CN103408567B - A kind of method preparing crystalline form I of clopidogrel bisulfate - Google Patents
A kind of method preparing crystalline form I of clopidogrel bisulfate Download PDFInfo
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- CN103408567B CN103408567B CN201310308173.5A CN201310308173A CN103408567B CN 103408567 B CN103408567 B CN 103408567B CN 201310308173 A CN201310308173 A CN 201310308173A CN 103408567 B CN103408567 B CN 103408567B
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Abstract
A kind of method that the invention provides new preparation crystalline form I of clopidogrel bisulfate, it is characterized in that comprising the following steps: be dissolved in organic solvent methanol or ethanol by bisulfate clopidogrel crystal formation products material, in the range of temperature 30 ~ 30 DEG C, the solution dissolving clarification is added drop-wise in acid and anti-solvent mixed solution, after stirring and evenly mixing, centrifugal 3 ~ 60 minutes, through being dried to obtain stable crystalline form I of clopidogrel bisulfate powder after centrifugal product anti-solvent washing, product is the aggregate of square structure crystal, has good stability.The present invention is easy and simple to handle, is suitable for industrialized production, environmental protection, and product purity is high, and yield is high.
Description
Technical field
The invention belongs to pharmaceutical formulating art, a kind of method of new preparation crystalline form I of clopidogrel bisulfate.
Background technology
Bisulfate clopidogrel (Clopidogrel Bisulfate), as a kind of new and effective antiplatelet drug,
Structural formula is as follows:
There is multiple crystal formation in bisulfate clopidogrel, owing to the thermodynamic stability of crystalline form I of clopidogrel bisulfate is more brilliant
Type II is poor, and therefore crystalline form I of clopidogrel bisulfate is long placed in rear section transformation, thus causes bisulfate clopidogrel crystal formation impure,
The stability of preparation is produced certain impact.Therefore the novel preparation method of crystal formation I is developed, the crystal formation I product tool of synthesizing stable
The using value having had.
United States Patent (USP) US7772398B2 discloses a kind of preparation method of crystalline form I of clopidogrel bisulfate, wherein uses
Organic solvent is isopropanol and sec-butyl alcohol, and the method is by the most heated for bisulfate clopidogrel salt concentration, so
After in anti-solvent stir, isolated.
Patent WO2011/052940A2 discloses the novel preparation method of crystalline form I of clopidogrel bisulfate.This invention be about
The preparation of bisulfate clopidogrel bulky grain crystal formation I and production method, its granule is actually spheroidal particle, and this structure is surely
All take advantage in qualitative and purity.It is mainly characterized by during salt-forming reaction, need to add acid or glacial acetic acid in solution
Or propanoic acid.
Patent CN1620293A discloses the novel crystal forms III, IV, V and VI of bisulfate clopidogrel and amorphous, also carries
Supply new preparation form I, form II, form III, form IV, form V, form VI and unbodied clopidogrel hydrogensulfate
The method of salt.The methanol solution of 4ml clopidogrel hydrogenesulphate is added drop-wise to the t-butyl methyl ether of 300ml by embodiment 18
In, the stirring through long-time 16 hours obtains crystal formation I product.The method consumes quantity of solvent greatly, and the longest, efficiency is low.
Summary of the invention
The invention provides a kind of easy and simple to handle, low-cost high-efficiency is suitable for industrialized production, and products obtained therefrom purity is high,
The method of the preparation crystalline form I of clopidogrel bisulfate of good stability.Said method comprising the steps of:
1) mixture of any for bisulfate clopidogrel crystal formation is dissolved in methanol or ethanol, it is thus achieved that hydrogen sulfate chlorine pyrrole lattice
Thunder solution；
2) being added drop-wise to by the bisulfate clopidogrel solution that step 1) obtains in the mixed solution of acid and anti-solvent, stirring is mixed
It is centrifuged after even；
3) by step 2) centrifugal product anti-solvent washing after through being dried to obtain stable crystalline form I of clopidogrel bisulfate
Powder.
By above technical scheme, the present invention utilizes and adds a small amount of weak acid and centrifugal force auxiliary crystallize preparation crystalline substance in anti-solvent
Type I, the invention have the advantages that and greatly reduce anti-solvent consumption, the shortest, and products obtained therefrom is stable square crystal.Used
Anti-solvent is about a times of bisulfate clopidogrel salt methanol solution volume；Crystal is separated out in the centrifugal process short time,
Yield is high, greatly reduces production cost, and the granule of the crystalline form I of clopidogrel bisulfate obtained is square structure crystal
Aggregate, particle size 100 microns, good stability；The whole crystallize time controls in one hour, and work efficiency is high, this
Inventing easy and simple to handle, be suitable for industrialized production, environmental protection, purity is high, and yield is high and product stability is good.
Accompanying drawing explanation
Fig. 1 is the X ray diffracting spectrum of the crystalline form I of clopidogrel bisulfate of embodiments of the invention 1；
Fig. 2 is the spectrogram of the differential scanning of the crystalline form I of clopidogrel bisulfate of embodiments of the invention 2；
Fig. 3 is the stereoscan photograph of the crystalline form I of clopidogrel bisulfate of embodiments of the invention 3；
Fig. 4 is the stereoscan photograph of the crystalline form I of clopidogrel bisulfate of embodiments of the invention 7.
Detailed description of the invention
The present invention is a kind of method preparing crystalline form I of clopidogrel bisulfate, comprises the following steps:
1) mixture of any for bisulfate clopidogrel crystal formation is dissolved in methanol or ethanol, it is thus achieved that hydrogen sulfate chlorine pyrrole lattice
Thunder solution；
2) being added drop-wise to by the bisulfate clopidogrel solution that step 1) obtains in the mixed solution of acid and anti-solvent, stirring is mixed
It is centrifuged after even；
3) by step 2) centrifugal product anti-solvent washing after through being dried to obtain stable crystalline form I of clopidogrel bisulfate
Powder.
The temperature range of described step 1) is-30～30 DEG C.
The mixture of described bisulfate clopidogrel crystal formation is 1:0.8～1.2 with the weight ratio of methanol or ethanol.
Described step 2) anti-solvent be methyl tertiary butyl ether(MTBE) or ethyl acetate.
Described step 2) acid be acid or glacial acetic acid or propanoic acid.
Described step 2) one times that the consumption of anti-solvent is the bisulfate clopidogrel liquor capacity that step 1) obtains with
On.
Described step 2) the consumption of acid be 0.1～0.5 times of bisulfate clopidogrel liquor capacity that step 1) obtains.
Described step 2) in, anti-solvent is that temperature range during methyl tertiary butyl ether(MTBE) is-30～30 DEG C, and anti-solvent is acetic acid
Temperature range during ethyl ester is-30～0 DEG C.
Described step 2) in, the centrifugal range of speeds is 5000～12000rpm, preferably 8000～10000rpm.
Bisulfate clopidogrel crystal formation mixture of the present invention, refers to bisulfate clopidogrel form I, form II, shape
State III, form IV, form V, form VI and amorphous in the mixture of any one or more.
Described anti-solvent refers to this solvent that product bisulfate clopidogrel is insoluble or dissolubility is extremely low, such as tertbutyl methyl
Ether, ethyl acetate, acetone, 4-methyl 2 pentanone etc..
Embodiment 1
Weigh 0.8g bisulfate clopidogrel crystal formation mixture in flask, drip 1ml methanol, vibrate molten clear after-18
At DEG C, mixed liquor is added drop-wise in the mixed solution of 0.2ml acetic acid and 2ml methyl tertiary butyl ether(MTBE), centrifugal after stirring, arrange
Centrifugal rotational speed is 9500rpm, and the time is 4 minutes；Centrifugal product adds 5ml methyl tertiary butyl ether(MTBE) and washs；Then sucking filtration, dry
Dry, obtain white powder.Detecting through X-ray diffractometer, product is crystalline form I of clopidogrel bisulfate, as shown in Figure 1.Calculate and receive
Rate is 85%.
Embodiment 2
Weigh 1g bisulfate clopidogrel crystal formation mixture in flask, drip 1.5ml methanol, vibrate molten clear after at 0 DEG C
In the lower mixed solution that mixed liquor is added drop-wise to 0.3ml formic acid and 3ml methyl tertiary butyl ether(MTBE), centrifugal after stirring, arrange from
Heart rotating speed is 8500rpm, and the time is 5 minutes；Centrifugal product adds 6ml methyl tertiary butyl ether(MTBE) and washs；Then sucking filtration, is dried,
Obtaining white powder, calculated yield is 82%.Product through differential scanning calorimeter test fusing point is 185.0 DEG C, result is shown in Fig. 2.
Embodiment 3
Weigh 1g bisulfate clopidogrel crystal formation mixture in flask, drip 1ml methanol, vibrate molten clear after at 0 DEG C
Mixed liquor is added drop-wise in the mixed solution of 0.5ml propanoic acid and 1.5ml methyl tertiary butyl ether(MTBE), centrifugal after stirring, arrange from
Heart rotating speed is 12000rpm, and the time is 4 minutes；Centrifugal product adds 7ml methyl tertiary butyl ether(MTBE) and washs；Then sucking filtration, is dried,
Obtain white powder.Detecting through X-ray diffractometer, product is crystalline form I of clopidogrel bisulfate, scanned electron microscopic observation pattern,
It is the aggregate of square structure crystal, and granular size is 100 microns.Calculated yield is 88%.
Embodiment 4
Weigh 1.5g bisulfate clopidogrel crystal formation mixture in flask, drip 1.8ml methanol, vibrate molten clear after-
At 18 DEG C, mixed liquor is added drop-wise in the mixed solution of 0.8ml acetic acid and 3ml ethyl acetate, centrifugal after stirring, arrange from
Heart rotating speed is 10000rpm, and the time is 5 minutes；Centrifugal product adds 5ml methyl tertiary butyl ether(MTBE) and washs；Then sucking filtration, is dried,
Obtain white powder.Detecting through X-ray diffractometer, product is crystalline form I of clopidogrel bisulfate, and calculated yield is 84%.
Embodiment 5
Weigh 1g bisulfate clopidogrel crystal formation mixture in flask, drip 1.5ml methanol, vibrate molten clear after-15
At DEG C, mixed liquor is added drop-wise in the mixed solution of 0.2ml acetic acid 4ml ethyl acetate, centrifugal after stirring, centrifugal turning is set
Speed is 8500rpm, and the time is 15 minutes；Centrifugal product adds 5ml ethyl acetate and washs；Then sucking filtration, is dried, obtains white
Powder.Detecting through X-ray diffractometer, product is crystalline form I of clopidogrel bisulfate, and calculated yield is 83%.
Embodiment 6
Weigh 2g bisulfate clopidogrel crystal formation mixture in flask, drip 2.4ml methanol, vibrate molten clear after at 25 DEG C
In the lower mixed solution that mixed liquor is added drop-wise to 1ml acetic acid and 5ml methyl tertiary butyl ether(MTBE), centrifugal after stirring, arrange centrifugal
Rotating speed is 9000rpm, and the time is 20 minutes；Centrifugal product adds 7ml methyl tertiary butyl ether(MTBE) and washs；Then sucking filtration, is dried,
To white powder.Detecting through X-ray diffractometer, product is crystalline form I of clopidogrel bisulfate, and calculated yield is 82%.
The crystalline form I of clopidogrel bisulfate of gained of the present invention is tested through differential scanning calorimeter, and its peak melt temperature is
185.0 ± 1 DEG C, heat content is 72.0 ± 2J/g, and it is shorter to melt journey, demonstrates more perfect growth state of crystal.And it is obtained
Crystalline form I of clopidogrel bisulfate, scanned electron microscopic observation finds the aggregate that its granule is square structure crystal, particle size
100 microns.Saying from crystallography, this structure has preferable thermodynamic stability.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all spirit in the present invention and
Any amendment, equivalent and the improvement etc. made within principle, within being all contained in protection scope of the present invention.
It is below comparative example:
Embodiment 7
Weigh 1g bisulfate clopidogrel crystal formation mixture in flask, drip 1ml methanol, vibrate molten clear after at 0 DEG C
Mixed liquor is added drop-wise in the mixed solution of 0.2ml acetic acid and 50ml methyl tertiary butyl ether(MTBE), centrifugal after stirring, arrange centrifugal
Rotating speed is 10000rpm, and the time is 30 minutes；Centrifugal product adds 7ml methyl tertiary butyl ether(MTBE) and washs；Then sucking filtration, is dried,
Obtain white powder.Detecting through X-ray diffractometer, product is crystalline form I of clopidogrel bisulfate, scanned electron microscopic observation pattern,
It mostly is the aggregate of rhabdolith, and granular size is 100 microns.Calculated yield 81%.
Embodiment 8
Weigh 2g bisulfate clopidogrel crystal formation mixture to be dissolved in 4ml methanol, vibrate molten clear after will mixing at 10 DEG C
Drop adds in 5ml methyl tertiary butyl ether(MTBE), stirs 16h, reacts without obvious crystallize, the most do not obtain in the case of not being centrifuged
Target product crystal form I.
Embodiment 9
Weigh 1g bisulfate clopidogrel crystal formation mixture and be dissolved in 1.2ml methanol, vibrate molten clear after at 0 DEG C by mixed liquor
In dropping 120ml ethyl acetate solution, stir 15 hours；Sucking filtration, is dried, obtains white powder.Detect through X-ray diffractometer,
Product is bisulfate clopidogrel crystal formation II, calculated yield 80%.
Embodiment 10
Weigh 3g bisulfate clopidogrel crystal formation mixture in flask, drip 4ml methanol, vibrate molten clear after at 35 DEG C
Being added drop-wise to by mixed liquor in the mixed solution of 4ml methyl tertiary butyl ether(MTBE), centrifugal after stirring, arranging centrifugal rotational speed is
8000rpm, the time is 20 minutes；Centrifugal product adds 7ml methyl tertiary butyl ether(MTBE) and washs；Then sucking filtration, is dried, obtains white
Powder.Detecting through X-ray diffractometer, product is bisulfate clopidogrel crystal formation II, calculated yield 64%.
Above-mentioned different embodiment is compared by following table, finds out by comparing, and is adding weak acid and centrifugal auxiliary crystallize
Under conditions of, products therefrom is pure bisulfate clopidogrel I type, and anti-solvent consumption is few, produces the shortest.Products therefrom
For stable quadratic crystal, yield is higher.
| Embodiment | Householder method | Anti-solvent consumption | Crystallize is time-consuming | Product form | Pattern | Yield |
| Embodiment 3 | Weak acid is also centrifuged | 1.5 again | 4 minutes | I | Square | 88% |
| Embodiment 7 | Centrifugal | 5 times | 1h | I | Bar-shaped | 81% |
| Embodiment 8 | - | 1.2 again | 16h | Separate out without crystal | - | - |
| Embodiment 9 | - | 100 times | 15h | II | - | 80% |
| Embodiment 10 | Centrifugal | 1 times | 2h | II | - | 64% |
By above comparative example 7,8,9,10 it is known that process conditions include centrifugal auxiliary, temperature, solvent formula etc. is right
The preparation impact of target crystal formation is the biggest.Do not adding centrifugal auxiliary or beyond temperature range beyond all can not get target crystal formation 1, not
The when of adding weak acid, it is impossible to obtain the crystal structure of square.Instant invention overcomes above technical difficulty, by centrifugal auxiliary analysis
Brilliant method, the crystalline form I of clopidogrel bisulfate purity obtained is high, Heat stability is good.And raw materials for production loss is few, the used time
Short, significantly reduce cost, improve efficiency.
Claims (4)
1. the method preparing crystalline form I of clopidogrel bisulfate, it is characterised in that comprise the following steps: by hydrogen sulfate chlorine pyrrole lattice
Thunder crystal formation mixture is dissolved in organic solvent methanol or ethanol, it is thus achieved that bisulfate clopidogrel solution, temperature-30 ~ 30 DEG C
In the range of by dissolve clarification solution be added drop-wise to acid and anti-solvent mixed solution in, acid is formic acid, acetic acid or propanoic acid, anti-solvent
For ethyl acetate or t-butyl methyl ether, after stirring and evenly mixing, centrifugal a period of time under certain rotating speed, rotating speed is at 5000-
12000rpm, through being dried to obtain stable crystalline form I of clopidogrel bisulfate powder after centrifugal product anti-solvent washing.
2. a kind of method preparing crystalline form I of clopidogrel bisulfate as described in claim 1, it is characterised in that centrifugal turns
Speed scope is 8000-10000rpm, and centrifugation time was at 3-60 minute.
3. a kind of method preparing crystalline form I of clopidogrel bisulfate as described in claim 1, it is characterised in that the sulfur obtained
The peak melt temperature of acid clopidogrel hydrogen crystal formation I is 185 ± 1 DEG C, and heat content is 72.0 ± 2J/g.
4. a kind of method preparing crystalline form I of clopidogrel bisulfate described in claim 2, it is characterised in that the hydrogen sulfate obtained
The granule of clopidogrel crystal formation I is the aggregate of square structure crystal, particle size 100 microns.
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| CN104045653A (en) * | 2014-07-15 | 2014-09-17 | 苏州天马精细化学品股份有限公司 | Method for purifying hydrosulfate clopidogrel |
| CN105012298B (en) * | 2015-07-17 | 2016-06-01 | 深圳信立泰药业股份有限公司 | A kind of pharmaceutical composition and its preparation method containing spherical bisulfate clopidogrel I crystal |
| CN104945413A (en) * | 2015-07-21 | 2015-09-30 | 浙江华海药业股份有限公司 | Preparation method of first hydrogen sulfate clopidogrel crystal form |
| CN111662304B (en) * | 2020-06-08 | 2022-03-29 | 天津大学 | Method for rapidly preparing clopidogrel hydrogen sulfate I crystal form spherical crystal |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620293A (en) * | 2001-12-18 | 2005-05-25 | 特瓦制药工业有限公司 | Polymorphs of clopidogrel hydrogensulfate |
| US20060047121A1 (en) * | 2004-09-01 | 2006-03-02 | Sawant Kamlesh D | Novel process for preparation of clopidogrel bisulfate polymorph - Form I |
| CN102924474A (en) * | 2012-11-08 | 2013-02-13 | 浙江海翔药业股份有限公司 | Preparation method of crystal form I of clopidogrel hydrogen sulfate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620293A (en) * | 2001-12-18 | 2005-05-25 | 特瓦制药工业有限公司 | Polymorphs of clopidogrel hydrogensulfate |
| US20060047121A1 (en) * | 2004-09-01 | 2006-03-02 | Sawant Kamlesh D | Novel process for preparation of clopidogrel bisulfate polymorph - Form I |
| CN102924474A (en) * | 2012-11-08 | 2013-02-13 | 浙江海翔药业股份有限公司 | Preparation method of crystal form I of clopidogrel hydrogen sulfate |
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| Ⅰ型氯吡格雷硫酸氢盐的合成及晶型转换;潘仙华，等;《精细化工》;20061231;第23卷(第12期);第1221-1226页 * |
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Effective date of registration: 20200701 Address after: 322118 Hengdian Industrial Zone, Jinhua, Zhejiang, China, Dongyang Co-patentee after: APELOA PHARMACEUTICAL Co.,Ltd. Patentee after: ZHEJIANG APELOA JIAYUAN PHARMACEUTICAL Co.,Ltd. Address before: 322100 Hengdian Industrial Zone, Jinhua, Zhejiang, China, Dongyang Patentee before: ZHEJIANG APELOA JIAYUAN PHARMACEUTICAL Co.,Ltd. |
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