CN106397402B - A kind of esomeprazole magnesium crystal-form compound and preparation method thereof - Google Patents
A kind of esomeprazole magnesium crystal-form compound and preparation method thereof Download PDFInfo
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- CN106397402B CN106397402B CN201610767662.0A CN201610767662A CN106397402B CN 106397402 B CN106397402 B CN 106397402B CN 201610767662 A CN201610767662 A CN 201610767662A CN 106397402 B CN106397402 B CN 106397402B
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- esomeprazole magnesium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
Abstract
The invention belongs to pharmaceutical technology fields.Specifically, the present invention relates to esomeprazole magnesium crystal-form compounds.The structural formula of the esomeprazole magnesium compound is as follows:The esomeprazole magnesium crystal-form compound is as shown in Figure 1 using the X-ray powder diffraction spectrogram that Cu-Ka radionetric survey obtains.Esomeprazole magnesium provided by the invention is a kind of crystal compound different from the prior art, the crystal compound water solubility increases, and has preferable bioavilability compared with the prior art using preparation made from Esomeprazole magnesium crystal compound of the invention.
Description
Technical field
The invention belongs to pharmaceutical technology fields, specifically, being related to a kind of esomeprazole magnesium crystalline compounds and its system
Preparation Method.
Background technique
Esomeprazole magnesium is the S configuration of Omeprazole, is that a kind of novel antiulcer drug and proton pump inhibit,
I.e. (S)-Omeprazole has better safety and curative effect, and the chiral proton pump for becoming the first listing in the whole world for 2001 inhibits
Agent, magnesium salts form will not change configuration, be still S configuration, the entitled bis- (5- methoxyl group -2- (S)-((4- methoxyl group -3,5- of chemistry
Dimethyl -2- pyridyl group) methyl)-sulfinyl) -1H- benzimidazole -1- base) magnesium salts, commercialized product is its trihydrate,
Structural formula (I) is as follows:
WO98/54171 makes public for the first time the crystal form of Esomeprazole magnesium salt, later WO2006/003163,
WO2004/089935, WO2004/046134 also disclose a variety of crystalline substances of Esomeprazole magnesium salt and its hydrate
Type.
However the dissolubility of the esomeprazole magnesium crystal for using the recrystallization method of the prior art to obtain in water is poor, it is raw
Object availability is not high, so that the effect of drug administration is affected, the poor compliance for patient.
The crystal form of drug affects the exploitation of pharmaceutical preparation.Studies have shown that the same drug of different crystal forms is in solubility, molten
Point, density, stability etc. may have significant difference, and then influence the stability, homogeneity, biological utilisation of drug
Degree, efficacy and saferry.In recent years, pharmaceutical production, quality control and new drug is had become for the crystal form research of drug to grind
Study carefully indispensable important component.In this regard, having been obtained a kind of different from existing skill present inventor has performed a large amount of research
The esomeprazole magnesium crystal compound of art, and surprisingly find that the crystal compound can improve water through solubility test
In dissolubility.
Summary of the invention
It is an object of the invention to provide a kind of esomeprazole magnesium crystal-form compound, which has stability height, water-soluble
Good, the high feature of bioavilability of property.
Another object of the present invention, which also resides in, discloses the preparation method of esomeprazole magnesium crystal-form compound.
To achieve the purpose of the present invention, the present invention adopts the following technical scheme:
Esomeprazole magnesium crystal-form compound shown in a kind of formula (I), wherein
The X-ray powder diffraction spectrogram that the esomeprazole magnesium crystal-form compound is obtained using Cu-K alpha ray measurement
As shown in Figure 1.
The present invention furthermore provides the preparation method of the esomeprazole magnesium crystal-form compound, and this method includes such as
Lower step:
1) prepare solution A: the mixed solvent A of ether and acetonitrile is sterile filtered into crystallizing tank, cooling 5~10 DEG C after to
With；
2) it prepares B solution: at room temperature, the mixed solvent B of water and ethyl alcohol being added in dissolving tank, add the drawing of Esso U.S.
Azoles magnesium crude product, is added active carbon, stirring decoloration after dissolution, filtering is washed with water, collects filtrate and cleaning solution, obtain B solution；
3) B solution is added in solution, controls temperature to 10 DEG C~15 DEG C, the temperature is kept to be stirred 35min；
4) again by greenhouse cooling to 0 DEG C~5 DEG C, 10~15 turns/min of mixing speed is controlled, controls thermometer stirring speed
1~3h of growing the grain is spent, suction filtration obtains esomeprazole magnesium.
Preferably, the volume ratio of ether and acetonitrile is 2~6:1 in mixed solvent A described in step 1).
Preferably, the volume ratio of water and ethyl alcohol is 3~5:1 in mixed solvent B described in step 2)；The institute
The mass volume ratio of the esomeprazole magnesium crude product and mixed solvent A, mixed solvent B stated is 1:20:2~4kg/L；The stirring
Bleaching time is 20~30min.
Preferably, the mixing speed of stirring described in step 3) is 18~24 turns/min.
The present inventor passes through a large amount of repetition test, constantly changes method for crystallising and including solvent, anti-solvent, temperature etc.
Crystallization condition, finally obtains a kind of novel crystal forms of esomeprazole magnesium, and the esomeprazole magnesium of the novel crystal forms has preferable steady
It is qualitative, and esomeprazole magnesium compared with the prior art improves dissolubility in water.
Meanwhile the present invention has surprisingly found that under prescription and the identical situation of preparation method in pharmacodynamics test, uses
The peak plasma concentrations of esomeprazole magnesium test film made from esomeprazole magnesium compound of the invention are higher than original and grind patent
The crystal-form compound that the embodiment 1 of CN98805521.X is prepared to photo, improve product bioavilability.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction figure of esomeprazole magnesium crystal-form compound prepared by the embodiment of the present invention 1；
Fig. 2 is the thermogravimetric analysis map of esomeprazole magnesium crystal-form compound prepared by the embodiment of the present invention 1；
After Fig. 3 is for animal pharmacodynamics test single oral dose esomeprazole magnesium test film and to photo 20mg, it is averaged
Drug-time curve figure.
Specific embodiment
The present invention can be further described by the following examples, however, invention of the invention and unlimited
In the following examples, these embodiments are not limited the scope of the invention in any way.Those skilled in the art is in right
Made certain changes and adjustment also are regarded as belonging to the scope of the present invention in the range of it is required that.
The preparation of 1 esomeprazole magnesium crystal-form compound of embodiment
1) prepare solution A: by the mixed solvent A of 500L ether and acetonitrile (wherein the volume ratio of ether and acetonitrile is 2:1)
Aseptic filtration is stand-by after being cooled to 5 DEG C into crystallizing tank, as solution A；
2) prepare B solution: at room temperature, by the mixed solvent B of 50L water and ethyl alcohol (wherein the volume ratio of water and ethyl alcohol is 3:
1) it is added in dissolving tank, adds esomeprazole magnesium crude product 25kg, active carbon 0.38kg, stirring decoloration are added after dissolution
20min is sterile filtered, is washed with 10kg water for injection, collects filtrate and cleaning solution.Obtain B solution；
3) B solution is added in solution A, is cooled to 10 DEG C, keep the temperature, stirred with the mixing speed of 20 turns/min
35min；
4) 0 DEG C is cooled the temperature to again, controls 10 turns/min of mixing speed, controls temperature growing the grain 1h, is filtered, dry angstrom
Rope magnesium draws azoles magnesium crystal-form compound.
Obtained esomeprazole magnesium is measured with powder x-ray diffraction measuring method, obtains X-ray powder diffraction collection
As shown in Figure 1.
Using Perkin-Elmer company, U.S. PE Pyris Diamond TG thermogravimetric analyzer, table is tested in thermogravimetric analysis
It is bright, as a result as shown in Fig. 2, crystal water content is 7.096wt%, contain 3 crystallizations water (theoretical value 7.045wt%) with theoretical value
As a result within the error range.
The preparation of 2 esomeprazole magnesium crystal-form compound of embodiment
1) prepare solution A: by the mixed solvent A of 500L ether and acetonitrile (wherein the volume ratio of ether and acetonitrile is 2:1)
Aseptic filtration is stand-by after being cooled to 10 DEG C into crystallizing tank, as solution A；
2) prepare B solution: at room temperature, by the mixed solvent B of 100L water and ethyl alcohol (wherein the volume ratio of water and ethyl alcohol is 3:
1) it is added in dissolving tank, adds esomeprazole magnesium crude product 25kg, active carbon 0.38kg, stirring decoloration are added after dissolution
30min is sterile filtered, is washed with 10kg water for injection, collects filtrate and cleaning solution.Obtain B solution；
3) B solution is added in solution A, is cooled to 10 DEG C, keep the temperature, stirred with the mixing speed of 20 turns/min
35min；
4) 5 DEG C are cooled the temperature to again, controls 10 turns/min of mixing speed, controls temperature growing the grain 1h, are filtered, dry angstrom
Rope magnesium draws azoles magnesium crystal-form compound.
The X-ray powder diffraction collection that resulting esomeprazole magnesium crystal-form compound is obtained using Cu-K alpha ray measurement
Consistent, the thermogravimetric obtained using Perkin-Elmer company, U.S. PE Pyris Diamond TG thermogravimetric analyzer with embodiment 1
It analyzes map and embodiment 1 is consistent.
The preparation of 3 esomeprazole magnesium crystal-form compound of embodiment
1) prepare solution A: by the mixed solvent A of 500L ether and acetonitrile (wherein the volume ratio of ether and acetonitrile is 6:1)
Aseptic filtration is stand-by after being cooled to 5 DEG C into crystallizing tank, as solution A；
2) prepare B solution: at room temperature, by the mixed solvent B of 50L water and ethyl alcohol (wherein the volume ratio of water and ethyl alcohol is 5:
1) it is added in dissolving tank, adds esomeprazole magnesium crude product 25kg, active carbon 0.38kg, stirring decoloration are added after dissolution
20min is sterile filtered, is washed with 10kg water for injection, collects filtrate and cleaning solution.Obtain B solution；
3) B solution is added in solution A, is cooled to 15 DEG C, keep the temperature, stirred with the mixing speed of 20 turns/min
35min；
4) 0 DEG C is cooled the temperature to again, controls 15 turns/min of mixing speed, controls temperature growing the grain 3h, is filtered, dry angstrom
Rope magnesium draws azoles magnesium crystal-form compound.
The X-ray powder diffraction collection that resulting esomeprazole magnesium crystal-form compound is obtained using Cu-K alpha ray measurement
Consistent, the thermogravimetric obtained using Perkin-Elmer company, U.S. PE Pyris Diamond TG thermogravimetric analyzer with embodiment 1
It analyzes map and embodiment 1 is consistent.
The preparation of 4 esomeprazole magnesium crystal-form compound of embodiment
1) prepare solution A: by the mixed solvent A of 500L ether and acetonitrile (wherein the volume ratio of ether and acetonitrile is 6:1)
Aseptic filtration is stand-by after being cooled to 10 DEG C into crystallizing tank, as solution A；
2) prepare B solution: at room temperature, by the mixed solvent B of 100L water and ethyl alcohol (wherein the volume ratio of water and ethyl alcohol is 5:
1) it is added in dissolving tank, adds esomeprazole magnesium crude product 25kg, active carbon 0.38kg, stirring decoloration are added after dissolution
30min is sterile filtered, is washed with 10kg water for injection, collects filtrate and cleaning solution.Obtain B solution；
3) B solution is added in solution A, is cooled to 15 DEG C, keep the temperature, stirred with the mixing speed of 20 turns/min
35min；
4) 5 DEG C are cooled the temperature to again, controls 15 turns/min of mixing speed, controls temperature growing the grain 3h, are filtered, dry angstrom
Rope magnesium draws azoles magnesium crystal-form compound.
The X-ray powder diffraction collection that resulting esomeprazole magnesium crystal-form compound is obtained using Cu-K alpha ray measurement
Consistent, the thermogravimetric obtained using Perkin-Elmer company, U.S. PE Pyris Diamond TG thermogravimetric analyzer with embodiment 1
It analyzes map and embodiment 1 is consistent.
Test example 1
Solubility test
The test example has investigated the esomeprazole magnesium of esomeprazole magnesium crystal-form compound and the prior art of the invention
Dissolubility in water.
Sample number into spectrum is as follows:
Sample 1: esomeprazole magnesium crystal-form compound is made in the embodiment of the present invention 1；
Sample 2: esomeprazole magnesium crystal-form compound made from the embodiment of the present invention 3；
Sample 3: esomeprazole magnesium trihydrate made from the method according to the embodiment 1 of patent CN98805521.X；
Sample 4: esomeprazole magnesium trihydrate made from the method according to the embodiment 10 of patent CN 103509001A
It is amorphous.
Solubility test method:
The solubility test of following several solvents has been done according to method as defined in Chinese Pharmacopoeia 2010 version two " note on the use ".
Method: weigh be ground into fine powder each sample it is appropriate (being accurate to ± 2.0%), the water of a certain amount of volume is added, 25
± 2 DEG C shook 30 seconds every 5 minutes at room temperature, and observation dissolved situation in 30 minutes, the results are shown in Table 1.
1 solubility test result of table
As can be seen from the test results, compared with prior art, the present invention esomeprazole magnesium crystal form produced by the present invention
The dissolubility of compound in water increases, suitable with amorphous products solubility.
Test example 2
Stability test
This experiment is according to 2010 editions second annex, Ⅺ Ⅹ C bulk pharmaceutical chemicals of Chinese Pharmacopoeia and drug preparation stability test direction
Principle carries out, accelerated test condition: 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%.Long term test condition: 25 DEG C of temperature ±
2 DEG C, relative humidity 60% ± 10%.Test result is shown in Table 2.
Table 2: stability test result
Test result shows that this product is placed 6 months under the conditions of 40 ± 2 DEG C of temperature, relative humidity 75% ± 5%, in temperature
25 DEG C ± 2 DEG C of degree, relative humidity 60% ± 10% are placed 12 months, and indices have no significant change, and it is good to illustrate that this product has
Good stability.
Test example 3
Animal pharmacodynamics test: Beagle dog
Dosage and mode: the esomeprazole magnesium crystal-form compound (test film) that preparation method obtains in embodiment 1
Plain piece (to photo) is made in the crystal-form compound being prepared with the embodiment 1 of CN98805521.X, and dosage is respectively
20mg, be administered orally in the morning after animal fasting, and average drug-time curve is shown in Fig. 3.
From figure 3, it can be seen that after using the administration of test film made from esomeprazole crystal-form compound of the invention, blood medicine
Concentration peak is significantly higher than reference substance blood concentration, shows that effective component bioavilability significantly improves.
Phase has also under equal conditions been carried out respectively to the esomeprazole magnesium crystal-form compound of other embodiments of the present invention
Same test has and significantly improves with upper identical trend, i.e. effective component bioavilability.
Claims (7)
1. a kind of esomeprazole magnesium crystal-form compound, which is characterized in that the knot of the esomeprazole magnesium crystal-form compound
Structure formula is as follows:
The X-ray powder diffraction spectrogram that the esomeprazole magnesium crystalline compounds are obtained using Cu-K alpha ray measurement is as schemed
Shown in 1.
2. a kind of preparation method of esomeprazole magnesium crystal-form compound described in claim 1, which is characterized in that the system
Preparation Method includes the following steps:
1) it prepares solution A: the mixed solvent A of ether and acetonitrile is sterile filtered into crystallizing tank, it is stand-by after 5~10 DEG C of cooling；
2) it prepares B solution: at room temperature, the mixed solvent B of water and ethyl alcohol being added in dissolving tank, esomeprazole magnesium is added
Crude product, is added active carbon, stirring decoloration after dissolution, filtering is washed with water, collects filtrate and cleaning solution, obtain B solution；
3) B solution is added in solution A, controls temperature to 10 DEG C~15 DEG C, the temperature is kept to be stirred 35min；
4) again by greenhouse cooling to 0 DEG C~5 DEG C, 10~15 turns/min of mixing speed is controlled, the thermometer mixing speed is controlled and supports
1~3h of crystalline substance, suction filtration obtain esomeprazole magnesium.
3. preparation method according to claim 2, which is characterized in that in mixed solvent A described in step 1) ether and
The volume ratio of acetonitrile is 2~6:1.
4. preparation method according to claim 2, which is characterized in that water and second in mixed solvent B described in step 2)
The volume ratio of alcohol is 3~5:1.
5. preparation method according to claim 2, which is characterized in that esomeprazole magnesium crude product described in step 2) with
Mixed solvent A, mixed solvent B mass volume ratio be 1:20:2~4kg/L.
6. preparation method according to claim 2, which is characterized in that described in step 2) stirring bleaching time be 20~
30min。
7. preparation method according to claim 2, which is characterized in that the mixing speed of stirring described in step 3) be 18~
24 turns/min.
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| WO2004046134A2 (en) * | 2002-11-18 | 2004-06-03 | Dr. Reddy's Laboratories Limited | Crystalline form ii of esomeprazole magnesium trihydrate and process for its preparation |
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| WO2004089935A1 (en) * | 2003-04-10 | 2004-10-21 | Hetero Drugs Limitd | Novel crystalline forms of s-omeprazole magnesium |
| WO2008149204A1 (en) * | 2007-06-07 | 2008-12-11 | Aurobindo Pharma Limited | An improved process for preparing an optically active proton pump inhibitor |
| CN103509001A (en) * | 2012-06-15 | 2014-01-15 | 石药集团中奇制药技术（石家庄）有限公司 | Esomeprazole magnesium trihydrate and preparation method thereof |
| CN104356114A (en) * | 2014-11-17 | 2015-02-18 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN104447699A (en) * | 2014-12-10 | 2015-03-25 | 哈药集团技术中心 | Preparation method of esomeprazole magnesium trihydrate |
| CN104610227A (en) * | 2015-01-08 | 2015-05-13 | 浙江亚太药业股份有限公司 | High-pressure hydrothermal preparation method for esomeprazole magnesium polymorphic compound |
| CN105111188A (en) * | 2015-08-19 | 2015-12-02 | 扬子江药业集团有限公司 | Preparation method for esomeprazole magnesium trihydrate crystalline form |
| CN105418589A (en) * | 2016-01-17 | 2016-03-23 | 青岛辰达生物科技有限公司 | Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases |
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2016
- 2016-08-30 CN CN201610767662.0A patent/CN106397402B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1161351C (en) * | 1997-05-30 | 2004-08-11 | 阿斯特拉公司 | Novel form of S-omeprazole |
| WO2004046134A2 (en) * | 2002-11-18 | 2004-06-03 | Dr. Reddy's Laboratories Limited | Crystalline form ii of esomeprazole magnesium trihydrate and process for its preparation |
| WO2004089935A1 (en) * | 2003-04-10 | 2004-10-21 | Hetero Drugs Limitd | Novel crystalline forms of s-omeprazole magnesium |
| WO2008149204A1 (en) * | 2007-06-07 | 2008-12-11 | Aurobindo Pharma Limited | An improved process for preparing an optically active proton pump inhibitor |
| CN103509001A (en) * | 2012-06-15 | 2014-01-15 | 石药集团中奇制药技术（石家庄）有限公司 | Esomeprazole magnesium trihydrate and preparation method thereof |
| CN104356114A (en) * | 2014-11-17 | 2015-02-18 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN104447699A (en) * | 2014-12-10 | 2015-03-25 | 哈药集团技术中心 | Preparation method of esomeprazole magnesium trihydrate |
| CN104610227A (en) * | 2015-01-08 | 2015-05-13 | 浙江亚太药业股份有限公司 | High-pressure hydrothermal preparation method for esomeprazole magnesium polymorphic compound |
| CN105111188A (en) * | 2015-08-19 | 2015-12-02 | 扬子江药业集团有限公司 | Preparation method for esomeprazole magnesium trihydrate crystalline form |
| CN105418589A (en) * | 2016-01-17 | 2016-03-23 | 青岛辰达生物科技有限公司 | Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases |
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