CN104725358A - Novel crystal form of rabeprazole sodium aquo-complex and preparation method of rabeprazole sodium aquo-complex - Google Patents
Novel crystal form of rabeprazole sodium aquo-complex and preparation method of rabeprazole sodium aquo-complex Download PDFInfo
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- CN104725358A CN104725358A CN201410733651.1A CN201410733651A CN104725358A CN 104725358 A CN104725358 A CN 104725358A CN 201410733651 A CN201410733651 A CN 201410733651A CN 104725358 A CN104725358 A CN 104725358A
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- dextral
- rabeprazole sodium
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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 novel crystal form of rabeprazole sodium aquo-complex and a preparation method of the novel crystal form. The novel crystal form is called the Z-type crystal. The Z-type crystal of the rabeprazole sodium aquo-complex is characterized in that in the X-ray powder diffraction pattern expressed by Cu-K alpha radiation and a 2theta+/-0.2DEG diffraction angle, the Z-type crystal has characteristic diffraction peaks at 9.3, 10.7, 18.2, 19.6, 21.2, 23.0, 27.2 and 29.9.
Description
Technical field
The present invention relates to a kind of new crystal drawing azole proton pump inhibitor medicine, be specifically related to new crystal of a kind of dextral-rabeprazole sodium hydrate and preparation method thereof.
Background technology
At present along with Chinese society development, the change of circumstances, the change of demographic structure and people life style, peptic ulcer rate increases gradually, has become a kind of common disease and the frequently-occurring disease that affect people's quality of life.H
+/ K
+-atpase inhibitor class medicine has become a kind of means of very effective treatment peptide ulceration, is wherein most widely used clinically with omeprazole, pantoprazole, esomeprazole, rabeprazole.Rabeprazole, by Japanese Eisai in exploitation listing in 1991, is the reversible H of a part
+/ K
+-atpase inhibitor, can act on H
+/ K
+4 positions of-ATP enzyme, owing to increasing in conjunction with target spot, compared with other similar drugs effects sooner, more lasting, acid suppression intensity is stronger.
Due to the existence of chiral sulfur atom, rabeprazole comprises two kinds of optical isomers, S-(-)-rabeprazole (left-handed) and, R-(+)-rabeprazole (dextrorotation).Experiment shows that the pharmacological action of rabeprazole dextrorotatory isomer will obviously be better than levoisomer and raceme.EMCURE pharmaceuticals of India carries out a large amount of clinical comparison test to dextral-rabeprazole sodium and racemization Sodium rabeprazole, result shows that dextrorotatory isomer subliminal dose is little compared with raceme, metabolic half life is long, curative effect can be significantly improved, reduce the generation of toxic side effect, and in 2007 in India's exploitation listing.The structure of dextral-rabeprazole sodium is as follows:
。
Due to the benzoglyoxaline containing instability in dextral-rabeprazole sodium structure and sulfoxide building stone, so it is to light, heat, wet less stable.The unstable of dextral-rabeprazole sodium has very large detrimentally affect, so prepare stable bulk drug to have important using value for the security of the formulation study of preparation, technical study, finished product and validity.Those skilled in the art know, the different crystal forms of bulk drug has very large impact for its stability, the stable crystal form of researching and developing out a kind of dextral-rabeprazole sodium will effectively improve its stability, also will be conducive to guaranteeing the security of finished product preparation, validity and quality controllability.At present, relatively less to the bibliographical information of dextral-rabeprazole sodium crystal, WO2011161421 reports a kind of amorphous dextral-rabeprazole sodium, and CN102924434A, CN103113350A report a kind of crystal-form compound of dextral-rabeprazole sodium respectively.
Amorphous dextral-rabeprazole sodium water absorbability is strong, less stable, easily to degrade variable color, and therefore, the dextral-rabeprazole sodium crystal obtaining a stable in properties is very necessary to drug development.
Summary of the invention
The object of the present invention is to provide new crystal of a kind of dextral-rabeprazole sodium hydrate and preparation method thereof, below this new crystal is called Z-type crystallization.
Dextral-rabeprazole sodium hydrate Z-type of the present invention crystallization, it is characterized in that, in the X-ray powder diffraction represented with Cu-K α radiation, 2 θ ± 0.2 ° diffraction angle, there is characteristic diffraction peak at 9.2,10.7,18.2,19.6,21.2,23.0,27.2,29.9 places.
Thermogravimetric analysis and the display of karl Fischer moisture titration results, dextral-rabeprazole sodium hydrate Z-type of the present invention crystallization contains a part crystal water.
The infrared spectra of dextral-rabeprazole sodium hydrate Z-type of the present invention crystallization about 3339.0,3183.7,2937.8,2891.9,1697.8,1583.2,1463.7,1382.5,1311.6,1294.6,1270.0,1250.6,1202.3,1157.7,1135.4,1073.0,1041.4,1030.0,829.3,804.8,750.3,741.1,624.1,596.7,521.4,431.6 cm
-1there is infrared absorption peak at place.
Dextral-rabeprazole sodium hydrate Z-type of the present invention crystallization, its Differential Scanning Calorimetry has Onset eigenwert at 144.9 DEG C, 178.2 DEG C, 222.3 DEG C places.
The present invention also provides the preparation method of a kind of dextral-rabeprazole sodium hydrate Z-type crystallization, and it comprises the following steps:
(1) in NaOH methanol solution, add dextral-rabeprazole, carry out salt-forming reaction, after reaction terminates, be evaporated to dry, obtain dextral-rabeprazole sodium solid;
(2) be dissolved in organic solvent of ketone by gained dextral-rabeprazole sodium, filtering insoluble solids, cooling crystallization, filters, dry, obtains the crystallization of described dextral-rabeprazole sodium hydrate Z-type.
In above-mentioned preparation method's step (1), the dextral-rabeprazole of various non-crystalline state in described dextral-rabeprazole general reference prior art, its preparation can be prepared with reference to the method described in prior art document, such as WO2011161421 etc.
In above-mentioned preparation method's step (2), described organic solvent of ketone is acetone or butanone, is preferably acetone.
A small amount of crystal seed can also be added further in above-mentioned preparation method's step (2), promote the growth of crystallization.
The present invention also provides a kind of pharmaceutical composition, comprise the described dextral-rabeprazole sodium hydrate Z-type crystallization for the treatment of significant quantity as activeconstituents and one or more pharmaceutically acceptable carrier, conveniently technology can prepare this pharmaceutical composition, as the dosage form that open source literature WO2008000463, WO2006011159 etc. describe, above-mentioned disclosure is all incorporated herein by reference.
The present invention also provides the crystallization of dextral-rabeprazole sodium hydrate Z-type for the preparation for the treatment of and the application in the medicine of gastric acid related disorder, is particularly treating the application in peptide ulceration, gastro oesophageal reflux disease (GORD) and Zhuo-Ellison syndrome medicine.
The invention has the advantages that: dextral-rabeprazole sodium hydrate Z-type provided by the invention crystallization has good stability, lower water absorbability, and product purity is high, be more conducive to store and use; In the process parameters range described in this crystal formation preparation method, repeat multiple batches, circulation ratio is fabulous, and the dextral-rabeprazole sodium hydrate Z stable crystal form adopting this preparation method to obtain, productive rate is high.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of embodiment 1 compound.
Fig. 2 is the infrared spectrogram of embodiment 1 compound.
Fig. 3 is the Differential Scanning Calorimetry of embodiment 1 compound.
Fig. 4 is the thermogravimetric analysis collection of illustrative plates of embodiment 1 compound.
Fig. 5 is the X-ray powder diffraction of embodiment 2 compound.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiments are never any limitation of the invention.
The present invention is characterized the crystal formation of obtained compound by conventional x-ray powder diffraction (D8 Advance type powder x-ray diffraction), infrared spectroscopy (TENSOR 27 type infrared spectrometer), dsc (NETZSCH DSC 204 type differential scanning calorimeter).Crystal water content is determined by karl Fischer moisture volumetry and thermogravimetry (NETZSCH TG 209 type thermogravimetric analyzer).Use C18 post to measure the purity of product by high performance liquid chromatography, use Chiral HPLC Determination enantiomeric excess (ee value), wherein concrete testing conditions is as follows.
The actual conditions that x-ray powder diffraction measures is:
Determining instrument: D8 Advance type powder x-ray diffraction, Bruker
Scan mode: continuous sweep type of drive: 0-2 θ links
Start angle: 0 ° of termination point: 50 °
Sweep velocity: 0.03 °/sec of sampling time: 1 second
Target: Cu wavelength value: 1.5418A
Tube voltage: 40kV tube current: 200mA
Monochromator: without divergent slit: 1 degree.
The actual conditions of infrared spectroscopic determination is:
Instrument is TENSOR 27 type infrared spectrometer, and sweep limit is 400 ~ 4000cm
-1, measuring method is as follows: sample thief is appropriate, with reference to the relevant requirements of Chinese Pharmacopoeia version annex IV C in 2010, adopts pressing potassium bromide troche, the infrared spectra of working sample.
The actual conditions of determine with dsc method is:
Instrument is NETZSCH DSC 204 type differential scanning calorimeter, and use t-zero bottle, heated perimeter is 30-400 DEG C, and rate of heating is per minute 10 DEG C, and nitrogen gas stream speed is per minute 80 milliliters.
The actual conditions that thermogravimetry measures is:
Instrument is NETZSCH TG 209 type thermogravimetric analyzer, and environmental gas is nitrogen, and heat-up rate is 10.00 DEG C/min, and sensitivity is 0.2uw.
The actual conditions of Chiral HPLC Determination enantiomeric excess (ee value) is:
Instrument is Agilent1200HPLC(DAD), NO.LC-PDSC-05; Chromatographic column: CHIRALPAKAGP4 * 150mm, 5 μm, Column:1167-503, Batch:1167; Condition determination is as follows:
Sampling volume: 10ul;
Flow velocity: 0.8ml/min;
Determined wavelength: 214nm;
Sample concentration: 0.5mg/ml;
Diluent: methyl alcohol-0.02mol/L sodium hydroxide solution (50: 50);
Column temperature: 30 DEG C;
Mobile phase A: measure 50ml acetonitrile in 950ml water, add 3g dipotassium hydrogen phosphate, after dissolving, by phosphoric acid adjust ph to 6.8;
Mobile phase B: measure 300ml acetonitrile in 700ml water, add 3g dipotassium hydrogen phosphate, after dissolving, by phosphoric acid adjust ph to 6.8;
Post time：10min
Gradient:
| Time (min) | %A | %B | Flow velocity (mL/min) |
| 0 | 100 | 0 | 0.8 |
| 2 | 100 | 0 | 0.8 |
| 7 | 70 | 30 | 0.8 |
| 12 | 55 | 45 | 0.8 |
| 20 | 55 | 45 | 0.8 |
Embodiment 1
NaOH 2.25 g is dissolved in methyl alcohol 100 mL, under stirring, adds dextral-rabeprazole 20 g, room temperature reaction 1 h.Reaction terminates, and suction filtration, gets filtrate, is evaporated to dry, obtains dextral-rabeprazole sodium solid.Added by gained solid in 50 mL acetone, 40 ~ 50 DEG C of stirrings, make dissolving, filter, removing insolubles.About 10 DEG C stirring and crystallizing 8 h.Suction filtration, washing with acetone, dries, obtains white solid 16.2 g, chemical purity 99.98%, ee value 99.99%.
By this crystal-form compound of X-ray powder diffraction analysis, its X-ray diffracting spectrum is shown in Fig. 1, and be Z-type crystallization hereinafter referred to as this crystal-form compound, data are listed in the table below 1, eliminate the peak that the other that provides in Fig. 1 is more weak in table 1, the error of 2 θ diffraction angle is ± 0.2 °.
The X-ray powder diffraction data of table 1 embodiment 1 compound
| Diffraction angle 2 θ (°) | Interplanar distance d () | Strength ratio I/I 0 (%) |
| 9.248 | 9.555 | 100.0 |
| 10.667 | 8.287 | 64.8 |
| 17.219 | 5.146 | 48.7 |
| 18.159 | 4.881 | 97.7 |
| 18.596 | 4.768 | 48.6 |
| 18.933 | 4.683 | 42.1 |
| 19.595 | 4.527 | 83.5 |
| 21.121 | 4.203 | 26.2 |
| 21.380 | 4.153 | 35.4 |
| 23.008 | 3.862 | 95.4 |
| 23.422 | 3.795 | 37.5 |
| 27.227 | 3.273 | 58.3 |
| 29.865 | 2.989 | 31.3 |
This crystal-form compound about 3339.0,3183.7,2937.8,2891.9,1697.8,1583.2,1463.7,1382.5,1311.6,1294.6,1270.0,1250.6,1202.3,1157.7,1135.4,1073.0,1041.4,1030.0,829.3,804.8,750.3,741.1,624.1,596.7,521.4,431.6 cm
-1there is infrared absorption peak at place, and its infrared spectrogram is shown in Fig. 2.
Differential scanning calorimetric analysis shows, and this crystal-form compound has Onset eigenwert at 144.9 DEG C, 172.8 DEG C, 222.3 DEG C places, and Fig. 3 is shown in by concrete collection of illustrative plates.
Measuring compound water-content by Karl_Fischer method is 4.7%.Thermal gravimetric analysis results is presented between 110 ~ 150 DEG C a weightlessness, and rate of weight loss is 4.20%.More than illustrate that this crystal-form compound is monohydrate.
Embodiment 2
NaOH 0.56 g is dissolved in methyl alcohol 20 mL, under stirring, adds dextral-rabeprazole 5 g, room temperature reaction 1 h.Reaction terminates, and suction filtration, gets filtrate, is evaporated to dry, obtains dextral-rabeprazole sodium solid.Added by gained solid in 15 mL butanone, 40 ~ 50 DEG C of stirrings, make dissolving, filter, removing insolubles.Add a small amount of crystal seed, about 5 DEG C stirring and crystallizing 8 h.Suction filtration, butanone washs, and dries, obtains white solid 4.5 g, chemical purity 99.97%, ee value 99.98%.
By this crystal-form compound of X-ray powder diffraction analysis, result shows this compound and has identical crystal formation with compound in embodiment 1.Concrete X-ray powder diffraction is shown in Fig. 5, and data are listed in the table below 2.Eliminate the peak that the other that provides in Fig. 5 is more weak in table 2, the error of 2 θ diffraction angle is ± 0.2 °.
The X-ray powder diffraction data of table 2 embodiment 2 compound
| Diffraction angle 2 θ (°) | Interplanar distance d () | Strength ratio I/I 0 (%) |
| 9.311 | 9.491 | 100.0 |
| 10.752 | 8.221 | 49.6 |
| 17.287 | 5.126 | 37.9 |
| 18.231 | 4.862 | 53.9 |
| 18.669 | 4.749 | 32.6 |
| 19.011 | 4.664 | 24.4 |
| 19.660 | 4.512 | 53.8 |
| 21.447 | 4.140 | 25.8 |
| 23.085 | 3.850 | 61.0 |
| 23.506 | 3.782 | 22.4 |
| 27.307 | 3.263 | 46.3 |
| 29.931 | 2.983 | 24.9 |
Embodiment 3 stability and water absorbability experiment
Get the embodiment of the present invention 1 gained Z crystal-form compound and amorphous dextral-rabeprazole sodium is appropriate, put in glass dish, in 40 DEG C, place 10 days under 75% humidity, respectively at sampling in the 0th, 5,10 day, investigate the stability of two kinds of different shape compounds, inspection target is outward appearance, weight, purity, the results are shown in Table 3.
Table 3 study on the stability result
Can be found by above experimental result, amorphous dextral-rabeprazole sodium water absorbability is strong, less stable, easily to degrade variable color.The dextral-rabeprazole sodium hydrate Z-type crystalline stability that the embodiment of the present invention 1 prepares is good, water absorbability is low, is conducive to standing storage.
The circulation ratio of embodiment 4 different batches Z-type crystallization
Three batches of dextral-rabeprazole sodium hydrate Z-types crystallization of different batches is prepared according to the method for embodiment 1, by the crystal-form compound of X-ray powder diffraction analysis different batches, its X-ray diffracting spectrum shows, three batch sample collection of illustrative plates all as shown in Figure 1, have the physical properties identical with embodiment 1 sample.
The preparation of embodiment 5 dextral-rabeprazole sodium tablet
Dextral-rabeprazole sodium hydrate Z-type crystallization in employing the present invention, as activeconstituents, becomes dextral-rabeprazole sodium tablet 1000 by the formula preparation of table 4.
Table 4 dextral-rabeprazole sodium tablet recipe (1000)
Claims (10)
1. dextral-rabeprazole sodium hydrate Z-type crystallization, it is characterized in that, in the X-ray powder diffraction represented with Cu-K α radiation, 2 θ ± 0.2 ° diffraction angle, there is characteristic diffraction peak at 9.2,10.7,18.2,19.6,21.2,23.0,27.2,29.9 places.
2. dextral-rabeprazole sodium hydrate Z-type according to claim 1 crystallization, wherein, the crystallization of described dextral-rabeprazole sodium hydrate Z-type contains a part crystal water.
3. dextral-rabeprazole sodium hydrate Z-type according to claim 1 crystallization, wherein, the infrared spectra of described dextral-rabeprazole sodium hydrate Z-type crystallization about 3339.0,3183.7,2937.8,2891.9,1697.8,1583.2,1463.7,1382.5,1311.6,1294.6,1270.0,1250.6,1202.3,1157.7,1135.4,1073.0,1041.4,1030.0,829.3,804.8,750.3,741.1,624.1,596.7,521.4,431.6 cm
-1there is infrared absorption peak at place.
4. dextral-rabeprazole sodium hydrate Z-type according to claim 1 crystallization, wherein, the Differential Scanning Calorimetry of described dextral-rabeprazole sodium hydrate Z-type crystallization has Onset eigenwert at 144.9 DEG C, 178.2 DEG C, 222.3 DEG C places.
5. a preparation method for the dextral-rabeprazole sodium hydrate Z-type crystallization according to any one of claim 1 ~ 4, it comprises the following steps:
(1) in NaOH methanol solution, add dextral-rabeprazole, carry out salt-forming reaction, after reaction terminates, be evaporated to dry, obtain dextral-rabeprazole sodium solid;
(2) be dissolved in organic solvent of ketone by gained dextral-rabeprazole sodium, filtering insoluble solids, cooling crystallization, filters, dry, obtains the crystallization of described dextral-rabeprazole sodium hydrate Z-type.
6. the preparation method of dextral-rabeprazole sodium hydrate Z-type according to claim 5 crystallization, wherein, in step (2), described organic solvent of ketone is acetone or butanone.
7. the preparation method of dextral-rabeprazole sodium hydrate Z-type according to claim 6 crystallization, wherein, in step (2), described organic solvent of ketone is acetone.
8. the preparation method of dextral-rabeprazole sodium hydrate Z-type according to claim 5 crystallization, wherein, in step (2), can also add a small amount of crystal seed further.
9. a pharmaceutical composition, is characterized in that, comprises the dextral-rabeprazole sodium hydrate Z-type crystallization as described in any one of claim 1 ~ 4 for the treatment of significant quantity as activeconstituents and one or more pharmaceutically acceptable carrier.
10. the application of the dextral-rabeprazole sodium hydrate Z-type crystallization described in any one of claim 1 ~ 4 in the medicine for the preparation for the treatment of gastric acid related disorder.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632306A (en) * | 2016-12-26 | 2017-05-10 | 珠海润都制药股份有限公司 | Amorphous dexrabeprazole sodium and preparation method thereof |
| CN106957302A (en) * | 2017-04-12 | 2017-07-18 | 山东裕欣药业有限公司 | A kind of method of RABEPRAZOLE SODIUM prepared by super-critical anti-solvent technology |
| WO2018233678A1 (en) * | 2017-06-23 | 2018-12-27 | 江苏奥赛康药业股份有限公司 | Dexrabeprazole sodium compound and pharmaceutical composition thereof |
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| US20080161359A1 (en) * | 2006-12-19 | 2008-07-03 | Dipharma Francis S.R.L. | Crystalline form of rabeprazole sodium |
| CN102924434A (en) * | 2012-10-18 | 2013-02-13 | 江苏诚信制药有限公司 | Dexrabeprazole sodium monohydrate crystal form and preparation method thereof |
| CN103113350A (en) * | 2013-02-27 | 2013-05-22 | 安徽省新星药物开发有限责任公司 | Novel crystal form of R-rabeprazole sodium hydrate, preparation method and application thereof |
| CN104031030A (en) * | 2014-04-21 | 2014-09-10 | 海南海力制药有限公司 | Dexrabeprazole sodium monohydrate crystal form and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20080161359A1 (en) * | 2006-12-19 | 2008-07-03 | Dipharma Francis S.R.L. | Crystalline form of rabeprazole sodium |
| CN102924434A (en) * | 2012-10-18 | 2013-02-13 | 江苏诚信制药有限公司 | Dexrabeprazole sodium monohydrate crystal form and preparation method thereof |
| CN103113350A (en) * | 2013-02-27 | 2013-05-22 | 安徽省新星药物开发有限责任公司 | Novel crystal form of R-rabeprazole sodium hydrate, preparation method and application thereof |
| CN104031030A (en) * | 2014-04-21 | 2014-09-10 | 海南海力制药有限公司 | Dexrabeprazole sodium monohydrate crystal form and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632306A (en) * | 2016-12-26 | 2017-05-10 | 珠海润都制药股份有限公司 | Amorphous dexrabeprazole sodium and preparation method thereof |
| CN106632306B (en) * | 2016-12-26 | 2019-11-15 | 珠海润都制药股份有限公司 | Unformed dextral-rabeprazole sodium and preparation method thereof |
| CN106957302A (en) * | 2017-04-12 | 2017-07-18 | 山东裕欣药业有限公司 | A kind of method of RABEPRAZOLE SODIUM prepared by super-critical anti-solvent technology |
| WO2018233678A1 (en) * | 2017-06-23 | 2018-12-27 | 江苏奥赛康药业股份有限公司 | Dexrabeprazole sodium compound and pharmaceutical composition thereof |
| US11078184B2 (en) | 2017-06-23 | 2021-08-03 | Jiangsu Aosaikang Pharmaceutical Co., Ltd. | Dexrabeprazole sodium compound and pharmaceutical composition thereof |
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Address after: 224200 Jiangsu Province, Yancheng City Dongtai City Ho duo Road No. 18 Applicant after: Jiangsu Shenlong pharmaceutical Limited by Share Ltd Address before: 224200 Jiangsu Province, Yancheng City Dongtai City Ho duo Road No. 18 Applicant before: Jiangsu Shenlong Pharmaceutical Co., Ltd. |
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Effective date of registration: 20200902 Address after: Room 814, block a, phase I, Zhongdan Life Science Industrial Park, No. 3-1, xinjinhu Road, Jiangbei new district, Nanjing, Jiangsu Province, 210046 Patentee after: Burning point (Nanjing) Biomedical Technology Co., Ltd Address before: 224200, No. 18 North Road, Dongtai, Jiangsu, Yancheng City Patentee before: JIANGSU SHENLONG PHARMACEUTICAL Co.,Ltd. |