CN104341392A - Novel esomeprazole sodium crystal form, preparing method thereof and applications of the crystal form - Google Patents
Novel esomeprazole sodium crystal form, preparing method thereof and applications of the crystal form Download PDFInfo
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- CN104341392A CN104341392A CN201310332166.9A CN201310332166A CN104341392A CN 104341392 A CN104341392 A CN 104341392A CN 201310332166 A CN201310332166 A CN 201310332166A CN 104341392 A CN104341392 A CN 104341392A
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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 relates to a control technology of crystal forms of crystals, and particularly relates to a novel esomeprazole sodium crystal (defined as a crystal form W) and a preparing method thereof. Characteristic peaks of an X-ray powder diffraction diagram of the crystal form are at 6.4+/-0.2, 8.8+/-0.2, 14.0+/-0.2, 15.7+/-0.2, 18.1+/-0.2, 19.5+/-0.2, 20.7+/-0.2, 21.2, 22.6+/-0.2, 23.7+/-0.2 and 26.6+/-0.2 (diffraction angle 2theta). The preparing method includes: dissolving esomeprazole into anhydrous acetonitrile, adding a trace amount of a reductant to control purity, adding a sodium hydroxide solution, and controlling the temperature to obtain the novel crystal form.
Description
Technical field
The present invention relates to the control techniques of crystal habit, more specifically, novel crystal (being hereafter defined as crystal formation W) relating to a kind of Esomeprazole sodium (Esomeprazole sodium) and preparation method thereof.
Background technology
As described in international patent application US5198952, the Esomeprazole sodium (Esomeprazole sodium) shown in known following formula has the purposes for the treatment of Non-Variceal Upper Gastrointestinal Bleeding.Within 2005, in U.S.'s listing, AstraZeneca company produces Esomeprazole sodium.
Esomeprazole sodium has multiple crystal formation.CN1972928A, US8063074B2, WO2006001755A1, EP2009058650 describe C, E, H, J, K, L, M, N, P, Q and hydrate and preparation method thereof of this compound.Wherein C, E, H crystal use toluene and methyl alcohol, ethanol, Virahol mixed solvent crystallization obtain; J, K, L, M, N crystal be use methyl alcohol and acetone, Virahol, ethyl acetate mixed solvent crystallization obtain; P crystal is in methyl alcohol after salify, by concentrated that crystal form P obtains; Q crystal is joined in methyl alcohol by P crystal formation, and when concentrated methanol content is less than 0.9%, obtain Q crystal formation after using nitrogen to dry up.
Above esomeprazole sodium crystal patent/patent application has some to enter China, there is no the research that relevant Chinese patent literature reports new esomeprazole sodium crystal and preparation method thereof at present.
The present inventor, in the process of research Esomeprazole sodium, finds that esomeprazole sodium crystal also has another new crystal.This crystal formation uses the identical recrystallisation solvent reported with patent WO9602535A1, but has different crystal formations, is a kind of new crystal formation.The crystal of this crystal formation has good stability, is suitable for being prepared into various stable pharmaceutical preparation and standing storage.
Summary of the invention
Therefore, the object of the present invention is to provide a kind of novel esomeprazole sodium crystal crystal, i.e. crystal formation W.Another object of the present invention is to provide the preparation method of esomeprazole sodium crystal W crystal and its application on the medicine of preparation treatment Non-Variceal Upper Gastrointestinal Bleeding.
According to the present invention, esomeprazole sodium crystal W crystal of the present invention, its feature is as follows:
Under following test condition:
X-ray tube: Cu-ka target
X-ray wavelength: 1.54056A pipe pressure: 40KV tube current: 60mA
Scanning angle: 2.5 ° ~ 50 ° sweep velocitys: 4 °/min
The X-ray powder diffraction figure of this crystal formation crystal is 6.4 ± 0.2,8.8 ± 0.2 at reflection angle 2 θ, and 14.0 ± 0.2,15.7 ± 0.2,18.1 ± 0.2,19.5 ± 0.2,20.7 ± 0.2,21.2,22.6 ± 0.2,23.7 ± 0.2 and 26.6 ± 0.2 degree of places have characteristic peak.
More specifically, the X-ray powder diffraction figure feature of this crystal is as follows:
Its X-ray powder diffraction pattern is shown in Fig. 1, and data are shown in Fig. 2.
The DSC figure of this crystal formation is single features peak (see figure 3) at about 255.84 DEG C, shows that this crystal formation is a single crystal form.
The infrared spectrogram of this crystal formation is at 3400cm
-1, 2800 ~ 3000cm
-1, 1630cm
-1, 1130cm
-1there is charateristic avsorption band at place.
The invention provides the preparation method of esomeprazole sodium crystal W crystal, comprise and esomeprazole dissolved in acetonitrile and uses reductive agent process, and add aqueous sodium hydroxide solution and carry out temperature control crystallization, wherein
First stage: drip 40% sodium hydroxide solution temperature and control below 10 DEG C;
Subordinate phase: after stirring 2 hours at 10 DEG C ~ 20 DEG C, be warming up to 20 DEG C ~ 30 DEG C, stir more than 10 hours;
Phase III drying under reduced pressure: drying at room temperature 6 hours, then 40 DEG C of dryings 6 hours, last 60 DEG C of dryings 6 hours.
In the inventive method, dissolve esomeprazole acetonitrile amount used and add weighing scale by esomeprazole, get relative to Esomeprazole sodium 5 ~ 20 times amount, be preferably 10 times of Esomeprazole sodium.
In the inventive method, reductive agent can adopt sodium borohydride, and its amount is 0.10% ~ 0.01% of Esomeprazole sodium.
In the inventive method, aqueous sodium hydroxide solution concentration is 30% ~ 45%, is preferably 40%.The sodium hydroxide solution prepared can with 0.45 μm of membrane filtration.
Method of the present invention, by the control of rate of temperature fall, obtains esomeprazole sodium crystal W crystal.
Solvent temperature can be 30 DEG C or higher, but preferable temperature is no more than 15 DEG C.Reason is as follows, and the solubleness of esomeprazole in acetonitrile is comparatively large, and temperature more high-dissolvability is larger, but along with the rising of temperature, its oxidation impurities is larger, therefore needs control temperature when dissolving.Therefore temperature is preferably no more than 15 DEG C.In order to make esomeprazole not be oxidized when dissolving, the sodium borohydride adding trace ensures the purity of esomeprazole.
Salification process temperature controls, and when dripping aqueous sodium hydroxide solution, temperature controls to be no more than 10 DEG C, and the too high meeting of temperature makes acetonitrile be hydrolyzed, thus produces sodium acetate, affects the content of final product.Drip after aqueous sodium hydroxide solution and keep 2 hours at 10 ~ 20 DEG C, be then warming up to 20 ~ 30 DEG C, more than keeping hour, be generally 10 ~ 12 hours.The product obtained under reduced pressure is dried, and its bake out temperature program is: room temperature keeps 6 hours, is then warming up to 40 DEG C and keeps 6 hours, is finally warming up to 60 DEG C and keeps 6 hours.
Recrystallization temperature controls to may be selected in 10 ~ 40 DEG C, and the too high acetonitrile of temperature can be hydrolyzed, and the too low product of temperature dissolves.Therefore recrystallization temperature preferably 20 ~ 30 DEG C.Dry after product more stable, but directly portioned product can be caused to melt in high temperature 60 DEG C of oven dry, therefore select procedure heats up.
In patent documentation CN1972928A, US8063074B2, WO2006001755A1 and EP2009058650, report the crystal formation that different solvents and the crystallization of different operating mode obtain respectively.Solvent has the mixed solvent of toluene and methyl alcohol, ethanol, Virahol respectively, the mixed solvent of methyl alcohol and acetone, the mixing solutions of methyl alcohol and ethyl acetate.The present invention uses single solvent acetonitrile, and toxicity is smaller, and cost is lower; And by the operation of special temperature control, obtain highly purified, stable crystal.Experiment proves in acetonitrile, more easily to obtain high-purity crystal after specific manipulation, by to the process of esomeprazole control of purity, aqueous sodium hydroxide solution, the control of temperature and under specific bake out temperature program, be more prone to obtain crystal formation W crystal, purity is greater than 99.5%.
The stability experiment display of esomeprazole sodium crystal W crystal, has good stability under under the airtight storage condition of lucifuge, can keep crystal formation well and chemical transformation not occur.This character illustrates that it is suitable for making stable pharmaceutical preparation.
Esomeprazole sodium crystal W crystal can be made into lyophilized injectable powder, is used for the treatment of the gastric acid secretion disorders such as Non-Variceal Upper Gastrointestinal Bleeding, gastro oesophageal reflux disease (GORD)-erosive reflux esophagitis as proton pump inhibitor.
Accompanying drawing explanation
The accompanying drawing that the application comprises is a component part of specification sheets, accompanying drawing and specification sheets together with claims for illustration of essence of an invention content, for understanding the present invention better.
Fig. 1 is the X-ray powder diffraction spectrogram of esomeprazole sodium crystal W crystal.
Fig. 2 is the X-ray powder diffraction spectral data of esomeprazole sodium crystal W crystal.
Fig. 3 is the DSC heating differential analysis spectrogram of esomeprazole sodium crystal W crystal.
Fig. 4 is the IR infrared spectrum of Esomeprazole sodium crystal C crystal.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiments do not form any restriction to the present invention.In following examples, X-ray powdery diffractometry measures the analytical instrument adopted is following model: X-ray:Cu K-ALPHAL/40Kv/60mA.
Embodiment 1
The preparation of esomeprazole sodium crystal W crystal:
Esomeprazole sodium is added in 5 volumes methylene chloride and 5 volume water, use 20% salt acid for adjusting pH to about 8.5, obtain organic phase, then be concentrated into dry, adding a small amount of acetonitrile continues concentrated, repeatedly after twice, add 10 volumes of acetonitrile, then trace B sodium hydride and a small amount of gac is added, stir at temperature 0 to 15 DEG C after 30 minutes and filter, after being cooled to 0 to 10 DEG C, drip the 40% cold aqueous sodium hydroxide solution that millipore filtration (0.45 μm) filters, stir 2 hours at 10 ~ 20 DEG C after dripping, then 20 DEG C are warming up to, keep at least 10 hours, crystallization filters, crystal is at drying under reduced pressure: first at room temperature dry 6 hours, next is warming up to 40 DEG C of dryings 6 hours, finally be warming up to 60 DEG C of dryings 6 hours, obtain stable W crystal.Content is greater than 99.5%, X-ray and sees Fig. 1.
Embodiment 2
The preparation of esomeprazole sodium crystal W crystal:
Esomeprazole sodium is added in 5 volumes methylene chloride and 5 volume water, use 20% salt acid for adjusting pH to about 8.5, obtain organic phase, then be concentrated into dry, adding a small amount of acetonitrile continues concentrated, repeatedly after twice, add 10 volumes of acetonitrile, then trace B sodium hydride and a small amount of gac is added, stir at temperature 0 to 15 DEG C after 30 minutes and filter, after being cooled to 0 to 10 DEG C, drip the 40% cold aqueous sodium hydroxide solution that millipore filtration (0.45 μm) filters, stir 2 hours at 10 ~ 20 DEG C after dripping, then 30 DEG C are warming up to, keep at least 10 hours, crystallization filters, crystal is at drying under reduced pressure: first at room temperature dry 6 hours, next is warming up to 40 DEG C of dryings 6 hours, finally be warming up to 60 DEG C of dryings 6 hours, obtain stable W crystal.Content is greater than 99.5%, X-ray and sees Fig. 1.
Embodiment 3
The preparation of esomeprazole sodium crystal W crystal:
Esomeprazole sodium is added in 5 volumes methylene chloride and 5 volume water, use 20% salt acid for adjusting pH to about 8.5, obtain organic phase, then be concentrated into dry, adding a small amount of acetonitrile continues concentrated, repeatedly after twice, add 10 volumes of acetonitrile, then trace B sodium hydride and a small amount of gac is added, stir at temperature 0 to 15 DEG C after 30 minutes and filter, after being cooled to 0 to 10 DEG C, drip the 40% cold aqueous sodium hydroxide solution that millipore filtration (0.45 μm) filters, stir 2 hours at 10 ~ 20 DEG C after dripping, then 25 DEG C are warming up to, keep at least 10 hours, crystallization filters, crystal is at drying under reduced pressure: first at room temperature dry 6 hours, next is warming up to 40 DEG C of dryings 6 hours, finally be warming up to 60 DEG C of dryings 6 hours, obtain stable W crystal.Content is greater than 99.5%, X-ray and sees Fig. 1, and DSC is shown in Fig. 3.
Embodiment 4
The accelerated stability test of esomeprazole sodium crystal W crystal
The accelerated stability test of crystal formation W crystal is carried out in following condition:
Under condition of storage 40 DEG C, relative humidity 75% condition, store 1 and 3 months in sealed states.
Result crystal formation W crystal all keeps stable under this storage condition, and when starting with experiment compared with, do not change in the total impurities of whole experimental session in this crystal formation crystal.
Stability data:
Note: the abbreviation in upper table and coded representation as follows:
NMT: be no more than; ND: do not detect;
Stability data shows: in acceleration 3 months study on the stability, and esomeprazole sodium crystal W crystal of the present invention is stable.
Claims (10)
1. Esomeprazole sodium W crystal, is characterized in that:
Under following test condition:
X-ray tube Cu-Ka target
X-ray wavelength: 1.54056A pipe pressure: 40KV tube current: 60mA
Scanning angle: 2.5 ° ~ 50 ° sweep velocitys: 4 °/min
The X-ray powder diffraction figure of this crystal formation crystal 6.4 ± 0.2,8.8 ± 0.2,14.0 ± 0.2,15.7 ± 0.2,18.1 ± 0.2,19.5 ± 0.2,20.7 ± 0.2,21.2,22.6 ± 0.2, the diffraction angle 2 θ place of 23.7 ± 0.2 and 26.6 ± 0.2 degree has characteristic peak.
2. esomeprazole sodium crystal W crystal according to claim 1, is characterized in that, the X-ray powder diffraction figure feature of this crystal is as follows:
3. esomeprazole sodium crystal W crystal according to claim 1 and 2, it is characterized in that, the infrared spectrogram of this crystal formation is at 3400cm
-1, 2800 ~ 3000cm
-1, 1630cm
-1, 1130cm
-1there is charateristic avsorption band at place.
4. a preparation method for the esomeprazole sodium crystal W crystal according to any one of claim 1-3, comprises and to be dissolved in acetonitrile by esomeprazole and to use reductive agent process, and adds aqueous sodium hydroxide solution and carry out temperature control crystallization, wherein
First stage: drip sodium hydroxide solution and temperature is controlled below 10 DEG C;
Subordinate phase: after stirring 2 hours at 10 DEG C ~ 20 DEG C, be warming up to 20 DEG C ~ 30 DEG C, stir more than 10 hours;
Phase III drying under reduced pressure: drying at room temperature 6 hours, then 40 DEG C of dryings 6 hours, last 60 DEG C of dryings 6 hours.
5. preparation method according to claim 4, is characterized in that, dissolves esomeprazole acetonitrile amount used and adds weighing scale by esomeprazole, get relative to Esomeprazole sodium 5 ~ 20 times amount.
6. preparation method according to claim 5, is characterized in that, acetonitrile amount is 10 times of Esomeprazole sodium.
7. preparation method according to claim 4, is characterized in that, described reductive agent is sodium borohydride, and its amount is 0.10% ~ 0.01% of Esomeprazole sodium.
8. preparation method according to claim 4, is characterized in that: aqueous sodium hydroxide solution concentration is 30% ~ 45%, the sodium hydroxide solution prepared 0.45 μm of membrane filtration.
9. preparation method according to claim 8, is characterized in that: aqueous sodium hydroxide solution concentration is 40%.
10. the application of the esomeprazole sodium crystal W crystal according to any one of claim 1-3 on the medicine of preparation treatment Non-Variceal Upper Gastrointestinal Bleeding.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628703A (en) * | 2014-06-24 | 2015-05-20 | 浙江亚太药业股份有限公司 | Esomeprazole sodium polycrystalline form compound and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813651A (en) * | 2011-06-07 | 2012-12-12 | 成都国为医药科技有限公司 | Pharmaceutical composition containing esomeprazole sodium, and preparation method thereof |
| CN102827147A (en) * | 2012-09-13 | 2012-12-19 | 山东罗欣药业股份有限公司 | Omeprazole sodium crystal compound and medicine composition containing omeprazole sodium crystal compound |
| CN103145694A (en) * | 2011-12-06 | 2013-06-12 | 重庆煜澍丰医药有限公司 | Crystal R of sodium esomeprazole, preparation method and purpose thereof |
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- 2013-08-01 CN CN201310332166.9A patent/CN104341392A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813651A (en) * | 2011-06-07 | 2012-12-12 | 成都国为医药科技有限公司 | Pharmaceutical composition containing esomeprazole sodium, and preparation method thereof |
| CN103145694A (en) * | 2011-12-06 | 2013-06-12 | 重庆煜澍丰医药有限公司 | Crystal R of sodium esomeprazole, preparation method and purpose thereof |
| CN102827147A (en) * | 2012-09-13 | 2012-12-19 | 山东罗欣药业股份有限公司 | Omeprazole sodium crystal compound and medicine composition containing omeprazole sodium crystal compound |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628703A (en) * | 2014-06-24 | 2015-05-20 | 浙江亚太药业股份有限公司 | Esomeprazole sodium polycrystalline form compound and preparation method thereof |
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Application publication date: 20150211 |
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