CN104693180A - Sodium rabeprazole monohydrate crystal form and preparation method thereof - Google Patents

Sodium rabeprazole monohydrate crystal form and preparation method thereof Download PDF

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Publication number
CN104693180A
CN104693180A CN201510092574.0A CN201510092574A CN104693180A CN 104693180 A CN104693180 A CN 104693180A CN 201510092574 A CN201510092574 A CN 201510092574A CN 104693180 A CN104693180 A CN 104693180A
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sodium rabeprazole
rabeprazole
crystal formation
preparation
sodium
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夏钊
谭淑珍
华坤鹏
王成
王述维
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HUNAN RHON PHARMACEUTICAL Co Ltd
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HUNAN RHON PHARMACEUTICAL Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention relates to the technical field of medicine, and particularly relates to a sodium rabeprazole monohydrate crystal form and a preparation method thereof. A crystal compound is characterized in that in an X-ray powder diffraction spectrum chart expressed by using CuKalpha radiation and a 2-theta angle, characteristic diffraction peaks with a relative strength of over 10% are shown at the positions of 8.919o, 9.521o, 10.340o, 13.240o, 13.820o, 15.320o, 16.935o, 17.821o, 18.280o, 18.580o, 19.259o, 21.018o, 22.699o, 23.080o, 23.620o, 25.160o, 26.880o, 27.539o, 27.918o, 29.479o, 31.360o, and 32.420o +/-0.2o. A differential scanning calorimetry analysis chart of the crystal compound has an absorption peak at the position of about 154.3 DEG C. A preparation method of the crystal compound comprises the following steps: adding amorphous sodium rabeprazole into a benign solvent, stirring, dissolving, adding active carbon for decoloring, and filtering; adding 4.5-6.0% of purified water in a filtrate under the condition of constant stirring; and adding a poor solvent, carrying out cooling crystallization, filtrating, and carrying out vacuum drying, so that the crystal compound is obtained. The crystal compound is low in hygroscopicity and good in stability.

Description

A kind of Sodium rabeprazole monohydrate crystal formation and preparation method thereof
Technical field
The present invention relates to medical art, particularly relate to a kind of Sodium rabeprazole monohydrate crystal formation and preparation method thereof.
Background technology
Sodium rabeprazole (Rabeprazole Sodium) is the sodium salt of rabeprazole, and its chemical name is: 2-{ [4-(3-methoxy propoxy)-3-picoline-2-base] methylsulfinyl }-1H-benzoglyoxaline sodium, its structural formula is:
Sodium rabeprazole is the proton pump inhibitor of new generation after omeprazole, lansoprazole, has higher pKa value, fast activating in vivo, by suppressing the H of parietal cell +/ K +the activity of-ATP enzyme, thus the secretion of gastric acid inhibitory.Be mainly used in the diseases such as treatment peptide ulceration, gastro oesophageal reflux disease (GORD), Zhuo-Emhorn syndromes clinically.Compared with omeprazole, Sodium rabeprazole suppresses H +/ K +the effect of-ATP enzyme is stronger, and suppresses to recover; Less on plasma gastrin levels impact, having the effect of selectivity strongly inhibited helicobacter pylori, is the very promising antisecretory of one, in 1997 first in Japan's listing, subsequently respectively in Europe, the U.S., Discussion on Chinese Listed.Research report about amorphous rabeprazole and sodium salt thereof in current document is more, and relatively less about the research report of Sodium rabeprazole crystalline compounds.
Chinese patent CN102584793B discloses a kind of Sodium rabeprazole crystalline compounds and preparation method thereof, and the fusing point of this crystalline compounds is 162-163 DEG C, uses CuK αray is that source of radiation carries out X-ray powder diffraction to measure the XRPD figure obtained be that 5.8o, 7.5o, 12.1o, 12.8o, 13.3o, 15.6o, 16.7o, 18.3o, 20.4o, 25.7o, 26.8o and 31.5o ± 0.2o place shows characteristic diffraction peak at 2 θ angles.This Sodium rabeprazole crystalline compounds takes following steps to prepare: bulk drug Sodium rabeprazole is added to the water by (1), stirs, and dissolves, obtains rabeprazole sodium water solution; (2) in the above-mentioned Sodium rabeprazole aqueous solution, under agitation add the mixing solutions of tetrahydrofuran (THF) and methyl alcohol, at 25-35 DEG C, gac insulation decolouring, filters, obtains filtrate; (3) instill in acetonitrile by filtrate, cooling crystallization, filter, vacuum-drying, to obtain final product.
Chinese patent CN102260244B discloses a kind of stable sodium rabeprazole compound and preparation method thereof, gained crystal CuK αray carries out X-ray powder diffraction mensuration as source of radiation, the XRPD figure obtained is the characteristic diffraction peak that 4.92o, 9.90o, 14.92o, 19.50o, 23.36o, 30.22o place shows relative intensity > 5% at 2 θ angles, the fusing point of this crystalline compounds is 242 ~ 242.5 DEG C, moisture content is less than 1%, good stability.This Sodium rabeprazole crystalline compounds takes following steps to prepare: (1) Sodium rabeprazole adds in 5-10 times of (weigh-volume ratio) water, the dimethyl formamide (DMF) of Sodium rabeprazole 0.5%-1% is added in the above-mentioned aqueous solution, stir 30 minutes, filter, filtrate is cooled to 5 DEG C-10 DEG C, for subsequent use; (2) mixed solution of Sodium rabeprazole 18-20 times of acetonitrile-methyl ethyl ketone=5:3 is cooled to 5 DEG C-10 DEG C, adds above-mentioned stock solution, insulation 15-20 hour, crystallization, filter, drying obtains.
Chinese patent CN103864755A discloses a kind of Sodium rabeprazole monohydrate crystal formation, uses CuK αray carries out powdery diffractometry mensuration as characteristic X-ray, and the XRPD figure obtained is the characteristic diffraction peak that 14.32o, 19.48o, 23.69o, 26.35o, 28.65o, 29.88o, 35.31o, 36.16o, 40.27o, 42.25o, 45.87o and 47.62o place shows relative intensity>=10% at 2 θ angles.This crystalline compounds is by being dissolved at Virahol-piperidines-heated in water solution by Sodium rabeprazole, naturally cooling to room temperature, then is incubated that for some time crystallization obtains.
Japanese Patent JP2001-039975 discloses a kind of method preparing rabeprazole salt crystalline compounds, by by the crystallization and obtaining in low-grade fatty acid ester of the acetone complex compound of rabeprazole salt, the XRPD figure of this crystalline compounds is that 14.22o, 17.20o, 17.60o, 18.04o, 19.52o, 20.92o, 21.20o, 24.76o, 25.00o, 26.60o, 29.40o place shows relative intensity >=10% characteristic diffraction peak at 2 θ angles.
International monopoly WO2003082858A1 discloses two kinds of rabeprazole sodium crystals and crystal form X and crystal formation Y, and fusing point is respectively 140-150 DEG C and 160-170 DEG C; US Patent No. 20040180935 discloses a kind of rabeprazole sodium crystal Z, by by the Sodium rabeprazole of non-Z-type at aromatic solvent as backflow certain hour in toluene, dimethylbenzene etc., then cooling crystallization and obtaining, its XRPD figure is the characteristic diffraction peak that 4.694o, 19.320o place shows relative intensity > 10% at 2 θ angles, and the fusing point of this crystal is 224-230 DEG C; US Patent No. 20060135565 discloses a kind of Sodium rabeprazole semihydrate crystal formation α and sesqui hydrate crystal forms β, good stability at room temperature; US Patent No. 8143409B2 discloses a kind of Sodium rabeprazole monohydrate crystal formation γ, its XRPD figure is that 10.5o, 18.0o, 18.4o, 19.4o, 21.1o, 21.7o, 22.9o, 23.3o, 27.1o, 31.6o ± 0.2o place has characteristic diffraction peak at 2 θ angles, and its thermodynamic stability is better than crystal formation α and crystal formation β.
Because the different crystal forms of same medicine often may exist notable difference in solubleness, dissolution rate, fusing point and biological effectiveness etc., thus affect the stability, bioavailability etc. of medicine.The final medicament production characteristic of improvement that is found to be of active pharmaceutical ingredient new crystal provides more possibilities, also provides more wide space for medical research staff designs prescription simultaneously.To acid, light, thermoae instability, especially having under water existent condition, more easily there is acute variation in Sodium rabeprazole.It is strong to there is water absorbability in amorphous Sodium rabeprazole, the shortcomings such as poor stability, and therefore develop water absorbability little, the rabeprazole sodium novel crystal form of good stability has very important meaning.
Summary of the invention
The object of the present invention is to provide a kind of Sodium rabeprazole monohydrate crystal formation and preparation method thereof, the water absorbability of this crystal formation Sodium rabeprazole monohydrate is lower, and stability is better.
The invention provides a kind of Sodium rabeprazole monohydrate crystal formation, it is characterized in that: with CuK αin the X-ray Powder Diffraction pattern that radiation, 2 θ angles represent, its XRPD collection of illustrative plates has following 2 θ diffraction angle and d value:
Spectral line number 2 θ angles (°) Spacing d() I/I 0(%, with maximum peak height for benchmark) I/I 0(%, with maximum peak area for benchmark)
1 8.919 9.9061 39.5 19.5
2 9.521 9.2816 10.0 3.6
3 10.340 8.5481 44.1 25.0
4 13.240 6.6818 16.0 10.1
5 13.820 6.4025 16.9 10.0
6 14.339 6.1718 6.2 2.8
7 15.320 5.7788 11.6 9.2
8 16.040 5.5209 5.2 2.0
9 16.935 5.2311 34.5 30.0
10 17.821 4.9731 100.0 100.0
11 18.280 4.8492 47.6 87.9
12 18.580 4.7715 39.1 55.3
13 19.259 4.6048 72.0 40.1
14 21.018 4.2232 30.6 40.0
15 22.699 3.9141 72.5 49.2
16 23.080 3.8503 22.4 26.1
17 23.620 3.7635 13.2 11.2
18 24.040 3.6987 7.5 4.5
19 25.160 3.5366 10.1 11.7
20 25.802 3.4501 1.9 0.6
21 26.880 3.3141 52.1 34.0
22 27.539 3.2362 11.5 14.4
23 27.918 3.1932 10.9 14.7
24 29.479 3.0275 25.3 20.2
25 30.719 2.9081 1.5 0.6
26 31.360 2.8501 13.5 9.8
27 32.420 2.7593 11.7 7.6
28 34.418 2.6036 7.5 8.8
29 35.539 2.5239 1.1 0.5
30 37.259 2.4113 4.1 2.7
31 38.000 2.3659 4.6 6.0
32 38.459 2.3387 6.6 9.2
33 38.841 2.3167 6.3 7.5
34 41.360 2.1812 5.3 5.4
35 42.320 2.1339 2.6 2.2
36 42.901 2.1063 3.1 2.5
37 44.119 2.0510 3.0 4.0
38 47.299 1.9202 4.7 4.3
39 48.000 1.8938 4.9 4.7
40 48.681 1.8689 3.4 1.7
Wherein the error at measurment of 2 θ diffraction angle is ± 0.2o.
The XRPD collection of illustrative plates of the rabeprazole sodium crystal XRPD collection of illustrative plates (see figure 1) of Sodium rabeprazole monohydrate crystals provided by the present invention and CN102584793B, CN102260244B, CN103864755A, JP2001-039975, WO2003082858A1, US20040180935, US20060135565 and US8143409B2 provided compares, finding all not identical, is a kind of new crystal formation.
The water content of Sodium rabeprazole monohydrate crystals provided by the invention is determined as 4.4 ~ 4.8% by " Chinese Pharmacopoeia " version in 2010 two annex VIII M first methods (expense Xiu Shi method).
The residual solvent of Sodium rabeprazole monohydrate crystals provided by the invention and the assay of noncrystalline water, by " Chinese Pharmacopoeia " version in 2010 two annex VIII L(dry weightless mensurations) carry out, trial-product is dried to constant weight in 105 DEG C, calculated by the weight of less loss and sampling amount, the weight loss on drying of trial-product is 0.61%.
Means of differential scanning calorimetry-thermogravimetric analysis (DSC-TG) the collection of illustrative plates (see figure 2) of Sodium rabeprazole monohydrate crystals provided by the invention has absorption peak at about 154.3 DEG C of places, weightlessness corresponding to this peak place is always changed to 5.28%, be 4.67% after the weight loss on drying rate of deduction 0.61%, for the content of crystal water, basically identical with the above-mentioned water content result taking expense Xiu Shi method to measure.
The present invention also provides the preparation method of described Sodium rabeprazole monohydrate crystal formation simultaneously, and the method comprises the steps:
(1) amorphous Sodium rabeprazole is added in good solvent, stir, dissolve, then add gac and be incubated decolouring at 25-35 DEG C, filter, obtain filtrate;
(2) under constantly stirring, in step (1) gained filtrate, add purified water, obtain mixing solutions.
(3) in step (2) gained mixing solutions, add poor solvent, cooling crystallization, filter, 45 DEG C of vacuum-dryings, to obtain final product.
According to aforesaid preparation method, wherein, the good solvent described in step (1) is selected from the mixture of one or more in acetonitrile, methylene dichloride, chloroform, ethyl acetate, butylacetate and tetrahydrofuran (THF).
According to aforesaid preparation method, wherein, in step (1), the volume (ml) of good solvent is 3.5 ~ 7.0: 1 with the ratio of the quality (g) of amorphous Sodium rabeprazole.
According to aforesaid preparation method, wherein, in step (2), the volume (ml) of purified water used is 4.5 ~ 6.0: 100 with the ratio of the quality (g) of amorphous Sodium rabeprazole.
According to aforesaid preparation method, wherein, in step (3), poor solvent used is selected from normal hexane, hexanaphthene, normal heptane, methyl tertiary butyl ether or isopropyl ether.
According to aforesaid preparation method, wherein, in step (3), the ratio of the volume of poor solvent volume and the middle good solvent of step (1) is 0.5 ~ 3.0: 1.
According to aforesaid preparation method, wherein, being cooled to described in step (3) is cooled to 2 ~ 6 DEG C.
The technique effect that the present invention is useful: Sodium rabeprazole monohydrate crystal formation provided by the present invention is for amorphous Sodium rabeprazole, it draws moist obvious reduction, thermostability obviously strengthens, foreign matter content is lower, can ensure the quality of pharmaceutical preparation better.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRPD) figure of Sodium rabeprazole monohydrate crystal formation provided by the present invention.
Means of differential scanning calorimetry-thermogravimetric analysis (DSC-TG) figure that Fig. 2 is compound shown in Fig. 1.
Embodiment
Further explain and describe content of the present invention below by way of specific embodiment, but described embodiment is not to be construed as limiting the scope of the invention.
The present invention's amorphous Sodium rabeprazole used is provided by certain pharmaceutical factory domestic, and its purity is determined as through HPLC normalization method: containing Sodium rabeprazole 99.862%, containing rabeprazole sulfone analogue 0.112%.
Embodiment 1: the preparation of Sodium rabeprazole monohydrate crystal formation
(1) amorphous Sodium rabeprazole 80g is joined in 400ml methylene dichloride, stir, dissolve, then add gac and be incubated decolouring at 25-35 DEG C, filter, obtain filtrate;
(2) under constantly stirring, in step (1) gained filtrate, add purified water 4.0ml, obtain mixing solutions;
(3) in step (2) gained mixing solutions, add normal heptane 700ml, be cooled to 3-5 DEG C, and maintain stirring and crystallizing at this temperature, filter, 45 DEG C of vacuum-dryings, obtain off-white color Sodium rabeprazole crystalline compounds 75.2g.
Adopt the water content three times of taking Xiu Shi method replicate(determination) gained Sodium rabeprazole crystalline compounds, water content mean value is 4.62%(weight percent).The theoretical water content of Sodium rabeprazole monohydrate is 4.5%, proves that gained Sodium rabeprazole crystalline compounds is monohydrate.
Measured by gained Sodium rabeprazole crystalline compounds x-ray powder diffraction, Fig. 1 is shown in by gained XRPD collection of illustrative plates.INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffractometer, with CuK αray is source of radiation, and Diffraction scans angular range is 3-60o, and scanning angle speed is 0.03o/ second.
Gained Sodium rabeprazole crystalline compounds is carried out means of differential scanning calorimetry-thermogravimetric analysis (DSC-TG) simultaneously, and Fig. 2 is shown in by gained collection of illustrative plates.Instrument is NETZSCH STA 449C simultaneous synthesis thermal analyzer, and heated perimeter is 35-600 DEG C, and rate of heating is 10 DEG C/min, and shielding gas is argon gas.
Embodiment 2: the preparation of Sodium rabeprazole monohydrate crystal formation
(1) amorphous Sodium rabeprazole 80g is joined in 400ml acetonitrile, stir, dissolve, then add gac and be incubated decolouring at 25-35 DEG C, filter, obtain filtrate;
(2) under constantly stirring, in step (1) gained filtrate, add purified water 4.0ml, obtain mixing solutions;
(3) in step (2) gained mixing solutions, add methyl tertiary butyl ether 800ml, be cooled to 3-5 DEG C, and maintain stirring and crystallizing at this temperature, filter, 45 DEG C of vacuum-dryings, obtain off-white color Sodium rabeprazole crystalline powder 73.6g.
Adopt the water content three times of taking Xiu Shi method replicate(determination) gained Sodium rabeprazole crystalline compounds, water content mean value is 4.70%(weight percent).
Measured by gained Sodium rabeprazole crystalline compounds x-ray powder diffraction, gained XRPD collection of illustrative plates is similar to embodiment 1.
Gained Sodium rabeprazole crystalline compounds NETZSCH STA 449C simultaneous synthesis thermal analyzer is carried out means of differential scanning calorimetry-thermogravimetric analysis (DSC-TG), and gained DSC-TG schemes similar to embodiment 1.
Property test example 1: hygroscopic investigation
According to the measuring method of " Chinese Pharmacopoeia " version in 2010 two annex XIX J " medicine draws moist test direction principle ", amorphous Sodium rabeprazole Sodium rabeprazole monohydrate crystals provided by the present invention and certain pharmaceutical factory domestic provided is each is placed in two weighing bottles in right amount respectively, share equally into about the thick thin layer of 1mm, uncoveredly be positioned over 25 DEG C, in the climatic chamber of RH80% ± 1%, take out after 24h, measure its percentage weight increase.Sodium rabeprazole monohydrate crystals provided by the present invention draws wet weightening finish for 1.52% and the wet weightening finish of drawing of amorphous Sodium rabeprazole that certain pharmaceutical factory domestic provides is 14.91%.Therefore Sodium rabeprazole monohydrate crystals provided by the present invention draw that moist will to be significantly less than drawing of the amorphous Sodium rabeprazole that certain pharmaceutical factory domestic provides moist.
Property test example 2: the investigation of thermostability
Amorphous Sodium rabeprazole Sodium rabeprazole monohydrate crystals provided by the present invention and certain pharmaceutical factory domestic provided is in right amount each, be loaded in two culture dish respectively, spread out into about the thick thin layer of 8mm, opening is positioned in 60 DEG C of baking ovens, in 10 days, sampling utilized high performance liquid chromatography (HPLC) method to carry out the mensuration of related substance afterwards, condition determination and method as follows: chromatographic instrument is Shimudazu LC-20A, chromatographic column is Agilent TC-C18(4.6 × 250mm, 5 μm), moving phase is 0.015mol/L SODIUM PHOSPHATE, MONOBASIC (adjusting pH to 6.0 with phosphoric acid)-acetonitrile (60:40), determined wavelength is 285nm.Get trial-product appropriate, accurately weighed, dissolve with 0.01mol/L potassium hydroxide solution and dilute the solution made and be about 0.5mg in every 1ml containing Sodium rabeprazole, precision measures this solution 20 μ l, injection liquid chromatography, record color atlas, calculate the content of each related substance by areas of peak normalization method, measurement result sees the following form:
From above-mentioned test-results, when sample is after 60 DEG C of high temperature place 10 days, the increase degree of the colour-change degree of Sodium rabeprazole monohydrate crystals provided by the present invention, rabeprazole sulfone analogue content and total impurities content is all significantly less than the amorphous Sodium rabeprazole that certain pharmaceutical factory domestic provides, and shows the amorphous Sodium rabeprazole that the thermostability of Sodium rabeprazole monohydrate crystals provided by the present invention obviously will be better than certain pharmaceutical factory domestic and provides.

Claims (10)

1. a Sodium rabeprazole monohydrate crystal formation, is characterized in that: with CuK αin the X-ray powder diffraction spectrum that radiation, 2 θ angles represent, its collection of illustrative plates has following 2 θ diffraction angle and d value:
Spectral line number 2 θ angles (°) Spacing d() I/I 0(%, with maximum peak height for benchmark) I/I 0(%, with maximum peak area for benchmark) 1 8.919 9.9061 39.5 19.5 2 9.521 9.2816 10.0 3.6 3 10.340 8.5481 44.1 25.0 4 13.240 6.6818 16.0 10.1 5 13.820 6.4025 16.9 10.0 6 14.339 6.1718 6.2 2.8 7 15.320 5.7788 11.6 9.2 8 16.040 5.5209 5.2 2.0 9 16.935 5.2311 34.5 30.0 10 17.821 4.9731 100.0 100.0 11 18.280 4.8492 47.6 87.9 12 18.580 4.7715 39.1 55.3 13 19.259 4.6048 72.0 40.1 14 21.018 4.2232 30.6 40.0 15 22.699 3.9141 72.5 49.2 16 23.080 3.8503 22.4 26.1 17 23.620 3.7635 13.2 11.2 18 24.040 3.6987 7.5 4.5 19 25.160 3.5366 10.1 11.7 20 25.802 3.4501 1.9 0.6 21 26.880 3.3141 52.1 34.0 22 27.539 3.2362 11.5 14.4 23 27.918 3.1932 10.9 14.7 24 29.479 3.0275 25.3 20.2 25 30.719 2.9081 1.5 0.6 26 31.360 2.8501 13.5 9.8 27 32.420 2.7593 11.7 7.6 28 34.418 2.6036 7.5 8.8 29 35.539 2.5239 1.1 0.5 30 37.259 2.4113 4.1 2.7 31 38.000 2.3659 4.6 6.0 32 38.459 2.3387 6.6 9.2 33 38.841 2.3167 6.3 7.5 34 41.360 2.1812 5.3 5.4 35 42.320 2.1339 2.6 2.2 36 42.901 2.1063 3.1 2.5 37 44.119 2.0510 3.0 4.0 38 47.299 1.9202 4.7 4.3 39 48.000 1.8938 4.9 4.7 40 48.681 1.8689 3.4 1.7
The error at measurment of 2 θ diffraction angle is ± 0.2o.
2. Sodium rabeprazole monohydrate crystal formation according to claim 1, is characterized in that differential calorimetric analysis (DSC) figure of described Sodium rabeprazole monohydrate has absorption peak at about 154.3 DEG C of places.
3. Sodium rabeprazole monohydrate crystal formation according to claim 1, is characterized in that, the water content of described Sodium rabeprazole monohydrate is 4.4 ~ 4.8%.
4. prepare a method for the Sodium rabeprazole monohydrate crystal formation in claim 1-3 described in arbitrary claim, it is characterized in that, carry out in accordance with the following steps:
(1) amorphous Sodium rabeprazole is added in good solvent, stir, dissolve, then add gac and be incubated decolouring at 25-35 DEG C, filter, obtain filtrate;
(2) under constantly stirring, in step (1) gained filtrate, add purified water, obtain mixing solutions;
(3) in step (2) gained mixing solutions, add poor solvent, cooling crystallization, filter, 45 DEG C of vacuum-dryings, to obtain final product.
5. the preparation method of Sodium rabeprazole monohydrate crystal formation according to claim 4, it is characterized in that, the good solvent described in step (1) is selected from the mixture of one or more in acetonitrile, methylene dichloride, chloroform, ethyl acetate, butylacetate and tetrahydrofuran (THF).
6. the preparation method of Sodium rabeprazole monohydrate crystal formation according to claim 4, is characterized in that, in step (1), the volume (ml) of good solvent is 3.5 ~ 7.0: 1 with the ratio of the quality (g) of amorphous Sodium rabeprazole.
7. the preparation method of Sodium rabeprazole monohydrate crystal formation according to claim 4, is characterized in that, in step (2), the volume (ml) of purified water used is 4.5 ~ 6.0: 100 with the ratio of the quality (g) of amorphous Sodium rabeprazole.
8. the preparation method of Sodium rabeprazole monohydrate crystal formation according to claim 4, is characterized in that, in step (3), poor solvent used is selected from normal hexane, hexanaphthene, normal heptane, methyl tertiary butyl ether or isopropyl ether.
9. the preparation method of Sodium rabeprazole monohydrate crystal formation according to claim 4, is characterized in that, in step (3), the ratio of the volume of poor solvent volume and the middle good solvent of step (1) is 0.5 ~ 3.0: 1.
10. the preparation method of Sodium rabeprazole monohydrate crystal formation according to claim 4, is characterized in that, being cooled to described in step (3) is cooled to 2 ~ 6 DEG C.
CN201510092574.0A 2015-03-02 2015-03-02 Sodium rabeprazole monohydrate crystal form and preparation method thereof Pending CN104693180A (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN114933588A (en) * 2022-06-16 2022-08-23 岳阳职业技术学院 Refining method of rabeprazole sodium crude product

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CN103864755A (en) * 2012-12-11 2014-06-18 天津市汉康医药生物技术有限公司 Rabeprazole sodium compound

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CN103864755A (en) * 2012-12-11 2014-06-18 天津市汉康医药生物技术有限公司 Rabeprazole sodium compound

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CN114933588A (en) * 2022-06-16 2022-08-23 岳阳职业技术学院 Refining method of rabeprazole sodium crude product

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