CN109771387A - A kind of clopidogrel bisulfate tablet and preparation method thereof - Google Patents
A kind of clopidogrel bisulfate tablet and preparation method thereof Download PDFInfo
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- CN109771387A CN109771387A CN201711109041.4A CN201711109041A CN109771387A CN 109771387 A CN109771387 A CN 109771387A CN 201711109041 A CN201711109041 A CN 201711109041A CN 109771387 A CN109771387 A CN 109771387A
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- bisulfate clopidogrel
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Abstract
The present invention relates to a kind of bisulfate clopidogrel II crystal form tablets and preparation method thereof.The piece is prepared from the following ingredients in percentage by weight: bisulfate clopidogrel II crystal form, filler, disintegrating agent, antioxidant, appropriate adhesive and appropriate lubricant.The features such as present invention improves the stability of gained preparation, and gained preparation has uniformity good, and piece surface is smooth, and tablet weight variation is small, and dissolving out capability meets clinical application requirement, to ensure that the validity and safety of clinical application.Also assure that there is no sticking problems in tableting processes in conjunction with preparation process.
Description
Technical field
The invention belongs to bisulfate clopidogrel formulation arts, and in particular to bisulfate clopidogrel II crystal form tablet and
Preparation method.
Background technique
Cardiovascular and cerebrovascular thrombotic diseases are a kind of diseases for seriously threatening human health.Platelet aggregation is normal solidifying
An important link in blood mechanism, the sticking, assemble of blood platelet discharge reaction and tend to lead to thrombosis.Therefore, press down
Platelet aggregation drugs processed play an important role in treatment thrombotic disease.Clopidogrel is platelet aggregation suppression in a kind of blood
Preparation and antithrombotic reagent active constituent, it by selective depression adenosine diphosphate (ADP) (ADP) in conjunction with its platelet receptor and
The activation for II b/ of GP, the III a compound that secondary ADP is mediated inhibits platelet aggregation.It furthermore can also be by blocking by discharging
ADP caused by platelet activation amplification, inhibit the platelet aggregation of other dynamic agent inductions.It is widely used in treatment cardiac muscle
Infarct breaking-out, atherosclerosis, acute coronary syndrome, apoplexy, prevention restenosis after coronary stenting and thrombus
Property complication etc..
There are two types of the common crystal forms of bisulfate clopidogrel: EP281459 discloses crystal form I, and US6429210 discloses crystalline substance
Type II.Crystal form II is compared with crystal form I: powder compactness is strong, and thermal stability is strong, and electrostatic is weak, preparation processing better performances, therefore brilliant
Type II is very potential clinical application crystal form.
Currently, main problem present in the production process of clopidogrel hydrogen sulfate tablet: (1) stability is poor: sulfuric acid
Clopidogrel hydrogen has carboxylate structure, to damp and hot unstable, easy hydrolysis degreasing, formation clopidogrel acid；(2) easy sticking:
Bisulfate clopidogrel raw material has hygroscopicity, is easily adsorbed on metal surface, and being rubbed and being overstock then generates rapidly bonding,
Sticking is caused to lead to poor product quality.These seriously limit the large-scale production of bisulfate clopidogrel medicine.
In conclusion a kind of better bisulfate clopidogrel oral tablet of stability is needed in clinical application to guarantee
The validity and safety of patient medication.Especially for cost is reduced, develop herein a kind of stable hydrogen sulfate chlorine pyrrole sound of laughing
Thunder II crystal form tablet become there is an urgent need to.
Summary of the invention
The purpose of the present invention is to provide a kind of bisulfate clopidogrel crystal form II tablet having good stability, at the same it is a kind of
The preparation method of the tablet.
In order to achieve the goal above, the used following technical scheme of the present invention: bisulfate clopidogrel II crystal form tablet, with
Parts by weight meter, ingredient are as follows: 98 parts of bisulfate clopidogrel, 45-60 parts of mannitol, 30-50 parts of pregelatinized starch, microcrystalline cellulose
25-30 parts plain, 25-35 parts of low-substituted hydroxypropyl cellulose, 2-15 parts of Macrogol 6000,2-10 parts of rilanit special, coating
1000 parts of material.
The mannitol is filler；The pregelatinized starch is filler, disintegrating agent；The microcrystalline cellulose is filling
Agent；The disintegrating agent is low-substituted hydroxypropyl cellulose；The Macrogol 6000, rilanit special are lubricant；The packet
Clothing material is selected from common commercially available or homemade coating material, such as Opadry, hydroxypropyl methylcellulose.
The technical solution adopted in the present invention, which also resides in, provides a kind of preparation side of bisulfate clopidogrel II crystal form tablet
Method, comprising the following steps:
1) microcrystalline cellulose, pregelatinized starch, 80 DEG C of mannitol are dried to moisture < 10%；Macrogol 6000 crosses 100 mesh
Sieve, it is spare；
2) preparation of coating solution: by coating material, it is added to 80%(V/V) in ethanol solution, stirring and dissolving is spare；
3) particle manufacture by bisulfate clopidogrel II crystal form, mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose,
Microcrystalline cellulose and Macrogol 6000 mixing, dry granulating machine granulation；
4) particle made from step 3) is crossed 30-40 mesh sieve with vibrating screen by total mix, and hydrogenation is added into whole good dry particl
Castor oil is uniformly mixed, and controls moisture < 10%；
5) bisulfate clopidogrel granule content is surveyed, determines slice weight, tabletting；
6) coating coating solution is coated, and is dried after coating, is obtained bisulfate clopidogrel II crystal form tablet.
The supplementary product kind and dosage of bisulfate clopidogrel II crystal form tablet is optimized in the present invention, by pelletizing
In the process, it is higher finally to guarantee that bisulfate clopidogrel II crystal form tablet obtained has for various auxiliary material selections and the optimization of proportion
Stability, to better assure that the validity and safety of clinical application；Rilanit special, dry granulation is added in outer addition
It further ensures and sticking problem is not present in tableting processes.Clopidogrel bisulfate tablet surface prepared by the present invention is smooth, clean
Only, there is stronger stability.Present invention process is simple, operating method, is easy to industrialization promotion.
Wherein, auxiliary material mannitol has complexing to the present invention, can play the role of antioxygen synergy, can effectively prevent dextrorotation
The conversion of isomers meeting；Macrogol 6000 is used as lubricant in this programme, and uniformity is good after tabletting, and piece surface is smooth, piece
The method of double differences is different small.
Specific embodiment
Below in conjunction with the embodiments, a kind of clopidogrel bisulfate tablet of the invention and preparation method thereof is further illustrated,
Following embodiments be it is illustrative, be not restrictive, cannot be limited the scope of protection of the present invention with following embodiments.It is all
Made any modification, equivalent replacement and improvement etc. within the spirit and principles in the present invention, should be included in the present invention
Protection scope within.
Embodiment 1
Prescription (preparation 1000)
| 1. project | 2. mass parts |
| 3. bisulfate clopidogrel II crystal form (in terms of C16H16ClNO2S) | 4.98 |
| 5. pregelatinized starch | 6.30 |
| 7. mannitol | 8.50 |
| 9. microcrystalline cellulose | 10.25 |
| 11. low-substituted hydroxypropyl cellulose | 12.30 |
| 13.PEG6000 | 14. 5 |
| 15. rilanit special | 16. 5 |
| 17. coating material | 18. 1000 |
Specific step is as follows when preparation:
1) microcrystalline cellulose, pregelatinized starch, 80 DEG C of mannitol are dried to moisture is respectively < 10%；With vibrating screen by poly- second
Glycol 6000 sieves with 100 mesh sieve, spare；
2) appropriate coating material is added in 80% ethanol solution of 1.2 times of its weight by the preparation of coating solution, and being sufficiently stirred makes
It is dissolved, spare；
3) particle manufacture adjusts blower frequency 30-50HZ, adjusts spray gun air pressure between 0-0.2MPa, and opening inlet valve will locate
The bisulfate clopidogrel II crystal form just measured, lactose, pregelatinized starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and poly-
Ethylene glycol 6000 carries out the pre- hot mixing of granulation procedure with mixing machine, and preheating incorporation time is 10-20 minutes；To on temperature of charge
When being raised to 60 DEG C of set temperature, feed flow frequency 8-20HZ, spray gun air pressure 0-0.2Mpa are adjusted, starts wriggling pump spraying, is sprayed into viscous
Mixture granulation controls temperature of charge between 40-60 DEG C, particle is made in said mixture；When grain forming, stop supply
Adhesive；Fluidisation drying is carried out to wet granular, drying temperature should be controlled at 60-70 DEG C, and the time is 10-20 minutes, after dry
Particle should be white particle, without miscellaneous point；
4) particle made from step 3) is crossed 30-40 mesh sieve with vibrating screen by total mix, and hydrogenation is added into whole good dry particl
Castor oil is sufficiently mixed 30 minutes in mixing machine, controls moisture < 10%；
5) tabletting surveys bisulfate clopidogrel particle according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015)
Content determines slice weight.With diameter 8.5mm scrobicula stamping, control hardness is 80N, tabletting, and surface is smooth；
6) art for coating of the coating art for coating using routine, 55-65 DEG C of inlet air temperature of setting, 40-60 DEG C of leaving air temp, mist
Change pressure 0.3-0.4Mpa；When temperature of charge rises to 40 DEG C, coating solution is sprayed into, control temperature of charge is 35-40 DEG C, depending on coating
Situation adjusts pot revolving speed 2-6 per minute and turns, and the slice weight after film coating should increase weight as the 2-5% of essence slice weight, and coating terminates laggard
Row heated-air drying, 35-40 DEG C of temperature.
Embodiment 2
Prescription (preparation 1000)
| 19. project | 20. mass parts |
| 21. bisulfate clopidogrel II crystal form (in terms of C16H16ClNO2S) | 22. 98 |
| 23. pregelatinized starch | 24. 25 |
| 25. mannitol | 26. 55 |
| 27. microcrystalline cellulose | 28. 30 |
| 29. low-substituted hydroxypropyl cellulose | 30. 20 |
| 31.PEG6000 | 32. 10 |
| 33. rilanit special | 34. 5 |
| 35. coating material | 36. 1000 |
Specific step is as follows when preparation:
1) microcrystalline cellulose, pregelatinized starch, 80 DEG C of mannitol are dried to moisture is respectively < 10%；With vibrating screen by poly- second
Glycol 6000 sieves with 100 mesh sieve, spare；
2) appropriate coating material is added in 80% ethanol solution of 1.2 times of its weight by the preparation of coating solution, and being sufficiently stirred makes
It is dissolved, spare；
3) particle manufacture adjusts blower frequency 30-50HZ, adjusts spray gun air pressure between 0-0.2MPa, and opening inlet valve will locate
Bisulfate clopidogrel, lactose, pregelatinized starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and the polyethylene glycol just measured
6000 carry out the pre- hot mixing of granulation procedure with mixing machine, and preheating incorporation time is 10-20 minutes；It rises to and sets to temperature of charge
When determining temperature 60 C, feed flow frequency 8-20HZ, spray gun air pressure 0-0.2Mpa are adjusted, starts wriggling pump spraying, sprays into adhesive system
Grain controls temperature of charge between 40-60 DEG C, particle is made in said mixture；When grain forming, stop supply bonding
Agent；Wet granular is dried, drying temperature should be controlled at 60-70 DEG C, and the time is 10-20 minutes, and the particle after drying should be
White particle, without miscellaneous point, surface is smooth；
4) step 3) is crossed 30-40 mesh sieve with vibrating screen by total mix, and rilanit special is added into whole good dry particl mixed
It is sufficiently mixed in conjunction machine 30 minutes, controls moisture < 10%；
5) tabletting surveys bisulfate clopidogrel particle according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015)
Content determines slice weight.With diameter 8.5mm scrobicula stamping, control hardness is 80N, tabletting；
6) art for coating of the coating art for coating using routine, 55-65 DEG C of inlet air temperature of setting, 40-60 DEG C of leaving air temp, mist
Change pressure 0.3-0.4Mpa；When temperature of charge rises to 40 DEG C, coating solution is sprayed into, control temperature of charge is 35-40 DEG C, depending on coating
Situation adjusts pot revolving speed 2-6 per minute and turns, and the slice weight after film coating should increase weight as the 2-5% of essence slice weight, and coating terminates laggard
Row heated-air drying, 35-40 DEG C of temperature.
Embodiment 3
Prescription (preparation 1000)
| 37. project | 38. mass parts |
| 39. bisulfate clopidogrel II crystal form (in terms of C16H16ClNO2S) | 40. 98 |
| 41. pregelatinized starch | 42. 30 |
| 43. mannitol | 44. 45 |
| 45. microcrystalline cellulose | 46. 30 |
| 47. low-substituted hydroxypropyl cellulose | 48. 25 |
| 49.PEG6000 | 50. 10 |
| 51. rilanit special | 52. 5 |
| 53. coating material | 54. 1000 |
Specific step is as follows when preparation:
1) microcrystalline cellulose, pregelatinized starch, 80 DEG C of mannitol are dried to moisture is respectively < 10%；With vibrating screen by poly- second
Glycol 6000 sieves with 100 mesh sieve, spare；
2) appropriate coating material is added in 80% ethanol solution of 1.2 times of its weight by the preparation of coating solution, and being sufficiently stirred makes
It is dissolved, spare；
3) particle manufacture adjusts blower frequency 30-50HZ, adjusts spray gun air pressure between 0-0.2MPa, and opening inlet valve will locate
Bisulfate clopidogrel, lactose, pregelatinized starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and the polyethylene glycol just measured
6000 carry out the pre- hot mixing of granulation procedure with mixing machine, and preheating incorporation time is 10-20 minutes；It rises to and sets to temperature of charge
When determining temperature 60 C, feed flow frequency 8-20HZ, spray gun air pressure 0-0.2Mpa are adjusted, starts wriggling pump spraying, sprays into adhesive system
Grain controls temperature of charge between 40-60 DEG C, particle is made in said mixture；When grain forming, stop supply bonding
Agent；Fluidisation drying is carried out to wet granular, drying temperature should be controlled at 60-70 DEG C, and the time is 10-20 minutes, the particle after drying
It should be white particle, without miscellaneous point, surface is smooth；
4) particle made from step 3) is crossed 30-40 mesh sieve with vibrating screen by total mix, and hydrogenation is added into whole good dry particl
Castor oil is sufficiently mixed 30 minutes in mixing machine, controls moisture < 10%；
5) tabletting surveys bisulfate clopidogrel particle according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015)
Content determines slice weight.With diameter 8.5mm scrobicula stamping, control hardness is 80N, tabletting；
6) art for coating of the coating art for coating using routine, 55-65 DEG C of inlet air temperature of setting, 40-60 DEG C of leaving air temp, mist
Change pressure 0.3-0.4Mpa；When temperature of charge rises to 40 DEG C, coating solution is sprayed into, control temperature of charge is 35-40 DEG C, depending on coating
Situation adjusts pot revolving speed 2-6 per minute and turns, and the slice weight after film coating should increase weight as the 2-5% of essence slice weight, and coating terminates laggard
Row heated-air drying, 35-40 DEG C of temperature.
Embodiment 6
Dissolution rate is investigated
According to standards of pharmacopoeia, dissolution determination is carried out to clopidogrel bisulfate tablet made from embodiment 1-3.Method: taking this product,
According to dissolution rate and drug release determination method (Chinese Pharmacopoeia 0,931 second method of version general rule in 2015), (taken with pH2.0 hydrochloride buffer
0.2mol/l Klorvess Liquid 250ml adds 0.2mol/l hydrochloric acid solution 65.0ml, is diluted with water to 1000ml) 1000ml be it is molten
Medium out, revolving speed are 50 turns per minute, operate according to methods, when through 30 minutes, take solution, filter, and precision measurement subsequent filtrate is appropriate, are used
Dissolution medium, which quantitatively dilutes, is made solution of every 1ml containing about 25 μ g of clopidogrel, shakes up, as test solution；Separately take sulfuric acid
Clopidogrel hydrogen is appropriate according to product, accurately weighed, adds methanol 20ml to make to dissolve, is made in every 1ml about with dissolution medium dissolved dilution
The solution of the 25 μ g containing clopidogrel, as reference substance solution；Above two solution is taken, according to UV-VIS spectrophotometry (China
Pharmacopeia version general rule 0401 in 2015), absorbance is measured at the wavelength of 240nm, calculates every the amount of dissolution.As a result it see the table below:
| 55. project | 56.30 minutes dissolution rates (%) |
| 57. embodiment 1 | 58.98.5 |
| 59. embodiment 2 | 60.99.2 |
| 61. embodiment 3 | 62.99.2 |
Embodiment 7
Study on the stability
According to standards of pharmacopoeia, study on the stability is carried out after embodiment 1-3 is obtained clopidogrel hydrogen sulfate tablet packaging,
Total miscellaneous changes of contents result see the table below:
| 63. project | 64.0 months (%) | 65. March (%) | 66. June (%) |
| 67. embodiment 1 | 68.0.35 | 69. 0.34 | 70. 0.38 |
| 71. embodiment 2 | 72.0.41 | 73. 0.35 | 74. 0.36 |
| 75. embodiment 3 | 76.0.38 | 77. 0.37 | 78. 0.33 |
It can be seen that the stability with higher during storage of preparation obtained by 1-3 of the embodiment of the present invention.
Claims (7)
1. the preparation method that the present invention designs a kind of bisulfate clopidogrel II crystal form tablet.
2. bisulfate clopidogrel II crystal form tablet according to claim 1, mainly by bisulfate clopidogrel crystal form II
It is formed with other auxiliary materials.
3. bisulfate clopidogrel II crystal form tablet according to claim 1, which is characterized in that the filler, which is selected from, to form sediment
One or more of powder, lactose, dextrin, amylum pregelatinisatum, microcrystalline cellulose and Icing Sugar, preferably microcrystalline cellulose.
4. bisulfate clopidogrel II crystal form tablet according to claim 1, which is characterized in that the disintegrating agent is selected from carboxylic
One of methyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium and sodium alginate
Or several, preferred low-substituted hydroxypropyl cellulose.
5. bisulfate clopidogrel II crystal form tablet according to claim 1, which is characterized in that described adhesive, which is selected from, forms sediment
One or more, preferably pregelatinized starch in powder, pregelatinized starch, hydroxypropylcellulose, hydroxypropyl methylcellulose and povidone.
6. bisulfate clopidogrel II crystal form tablet according to claim 1, which is characterized in that the lubricant is selected from hard
One or more of fatty acid magnesium, talcum powder, Macrogol 6000 and rilanit special, preferably Macrogol 6000 and hydrogenation castor
Sesame oil.
7. the preparation method of bisulfate clopidogrel II crystal form tablet described in claim 1-7, which is characterized in that this method packet
Include following steps: by bisulfate clopidogrel crystal form II, mannitol, pregelatinized starch, the low substituted hydroxy-propyl fiber of recipe quantity
Element, microcrystalline cellulose and Macrogol 6000 mixing, dry granulation are crossed 30-40 mesh sieve, are added into whole good dry particl
Rilanit special is uniformly mixed, and controls moisture < 10%；Bisulfate clopidogrel granule content is surveyed, determines slice weight, tabletting；Using
Conventional art for coating is coated, be dried after coating to get.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711109041.4A CN109771387A (en) | 2017-11-11 | 2017-11-11 | A kind of clopidogrel bisulfate tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711109041.4A CN109771387A (en) | 2017-11-11 | 2017-11-11 | A kind of clopidogrel bisulfate tablet and preparation method thereof |
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| CN109771387A true CN109771387A (en) | 2019-05-21 |
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| CN201711109041.4A Pending CN109771387A (en) | 2017-11-11 | 2017-11-11 | A kind of clopidogrel bisulfate tablet and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112999180A (en) * | 2019-12-20 | 2021-06-22 | 青岛黄海制药有限责任公司 | Clopidogrel hydrogen sulfate crystal form II tablet and preparation method thereof |
| CN115581679A (en) * | 2021-07-05 | 2023-01-10 | 上海复星星泰医药科技有限公司 | Preparation method of anti-sticking tablet and tablet |
-
2017
- 2017-11-11 CN CN201711109041.4A patent/CN109771387A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112999180A (en) * | 2019-12-20 | 2021-06-22 | 青岛黄海制药有限责任公司 | Clopidogrel hydrogen sulfate crystal form II tablet and preparation method thereof |
| CN112999180B (en) * | 2019-12-20 | 2022-08-30 | 青岛黄海制药有限责任公司 | Clopidogrel hydrogen sulfate crystal form II tablet and preparation method thereof |
| CN115581679A (en) * | 2021-07-05 | 2023-01-10 | 上海复星星泰医药科技有限公司 | Preparation method of anti-sticking tablet and tablet |
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Application publication date: 20190521 |