 1645 ± 1 cm -1 -1, 1513 ± 1 cm -1 -1, 1455 ± 1 cm -1 -1, 1387 ± 1 cm -1 -1, 1278 ± 1 cm -1 -1, 1193 ± 1 cm -1 -1, 1111 ± 1 cm -1 -1, 938 ± 1 cm -1 -1, 839 ± 1 cm -1 -1, 804 ± 1 cm -1 -1, 692 ± 1 cm -1 -1.

5. A process for preparing a crystalline form of tiazafenitin according to any one of claims 1 to 4, characterized in that, After the solid tizanidine is dissolved in a solvent, the tizanidine crystal form is obtained by cooling crystallization, suspension crystallization or solvent evaporation crystallization and drying.

6. A process for preparing a crystalline form of tizanidine according to claim 5, characterized in that, The cooling crystallization method is to completely dissolve tizanidine in a solvent at a high temperature end, to cool to a low temperature end at a certain cooling rate, to filter and to dry; wherein the high temperature end is 40-50℃, the ratio of the solid to the solvent is 3.62-6.34g / L, the cooling rate is 0.1-1℃ / min, and the low temperature end is 0-5℃.

7. A process for preparing a crystalline form of tizanidine according to claim 5, characterized by, The suspension crystallization method is to suspend tizanidine in a solvent, to filter and to dry; wherein the ratio of tizanidine to the solvent is 0.05-0.10g / mL, and the suspension time is 12-24h.

8. A process for preparing a crystalline form of tizanidine according to claim 5, characterized by, The solvent evaporation crystallization method is to completely dissolve tizanidine in a solvent, and to evaporate until crystals are precipitated; wherein the volume of the solvent added is enough to completely dissolve tizanidine, and the evaporation time is determined by the precipitation of crystals.

9. A process for preparing a crystalline form of tizanidine according to claim 5, characterized by, The solvent is selected from one of acetone, butanone, benzene and diethyl ether.

10. A process for preparing a crystalline form of tizanidine according to claim 5, characterized in that, The drying condition is air blowing drying at 40-60℃ for 8-12h.

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