CN104725358B - A kind of crystal form and preparation method thereof of dextral-rabeprazole sodium hydrate - Google Patents
A kind of crystal form and preparation method thereof of dextral-rabeprazole sodium hydrate Download PDFInfo
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- 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
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Abstract
The present invention relates to a kind of novel crystal forms and preparation method thereof of dextral-rabeprazole sodium hydrate, the novel crystal forms are known as Z-type crystallization, the dextral-rabeprazole sodium hydrate Z-type crystallization, it is characterized in that, in the X-ray powder diffraction collection indicated with Cu-K α radiation, the 2 θ ± 0.2 ° angles of diffraction, there is characteristic diffraction peak at 9.3,10.7,18.2,19.6,21.2,23.0,27.2,29.9.
Description
Technical field
The present invention relates to a kind of novel crystal forms for drawing azole proton pump inhibitor drug, and in particular to a kind of dextral-rabeprazole
Novel crystal forms of sodium hydrate and preparation method thereof.
Background technique
Develop now with Chinese society, the change of circumstances, the variation of population structure and people life style, digestibility is burst
Ulcer disease incidence gradually increases, and has become a kind of common disease and frequently-occurring disease for influencing people's quality of life. H+/K+ATP enzyme inhibits
Agent class drug has become a kind of means of very effective treatment peptic ulcer, wherein with Omeprazole, Pantoprazole, angstrom
Suo Meila azoles, Rabeprazole are clinically most widely used.Rabeprazole is listed in exploitation in 1991 by Japanese Eisai, is one
The reversible H in a part+/K+Atpase inhibitor may act on H+/K+4 positions of ATP enzyme, due to increasing in conjunction with target spot, compared with
The effect of other similar drugs is faster, more longlasting, acid suppression intensity is stronger.
Due to the presence of chiral sulfur atom, Rabeprazole includes two kinds of optical isomers, S- (-)-Rabeprazole (left-handed)
With R- (+)-Rabeprazole (dextrorotation).It is left-handed different that experiment shows that the pharmacological action of Rabeprazole dextroisomer will be significantly stronger than
Structure body and raceme.EMCURE pharmaceuticals of India carries out dextral-rabeprazole sodium and racemization RABEPRAZOLE SODIUM a large amount of clinical
Comparative test, the results showed that dextroisomer minimum effective dose is small compared with raceme, and metabolic half life is long, can significantly improve treatment
Effect, the generation for reducing toxic side effect, and developed and list in India in 2007.The structure of dextral-rabeprazole sodium is as follows:
。
Due to containing unstable benzimidazole and sulfoxide building stone in dextral-rabeprazole sodium structure, so its is right
Light, heat, wet stability are poor.The unstability of dextral-rabeprazole sodium is for the formulation study of preparation, technical study, finished product
Safety and validity have very big adverse effect, so preparing stable bulk pharmaceutical chemicals with important application value.
As known to those skilled in the art, the different crystal forms of bulk pharmaceutical chemicals have very big influence for its stability, research and develop out one
The stable crystal form of kind dextral-rabeprazole sodium will effectively improve its stability, also be beneficial to ensure the safety of finished product preparation
Property, validity and quality controllability.Currently, it is relatively fewer to the document report of dextral-rabeprazole sodium crystal,
WO2011161421 reports a kind of amorphous dextral-rabeprazole sodium, and CN102924434A, CN103113350A are reported respectively
A kind of crystal-form compound of dextral-rabeprazole sodium.
Amorphous dextral-rabeprazole sodium hygroscopicity is strong, stability is poor, degradable discoloration, therefore, obtains a property
Stable dextral-rabeprazole sodium crystal is very necessary to drug development.
Summary of the invention
The purpose of the present invention is to provide a kind of novel crystal forms and preparation method thereof of dextral-rabeprazole sodium hydrate, below
The novel crystal forms are known as Z-type crystallization.
Dextral-rabeprazole sodium hydrate Z-type of the present invention crystallization, which is characterized in that with Cu-K α radiation, 2 θ ±
In the X-ray powder diffraction collection that 0.2 ° of angle of diffraction indicates, 9.2,10.7,18.2,19.6,21.2,23.0,27.2,29.9
There is characteristic diffraction peak at place.
Thermogravimetric analysis and karl Fischer moisture titration results show, dextral-rabeprazole sodium hydrate Z of the present invention
Type crystallization contains a molecular crystalline water.
The infrared spectroscopy 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, Differential Scanning Calorimetry 144.9 DEG C,
There is Onset characteristic value at 178.2 DEG C, 222.3 DEG C.
The present invention also provides a kind of preparation methods of dextral-rabeprazole sodium hydrate Z-type crystallization comprising following steps:
(1) into NaOH methanol solution, dextral-rabeprazole is added, carries out salt-forming reaction, after reaction, is concentrated under reduced pressure
To doing, dextral-rabeprazole sodium solid is obtained；
(2) gained dextral-rabeprazole sodium is dissolved in organic solvent of ketone, filters out insoluble solids, cool down crystallization, mistake
Filter, it is dry, obtain the dextral-rabeprazole sodium hydrate Z-type crystallization.
In above-mentioned preparation method step (1), the dextral-rabeprazole refers to various non-crystalline states in the prior art
Dextral-rabeprazole, preparation is referred to method described in existing technical literature and prepared, such as
WO2011161421 etc..
In above-mentioned preparation method step (2), the organic solvent of ketone is acetone or butanone, preferably acetone.
A small amount of crystal seed can also further be added in above-mentioned preparation method step (2), promote the growth of crystallization.
The present invention also provides a kind of pharmaceutical compositions, the dextral-rabeprazole sodium hydrate including therapeutically effective amount
Z-type crystallization is used as active constituent and one or more pharmaceutical acceptable carrier, and the pharmaceutical composition can be prepared according to routine techniques,
Such as the dosage form described in open source literature WO2008000463, WO2006011159 etc., above disclosure is fully incorporated this
Text is as reference.
The present invention also provides the crystallization of dextral-rabeprazole sodium hydrate Z-type in preparation for treating and gastric acid related disorder
Application in drug, especially answering in treatment peptic ulcer, gastroesophageal reflux disease and Zhuo-Ellison syndrome drug
With.
The present invention has the advantages that dextral-rabeprazole sodium hydrate Z-type crystallization provided by the invention has preferably surely
Qualitative, lower hygroscopicity, product purity is high, more conducively stores and uses；The technological parameter described in the crystal form preparation method
In range, multiple batches are repeated, reproducibility is fabulous, the dextral-rabeprazole sodium hydrate Z crystal form obtained using the preparation method
Stablize, yield is high.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction collection of 1 compound of embodiment.
Fig. 2 is the infrared spectrogram of 1 compound of embodiment.
Fig. 3 is the Differential Scanning Calorimetry of 1 compound of embodiment.
Fig. 4 is the thermogravimetric analysis map of 1 compound of embodiment.
Fig. 5 is the X-ray powder diffraction collection of 2 compound of embodiment.
Specific embodiment
Below with reference to embodiment, the present invention is further elaborated, but these embodiments are definitely not to any limit of the invention
System.
The present invention passes through conventional x-ray powder diffraction (D8 Advance type powder x-ray diffraction), infrared spectroscopy
Method (27 type infrared spectrometer of TENSOR), differential scanning calorimetry (204 type differential scanning calorimeter of NETZSCH DSC) are right
The crystal form of compound obtained is characterized.Pass through karl Fischer moisture titration and thermogravimetry (NETZSCH TG
209 type thermogravimetric analyzers) determine crystal water content.The purity for being measured product using C18 column by high performance liquid chromatography, is made
With Chiral HPLC Determination enantiomeric excess (ee value), wherein specific testing conditions are as follows.
The actual conditions of x-ray powder diffraction measurement are as follows:
Determining instrument: D8 Advance type powder x-ray diffraction, Bruker
Scanning mode: continuous scanning driving method: 0-2 θ linkage
Start angle: 0 ° of termination point: 50 °
Scanning speed: 0.03 °/sec of sampling time: 1 second
Target: Cu wavelength value: 1.5418A
Tube voltage: 40kV tube current: 200mA
Monochromator: divergence-free slit: 1 degree.
The actual conditions of infrared spectroscopic determination are as follows:
Instrument is 27 type infrared spectrometer of TENSOR, and scanning range is 400 ~ 4000cm-1, measuring method is as follows: taking
Appropriate sample measures the infrared of sample using pressing potassium bromide troche referring to the related requirement of Chinese Pharmacopoeia IV C of version annex in 2010
Spectrum.
The actual conditions of differential scanning calorimetry measurement are as follows:
Instrument is 204 type differential scanning calorimeter of NETZSCH DSC, using t-zero bottles, heated perimeter 30-
400 DEG C, heating speed is 10 DEG C per minute, and nitrogen stream speed is 80 milliliters per minute.
The actual conditions of thermogravimetry measurement are as follows:
Instrument is 209 type thermogravimetric analyzer of NETZSCH TG, and environmental gas is nitrogen, heating rate 10.00
DEG C/min, sensitivity 0.2uw.
The actual conditions of Chiral HPLC Determination enantiomeric excess (ee value) are as follows:
Instrument is Agilent1200HPLC(DAD), NO.LC-PDSC-05；Chromatographic column: CHIRALPAKAGP4 *
150mm, 5 μm, Column:1167-503, Batch:1167；Determination condition is as follows:
Sampling volume: 10ul；
Flow velocity: 0.8ml/min；
Detection wavelength: 214nm；
Sample concentration: 0.5mg/ml；
Dilution: methanol -0.02mol/L sodium hydroxide solution (50: 50)；
Column temperature: 30 DEG C；
Mobile phase A: 50ml acetonitrile is measured in 950ml water, 3g dipotassium hydrogen phosphate is added, after dissolution, with phosphorus acid for adjusting pH
It is worth to 6.8；
Mobile phase B: 300ml acetonitrile is measured in 700ml water, 3g dipotassium hydrogen phosphate is added, after dissolution, with phosphorus acid for adjusting pH
It is worth 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
2.25 g of NaOH is dissolved in 100 mL of methanol, under stirring, 20 g of dextral-rabeprazole, room temperature reaction 1 is added
h.Reaction terminates, and filters, takes filtrate, be concentrated to dryness, obtain dextral-rabeprazole sodium solid.50 mL are added in obtained solid
In acetone, 40 ~ 50 DEG C of stirrings make to dissolve, filter, remove insoluble matter.10 DEG C or so 8 h of stirring and crystallizing.It filters, acetone washing,
Drying, obtains 16.2 g of white solid, chemical purity 99.98%, ee value 99.99%.
The crystal-form compound is analyzed by X-ray powder diffraction, X-ray diffracting spectrum is shown in Fig. 1, the hereinafter referred to as crystal form
Compound is Z-type crystallization, and data are listed in the table below 1, the weaker peak of the other provided in Fig. 1, the 2 θ angles of diffraction are omitted in table 1
Error be ± 0.2 °.
The X-ray powder diffraction data of 1 embodiment of table, 1 compound
| 2 θ (°) of the angle of diffraction | Interplanar distance d () | Intensity ratio I/I0 (%) |
| 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 |
The 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 are infrared absorption peak, infrared spectroscopy in place
Figure is shown in Fig. 2.
Differential scanning calorimetric analysis shows that the crystal-form compound has Onset special at 144.9 DEG C, 172.8 DEG C, 222.3 DEG C
Value indicative, specific map are shown in Fig. 3.
Measuring compound water content by Karl_Fischer method is 4.7%.Thermal gravimetric analysis results are shown between 110 ~ 150 DEG C
There are a weightlessness, weight-loss ratio 4.20%.The crystal-form compound described above is monohydrate.
Embodiment 2
0.56 g of NaOH is dissolved in 20 mL of methanol, under stirring, 5 g of dextral-rabeprazole is added, reacts at room temperature 1 h.
Reaction terminates, and filters, takes filtrate, be concentrated to dryness, obtain dextral-rabeprazole sodium solid.15 mL fourths are added in obtained solid
In ketone, 40 ~ 50 DEG C of stirrings make to dissolve, filter, remove insoluble matter.A small amount of crystal seed, 5 DEG C or so 8 h of stirring and crystallizing are added.It filters,
Butanone washing, drying obtain 4.5 g of white solid, chemical purity 99.97%, ee value 99.98%.
The crystal-form compound is analyzed by X-ray powder diffraction, as the result is shown the compound and compound in embodiment 1
Crystal form having the same.Specific X-ray powder diffraction collection is shown in Fig. 5, and data are listed in the table below 2.It is omitted in Fig. 5 and provides in table 2
The weaker peak of other, the error of the 2 θ angles of diffraction is ± 0.2 °.
The X-ray powder diffraction data of 2 embodiment of table, 2 compound
| 2 θ (°) of the angle of diffraction | Interplanar distance d () | Intensity ratio I/I0 (%) |
| 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 |
3 stability of embodiment and hygroscopicity experiment
It takes 1 gained Z crystal-form compound of the embodiment of the present invention and amorphous dextral-rabeprazole sodium appropriate, sets glass dish
In, it is placed 10 days under 40 DEG C, 75% humidity, was sampled respectively at the 0th, 5,10 day, investigate the stabilization of two kinds of different shape compounds
Property, inspection target is appearance, weight, purity, the results are shown in Table 3.
3 study on the stability result of table
By the above experimental result it can be found that amorphous dextral-rabeprazole sodium hygroscopicity is strong, stability is poor, easy drop
Solution discoloration.The dextral-rabeprazole sodium hydrate Z-type crystalline stability that the embodiment of the present invention 1 is prepared is good, hygroscopicity is low, has
Conducive to long term storage.
The reproducibility of 4 different batches Z-type of embodiment crystallization
The three batches of dextral-rabeprazole sodium hydrate Z-types crystallization for preparing different batches according to the method for embodiment 1, passes through X-
The crystal-form compound of ray powder diffraction analysis different batches, X-ray diffracting spectrum show that three batches of sample maps are such as Fig. 1
It is shown, there is physical property identical with 1 sample of embodiment.
The preparation of 5 dextral-rabeprazole sodium tablet of embodiment
Active constituent is used as using the dextral-rabeprazole sodium hydrate Z-type crystallization in the present invention, is prepared by the prescription of table 4
At dextral-rabeprazole sodium tablet 1000.
4 dextral-rabeprazole sodium tablet recipe (1000) of table
Claims (8)
1. a kind of dextral-rabeprazole sodium hydrate Z-type crystallization, which is characterized in that with Cu-K α radiation, the 2 θ ± 0.2 ° angles of diffraction
There is following characteristics diffraction maximum in the X-ray powder diffraction collection of expression:
Its Differential Scanning Calorimetry has Onset characteristic value at 144.9 DEG C, 178.2 DEG C, 222.3 DEG C；The dextrorotation Lei Beila
The crystallization of azoles sodium hydrate Z-type contains a molecular crystalline water.
2. dextral-rabeprazole sodium hydrate Z-type crystallization according to claim 1, wherein the dextral-rabeprazole sodium
The infrared spectroscopy of 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、431.6cm-1There is infrared absorption peak at place.
3. a kind of preparation method of dextral-rabeprazole sodium hydrate Z-type crystallization of any of claims 1 or 2 comprising following
Step:
(1) into NaOH methanol solution, dextral-rabeprazole is added, carries out salt-forming reaction and is concentrated under reduced pressure into after reaction
It is dry, obtain dextral-rabeprazole sodium solid；
(2) gained dextral-rabeprazole sodium is dissolved in organic solvent of ketone, filters out insoluble solids, cool down crystallization, filters, and does
It is dry, obtain the dextral-rabeprazole sodium hydrate Z-type crystallization.
4. the preparation method of dextral-rabeprazole sodium hydrate Z-type crystallization according to claim 3, wherein step (2)
In, the organic solvent of ketone is acetone or butanone.
5. the preparation method of dextral-rabeprazole sodium hydrate Z-type crystallization according to claim 4, wherein step (2)
In, the organic solvent of ketone is acetone.
6. the preparation method of dextral-rabeprazole sodium hydrate Z-type crystallization according to claim 3, wherein step (2)
In, a small amount of crystal seed can also further be added.
7. a kind of pharmaceutical composition, which is characterized in that the dextrorotation thunder shellfish as claimed in claim 1 or 2 including therapeutically effective amount
The crystallization of azoles sodium hydrate Z-type is drawn to be used as active constituent and one or more pharmaceutical acceptable carrier.
8. dextral-rabeprazole sodium hydrate Z-type crystallization of any of claims 1 or 2 is in preparation for treating gastric acid related disorder
Drug in application.
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| 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 |
| US11078184B2 (en) | 2017-06-23 | 2021-08-03 | Jiangsu Aosaikang Pharmaceutical Co., Ltd. | Dexrabeprazole sodium compound and pharmaceutical composition thereof |
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| 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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| 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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