CN110614153A - Preparation method of micronized ticagrelor - Google Patents
Preparation method of micronized ticagrelor Download PDFInfo
- Publication number
- CN110614153A CN110614153A CN201810627691.6A CN201810627691A CN110614153A CN 110614153 A CN110614153 A CN 110614153A CN 201810627691 A CN201810627691 A CN 201810627691A CN 110614153 A CN110614153 A CN 110614153A
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- CN
- China
- Prior art keywords
- ticagrelor
- mpa
- crushing chamber
- pressure
- micronized
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C19/00—Other disintegrating devices or methods
- B02C19/06—Jet mills
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C23/00—Auxiliary methods or auxiliary devices or accessories specially adapted for crushing or disintegrating not provided for in preceding groups or not specially adapted to apparatus covered by a single preceding group
- B02C23/18—Adding fluid, other than for crushing or disintegrating by fluid energy
- B02C23/20—Adding fluid, other than for crushing or disintegrating by fluid energy after crushing or disintegrating
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Disintegrating Or Milling (AREA)
Abstract
The invention relates to a preparation method of micronized ticagrelor, in particular to a method for micronizing a ticagrelor raw material medicine by using a disc type air flow pulverizer, wherein the crystal form is not changed after micronization treatment and is consistent with the crystal form II for the original medicine, the particle size of the micro powder prepared by controlling the pulverization parameters can reach below D9030 mu m, and the dissolution requirement of a preparation can be ensured.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a micronization method of ticagrelor.
Background
Ticagrelor (Ticagrelor) belongs to the class of cyclopentyltriazolopyrimidines, and is chemically (1S,2S, 3R, 5S) -3- [7- [ (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamino ] -5- (thiopropyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-3-yl ] -5- (2-hydroxyethoxy) cyclopentane-1, 2-diol of the formula: C23H 28F 2N 6O 4S; molecular weight: 522.574, respectively; CAS accession number: 274693-27-5, the structural formula is as follows:
ticagrelor is a new drug developed by AstraZeneca pharmaceutical company (AstraZeneca) in the united kingdom and approved by the U.S. FDA to be marketed in 2011 at 7/20 and 2012 at 11/2012, and approved by the national food and drug administration (SFDA) for marketing in china. Under the trade name Brilina.
WO9905143, CN 103992323, WO2015162630 and the like report synthetic methods for ticagrelor, and CN01810582.3, CN100354268C disclose crystal forms and amorphous forms of various compounds of ticagrelor.
Currently marketed ticagrelor formulations are in tablet form, with specifications of 90mg and 60 mg. Ticagrelor is a poorly soluble drug with a solubility in water of 10 μ g/mL at room temperature, and the Biopharmaceutical Classification System (BCS) is class iv: low solubility, low permeability. Therefore, bulk drugs for producing tablets need to be micronized, but currently, a process for micronizing ticagrelor is only reported, CN 104650091 reports a process for micronizing ticagrelor by crystallization in water and alcohol solvents, but the process causes the crystal form of ticagrelor to be changed, and the formed micronized ticagrelor crystal form is different from the original pharmaceutical crystal form II (the powder diffraction pattern is shown in fig. 1), which will affect the dissolution performance of tablets and is not beneficial to the bioequivalence with the original product.
The invention provides a method for micronizing ticagrelor raw material medicine by using a disc type jet mill, and the crystal form is not transformed after micronization treatment, the particle size can reach below D9030 mu m, and the requirement of dissolution of a preparation can be ensured.
In addition, the invention also provides specific parameters of the jet milling.
Disclosure of Invention
The invention discloses a micronization method of ticagrelor, which comprises the following steps:
a) taking a sample of ticagrelor after crystallization.
b) And opening a gas source main valve of the jet mill, sequentially opening a gas valve of the feeding port and a gas valve of the crushing chamber, and adjusting the pressure of the feeding port and the pressure of the crushing chamber by adjusting the opening angle of the valves.
c) And adjusting the vibration voltage of the electromagnetic vibration feeder, and gradually adding the crystallized ticagrelor sample into a jet mill.
d) And (3) crushing the sample in the crushing chamber, and then classifying the crushed sample by using a cyclone separator, so that micronized ticagrelor with required particle size can be collected.
The gas source of the airflow pulverizer in the step b) is nitrogen, compressed air, argon and the like, and preferably compressed air.
The pressure range of the feed inlet in the step b) is 0.03MPa ~ 0.07.07 MPa, and preferably 0.04 ~ 0.06.06 MPa.
The pressure of the crushing chamber in the step b) is in the range of 0.02MPa ~ 0.06.06 MPa, preferably 0.03 ~ 0.05.05 MPa.
The vibration voltage range of the electromagnetic vibration feeder in the step c) is 50 ~ 150mv, preferably 80 ~ 100 mv.
The required particle size in the step D) refers to D9030 mu m or less
The specific implementation mode is as follows:
micronized ticagrelor coarse powder was prepared according to WO9905143 with ethyl acetate and isooctane as crystallization solvents; the jet mill manufacturer is Shanghai Fine-wound powder equipment Co., Ltd, and the model is QS-100; the particle size measurement method is a laser diffraction method.
Example 1:
20kg of the crystalline ticagrelor powder (prepared according to WO9905143, the crystallization solvent being ethyl acetate and isooctane) was jet-milled. Before micronizing, checking whether each component of the jet mill is connected tightly to ensure no air leakage; then opening a compressed air main valve, then opening a feed inlet air valve and a crushing chamber air valve in sequence, and adjusting the opening angle of the valves to adjust the pressure of the feed inlet and the pressure of the crushing chamber to respectively reach 0.6MPa and 0.4 MPa; switching on a power supply of the electromagnetic vibration feeder, and turning on a switch to adjust the vibration voltage to 100 mv; gradually adding the ticagrelor coarse powder into a jet mill through a feeder for micronization treatment, and collecting the powder from a material collecting barrel to obtain the product with yield of 85% of micronization and particle size of D9015 μm. The powder diffraction (XPRD) spectrum is shown in figure 2.
Implementation 2:
20kg of the crystalline ticagrelor powder (prepared according to WO9905143, the crystallization solvent being ethyl acetate and isooctane) was jet-milled. Before micronizing, checking whether each component of the jet mill is connected tightly to ensure no air leakage; then opening a compressed air main valve, then opening a feed inlet air valve and a crushing chamber air valve in sequence, and adjusting the opening angle of the valves to adjust the pressure of the feed inlet and the pressure of the crushing chamber to respectively reach 0.5MPa and 0.3 MPa; switching on a power supply of the electromagnetic vibration feeder, and turning on a switch to adjust the vibration voltage to 80 mv; gradually adding the ticagrelor coarse powder into a jet mill through a feeder for micronization treatment, and collecting the powder from a material collecting barrel to obtain the product with yield of 85% of micronization and particle size of D9023 μm.
Description of the drawings:
FIG. 1 is a powder diffractogram of CN 104650091 crystal form II;
figure 2 diffraction pattern of micronized ticagrelor powder according to the invention.
Claims (5)
1. The invention discloses a micronization method of ticagrelor, which comprises the following steps:
a) taking a sample of the crystallized ticagrelor;
b) opening a gas source main valve of the jet mill, sequentially opening a gas valve of a feeding port and a gas valve of a crushing chamber, and adjusting the pressure of the feeding port and the pressure of the crushing chamber by adjusting the opening angle of the valves;
c) adjusting the vibration voltage of an electromagnetic vibration feeder, and gradually adding the crystallized ticagrelor sample into a jet mill;
d) after being crushed in the crushing chamber, the sample is graded by a cyclone separator, and micronized ticagrelor with required particle size can be collected;
the gas source of the airflow pulverizer in the step b) is nitrogen, compressed air, argon and the like, and preferably compressed air.
2. The pressure range of the feed inlet in the step b) is 0.03MPa ~ 0.07.07 MPa, and preferably 0.04 ~ 0.06.06 MPa.
3. The pressure of the crushing chamber in the step b) is in the range of 0.02MPa ~ 0.06.06 MPa, preferably 0.03 ~ 0.05.05 MPa.
4. The vibration voltage range of the electromagnetic vibration feeder in the step c) is 50 ~ 150mv, preferably 80 ~ 100 mv.
5. The required particle size in the step D) is D9030 mu m or less.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810627691.6A CN110614153A (en) | 2018-06-19 | 2018-06-19 | Preparation method of micronized ticagrelor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810627691.6A CN110614153A (en) | 2018-06-19 | 2018-06-19 | Preparation method of micronized ticagrelor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110614153A true CN110614153A (en) | 2019-12-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810627691.6A Pending CN110614153A (en) | 2018-06-19 | 2018-06-19 | Preparation method of micronized ticagrelor |
Country Status (1)
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| CN (1) | CN110614153A (en) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN201082390Y (en) * | 2007-07-25 | 2008-07-09 | 宁波江东杰特梅尔科技有限公司 | Continuously charging device for air-flow disintegrator |
| CN201791582U (en) * | 2010-08-03 | 2011-04-13 | 无锡晶石新型能源有限公司 | Airflow pressure stabilizer |
| CN102659819A (en) * | 2011-02-18 | 2012-09-12 | 浙江尖峰药业有限公司 | Cefmenoxime hydrochloride compound and micronization method thereof |
| CN103657816A (en) * | 2013-12-31 | 2014-03-26 | 昆明特康科技有限公司 | Airflow grinding equipment and wall breaking method with same for pollen pini |
| CN104650091A (en) * | 2014-01-24 | 2015-05-27 | 福州乾正药业有限公司 | Micronization and crystal form of ticagrelor and preparation method and pharmaceutical application of crystal form of ticagrelor |
| CN204996527U (en) * | 2015-09-07 | 2016-01-27 | 安徽纽曼精细化工有限公司 | Disc type fluid energy mill |
| CN105944816A (en) * | 2016-06-21 | 2016-09-21 | 江苏密友粉体新装备制造有限公司 | Safe explosion-proof airflow pulverization system |
| JP2018051474A (en) * | 2016-09-29 | 2018-04-05 | 日立金属株式会社 | Dry pulverizer |
| CN107930819A (en) * | 2016-10-13 | 2018-04-20 | 上海化三粉体设备有限公司 | A kind of air-flow crushing unit |
-
2018
- 2018-06-19 CN CN201810627691.6A patent/CN110614153A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN201082390Y (en) * | 2007-07-25 | 2008-07-09 | 宁波江东杰特梅尔科技有限公司 | Continuously charging device for air-flow disintegrator |
| CN201791582U (en) * | 2010-08-03 | 2011-04-13 | 无锡晶石新型能源有限公司 | Airflow pressure stabilizer |
| CN102659819A (en) * | 2011-02-18 | 2012-09-12 | 浙江尖峰药业有限公司 | Cefmenoxime hydrochloride compound and micronization method thereof |
| CN103657816A (en) * | 2013-12-31 | 2014-03-26 | 昆明特康科技有限公司 | Airflow grinding equipment and wall breaking method with same for pollen pini |
| CN104650091A (en) * | 2014-01-24 | 2015-05-27 | 福州乾正药业有限公司 | Micronization and crystal form of ticagrelor and preparation method and pharmaceutical application of crystal form of ticagrelor |
| CN204996527U (en) * | 2015-09-07 | 2016-01-27 | 安徽纽曼精细化工有限公司 | Disc type fluid energy mill |
| CN105944816A (en) * | 2016-06-21 | 2016-09-21 | 江苏密友粉体新装备制造有限公司 | Safe explosion-proof airflow pulverization system |
| JP2018051474A (en) * | 2016-09-29 | 2018-04-05 | 日立金属株式会社 | Dry pulverizer |
| CN107930819A (en) * | 2016-10-13 | 2018-04-20 | 上海化三粉体设备有限公司 | A kind of air-flow crushing unit |
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Application publication date: 20191227 |