CN105777775A - Crystal form IX of Tipidogrel free alkali and preparation method and application thereof - Google Patents
Crystal form IX of Tipidogrel free alkali and preparation method and application thereof Download PDFInfo
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- CN105777775A CN105777775A CN201610119015.9A CN201610119015A CN105777775A CN 105777775 A CN105777775 A CN 105777775A CN 201610119015 A CN201610119015 A CN 201610119015A CN 105777775 A CN105777775 A CN 105777775A
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- KPEODKSJPBHQJF-UHFFFAOYSA-N CC(Oc1cc(CN(Cc(cccc2)c2C#N)CC2)c2[s]1)=O Chemical compound CC(Oc1cc(CN(Cc(cccc2)c2C#N)CC2)c2[s]1)=O KPEODKSJPBHQJF-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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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
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Abstract
The invention belongs to the technical field of medicine and particularly provides a crystal form IX of (5-(2-cyanobenzy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)acetate.The invention further provides a preparation method of the crystal form and application of the crystal form in preparation of anti-platelet aggregation pharmaceutical compositions.(Please see the chemical formula in the description.).
Description
Technical field
The invention belongs to pharmaceutical technology field, more precisely, relate to a kind of (5-with antiplatelet aggregative activity
(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas crystal formation Ⅸ and preparation method thereof and
Application.
Background technology
The formation of thrombosis may result in the heart, brain, the pulmonary circulation illness such as acute myocardial infarction, apoplexy, pulmonary infarction, serious threat people
The health and lives of class, be also factor inaccessible again after complication common in surgical operation and interventional angioplasty it
One.
Cause thrombotic a lot because have, the adhesion on the blood vessel wall surface of damage of the such as platelet and gathering,
Blood stream stasis, the activation of thrombin promote the formation of thrombin, antiplasmin activity low inferior.In above-mentioned factor, platelet is
Thrombotic required material, therefore suppressing hematoblastic gathering is one of prevention and the important means treating thrombus disease.
The present inventor once have submitted with regard to " the thienopyridine esters derivative of a class nitrile group-containing, Preparation Method And The Use "
Chinese invention patent application (publication number: CN102241690).A kind of chemical structural formula change as shown in formula I of this disclosure of the invention
Compound: (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas (hereinafter referred to as formula I
Compound).
Above invention discloses compound (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-
Base) acetas is effective for the treatment disease that causes because of platelet aggregation of the mankind, such as thrombotic disease.
The most above-mentioned patent " the thienopyridine esters derivative of a class nitrile group-containing, Preparation Method And The Use " is also disclosed
The preparation method of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas:
Equipped with stirring, condenser, thermometer reaction bulb in add 2.7g intermediate1, with 10mL dichloromethane by it
Dissolving, stirring is lower adds sodium hydroxide 1.2g.Reaction system is cooled to-20 DEG C, 1.02g acetic anhydride is dividedly in some parts reactant
System.Add, continue stirring reaction 1h (flaggy display reaction is completely) at room temperature.Wash reactant liquor with 3 × 15mL water, divide and take two
Chloromethanes layer, the driest with anhydrous sodium sulfate, to filter, dichloromethane to the greatest extent is steamed in decompression, and post separates, obtains white solid product
(HPLC:99.6%).Rf=0.58 [single-point, developing solvent: v (petroleum ether): v (ethyl acetate)=4:1].1H NMR(DMSO-
D6,400MHz) δ: 2.253 (s, 3H), 2.700 (s, 2H), 2.767~2.780 (d, 2H), 3.402 (s, 2H), 3.816 (s,
2H), 6.421 (s, 1H), 7.452~7.489 (t, 1H), 7.606~7.625 (d, 1H), 7.660~7.697 (t, 1H),
7.803~7.822 (d, 1H).MS, m/Z:312.0 (M).
In research afterwards, repeating above-mentioned preparation method, the product fusing point obtained is 85 DEG C-85.5 DEG C, and it uses X-
Powder diffraction characterizes, such as accompanying drawing 1 (hereinafter referred to as patent CN102241690 crystal formation).
Inventor finds in research process, has obtained a kind of being different from the new of above-mentioned white solid product with refining methanol
Crystal formation.This crystal formation has embodied the technical advantage being better than prior art CN102241690 crystal formation, has the most also applied for that novel crystal forms is special
Profit.
Patent " crystal formation of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3_2-c] pyridine-2-base) acetas "
(CN104098586) (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic acid is disclosed in
A kind of crystal formation of ester:
Monoclinic system, P21/n space group, the molecular number in structure cell is 4,
A=14.174 (3) A, alpha=90deg.,
B=5.9321 (12) A, beta=99.06 (3) deg.,
C=18.796 (4) A, gamma=90deg.,
Unit cell volume
Packing of molecules in structure cell is shown in accompanying drawing 2.
It characterizes with X-powder diffraction, such as accompanying drawing 3.
The preparation method of crystal, it is characterised in that: type I compound is added in the methanol of 8 times (w/vs), stir
Mixing and be heated to 60 DEG C, after being completely dissolved, filter, filtrate room temperature is placed 20-24 hour, separates out crystallization.Leach this crystallization, through indoor
It is dried to obtain.Purity (HPLC:99.0%), fusing point: 91.1-91.8 DEG C.
It is referred to as polytropism, it is known that it is present in many organic with the ability that different crystal forms compound structure exists
In compound.These different crystal formations are referred to as " polymorph ", and the accumulation mode of its crystalline solid state, geometry arrangement and its
His descriptive nature aspect and different.Different polymorphs has different lattice energies, and thus it illustrates not when solid-state
Same physical property, such as shape, color density, hardness, deformability, stability and dissolubility etc..
To this end, present inventors studied 5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base)
The polymorphism of acetas, and wish to find the crystal habit with excellent physicochemical property, thus provide more for medicine manufacture
Material choice.
Summary of the invention
It is an object of the invention to the defect overcoming the known crystal formation of both the above to exist, it is provided that the one of formula I compound
Kind of novel crystal forms, this crystal formation has stable apparent condition and good long-term storing stability, can be stably supplied prepare former
Material medicine.Present invention also offers the preparation method and application of this crystal formation.
A further object of the invention is, it is provided that formula I compound is as the application in terms of antiplatelet drug, special
It not for preparing prevention or treating the coronary syndrome caused because of platelet aggregation, myocardial infarction, myocardial ischemia
Deng the purposes in terms of cardiovascular and cerebrovascular diseases medicament.
Present invention relates particularly to the crystal formation of the compound of structure shown in formula I:
The i.e. crystal formation Ⅸ of (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base) acetas,
It is characterized in that:
Measuring with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates has
The angle of diffraction (2 θ), as shown in Figure 4, the error of 2 θ is ± 0.2 for interplanar distance (d value) and intensity (%).
According to the crystal formation of the present invention, wherein, the fusing point of this crystal formation can be 86.8-87.3 DEG C.It addition, the purity of this crystal formation
Can be 99.0% or more than.
According to the crystal formation of the present invention, wherein, the X powder diffraction of this crystal formation can be as shown in Figure 4.
Present invention also offers the method for preparing above-mentioned crystal formation, the method comprises the following steps:
The crystal formation Ⅸ of type I compound is to crystallize to obtain in the mixed liquor of petroleum ether oxolane.The use of mixed liquor
Amount is 2~10 times (volume-mass ratio, mL/g) of type I compound quality, the most preferably 5 times.
Oxolane accounts for the 10%~40% of mixed liquor cumulative volume;Preferably 25%.
Temperature during dissolving is 30 DEG C~70 DEG C, preferably 50 DEG C.Then it is naturally cooling to room temperature, places 3~11 hours, excellent
Choosing is placed 7 hours;I.e. obtain novel crystal forms Ⅸ type of type I compound.
Specific operation process is:
Take a certain amount of type I compound, add petroleum ether oxolane mixed liquor, heated and stirred, after dissolving, the coldest
But to room temperature.Separate out solid, filter, obtain type I compound crystal formation Ⅸ.
Purity (HPLC:99.6%), fusing point: 86.8-87.3 DEG C.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition comprises above-mentioned crystal formation and the one of effective dose
Or multiple pharmaceutically acceptable adjuvant.Described pharmaceutically acceptable adjuvant can be to maintain the substrate of pharmaceutical dosage form or auxiliary
Material, by selecting according to different medicaments or be applied in combination, is optionally included with carrier, excipient, diluent, filling
Agent, binding agent, disintegrating agent, lubricant, fluidizer, effervescent, correctives, preservative, coating material etc..Excipient includes such as
Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, mannitol, sorbitol, Fructus Vitis viniferae
The compositions of one or more in sugar, fructose, water, Polyethylene Glycol, propylene glycol, glycerol, cyclodextrin, cyclodextrin derivative.Fill out
Fill agent and include such as lactose, sucrose, dextrin, starch, pregelatinized Starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, carbonic acid
Calcium, the compositions of one or more of microcrystalline Cellulose.Binding agent includes such as sucrose, starch, polyvidone, carboxymethyl cellulose
Sodium, carboxylic the third methylcellulose, carboxylic the third cellulose, methylcellulose, Polyethylene Glycol, medicinal alcohol, the combination of one or more of water
Thing.Disintegrating agent includes such as starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxylic first fibre
Dimension element sodium, the compositions of one or more of gas-producing disintegrant.
According to the pharmaceutical composition of the present invention, wherein, described pharmaceutical composition can be solid orally ingestible, liquid port
Formulation or injection.Preferably, described solid orally ingestible include dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, capsule or
Granule;Described liquid oral medicine includes oral solution;Described injection includes injection liquid drugs injection, injection lyophilized powder
Pin, infusion solutions or primary infusion.
Present invention also offers above-mentioned crystal formation or the crystal formation prepared according to the said method of the present invention is being prepared for anti-blood
Purposes in the pharmaceutical composition that platelet is assembled.It addition, present invention also offers above-mentioned crystal formation or the above-mentioned side according to the present invention
Crystal formation prepared by method preparation for treatment cause because of antiplatelet aggregation coronary syndrome, myocardial infarction, cardiac muscle
Ischemia, cardiovascular and cerebrovascular disease pharmaceutical composition in purposes.The present inventor is by assembling inhibitory action to mouse platelets
It is experimentally confirmed that the crystal formation of the formula I compound of the present invention has the platelet aggregation that obvious anti-ADP induces, therefore it can
Be used for preventing or treat cause because of platelet aggregation coronary syndrome, myocardial infarction, the heart and brain blood such as myocardial ischemia
Pipe disease.
The crystal formation of the present invention is effective in comparatively wide dosage range.The dosage that such as every day takes is about at 10mg-
In the range of 500mg, it is divided into once or is administered for several times.The actual dosage taking crystal formation of the present invention can be by doctor according to relevant situation
Determine.These situations include: the condition of patient, route of administration, age, body weight, individual reaction to medicine, disease
The order of severity etc. of shape.
White solid product phase with the formula I compound obtained by direct solvent evaporated (such as dichloromethane) mode
Ratio, the crystal formation prepared by the present invention has good appearance stability and repeatability between batch.Such as, the present inventor is by real
Issuing after examination and approval existing, this crystal formation is in the range of the batch of preparation 7 batches continuously, and its outward appearance is stable, is all normally white solid, and warp
Measuring every batch is all stable crystal formation (test result is as shown in table 1).
Table 1 stability of crystal form is tested
Additionally, the crystal formation of the present invention also has good long-term storing stability.Such as, the present inventor is tested by experiment
Card, this crystal formation schedules to last trimestral in light, heat, wet stability experiment, and its impurity is not significantly increased, thus has more
Good long term storage stability.
Based on features described above, the crystal formation of the present invention can be more suitable for as the stable supplying source of formula I raw materials of compound medicine
Industrialized production.
Meanwhile, in view of the crystal formation of the present invention has preferable long-time stability, can affirm, the system prepared for raw material with it
Agent should have the longer limited time limit, and the requirement to preservation condition is the lowest simultaneously.
Accompanying drawing explanation
Hereinafter, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:
Fig. 1 shows the X-ray powder diffraction pattern being prepared crystal formation by patent CN102241690 method;
Fig. 2 shows the structure cell packing of molecules figure being prepared crystal formation by patent CN104098586 method;
Fig. 3 shows the X-ray powder diffraction pattern being prepared crystal formation by patent CN104098586 method;
Fig. 4 shows the X-ray powder diffraction pattern of crystal formation Ⅸ.
Detailed description of the invention
The present invention is further illustrated below by specific embodiment, it should be understood, however, that, these embodiments are only
It is used for specifically describing in more detail, and is not to be construed as limiting in any form the present invention.
This part to the present invention test used in material and test method carry out general description.Although it is
Realize many materials that the object of the invention used and operational approach is to it is known in the art that but the present invention still uses up at this
May describe in detail.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and behaviour
It is well known in the art as method.
With the following Examples, the present invention is as follows to the condition determination of crystal formation:
Measuring with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates has
The angle of diffraction (2 θ), as shown in Figure 3, the error of 2 θ is ± 0.2 for interplanar distance (d value) and intensity (%).
Fusing point test:
Instrument: YTR-3 type melting point apparatus (purchased from Precision Instrument Factory, Tianjin Univ.)
High performance liquid chromatography (HPLC) condition:
Chromatographic column: C18, 150mm × 4.6mm, 5um
Flowing phase: methanol: water: acetic acid=70:30:0.25
Wavelength: 230nm
Flow velocity: 0.8ml/min
Sample size: 10uL
Column temperature: 35 DEG C
Instrument:
General analysis general L6 chromatograph of liquid
Hitachi's L-7250 automatic sampler
General analysis general LC Win chromatographic work station
Embodiment 1
The present embodiment is for illustrating (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole of the present invention
Pyridine-2-base) crystal formation of acetas and preparation process thereof.
Preparation (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetas is as former
Material.Its preparation process is referred to the open reaction process described in CN102241690 of Chinese invention patent.Such as, its reaction
Flow process can be:
Intermediate1Preparation:
Equipped with stirring, condenser, thermometer reaction bulb in add 5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine-
2 (4H)-one 19.2g, is dissolved with 70mL acetonitrile, is cooled to-10 DEG C under stirring, adds Anhydrous potassium carbonate 41.5g.By 2-cyanogen
Bromide benzyl 19.6g is dividedly in some parts in reaction system, finishes and is warming up to 45 DEG C of continuation reaction 4h (flaggy display reaction is completely).Cross
Filter, filtrate solvent evaporated acetonitrile, add 50mL dichloromethane, wash reactant liquor with 3 × 50mL water, divide and take dichloromethane layer, use
Anhydrous sodium sulfate is the driest, filters, and dichloromethane to the greatest extent is steamed in decompression, obtains yellow oil product 22.6g (HPLC:97.2%).
Rf=0.47 [single-point, developing solvent: v (petroleum ether): v (ethyl acetate)=1: 2].MS, m/Z:270.0 (M).
Formula (I) compound ((5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-2-base) acetic acid
Ester) preparation:
Equipped with stirring, condenser, thermometer reaction bulb in add the above-mentioned prepared intermediate 1 of 2.7g, with 10mL bis-
Chloromethanes is dissolved, and stirring is lower adds sodium hydroxide 1.2g.Reaction system is cooled to-20 DEG C, by 1.02g acetic anhydride in batches
Add reaction system.Add, continue stirring reaction 1h (flaggy display reaction is completely) at room temperature.Anti-with the washing of 3 × 15mL water
Answer liquid, divide and take dichloromethane layer, the driest with anhydrous sodium sulfate, to filter, dichloromethane to the greatest extent, post separation are steamed in decompression, obtain white
Color solid product (HPLC:99.6%).Rf=0.58 [single-point, developing solvent: v (petroleum ether): v (ethyl acetate)=4:1].1H
NMR (DMSO-d6,400MHz) δ: 2.253 (s, 3H), 2.700 (s, 2H), 2.767~2.780 (d, 2H), 3.402 (s, 2H),
3.816 (s, 2H), 6.421 (s, 1H), 7.452~7.489 (t, 1H), 7.606~7.625 (d, 1H), 7.660~7.697 (t,
1H), 7.803~7.822 (d, 1H).MS, m/Z:312.0 (M).
White solid product (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole to above-mentioned gained
Pyridine-2-base) acetas carry out X-ray powder diffraction (PXRD) characterize, its PXRD collection of illustrative plates is as shown in Figure 1.Repeat above-mentioned preparation side
Method, the fusing point of the white solid product measuring gained is 85-85.5 DEG C.
The preparation of crystal formation of the present invention:
Take white solid (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole that 3g said method prepares
Pyridine-2-base) acetas, (oxolane accounts for mixed liquor cumulative volume to the mixed liquor of the petroleum ether-oxolane of addition 6ml
40%), under agitation it is heated to 70 DEG C so that it is all dissolve, filters, take filtrate;Gained filtrate is at room temperature placed 3h analysis
Crystalline substance, collected by filtration, it is dried, obtains the crystal 2.78g of the present invention.
The fusing point recording this crystal formation is 87.0-87.2 DEG C, and the purity using HPLC to record this crystal formation is 99.6%.
Embodiment 2
The present embodiment is for illustrating (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole of the present invention
Pyridine-2-base) crystal formation of acetas and preparation process thereof.
Formula (I) compound is prepared as raw material according to method in the same manner as in Example 1.
Take white solid (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole that 3g said method prepares
Pyridine-2-base) acetas, (oxolane accounts for mixed liquor cumulative volume to the mixed liquor of the petroleum ether-oxolane of addition 15ml
25%), under agitation it is heated to 50 DEG C so that it is all dissolve, filters, take filtrate;Gained filtrate is at room temperature placed 7h analysis
Crystalline substance, collected by filtration, it is dried, obtains the crystal 2.88g of the present invention.
The fusing point recording this crystal formation is 86.9-87.1 DEG C, and the purity using HPLC to record this crystal formation is 99.7%.
Embodiment 3
The present embodiment is for illustrating (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole of the present invention
Pyridine-2-base) crystal formation of acetas and preparation process thereof.
Formula (I) compound is prepared as raw material according to method in the same manner as in Example 1.
Take white solid (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyrrole that 3g said method prepares
Pyridine-2-base) acetas, (oxolane accounts for mixed liquor cumulative volume to the mixed liquor of the petroleum ether-oxolane of addition 30ml
10%), under agitation it is heated to 30 DEG C so that it is all dissolve, filters, take filtrate;Gained filtrate is at room temperature placed 11h analysis
Crystalline substance, collected by filtration, it is dried, obtains the crystal 2.81g of the present invention.
The fusing point recording this crystal formation is 87.1-87.3 DEG C, and the purity using HPLC to record this crystal formation is 99.8%.
Embodiment 4
The present embodiment contains the preparation of the tablet of crystal formation of the present invention for explanation.
Sample crystal formation, pregelatinized Starch and microcrystalline Cellulose that embodiment 1 prepares are sieved, are sufficiently mixed with recipe quantity,
Add the solution containing recipe quantity polyvinylpyrrolidone, mixing, soft material processed, sieve, wet granular processed, it is dried in 50-60 DEG C;So
After Sodium carboxymethyl starch, magnesium stearate and Pulvis Talci are sieved in advance, join in above-mentioned dried granule with recipe quantity,
Tabletting, obtains the tablet of the crystal formation containing the present invention.
Embodiment 5
This test example is used for the crystal formation that the present invention the is described inhibitory action to rat platelet aggregation.
1, Experimental agents and reagent:
The crystal formation of embodiment 1 preparation;
ADP:SIGMA Products;
Sodium carboxymethyl cellulose 800-1200: Chemical Reagent Co., Ltd., Sinopharm Group, lot number: F20051103.
2, laboratory animal:
Wistar rat: SPF level, male, Institute of Experimental Animals, Chinese Academy of Medical Sciences provides, credit number SCXK
(capital) 2005-0013.
3, experimental apparatus:
PAM-3 type dual pathways platelet aggregation instrument: Danyang, Jiangsu Province radio factory product.
4, experimental technique and result:
Select healthy male Wistar rat, body weight 210-250g, random packet.Every batch is all provided with Normal group and crystal formation
Administration group.The dosage of crystal formation administration group is 30mg/kg.Use gastric infusion, be administered volume and be 10mL/kg bw, the most right
Giving equivalent 0.5%CMC-Na according to group, 2h after administration, lumbar injection 40mg/kg pentobarbital sodium (1mL/kg) anesthesia, abdomen is actively
Arteries and veins is taken a blood sample, and with 3.8% sodium citrate anticoagulant, prepares platelet rich plasma (PRP) and platelet poor plasma (PPP) respectively,
PAM-3 type dual pathways platelet aggregation instrument measures the platelet maximum gathering percentage rate that ADP (final concentration: 1.08 μMs) induces.Knot
Fruit is shown in Table 2.
The table 2 impact on the platelet aggregation that ADP induces
From table 2, compared with Normal group, the crystal formation (30mg/kg) of the present invention has the blood that obvious anti-ADP induces
Platelet aggregation.Therefore it may be used for prevention or treats coronary syndrome, the cardiac muscle caused because of platelet aggregation
The cardiovascular and cerebrovascular disease such as infarction, myocardial ischemia.
Embodiment 6
The crystal formation of the present invention that embodiment 1 is prepared and patent CN102241690 crystal formation and patent CN104098586 crystal formation
Carry out influence factor's test, respectively at illumination (4500 ± 500Lx), high temperature (60 DEG C) and the bar of high humidity (92.5% relative humidity)
Place three months under part, compared outward appearance, impurity number and impurity level (measuring with HPLC) with the 0th day.Result of the test is shown in Table respectively
3-5。
Table 3 light durability test data
Table 4 thimble test data
Table 5 high humidity stability test data
From table 3-5, in the stability test under the illumination of 3 months by a definite date, high temperature, super-humid conditions, the present invention is brilliant
The long-time stability of type are preferable, are especially better than CN102241690 crystal formation and CN104098586 crystal formation, measured by HPLC simultaneously,
Its impurity number and gathering way of total impurities are also considerably slower than CN102241690 crystal formation and CN104098586 crystal formation, it is seen that this
The crystal formation of invention has preferable long term storage stability, can be as the stable source of formula (I) raw materials of compound medicine.
Although present invention has been a certain degree of description, it will be apparent that, without departing from the spirit and scope of the present invention
Under the conditions of, the suitable change of each condition can be carried out.It is appreciated that and the invention is not restricted to described embodiment, and be attributed to right
The scope required, it includes the equivalent of described each factor.
Claims (9)
1. the crystal formation Ⅸ of one kind (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine-2-base) acetas,
It is characterized in that, the X-ray powder diffraction spectrum of described crystal formation is as shown in Figure of description 4.
Crystal formation Ⅸ the most according to claim 1, it is characterised in that the fusing point of this crystal formation is 86.8-87.3 DEG C.
The preparation method of crystal formation Ⅸ the most according to claim 1 and 2, it is characterised in that the method comprises the following steps:
(1) according to 1:2-10 w/v will (5-(2-itrile group benzyl)-4,5,6,7-Tetramethylene sulfide also [3,2-c] pyridine-
2-yl) acetas add petroleum ether oxolane mixed liquor in, wherein oxolane account for mixed liquor cumulative volume 10%~
40%, under agitation 30 DEG C~70 DEG C of heating for dissolving, filter;
(2) filtrate that step (1) filters gained at room temperature places 3-11h crystallize, collected by filtration, is dried, obtains institute
State crystal formation Ⅸ.
Preparation method the most according to claim 3, it is characterised in that in step (1), described w/v is 1:5;
In the mixed liquor of petroleum ether oxolane, water accounts for the 25% of mixed liquor cumulative volume;Preferably, under agitation it is heated to 50 DEG C,
Crystallize 7h.
5. a pharmaceutical composition, it is characterised in that described pharmaceutical composition comprises described in the claim 1 or 2 of effective dose
Crystal formation Ⅸ and one or more pharmaceutically acceptable adjuvants.
Pharmaceutical composition the most according to claim 5, it is characterised in that described pharmaceutical composition be solid orally ingestible,
Liquid oral medicine or injection.
Pharmaceutical composition the most according to claim 6, it is characterised in that described solid orally ingestible includes dispersible tablet, intestinal
Molten, chewable tablet, oral cavity disintegration tablet, capsule or granule;Described liquid oral medicine includes oral solution;Described injection includes
Injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
8. the crystal formation Ⅸ described in claim 1 or 2 or the crystal formation Ⅸ prepared according to the method described in claim 3 or 4 are in system
The purposes being ready for use in the pharmaceutical composition of antiplatelet aggregation.
9. crystal formation Ⅸ described in claim 1 or 2 or the crystal formation Ⅸ prepared according to the method described in claim 3 or 4 are in preparation
The coronary syndrome that causes because of antiplatelet aggregation for treatment, myocardial infarction, myocardial ischemia, cardiovascular and cerebrovascular disease
Purposes in pharmaceutical composition.
Priority Applications (1)
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CN201610119015.9A CN105777775A (en) | 2016-03-02 | 2016-03-02 | Crystal form IX of Tipidogrel free alkali and preparation method and application thereof |
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CN201610119015.9A CN105777775A (en) | 2016-03-02 | 2016-03-02 | Crystal form IX of Tipidogrel free alkali and preparation method and application thereof |
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