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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- rabeprazole sodium
- rabeprazole
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- sodium
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- ZGDLVKWIZHHWIR-UHFFFAOYSA-N 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(N2CCOCC2)N=C1 ZGDLVKWIZHHWIR-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960001778 rabeprazole sodium Drugs 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 19
- 239000012296 anti-solvent Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 239000013078 crystal Substances 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 41
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 20
- 239000001569 carbon dioxide Substances 0.000 claims description 20
- 238000004062 sedimentation Methods 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229960004157 rabeprazole Drugs 0.000 claims description 9
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 150000003851 azoles Chemical class 0.000 claims description 3
- 235000015170 shellfish Nutrition 0.000 claims description 3
- 241000186216 Corynebacterium Species 0.000 claims description 2
- 229910017488 Cu K Inorganic materials 0.000 claims description 2
- 229910017541 Cu-K Inorganic materials 0.000 claims description 2
- 229960004424 carbon dioxide Drugs 0.000 claims 3
- 229910002090 carbon oxide Inorganic materials 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 15
- 238000002425 crystallisation Methods 0.000 abstract description 13
- 230000008025 crystallization Effects 0.000 abstract description 10
- 239000002245 particle Substances 0.000 abstract description 10
- 238000009826 distribution Methods 0.000 abstract description 3
- 239000004519 grease Substances 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 229940126409 proton pump inhibitor Drugs 0.000 description 8
- 239000000612 proton pump inhibitor Substances 0.000 description 8
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 6
- 229960000381 omeprazole Drugs 0.000 description 6
- 206010067484 Adverse reaction Diseases 0.000 description 5
- 208000008469 Peptic Ulcer Diseases 0.000 description 5
- 230000006838 adverse reaction Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001808 supercritical antisolvent technique Methods 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000590002 Helicobacter pylori Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229910000831 Steel Inorganic materials 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229940037467 helicobacter pylori Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 208000011906 peptic ulcer disease Diseases 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000010959 steel Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002183 duodenal effect Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 239000003595 mist Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- 102100021022 Gastrin Human genes 0.000 description 1
- 108010052343 Gastrins Proteins 0.000 description 1
- 101150056637 Hrh2 gene Proteins 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009858 acid secretion Effects 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 235000019621 digestibility Nutrition 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940106977 lansoprazole 30 mg Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940086977 rabeprazole sodium 10 mg Drugs 0.000 description 1
- 229940086969 rabeprazole sodium 20 mg Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008542 thermal sensitivity Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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