CN102120746A - Clopidogrel hydrochloride crystal form II as well as preparation method and application thereof - Google Patents
Clopidogrel hydrochloride crystal form II as well as preparation method and application thereof Download PDFInfo
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- CN102120746A CN102120746A CN 201110033048 CN201110033048A CN102120746A CN 102120746 A CN102120746 A CN 102120746A CN 201110033048 CN201110033048 CN 201110033048 CN 201110033048 A CN201110033048 A CN 201110033048A CN 102120746 A CN102120746 A CN 102120746A
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Abstract
The invention relates to a novel crystal form of a compound, in particular to a clopidogrel hydrochloride crystal form II as well as a preparation method and application thereof. In the clopidogrel hydrochloride crystal form II presented by the invention, X-powder diffraction has the characteristic peaks in 2-theta angles of 8.900 degrees, 14.860 degrees, 16.760 degrees, 18.680 degrees, 23.240 degrees, 24.700 degrees, 25.080 degrees, 26.380 degrees and 26.940 degrees.
Description
Technical field
The present invention relates to a kind of new crystalline form of compound, be specifically related to a kind of medical compounds hydrochloric acid clopidogrel crystal form II and its production and use.
Background technology
Clopidogrel [2-(2-chloro-phenyl-)-2-(6, the 7-dihydro-thiophene is [3,2-c] pyridine-5-yl also) methyl acetate hydrosulfate] is a kind of anticoagulant.Since 2005, chlorine pyrroles thunder is used for the treatment of clinically as anticoagulation medicine and prevents myocardial infarction to begin to widely apply in clinical cardiac, take the occurrence probability that chlorine pyrroles thunder can obviously reduce myocardial infarction, chlorine pyrroles thunder has become the medicine of global marketing volume rank front three, and annual sales amount is above 6,000,000,000 dollars.Can be used for preventing and treating myocardial infarction, ischemia cerebral thrombosis, the complication that thromboangiitis obliterans and atherosclerosis and thromboembolism cause.Be applied to apoplexy, the myocardial infarction that takes place in the recent period or made a definite diagnosis the patient of peripheral arterial disease, can reduce the generation (myocardial infarction, apoplexy and vascular death) of atherosclerotic event after the treatment.
Present domestic research mainly be chlorine pyrroles thunder hydrosulfate, the inventor the test process in, grope by test, obtain a kind of good stability, the new clopidogrel hydrochloride crystal form II of favorable reproducibility.
Summary of the invention
The object of the present invention is to provide the hydrochloric acid clopidogrel crystal form II of a kind of good stability, favorable reproducibility.
Hydrochloric acid clopidogrel crystal form II of the present invention, its structural formula is as follows:
Hydrochloric acid clopidogrel crystal form II of the present invention, through the X-powder diffraction method, infrared absorption spectrum, dsc (DSC) differential thermal analysis method have been measured its feature.
Hydrochloric acid clopidogrel crystal form II of the present invention, has following spectrum characteristic, adopt Japanese Rigaku D max-2500 type X powder diffraction of science (XRD) instrument that the crystalline phase of sample is analyzed, Cu K α target, tube voltage 40KV, tube current 100mA, its X-powdery diffractometry has following characteristic peak: there is the peak at 2 θ places at 8.900,14.860,16.760,18.680,23.240,24.700,25.080,26.380,26.940 degree.
Hydrochloric acid clopidogrel crystal form II of the present invention has following spectrum characteristic and physics-chem characteristic:
1.X-powdery diffractometry
Adopt Japanese Rigaku D max-2500 type X powder diffraction of science (XRD) instrument the crystalline phase of sample to be analyzed Cu K
αTarget, tube voltage 40KV, tube current 100mA.Its X powder diffraction has following characteristic peak:
Table 1
| Peak number | Angle (2 θ) | The d-value | Intensity (Cps) | I/I0 |
| 1 | 7.240 | 12.1998 | ?839 | 10 |
| 2 | 7.600 | 11.6227 | ?1019 | 12 |
| 3 | 8.080 | 10.9333 | ?2374 | 29 |
| 4 | 8.900 | 9.9277 | ?8159 | 100 |
| 5 | 9.640 | 9.1672 | ?956 | 12 |
| 6 | 11.320 | 7.8102 | ?1101 | 13 |
| 7 | 13.860 | 6.3841 | ?1111 | 14 |
| 8 | 14.460 | 6.1205 | ?1623 | 20 |
| 9 | 14.860 | 5.9566 | ?7692 | 94 |
| 10 | 15.280 | 5.7938 | ?2437 | 30 |
| 11 | 16.760 | 5.2854 | ?3957 | 49 |
| 12 | 17.900 | 4.9513 | ?1712 | 21 |
| 13 | 18.680 | 4.7462 | ?7004 | 86 |
| 14 | 19.420 | 4.5670 | ?1803 | 22 |
| 15 | 20.060 | 4.4227 | ?1471 | 18 |
| 16 | 20.540 | 4.3205 | ?1073 | 13 |
| 17 | 20.940 | 4.2388 | ?2769 | 34 |
| 18 | 21.420 | 4.1449 | ?2354 | 29 |
| 19 | 21.840 | 4.0661 | ?2149 | 26 |
| 20 | 22.320 | 3.9798 | ?1666 | 20 |
| 21 | 23.240 | 3.8243 | ?5233 | 64 |
| 22 | 24.700 | 3.6014 | 3853 | 47 |
| 23 | 25.080 | 3.5477 | 5223 | 64 |
| 24 | 25.800 | 3.4503 | 2472 | 30 |
| 25 | 26.380 | 3.3757 | 4134 | 51 |
| 26 | 26.940 | 3.3068 | 5656 | 69 |
| 27 | 27.600 | 3.2292 | 2567 | 31 |
| 28 | 28.180 | 3.1641 | 1460 | 18 |
| 29 | 28.780 | 3.0995 | 1142 | 14 |
| 30 | 29.280 | 3.0477 | 1214 | 15 |
| 31 | 29.740 | 3.0016 | 1282 | 16 |
| 32 | 30.420 | 2.9360 | 1075 | 13 |
| 33 | 30.740 | 2.9062 | 1340 | 16 |
| 34 | 31.400 | 2.8466 | 959 | 12 |
| 35 | 32.120 | 2.7844 | 1168 | 14 |
| 36 | 32.620 | 2.7428 | 961 | 12 |
| 37 | 33.080 | 2.7057 | 1256 | 15 |
| 38 | 33.320 | 2.6868 | 1397 | 17 |
| 39 | 33.920 | 2.6406 | 930 | 11 |
| 40 | 34.400 | 2.6049 | 1205 | 15 |
| 41 | 35.240 | 2.5447 | 938 | 11 |
| 42 | 36.280 | 2.4741 | 665 | 8 |
| 43 | 37.340 | 2.4062 | 1022 | 13 |
| 44 | 40.760 | 2.2119 | 1171 | 14 |
| 45 | 41.500 | 2.1741 | 1346 | 17 |
| 46 | 43.220 | 2.0915 | 861 | 11 |
| 47 | 45.740 | 1.9820 | 938 | 11 |
2. fusing/decomposition temperature
Fusing/decomposition temperature with Japan's standard type TG-DTA analysis-e/or determining of science hydrochloric acid clopidogrel.4.0mg hydrochloric acid clopidogrel is placed in one, with about 10 ℃/minute heat-up rate heating.Fusing/decomposition temperature from fusing/decomposition endotherm extrapolation begin define to maximum value.The fusing of hydrochloric acid clopidogrel is with decomposition, and the influence of solids treatment before being analyzed.Fusing/the decomposition temperature of this crystal formation is 111～123 ℃.
3. the characteristic absorbance following (seeing accompanying drawing 2) that shows of infrared spectra:
3428.81cm
-1, 2377.80cm
-1, 2348.87cm
-1, 1689.34cm
-1, 1039.44cm
-1There is the infrared absorption at peak at the place.
Another object of the present invention is to provide the preparation method of hydrochloric acid clopidogrel crystal form II.
The preparation method of hydrochloric acid clopidogrel crystal form II of the present invention may further comprise the steps:
The clopidogrel that takes by weighing adds in the ether, stirs, and makes whole dissolvings and even, cooling, and the dripping hydrochloric acid diethyl ether solution to not producing till the precipitation, keeps temperature to stir, filtration, vacuum-drying promptly gets hydrochloric acid clopidogrel crystal form II.
Preferably, preparation method of the present invention in an embodiment.
Another object of the present invention is to provide a kind of pharmaceutical composition that contains hydrochloric acid clopidogrel crystal form II.
Pharmaceutical composition of the present invention contains the hydrochloric acid clopidogrel crystal form II and the pharmaceutically acceptable carrier of effective dose.
Pharmaceutical composition of the present invention becomes preparation by adding pharmaceutically acceptable preparing carriers.
Preparation of the present invention can be prepared into any pharmaceutically useful formulation, and these formulations comprise: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, pulvis, solution, injection, suppository, ointment, plaster, creme, sprays, drops, patch.Preparation of the present invention, oral dosage form preferably, as: capsule, tablet, oral liquid, granule, pill, powder, sublimed preparation, paste etc.Most preferably tablet or capsule.
Hydrochloric acid clopidogrel crystal form II preparation of drug combination method of the present invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis or the like.
The amount of the active ingredient that contains in pharmaceutical composition of the present invention and the unit dosage form can specifically be applied according to patient's the state of an illness, the situation of diagnosis, the amount of used compound or concentration are regulated in the scope of a broad, usually, the weight range of active compound is 0.5%～90% (weight) of composition.Another preferred range is 0.5%～70%.
Another object of the present invention is to provide the application of hydrochloric acid clopidogrel crystal form II in the medicine for preparing the ischemic cerebrovascular that improves and prevent to be caused by multiple reason.
Wherein, described ischemic cerebrovascular comprises: behind the tardy property cerebro-vascular diseases that causes after cerebral infarction, vertebro-basilar artery insufficiency, the subarachnoid hemorrhage, the cerebral surgery operation and cerebral ischemia relative diseases such as the cerebral vasospasm, the transient ischemic attack that cause after the interventional therapy, hematencephalon decubation, Neurology Department cerebral infarction.
Hydrochloric acid clopidogrel crystal form II of the present invention, its circulation ratio is fabulous, and good stability is easy to synthesize, and the preparation method is easy, easy handling, time spent short, and cost is low, is easy to suitability for industrialized production.
Description of drawings
What accompanying drawing 1 was represented is the X-ray powder diffraction pattern of hydrochloric acid clopidogrel.
What accompanying drawing 2 was represented is dsc (DSC) differential thermogram of hydrochloric acid clopidogrel.
What accompanying drawing 3 was represented is the infrared light collection of illustrative plates of hydrochloric acid clopidogrel.
Embodiment
Below in conjunction with embodiment the present invention is described further, embodiment only is indicative, means that never it limits the scope of the invention by any way.
Embodiment 1:Hydrochloric acid clopidogrel crystal form II
Take by weighing clopidogrel 20.0g, add in the 60mL ether, stir, make whole dissolvings and mix, be cooled to 5 ℃, the about 5ml of hydrochloric acid diethyl ether solution of Dropwise 5 mol/L to not producing precipitation, keeps temperature to stir 4 hours, filter, about 24 hours of vacuum-drying gets white crystalline powder.
Embodiment 2:Hydrochloric acid clopidogrel crystal form II
Take by weighing clopidogrel 20.0g, add in the 150mL ether, stir, make whole dissolvings and mix, be cooled to 5 ℃, the about 5ml of hydrochloric acid diethyl ether solution of Dropwise 5 mol/L to not producing precipitation, keeps temperature to stir 4 hours, filter, about 24 hours of vacuum-drying gets white crystalline powder.
Embodiment 3:Hydrochloric acid clopidogrel crystal form II
Take by weighing clopidogrel 20.0g, add in the 240mL ether, stir, make whole dissolvings and mix, be cooled to 5 ℃, the about 5ml of hydrochloric acid diethyl ether solution of Dropwise 5 mol/L to not producing precipitation, keeps temperature to stir 4 hours, filter, about 24 hours of vacuum-drying gets white crystalline powder.
Embodiment 4:Tablet of the present invention
Every tablet preparation that contains the 75mg activeconstituents:
Consumption/sheet
Hydrochloric acid clopidogrel crystal form II 75mg (in clopidogrel)
Lactose 80mg
Microcrystalline Cellulose 20mg
Starch 50mg
Hypromellose 10mg
Add 5mg in the carboxymethylstach sodium, add 5mg
Magnesium Stearate 1mg
Technology: activeconstituents, lactose, starch, Microcrystalline Cellulose are crossed 100 mesh sieves respectively, take by weighing and abundant mixing by recipe quantity, the 2% hypromellose aqueous solution joined in the said mixture granulate, cross 20 mesh sieve system softwoods, make wet granular in about 2～3 hours of 45～55 ℃ of dryings, residue carboxymethylstach sodium, Magnesium Stearate are joined compressing tablet in the above-mentioned dried particles.
Embodiment 5:Capsule of the present invention
Every capsule contains the capsule preparation of 75mg clopidogrel activeconstituents:
Consumption/capsule
Hydrochloric acid clopidogrel crystal form II 75mg (in clopidogrel)
Microcrystalline Cellulose 20mg
Lactose 60mg
Sodium starch glycolate 6mg
Hypromellose 5mg
Micropowder silica gel 5mg
Magnesium Stearate 1mg
Talcum powder 1mg
Technology: activeconstituents, auxiliary material are crossed 100 mesh sieves respectively; take by weighing the main ingredient and the auxiliary material thorough mixing of recipe quantity; add hypromellose solution and make softwood in right amount; cross 24 mesh sieves; make wet granular in 50～60 ℃ of baking ovens dry about 2～3 hours, Magnesium Stearate and talcum powder are mixed whole with particle; measure intermediate content, with No. 2 capsule cans.
Embodiment 6:Other formulations of the present invention
Hydrochloric acid clopidogrel crystal form II of the present invention, the auxiliary material pharmaceutically commonly used in adding is prepared into common formulations such as granule, oral liquid, injection.
Embodiment 7,Effect test
Test group: select hydrochloric acid clopidogrel crystal form II of the present invention for use
Control group: select existing hydrochloric acid clopidogrel crystal formation for use
The yield of the yield of existing hydrochloric acid clopidogrel crystal formation and invention hydrochloric acid clopidogrel crystal form II relatively.
Test-results shows: hydrochloric acid clopidogrel crystal formation I of the present invention still keeps satisfactory stability under hot and humid condition, and is better than existing hydrochloric acid clopidogrel crystal formation aspect yield.
Claims (10)
1. hydrochloric acid clopidogrel crystal form II, it is characterized in that: its X-powdery diffractometry has following characteristic peak: there is the peak at 2 θ places at 8.900,14.860,16.760,18.680,23.240,24.700,25.080,26.380,26.940 degree.
2. according to the described hydrochloric acid clopidogrel of claim 1 crystal form II, it is characterized in that: have following spectrum characteristic: adopt D/Max-2500 type x-ray diffractometer that the crystalline phase of sample is analyzed, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA, its X-powdery diffractometry has following characteristic peak:
3. according to the hydrochloric acid clopidogrel crystal form II of claim 1, it is characterized in that the temperature during its dissolving is 111～123 ℃.
4. according to the hydrochloric acid clopidogrel crystal form II of claim 1, it is characterized in that it is at 3428.81cm
-1, 2377.80cm
-1, 2348.87cm
-1, 1689.34cm
-1, 1039.44cm
-1There is the infrared absorption at peak at the place.
5. method for preparing the described hydrochloric acid clopidogrel of claim 1 crystal form II may further comprise the steps:
Take by weighing clopidogrel, add in the ether, stir, make whole dissolvings and even, cooling, the dripping hydrochloric acid diethyl ether solution to not producing till the precipitation, keeps temperature to stir, filtration, vacuum-drying promptly gets hydrochloric acid clopidogrel crystal form II.
6. according to the method for claim 5, it is characterized in that, may further comprise the steps: take by weighing clopidogrel 20.0g, add in the 60mL ether, stir, make whole dissolvings and mix, be cooled to 5 ℃, the hydrochloric acid diethyl ether solution 5ml of Dropwise 5 mol/L to not producing precipitation, keeps temperature to stir 4 hours, filter, vacuum-drying 24 hours gets white crystalline powder
Perhaps
Take by weighing clopidogrel 20.0g, add in the 150mL ether, stir, make whole dissolvings and mix, be cooled to 5 ℃, the hydrochloric acid diethyl ether solution 5ml of Dropwise 5 mol/L to not producing precipitation, keeps temperature to stir 4 hours, filter, vacuum-drying 24 hours gets white crystalline powder
Perhaps
Take by weighing clopidogrel 20.0g, add in the 240mL ether, stir, make whole dissolvings and mix, be cooled to 5 ℃, the hydrochloric acid diethyl ether solution 5ml of Dropwise 5 mol/L to not producing precipitation, keeps temperature to stir 4 hours, filter, vacuum-drying 24 hours gets white crystalline powder.
7. the pharmaceutical composition that contains the described hydrochloric acid clopidogrel of claim 1 crystal form II.
8. according to the described pharmaceutical composition of claim 7, be processed into by following raw material process:
Hydrochloric acid clopidogrel crystal form II 75mg (in clopidogrel)
Lactose 80mg
Microcrystalline Cellulose 20mg
Starch 50mg
Hypromellose 10mg
Add 5mg in the carboxymethylstach sodium, add 5mg
Magnesium Stearate 1mg
Technology: hydrochloric acid clopidogrel crystal form II, lactose, starch, Microcrystalline Cellulose are crossed 100 mesh sieves respectively, take by weighing and abundant mixing by recipe quantity, the 2% hypromellose aqueous solution joined in the said mixture granulate, cross 20 mesh sieve system softwoods, make wet granular in about 2～3 hours of 45～55 ℃ of dryings, residue carboxymethylstach sodium, Magnesium Stearate are joined compressing tablet in the above-mentioned dried particles.
9. according to the described pharmaceutical composition of claim 7, be processed into by following raw material process:
Hydrochloric acid clopidogrel crystal form II 75mg (in clopidogrel)
Microcrystalline Cellulose 20mg
Lactose 60mg
Sodium starch glycolate 6mg
Hypromellose 5mg
Micropowder silica gel 5mg
Magnesium Stearate 1mg
Talcum powder 1mg
Technology: hydrochloric acid clopidogrel crystal form II, auxiliary material are crossed 100 mesh sieves respectively; take by weighing the main ingredient and the auxiliary material thorough mixing of recipe quantity; add hypromellose solution and make softwood in right amount; cross 24 mesh sieves; make wet granular in 50～60 ℃ of baking ovens dry 2～3 hours, Magnesium Stearate and talcum powder are mixed whole with particle; measure intermediate content, with No. 2 capsule cans.
The hydrochloric acid clopidogrel crystal form II of claim 1 preparation improve and the medicine of the ischemic cerebrovascular that prevention is caused by multiple reason in application, wherein said ischemic cerebrovascular comprises: behind the tardy property cerebro-vascular diseases that causes after cerebral infarction, vertebro-basilar artery insufficiency, the subarachnoid hemorrhage, the cerebral surgery operation and cerebral ischemia relative diseases such as the cerebral vasospasm that causes after the interventional therapy, transient ischemic attack, hematencephalon decubation, Neurology Department cerebral infarction.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927863A (en) * | 2005-09-08 | 2007-03-14 | 浙江华海药业股份有限公司 | Preparation method of thienotetrahydropyridinacetic acid and salt thereof |
| WO2008068569A2 (en) * | 2006-12-01 | 2008-06-12 | Wockhardt Research Centre | Processes for the preparation of clopidogrel hydrochloride |
| CN101775001A (en) * | 2010-01-28 | 2010-07-14 | 天津市中央药业有限公司 | Method for synthesizing clopidogrel hydrogen sulfate intermediate by adopting solid acid catalytic esterification |
-
2011
- 2011-01-31 CN CN 201110033048 patent/CN102120746B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927863A (en) * | 2005-09-08 | 2007-03-14 | 浙江华海药业股份有限公司 | Preparation method of thienotetrahydropyridinacetic acid and salt thereof |
| WO2008068569A2 (en) * | 2006-12-01 | 2008-06-12 | Wockhardt Research Centre | Processes for the preparation of clopidogrel hydrochloride |
| CN101775001A (en) * | 2010-01-28 | 2010-07-14 | 天津市中央药业有限公司 | Method for synthesizing clopidogrel hydrogen sulfate intermediate by adopting solid acid catalytic esterification |
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