CN102260244B - Stable rabeprazole sodium compound - Google Patents
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- CN102260244B CN102260244B CN 201110228091 CN201110228091A CN102260244B CN 102260244 B CN102260244 B CN 102260244B CN 201110228091 CN201110228091 CN 201110228091 CN 201110228091 A CN201110228091 A CN 201110228091A CN 102260244 B CN102260244 B CN 102260244B
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Abstract
The invention belongs to the technical field of medicines and particularly relates to a rabeprazole sodium compound and a preparation method thereof. Rabeprazole sodium provided by the invention contains less water and has the advantages of chemical purity up to 99.9%, maximum impurity content less than 0.1%, optical purity up to 99.96%ee and good stability. The compound provided by the invention has low production cost and stable quality, and is suitable for industrial production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to sodium rabeprazole compound and preparation method thereof.
Background technology
Hydrochloric acid in gastric juice can help digest, if but hyperchlorhydria can injure Stomach duodenum on the contrary.Work as gastroxia, the symptom of acid regurgitation, acid regurgitation, sour regurgitation can occur, except meeting causes Stomach duodenum ulcer, also can cause reflux esophagitis.The disease that Stomach duodenum ulcer right and wrong are usually seen such as untimely treatment, also can cause many serious complication, such as hemorrhage, pyloric obstruction, perforation, in addition canceration, threat to life.And reflux esophagitis also increases year by year at China's sickness rate.So the too much secretion of gastric acid inhibitory seems particularly important.Clinically, acid inhibitor commonly used has three kinds: antacid, proton pump inhibitor (PPIs) and H
2Receptor antagonist.
The appearance of proton pump inhibitor has promoted the development of gastroenterology, and a series of analysis-by-synthesis shows, no matter is to press down sour onset speed or pressing down on the effect of acid the antacid that proton pump inhibitor all is better than and H
2Receptor antagonist especially increases the curative effect of disease to reflux esophagitis, peptide ulceration and idiopathic gastric acid secretion more obvious
[3]So proton pump inhibitor is the choice drug of gastric acid secretion inhibiting clinically.First-generation proton pump inhibitor omeprazole, pantoprazole and lansoprazole, because there are certain limitation in its pharmacodynamics and pharmacokinetics aspect, affected its curative effect, slow such as onset time, need repeatedly take medicine just can reach maximum and press down sour effect, can not press down acid in 24 hours, have night acid rebound occur, promote the effect of ulcer healing and remission unstable, the interactional incidence of clinical medicine metabolic is more high.And by comparison, there is obvious advantage in rabeprazole pharmacodynamics pharmacokinetics, and its bioavailability is high, rapid-action, energy is comprehensive and the secretion of long-acting gastric acid inhibitory.In addition, rabeprazole can be non-competing ground, irreversibly suppress the urase of helicobacter pylori, reach the effect of anti-helicobacter pylori, and helicobacter pylori is one of principal element that causes Stomach duodenum ulcer
[3]
A large amount of clinical datas demonstrations, Sodium rabeprazole short-term and long-term prescription security are good.FDA relevant expert once estimated some documents, inferred that patient's life-time service PPIs of helicobacter pylori infection can not promote atrophic gastritis, intestinesization are living or the generation of cancer of the stomach
[4]And, to compare with in the past PPIs, life-time service Sodium rabeprazole treatment gastrinoma can not only more effective control hydrochloric acid in gastric juice level, can also prevent that its histology from further changing.The Sodium rabeprazole side effect is little, better tolerance, and relative side effect is headache, fash, diarrhoea and cold symptoms etc., but can tolerate.Go on the market in the time in more than ten years, the researchist constantly studies it, has fully verified its validity and security.It presses down sour effect and the anti-helicobacter pylori effect has surpassed in the past all proton pump inhibitors, and similar to latest generation proton pump inhibitor esomeprazole, but its price is lower than esomeprazole, is more suitable for the general patient medication.So we have reason to believe, Sodium rabeprazole will become the first-selected curative in the acid inhibitor, benefit extensive patients.
As everyone knows, because the disease clinical onset rate that gastroxia causes is very high, sickness rate just surpasses more than 10% among the Stomach duodenum ulcer crowd, people in the U.S. more than 44% has heartburn symptom (for the reflux esophagitis cardinal symptom), and reflux esophagitis is at China's sickness rate also cumulative year after year, so very large for the demand of acid inhibitor.
As the most promising antisecretory, the Sodium rabeprazole that existing market is sold exists enteric coated tablet and two kinds of formulations of enteric coated capsule simultaneously.Relative tablet, capsule has many advantages: (1) capsule shell can be covered the unpleasant odor of medicine; (2) capsule shell can completely cut off contacting of medicine and light, air and moisture, improves medicine stability; (3) preparation because of capsule does not generally add vehicle, and also plus-pressure not therefore disperse fast, good absorption than pill, tablet in stomach and intestine, can improve the bioavailability of medicine.
In the face of the more than one hundred million patient of China, the Sodium rabeprazole medicine of selling on the existing market can not satisfy the market requirement of expanding day.My researchist of company is through repeatedly experiment, filter out optimum pharmaceutical adjunct, on the basis of cost, also guaranteed quality, not only have the curative effect suitable with import drugs, the while reasonable price, especially need to be fit to the patient of long-term prescription, when meeting the need of market, also to have benefited extensive patients.
Sodium rabeprazole was developed by Japanese Eisai Co., Ltd, goes on the market at UK and USA respectively in 1998,1999 afterwards in Japanese Initial Public Offering in 1997, and China food and medicine Surveillance Authority ratified its import, trade(brand)name: Pariet in 2000.Sodium rabeprazole is proton pump inhibitor (PPIs), the secretion of energy establishment hydrochloric acid in gastric juice.Clinically be mainly used in treating Stomach duodenum ulcer, reflux esophagitis and Zhuo-Emhorn syndrome, common dose is 10mg and 20mg.
Sodium rabeprazole
Chemical name: the 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-1H-benzoglyoxaline sodium;
Molecular formula: C
18H
20N
3O
3SNa;
Molecular weight: 381.43;
Proterties: this product is white or off-white color particle and powder;
Structural formula:
The Sodium rabeprazole structural formula
The pharmacology type: Sodium rabeprazole is the potent inhibitor of benzimidazoles parietal cell most advanced and sophisticated secretion film endoplasm pump (being proton pump).
Mechanism of action: Sodium rabeprazole can suppress the H+-K+-ATP enzymic activity of parietal cell, thus the secretion of gastric acid inhibitory.
Indication: stomach ulcer, duodenal ulcer, stoma ulcer, reflux esophagitis, Zhuo-Emhorn (Zollinger-Ellison) syndrome.
Usage and dosage: usually, oral 1 Sodium rabeprazole meter 10mg every day that is grown up, but according to oral 1 20mg of the state of an illness also every day.In the ordinary course of things, be that be 6 weeks the course for the treatment of of 8 weeks, duodenal ulcer the course for the treatment of of stomach ulcer, stoma ulcer, reflux esophagitis.
Rabeprazole comprises left-handed and two kinds of optical isomers of dextrorotation, actual employed activeconstituents is the racemic mixture of two kinds of optical isomers, but experiment shows that the pharmacological action of rabeprazole dextrorotatory isomer will obviously be better than levoisomer and the little selected topic thereof, its dextrorotatory isomer subliminal dose is little than raceme, metabolic half life is long, can obviously improve the generation of curative effect and reduction toxic side effects.
Patent documentation about the Sodium rabeprazole preparation is many, such as US5045552, US20050234103, WO2006117802, US20080161579, WO2006024890, WO03101452 etc., all used sodium hydroxide and rabeprazole in alcohol or water, to react in these patents, generate Sodium rabeprazole, but all have some problems.
1) with aqueous sodium hydroxide solution and rabeprazole reaction, then adopt freeze drying process to obtain Sodium rabeprazole, such as patent WO03101452, this method exists facility investment large, and energy consumption is high, the weakness such as production cycle length.
2) with aqueous sodium hydroxide solution or alcoholic solution and rabeprazole reaction, then repeatedly concentrated, residue is used other solvent crystallizations again, gets Sodium rabeprazole, such as patent US5045552, US20050234103, US20080161579, WO2006024890.This method needs repeatedly concentrated, easily makes product decomposition, variable color; The concentrating residues thing is syrupy shape in addition, easily sticks to reactor vessel wall and stirs, and when using other solvent crystallizations, may occur that crystallization is incomplete, yield is low again, and energy consumption is high.
3) with aqueous sodium hydroxide solution and rabeprazole reaction, then use dichloromethane extraction, concentrate methylene dichloride, use the acetic acid ethyl dissolution enriched material, with inert solvent Sodium rabeprazole is separated out again, such as patent WO2006117802.Because the solubleness of Sodium rabeprazole in water is larger, when extraction, need to make system saturated with a large amount of sodium-chlor first, use again a large amount of dichloromethane extraction, so it is difficult to contain a large amount of sodium-chlor in the waste water, and same the existence needs concentrated problem.
In research process, repeat the method for above-mentioned patent documentation, the rabeprazole sodium impurity number that obtains is more, and total impurities is higher, and optical purity is low.The Sodium rabeprazole that the present invention obtains has advantages of: chemical purity is high, and maximum contaminant is less than 1 ‰, and optical purity is high; Good stability is especially to wet good stability.
Summary of the invention
One object of the present invention discloses a kind of sodium rabeprazole compound.
Another object of the present invention discloses the preparation method of sodium rabeprazole compound.
Another purpose of the present invention discloses the pharmaceutical composition that comprises sodium rabeprazole compound.
Now in conjunction with purpose of the present invention content of the present invention is specifically described.
The invention provides a kind of sodium rabeprazole compound (shown in the formula I),
（Ⅰ）
Karl Fischer method (Karl Fischer method) is in a kind of all kinds of chemical processes of measuring moisture in the 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, organic compound especially, reliable results.Through 6 batches of mensuration, its moisture is less than 1 ‰:
| Batch | Moisture (‰) | Batch | Moisture (‰) |
| 1 | 0.15 | 4 | 0.19 |
| 2 | 0.21 | 5 | 0.20 |
| 3 | 0.18 | 6 | 0.13 |
This sodium rabeprazole compound crystal 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) and D value are as follows,
| Peak number | 2 θ angles (°) measured value | D() measured value | I/I 0 |
| 1 | 4.920 | 17.9461 | 100 |
| 2 | 9.900 | 8.9270 | 38 |
| 3 | 11.700 | 7.5574 | 2 |
| 4 | 12.420 | 7.1208 | 1 |
| 5 | 14.920 | 5.9328 | 27 |
| 6 | 16.160 | 5.4803 | 2 |
| 7 | 18.280 | 4.8492 | 2 |
| 8 | 19.500 | 4.5485 | 80 |
| 9 | 20.880 | 4.2509 | 4 |
| 10 | 22.640 | 3.9242 | 2 |
| 11 | 23.360 | 3.8049 | 6 |
| 12 | 24.340 | 3.6539 | 4 |
| 13 | 24.740 | 3.5957 | 4 |
| 14 | 25.120 | 3.5421 | 3 |
| 15 | 26.240 | 3.3934 | 4 |
| 16 | 26.580 | 3.3508 | 4 |
| 17 | 27.980 | 3.1862 | 3 |
| 18 | 29.000 | 3.0764 | 3 |
| 19 | 30.220 | 2.9550 | 7 |
| 20 | 30.440 | 2.9341 | 5 |
See Fig. 1.
?[0025]?
The mensuration of 2 θ values is used light source among the present invention, and precision is ± 0.2 °, therefore represents above-mentioned value of getting and has allowed certain reasonably limit of error, and its limit of error is ± 0.2 °.
The fusing point of this crystal formation is 242 ℃-242.5 ℃, presses the method for Chinese Pharmacopoeia and measures, and this is that those skilled in the art are in common knowledge.
Another object of the present invention discloses the preparation method of sodium rabeprazole compound crystal,
Specifically comprise the following steps:
1) Sodium rabeprazole adds 5-10 doubly in (weight or measurement (WM) ratio) water, adds the dimethyl formamide (DMF) of Sodium rabeprazole 0.5%-1% in the above-mentioned aqueous solution, stirred 30 minutes, and filtration, filtrate is cooled to 5 ℃-10 ℃, and is for subsequent use;
2) mixed solution with Sodium rabeprazole 18-20 times acetonitrile-methyl ethyl ketone=5:3 is cooled to 5 ℃-10 ℃, adds above-mentioned stock solution, is incubated 15-20 hour, and crystallization filters, and drying obtains.Chemical purity is up to 99.9%, and maximum contaminant is less than 1 ‰, and optical purity is up to more than the 99.9%ee.
Among the above-mentioned preparation method, Sodium rabeprazole moisture is low, and good stability can guarantee the quality of pharmaceutical preparation.
The chemical structure of used Sodium rabeprazole proves that through determination of elemental analysis chemical structure is correct.
Another purpose of the present invention provides the composition that comprises the sodium rabeprazole compound that the pharmaceutically acceptable carrier of sodium rabeprazole compound crystal and one or more forms.
Pharmaceutical composition of the present invention is prepared as follows: Application 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, injection.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (the compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, the amount of used compound or concentration are regulated in a wider scope, and the weight range of active compound is 1%～30%(weight of composition).
Stability test
The contriver is studied the stability of crystal formation of the present invention, and the investigation condition is high temperature (60 ℃ ± 2 ℃), (4500Lx ± 500lx), (92.5%, RH) investigate index is outward appearance to high humidity to strong illumination, content and related substance.
The result: under high light, high temperature, super-humid conditions from 0-15 days, outward appearance, related substance, content do not change, and illustrates that chemical stability is good, manufacturing and the standing storage of suitable pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), the mensuration of moisture in the sodium rabeprazole compound crystal:
The result: at 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), it is constant that moisture keeps, and explanation has good stability, and is fit to manufacturing and the standing storage of pharmaceutical preparation.
Figure of description:
Fig. 1, the X-ray diffractogram of sodium rabeprazole compound crystal;
Embodiment:
The present invention is described further below in conjunction with embodiment, makes this area professional and technical personnel better understand the present invention.Embodiment only is indicative, means that never it limits the scope of the invention by any way.
Used Sodium rabeprazole purity 98.3% (HPLC normalization method) among the present invention, optical purity 99.1%ee, its chemical structure proves that through determination of elemental analysis chemical structure is correct.
Results of elemental analyses:
Measured value (calculated value), C:56.68 (56.68), H:5.29 (5.30), N:11.02 (11.00),
O:12.58(12.59)?,?S:8.41(8.40)；
The proof chemical structure is correct.
Embodiment 1
In the 500ml reaction flask of stirring, thermometer, condenser is housed, add 60 gram Sodium rabeprazole and 300 ml waters, in the above-mentioned aqueous solution, add 0.5 gram dimethyl formamide (DMF), stirred 30 minutes, to filter, filtrate is cooled to 12 ℃, and is for subsequent use.
The mixed solution of 1150ml acetonitrile-methyl ethyl ketone=5:5 is cooled to 13 ℃, stirs the lower above-mentioned stock solution that adds, be incubated 18 hours, crystallization filters, and drying obtains white crystals 53.3 and restrains.Measure 3 times through the karl Fischer method, get average, contain the moisture of 2.40% (weight percent).Purity 99.9% (HPLC normalization method), optical purity 99.96%ee (chirality HPLC).
Results of elemental analyses:
Measured value (calculated value), C:56.68 (56.68), H:5.29 (5.29), N:11.02 (11.01),
O:12.58(12.60)?,?S:8.41(8.40)。
The X-ray diffractogram of this crystallization is seen Fig. 1.Instrument model and condition determination: Rigaku D/max 2500 type diffractometers; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°
Embodiment 2
Contain the sodium rabeprazole compound capsule
Prescription: sodium rabeprazole compound 20 grams, N.F,USP MANNITOL 100 grams, lactose 140 grams, calcium carbonate 50 grams, Magnesium Stearate 5 grams, 8% ethyl cellulose solution is an amount of, and 1000 of enteric coated capsulees are made 1000.
Technique: get sodium rabeprazole compound, N.F,USP MANNITOL, lactose, calcium carbonate and mix; Add suitable amount of adhesive 8% ethyl cellulose solution softwood processed, 20 eye mesh screens are granulated, 40 ℃ ± 2 ℃ oven dry, and whole grain is mixed Magnesium Stearate outside adding and is mixed, the dress capsule, and get final product.
Claims (4)
1. the crystal of the sodium rabeprazole compound shown in the formula I,
The crystal of described sodium rabeprazole compound, as in the characteristic X-ray powder mensuration, its collection of illustrative plates has following 2 θ diffraction angle and d value with the CuKa ray,
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of the described sodium rabeprazole compound crystal of claim 1 comprises the steps:
1) Sodium rabeprazole adds 5-10 doubly in (weight or measurement (WM) ratio) water, adds the dimethyl formamide (DMF) of Sodium rabeprazole 0.5%-1% in the above-mentioned aqueous solution, stirred 30 minutes, and filtration, filtrate is cooled to 5 ℃-10 ℃, and is for subsequent use;
2) mixed solution with Sodium rabeprazole 18-20 times acetonitrile-methyl ethyl ketone=5:3 is cooled to 5 ℃-10 ℃, add above-mentioned stock solution, be incubated 15-20 hour, crystallization, filter, drying obtains, and chemical purity is up to 99.9%, maximum contaminant is less than 1 ‰, and optical purity is up to more than the 99.9%ee.
3. the composition of the sodium rabeprazole compound that forms of the pharmaceutically acceptable carrier of described sodium rabeprazole compound crystal and one or more according to claim 1.
4. composition according to claim 3 is characterized in that said composition is for the preparation of solid preparation, injection.
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| CN103709141A (en) * | 2013-10-14 | 2014-04-09 | 寿光富康制药有限公司 | Crystal forms and amorphous forms of rabeprazole sodium |
| CN104072482A (en) * | 2014-06-17 | 2014-10-01 | 江苏奥赛康药业股份有限公司 | Rabeprazole sodium compound and pharmaceutical composition thereof |
| 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 |
| CN113336741B (en) * | 2021-05-07 | 2022-06-24 | 湖南德虹制药有限公司 | Rabeprazole sodium anhydride crystal form and preparation method thereof |
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| CN101704811B (en) * | 2009-12-09 | 2012-05-09 | 陶灵刚 | High-purity sodium rabeprazole compound |
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Effective date of registration: 20180921 Address after: 300409 88 Huashi Road, Beichen science and Technology Park, Tianjin Patentee after: TIANJIN HANRUI PHARMACEUTICAL CO., LTD. Address before: 300203 Tianjin Hexi District Dagu South Road 4, 3 Patentee before: Tianjin Hankang Pharmaceutical Biotechnology Co., Ltd. |