CN105294652A - Rabeprazole sodium compound - Google Patents
Rabeprazole sodium compound Download PDFInfo
- Publication number
- CN105294652A CN105294652A CN201510749680.1A CN201510749680A CN105294652A CN 105294652 A CN105294652 A CN 105294652A CN 201510749680 A CN201510749680 A CN 201510749680A CN 105294652 A CN105294652 A CN 105294652A
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- CN
- China
- Prior art keywords
- rabeprazole
- hydrate
- sodium
- rabeprazole sodium
- sodium hydrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
-
- 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 the technical field of medicine and particularly relates to rabeprazole sodium sesqui-hydrate and a preparation method thereof. The obtained rabeprazole sodium sesqui-hydrate contains sesqui-crystal-water and has the advantages of being high in purity and good in stability and moisture absorption and weight gain even under the condition of high humidity are not obvious; by means of the rabeprazole sodium sesqui-hydrate, the gastric acid secretion inhibition effect is raised by approximately 20%. The invention further relates to the application of a compound using the hydrate for treating digestive system diseases such as duodenal ulcer, gastric ulcer and reflux esophagitis.
Description
The divisional application that the application is the applying date is on October 25th, 2012, application number is 201210411785.2, denomination of invention is the application for a patent for invention of " sodium rabeprazole compound ".
Technical field
The invention belongs to medical art, be specifically related to rabeprazole sodium hydrate and preparation method thereof, the invention still further relates to the application of composition treatment duodenal ulcer and the digestive system such as stomach ulcer, reflux esophagitis using this hydrate.
Background technology
Along with the progress of society, 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 human morbidity's 10%-12% 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 and proton pump inhibitor are the most frequently used 2 kinds of medicines of the relevant digestion disease of therapic acid, they all raise stomach pH, 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 (PPI) of effectively treating this type of disease is also being increased year by year.
Sodium rabeprazole (rabeprazolesodium), is a kind of novel proton pump inhibitor class medicine 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 third oxygen)-3-picoline-2-base] methylsulfinyl]-1H benzoglyoxaline sodium salt,
Molecular formula: C
18h
20n
3naO
3s
Molecular weight: 381.42
This product is fine white powder shape, 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 developed after lansoprazole and pantoprazole.Compared with omeprazole, rabeprazole suppresses the effect of H+/K+-ATP enzyme stronger, and suppresses to recover; Have selectivity strongly inhibited helicobacter pylori (HP) effect, in addition, this medicine is in vivo without Accumulation Phenomenon.Clinically be used for the treatment of duodenal ulcer and the digestive system such as stomach ulcer, reflux esophagitis.This product is rapid-action, acid suppression is effective, can continue acid suppression, relief of symptoms by 24h.The specification of this medicine has every sheet 10mg, and adult human dose is 10mg, qd, and when 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 makes its sodium salt can effectively reduce impurity, purified product, but impurity is still higher, also has certain moisture absorption weightening finish.
The Sodium rabeprazole times semihydrate that the present invention obtains on the basis of great many of experiments, the advantage had: purity is high, maximum contaminant is less than 1 ‰; Good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions.
Allow people surprisingly, identical prescription and technique, wait Sodium rabeprazole times semihydrate tablet and the rabeprazole sodium tablet of dosage (Sodium rabeprazole times semihydrate is converted into Sodium rabeprazole), to the restraining effect of gastric acid secretion, the former exceeds the latter about 20%.
Summary of the invention
One object of the present invention, discloses a kind of Sodium rabeprazole times semihydrate.
Another object of the present invention, discloses the preparation method of Sodium rabeprazole times semihydrate.
Another object of the present invention, discloses the pharmaceutical composition comprising Sodium rabeprazole times semihydrate.
The invention also discloses Sodium rabeprazole times semihydrate and prepare treatment use.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of Sodium rabeprazole times semihydrate (shown in formula I),
（I）
Karl_Fischer method (KarlFischer method) a kind ofly measures in all kinds of chemical processes of moisture in material, and, method the most accurately 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 6.50%-6.72% (weight percent).In Sodium rabeprazole times semihydrate, the theoretical content of water is 6.61%, can assert that invention compound contains a hypocrystalline water.
Wherein the measurement result of 6 batches is as follows:
This Sodium rabeprazole times semihydrate, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: CuKa 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.
。
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, 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 recorded is 122.3 DEG C-123.2 DEG C.
Another object of the present invention, discloses the preparation method of Sodium rabeprazole times semihydrate, by being dissolved at Virahol-piperidines-heated in water solution by Sodium rabeprazole, 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 29 DEG C-33 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
A large amount of experiments proves: the adding of piperidines, the proportioning of mixed solution, standing temperature and time are most important to obtaining Sodium rabeprazole of the present invention times semihydrate.
Sodium rabeprazole used can pass through Chinese patent (application number 87107777), US5045552, or EP1818331A1, EP268956 are convenient obtained, also can buy and obtain.
Another object of the present invention, provides the composition comprising the rabeprazole sodium hydrate that rabeprazole sodium hydrate and one or more pharmaceutically acceptable carriers form.
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 be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.
Allow people surprisingly, identical prescription and technique, wait Sodium rabeprazole times semihydrate tablet and the rabeprazole sodium tablet of dosage (Sodium rabeprazole times semihydrate is converted into Sodium rabeprazole), to the restraining effect of gastric acid secretion, the former exceeds the latter about 20%.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 30%(weight of composition).
Present invention also offers the application of rabeprazole sodium hydrate in the medicine manufacturing treatment duodenal ulcer and the digestive system such as stomach ulcer, reflux esophagitis.
to the inhibition of gastric acid secretion
Adopt Beagle dog, the gastric acid secretion of every dog is injected 100 microgram histamine by per kilogram stimulated by per hour.After histamine injects one hour, give Sodium rabeprazole times semihydrate tablet and rabeprazole sodium tablet (prescription is identical with technique), both wait dosage (a Sodium rabeprazole times semihydrate is converted into Sodium rabeprazole), carry out intraduodenal administration to dog.Administration, after one hour, measures the gastric acid output of every dog.Result is compared with blank group, and represents with inhibition percentage.The ID50 value obtained by dosage-suppression curve is 50.2 micro-gs/kg and 60.9 micro-gs/kg respectively.Show that the inhibition of Sodium rabeprazole times semihydrate to gastric acid secretion is better than Sodium rabeprazole.
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%), water tariff collection is constant, 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 to increase weight, to moist lability.
figure of description:
Fig. 1, the X-ray diffractogram of Sodium rabeprazole times semihydrate;
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, fusing point 139 DEG C-140.2 DEG C, purity 98.1% (HPLC normalization method), through proton nmr spectra, ultimate analysis confirmation, its chemical structure proves that chemical structure is correct.
After being dried to constant weight, the moisture recorded with 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 30 DEG C-32 DEG C, then leaves standstill insulation 4 hours, crystallization, filter, through indoor seasoning, obtain Sodium rabeprazole times semihydrate white crystals 230.6 grams, fusing point is the fusing point recorded is 122.3 DEG C-123.2 DEG C, content 99.76%, single contaminant is less than 0.06%.Measure through Karl_Fischer method, the moisture containing 6.57% (weight percent).
The X-ray diffractogram of this crystallization is shown in Fig. 1.INSTRUMENT MODEL and condition determination: Rigaku D/max2500 type diffractometer; CuKa40Kv100mA; 2 θ sweep limit: 0-50
°.
Use standard and conventional technology, make the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics be combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.Only citing is illustrated, and never means that it limits the scope of the invention by any way.
embodiment 2
Tablet containing Sodium rabeprazole times semihydrate
Prescription: Sodium rabeprazole times semihydrate 10.7 grams, Microcrystalline Cellulose 12g, pregelatinized Starch 16g, carboxymethylstach sodium 5g, lactose 210 grams, 25 grams of PEG-4000, Magnesium Stearate 6 grams, 30 grams of PVP K30s, croscarmellose sodium 33 grams, distilled water is appropriate, makes 10000.
Technique:
The preparation of label: mixed with auxiliary material by main ingredient by determined prescription, granulate, particle air seasoning below 40 DEG C, with the whole grain of l6 mesh sieve, adds Magnesium Stearate and remaining starch, compressing tablet, to obtain final product.
Sealing coat dressing: added by talcum powder in 5% polyvinylpyrrolidone (PVP) anhydrous alcohol solution, stir, is mixed with the suspension of 20% as sealing coat coating liquid.In fluidized-bed, carry out dressing, its processing condition are as follows: spray pressure 0.3MPa, feed liquor speed 5mL/min, inlet temperature 37 DEG C, temperature out 31 DEG C, dry air flow 200m
3/ h, sealing coat weightening finish for essence blade heavy 9%.
Enteric layers dressing: No. II resin is dissolved in dehydrated alcohol, clothing liquid concentration is 10% (w/v), its processing condition except spray speed be except 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）
Measure with Karl_Fischer method, described hydrate contains the moisture of weight percent 6.50%-6.72%;
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 being dissolved at Virahol-piperidines-heated in water solution by Sodium rabeprazole, naturally cools to room temperature, then is incubated for some time and obtains.
3. method according to 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 29 DEG C-33 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
4. the composition of the rabeprazole sodium hydrate formed containing rabeprazole sodium hydrate according to claim 1 and one or more pharmaceutically acceptable carriers.
5. the composition of rabeprazole sodium hydrate according to claim 4, is characterized in that said composition is for the preparation of oral preparations.
6. the application of rabeprazole sodium hydrate described in claim 1 in the medicine manufacturing treatment duodenal ulcer and the digestive system such as stomach ulcer, reflux esophagitis.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210411785.2A CN103772355B (en) | 2012-10-25 | 2012-10-25 | Sodium rabeprazole compound |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210411785.2A Division CN103772355B (en) | 2012-10-25 | 2012-10-25 | Sodium rabeprazole compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105294652A true CN105294652A (en) | 2016-02-03 |
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ID=50565173
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510749680.1A Pending CN105294652A (en) | 2012-10-25 | 2012-10-25 | Rabeprazole sodium compound |
| CN201210411785.2A Active CN103772355B (en) | 2012-10-25 | 2012-10-25 | Sodium rabeprazole compound |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN201210411785.2A Active CN103772355B (en) | 2012-10-25 | 2012-10-25 | Sodium rabeprazole compound |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109111429A (en) * | 2017-06-23 | 2019-01-01 | 南京海润医药有限公司 | Dextral-rabeprazole sodium compound and its pharmaceutical composition |
| CN109111428A (en) * | 2017-06-23 | 2019-01-01 | 南京海润医药有限公司 | A kind of dextral-rabeprazole sodium compound and its pharmaceutical composition |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006024890A1 (en) * | 2004-08-30 | 2006-03-09 | Apollo International Limited | Improved process for rabeprazole sodium in amorphous form |
| EP1674463A1 (en) * | 2004-12-21 | 2006-06-28 | Dipharma S.p.A. | Rabeprazole sodium salt in crystalline hydrate form |
| WO2007091276A2 (en) * | 2006-02-10 | 2007-08-16 | Rajasthan Antibiotic Limited | Novel crystal form of omeprazol sodium |
| EP1935891A1 (en) * | 2006-12-19 | 2008-06-25 | Dipharma Francis S.r.l. | Crystalline forms of rabeprazole sodium |
| WO2008152462A1 (en) * | 2007-06-15 | 2008-12-18 | Emcure Pharmaceuticals Limited | A process of sulfoxidation of biologically active compounds |
| WO2009116072A2 (en) * | 2008-02-08 | 2009-09-24 | Ipca Laboratories Limited | Process for preparation of pyridinylmethylsulphinyl benzimidazole compounds and pyridine intermediates |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101580502A (en) * | 2009-06-30 | 2009-11-18 | 常州康丽制药有限公司 | Method for preparing Rabeprazole sodium |
| CN101704811B (en) * | 2009-12-09 | 2012-05-09 | 陶灵刚 | High-purity sodium rabeprazole compound |
-
2012
- 2012-10-25 CN CN201510749680.1A patent/CN105294652A/en active Pending
- 2012-10-25 CN CN201210411785.2A patent/CN103772355B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006024890A1 (en) * | 2004-08-30 | 2006-03-09 | Apollo International Limited | Improved process for rabeprazole sodium in amorphous form |
| EP1674463A1 (en) * | 2004-12-21 | 2006-06-28 | Dipharma S.p.A. | Rabeprazole sodium salt in crystalline hydrate form |
| WO2007091276A2 (en) * | 2006-02-10 | 2007-08-16 | Rajasthan Antibiotic Limited | Novel crystal form of omeprazol sodium |
| EP1935891A1 (en) * | 2006-12-19 | 2008-06-25 | Dipharma Francis S.r.l. | Crystalline forms of rabeprazole sodium |
| WO2008152462A1 (en) * | 2007-06-15 | 2008-12-18 | Emcure Pharmaceuticals Limited | A process of sulfoxidation of biologically active compounds |
| WO2009116072A2 (en) * | 2008-02-08 | 2009-09-24 | Ipca Laboratories Limited | Process for preparation of pyridinylmethylsulphinyl benzimidazole compounds and pyridine intermediates |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103772355A (en) | 2014-05-07 |
| CN103772355B (en) | 2016-03-02 |
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