CN106957302A - A kind of method of RABEPRAZOLE SODIUM prepared by super-critical anti-solvent technology - Google Patents
A kind of method of RABEPRAZOLE SODIUM prepared by super-critical anti-solvent technology Download PDFInfo
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- CN106957302A CN106957302A CN201710235111.4A CN201710235111A CN106957302A CN 106957302 A CN106957302 A CN 106957302A CN 201710235111 A CN201710235111 A CN 201710235111A CN 106957302 A CN106957302 A CN 106957302A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Abstract
A kind of method of the RABEPRAZOLE SODIUM prepared the invention discloses super-critical anti-solvent technology, the obtained finished product RABEPRAZOLE SODIUM of the present invention.Preparation method of the present invention is different from traditional preparation technology, super-critical anti-solvent technology of employing new technology prepares RABEPRAZOLE SODIUM, technique is simple, mild condition, favorable reproducibility, products obtained therefrom crystal formation particle diameter is smaller and narrower particle size distribution, and solubility is higher, it is to avoid (crystallization is difficult for traditional solvent crystal drawback, the shortcomings of easily forming grease), prepared product purity is high, and no solvent residue will not produce any pollution.
Description
Technical field
The invention belongs to technical field of medicine synthesis, Rabeprazole prepared by more particularly to a kind of super-critical anti-solvent technology
The method of sodium.
Background technology
RABEPRAZOLE SODIUM, its chemical entitled 2- { 4- (3- methoxy propoxies) -3- picoline -2- base first sulfenyl
Base } -1H- benzimidazole sodium, belong to the medicine for suppressing secretion, be the substitute of benzimidazole, no anticholinergic and anti-H2Histamine
Characteristic, but parietal cell surface is can adhere to by suppressing H+/K+- ATP enzyme carrys out the secretion of gastric acid inhibitory.This enzyme system is counted as
It is sour proton pump, therefore RABEPRAZOLE SODIUM blocks the generation of hydrochloric acid in gastric juice as the proton pump inhibitor in stomach, this effect is that dosage is related
Property.Animal experiment confirms that RABEPRAZOLE SODIUM can be discharged from blood plasma and gastric mucosa soon after medication.
RABEPRAZOLE SODIUM is a kind of new proton pump inhibitor, can in treatment acid-related disease, such as peptic ulcer,
GORD, Zhuo-Ellison syndrome etc..H2Receptor antagonist and proton pump inhibitor are the related digestibilities of therapic acid
2 kinds of the most frequently used medicines of disease, they raise stomach pH, but proton pump inhibitor acts on H+/K+-ATP enzymes, strong inhibition stomach
Acid secretion, and stomach pH is produced larger and lasting rise, RABEPRAZOLE SODIUM is newest proton pump inhibitor, its anti-hydrochloric acid in gastric juice point
Secrete activity and be more than original proton pump inhibitor Omeprazole.
Compared with Omeprazole, Rabeprazole suppression H+/K+-ATP enzyme effects are stronger, and suppress to recover；To blood plasma
Gastrin Levels influence is less；With the effect of selective strong inhibition helicobacter pylori (HP).Intersect in a double blinding of Switzerland
In experiment, asymptomatic patient negative HP receives placebo, RABEPRAZOLE SODIUM 20mg, Omeprazole (many unitary tablet bodies respectively
System) 20mg, omeprazole capsule 20mg or Lansoprazole 30mg treatment.D1 is treated, the curative effect of RABEPRAZOLE SODIUM group is substantially good
In other test groups, its pH median is about 3.5.Show that compared with other proton pump inhibitors, Rabeprazole is in medication 24h
Show significant acid suppression effect.In a research of Japan, receive RABEPRAZOLE SODIUM 10mg (n=48) akg20mg (n=
27), other matter pump inhibitor (n=31) or H2Blocker treatment Peptic Ulcers, it is each after comparing medication 1 week
The remission status of group.As a result show, after treatment 3d, RABEPRAZOLE SODIUM is compared with other proton pump inhibitors or H2 receptor blockings
Agent, there is more significant relief of symptoms ability.To 137 Peptic Ulcers (wherein duodenal bulbar ulcer patient 102
Example, patients w ith peptic ulcer disease 35) clinical test is carried out using random open counter point.Be divided into RABEPRAZOLE SODIUM group 10mg, po, qd and
Omeprazole group 20mg, po, qd.Treatment time duodenal bulbar ulcer is 4 weeks, and gastric ulcer is 6 weeks.As a result show：To ten
Two duodenum 12 bulbs rush ulcer and patients w ith peptic ulcer disease, after this product treatment pain symptom be obviously improved and pain time disappearance, with Aomei
Azoles group is drawn to compare no difference of science of statistics.In whole experiment, 3 there is adverse reaction in RABEPRAZOLE SODIUM group, and adverse reaction rate is
4.29%, Omeprazole group adverse reaction rate is 4.48%.The adverse reaction of this product is slight, and patient does not move back because of adverse reaction
Go out experiment.In addition, this medicine is in vivo without Accumulation Phenomenon.Chemical structural formula is：
The content of the invention
Current RABEPRAZOLE SODIUM preparation method mainly has two methods, and one kind is solvent crystallization method, and one kind is lyophilized crystallization
Method.What lyophilized crystallization method was obtained is amorphous article, and impurity, which is wrapped in product, causes that product purity is low, stability is poor.So state
The solvent crystallization for being all in inside and outside most of document report and enterprise practical production prepares RABEPRAZOLE SODIUM.Again because thunder shellfish
Drawing azoles sodium solution viscosity is big, RABEPRAZOLE SODIUM is easily degraded, so causing the crystallization technique of RABEPRAZOLE SODIUM unstable, it is easy to
There are various problems, such as separate out grease, not crystallization or crystallization not exclusively, the problems such as crystal of precipitation redissolves again.It is directed to
Above-mentioned problem, it has been found that a kind of RABEPRAZOLE SODIUM method prepared by super-critical anti-solvent technology.
A Supercritical Anti-solvent Process is exactly overcritical particulate preparation method propose in recent years and very promising
One of.Although proposing to have the history in more than 20 years so far first, until in recent years, just by the common concern of researcher.
Requirement more and more higher especially as chemical material, energy raw material and medicine to the crystal formation of particulate, granularity and size distribution is super to face
Boundary's anti-solvent process exactly provides wide development space for this.Because the diffusion rate of supercritical fluid is higher than liquid two
The order of magnitude, he is diffused into after solution rapid generation degree of supersaturation and crystallizes out small particles.With traditional mechanical crushing or grinding
Particulate manufacturing process is compared, and A Supercritical Anti-solvent Process preparation condition is gentle, the good, granularity of product pellet flowing property is controllable.Can be with
Improve the availability of medicine, and make drug microparticles that there is good transport properties, and the number that balances each other of most of solvent systems
According to that can look into, make it that there is good application prospect in medical industry.
The principle of A Supercritical Anti-solvent Process is：The solid solute that superfine powder will be made is dissolved in a certain solvent and forms molten
Liquid, selects a kind of supercritical fluid to be used as anti-solvent.This anti-solvent is typically unable to the solute in solvent soln, but can with it is molten
Agent is dissolved each other, and when anti-solvent is contacted with solution, anti-solvent diffuses to rapidly the solution, makes its rapid spatial expansion, solute is molten
Solubility is greatly reduced in agent, and very big degree of supersaturation is formed within the extremely short time, promotes solute crystallization rapid.The process wink
Between complete, form that purity is high, the uniform ultrafine dust of particle diameter distribution.Solvent resistant selects critical-temperature and the low stream of critical pressure
Body, so as to reduce operation temperature and pressure, reduces the requirement to equipment, improves processing safety.It is therefore highly preferred that critical-temperature
31.1 DEG C are used as solvent resistant with the carbon dioxide of 7.2 MPas of critical pressure.Carbon dioxide is soluble in many under compression to be had
Machine solvent, thus greatly expand solvent range of choice.And because carbon dioxide is nontoxic, it is nonflammable, it is readily available, price is low
Honest and clean the features such as and be used widely.A Supercritical Anti-solvent Process operating condition is gentle, close to normal temperature, it is adaptable to thermal sensitivity,
Be afraid of shock, the micronizing of the biologically active drug of malleable and the preparation for controlling sustained-release micro-spheres, this is that many micro mist methods can not
Accomplish.In addition, the superfine powder that particle diameter is small and is evenly distributed can be obtained by the process, and the particle of preparation can be entered
The control of row setting sizing.Prepared product purity is high, and no solvent residue will not produce any pollution, equally without carrying out
Post processing.
Present invention aims at there is provided a kind of preparation method of new RABEPRAZOLE SODIUM, institute in view of the shortcomings of the prior art
The method of preparation comprises the following steps：
A, Rabeprazole is dissolved in methanol, ethanol or acetone, wiring solution-forming A；
B, 10-30% sodium hydroxide solution B added in solution A, stirred 10-30 minute, addition activated carbon decolorizing 30
Minute, filtering, filtrate is standby；
C, using supercritical carbon dioxide as anti-solvent, 35-40 DEG C of sedimentation kettle temperature degree is set, settling pressure in 80-120bar,
Rabeprazole sodium solution sample introduction flow velocity is 0.25-2.0ml/min, and RABEPRAZOLE SODIUM solution concentration is 0.25-5mg/ml, works as system
During in stable state, Rabeprazole sodium solution is entered sedimentation kettle by nozzle, sample introduction is finished, thunder shellfish is obtained in sedimentation kettle
Draw azoles sodium novel crystal form.
Preferably, the Rabeprazole sodium crystal that prepared by this method is corynebacterium, is obtained using Cu-K alpha ray measurements
X-ray powder diffraction spectrogram as shown in figure 1, its X-ray powder diffraction figure represented with the 2 θ ± 0.2 ° angles of diffraction exists
10.17°、13.02°、13.50°、15.06°、18.35°、20.30°、24.52°、25.38°、27.65°、29.70°、30.30°、
Characteristic diffraction peak is shown at 31.50 °, 31.68 °, 32.55 °, 35.61 ° and 39.40 °, the granularity D0.9 of the crystal formation is in 50 μ
Below m, particle size range is at 20-50 μm.
Preferably, described in step a, RABEPRAZOLE SODIUM solution concentration is 2.5-50mg/ml.
Preferably, described in step b, stream of supercritical carbon dioxide speed is 15g/min-25g/min；The Rabeprazole
Sodium solution sample introduction flow velocity is 0.25-2.0ml/min.
Preferably, described in step c, sample introduction continues to be passed through carbon dioxide 40-50min after finishing.
Compared to prior art, the beneficial effects of the present invention are：
(1) preparation method easily occurs separating out grease, not crystallization or crystallization mistake during avoiding tradition crystallization
The problems such as journey is unstable.
(2) A Supercritical Anti-solvent Process operating condition it is gentle, close to normal temperature.Present invention process is simple, and course of reaction is held
Easy to operate, product yield and purity are high, and accessory substance is less, are adapted to industrialized production.
(3) carbon dioxide is used as solvent resistant, because its is nontoxic, avoids using substantial amounts of organic solvent again, it is solvent-free residual
Stay, drug safety is protected, any environmental pollution will not be produced without carrying out post processing；Carbon dioxide is cheap, hold
Easily obtain, cost of drugs can be saved；Carbon dioxide is soluble in many organic solvents under compression, thus greatly expands
Dissolution solvent range of choice.
(4) superfine powder that particle diameter is small and is evenly distributed can be obtained by the process, and the particle of preparation can be entered
The control of row setting sizing, the good, granularity of product pellet flowing property is controllable.This be many micro mist methods too far behind to catch up, the mistake
Journey can improve the availability of medicine, and drug microparticles is had good mobility.
Brief description of the drawings
The X-ray powder diffraction collection for the RABEPRAZOLE SODIUM that Fig. 1 is prepared for the present invention；
The TG-DSC collection of illustrative plates of RABEPRAZOLE SODIUM prepared by Fig. 2 present invention；
The crystallographic microscope figure of RABEPRAZOLE SODIUM prepared by Fig. 3 present invention；
The granularity Detection report of RABEPRAZOLE SODIUM prepared by Fig. 4 present invention.
Embodiment
The content of the invention of the present invention is described in further detail below by specific embodiment, but therefore not limited
Determine present disclosure.
The preparation of the RABEPRAZOLE SODIUM of embodiment 1
Rabeprazole 100g is added in reaction vessel, 40L methanol stirring and dissolvings, wiring solution-forming A is added.Add 10%
Sodium hydroxide solution 111.29g, is stirred 30 minutes, is added activated carbon 10g and is decolourized 30 minutes, filtering, filtrate is standby；
By high pressure sedimentation kettle temperature degree be set to 40 DEG C, pressure is 80bar, open steel cylinder, with high-pressure pump by carbon dioxide with
The top of 15g/min flow velocity from sedimentation kettle is passed through, and when temperature, pressure reach above-mentioned setting value in question response kettle, uses another
High-pressure pump by methanol with 0.25ml/min speed by settling kettle, after 15 minutes, system reaches poised state in reactor, stops
Methanol is only passed through, the Rabeprazole sodium solution of above-mentioned preparation is passed through at the same rate, after finishing, continues to be passed through carbon dioxide
40min, stops carbon dioxide pump, and sedimentation kettle pressure is reduced to after atmospheric pressure and taken out, and compound is obtained in sedimentation bottom portion.
The preparation of the RABEPRAZOLE SODIUM of embodiment 2
Rabeprazole 100g is added in reaction vessel, 4L ethanol stirring and dissolvings, wiring solution-forming A is added.Add 10%
Sodium hydroxide solution 55.65g, is stirred 30 minutes, is added activated carbon 10g and is decolourized 30 minutes, filtering, filtrate is standby；
By high pressure sedimentation kettle temperature degree be set to 35 DEG C, pressure is 90bar, open steel cylinder, with high-pressure pump by carbon dioxide with
The top of 25g/min flow velocity from sedimentation kettle is passed through, and when temperature, pressure reach above-mentioned setting value in question response kettle, uses another
High-pressure pump by ethanol with 1.0ml/min speed by settling kettle, after 15 minutes, system reaches poised state in reactor, stops
Ethanol is only passed through, the Rabeprazole sodium solution of above-mentioned preparation is passed through at the same rate, after finishing, continues to be passed through carbon dioxide
45min, stops carbon dioxide pump, and sedimentation kettle pressure is reduced to after atmospheric pressure and taken out, and compound is obtained in sedimentation bottom portion.
The preparation of the RABEPRAZOLE SODIUM of embodiment 3
Rabeprazole 100g is added in reaction vessel, 2L acetone stirring and dissolvings, wiring solution-forming A is added.Add 30%
Sodium hydroxide solution 37.10g, is stirred 30 minutes, is added activated carbon 10g and is decolourized 30 minutes, filtering, filtrate is standby；
By high pressure sedimentation kettle temperature degree be set to 37 DEG C, pressure is 120bar, open steel cylinder, with high-pressure pump by carbon dioxide with
The top of 20g/min flow velocity from sedimentation kettle is passed through, and when temperature, pressure reach above-mentioned setting value in question response kettle, uses another
High-pressure pump by acetone with 2.0ml/min speed by settling kettle, after 15 minutes, system reaches poised state in reactor, stops
Acetone is only passed through, the Rabeprazole sodium solution of above-mentioned preparation is passed through at the same rate, after finishing, continues to be passed through carbon dioxide
50min, stops carbon dioxide pump, and sedimentation kettle pressure is reduced to after atmospheric pressure and taken out, and compound is obtained in sedimentation bottom portion.
Comparative example 4
The RABEPRAZOLE SODIUM prepared using existing process solvent crystallization.From accompanying drawing 4 as can be seen that preparing in aforementioned manners
RABEPRAZOLE SODIUM granularity D0.9 below 50 μm, particle size range is at 20-50 μm.
Claims (8)
1. a kind of novel crystal forms of RABEPRAZOLE SODIUM, it is characterised in that the X-ray powder diffraction represented with the 2 θ ± 0.2 ° angles of diffraction
Figure 10.17 °, 13.02 °, 13.50 °, 15.06 °, 18.35 °, 20.30 °, 24.52 °, 25.38 °, 27.65 °, 29.70 °,
Characteristic diffraction peak is shown at 30.30 °, 31.50 °, 31.68 °, 32.55 °, 35.61 ° and 39.40 °.
2. crystal formation according to claim 1, it is characterised in that the Rabeprazole sodium crystal is measured using Cu-K alpha rays
Obtained X-ray powder diffraction spectrogram is as shown in Figure 1.
3. crystal formation according to claim 1, it is characterised in that the Rabeprazole sodium crystal is corynebacterium.
4. according to the preparation method of any described Rabeprazole sodium crystal of claim 1 or 2, it is characterised in that the preparation side
Method comprises the following steps：
A, Rabeprazole is dissolved in methanol, ethanol or acetone, wiring solution-forming A；
B, 10-30% sodium hydroxide solution B added in solution A, stirred 10-30 minute, addition activated carbon decolorizing 30 minutes,
Filtering, filtrate is standby；
C, using supercritical carbon dioxide as anti-solvent, 35-40 DEG C of sedimentation kettle temperature degree is set, and settling pressure is in 80-120bar, thunder shellfish
It is 0.25-2.0ml/min to draw azoles sodium solution sample introduction flow velocity, and RABEPRAZOLE SODIUM solution concentration is 0.25-5mg/ml, when system is in
During stable state, Rabeprazole sodium solution is entered sedimentation kettle by nozzle, sample introduction is finished, Rabeprazole is obtained in sedimentation kettle
Sodium novel crystal form.
5. preparation method according to claim 4, it is characterised in that the granularity D0.9 of the crystal formation is below 50 μm, grain
Scope is spent at 20-50 μm.
6. preparation method according to claim 4, it is characterised in that in the step a, RABEPRAZOLE SODIUM solution concentration is
2.5-50mg/ml。
7. preparation method according to claim 4, it is characterised in that in the step b, stream of supercritical carbon dioxide speed is
15g/min-25g/min；The Rabeprazole sodium solution sample introduction flow velocity is 0.25-2.0ml/min.
8. preparation method according to claim 4, it is characterised in that in the step c, sample introduction continues to be passed through two after finishing
Carbonoxide 40-50min.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109796470A (en) * | 2019-01-23 | 2019-05-24 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of high-purity cefoperazone sodium micro mist |
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