CN109535151B - Crystal form A of tizanidine tosylate, preparation method and application thereof - Google Patents
Crystal form A of tizanidine tosylate, preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a tizanidine p-toluenesulfonate crystal form A, a preparation method and application thereof. The tizanidine p-toluenesulfonate crystal form A provided by the invention uses a Cu-K alpha radiation source to carry out X-ray powder diffraction, and the 2 theta diffraction angles are 6.7+/-0.2, 13.5+/-0.2, 20.4+/-0.2, 21.4+/-0.2 and 24.3+/-0.2 degrees, so that the tizanidine p-toluenesulfonate crystal form A has characteristic absorption peaks. The product of the invention has high chemical purity, stable property and low hygroscopicity, and provides an effective solution for improving the safety and effectiveness of the medicine; in addition, the preparation process of the product of the invention is simple, the reaction time is short, the yield is high, the reproducibility is good, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to a tizanidine p-toluenesulfonate crystal form A, and a preparation method and application thereof, belonging to the technical field of pharmaceutical chemistry.
Background
Tizanidine (Tizanidine) is a central skeletal muscle relaxant with an imidazoline structure, and has the chemical name 5-chloro-N- (4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazol-4-amine, and the molecular formula: c (C) 9 H 8 ClN 5 S, molecular weight: 253.71, which has the following chemical structural formula:
tizanidine is the only novel central skeletal muscle relaxant and central alpha 2 adrenergic receptor agonist on the market at present with gastrointestinal tract protection, and is first developed by the company of northwest, switzerland, and is first marketed in denmark and switzerland in 1988, and then subsequently received sales approval in more than 20 countries in europe, the united states, japan, etc. Can be used for treating diseases caused by central injury such as skeletal muscle tension increase, muscle spasm and myotonia. Has good effects on tension headache, trigeminal neuralgia, myofascial pain syndrome and the like. Can also be used as general anesthesia or regional anesthesia auxiliary drug, preoperative and postoperative sedative drug and postoperative analgesic drug. Tizanidine can relieve spasticity, but does not cause muscle weakness, and the therapeutic dose does not produce psychological dependence, so that the tizanidine is a central muscle relaxant with better tolerance and curative effect.
As a novel central alpha 2 adrenergic receptor agonist, tizanidine has the effects of sedation, analgesia and anxiolytic, has small influence on respiratory and cardiovascular systems, can provide stable hemodynamics, has small side effect and good safety. Has wide application prospect in aspects of anti-spasmodic, curing various pains and anesthesia.
In clinical use, nearly half of the active drug molecules are ultimately present and administered in the form of salts. Compared with the free form of the drug, the salt formation of the drug with the oppositely charged molecules or ions can effectively improve certain undesirable physicochemical or biopharmaceutical properties of the drug, such as changing the solubility of the drug, reducing hygroscopicity, improving stability, changing melting point, improving grinding performance, facilitating preparation and purification, improving permeability, reducing adverse reactions of the drug, and the like. Tizanidine has poor water solubility, and can effectively improve the water solubility and the physical and chemical stability of tizanidine after salification, thereby improving the bioavailability. Therefore, tizanidine salts tend to have advantages over the original form of tizanidine in medical applications, which is beneficial to the maximum exertion of the drug action. For example, tizanidine hydrochloride, which is mainly marketed at present, is generally widely used in the form of tablets or capsules for treating diseases such as increased skeletal muscle tone, muscle spasms, myotonia, and the like caused by brain and spinal cord trauma, cerebral hemorrhage, encephalitis, multiple sclerosis, and the like. Has a relatively mature clinical study. Therefore, the exploration and research on the salt form of the medicine can play a positive role in promoting clinical medication.
Currently, studies on tizanidine salts have focused mainly on tizanidine hydrochloride. For example, processes for preparing tizanidine hydrochloride are reported in the documents of US3843668A, AU505664B2, EP0644192B1, CN102140095, etc., and crystalline forms of tizanidine hydrochloride are also disclosed in patent CN105566314 a. Tizanidine hydrochloride prepared according to the technology disclosed at present is often more in impurity, and needs to be refined and purified by processes such as recrystallization and the like. However, the tizanidine hydrochloride finished product obtained after refining is mostly yellow or light yellow solid, and still contains a plurality of colored impurities which are not easy to remove, so that the quality of the finished product is difficult to reach the standard.
It is well known that for pharmaceuticals, different salt forms have different crystalline forms, and that the same salt form may also exist as a polymorph. Different crystal forms may have different colors, melting points, stability, apparent solubility, dissolution rate, etc., which directly affect the stability, solubility, hygroscopicity, bioavailability, etc., of the pharmaceutical preparation, and thus cause differences in the quality and clinical efficacy of the pharmaceutical product. Therefore, it is very interesting to develop various crystalline salts of tizanidine of high purity and a process for their preparation.
Disclosure of Invention
The invention aims to provide the tizanidine p-toluenesulfonate crystal form A with high chemical purity, stable property and low hygroscopicity.
The invention also provides a preparation method, a pharmaceutical composition and application of the tizanidine p-toluenesulfonate crystal form A.
The structural formula of the tizanidine tosylate is as follows:
when the tizanidine p-toluenesulfonate crystal form A provided by the invention adopts a Cu-K alpha radiation source to carry out X-ray powder diffraction, the tizanidine p-toluenesulfonate crystal form A has characteristic absorption peaks at the 2 theta diffraction angles of 6.7+/-0.2, 13.5+/-0.2, 20.4+/-0.2, 21.4+/-0.2 and 24.3+/-0.2 degrees in an X-ray powder diffraction pattern.
Further, the tizanidine tosylate crystal form A has characteristic absorption peaks at 12.3+/-0.2 degrees and 27.3+/-0.2 degrees in an X-ray powder diffraction diagram.
Further, the tizanidine tosylate crystal form A has characteristic absorption peaks at 18.5+/-0.2, 22.6+/-0.2 and 25.9+/-0.2 degrees of 2 theta diffraction angles in an X-ray powder diffraction diagram.
Further, in the X-ray powder diffraction pattern of the tizanidine tosylate crystal form a, the relative intensity value of the characteristic peak of the 2 theta diffraction angle is as follows:
further, the X-ray powder diffraction of tizanidine p-toluenesulfonate form a is shown in fig. 1.
The invention provides a preparation method of the tizanidine p-toluenesulfonate crystal form A, which comprises the following operation steps:
(a) Taking tizanidine, adding an organic solvent and p-toluenesulfonic acid, heating and stirring for reaction;
(b) Cooling, crystallizing, filtering, washing and drying to obtain the tizanidine p-toluenesulfonate crystal form A.
Further, in the step (a), the organic solvent is selected from one or more of C1-C4 alcohol solvents and ether solvents; preferably one or more of methanol, ethanol, n-propanol, isopropanol, ethylene glycol, diethyl ether, tetrahydrofuran, methyl tert-butyl ether and isopropyl ether.
Further, in the step (a), the mass-volume ratio of tizanidine to the solvent is 1:8-1:50 g/mL; preferably 1:10 to 1:30g/mL.
Further, in step (a), the molar ratio of p-toluenesulfonic acid to tizanidine is from 0.8:1 to 3:1, preferably from 1:1 to 1.3:1.
Further, in the step (a), the heating and stirring reaction is performed at a temperature ranging from 10 ℃ to 120 ℃; preferably at a temperature in the range of room temperature to 50 ℃.
Further, in the step (b), the crystallization is performed at a temperature ranging from-10 to 40 ℃; preferably in the temperature range of 0 to 15 ℃; the crystallization is standing crystallization; the drying is vacuum drying at 35 ℃.
The invention also provides a pharmaceutical composition which comprises the tizanidine p-toluenesulfonate crystal form A as an active ingredient and a pharmaceutically acceptable excipient. The pharmaceutical composition can be prepared into various preparations.
The preparation of the invention can be liquid preparation, gas preparation, solid preparation and semisolid preparation, such as aromatic water agent, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, capsule, film, ointment, suppository, paste and other common dosage forms.
The pharmaceutically acceptable excipient refers to an additive except a main drug in a pharmaceutical preparation, and can also be called an auxiliary material. Excipients commonly used for oral or external preparations include, but are not limited to, fillers (diluents), lubricants (glidants or anti-adherents), dispersants, wetting agents, binders, conditioning agents, solubilizing agents, antioxidants, bacteriostats, emulsifiers, disintegrants, and the like. Binders such as syrup, acacia, gelatin, starch slurry, povidone, cellulose derivatives, etc.; fillers such as lactose, dextrin, starch and derivatives thereof, cellulose derivatives, inorganic calcium salts, mannitol, agar powder, etc.; lubricants such as silica gel micropowder, stearic acid and its salts, talc, hydrogenated vegetable oil, polyethylene glycols, etc.; disintegrants such as starch and its derivatives, crospovidone, cellulose derivatives, etc.; wetting agents such as water, alcohols or other organic solvents, and the like. Common excipients for such injections include, but are not limited to: antioxidants such as sodium sulfite, sodium bisulfite, sodium metabisulfite, succinic acid, and the like; bacteriostats such as 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol, and the like; regulators such as hydrochloric acid, citric acid, potassium hydroxide (sodium), buffers, etc.; emulsifying agents such as polysorbate-80, lecithin, soybean lecithin, etc.; solubilizing agents such as tween-80, bile, glycerol, etc. In addition, the active ingredient and a pharmaceutically acceptable sustained and controlled release carrier can be prepared into a sustained and controlled release preparation according to the preparation method of the sustained and controlled release preparation well known in the art.
The invention also provides application of the tizanidine p-toluenesulfonate crystal form A in preparing medicaments for treating diseases related to central skeletal muscle relaxation.
The tizanidine p-toluenesulfonate crystal form A fills the blank of the prior art; compared with the prior product tizanidine hydrochloride, the tizanidine p-toluenesulfonate crystal form A provided by the invention has high chemical purity, good high-temperature stability, high-humidity stability and illumination stability, and lower hygroscopicity, and provides an effective solution for improving the safety and effectiveness of medicaments; has important significance for further researching the curative effect of the solid medicine. In addition, the preparation process of the product of the invention is simple, the reaction time is short, the yield is high, the reproducibility is good, and the method is suitable for industrial production.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of tizanidine p-toluenesulfonate crystalline form A obtained in example 1 of the present invention.
Detailed Description
The raw material tizanidine used in the invention can be prepared according to a method reported in literature, such as documents EP644192, CN102140095, journal of Chinese medicine industry, 2005,36,593, journal of Chinese New medicine, 2006,15,621, university of Yanbian (Nature science edition), 2001,27,277 and the like, and can also be purchased and marketed.
EXAMPLE 1 preparation of tizanidine p-toluenesulfonate form A
Weighing 10g of tizanidine, adding 150mL of methanol and 150mL of ethanol, adding 8.82g of p-toluenesulfonic acid under stirring, heating to 45-50 ℃ and stirring for reaction, stopping heating when the reaction is complete, slowly cooling to 0 ℃, and standing for crystallization for 4 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 16.02g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 95.4% and the HPLC purity is 99.91%. Mass spectra showed its MS (m/z): 253 (M) + )。
The X-ray powder diffractometer of DX-2700 type is adopted to analyze the crystalline phase of the sample, cu-K alpha radiation, tube voltage of 35KV and tube current of 30mA are adopted, the X-ray powder diffractogram of the tizanidine p-toluenesulfonic acid crystalline form A is shown in figure 1, and diffraction related data are shown in table 1. Wherein, 2 theta measurement error is + -0.2 DEG, relative intensity measurement error is + -5%, and sometimes even + -20%.
TABLE 1X-ray powder diffraction data for tizanidine tosylate form A
Further, the crystal form a has the following X-ray powder diffraction characteristics:
experiment 2 preparation of tizanidine p-toluenesulfonate form A
10g of tizanidine is weighed, 100mL of diethyl ether and 100mL of methyl tertiary butyl ether are added, 7.47g of p-toluenesulfonic acid is added under stirring, stirring reaction is carried out at room temperature, after the reaction is complete, heating is stopped, the temperature is slowly reduced to 10 ℃, and then standing crystallization is carried out for 3 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 15.75g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 93.8% and the HPLC purity is 99.95%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
Weighing 10g of tizanidine, adding 200mL of isopropanol, adding 7.47g of p-toluenesulfonic acid under stirring, heating to 45-50 ℃ for stirring reaction, stopping heating when the reaction is complete, slowly cooling to 5 ℃, and standing for crystallization for 3 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 16.35g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 97.4% and the HPLC purity is 99.93%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
Experiment 4 preparation of tizanidine p-toluenesulfonate Crystal form A
Weighing 10g of tizanidine, adding 300mL of n-propanol, adding 9.0g of p-toluenesulfonic acid monohydrate under stirring, heating to 40-45 ℃ and stirring for reaction, stopping heating when the reaction is complete, slowly cooling to 15 ℃, and standing for crystallization for 2 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 16.55g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 98.6% and the HPLC purity is 99.94%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
Experiment 5 preparation of tizanidine p-toluenesulfonate form A
Weighing 10g of tizanidine, adding 100mL of glycol, adding 7.47g of p-toluenesulfonic acid under stirring, heating to 30-35 ℃ for stirring reaction, stopping heating when the reaction is complete, slowly cooling to 0 ℃, and standing for crystallization for 3 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 15.91g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 94.8% and the HPLC purity is 99.97%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
Experiment 6 preparation of tizanidine p-toluenesulfonate Crystal form A
Weighing 10g of tizanidine, adding 150mL of diethyl ether, adding 7.13g of p-toluenesulfonic acid under stirring, stirring at room temperature for reaction, stopping heating after the reaction is complete, slowly cooling to 10 ℃, and standing for crystallization for 4 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 16.07g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 95.7% and the HPLC purity is 99.95%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
Experiment 7 preparation of tizanidine p-toluenesulfonate form A
Weighing 10g of tizanidine, adding 250mL of methyl tertiary butyl ether, adding 8.25g of p-toluenesulfonic acid monohydrate under stirring, heating to 30-35 ℃ for stirring reaction, stopping heating when the reaction is complete, slowly cooling to 15 ℃, and standing for crystallization for 2 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 16.13g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 96.1% and the HPLC purity is 99.94%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
Experiment 8 preparation of tizanidine p-toluenesulfonate Crystal form A
10g of tizanidine is weighed, 200mL of tetrahydrofuran is added, 6.79g of p-toluenesulfonic acid is added under stirring, stirring reaction is carried out at room temperature, heating is stopped after the reaction is complete, and after the temperature is slowly reduced to 15 ℃, standing crystallization is carried out for 2 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 16.45g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 98.0% and the HPLC purity is 99.99%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
Weighing 10g of tizanidine, adding 100mL of isopropyl ether, adding 8.14g of p-toluenesulfonic acid under stirring, heating to 30-35 ℃ for stirring reaction, stopping heating when the reaction is complete, slowly cooling to 10 ℃, and standing for crystallization for 4 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 15.73g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 93.7% and the HPLC purity is 99.96%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
Experiment 10 preparation of tizanidine p-toluenesulfonate form A
10g of tizanidine is weighed, 300mL of methanol is added, 7.50g of p-toluenesulfonic acid monohydrate is added under stirring, the reaction is stirred at room temperature, heating is stopped when the reaction is complete, the temperature is slowly reduced to 5 ℃, and the mixture is kept stand for 3 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 15.86g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 94.5% and the HPLC purity is 99.92%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
Experiment 11 preparation of tizanidine p-toluenesulfonate Crystal form A
Weighing 10g of tizanidine, adding 200mL of ethanol, adding 6.79g of p-toluenesulfonic acid under stirring, stirring at room temperature for reaction, stopping heating after the reaction is complete, slowly cooling to 5 ℃, and standing for crystallization for 2 hours. Filtering, washing and vacuum drying at 35 ℃ to obtain 16.23g white powdery tizanidine p-toluenesulfonate crystals, wherein the yield is 96.7% and the HPLC purity is 99.96%. The obtained sample was subjected to X-ray powder diffraction analysis, and the diffraction pattern thereof was substantially as shown in fig. 1, in accordance with the identification result of example 1.
The beneficial effects of the present invention are described below by test examples
Test example 1 solubility test of tizanidine p-toluenesulfonate form A
Test group: tizanidine p-toluenesulfonate crystal form a prepared in example 1;
control group: tizanidine (prepared according to the method reported in prior art CN 102140095).
The test method comprises the following steps: weighing a sample to be ground into fine powder, and placing the sample in water at 25+/-2 ℃ for strong shaking for 30 seconds every 5 minutes; dissolution was observed within 30 minutes, i.e., when no visually observable solute particles were present, i.e., deemed complete dissolution, and the results are shown in table 2.
TABLE 2 solubility of tizanidine p-toluenesulfonate form A
| Test article | Solubility of |
| Test group | 19.14mg/mL |
| Control group | 0.27mg/mL |
The solubility test results in Table 2 show that the solubility of the tizanidine p-toluenesulfonate crystal form A prepared by the invention is greatly improved relative to that of tizanidine. Under the general condition, the good water solubility is beneficial to improving the bioavailability of the medicine, improving the curative effect and the safety of the medicine, reducing the stimulation generated during clinical medication and improving the compliance of patients.
Test example 2 stability Effect test of tizanidine p-toluenesulfonate form A
(1) Influence factor test
The conditions under investigation were intense light irradiation (4500.+ -. 500 lx), high temperature (60 ℃) and high humidity (relative humidity 92.5%,25 ℃). The tizanidine p-toluenesulfonate crystal form A prepared in the example 1 of the invention is respectively placed for 10 days under different investigation conditions, and is respectively sampled and measured on the 5 th day and the 10 th day, and compared with the data of the same batch of samples on the 0 th day, and the results are shown in Table 3.
TABLE 3 influence factor test results for tizanidine tosylate form A
The test results in Table 3 show that the tizanidine p-toluenesulfonate crystal form A prepared by the invention has unchanged product properties under the conditions of illumination, high temperature and high humidity, and the content and the total impurity amount have no obvious change, thus indicating that the product has good stability.
(2) Acceleration test
Sealing and packaging the tizanidine p-toluenesulfonate crystal form A prepared in the embodiment 1 by using a polyethylene film plastic bag, placing the tizanidine p-toluenesulfonate crystal form A in a constant temperature and humidity incubator with the temperature of 40+/-2 ℃ and the relative humidity of 75+/-5%, placing the tizanidine p-toluenesulfonate crystal form A in the incubator for six months, sampling and detecting at the end of 1,2,3 and 6 months respectively, and comparing the results with the results of 0 month. The results are shown in Table 4.
TABLE 4 accelerated test results for tizanidine p-toluenesulfonate form A
The test results in Table 4 show that the tizanidine p-toluenesulfonate crystal form A provided by the invention has unchanged properties, no obvious reduction in content and no obvious increase in total impurity content under the condition of acceleration test within six months, and meets the quality standard. Therefore, the tizanidine p-toluenesulfonate crystal form A provided by the invention has stable properties and is suitable for long-term storage. Test example 3 hygroscopicity effect test of tizanidine p-toluenesulfonate form A
The hygroscopicity of a drug refers to the property of the substance to absorb water at a certain temperature and humidity.
The test samples were as follows:
test group 1: the tizanidine p-toluenesulfonate crystal form A prepared according to the embodiment 1 of the invention;
test group 2: the tizanidine p-toluenesulfonate crystal form A prepared according to the embodiment 2 of the invention;
test group 3: the tizanidine p-toluenesulfonate crystal form A prepared according to the invention example 5;
test group 4: tizanidine p-toluenesulfonate crystal form A prepared in example 9 of the invention;
control group: tizanidine hydrochloride (prepared according to the method reported in document CN 105566314).
And taking a proper amount of a test sample, and testing according to the rule of guiding the moisture permeability test of the XIX J medicine of the two appendices of Chinese pharmacopoeia (2010 edition).
The specific test method is as follows:
1. the dried glass weighing bottle with plug (with the outer diameter of 50mm and the height of 15 mm) is placed in a proper constant temperature dryer (with ammonium chloride or ammonium sulfate saturated solution placed at the lower part) or a climatic box (with the set temperature of 25 ℃ +/-1 ℃ and the relative humidity of 80% +/-2%) at the temperature of 25 ℃ +/-1 ℃ on the previous day, and is precisely weighed (m 1).
2. And (3) taking a proper amount of a test sample, placing the test sample into the weighing bottle, spreading the test sample in the weighing bottle, and precisely weighing the test sample with the thickness of about 1mm (m 2).
3. The weighing bottle is opened and placed under the constant temperature and humidity condition for 24 hours together with the bottle cap.
4. The lid of the weighing bottle is covered, and the bottle is precisely weighed (m 3).
Percentage of weight gain = (m 3-m 2)/(m 2-m 1) ×100%
5. Characterization of hygroscopicity and definition of the weight gain of hygroscopicity
Deliquescence: absorbing a sufficient amount of moisture to form a liquid.
The moisture absorption performance is very good: the weight gain caused by moisture is not less than 15%.
Moisture permeability: the weight gain by moisture absorption is less than 15 percent but not less than 2 percent.
Slightly hygroscopic: the weight gain by moisture absorption is less than 2 percent but not less than 0.2 percent.
No or little hygroscopicity: the weight gain caused by moisture is less than 0.2 percent.
The test results are shown in Table 5.
TABLE 5 results of moisture absorption test
The test results in Table 5 show that tizanidine hydrochloride in the control group is placed for 24 hours under the relative humidity condition, and the moisture absorption weight gain is obvious, so that the tizanidine hydrochloride in the prior art has the moisture absorption property. And the tizanidine tosylate crystal form A of the test group is placed for 24 hours under the same condition, so that the moisture absorption and weight gain are not obvious, and the product has no or almost no moisture absorption. Compared with tizanidine hydrochloride in the prior art, the tizanidine p-toluenesulfonate crystal form A prepared by the invention has obviously reduced hygroscopicity, can effectively avoid the moisture absorption and deliquescence of the product in the long-term storage process, is beneficial to long-term stable storage and transportation of the product, does not need to particularly control the environmental humidity when preparing the preparation, and is more beneficial to the preparation of the preparation.
In summary, compared with tizanidine hydrochloride in the prior art, the tizanidine p-toluenesulfonate crystal form A provided by the invention has unexpected property improvement, and the product has stable property, high purity and low hygroscopicity, thereby providing an effective solution for improving the safety and effectiveness of medicaments; in addition, the preparation process of the tizanidine p-toluenesulfonate crystal form A provided by the invention is simple, the reaction time is short, no special requirements are made on equipment, the product yield is high, and the preparation process is suitable for industrial production.
Claims (8)
1. A crystalline form a of tizanidine p-toluenesulfonate, characterized in that: in the X-ray powder diffraction diagram of the crystal form A, the diffraction angles of 2 theta are 6.7+/-0.2, 12.3+/-0.2, 13.5+/-0.2, 18.5+/-0.2, 20.4+/-0.2, 21.4+/-0.2, 22.6+/-0.2, 24.3+/-0.2, 25.9+/-0.2 and 27.3+/-0.2 degrees, and the characteristic absorption peaks are formed.
2. Crystalline form a of tizanidine p-toluenesulfonate according to claim 1, characterized in that: form a has an X-ray powder diffraction pattern substantially as shown in figure 1.
3. The preparation method of the tizanidine p-toluenesulfonate crystal form A as claimed in claim 1 or 2, comprising the following steps:
(a) Taking tizanidine, adding an organic solvent and p-toluenesulfonic acid, heating and stirring for reaction;
(b) Cooling, crystallizing, filtering, washing and drying to obtain tizanidine p-toluenesulfonate crystal form A;
in the step (a), the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, ethylene glycol, diethyl ether, tetrahydrofuran, methyl tertiary butyl ether and isopropyl ether; the heating and stirring reaction is carried out within the temperature range of room temperature to 50 ℃;
in the step (b), the crystallization is performed at a temperature ranging from 0 to 15 ℃; and the crystallization is standing crystallization.
4. A process for the preparation of tizanidine p-toluenesulfonate form a according to claim 3 characterized in that: in the step (a), the mass-volume ratio of tizanidine to the organic solvent is 1:10-1:30 g/mL.
5. A process for the preparation of tizanidine p-toluenesulfonate form a according to claim 3 characterized in that: in the step (a), the molar ratio of the p-toluenesulfonic acid to the tizanidine is 1:1-1.3:1.
6. A process for the preparation of tizanidine p-toluenesulfonate form a according to claim 3 characterized in that: in step (b), the drying is vacuum drying at 35 ℃.
7. A pharmaceutical composition characterized by comprising as an active ingredient tizanidine p-toluenesulfonate crystalline form a according to claim 1 or 2, together with pharmaceutically acceptable excipients.
8. Use of tizanidine p-toluenesulfonate form a according to claim 1 or 2 for the preparation of a medicament for the treatment of diseases related to central skeletal muscle relaxation.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101045051A (en) * | 2006-04-12 | 2007-10-03 | 四川科瑞德制药有限公司 | Novel use of tizanidine or its derivatives |
| CN101190218A (en) * | 2006-11-20 | 2008-06-04 | 四川科瑞德制药有限公司 | New use of tizanidine and its derivatives |
| WO2010069280A2 (en) * | 2008-12-18 | 2010-06-24 | Farmak, A.S. | A method for the preparation of tizanidine hydrochloride |
| CN106946874A (en) * | 2017-04-07 | 2017-07-14 | 四川智强医药科技开发有限公司 | The discoloration method of Tizanidine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101045051A (en) * | 2006-04-12 | 2007-10-03 | 四川科瑞德制药有限公司 | Novel use of tizanidine or its derivatives |
| CN101190218A (en) * | 2006-11-20 | 2008-06-04 | 四川科瑞德制药有限公司 | New use of tizanidine and its derivatives |
| WO2010069280A2 (en) * | 2008-12-18 | 2010-06-24 | Farmak, A.S. | A method for the preparation of tizanidine hydrochloride |
| CN106946874A (en) * | 2017-04-07 | 2017-07-14 | 四川智强医药科技开发有限公司 | The discoloration method of Tizanidine |
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