CN103664889A - Lansoprazole compound - Google Patents
Lansoprazole compound Download PDFInfo
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- CN103664889A CN103664889A CN201310702959.5A CN201310702959A CN103664889A CN 103664889 A CN103664889 A CN 103664889A CN 201310702959 A CN201310702959 A CN 201310702959A CN 103664889 A CN103664889 A CN 103664889A
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- 229960003174 lansoprazole Drugs 0.000 title claims abstract description 174
- -1 Lansoprazole compound Chemical class 0.000 title abstract 4
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims abstract description 170
- 239000013078 crystal Substances 0.000 claims abstract description 51
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 18
- 239000000126 substance Substances 0.000 claims abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 62
- 150000001875 compounds Chemical class 0.000 claims description 58
- 238000002360 preparation method Methods 0.000 claims description 39
- 239000003960 organic solvent Substances 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000706 filtrate Substances 0.000 claims description 22
- 239000012046 mixed solvent Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 238000003556 assay Methods 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 7
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- 239000003814 drug Substances 0.000 abstract description 25
- 229940079593 drug Drugs 0.000 abstract description 9
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- 238000005755 formation reaction Methods 0.000 description 31
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 14
- 238000010521 absorption reaction Methods 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 230000036470 plasma concentration Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 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 4
- 238000001816 cooling Methods 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229960000381 omeprazole Drugs 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 210000001711 oxyntic cell Anatomy 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
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- 238000009505 enteric coating Methods 0.000 description 2
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- 210000004051 gastric juice Anatomy 0.000 description 2
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- 239000008187 granular material Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000010583 slow cooling Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
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- 238000009501 film coating Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 238000005374 membrane filtration Methods 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000009183 running Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- RVEZZJVBDQCTEF-UHFFFAOYSA-N sulfenic acid Chemical compound SO RVEZZJVBDQCTEF-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
Images
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines and in particular relates to a lansoprazole compound. The lansoprazole compound has a chemical structural formula and is measured by a powder X-ray diffraction measurement method, and an X-ray diffraction pattern represented by a diffraction angle of 2 theta +/- 0.2 degree is as shown in a figure. The lansoprazole compound provided by the invention is a novel lansoprazole crystal form different from that in the prior art, and the crystal form is lower in moisture absorptivity and better in solubility.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to a kind of compound of Lansoprazole.
Background technology
Lansoprazole is the benzimidazoles derivative with antiacid effect by the exploitation of Japanese Wu Tian company in December, 1991, and it acts on the H of parietal cell
+-K
+-ATP enzyme, makes the H of parietal cell
+can not be transported in stomach and go, so that in gastric juice, hydrochloric acid in gastric juice amount greatly reduces, be used for the treatment of stomach ulcer, duodenal ulcer and reflux esophagitis, and be used for eliminating pylorus.
Lansoprazole is novel proton pump inhibitor, it is the upgraded product of omeprazole, lansoprazole is because importing fluorine and have trifluoro ethoxy substituting group at 4 side chains of pyridine ring, make its bioavailability improve more than 30% compared with omeprazole, lipotropy is also better than omeprazole, therefore this product can promptly see through parietal cell film and change sulfenic acid and time sulfonyl derivative into and bring into play drug effect under acidic conditions, the bacteriostatic activity of HP is risen to four times of omeprazole.
The crystal formation of existing lansoprazole is a lot, as described the preparation method of anhydrous crystal forms (I type) and 1.5 crystal types (II type) in CN1355798A.
The preparation method of lansoprazole A crystal formation has been described in US2009/0018339A1: lansoprazole (100g) is dissolved in acetone (1500mL), slow cooling to 0 ℃, cooling 3h, filters, and at 50 ℃, dry 2h, obtains lansoprazole A crystal formation.Lansoprazole (35g) is dissolved in ethanol (300mL) under 55 ℃ of conditions, solution is cooled to 0 ℃, by 50mL washing with alcohol precipitation, the dry B crystal formation that obtains.
The lansoprazole anhydrous crystal forms of describing in CN1355798A (I type) preparation method, successively through four recrystallizations, preparation process is complicated, consuming time; The lansoprazole B crystal formation of describing in US2009/0018339A1 is metastable-state crystal, can experience solid-to-solid transition under certain condition, forms A crystal formation.
CN102180866A discloses two kinds of new crystal of lansoprazole, is respectively M and N crystal formation.CN1681802A discloses three kinds of solid crystal formations of lansoprazole, is respectively D, E and F type.
Visible, the multiple crystal formation of lansoprazole is disclosed in prior art.Yet, due to lansoprazole less stable, and indissoluble in water, it is had difficulties in formulation application, prior art attempts to solve this problem from crystalline structure research, as CN102558154A, to disclose a kind of solubility property suitable with commercially available lansoprazole, but the good lansoprazole crystalline compounds of stability, the X-ray powder diffraction collection of illustrative plates that this crystalline compounds represents with 2 θ ± 0.2 ° diffraction angle is at 5.8 °, 7.5 °, 9.1 °, 11.8 °, 12.1 °, 12.8 °, 13.3 °, 15.6 °, 16.7 °, 18.3 °, 20.4 °, 25.7 °, 26.8 °, with 31.5 ° locate to demonstrate characteristic diffraction peak.CN103254174A also discloses compound of Lansoprazole and the pharmaceutical composition thereof that a kind of solvability and stability are significantly increased.Described compound of Lansoprazole is crystal, adopts X-ray powder diffraction to measure, and its characteristic peak in 2 θ ± 0.2 ° is 3.6,4.8,10.9,14.0,15.4,16.9,22.6,24.7,28.5,32.1,35.2,36.7,39.3 to show.
Yet, lansoprazole also has stronger water absorbability, after moisture absorption, can cause the variation of the physico-chemical properties such as caking, mobility decline, deliquescence, crystal formation change, thereby affect the interior qualities such as product stability, validity, security, drug effect, be unfavorable for the operation of preparation process.Therefore, be necessary to provide the compound of Lansoprazole that a kind of water absorbability is improved, performance is more superior.
The inventor is carrying out after a large amount of research lansoprazole, has obtained a kind of lansoprazole new crystal that is different from prior art, and this crystal formation not only has lower water absorbability, and solvability is better simultaneously, and has good drug effect, thereby has completed the present invention.
Summary of the invention
The object of the invention is to just provide a kind of compound of Lansoprazole, the water absorbability that this compound tool is significantly improved.
For achieving the above object, the present invention adopts following technical scheme:
A compound of Lansoprazole, wherein, the chemical structural formula of described compound of Lansoprazole is as follows:
Described compound of Lansoprazole is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle as shown in Figure 1.
Material owing to affected by various factors, makes in molecule or molecular linkage mode changes when crystallization, causes molecule or atom to be arranged at lattice vacancy different, forms different crystalline structure.The multiple crystalline structure of lansoprazole is disclosed in prior art, but find after deliberation, the crystal formation of prior art does not improve the water absorbability of lansoprazole, after moisture absorption, can cause the variation of the physico-chemical properties such as caking, mobility decline, deliquescence, crystal formation change, thereby affect the interior qualities such as product stability, validity, security, drug effect, be unfavorable for the operation of preparation process.
The inventor, lansoprazole having been carried out to, after a large amount of research, obtained the crystal formation that a kind of lansoprazole is new, by wettability test, shows the water absorbability that compound of Lansoprazole tool provided by the present invention is significantly improved.By dissolubility test, find, compound of Lansoprazole provided by the present invention also has good solvability, and is surprised to find that simultaneously, and lansoprazole of the present invention has the plasma concentration curve more relaxing, and bioavailability is significantly improved.
The preparation method of the compound of Lansoprazole described in the present invention also provides simultaneously, the method comprises the steps:
1) get lansoprazole crude product, at 50～60 ℃, be dissolved in acetone, obtain lansoprazole acetone soln;
2) in the lansoprazole acetone soln of step 1) gained, add gac, stir, suction filtration, gets filtrate;
3) filtrate is cooled to room temperature naturally, then under agitation to stream in filtrate, adds organic solvent A, form turbid solution, wherein said organic solvent A is the mixed solvent that methyl alcohol and methylene dichloride form with volume ratio 2～5:1;
4) in the turbid solution of the backward step 3) of adjustment stirring velocity, stream adds organic solvent B, finishes, and is cooled to 0～5 ℃, has crystal to separate out, and wherein said organic solvent B is the mixed solvent that ethyl acetate and dimethyl formamide form with volume ratio 5～10:1;
5) in the environment of 0～5 ℃ of temperature standing 2～4 hours, filter filter cake absolute ethanol washing, the lansoprazole described in vacuum-drying obtains.
In prior art, there is the multiple different crystal formation of lansoprazole, in order to obtain a kind of new crystal of lansoprazole, contriver is through experiment repeatedly, the commercially available lansoprazole crude product of take is raw material, constantly change crystallization means, crystallization path and crystallization condition, as crystallization conditions such as temperature, solvent, anti-solvents, finally obtained a kind of brand-new lansoprazole new crystal compound, its X-RD spectrogram shows, the solid interior molecule arranging structure of compound of Lansoprazole provided by the invention is different from lansoprazole of the prior art.
In the preparation method of compound of Lansoprazole of the present invention, the mass volume ratio of the lansoprazole crude product described in step 1) and acetone is 1:1.2～2.6kg/L.
In the preparation method of compound of Lansoprazole of the present invention, the volume ratio of described organic solvent A, organic solvent B and acetone is 2～5:3～8:1.
In the preparation method of compound of Lansoprazole of the present invention, the speed stirring described in step 3) is 50～60r/min.
In the preparation method of compound of Lansoprazole of the present invention, the stirring velocity described in step 4) is 15～25r/min.
In the preparation method of compound of Lansoprazole of the present invention, the flow acceleration of organic solvent A described in step 3) is 13～20L/min.
In the preparation method of compound of Lansoprazole of the present invention, the flow acceleration of organic solvent B described in step 4) is 6～12L/min.
The prepared lansoprazole of the present invention has lower water absorbability and water-soluble preferably, can guarantee the quality of pharmaceutical preparation.
The inventor has further investigated at prescription identical with preparation method in the situation that, adopts the Plasma Concentration of the lansoprazole medicine that the lansoprazole of compound of Lansoprazole of the present invention and prior art makes.The lansoprazole that pleasantly surprised discovery adopts compound of Lansoprazole of the present invention to make is subject to the Plasma Concentration peak value of reagent higher than the lansoprazole contrast medicine that adopts commercially available lansoprazole bulk drug to make, and more relaxed by the plasma concentration curve of reagent, show that its bioavailability is high.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction collection of illustrative plates of compound of Lansoprazole of the present invention;
Fig. 2 is the lansoprazole drug-time curve figure of the lansoprazole medicine that makes of the lansoprazole of the present invention and prior art.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
The preparation of [embodiment 1] compound of Lansoprazole
1) get lansoprazole crude product 10kg, at 50 ℃, be dissolved in 12L acetone, obtain lansoprazole acetone soln;
2) in the lansoprazole acetone soln of step 1) gained, add 0.01g gac, stir 15 minutes, suction filtration, gets filtrate;
3) filtrate is cooled to room temperature naturally, then under the stirring that is 50r/min in speed, to the speed stream with 13L/min in filtrate, add 24L organic solvent A, form turbid solution, wherein said organic solvent A is the mixed solvent that methyl alcohol and methylene dichloride form with volume ratio 2:1;
4) stirring velocity is adjusted into 25r/min, then to the speed stream with 12L/min in the turbid solution of step 3), add 36L organic solvent B, finish, be cooled to 0 ℃, have crystal to separate out, wherein said organic solvent B is the mixed solvent that ethyl acetate and dimethyl formamide form with volume ratio 5:1;
5) in the environment of 0 ℃ of temperature standing 2 hours, filter filter cake 1L absolute ethanol washing, the lansoprazole described in vacuum-drying obtains.
The compound of Lansoprazole of gained is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle as shown in Figure 1.
The preparation of [embodiment 2] compound of Lansoprazole
1) get lansoprazole crude product 10kg, at 60 ℃, be dissolved in 26L acetone, obtain lansoprazole acetone soln;
2) in the lansoprazole acetone soln of step 1) gained, add 0.01g gac, stir 15 minutes, suction filtration, gets filtrate;
3) filtrate is cooled to room temperature naturally, then under the stirring that is 60r/min in speed, to the speed stream with 20L/min in filtrate, add 130L organic solvent A, form turbid solution, wherein said organic solvent A is the mixed solvent that methyl alcohol and methylene dichloride form with volume ratio 5:1;
4) stirring velocity is adjusted into 25r/min, then to the speed stream with 6L/min in the turbid solution of step 3), add 78L organic solvent B, finish, be cooled to 5 ℃, have crystal to separate out, wherein said organic solvent B is the mixed solvent that ethyl acetate and dimethyl formamide form with volume ratio 10:1;
5) in the environment of 5 ℃ of temperature standing 4 hours, filter filter cake 1L absolute ethanol washing, the lansoprazole described in vacuum-drying obtains.
The compound of Lansoprazole of gained is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is consistent with embodiment 1.
The preparation of [embodiment 3] compound of Lansoprazole
1) get lansoprazole crude product 10kg, at 55 ℃, be dissolved in 20L acetone, obtain lansoprazole acetone soln;
2) in the lansoprazole acetone soln of step 1) gained, add 0.01g gac, stir 15 minutes, suction filtration, gets filtrate;
3) filtrate is cooled to room temperature naturally, then under the stirring that is 55r/min in speed, to the speed stream with 18L/min in filtrate, add 60L organic solvent A, form turbid solution, wherein said organic solvent A is the mixed solvent that methyl alcohol and methylene dichloride form with volume ratio 4:1;
4) stirring velocity is adjusted into 20r/min, then to the speed stream with 8L/min in the turbid solution of step 3), add 160L organic solvent B, finish, be cooled to 3 ℃, have crystal to separate out, wherein said organic solvent B is the mixed solvent that ethyl acetate and dimethyl formamide form with volume ratio 8:1;
5) in the environment of 3 ℃ of temperature standing 3 hours, filter filter cake 1L absolute ethanol washing, the lansoprazole described in vacuum-drying obtains.
The compound of Lansoprazole of gained is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is consistent with embodiment 1.
The preparation of [embodiment 4] compound of Lansoprazole
1) get lansoprazole crude product 10kg, at 53 ℃, be dissolved in 15L acetone, obtain lansoprazole acetone soln;
2) in the lansoprazole acetone soln of step 1) gained, add 0.01g gac, stir 15 minutes, suction filtration, gets filtrate;
3) filtrate is cooled to room temperature naturally, then under the stirring that is 52r/min in speed, to the speed stream with 15L/min in filtrate, add 45L organic solvent A, form turbid solution, wherein said organic solvent A is the mixed solvent that methyl alcohol and methylene dichloride form with volume ratio 3:1;
4) stirring velocity is adjusted into 23r/min, then to the speed stream with 11L/min in the turbid solution of step 3), add 75L organic solvent B, finish, be cooled to 2 ℃, have crystal to separate out, wherein said organic solvent B is the mixed solvent that ethyl acetate and dimethyl formamide form with volume ratio 7:1;
5) in the environment of 4 ℃ of temperature standing 3.5 hours, filter filter cake 1L absolute ethanol washing, the lansoprazole described in vacuum-drying obtains.
The compound of Lansoprazole of gained is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is consistent with embodiment 1.
The preparation of [embodiment 5] compound of Lansoprazole
1) get lansoprazole crude product 10kg, at 57 ℃, be dissolved in 13L acetone, obtain lansoprazole acetone soln;
2) in the lansoprazole acetone soln of step 1) gained, add 0.01g gac, stir 15 minutes, suction filtration, gets filtrate;
3) filtrate is cooled to room temperature naturally, then under the stirring that is 51r/min in speed, to the speed stream with 14L/min in filtrate, add 52L organic solvent A, form turbid solution, wherein said organic solvent A is the mixed solvent that methyl alcohol and methylene dichloride form with volume ratio 3.5:1;
4) stirring velocity is adjusted into 24r/min, then to the speed stream with 9L/min in the turbid solution of step 3), add 65L organic solvent B, finish, be cooled to 1 ℃, have crystal to separate out, wherein said organic solvent B is the mixed solvent that ethyl acetate and dimethyl formamide form with volume ratio 8.5:1;
5) in the environment of 3 ℃ of temperature standing 2.5 hours, filter filter cake 1L absolute ethanol washing, the lansoprazole described in vacuum-drying obtains.
The compound of Lansoprazole of gained is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is consistent with embodiment 1.
[comparative example 1] lansoprazole A crystal formation
Lansoprazole (100g) is dissolved in acetone (1500mL), slow cooling to 0 ℃, cooling 3h, filters, and at 50 ℃, dry 2h, obtains lansoprazole A crystal formation.
[comparative example 2] lansoprazole B crystal formation
Lansoprazole (35g) is dissolved in ethanol (300mL) under 55 ℃ of conditions, solution is cooled to 0 ℃, by 50mL washing with alcohol precipitation, the dry B crystal formation that obtains.
[comparative example 3] lansoprazole I crystal formation
Amorphous lansoprazole (9.17g) is dissolved in acetone (20mL), under thermal condition, adds water (15mL), standing over night at room temperature, then add water (20mL), after supersound process, solid collected by filtration, completes recrystallization for the first time; Then gained solid is dissolved in after acetone (30mL) filters and adds diisopropyl ether (50mL), add crystal seed, mixture is standing over night at room temperature, and filtration drying completes recrystallization for the second time; Gained solid is dissolved in acetone, aqueous precipitation, standing 1h collects solid, and drying under reduced pressure, obtains white solid, completes recrystallization for the third time; Finally by gained lansoprazole solid (3.88
g) be dissolved in acetone (4mL), add Di Iso Propyl Ether (14mL), at room temperature standing this solution is 30 minutes, filters, and the crystallization that collecting precipitation goes out, by Di Iso Propyl Ether (6mL) washed twice, obtains anhydrous crystal forms (I) lansoprazole solid.
[comparative example 4] lansoprazole M crystal formation
1) 50mg lansoprazole is dissolved in 0.1mL methanol solution;
2) in gained solution, drip 0.06mL water, filter;
3) settled solution is cooled to-15 ℃, its sufficient crystallising is separated out, filter, dry.Obtain off-white color crystalline powder 43.2mg, be lansoprazole M crystal formation.
[comparative example 5] lansoprazole N crystal formation
1) 50mg lansoprazole is dissolved in 0.1mL ethyl acetate, filters;
2) settled solution is cooled to-10 ℃, its sufficient crystallising is separated out, filter, dry.Obtain off-white color crystalline powder 42.7mg, be lansoprazole N crystal formation.
The compound of Lansoprazole that [comparative example 6] makes according to CN103254174A
60 ℃, under the stirring velocity of 100 revs/min, it is in the methyl alcohol of 7:1 and the mixing solutions of ethanol that lansoprazole is dissolved in to volume ratio by weight 1:12; Keep 60 ℃, add the gac of lansoprazole weight 1.5%, 150 revs/min are stirred 25 minutes, filter carbon removal, and filtrate is obtained to solution I through 0.22 μ m membrane filtration; Be cooled to 30 ℃, under the stirring velocity of 100 revs/min, toward take the speed of 70mL/min in solution I, slowly at the uniform velocity drip water that the volume ratio of 10 times of mixing solutionss that weight is methyl alcohol and ethanol is 7:1 and the mixing solutions of ether while stirring; Simultaneously the cooling rate with 1.5 ℃/min is at the uniform velocity cooled to 10 ℃, stops stirring, and with the cooling rate of 0.1 ℃/min, is at the uniform velocity cooled to 2 ℃ of standing growing the grains 10 hours, filters to obtain filter cake; The water that is 7:1 by the volume ratio of 3 times of weight by filter cake and the washing of the mixing solutions of ether 2 times, dry, obtain described compound of Lansoprazole.
Test example 1
Dissolubility test
The solubleness of the lansoprazole that this test example has been measured compound of Lansoprazole provided by the present invention and prior art by OT-42 method in water.
Sample number into spectrum is as follows;
Sample 1: the compound of Lansoprazole that the embodiment of the present invention 1 obtains;
Sample 2: the compound of Lansoprazole that the embodiment of the present invention 2 obtains;
Sample 3: the compound of Lansoprazole that the embodiment of the present invention 3 obtains;
Sample 4: the lansoprazole A crystal formation making according to comparative example 1;
Sample 5: the lansoprazole B crystal formation making according to comparative example 2;
Sample 6: the lansoprazole I crystal formation making according to comparative example 3;
Sample 7: the lansoprazole M crystal formation making according to comparative example 4;
Sample 8: the lansoprazole N crystal formation making according to comparative example 5.
Test-results is in Table 1:
Table 1, solubility test result
| Sample | 25 ℃ of |
| Sample | |
| 1 | 2.63mg/ |
| Sample | |
| 2 | 2.67mg/ml |
| Sample 3 | 2.65mg/ml |
| Sample 4 | 0.097mg/ml |
| Sample 5 | 0.096mg/ |
| Sample | |
| 6 | 0.095mg/ml |
| Sample 7 | 0.096mg/ |
| Sample | |
| 8 | 0.094mg/ml |
From above-mentioned test-results, to compare with the lansoprazole crystal formation of prior art, lansoprazole provided by the present invention has good solubleness in water.
Test example 2
This test example is investigated the water absorbability of the lansoprazole of compound of Lansoprazole of the present invention and prior art.
1, instrument and reagent
1.1 instrument
YA100 THE CONSTANT TEMPERATURE AND HUMIDITY BIOLOGICAL CABINET (Harbin, Heilungkiang Dong Lian testing installation company limited); MD50 electronic balance (German Sai Duolisi group); Testing chamber for medicine stability (Chongqing City Yongsheng test apparatus factory).
1.2 reagent
Test drug 1: the compound of Lansoprazole that the embodiment of the present invention 1 makes;
Test drug 2: the compound of Lansoprazole that the embodiment of the present invention 2 makes;
Contrast medicine 1: the lansoprazole A crystal formation making according to comparative example 1;
Contrast medicine 2: the compound of Lansoprazole making according to comparative example 6.
2 methods and result
The preparation of 2.1 saturated salt solutions and relative humidity (RH)
The principle of critical relative humidity (CRH) is: when the vapour pressure of saturated solution equates with airborne steam partial pressure, reach CRH.According to different saturated salt solutions, can set up the environment of different RH for this reason.According to the method for prior art, preparation is with CaCl
26H
2o, K
2cO
32H
2o, NaCl and KNO
3for the saturated salt solution that solute forms, its RH is respectively 31%, 43%, 75% and 92.5%.
The mensuration of 2.2 rate of moisture absorption
Get " 2.1 " lower different saturated salt solution, be placed in respectively different glass moisture eliminator bottoms, in the mid-way of moisture eliminator, add after a baffle plate, built-in weighing bottle, and glass moisture eliminator is placed to 24h to constant humidity in THE CONSTANT TEMPERATURE AND HUMIDITY BIOLOGICAL CABINET.Take respectively test drug and contrast medicine about 2g, be placed in weighing bottle, accurately weighed, bottle cap is opened, put into moisture eliminator top, be placed in 25 ℃ of fixed temperature and humidity incubators, 3 parts of parallel runnings, take out and weigh respectively at 2,4,8, when 24h and 3,5,10d.Under every kind of humidity condition, mixed grain weight amount is constant or increase hour, can judge that under this kind of humidity condition, mixed powder wettability test finishes.According to moisture absorption weightening finish under different humidity condition, change, calculate rate of moisture absorption.Mixed grain weight amount * 100% before rate of moisture absorption=(mixing grain weight amount before mixed grain weight amount-moisture absorption after moisture absorption)/moisture absorption.Under different humidity condition, different lansoprazole rate of moisture absorption the results are shown in Table 2.
Different lansoprazole rate of moisture absorption results (%, n=3) under table 2, different humidity
As can be seen from the above table, compare with the lansoprazole of prior art, the water absorbability of compound of Lansoprazole of the present invention obviously reduces.
The compound of Lansoprazole prepared to other embodiment of the present invention also carried out above-mentioned wettability test, and the result of its acquisition is similar.
Test example 3
Pharmacokinetics is investigated
This test example is investigated the pharmacokinetics of the compound of Lansoprazole of compound of Lansoprazole of the present invention and prior art.
1, instrument and equipment
Japan Shimadzu liquid chromatograph; Lansoprazole bulk drug: Essen, Zhejiang pharmaceutical Co. Ltd, content 99%, lot number 1003-0910004; Acetonitrile, triethylamine are chromatographically pure; Ether, methylene dichloride, propylene glycol are analytical pure; Blank plasma is provided by clinical laboratory of Attached Hospital No.1, dalian Medical Univ..
2, test method
2.1 medicine preparations:
Core formulation (1000)
Amount to 1000
Barrier gown coating fluid prescription (1000)
Opadry Y-1-7000 16.0
95% ethanol 140ml
Purified water 60ml
Enteric coating coating fluid prescription
Opadry OY-P, 91S 16.0
88% ethanol 140ml
Preparation method:
(1) it is standby that lactose, pregelatinized Starch, croscarmellose sodium are crossed 80 mesh sieves;
(2) taking recipe quantity lansoprazole increases progressively and mixes with recipe quantity lactose, pregelatinized Starch, croscarmellose sodium and sodium lauryl sulphate equivalent;
(3) press sheet, with 18 mesh sieves, granulate;
(4) add the Magnesium Stearate of recipe quantity, mix;
(5) measure granule content, calculate the theoretical tablet weight;
(6) compressing tablet (adopting the punching of φ 7mm scrobicula), controlling label hardness is 3～7kg;
(7) preparation barrier gown liquid: get recipe quantity Opadry (Y-1-7000) powder and under agitation add in 140ml95 volume % ethanol, be stirred to dispersion, then add 60ml purified water to stir 45 minutes;
(8) film coating, weightening finish 3～4%;
(9) preparation enteric coating liquid: get recipe quantity Opadry OY-P91S type and under agitation join in the ethanol of 100ml88 volume %, continue to stir 45 minutes;
(10) enteric coated, weightening finish 13～14%;
(11) inspection after construction, packing.
Be subject to reagent: according to above-mentioned prescription and preparation method's preparation, wherein lansoprazole used is the compound of Lansoprazole that the embodiment of the present invention 1 makes;
Contrast medicine: according to above-mentioned prescription and preparation method's preparation, wherein lansoprazole used is commercially available lansoprazole bulk drug (Essen, Zhejiang pharmaceutical Co. Ltd, content 99%, lot number 1003-0910004).
2.2 chromatographic condition
Adopt HypersilBDS C
18chromatographic column (4.6mm * 150mm, 5 μ m); Moving phase is water-acetonitrile-triethylamine (620:380:1), and detection wavelength is 285nm, 40 ℃ of column temperatures, and flow velocity is 1.0mL/min.
2.3 plasma samples are processed
Get blank serum (or application of sample serum, serum sample) 0.5mL, with extraction liquid ether-methylene dichloride (7:3) 5mL, 1min vortex mixes, the centrifugal 5min of 2000r/min, get supernatant liquor 3.8mL, add again extraction liquid (methylene dichloride: ether: propylene glycol) (60:140:1) 0.5mL, in 35 ℃ of aqueous solution, use N
2dry up moving phase 50 for residue
μafter the restructuring of L vortex is dissolved, standby.
The mensuration of 2.4 experimenter's lansoprazole Plasma Concentrations
Experimenter is divided into two groups at random, respectively at test proxima luce (prox. luc), 8:00 in evening starts fasting, test 7:30 (medicine) being taken before meals in morning on the same day is subject to reagent and contrast medicine 30mg, respectively at (0h) before taking medicine and after taking medicine 0.5,1,1.5,2.0,2.5,3.0,4.0,6.0,8.0,12.0h gets blood 3mL, after the lower manipulation of " 2.2 " item, get 20 μ L sample introductions, record the Plasma Concentration of each moment lansoprazole of each experimenter.
3, test-results
Be subject to the lansoprazole drug-time curve of reagent and contrast medicine to see Fig. 2.As can be seen from Figure 2, in the situation that prescription is identical with preparation method, the lansoprazole that adopts compound of Lansoprazole of the present invention to make is subject to the Plasma Concentration peak value of reagent higher than the lansoprazole contrast medicine that adopts commercially available lansoprazole bulk drug to make, and more relaxed by the plasma concentration curve of reagent, show that its bioavailability is high.
The present invention also prepares lansoprazole tablet according to above-mentioned prescription and technique by the lansoprazole of other comparative example, and measures according to the method described above its lansoprazole drug-time curve, result with in Fig. 2 to contrast medicine basically identical.Visible, in the situation that prescription is identical with preparation method, the lansoprazole tablet that the lansoprazole that adopts compound of Lansoprazole of the present invention to make is made higher than the lansoprazole bulk drug that adopts prior art by the Plasma Concentration peak value of reagent, and more relaxed by the plasma concentration curve of reagent, show that its bioavailability is high.
The compound of Lansoprazole prepared to other embodiment of the present invention also carried out identical test, and the result of its acquisition is similar.
Claims (8)
1. a compound of Lansoprazole, is characterized in that, the chemical structural formula of described compound of Lansoprazole is as follows:
Described compound of Lansoprazole is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle as shown in Figure 1.
2. a preparation method for compound of Lansoprazole claimed in claim 1, is characterized in that, described preparation method comprises the steps:
1) get lansoprazole crude product, at 50～60 ℃, be dissolved in acetone, obtain lansoprazole acetone soln;
2) in the lansoprazole acetone soln of step 1) gained, add gac, stir, suction filtration, gets filtrate;
3) filtrate is cooled to room temperature naturally, then under agitation to stream in filtrate, adds organic solvent A, form turbid solution, wherein said organic solvent A is the mixed solvent that methyl alcohol and methylene dichloride form with volume ratio 2～5:1;
4) in the turbid solution of the backward step 3) of adjustment stirring velocity, stream adds organic solvent B, finishes, and is cooled to 0～5 ℃, has crystal to separate out, and wherein said organic solvent B is the mixed solvent that ethyl acetate and dimethyl formamide form with volume ratio 5～10:1;
5) in the environment of 0～5 ℃ of temperature standing 2～4 hours, filter filter cake absolute ethanol washing, the lansoprazole described in vacuum-drying obtains.
3. preparation method according to claim 2, is characterized in that, the mass volume ratio of the lansoprazole crude product described in step 1) and acetone is 1:1.2～2.6kg/L.
4. preparation method according to claim 2, is characterized in that, the volume ratio of described organic solvent A, organic solvent B and acetone is 2～5:3～8:1.
5. preparation method according to claim 2, is characterized in that, the speed stirring described in step 3) is 50～60r/min.
6. preparation method according to claim 5, is characterized in that, the stirring velocity described in step 4) is 15～25r/min.
7. preparation method according to claim 2, is characterized in that, the flow acceleration of organic solvent A described in step 3) is 13～20L/min.
8. preparation method according to claim 7, is characterized in that, the flow acceleration of organic solvent B described in step 4) is 6～12L/min.
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| CN104829594A (en) * | 2015-05-15 | 2015-08-12 | 苗怡文 | Pharmaceutical lansoprazole compound for treating gastric ulcer |
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