CN109535151A - P-methyl benzenesulfonic acid Tizanidine crystal form A and its preparation method and application - Google Patents
P-methyl benzenesulfonic acid Tizanidine crystal form A and its preparation method and application Download PDFInfo
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- 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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Abstract
The present invention provides a kind of p-methyl benzenesulfonic acid Tizanidine crystal form A and its preparation method and application.P-methyl benzenesulfonic acid Tizanidine crystal form A provided by the invention carries out X-ray powder diffraction using Cu-K α radiation source, and the 2 θ angles of diffraction have characteristic absorption peak at 6.7 ± 0.2,13.5 ± 0.2,20.4 ± 0.2,21.4 ± 0.2,24.3 ± 0.2 degree.Product of the present invention chemical purity is high, property is stable, low in hygroscopicity, provides effective solution approach for the raising of drug safety and validity；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.
Description
Technical field
The present invention relates to the preparation methods and purposes of a kind of p-methyl benzenesulfonic acid Tizanidine crystal form A and the crystal form, 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 the p-methyl benzenesulfonic acid of a kind of chemical purity height, property stabilization, low in hygroscopicity for pricking
Buddhist nun determines crystal form A.
The present invention also provides the preparation method of p-methyl benzenesulfonic acid Tizanidine crystal form A, pharmaceutical composition and purposes.
The structural formula of p-methyl benzenesulfonic acid Tizanidine of the present invention is as follows:
P-methyl benzenesulfonic acid Tizanidine crystal form A provided by the invention carries out X-ray powder diffraction using Cu-K α radiation source
When, in X-ray powder diffraction figure, the 2 θ angles of diffraction 6.7 ± 0.2,13.5 ± 0.2,20.4 ± 0.2,21.4 ± 0.2,
24.3 ± 0.2 degree have characteristic absorption peak.
Further, in X-ray powder diffraction figure, the 2 θ angles of diffraction also exist the p-methyl benzenesulfonic acid Tizanidine crystal form A
12.3 ± 0.2,27.3 ± 0.2 degree have characteristic absorption peak.
Further, in X-ray powder diffraction figure, the 2 θ angles of diffraction also exist the p-methyl benzenesulfonic acid Tizanidine crystal form A
18.5 ± 0.2,22.6 ± 0.2,25.9 ± 0.2 degree have characteristic absorption peak.
Further, in the X-ray powder diffraction figure of the p-methyl benzenesulfonic acid Tizanidine crystal form A, 2 θ angle of diffraction are special
Levy the relative intensity value at peak are as follows:
Further, the X-ray powder diffraction of the p-methyl benzenesulfonic acid Tizanidine crystal form A is as shown in Figure 1.
The present invention provides the preparation methods of above-mentioned p-methyl benzenesulfonic acid Tizanidine crystal form A, it includes following operating procedure:
(a), Tizanidine is taken, organic solvent and p-methyl benzenesulfonic acid, heating stirring reaction is added；
(b), cool down crystallization, filters, washing, dry to get p-methyl benzenesulfonic acid Tizanidine crystal form A.
Further, in step (a), the organic solvent be selected from one of C1~C4 alcohols solvent, ether solvent or
It is a variety of；It is preferred that in methanol, ethyl alcohol, normal propyl alcohol, isopropanol, ethylene glycol, ether, tetrahydrofuran, methyl tertiary butyl ether(MTBE), isopropyl ether
It is one or more.
Further, in step (a), the mass volume ratio of Tizanidine and solvent is 1:8~1:50g/mL；Preferably 1:
10~1:30g/mL.
Further, in step (a), the molar ratio of p-methyl benzenesulfonic acid and Tizanidine is 0.8:1~3:1, preferably 1:1
~1.3:1.
Further, in step (a), the heating stirring reaction carries out within the temperature range of 10~120 DEG C；It is preferred that
It is carried out within the temperature range of room temperature~50 DEG C.
Further, in step (b), the crystallization carries out within the temperature range of -10~40 DEG C；It is preferred that at 0~15 DEG C
Within the temperature range of carry out；The crystallization is to stand crystallization；The drying is 35 DEG C of vacuum drying.
The present invention also provides a kind of pharmaceutical compositions, comprising above-mentioned p-methyl benzenesulfonic acid Tizanidine crystal form A as activity
Ingredient and pharmaceutically acceptable excipient.The pharmaceutical composition can be prepared to various preparations.
Preparation of the present invention can be liquid preparation, gaseous formulation, solid pharmaceutical preparation and semisolid preparation, such as fragrance
It is aqua, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, capsule, film, soft
The common formulations such as paste, 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 p-methyl benzenesulfonic acid Tizanidine crystal form A to treat central skeletal muscle relaxation phase in preparation
Purposes in the drug of related disorders.
P-methyl benzenesulfonic acid Tizanidine crystal form A provided by the invention, has filled up the blank of the prior art；With existing product salt
Sour Tizanidine is compared, p-methyl benzenesulfonic acid Tizanidine crystal form A provided by the invention, and not only chemical purity is high, it is good to have
High-temperature stability, high wet stability and light durability, and have it is lower draw it is moist, for mentioning for drug safety and validity
Height provides effective solution approach；Have great importance to the curative effect for further studying such solid drugs.In addition, this hair
The preparation process of bright product is simple, and 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 p-methyl benzenesulfonic acid Tizanidine crystal form A 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 p-methyl benzenesulfonic acid Tizanidine crystal form A of embodiment
10g Tizanidine is weighed, 150mL methanol and 150mL ethyl alcohol is added, is added with stirring 8.82g p-methyl benzenesulfonic acid, adds
Heat is warming up to 45~50 DEG C and is stirred to react, and to fully reacting, stops heating, and slow cooling stands crystallization 4 hours to after 0 DEG C.It crosses
Filter is washed, and to get 16.02g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield is for vacuum drying under the conditions of 35 DEG C
95.4%, HPLC purity are 99.91%.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 p-methyl benzenesulfonic 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 p-methyl benzenesulfonic acid Tizanidine crystal form A of table
Further, the crystal form A has following X-ray powder diffraction feature:
Test the preparation of 2 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 100mL ether and 100mL methyl tertiary butyl ether(MTBE) is added, is added with stirring 7.47g to first
Reaction is stirred at room temperature in benzene sulfonic acid, to fully reacting, stops heating, and slow cooling stands crystallization 3 hours to after 10 DEG C.Filtering,
It washs, to get 15.75g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield is for vacuum drying under the conditions of 35 DEG C
93.8%, HPLC purity are 99.95%.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.
Test the preparation of 3 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 200mL isopropanol is added, is added with stirring 7.47g p-methyl benzenesulfonic acid, is heated to
45~50 DEG C are stirred to react, and to fully reacting, stop heating, and slow cooling stands crystallization 3 hours to after 5 DEG C.Filtering, washing,
It is dried in vacuo under the conditions of 35 DEG C to get 16.35g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield 97.4%,
HPLC purity is 99.93%.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.
Test the preparation of 4 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 300mL normal propyl alcohol is added, is added with stirring 9.0g p-methyl benzenesulfonic acid monohydrate, is heated
It is warming up to 40~45 DEG C to be stirred to react, to fully reacting, stops heating, slow cooling stands crystallization 2 hours to after 15 DEG C.It crosses
Filter is washed, and to get 16.55g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield is for vacuum drying under the conditions of 35 DEG C
98.6%, HPLC purity are 99.94%.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.
Test the preparation of 5 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 100mL ethylene glycol is added, is added with stirring 7.47g p-methyl benzenesulfonic acid, is heated to
30~35 DEG C are stirred to react, and to fully reacting, stop heating, and slow cooling stands crystallization 3 hours to after 0 DEG C.Filtering, washing,
It is dried in vacuo under the conditions of 35 DEG C to get 15.91g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield 94.8%,
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 Figure 1,
It is consistent with the qualification result of embodiment 1.
Test the preparation of 6 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 150mL ether is added, is added with stirring 7.13g p-methyl benzenesulfonic acid, reaction is stirred at room temperature,
To fully reacting, stop heating, slow cooling stands crystallization 4 hours to after 10 DEG C.Filtering is washed, and vacuum is dry under the conditions of 35 DEG C
It is dry to get 16.07g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield 95.7%, HPLC purity is 99.95%.
X-ray powder diffraction analysis carried out to the sample of acquisition, diffracting spectrum is basic as shown in Figure 1, qualification result with embodiment 1
Unanimously.
Test the preparation of 7 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 250mL methyl tertiary butyl ether(MTBE) is added, is added with stirring the hydration of 8.25g p-methyl benzenesulfonic acid one
Object is heated to 30~35 DEG C and is stirred to react, and to fully reacting, stops heating, and slow cooling stands crystallization 2 to after 15 DEG C
Hour.Filtering is washed, and is dried in vacuo under the conditions of 35 DEG C to get 16.13g white powder p-methyl benzenesulfonic acid Tizanidine crystal,
Yield is that 96.1%, HPLC purity is 99.94%.X-ray powder diffraction analysis, diffracting spectrum base are carried out to the sample of acquisition
This is as shown in Figure 1, consistent with the qualification result of embodiment 1.
Test the preparation of 8 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 200mL tetrahydrofuran is added, is added with stirring 6.79g p-methyl benzenesulfonic acid, is stirred at room temperature
Reaction stops heating to fully reacting, and slow cooling stands crystallization 2 hours to after 15 DEG C.Filtering is washed, under the conditions of 35 DEG C
It is dried in vacuo to get 16.45g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield 98.0%, 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.
Test the preparation of 9 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 100mL isopropyl ether is added, is added with stirring 8.14g p-methyl benzenesulfonic acid, is heated to
30~35 DEG C are stirred to react, and to fully reacting, stop heating, and slow cooling stands crystallization 4 hours to after 10 DEG C.Filtering, is washed
It washs, to get 15.73g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield is for vacuum drying under the conditions of 35 DEG C
93.7%, 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.
Test the preparation of 10 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 300mL methanol is added, is added with stirring 7.50g p-methyl benzenesulfonic acid monohydrate, room temperature
It is stirred to react, to fully reacting, stops heating, slow cooling stands analysis 3 hours to after 5 DEG C.Filtering is washed, under the conditions of 35 DEG C
It is dried in vacuo to get 15.86g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield 94.5%, HPLC purity is
99.92%.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.
Test the preparation of 11 p-methyl benzenesulfonic acid Tizanidine crystal form A
10g Tizanidine is weighed, 200mL ethyl alcohol is added, is added with stirring 6.79g p-methyl benzenesulfonic acid, reaction is stirred at room temperature,
To fully reacting, stop heating, slow cooling stands crystallization 2 hours to after 5 DEG C.Filtering is washed, and vacuum is dry under the conditions of 35 DEG C
It is dry to get 16.23g white powder p-methyl benzenesulfonic acid Tizanidine crystal, yield 96.7%, HPLC purity is 99.96%.
X-ray powder diffraction analysis carried out to the sample of acquisition, diffracting spectrum is basic as shown in Figure 1, qualification result with embodiment 1
Unanimously.
Illustrate beneficial effects of the present invention below by way of test example
The solubility test of 1 p-methyl benzenesulfonic acid Tizanidine crystal form A of test example
Test group: the p-methyl benzenesulfonic acid Tizanidine crystal form A that embodiment 1 is prepared；
Control group: Tizanidine (is prepared) according to the method for prior art CN102140095 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
2。
The solubility of 2 p-methyl benzenesulfonic acid Tizanidine crystal form A of table
| Test sample | Solubility |
| Test group | 19.14mg/mL |
| Control group | 0.27mg/mL |
Solubility test in table 2 the result shows that, the p-methyl benzenesulfonic acid Tizanidine crystal form A that the present invention is prepared is opposite
It is greatly improved in the dissolubility of Tizanidine.Under normal conditions, good water solubility not only contributes to the life for improving drug
Object availability improves curative effect of medication and safety, can also reduce the stimulation generated when clinical application, improve the compliance of patient
Property.
The stabilizing effect of 2 p-methyl benzenesulfonic acid Tizanidine crystal form A 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 p-methyl benzenesulfonic acid Tizanidine crystal form A that the embodiment of the present invention 1 is prepared is placed 10 days respectively under the conditions of different investigations,
It was measured by sampling respectively in the 5th and the 10th day, was compared with 0 day with batch sample data, the results are shown in Table 3.
The influence factor test result of 3 p-methyl benzenesulfonic acid Tizanidine crystal form A of table
P-methyl benzenesulfonic acid Tizanidine crystal form A prepared by the present invention is shown by the test result in table 3, in illumination, high temperature
And under super-humid conditions, product characteristics do not change, and content and total impurities have no significant change, and illustrate that this product stability is good
It is good.
(2) accelerated test
The p-methyl benzenesulfonic acid Tizanidine crystal form A that the embodiment of the present invention 1 is prepared is close with polyethylene film polybag
Package dress, is placed in 40 DEG C ± 2 DEG C, in the constant temperature and humidity incubator of relative humidity 75 ± 5%, places six months, respectively at 1,2,
3,6 the end of month sample detections, and compareed with 0 month result.It the results are shown in Table 4.
The accelerated test result of 4 p-methyl benzenesulfonic acid Tizanidine crystal form A of table
P-methyl benzenesulfonic acid Tizanidine crystal form A provided by the invention is shown by the test result in table 4, in six months
Accelerated test under the conditions of, character does not change, and without being substantially reduced, total impurities have no to be obviously increased content, meets matter
Amount standard.It can be seen that p-methyl benzenesulfonic acid Tizanidine crystal form A property provided by the invention is stablized, it is suitable for long-term preservation.Test
3 p-methyl benzenesulfonic acid Tizanidine crystal form A's of 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 p-methyl benzenesulfonic acid Tizanidine crystal form A being prepared according to the embodiment of the present invention 1；
Test group 2: the p-methyl benzenesulfonic acid Tizanidine crystal form A being prepared according to the embodiment of the present invention 2；
Test group 3: the p-methyl benzenesulfonic acid Tizanidine crystal form A being prepared according to the embodiment of the present invention 5；
Test group 4: the p-methyl benzenesulfonic acid Tizanidine crystal form A being prepared according to the embodiment of the present invention 9；
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 5.
5 draws moist test result of table
Show that the Tizanidine of control group is placed 24 hours under above-mentioned relative humidities by 5 test result of table,
Draw wet weight gain obviously, illustrates that the Tizanidine of the prior art is moist with drawing.And the p-methyl benzenesulfonic acid of test group is for bundle Buddhist nun
Determine crystal form A to place under the same conditions 24 hours, draws wet weight gain and be not obvious, illustrate that product of the present invention is wet without or almost without draw
Property.Compared with the Tizanidine of the prior art, the present invention prepares resulting p-methyl benzenesulfonic acid Tizanidine crystal form A with bright
Drawing for aobvious reduction is moist, can effectively avoid moisture absorption of the product in prolonged storage from deliquescing, store up steadily in the long term conducive to product
It deposits, is readily transported, and when preparing preparation without especially control ambient humidity, the more conducively preparation of preparation.
In conclusion p-methyl benzenesulfonic acid Tizanidine crystal form A provided by the invention, compared with the existing technology in hydrochloric acid replace
There is Zha Niding unexpected property to improve, and product property is stablized, purity is high, and low in hygroscopicity for drug safety and has
The raising of effect property provides effective solution approach；In addition, the preparation of p-methyl benzenesulfonic acid Tizanidine crystal form A provided by the invention
Simple process, 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 p-methyl benzenesulfonic acid Tizanidine crystal form A, it is characterised in that: in the X-ray powder diffraction figure of the crystal form A, 2 θ
The angle of diffraction has characteristic absorption peak at 6.7 ± 0.2,13.5 ± 0.2,20.4 ± 0.2,21.4 ± 0.2,24.3 ± 0.2 degree；It is preferred that
Ground, the 2 θ angles of diffraction also have characteristic absorption peak at 12.3 ± 0.2,27.3 ± 0.2 degree；It is highly preferred that the 2 θ angles of diffraction also 18.5 ±
0.2, there is characteristic absorption peak for 22.6 ± 0.2,25.9 ± 0.2 degree.
2. p-methyl benzenesulfonic acid Tizanidine crystal form A according to claim 1, it is characterised in that: the crystal form A has basic
X-ray powder diffraction figure as shown in Figure 1.
3. p-methyl benzenesulfonic acid Tizanidine crystal form A according to claim 1 or 2, it is characterised in that the preparation side of crystal form A
Method includes following operating procedure:
(a), Tizanidine is taken, organic solvent and p-methyl benzenesulfonic acid, heating stirring reaction is added；
(b), cool down crystallization, filters, washing, dry to get p-methyl benzenesulfonic acid Tizanidine crystal form A.
4. the preparation method of p-methyl benzenesulfonic acid Tizanidine crystal form A according to claim 3, it is characterised in that: step (a)
In, the organic solvent is selected from one of C1~C4 alcohols solvent, ether solvent or a variety of；It is preferred that methanol, ethyl alcohol, positive third
One of alcohol, isopropanol, ethylene glycol, ether, tetrahydrofuran, methyl tertiary butyl ether(MTBE), isopropyl ether are a variety of.
5. the preparation method of p-methyl benzenesulfonic acid Tizanidine crystal form A according to claim 3 or 4, it is characterised in that: step
(a) in, the mass volume ratio of Tizanidine and organic solvent is 1:8~1:50g/mL；Preferably 1:10~1:30g/mL.
6. according to the preparation method of the described in any item p-methyl benzenesulfonic acid Tizanidine crystal form A of claim 3~5, feature exists
In: in step (a), the molar ratio of p-methyl benzenesulfonic acid and Tizanidine is 0.8:1~3:1, preferably 1:1~1.3:1.
7. according to the preparation method of the described in any item p-methyl benzenesulfonic acid Tizanidine crystal form A of claim 3~6, feature exists
In: in step (a), the heating stirring reaction carries out within the temperature range of 10~120 DEG C, preferably the temperature in room temperature~50 DEG C
It spends in range and carries out.
8. according to the preparation method of the described in any item p-methyl benzenesulfonic acid Tizanidine crystal form A of claim 3~7, feature exists
In: in step (b), the crystallization carries out within the temperature range of -10~40 DEG C, preferably within the temperature range of 0~15 DEG C into
Row；The crystallization is to stand crystallization；The drying is 35 DEG C of vacuum drying.
9. a kind of pharmaceutical composition, it is characterised in that include p-methyl benzenesulfonic acid Tizanidine crystal form A of any of claims 1 or 2
As active constituent and pharmaceutically acceptable excipient.
10. p-methyl benzenesulfonic acid Tizanidine crystal form A of any of claims 1 or 2 treats central skeletal muscle relaxation phase in preparation
Purposes in the drug of related disorders.
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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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