CN109535149A - Methanesulfonic acid Tizanidine compound and its preparation method and application - Google Patents
Methanesulfonic acid Tizanidine compound and its preparation method and application Download PDFInfo
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- CN109535149A CN109535149A CN201710864370.3A CN201710864370A CN109535149A CN 109535149 A CN109535149 A CN 109535149A CN 201710864370 A CN201710864370 A CN 201710864370A CN 109535149 A CN109535149 A CN 109535149A
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- methanesulfonic acid
- tizanidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention provides a kind of methanesulfonic acid Tizanidine compounds and its preparation method and application.Methanesulfonic acid Tizanidine compound provided by the invention is existed in the form of crystal, and chemical purity is high, property is stable, dissolubility is good, low in hygroscopicity, provides effective solution approach for the raising of drug safety and validity；In addition, the preparation process of the compounds of this invention is simple, the reaction time is short, high income, favorable reproducibility, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of methanesulfonic acid Tizanidine compounds, and in particular to the crystal form of the compound and its preparation
Method and purposes, belong to field of pharmaceutical chemistry technology.
Background technique
Tizanidine (Tizanidine) is a kind of central skeletal muscle relaxant with imidazoline structure, and chemistry is entitled
The chloro- N- of 5- (4,5- dihydro -1H- imidazoles -2- base) -2,1,3- diazosulfide -4- amine, molecular formula: C9H8ClN5S, molecular weight:
253.71, chemical structural formula is as follows:
Tizanidine be currently on the market uniquely with pipe intestinal protection effect novel central skeletal muscle relaxant with
2 adrenoceptor agonists of central α are developed by Novartis Co., Ltd, Switzerland earliest, in 1988 for the first time in Denmark and
Switzerland's listing then obtains selling license in more than 20 countries such as Europe, the U.S., Japan successively.Clinically for treating maincenter
Property damage caused by the diseases such as bone hypermyotonia, muscle spasmus and myotonia.To tension headache, trigeminal neuralgia and flesh muscle
Film pain syndrome etc. has good result.Also general anesthesia or regional anesthesia adjuvant, preoperative and postoperative sedative, postoperative be can be used as
Analgesic.Tizanidine can alleviate spasticity, but not cause myasthenia, and therapeutic dose does not generate psychologic dependence, be
Tolerance and the preferable central muscle relaxant of curative effect.
As novel 2 adrenoceptor agonists of maincenter α, Tizanidine has both calm, analgesia and angst resistance effect, right
Breathing, cardiovascular system influence are small, can provide stable haemodynamics, Small side effects, safety are good.In anti-spasm, treatment
Various pain and anesthesia aspect application prospect are extensive.
In clinical application, the active drug molecule of nearly half is all finally to exist and be administered in a salt form.With medicine
The free form of object is compared, and after the molecule or ion of drug and oppositely charged are at salt, can be effectively improved that drug is certain to be paid no attention to
The physical chemistry or biopharmaceutical properties thought, such as change the solubility of drug, reduce hygroscopicity, improve stability, changing and melt
Point improves grinding performance, convenient for preparation purifying, raising permeability, the adverse reaction for reducing drug etc..The water solubility of Tizanidine
It is poor, at its water-soluble and physical and chemical stability can be effectively improved after salt, improve bioavilability.Therefore, Tizanidine
Salt is often more more advantageous than its original shape drug Tizanidine in medical application, is conducive to play drug to greatest extent
Effect.Such as current market sales of predominantly Tizanidine, it is usually answered in the form of tablet or capsule extensively
For treating bone hypermyotonia, muscle spasmus caused by brain and trauma of spinal cord, cerebral hemorrhage, encephalitis and multiple sclerosis etc.
With the diseases such as myotonia.Clinical research with comparative maturity.As it can be seen that the exploration and research to drug salt form can use clinic
Medicine plays positive impetus.
Currently, the research for Tizanidine salt is concentrated mainly on Tizanidine hydrochloride.For example, US3843668A,
The preparation method of Tizanidine, patent are reported in the documents such as AU505664B2, EP0644192B1, CN102140095
The crystal form of Tizanidine is also disclosed in CN105566314A.According to the hydrochloric acid that presently disclosed technology is prepared for bundle
The fixed often impurity of Buddhist nun is more, needs to undergo the techniques refining and edulcorations such as recrystallization.But the Tizanidine obtained after purification at
Product are mostly yellow or faint yellow solid, still band there are many being not easy the foreign pigment removed so that final product quality be difficult to it is up to standard.
It is well known that different salt form has different crystal forms, and there is likely to be more for same salt form for drug
Crystal form.And different crystal forms is possible to have different colors, fusing point, stability, apparent solubility, rate of dissolution etc.,
These properties will have a direct impact on stability, solubility, hygroscopicity, bioavilability of pharmaceutical preparation etc., and thus lead to medicine
The difference of quality and clinical drug effect.Therefore, the various crystal salts of the Tizanidine of high-purity and preparation method thereof right and wrong are developed
It is often significant.
Summary of the invention
The purpose of the present invention is to provide a kind of chemical purity height, property is stable, dissolubility is good, low in hygroscopicity methanesulfonic acid
Tizanidine compound.
The present invention also provides the preparation method of the methanesulfonic acid Tizanidine compound, pharmaceutical composition and purposes.
The structural formula of methanesulfonic acid Tizanidine compound of the present invention is as follows:
Methanesulfonic acid Tizanidine compound provided by the invention, it is characterised in that it is existed in the form of crystal form A, this hair
When bright compound carries out X-ray powder diffraction using Cu-K α radiation source, in X-ray powder diffraction figure, the 2 θ angles of diffraction exist
10.3 ± 0.2,14.1 ± 0.2,20.6 ± 0.2,21.9 ± 0.2,22.2 ± 0.2 degree have characteristic absorption peak.
Further, the methanesulfonic acid Tizanidine compound is in X-ray powder diffraction figure, and the 2 θ angles of diffraction are also 23.3
± 0.2,24.0 ± 0.2,25.4 ± 0.2,31.1 ± 0.2 degree has characteristic absorption peak.
Further, in the X-ray powder diffraction figure of the methanesulfonic acid Tizanidine compound, 2 θ angle of diffraction characteristic peaks
Relative intensity value are as follows:
Further, the X-ray powder diffraction of the methanesulfonic acid Tizanidine compound is as shown in Figure 1.
The present invention provides the preparation methods of above-mentioned methanesulfonic acid Tizanidine compound, it includes following operating procedure:
(a), Tizanidine is taken, organic solvent and methanesulfonic acid, heating stirring reaction is added；
(b), cool down crystallization, filters, washing, dry to get methanesulfonic acid Tizanidine crystal form A.
Wherein, organic solvent described in step (a) is selected from one of alcohols solvent or a variety of；It is preferred that methanol, ethyl alcohol, just
One of propyl alcohol, isopropanol, ethylene glycol are a variety of.
Further, in step (a), the mass volume ratio of the Tizanidine and solvent is 1:10~1:100g/mL, excellent
It is selected as 1:30~1:60g/mL.
Further, in step (a), the molar ratio of the methanesulfonic acid and Tizanidine is 0.8:1~3:1, preferably 1:1
~1.2:1.
Further, in step (a), the heating stirring reaction carries out within the temperature range of 10~120 DEG C, preferably exists
It is carried out within the temperature range of 45~70 DEG C.
Further, in step (b), the crystallization carries out within the temperature range of -10~40 DEG C, preferably room temperature into
Row；The crystallization is to stand crystallization；The drying is 35 DEG C of vacuum drying.
The present invention also provides a kind of pharmaceutical composition, comprising above-mentioned methanesulfonic acid Tizanidine crystal form A as active constituent,
And the pharmaceutical preparation that pharmaceutically acceptable excipient is prepared.
Pharmaceutical preparation of the present invention can be liquid preparation, gaseous formulation, solid pharmaceutical preparation and semisolid preparation, preferably
Aromatic waters, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, capsule, film
Agent, ointment, suppository, paste.
Pharmaceutically acceptable excipient of the present invention, refers to the additives in pharmaceutical preparation in addition to main ingredient,
It can be described as auxiliary material.Oral preparation or the common excipient of external preparation include but are not limited to filler (diluent), lubricant
(glidant or antitack agent), dispersing agent, adhesive, regulator, solubilizer, antioxidant, bacteriostatic agent, emulsifier, collapse wetting agent
Solve agent etc..Adhesive such as syrup, Arabic gum, gelatin, starch slurry, povidone, cellulose derivative etc.；Filler such as cream
Sugar, dextrin, starch and its derivative, cellulose derivative, inorganic calcium salt, mannitol, agar powder etc.；Lubricant such as micro mist silicon
Glue, stearic acid and its esters, talcum powder, hydrogenated vegetable oil, polyethylene glycols etc.；Disintegrating agent such as starch and its derivative, crosslinking
Povidone, cellulose derivative etc.；Wetting agent such as water, alcohols or other organic solvents etc..The common figuration of injection
Agent includes but are not limited to: antioxidant such as sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, two phenylpropenoic acid of fourth etc.；Bacteriostatic agent is such as
0.5% phenol, 0.3% cresols, 0.5% anesin etc.；Regulator such as hydrochloric acid, citric acid, potassium hydroxide (sodium), buffer
Deng；Emulsifier such as Tween-80, lecithin, Fabaceous Lecithin etc.；Solubilizer such as Tween-80, bile, glycerol etc..In addition, may be used also
By active constituent and pharmaceutically acceptable slow controlled release carrier, according to the preparation method system of sustained-release preparation known in the art
At sustained-release preparation.
The present invention also provides above-mentioned methanesulfonic acid Tizanidine crystal form A to treat central skeletal muscle relaxation correlation disease in preparation
Purposes in the drug of disease.
The present invention also provides a kind of methanesulfonic acid Tizanidine compounds, it is characterised in that it is deposited in the form of crystal form B
When, the compounds of this invention carries out X-ray powder diffraction using Cu-K α radiation source, in X-ray powder diffraction figure, 2 θ spread out
Firing angle has characteristic absorption peak at 14.1 ± 0.2,19.3 ± 0.2,20.6 ± 0.2,21.9 ± 0.2,25.4 ± 0.2 degree.
Further, the methanesulfonic acid Tizanidine compound is in X-ray powder diffraction figure, and the 2 θ angles of diffraction are also 12.6
± 0.2,17.6 ± 0.2,23.7 ± 0.2,23.8 ± 0.2,26.4 ± 0.2,27.5 ± 0.2 degree has characteristic absorption peak.
Further, in the X-ray powder diffraction figure of the methanesulfonic acid Tizanidine compound, 2 θ angle of diffraction characteristic peaks
Relative intensity value are as follows:
Further, the X-ray powder diffraction of the methanesulfonic acid Tizanidine compound is as shown in Figure 2.
The present invention provides the preparation methods of above-mentioned methanesulfonic acid Tizanidine compound, it includes following operating procedure:
(a), methanesulfonic acid Tizanidine is taken, the mixed solvent of water and organic solvent composition, heating stirring reaction is added；
(b), cool down crystallization, filters, washing, dry to get methanesulfonic acid Tizanidine crystal form B.
Wherein, water described in step (a) and organic solvent composition mixed solvent be selected from acetone-water, tetrahydrofuran-water,
The mixed solvent of acetonitrile-water composition.
Further, in step (a), the mass volume ratio of the methanesulfonic acid Tizanidine and water is 1:0.5~1:5g/
mL。
Further, in step (a), the mass volume ratio of the methanesulfonic acid Tizanidine and organic solvent is 1:20~1:
60g/mL。
Further, in step (a), the heating stirring reaction carries out within the temperature range of 10~120 DEG C, preferably exists
It is carried out within the temperature range of 30 DEG C~reflux.
Further, in step (b), the crystallization carries out within the temperature range of -10~40 DEG C, preferably at 10~20 DEG C
Within the temperature range of carry out；The crystallization is stirring and crystallizing；The drying is 35 DEG C of vacuum drying.
The present invention also provides a kind of pharmaceutical composition, comprising above-mentioned methanesulfonic acid Tizanidine crystal form B as active constituent,
And the pharmaceutical preparation that pharmaceutically acceptable excipient is prepared.
Pharmaceutical preparation of the present invention can be liquid preparation, gaseous formulation, solid pharmaceutical preparation and semisolid preparation, preferably
Aromatic waters, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, capsule, film
Agent, ointment, suppository, paste.
Pharmaceutically acceptable excipient of the present invention, refers to the additives in pharmaceutical preparation in addition to main ingredient,
It can be described as auxiliary material.Oral preparation or the common excipient of external preparation include but are not limited to filler (diluent), lubricant
(glidant or antitack agent), dispersing agent, adhesive, regulator, solubilizer, antioxidant, bacteriostatic agent, emulsifier, collapse wetting agent
Solve agent etc..Adhesive such as syrup, Arabic gum, gelatin, starch slurry, povidone, cellulose derivative etc.；Filler such as cream
Sugar, dextrin, starch and its derivative, cellulose derivative, inorganic calcium salt, mannitol, agar powder etc.；Lubricant such as micro mist silicon
Glue, stearic acid and its esters, talcum powder, hydrogenated vegetable oil, polyethylene glycols etc.；Disintegrating agent such as starch and its derivative, crosslinking
Povidone, cellulose derivative etc.；Wetting agent such as water, alcohols or other organic solvents etc..The common figuration of injection
Agent includes but are not limited to: antioxidant such as sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, two phenylpropenoic acid of fourth etc.；Bacteriostatic agent is such as
0.5% phenol, 0.3% cresols, 0.5% anesin etc.；Regulator such as hydrochloric acid, citric acid, potassium hydroxide (sodium), buffer
Deng；Emulsifier such as Tween-80, lecithin, Fabaceous Lecithin etc.；Solubilizer such as Tween-80, bile, glycerol etc..In addition, may be used also
By active constituent and pharmaceutically acceptable slow controlled release carrier, according to the preparation method system of sustained-release preparation known in the art
At sustained-release preparation.
The present invention also provides above-mentioned methanesulfonic acid Tizanidine crystal form B to treat central skeletal muscle relaxation correlation disease in preparation
Purposes in the drug of disease.
Methanesulfonic acid Tizanidine compound provided by the invention, has filled up the blank of the prior art；With existing product hydrochloric acid
Tizanidine is compared, methanesulfonic acid Tizanidine compound provided by the invention, and not only chemical purity is high, have good high temperature,
High humidity and light durability, product low in hygroscopicity, and there is the dissolubility for being substantially better than Tizanidine, it is drug safety
Raising with validity provides effective solution approach；There is important meaning to the curative effect for further studying such solid drugs
Justice.In addition, the preparation process of product of the present invention is simple, the reaction time is short, high income, favorable reproducibility, is suitable for industrialized production.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction pattern of 1 gained methanesulfonic acid Tizanidine crystal form A of the embodiment of the present invention.
Fig. 2 is the X-ray powder diffraction pattern of 9 gained methanesulfonic acid Tizanidine crystal form B of the embodiment of the present invention.
Specific embodiment
The raw materials used in the present invention Tizanidine can method according to the literature be prepared, as document EP644192,
CN102140095, " Chinese Journal of Pharmaceuticals ", 2005,36,593, " Chinese Journal of New Drugs ", 2006,15,621, " Yan Bian great
Learn journal (natural science edition) ", 2001,27,277 etc., it can also be commercially available by purchase.
The preparation of 1 methanesulfonic acid Tizanidine crystal form A of embodiment
50g Tizanidine is weighed, 2.5L methanol and 22.73g methanesulfonic acid is added, it is anti-to be heated to 50~55 DEG C of stirrings
It answers, to fully reacting, stops heating, after slow cooling to room temperature, stand crystallization 4 hours.Filtering is washed, true under the conditions of 35 DEG C
Sky is dried to get 65.84g transparent grain shape methanesulfonic acid Tizanidine crystal form A, yield 95.5%, and HPLC purity is
99.92%.Mass spectrum show its MS (m/z): 253 (M+)。
Sample crystal phase is analyzed using DX-2700 type X-ray powder diffraction instrument, Cu-K α radiation, tube voltage 35KV,
Tube current 30mA, the X-ray powder diffraction pattern for measuring methanesulfonic acid Tizanidine crystal form A are shown in Fig. 1, and diffraction related data is shown in Table 1.
Wherein, 2 θ measurement errors are ± 0.2 °, and relative intensity measure error is ± 5%, are even up to ± 20% sometimes.
The X-ray powder diffraction data of 1 methanesulfonic acid Tizanidine crystal form A of table
Further, the methanesulfonic acid Tizanidine crystal form A has following X-ray powder diffraction feature:
The preparation of 2 methanesulfonic acid Tizanidine crystal form A of embodiment
50g Tizanidine is weighed, 2.0L ethyl alcohol and 18.94g methanesulfonic acid is added, it is anti-to be heated to 60~65 DEG C of stirrings
It answers, to fully reacting, stops heating, after slow cooling to room temperature, stand crystallization 5 hours.Filtering is washed, true under the conditions of 35 DEG C
Sky is dried to get 66.39g transparent grain shape methanesulfonic acid Tizanidine crystal form A, yield 96.3%, and HPLC purity is
99.93%.X-ray powder diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is basic as shown in Figure 1, with embodiment 1
Qualification result is consistent.
The preparation of 3 methanesulfonic acid Tizanidine crystal form A of embodiment
50g Tizanidine is weighed, 1.75L isopropanol and 19.89g methanesulfonic acid is added, is heated to 65~70 DEG C of stirrings
Reaction stops heating to fully reacting, after slow cooling to room temperature, stands crystallization 4 hours.Filtering is washed, under the conditions of 35 DEG C
It is dried in vacuo to get 68.04g transparent grain shape methanesulfonic acid Tizanidine crystal form A, yield 98.7%, HPLC purity is
99.94%.X-ray powder diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is basic as shown in Figure 1, with embodiment 1
Qualification result is consistent.
The preparation of 4 methanesulfonic acid Tizanidine crystal form A of embodiment
50g Tizanidine is weighed, 2.0L normal propyl alcohol and 20.84g methanesulfonic acid is added, it is anti-to be heated to 65~70 DEG C of stirrings
It answers, to fully reacting, stops heating, after slow cooling to room temperature, stand crystallization 3 hours.Filtering is washed, true under the conditions of 35 DEG C
Sky is dried to get 67.15g transparent grain shape methanesulfonic acid Tizanidine crystal form A, yield 97.4%, and HPLC purity is
99.94%.X-ray powder diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is basic as shown in Figure 1, with embodiment 1
Qualification result is consistent.
The preparation of 5 methanesulfonic acid Tizanidine crystal form A of embodiment
50g Tizanidine is weighed, 1.5L ethylene glycol and 20.84g methanesulfonic acid is added, it is anti-to be heated to 65~70 DEG C of stirrings
It answers, to fully reacting, stops heating, after slow cooling to room temperature, stand crystallization 3 hours.Filtering is washed, true under the conditions of 35 DEG C
Sky is dried to get 66.05g transparent grain shape methanesulfonic acid Tizanidine crystal form A, yield 95.8%, and HPLC purity is
99.99%.X-ray powder diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is basic as shown in Figure 1, with embodiment 1
Qualification result is consistent.
The preparation of 6 methanesulfonic acid Tizanidine crystal form A of embodiment
50g Tizanidine is weighed, 1.5L methanol and 500mL ethyl alcohol is added, is added with stirring 18.94g methanesulfonic acid, heating rises
Temperature is stirred to react to 45~50 DEG C, to fully reacting, stops heating, after slow cooling to room temperature, stands crystallization 4 hours.Filtering,
It washs, is dried in vacuo under the conditions of 35 DEG C to get 67.70g transparent grain shape methanesulfonic acid Tizanidine crystal form A, yield 98.2%,
HPLC purity is 99.94%.X-ray powder diffraction analysis carried out to the sample of acquisition, diffracting spectrum it is basic as shown in Figure 1,
It is consistent with the qualification result of embodiment 1.
The preparation of 7 methanesulfonic acid Tizanidine crystal form A of embodiment
50g Tizanidine is weighed, 1.0L ethyl alcohol and 1.0L isopropanol is added, is added with stirring 22.73g methanesulfonic acid, is heated
It is warming up to 55~60 DEG C to be stirred to react, to fully reacting, stops heating, after slow cooling to room temperature, stand crystallization 2 hours.It crosses
Filter is washed, and to get 66.67g transparent grain shape methanesulfonic acid Tizanidine crystal form A, yield is for vacuum drying under the conditions of 35 DEG C
96.7%, HPLC purity are 99.97%.X-ray powder diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is substantially as schemed
It is consistent with the qualification result of embodiment 1 shown in 1.
The preparation of 8 methanesulfonic acid Tizanidine crystal form A of embodiment
50g Tizanidine is weighed, 750mL ethyl alcohol and 750mL ethylene glycol is added, is added with stirring 22.73g methanesulfonic acid, adds
Heat is warming up to 65~70 DEG C and is stirred to react, and to fully reacting, stops heating, after slow cooling to room temperature, stands crystallization 3 hours.
Filtering is washed, and to get 67.36g transparent grain shape methanesulfonic acid Tizanidine crystal form A, yield is for vacuum drying under the conditions of 35 DEG C
97.7%, HPLC purity are 99.96%.X-ray powder diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is substantially as schemed
It is consistent with the qualification result of embodiment 1 shown in 1.
The preparation of 9 methanesulfonic acid Tizanidine crystal form B of embodiment
The methanesulfonic acid Tizanidine that 10g embodiment 1 is prepared is weighed, 300mL tetrahydrofuran and 50mL water, heating is added
30~35 DEG C are warming up to be stirred to react 2 hours.Stop heating, it is small to continue stirring and crystallizing 2 to after 10 DEG C for reaction solution slow cooling
When.Filtering is washed, and to get 9.84g white powder methanesulfonic acid Tizanidine crystal form B, yield is for vacuum drying under the conditions of 35 DEG C
98.4%, HPLC purity are 99.99%.Mass spectrum show its MS (m/z): 253 (M+)。
Sample crystal phase is analyzed using DX-2700 type X-ray powder diffraction instrument, Cu-K α radiation, tube voltage 35KV,
Tube current 30mA, the X-ray powder diffraction pattern for measuring methanesulfonic acid Tizanidine crystal form B are shown in Fig. 2, and diffraction related data is shown in Table 2.
Wherein, 2 θ measurement errors are ± 0.2 °, and relative intensity measure error is ± 5%, are even up to ± 20% sometimes.2 methanesulfonic acid of table
The X-ray powder diffraction data of Tizanidine crystal form B
Further, the methanesulfonic acid Tizanidine crystal form B has following X-ray powder diffraction feature:
The preparation of 10 methanesulfonic acid Tizanidine crystal form B of embodiment
The methanesulfonic acid Tizanidine that 10g embodiment 1 is prepared is weighed, 400mL tetrahydrofuran and 50mL water, heating is added
35~40 DEG C are warming up to be stirred to react 2 hours.Stop heating, it is small to continue stirring and crystallizing 5 to after 15 DEG C for reaction solution slow cooling
When.Filtering is washed, and to get 9.73g white powder methanesulfonic acid Tizanidine crystal form B, yield is for vacuum drying under the conditions of 35 DEG C
97.3%, HPLC purity are 99.97%.X-ray powder diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is substantially as schemed
It is consistent with the qualification result of embodiment 9 shown in 2.
The preparation of 11 methanesulfonic acid Tizanidine crystal form B of embodiment
The methanesulfonic acid Tizanidine that 10g embodiment 1 is prepared is weighed, 200mL acetone and 5mL water, heat temperature raising is added
It is reacted 2 hours to return stirring.Stop heating, reaction solution slow cooling continues stirring and crystallizing 3 hours to after 20 DEG C.Filtering, is washed
It washs, is dried in vacuo under the conditions of 35 DEG C to get 9.66g white powder methanesulfonic acid Tizanidine crystal form B, yield 96.6%,
HPLC purity is 99.96%.X-ray powder diffraction analysis carried out to the sample of acquisition, diffracting spectrum it is basic as shown in Fig. 2,
It is consistent with the qualification result of embodiment 9.
The preparation of 12 methanesulfonic acid Tizanidine crystal form B of embodiment
The methanesulfonic acid Tizanidine that 10g embodiment 1 is prepared is weighed, 400mL acetone and 10mL water, heat temperature raising is added
It is reacted 2 hours to return stirring.Stop heating, reaction solution slow cooling continues stirring and crystallizing 4 hours to after 15 DEG C.Filtering, is washed
It washs, is dried in vacuo under the conditions of 35 DEG C to get 9.77g white powder methanesulfonic acid Tizanidine crystal form B, yield 97.7%,
HPLC purity is 99.96%.X-ray powder diffraction analysis carried out to the sample of acquisition, diffracting spectrum it is basic as shown in Fig. 2,
It is consistent with the qualification result of embodiment 9.
The preparation of 13 methanesulfonic acid Tizanidine crystal form B of embodiment
The methanesulfonic acid Tizanidine that 10g embodiment 1 is prepared is weighed, 600mL acetone and 30mL water, heat temperature raising is added
It is reacted 2 hours to return stirring.Stop heating, reaction solution slow cooling continues stirring and crystallizing 2 hours to after 10 DEG C.Filtering, is washed
It washs, is dried in vacuo under the conditions of 35 DEG C to get 9.85g white powder methanesulfonic acid Tizanidine crystal form B, yield 98.5%,
HPLC purity is 99.97%.X-ray powder diffraction analysis carried out to the sample of acquisition, diffracting spectrum it is basic as shown in Fig. 2,
It is consistent with the qualification result of embodiment 9.
The preparation of 14 methanesulfonic acid Tizanidine crystal form B of embodiment
The methanesulfonic acid Tizanidine that 10g embodiment 1 is prepared is weighed, 300mL acetone and 10mL water, heat temperature raising is added
It is reacted 2 hours to return stirring.Stop heating, reaction solution slow cooling continues stirring and crystallizing 3 hours to after 10 DEG C.Filtering, is washed
It washs, is dried in vacuo under the conditions of 35 DEG C to get 9.91g white powder methanesulfonic acid Tizanidine crystal form B, yield 99.1%,
HPLC purity is 99.98%.X-ray powder diffraction analysis carried out to the sample of acquisition, diffracting spectrum it is basic as shown in Fig. 2,
It is consistent with the qualification result of embodiment 9.
The preparation of 15 methanesulfonic acid Tizanidine crystal form B of embodiment
The methanesulfonic acid Tizanidine that 10g embodiment 1 is prepared is weighed, 300mL acetonitrile and 5mL water, heat temperature raising is added
It is stirred to react 2 hours to 40~45 DEG C.Stop heating, reaction solution slow cooling continues stirring and crystallizing 5 hours to after 20 DEG C.It crosses
Filter is washed, and to get 9.62g white powder methanesulfonic acid Tizanidine crystal form B, yield is for vacuum drying under the conditions of 35 DEG C
96.2%, HPLC purity are 99.98%.X-ray powder diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is substantially as schemed
It is consistent with the qualification result of embodiment 9 shown in 2.
The preparation of 16 methanesulfonic acid Tizanidine crystal form B of embodiment
The methanesulfonic acid Tizanidine that 10g embodiment 1 is prepared is weighed, 500mL acetonitrile and 15mL water, heat temperature raising is added
It is reacted 2 hours to return stirring.Stop heating, reaction solution slow cooling continues stirring and crystallizing 2 hours to after 10 DEG C.Filtering, is washed
It washs, is dried in vacuo under the conditions of 35 DEG C to get 9.87g white powder methanesulfonic acid Tizanidine crystal form B, yield 98.7%,
HPLC purity is 99.99%.X-ray powder diffraction analysis carried out to the sample of acquisition, diffracting spectrum it is basic as shown in Fig. 2,
It is consistent with the qualification result of embodiment 9.
Illustrate beneficial effects of the present invention below by way of test example
The solubility test of 1 methanesulfonic acid Tizanidine compound of test example
Test group 1: the methanesulfonic acid Tizanidine crystal form A that embodiment 1 is prepared；
Test group 2: the methanesulfonic acid Tizanidine crystal form B that embodiment 9 is prepared；
Control group 1: Tizanidine (is prepared) according to the method for prior art CN102140095 report；
Control group 2: Tizanidine (is prepared) according to the method for document CN105566314 report.
Test method: weighing the test sample for being ground into fine powder, is placed in 25 DEG C ± 2 DEG C of water, every strength shaking 30 in 5 minutes
Second；Dissolution situation in observation 30 minutes is considered as and is completely dissolved, the results are shown in Table when as without visual visible particles of solute
3。
The solubility of 3 methanesulfonic acid Tizanidine compound of table
| Test sample | Solubility |
| Control group 1 | 0.27mg/mL |
| Control group 2 | 50mg/mL |
| Test group 1 | 100mg/mL |
| Test group 2 | 100mg/mL |
Solubility test in table 3 the result shows that, compared to existing Tizanidine product, the present invention is prepared
Crystal form A and crystal form the B dissolubility in water of methanesulfonic acid acid Tizanidine compound have and be obviously improved.Usual situation
Under, good water solubility not only contributes to the bioavilability for improving drug, improves curative effect of medication and safety, can also reduce
The stimulation generated when clinical application improves the compliance of patient.Although Tizanidine is usually prepared into phase in the prior art
The hydrochloride answered improves its dissolubility in water.But the inventors discovered that the water solubility of existing product Tizanidine
Still it is not effectively improved.Methanesulfonic acid Tizanidine compound of the present invention significantly improves the water solubility of Tizanidine, phase
There is significant progress compared with the prior art.
The stabilizing effect of 2 methanesulfonic acid Tizanidine compound of test example is tested
(1) influence factor is tested
Investigation condition is strong illumination (4500 ± 500lx), high temperature (60 DEG C), high humidity (relative humidity 92.5%, 25 DEG C).
The methanesulfonic acid Tizanidine crystal form A that the embodiment of the present invention 1 is prepared and the methanesulfonic acid that the embodiment of the present invention 9 is prepared are replaced
Zha Niding crystal form B was placed 10 days respectively under the conditions of different investigations, is measured by sampling respectively in the 5th and the 10th day, with 0 day same lot sample
Product data are compared, and the results are shown in Table 4.
The influence factor test result of 4 methanesulfonic acid Tizanidine compound of table
Show the crystal form A and crystal form B of methanesulfonic acid Tizanidine compound prepared by the present invention by the test result in table 4,
Under illumination, high temperature and super-humid conditions, product characteristics do not change, and content and total impurities have no significant change, and illustrate this
Invention product stability is good.
(2) accelerated test
Methanesulfonic acid Tizanidine crystal form A and the embodiment of the present invention 9 that the embodiment of the present invention 1 is prepared are prepared
Methanesulfonic acid Tizanidine crystal form B is packed with polyethylene film plastic bag sealing, is placed in 40 DEG C ± 2 DEG C, relative humidity 75 ± 5%
It in constant temperature and humidity incubator, places six months, is carried out pair respectively at 1,2,3,6 the end of month sample detection, and with 0 month result
According to.It the results are shown in Table 4.
The accelerated test result of 5 methanesulfonic acid Tizanidine compound of table
Show the crystal form A and crystal form B of methanesulfonic acid Tizanidine compound provided by the invention by the test result in table 5,
Under the conditions of accelerated test in six months, character does not change, and for content without being substantially reduced, total impurities have no obvious increasing
Add, meets the quality standard.It can be seen that methanesulfonic acid Tizanidine compound property provided by the invention is stablized, it is suitable for long-term protect
It deposits.
3 methanesulfonic acid Tizanidine compound of test example draws moist effect test
Drawing for drug moist refers to the characteristic of the material absorbing moisture ability or degree under certain temperature and damp condition.
Test sample is as follows:
Test group 1: the nitric acid Tizanidine crystal form A being prepared according to the embodiment of the present invention 1；
Test group 2: the nitric acid Tizanidine crystal form A being prepared according to the embodiment of the present invention 4；
Test group 3: the nitric acid Tizanidine crystal form A being prepared according to the embodiment of the present invention 7；
Test group 4: the nitric acid Tizanidine crystal form B being prepared according to the embodiment of the present invention 9；
Test group 5: the nitric acid Tizanidine crystal form B being prepared according to the embodiment of the present invention 12；
Test group 6: the nitric acid Tizanidine crystal form B being prepared according to the embodiment of the present invention 15；
Control group: Tizanidine (is prepared) according to the method for document CN105566314 report.
Take test sample appropriate, according to " Chinese Pharmacopoeia " (version in 2010) two annex XIX J drug draws moist test guidances
Principle is tested.
Specific test method is as follows:
1, take dry stuffed glass weighing bottle (outer diameter 50mm, a height of 15mm) be placed in the previous day suitable 25 DEG C ±
(set temperature is 25 DEG C ± 1 for 1 DEG C of thermostatic drier (placing ammonium chloride or ammonium sulfate saturated solution in lower part) or growth cabinet
DEG C, relative humidity is 80% ± 2%) in, precise weighing (m1).
2, it taking test sample appropriate, set in above-mentioned weighing bottle and is laid in weighing bottle, test sample thickness is typically about 1mm,
Precise weighing (m2).
3, by weighing bottle opening, and with bottle cap with being placed under the conditions of above-mentioned constant temperature and humidity 24 hours.
4, weighing bottle lid, precise weighing (m3) are covered.
Percentage weight increase=(m3-m2)/(m2-m1) × 100%
5, draw moist feature description and draw defining for moist weight gain
It deliquesces: absorbing enough moisture and form liquid.
It is great draw it is moist: draw wet weight gain not less than 15%.
Have draw it is moist: draw wet weight gain less than 15% but not less than 2%.
Slightly draw moist: drawing wet weight gain less than 2% but not less than 0.2%.
Nothing is moist almost without drawing: drawing wet weight gain less than 0.2%.
Test result is shown in Table 6.
6 draws moist test result of table
Show that the Tizanidine of control group is placed 24 hours under above-mentioned relative humidities by 6 test result of table,
Draw wet weight gain obviously, illustrates that the Tizanidine of the prior art is moist with drawing.And the methanesulfonic acid Tizanidine of test group
The crystal form A and crystal form B for closing object are placed 24 hours under the same conditions, are drawn wet weight gain and are not obvious, illustrate that product of the present invention is drawn
It is moist lower.Compared with the Tizanidine of the prior art, the present invention prepares resulting methanesulfonic acid Tizanidine compound tool
There is drawing of being substantially reduced moist, can effectively avoid moisture absorption of the product in prolonged storage from deliquescing, it is steady for a long time to be conducive to product
Fixed storage, is readily transported, and when preparing preparation without especially control ambient humidity, the more conducively preparation of preparation.
In conclusion methanesulfonic acid Tizanidine compound provided by the invention, compared with the existing technology in hydrochloric acid for pricking
Surely there is Buddhist nun unexpected property to improve, and product property is stablized, and purity is high, dissolubility is good, low in hygroscopicity, be drug safety
The raising of property and validity provides effective solution approach；In addition, methanesulfonic acid Tizanidine compound provided by the invention
Preparation process is simple, and the reaction time is short, and to equipment without particular/special requirement, product yield is high, is suitable for industrialized production.
Claims (10)
1. a kind of methanesulfonic acid Tizanidine compound, it is characterised in that: the compound is existed in the form of crystal form A, describedization
In the X-ray powder diffraction figure for closing object, the 2 θ angles of diffraction 10.3 ± 0.2,14.1 ± 0.2,20.6 ± 0.2,21.9 ± 0.2,
22.2 ± 0.2 degree have characteristic absorption peak；Preferably, the 2 θ angles of diffraction are also 23.3 ± 0.2,24.0 ± 0.2,25.4 ± 0.2,31.1
± 0.2 degree has characteristic absorption peak；More preferably there is X-ray powder diffraction figure substantially as shown in Figure 1.
2. methanesulfonic acid Tizanidine compound according to claim 1, it is characterised in that the preparation method packet of the compound
Include following operating procedure:
(a), Tizanidine is taken, organic solvent and methanesulfonic acid, heating stirring reaction is added；
(b), cool down crystallization, filters, washing, dry to get methanesulfonic acid Tizanidine crystal form A.
Wherein, organic solvent described in step (a) is selected from one of alcohols solvent or a variety of；It is preferred that methanol, ethyl alcohol, positive third
One of alcohol, isopropanol, ethylene glycol are a variety of.
3. the preparation method of methanesulfonic acid Tizanidine compound according to claim 2, it is characterised in that: in step (a),
The mass volume ratio of the Tizanidine and organic solvent is 1:10~1:100g/mL, preferably 1:30~1:60g/mL；It is described
The molar ratio of methanesulfonic acid and Tizanidine is 0.8:1~3:1, preferably 1:1~1.2:1；Heating stirring reaction 10~
It carries out within the temperature range of 120 DEG C, is preferably carried out within the temperature range of 45~70 DEG C；
In step (b), the crystallization carries out within the temperature range of -10~40 DEG C, preferably carries out in room temperature；The crystallization is quiet
Set crystallization；The drying is 35 DEG C of vacuum drying.
4. a kind of methanesulfonic acid Tizanidine compound, it is characterised in that: the compound is existed in the form of crystal form B, describedization
In the X-ray powder diffraction figure for closing object, the 2 θ angles of diffraction 14.1 ± 0.2,19.3 ± 0.2,20.6 ± 0.2,21.9 ± 0.2,
25.4 ± 0.2 degree have characteristic absorption peak；Preferably, the 2 θ angles of diffraction are also 12.6 ± 0.2,17.6 ± 0.2,23.7 ± 0.2,23.8
± 0.2,26.4 ± 0.2,27.5 ± 0.2 degree has characteristic absorption peak；More preferably there is x-ray powder substantially as shown in Figure 2
Diffraction pattern.
5. methanesulfonic acid Tizanidine compound according to claim 4, it is characterised in that: the preparation method packet of the compound
Include following operating procedure:
(a), methanesulfonic acid Tizanidine is taken, the mixed solvent of water and organic solvent composition, heating stirring reaction is added；
(b), cool down crystallization, filters, washing, dry to get methanesulfonic acid Tizanidine crystal form B.
Wherein, the mixed solvent of water described in step (a) and organic solvent composition is selected from acetone-water, tetrahydrofuran-water, acetonitrile-
The mixed solvent of water composition.
6. the preparation method of methanesulfonic acid Tizanidine compound according to claim 5, it is characterised in that: in step (a),
The mass volume ratio of the methanesulfonic acid Tizanidine and water is 1:0.5~1:5g/mL；The methanesulfonic acid Tizanidine with it is organic molten
The mass volume ratio of agent is 1:20~1:60g/mL；The heating stirring reaction carries out within the temperature range of 10~120 DEG C, excellent
Be selected in 30 DEG C~reflux within the temperature range of carry out.
7. the preparation method of methanesulfonic acid Tizanidine compound according to claim 5 or 6, it is characterised in that: step (b)
In, the crystallization carries out within the temperature range of -10~40 DEG C, preferably carries out within the temperature range of 10~20 DEG C；The analysis
Crystalline substance is stirring and crystallizing；The drying is 35 DEG C of vacuum drying.
8. a kind of pharmaceutical composition, it is characterised in that include methanesulfonic acid Tizanidine compound conduct described in claim 1 or 4
The pharmaceutical preparation that active constituent and pharmaceutically acceptable excipient are prepared.
9. pharmaceutical composition according to claim 8, it is characterised in that: the pharmaceutical preparation is liquid preparation, gas system
Agent, solid pharmaceutical preparation and semisolid preparation, preferred fragrance aqua, injection, mixture, lotion, liniment, aerosol, are sprayed solution
Agent, powder, pill, tablet, film, ointment, suppository, paste.
10. methanesulfonic acid Tizanidine compound described in claim 1 or 4 treats central skeletal muscle relaxation correlation disease in preparation
Purposes in the drug of disease.
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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 |
-
2017
- 2017-09-22 CN CN201710864370.3A patent/CN109535149B/en active Active
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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