CN103864755A - Rabeprazole sodium compound - Google Patents
Rabeprazole sodium compound Download PDFInfo
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- CN103864755A CN103864755A CN201210528744.1A CN201210528744A CN103864755A CN 103864755 A CN103864755 A CN 103864755A CN 201210528744 A CN201210528744 A CN 201210528744A CN 103864755 A CN103864755 A CN 103864755A
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- rabeprazole
- hydrate
- rabeprazole sodium
- sodium hydrate
- sodium
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- 0 Cc1c(C[S@](c2nc3ccccc3[n]2)=IC)nccc1OCCCO* Chemical compound Cc1c(C[S@](c2nc3ccccc3[n]2)=IC)nccc1OCCCO* 0.000 description 2
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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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Abstract
The invention belongs to the technical field of medicines, and concretely relates to a rabeprazole sodium hydrate and its preparation method. The rabeprazole sodium hydrate obtained in the invention contains one crystal water, has a good stability, and has an unobvious moisture absorption weight increment under highly humid conditions, and the gastric acid secretion inhibition effect of the hydrate is 20% higher than that of a rabeprazole sodium tablet. The invention also relates to applications of compositions of the hydrate in the treatment of digestive system diseases comprising duodenal ulcer, gastric ulcer, reflux esophagitis and the like.
Description
Technical field
The invention belongs to medical technical field, be specifically related to rabeprazole sodium hydrate and preparation method thereof, the invention still further relates to the application of digestive system such as using the composition treatment duodenal ulcer of this hydrate and stomach ulcer, reflux esophagitis.
Background technology
Along with social progress, the quickening of rhythm of life, digestive system sickness rate is also raising year by year, and the sickness rate of global Digestive tract accounts for 10%-12% of mankind's sickness rate according to statistics; The sickness rate of China's cities and towns digestive system reaches 11.43%, wherein gastroxia is the major reason of digestive system, bisfentidine is 2 kinds of the most frequently used medicines of the relevant digestion disease of therapic acid with proton pump inhibitor, their stomach pH that all raises, but proton pump inhibitor acts on H+/K+-ATP enzyme, strongly inhibited gastric acid secretion, and make stomach pH produce larger and lasting rising, therewith accordingly, the market demand of the proton pump inhibitor to effective this type of disease for the treatment of (PPI) is also at increase year after year.
Sodium rabeprazole (rabeprazole sodium), is a kind of novel proton pump inhibitor class medicine of being developed by Japanese Wei Cai company, goes on the market first in January, 1998 in Japan.
Sodium rabeprazole structural formula:
Chemical name; 2-[[3-methyl-4-(3-methoxy the third oxygen)-3-picoline-2-yl] methylsulfinyl]-1H benzoglyoxaline sodium salt,
Molecular formula: C
18h
20n
3naO
3s
Molecular weight: 381.42
It is Powdered that this product is pure white, tasteless.Soluble in water, methyl alcohol, can be dissolved in straight alcohol and ether on a small quantity.
This medicine is the omeprazole that continues, the 4th kind of proton pump inhibitor of exploitation after lansoprazole and pantoprazole.Compared with omeprazole, it is stronger that rabeprazole suppresses the effect of H+/K+-ATP enzyme, and suppress to recover; Have selectivity strongly inhibited helicobacter pylori (HP) effect, in addition, this medicine is in vivo without Accumulation Phenomenon.The clinical digestive system such as duodenal ulcer and stomach ulcer, reflux esophagitis that are used for the treatment of.This product is rapid-action, it is effective to press down acid, can continue to press down acid, relief of symptoms by 24 h.The specification of this medicine has every 10mg, and adult's dosage is 10mg, qd, and while being in a bad way, dosage rises to 20mg, bid.
The preparation method of rabeprazole and Sodium rabeprazole is more, WO2008017020, WO2006049486, WO2003101452, WO2009116072, US20040209918A1, US2004138466A1, US20090005570, US5045552 (1991-09-03), EP1818331, US5998445, EP2022789A1, WO9854171A1, WO0044744A1, EP1085019, EP268956, US20050234103, WO2006024890, WO2006117802, US20080161579, CA2608608A1, EP1674463, EP1452533A1, EP1818331A1, EP1847538A1, Chinese patent: 200610023956.9, 200610020206.6, 02813961.5, 01808879.1, 200410066061.4, 201010153033.1, 02804485.1, 98808308.6, 200510086094, 200610081920.6, 200880016566.6, 201010158822.4 etc.
Above-mentioned rabeprazole method purification of products difficulty, rabeprazole is made its sodium salt can effectively reduce impurity, purified product, but impurity is still higher, also has certain moisture absorption weightening finish.
The rabeprazole sodium hydrate that the present invention obtains on the basis of great many of experiments, has advantages of: purity is high, maximum contaminant is less than 1 ‰; Good stability, even moisture absorption weightening finish is also not obvious under high humidity.
Make people surprised, identical prescription and technique, wait rabeprazole sodium hydrate tablet and the rabeprazole sodium tablet of dosage (rabeprazole sodium hydrate is converted into Sodium rabeprazole), and to the restraining effect of gastric acid secretion, the former exceeds the latter approximately 20%.
Summary of the invention
One object of the present invention, discloses a kind of rabeprazole sodium hydrate.
Another object of the present invention, discloses the preparation method of rabeprazole sodium hydrate.
Another object of the present invention, discloses the pharmaceutical composition that comprises rabeprazole sodium hydrate.
The invention also discloses rabeprazole sodium hydrate in preparation treatment application.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of rabeprazole sodium hydrate (shown in formula I),
（I）
Karl Fischer method (Karl Fischer method) is in a kind of all kinds of chemical processes of measuring moisture in material, and, the most accurately method the most single-minded to water, has been listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.Through multiple batches of mensuration, the moisture that described invention compound contains is between 4.40%-4.62% (weight percent).In rabeprazole sodium hydrate, the theoretical content of water is 4.51%, can assert that invention compound contains a crystal water.
Wherein the measurement result of 6 batches is as follows:
| Batch | Moisture (%) | Batch | Moisture (%) |
| 1 | 4.57 | 4 | 4.56 |
| 2 | 4.40 | 5 | 4.62 |
| 3 | 4.55 | 6 | 4.60 |
This rabeprazole sodium hydrate, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ), D value and relative intensity are as follows, see Fig. 1.
| Spectrum wire size | 2 θ (degree) | Spacing (d) | I/I 0 |
| 1 | 14.320 | 6.2671 | 28 |
| 2 | 14.610 | 6.1459 | 3 |
| 3 | 15.180 | 5.7938 | 4 |
| 4 | 19.480 | 4.5301 | 38 |
| 5 | 20.160 | 4.4227 | 7 |
| 6 | 23.690 | 3.7857 | 13 |
| 7 | 24.240 | 3.6539 | 6 |
| 8 | 25.560 | 3.4956 | 7 |
| 9 | 26.350 | 3.4062 | 17 |
| 10 | 27.010 | 3.2853 | 3 |
| 11 | 27.750 | 3.1907 | 8 |
| 12 | 28.090 | 3.1641 | 4 |
| 13 | 28.650 | 3.0827 | 29 |
| 14 | 29.880 | 2.9800 | 100 |
| 15 | 30.910 | 2.8988 | 5 |
| 16 | 31.750 | 2.8082 | 6 |
| 17 | 32.440 | 2.7576 | 8 |
| 18 | 33.000 | 2.7121 | 5 |
| 19 | 33.340 | 2.6852 | 6 |
| 20 | 33.560 | 2.6681 | 9 |
| 21 | 35.310 | 2.5391 | 59 |
| 22 | 36.160 | 2.4833 | 10 |
| 23 | 37.720 | 2.3829 | 7 |
| 24 | 39.780 | 2.2641 | 8 |
| 25 | 40.270 | 2.2371 | 13 |
| 26 | 40.960 | 2.2016 | 3 |
| 27 | 41.520 | 2.1731 | 4 |
| 28 | 42.250 | 2.1387 | 12 |
| 29 | 42.520 | 2.1243 | 4 |
| 30 | 44.090 | 2.0474 | 2 |
| 31 | 45.870 | 1.9812 | 21 |
| 32 | 46.810 | 1.9474 | 2 |
| 33 | 47.180 | 1.9248 | 4 |
| 34 | 47.620 | 1.8968 | 14 |
| 35 | 48.950 | 1.8582 | 5 |
| 36 | 49.440 | 1.8462 | 5 |
In the present invention, the mensuration of 2 θ values is used light source, and precision is ± 0.2 °, therefore represents that above-mentioned got value has allowed certain reasonably limit of error, and its limit of error is ± 0.2 °.
Fusing point test: measure fusing point according to Pharmacopoeia of People's Republic of China (2010 editions, two) annex VI C first method, the fusing point recording is 120.3 DEG C-122.2 DEG C.
Another object of the present invention, discloses the preparation method of rabeprazole sodium hydrate, by Sodium rabeprazole is dissolved in Virahol-piperidines-heated in water solution, naturally cools to room temperature, then is incubated for some time and obtains.
Specifically comprise the following steps: that Sodium rabeprazole adds in the mixed solution of 7-9 times of (weight or measurement (WM) ratio) Virahol-piperidines-water=4-5:0.05-0.1:4-5.5, be heated to dissolve, filtrate naturally cools to 26 DEG C-28 DEG C, leave standstill again insulation 6-7 hour, crystallization, filter, drying obtains.
A large amount of experimental results show that: the proportioning of the adding of piperidines, mixed solution, standing temperature and time are most important to obtaining rabeprazole sodium hydrate of the present invention.
Sodium rabeprazole used can pass through Chinese patent (application number 87107777), US5045552, or EP1818331A1, and EP268956 conveniently makes, and also can buy and obtain.
Another object of the present invention, provides the composition of the rabeprazole sodium hydrate that comprises rabeprazole sodium hydrate and one or more pharmaceutically acceptable carriers composition.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.
Make people surprised, identical prescription and technique, wait rabeprazole sodium hydrate tablet and the rabeprazole sodium tablet of dosage (rabeprazole sodium hydrate is converted into Sodium rabeprazole), and to the restraining effect of gastric acid secretion, the former exceeds the latter approximately 20%.
The amount of the active ingredient (the compounds of this invention) containing in pharmaceutical composition and unit dosage form can specifically be applied according to the situation of patient's the state of an illness, diagnosis, the amount of compound used or concentration regulate in a wider scope, 1%～30%(weight that the weight range of active compound is composition).
The present invention also provides the application of rabeprazole sodium hydrate in the medicine of manufacturing the digestive system such as treatment duodenal ulcer and stomach ulcer, reflux esophagitis.
to the inhibition of gastric acid secretion
Adopt than lattice dog, the gastric acid secretion of every dog is to be injected 100 microgram histamine by per kilogram and stimulated by per hour.Histamine injection, after one hour, gives rabeprazole sodium hydrate tablet and rabeprazole sodium tablet (writing out a prescription identical with technique), and both wait dosage (rabeprazole sodium hydrate is converted into Sodium rabeprazole), and dog is carried out to intraduodenal administration.After administration one hour, measure the gastric acid output of every dog.By result and the comparison of blank group, and represent with inhibition percentage.The ID50 value of being obtained by dosage-inhibition curve is respectively 49 micro-gs/kg and 60.9 micro-gs/kg.Show that rabeprazole sodium hydrate is better than Sodium rabeprazole to the inhibition of gastric acid secretion.
stability test
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in hydrate of the present invention:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), it is constant that moisture keeps, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in Sodium rabeprazole:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), Sodium rabeprazole has moisture absorption weightening finish, to moist lability.
brief description of the drawings:
Fig. 1, the X-ray diffractogram of rabeprazole sodium hydrate;
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Sodium rabeprazole used in the present invention obtains with reference to the method for Chinese patent (application number 87107777) and US5045552,139 DEG C-140.2 DEG C of fusing points, purity 98.1% (HPLC normalization method), its chemical structure, through proton nmr spectra, ultimate analysis confirmation, proves that chemical structure is correct.
Be dried to after constant weight, the moisture recording by karl Fischer method is 0.24%.
embodiment 1
In the 5l reactor that stirring, thermometer, condenser are housed, add 240 grams of Sodium rabeprazoles and 970.0ml Virahol, 16.5ml piperidines, 980.0ml water, starts stirring, is heated to dissolve, filtrate naturally cools to 28 DEG C, then leaves standstill insulation 6 hours, crystallization, filter, through indoor seasoning, obtain 230.6 grams of rabeprazole sodium hydrate white crystals, fusing point is that the fusing point recording is 120.3 DEG C-122.2 DEG C, content 99.76%, single contaminant is less than 0.06%.Measure the moisture that contains 4.57% (weight percent) through karl Fischer method.
The X-ray diffractogram of this crystallization is shown in Fig. 1.Instrument model and condition determination: Rigaku D/max 2500 type diffractometers; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°.
Use standard and conventional technology, be combined the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.Only be illustrated for example, never mean that it limits the scope of the invention by any way.
embodiment 2
The tablet that contains rabeprazole sodium hydrate
Prescription: 10.7 grams of rabeprazole sodium hydrates, Microcrystalline Cellulose 12 g, pregelatinized Starch 16g, carboxymethylstach sodium 5 g, 210 grams of lactose, 25 grams of PEG-4000,6 grams of Magnesium Stearates, 30 grams of PVP K30s, 33 grams of croscarmellose sodiums, distilled water is appropriate, makes 10000.
Technique:
The preparation of label: by determined prescription, main ingredient is mixed with auxiliary material, granulate, particle air seasoning below 40 DEG C, with the whole grain of l6 mesh sieve, adds Magnesium Stearate and remaining starch, and compressing tablet, to obtain final product.
Sealing coat dressing: talcum powder is added in 5% polyvinylpyrrolidone (PVP) anhydrous alcohol solution, stir, be mixed with 20% suspension as sealing coat coating liquid.In fluidized-bed, carry out dressing, its processing condition are as follows: spray pressure 0.3 MPa, feed liquor speed 5mL/min, 37 DEG C of inlet temperatures, 31 DEG C of temperature outs, dry air flow 200 m
3/ h, sealing coat weightening finish for essence sheet sheet heavy 9%.
Enteric layers dressing: II resin is dissolved in dehydrated alcohol, and clothing liquid concentration is 10% (w/v), its processing condition except spray speed be 4mL/min, all the other are with sealing coat coating conditions, enteric layers weightening finish for wrap isolate synusia heavy 6%.
Claims (6)
1. the hydrate of Sodium rabeprazole shown in formula I,
（Ⅰ）
With karl Fischer method mensuration, the moisture that described hydrate contains weight percent 4.40%-4.62%;
Described rabeprazole sodium hydrate, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle, spacing (d value) and relative intensity (I/I
0),
The error of 2 θ diffraction angle is ± 0.2 °.
2. the preparation method of rabeprazole sodium hydrate described in claim 1, by Sodium rabeprazole is dissolved at Virahol-piperidines-heated in water solution, naturally cools to room temperature, then is incubated for some time and obtains.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that Sodium rabeprazole adds in the mixed solution of 7-9 times of (weight or measurement (WM) ratio) Virahol-piperidines-water=4-5:0.05-0.1:4-5.5, be heated to dissolve, filtrate naturally cools to 26 DEG C-28 DEG C, leave standstill again insulation 6-7 hour, crystallization, filters, and drying obtains.
4. the composition of a rabeprazole sodium hydrate that contains rabeprazole sodium hydrate claimed in claim 1 and one or more pharmaceutically acceptable carrier compositions.
5. the composition of rabeprazole sodium hydrate claimed in claim 4, is characterized in that said composition is for the preparation of oral preparations.
6. the application of rabeprazole sodium hydrate in the medicine of manufacturing the digestive system such as treatment duodenal ulcer and stomach ulcer, reflux esophagitis described in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210528744.1A CN103864755A (en) | 2012-12-11 | 2012-12-11 | Rabeprazole sodium compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210528744.1A CN103864755A (en) | 2012-12-11 | 2012-12-11 | Rabeprazole sodium compound |
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| CN103864755A true CN103864755A (en) | 2014-06-18 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104693180A (en) * | 2015-03-02 | 2015-06-10 | 湖南如虹制药有限公司 | Sodium rabeprazole monohydrate crystal form and preparation method thereof |
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- 2012-12-11 CN CN201210528744.1A patent/CN103864755A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104693180A (en) * | 2015-03-02 | 2015-06-10 | 湖南如虹制药有限公司 | Sodium rabeprazole monohydrate crystal form and preparation method thereof |
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Application publication date: 20140618 |