CN101250181A - S-pantoprazole sodium - Google Patents
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- CN101250181A CN101250181A CNA2008100245338A CN200810024533A CN101250181A CN 101250181 A CN101250181 A CN 101250181A CN A2008100245338 A CNA2008100245338 A CN A2008100245338A CN 200810024533 A CN200810024533 A CN 200810024533A CN 101250181 A CN101250181 A CN 101250181A
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Abstract
The invention relates to S-pantoprazole sodium, a relative preparation method and an application. The S-pantoprazole sodium is characterized in that its chemical approved name is (S)-5-difluoromethoxy-2-[(3, 4-dimethoxy-2-pyridyl) methyl] sulfinyl-1H-sodium benzimidazole in amorphous solid type, whose water content is 0.1-1.9%. The preparation method comprises (a) mixing S-pantoprazole and tetrahydrofuran, adding sodium hydride and reacting, wherein the mol ratio between the sodium hydride and S-pantoprazole is 1:1, and the volume of the added tetrahydrofuran is 2-50 times of the mass of S-pantoprazole, (b) adding ether into the reaction liquor to crystallize S-pantoprazole sodium, wherein the added amount of ether is 1-10 times of the volume of tetrahydrofuran, (c) filtering the crystallization liquid and drying in vacuum to obtain amorphous S-pantoprazole sodium, wherein the drying temperature is 20-50DEG C.
Description
Technical field
What S-Pantoprazole Sodium of the present invention related to is a kind of amorphous S-pantoprazole sodium and preparation method thereof, application.
Background technology
2-(2-picolyl) the sulfinyl-1 H-benzimidazole derivative that replaces is known gastric proton pump inhibit, and these benzimidizole derivatives comprise omeprazole, pantoprazole, lansoprazole and rabeprazole etc.They have identical gastric acid inhibitory excretory function, therefore usually as anti ulcer agent.
Pantoprazole Sodium (pantoprazole sodium) chemistry 5-difluoro-methoxy-2-[(3 by name, 4-dimethoxy-2-pyridyl) methyl] sulfinyl-1H-benzimidazolyl sodium, structural formula is
Pantoprazole is sulfoxide and chipal compounds, and wherein sulphur atom is to form the spatial center.Therefore, pantoprazole is the racemic mixture of two kinds of single enantiomer R and S type enantiomorph, and its salt also has corresponding configuration.Describing the S-Pantoprazole Sodium in the U.S. Pat 5888535 has than racemic modification Pantoprazole Sodium and the stronger gastric acid inhibitory excretory effect of R type isomer.The S-Pantoprazole Sodium can be used for the treatment of as proton pump inhibitor research and the disorderly diseases associated of gastric acid secretion as Esso omeprazole (esomeprazole), as is used for peptide ulceration (stomach ulcer, duodenal ulcer, stoma ulcer etc.) and treatment of diseases such as hemorrhage, reflux esophagitis, Zollinger Ellison syndrome thereof.
The preparation method of pantoprazole single enantiomer describes in patents such as WO92/08716, CN1070489, CN1717402 to some extent, and what wherein CN1070489 adopted is the method for chiral oxidization.
Chinese patent CN1369491 discloses the preparation method of S-Pantoprazole Sodium, potassium, magnesium, calcium, zinc salt, and wherein the S-Pantoprazole Sodium of disclosed preparation is a S-pantoprazole sodium-hydrate.
Chinese patent CN1822835 discloses a series of basic salt compounds such as S-pantoprazole hydroxyl magnesium monohydrate, S-pantoprazole hydroxyl two magnesium pentahydrates, S-pantoprazole hydroxyl calcium monohydrate, S-pantoprazole hydroxyl zinc monohydrate.
International Patent Application WO 2005/070426, WO2005/074929, US2006/0216346 etc. disclose the preparation method of S-pantoprazole sodium salt and magnesium salts thereof, and said hydration S-Pantoprazole Sodium all is a crystalline form in the patent.
Chinese patent CN1312150 discloses the synthetic of S-pantoprazole-magnesium dihydrate and S-pantoprazole sodium hydrate, and the hydration S-Pantoprazole Sodium enhydrous amount of its preparation is between 2%～12%.Disclosing the crystallization of its hydration S-Pantoprazole Sodium in the patent is not a stable form, and it is deposited all colors and becomes brown under 70 ℃, and forms a large amount of degradation productions.
Summary of the invention
The objective of the invention is provides a kind of S-Pantoprazole Sodium and preparation method thereof at above-mentioned weak point, and the S-Pantoprazole Sodium is a kind of new solid form, and described solid form is amorphous.S-Pantoprazole Sodium amorphous form and S-Pantoprazole Sodium crystal habit relatively are to demonstrate favorable properties, and stability study finds that S-Pantoprazole Sodium amorphous form is stable than crystal habit, and especially related substance is much smaller than crystal habit.S-Pantoprazole Sodium amorphous form isomer in put procedure does not change substantially yet, and the racemization phenomenon does not take place.Uniform particles, prevented from caking and the moisture absorption of S-Pantoprazole Sodium amorphous form crystallizing and separating.
The S-Pantoprazole Sodium takes following scheme to realize:
The S-Pantoprazole Sodium; it is characterized in that general (the S)-5-difluoro-methoxy-2-[(3 by name of chemistry; 4-dimethoxy-2-pyridyl) methyl] solid form of sulfinyl-1H-benzimidazolyl sodium, described solid form is amorphous, its contained humidity is 0.1%～1.9%.
By the research to S-Pantoprazole Sodium preparation and process for purification, unexpected discovery S-Pantoprazole Sodium is except can be with monohydrate and sesquialter hydrate (1.5H
2O) also there is the amorphous solid form in crystal habit outside existing, and its contained humidity is 0.1%～1.9%.S-pantoprazole sodium-hydrate and sesquialter hydrate (1.5H in the following explanation
2O) be referred to as S-Pantoprazole Sodium crystal habit, S-Pantoprazole Sodium amorphous form (its contained humidity is 0.1%～1.9%) is referred to as S-Pantoprazole Sodium amorphous form.
A kind of preparation method of S-Pantoprazole Sodium comprises the steps:
(a) the S-pantoprazole is mixed stirring with tetrahydrofuran (THF), add the sodium hydride reaction, the sodium hydride of adding and S-pantoprazole mol ratio are 1: 1, and the tetrahydrofuran (THF) volume of adding is 2～50 times of S-pantoprazole weight;
(b) add ether in last step reaction solution and separate out the S-Pantoprazole Sodium, the amount that adds ether is 1～10 times of tetrahydrofuran (THF) volume;
(c) the crystallization liquid that will go up step gained S-Pantoprazole Sodium filters, and vacuum-drying gets unbodied S-Pantoprazole Sodium, and drying temperature is 20～50 ℃.
The volume that adds tetrahydrofuran (THF) among the preparation method of above-mentioned a kind of S-Pantoprazole Sodium is preferably 5～20 times of S-pantoprazole weight, and the amount that adds ether is preferably 2～5 times of tetrahydrofuran (THF) volume, and the exsiccant temperature is preferably 30～45 ℃.
S-Pantoprazole Sodium amorphous form and S-Pantoprazole Sodium crystal habit relatively are to demonstrate favorable properties, stability study finds that S-Pantoprazole Sodium amorphous form is stable than crystal habit, and especially related substance is than crystal habit much smaller (see Table 1, table 2).S-Pantoprazole Sodium amorphous form isomer in put procedure does not change substantially yet, and the racemization phenomenon does not take place.The uniform particles of S-Pantoprazole Sodium amorphous form crystallizing and separating, prevented from caking and moisture absorption, therefore can be in industrial processes, as feeding with fixed amount in the pharmaceutical technology, opposite, S-Pantoprazole Sodium crystal habit must be with up-to-date S-Pantoprazole Sodium analytical results or is calculated charging capacity from the latest analysis result of its water-content indirectly.
The application of described amorphous S-pantoprazole sodium in preparation treatment gastrointestinal illness pharmaceutical preparation.
The S-Pantoprazole Sodium is effectively as gastric acid secretion inhibitor, and can be used as anti ulcer agent.With S-Pantoprazole Sodium amorphous form is that the pharmaceutical composition of activeconstituents is mainly used in peptide ulceration (stomach ulcer, duodenal ulcer, stoma ulcer etc.) and hemorrhage, comprise acute gastric mucosa damage and stress ulcer hemorrhage that non-steroidal anti-inflammatory drugs causes, also can be used for reflux esophagitis, also be used for after whole body fiber crops acid or the major operation and weak comatose patient, to prevent that regurgitation of gastric juice from merging aspiration pneumonitis, tall and erect Emhorn condensation is levied.With other antibacterials (as clarithromycin.Amoxycilline Trihydrate bp and metronidazole) coupling, treatment helicobacter pylori (Hp) infects, and reduces duodenal ulcer and gastric ulcer recurrence.
Any suitable route of administration may be used to provide the S-Pantoprazole Sodium amorphous form of significant quantity to the patient.For example, can use oral or parenteral administration etc.Formulation comprises capsule, tablet, powder, solution, crystallization liquid or the like.Because it has very high solubleness in water, S-Pantoprazole Sodium amorphous form is particularly suitable for parenteral administration, as is used for the preparation of intravenous administration.
In practice of the present invention, the therapeutic dose of only route of administration and S-Pantoprazole Sodium amorphous form all will depend on by the character and the seriousness of treatment disease under any given situation.Dosage and administration frequency also can change according to each patient's age, body weight and reaction.The patient of children and liver problem sufferer and long-term treatment generally will lack on dosage, and is lower than mean value sometimes.Therefore, in some cases, need to use the dosage outside the described below scope.
In general, the suitable dose of administered parenterally is 5mg to 100mg, is preferably 10mg to 60mg.
Description of drawings
The invention will be further described below with reference to accompanying drawing.
Fig. 1 is the X-ray powder diffraction figure of S-Pantoprazole Sodium amorphous form.
Fig. 2 is the X-ray powder diffraction figure of S-Pantoprazole Sodium crystal habit.
Fig. 3 is the Fourier infrared spectrum figure of S-Pantoprazole Sodium amorphous form.
Fig. 4 is the Fourier infrared spectrum figure of S-Pantoprazole Sodium crystal habit.
With reference to accompanying drawing 1, accompanying drawing 2: S-pantoprazole sodium amorphous form prepared in accordance with the present invention can lead to Cross a kind of known technology X-ray powder diffraction carry out analysis and characterization and with the S-pantoprazole sodium crystal habit Distinguished. Do not demonstrate in the X-ray powder diffraction pattern of S-pantoprazole sodium amorphous form and can show Levy the characteristic peak (seeing Fig. 1) of S-pantoprazole sodium crystal habit, and the X of S-pantoprazole sodium crystal habit Show the characteristic peak (seeing Fig. 2) of obvious crystal habit in the-ray powder diffraction pattern, it is about at 2 θ angles 6.02,9.88,11.38,11.80,12.04,14.92,15.26,16.90,17.80,18.08,19.36, 20.28,20.54,21.04,22.74,24.54,25.16,25.66,26.10,26.46,27.54,29.28, 29.66 29.86 degree places have the feature at peak. The X-ray powder diffraction adopts rotation sun level X-ray diffractometer D/max-YA Rigaku (day) measures, condition determination: tube voltage 40KV, and tube current 40mA, the target type is Cu, 8 ° of min of sweep speed-1, 45 ° at scan abort angle, 0.02 ° of stepped intervals.
With reference to accompanying drawing 3, accompanying drawing 4: S-pantoprazole sodium amorphous form prepared in accordance with the present invention and S-Another appropriate technology that the Pantoprazole Sodium crystal habit is distinguished is conventional Fourier infrared spectrum (FTIR). By comparison shows that the infrared signature of two kinds of solid forms absorbs different (seeing accompanying drawing 3, accompanying drawing 4). The infrared spectrum analyser model is WQF-510, and sample carries out infrared spectrum measurement through pressing potassium bromide troche.
Embodiment
Further specify the present invention below by embodiment.Should correct understanding be: the method in the embodiments of the invention is only used for the present invention is described and provides, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
Embodiment 1:
The preparation of S-Pantoprazole Sodium amorphous form:
S-pantoprazole 20g (0.052mol) and 200ml tetrahydrofuran (THF) are mixed stirring, slowly add sodium hydride 2.09g (content 60%, 0.052mol), stirring reaction 30 minutes, be added dropwise to ether 400ml, separate out a large amount of white solids, filter, 40 ℃ of vacuum-drying 4h get white unbodied S-Pantoprazole Sodium 19.5g, yield: 92.5%.Moisture: 0.72%, it is 99.82% that HPLC detects chemical purity, optical purity is 99.92%.
The preparation method of attached S-Pantoprazole Sodium crystal habit:
The S-Pantoprazole Sodium of crystal habit can adopt patent CN1369491 or the disclosed technology preparation of CN1312150.
In reaction flask, add S-pantoprazole 18g (0.047mol), 90ml methyl iso-butyl ketone (MIBK), 9ml Virahol respectively, open and stir, be heated to 45 ℃, stir 15min, be warming up to 50 ℃ then, (concentration 30% is W/W) to reaction solution, behind the insulated and stirred 15min slowly to be added dropwise to the 5.5g sodium hydroxide solution, filter, filtrate is cooled to 10 ℃, separates out a large amount of solids, crystallization 2h, filter, filter cake washs with methyl iso-butyl ketone (MIBK), and 40 ℃ of vacuum-drying 4h get off-white color-beige crystallized product 17g, yield 83.6%.Moisture: 6.50%, it is 99.75% that HPLC detects chemical purity, optical purity is 99.56%.
High temperature test:
The sample of getting S-Pantoprazole Sodium amorphous form and S-Pantoprazole Sodium crystal habit is an amount of, put in the glass dish, respectively at placing 10 days under 40 ℃, the 60 ℃ conditions, during this period, respectively at sampling in the 5th, 10 day, investigate every index by study on the stability content and method, the results are shown in Table 1, table 2.From table, can find out that S-Pantoprazole Sodium amorphous form is stable than crystal habit.
Chemical purity detection method: lucifuge operation.It is an amount of that precision takes by weighing this product fine powder, adds the moving phase dissolving and make the solution that contains S-Pantoprazole Sodium 0.2mg among every 1ml approximately, filters, and gets subsequent filtrate as need testing solution; Precision is measured in right amount, makes the solution solution in contrast that contains 2 μ g among every 1ml with moving phase dilution.Measuring according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2005 D), is weighting agent with octadecylsilane chemically bonded silica; Be moving phase with phosphate buffered saline buffer (get Sodium phosphate dibasic 1.12g and SODIUM PHOSPHATE, MONOBASIC 0.18g, be dissolved in water and be diluted to 1000ml)-acetonitrile (70: 30); The detection wavelength is 288nm; Number of theoretical plate calculates by the pantoprazole peak and is not less than 2500.Get contrast solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, the peak height that makes the principal constituent chromatographic peak is 10%～20% of a full range; Precision is measured need testing solution and each 20 μ l of contrast solution again, injects liquid chromatograph respectively, and the record color atlas is to 2 times of principal constituent peak retention time.In the color atlas of need testing solution if any impurity peaks, measure with principal constituent peak relative retention time more than 0.24 each impurity peak area and must not be greater than 1.5 times of contrast solution main peak area.
Optical purity detection method: lucifuge operation.It is an amount of that precision takes by weighing this product fine powder, adds the moving phase dissolving and make the solution that contains S-Pantoprazole Sodium 0.2mg among every 1ml approximately, filters, and gets subsequent filtrate as need testing solution; Precision is measured the Pantoprazole Sodium raceme, makes the solution solution in contrast that contains 2 μ g among every 1ml with moving phase dilution.Measure chromatographic column: AD-H post according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2005 D); With normal hexane: dehydrated alcohol: acetate (200ml: 200ml: be moving phase 20 μ L); The detection wavelength is 302nm; Number of theoretical plate calculates by S-Pantoprazole Sodium peak and is not less than 2500.Get contrast solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, the peak height that makes the principal constituent chromatographic peak is 40%～50% of a full range; Precision is measured need testing solution 20 μ l again, injects liquid chromatograph, the record color atlas.If any impurity peaks, contain the R-isomer and must not cross 0.5% in the color atlas of need testing solution.
The stability result of table 1S-Pantoprazole Sodium amorphous form high temperature test
The stability result of table 2S-Pantoprazole Sodium crystal habit high temperature test
High wet test:
Get S-Pantoprazole Sodium amorphous form and S-Pantoprazole Sodium crystal habit is an amount of, put in the glass dish, the stand is into about the thick thin layer of 4mm, place 25 ℃, in the encloses container of relative humidity 92.5%, placed 10 days, during this period respectively at sampling in the 5th, 10 day, investigate every index by this product study on the stability content and method, test-results sees Table 3.Can find out that from table 3 S-Pantoprazole Sodium amorphous form is little than the crystal habit water absorbability.
The moisture determination result of the high wet test of table 3S-Pantoprazole Sodium
The X-ray powder diffraction is analyzed
S-Pantoprazole Sodium amorphous form prepared in accordance with the present invention can carry out analysis and characterization and distinguished with S-Pantoprazole Sodium crystal habit by a kind of known technology X-ray powder diffraction.Do not demonstrate the characteristic peak (see figure 1) that can characterize S-Pantoprazole Sodium crystal habit in the X-ray powder diffraction pattern of S-Pantoprazole Sodium amorphous form, and show the characteristic peak (see figure 2) of tangible crystal habit in the X-ray powder diffraction pattern of S-Pantoprazole Sodium crystal habit, it is about 6.02,9.88,1138 at 2 θ angles, 11.80,12.04,14.92,15.26,16.90,17.80,18.08,19.36,20.28,20.54,21.04,22.74,24.54,25.16,25.66,26.10,26.46,27.54,29.28,29.66 29.86 degree places have the feature at peak.The X-ray powder diffraction adopts rotation sun level X-ray diffractometer D/max-YA Rigaku (day) to measure condition determination: tube voltage 40KV, and tube current 40mA, the target type is Cu, 8 ° of min of sweep velocity
-1, 45 ° at scan abort angle, 0.02 ° of stepped intervals.
Fourier infrared spectrum (FTIR) is analyzed
Characterize S-Pantoprazole Sodium amorphous form and S-Pantoprazole Sodium crystal habit with Fourier infrared spectrum (FTIR).By comparing the infrared absorption peak difference (seeing accompanying drawing 3, accompanying drawing 4) that infared spectrum shows two kinds of crystal formations.
The infrared spectrum analyser model is WQF-510, and sample carries out infrared measurement through pressing potassium bromide troche.
Embodiment 2:
The preparation of S-Pantoprazole Sodium amorphous form:
S-pantoprazole 5g (0.013mol) and 100ml tetrahydrofuran (THF) mixed stir, slowly add sodium hydride 0.52g (content 60%, 0.013mol), stirring reaction 30 minutes is added dropwise to ether 500ml, separates out solid, filter, 35 ℃ of vacuum-drying 4h get product 4.6g, yield: 87.3%.Moisture: 0.52%, it is 99.79% that HPLC detects chemical purity, optical purity is 99.90%.
Embodiment 3:
The preparation of S-Pantoprazole Sodium amorphous form:
S-pantoprazole 5g (0.013mol) and 25ml tetrahydrofuran (THF) mixed stir, slowly add sodium hydride 0.52g (content 60%, 0.013mol), stirring reaction 30 minutes is added dropwise to ether 250ml, separates out solid, filter, room temperature (23 ℃) vacuum-drying 4h gets product 4.7g, yield: 89.2%.Moisture: 0.83%, it is 99.69% that HPLC detects chemical purity, optical purity is 99.87%.
Embodiment 4:
The preparation of S-Pantoprazole Sodium amorphous form:
S-pantoprazole 2.5g (6.5mmol) and 10ml tetrahydrofuran (THF) mixed stir, slowly add sodium hydride 0.26g (content 60%, 6.5mmol), stirring reaction 30 minutes is added dropwise to ether 40ml, separates out solid, filter, 40 ℃ of vacuum-drying 4h get product 2.1g, yield: 79.7%.Moisture: 1.65%, it is 99.76% that HPLC detects chemical purity, optical purity is 99.84%.
Embodiment 5:
The preparation of S-Pantoprazole Sodium amorphous form:
S-pantoprazole 2.5g (6.5mmol) and 5ml tetrahydrofuran (THF) mixed stir, slowly add sodium hydride 0.26g (content 60%, 6.5mmol), stirring reaction 30 minutes is added dropwise to ether 5ml, separates out solid, filter, 50 ℃ of vacuum-drying 4h get product 1.9g, yield: 72.1%.Moisture: 0.10%, it is 99.72% that HPLC detects chemical purity, optical purity is 99.81%.
Embodiment 6:
The preparation of S-Pantoprazole Sodium amorphous form:
S-pantoprazole 2.5g (6.5mmol) and 125ml tetrahydrofuran (THF) mixed stir, slowly add sodium hydride 0.26g (content 60%, 6.5mmol), stirring reaction 30 minutes is added dropwise to ether 125ml, separates out solid, filter, 30 ℃ of vacuum-drying 4h get product 2.0g, yield: 75.9%.Moisture: 1.90%, it is 99.81% that HPLC detects chemical purity, optical purity is 99.93%.
Embodiment 7:
The preparation of S-Pantoprazole Sodium amorphous form:
S-pantoprazole 400g (1.04mol) and 4000ml tetrahydrofuran (THF) mixed stir, slowly add sodium hydride 41.6g (content 60%, 1.04mol), stirring reaction 30 minutes is added dropwise to ether 12L, separates out solid, filter, 40 ℃ of vacuum-drying 4h get product 389g, yield: 92.3%.Moisture: 0.68%, it is 99.43% that HPLC detects chemical purity, optical purity is 99.87%.
Embodiment 8:
Contain the preparation of the lyophilized injectable powder (20mg) of S-Pantoprazole Sodium amorphous form:
1, prescription
S-Pantoprazole Sodium amorphous form 44.2g
(being equivalent to the S-pantoprazole) 40.0g
Water for injection adds to 2000ml
The packing freeze-drying is made 2000 bottles
2, sample solution preparation
In the aseptic technique environment, get the recipe quantity Pantoprazole Sodium, add 80% amount water for injection, stirring makes dissolving, adds lactose again and stirs evenly, and adds to the full amount of water for injection, measure intermediate content, after qualified, with 0.22 μ m filtering with microporous membrane, filtrate is sub-packed in the 10ml cillin bottle by every bottle of 2.0ml, part is the isoprene-isobutylene rubber base beyond the Great Wall, freeze drying box is sent in sabot, freeze-drying.
3, freeze drying process
Sabot is treated that the freeze-drying sample puts in the freeze drying box, close chamber door, the start refrigeration, utilize thermal oil that the product temperature is descended, continued freezing 2 hours when following when the product temperature reaches eutectic point, in the time of product Wen Da-40 ℃, stop thermal oil, the open cold condenser is when condenser temperature reaches-40 ℃, open vacuum system, with the 2-4 ℃ of sublimation drying that heats up that per hour raise, the final drying temperature is 33～35 ℃, keep this temperature after 3 hours, tamponade, outlet are used the aluminium-plastic cap tying, packing after quality inspection is qualified, promptly.
Embodiment 9:
Contain the preparation of the enteric-coated pellet capsule (10mg) of S-Pantoprazole Sodium amorphous form:
1, prescription
(1) micropill
Whenever make 4000
S-Pantoprazole Sodium amorphous form 44.3g
(being equivalent to S-Pantoprazole Sodium 40g)
Starch 60g
Lactose 40g
N.F,USP MANNITOL 35g
Low-substituted hydroxypropyl cellulose 30g
Microcrystalline Cellulose PH101 20g
5% 30 POVIDONE K 30 BP/USP
30Ethanolic soln is an amount of
(2) barrier gown
Gastric soluable Opadry 100g
80% aqueous ethanolic solution is made 1000ml
(3) enteric coating
Enteric solubility Opadry 100g
88% aqueous ethanolic solution is made 1000ml
2, operating process
(1) micropill preparation
Get the raw material of recipe quantity and cross 200 mesh sieves; supplementary product starch, lactose, N.F,USP MANNITOL, low-substituted hydroxypropyl cellulose and Microcrystalline Cellulose PH101 cross 120 mesh sieves respectively; with the equivalent method of progressively increasing raw material and other auxiliary material are crossed 80 mesh sieves and mix, the gained compound is used 5% 30 POVIDONE K 30 BP/USP in the coating pelletizing machine
30Ethanolic soln is rolled onto micropill as tackiness agent, in 35～40 ℃ of forced air dryings, gets micropill between 18～24 orders, and is standby after quality inspection is qualified.
(2) bag barrier gown
Above-mentioned ball core is put in the fluidized-bed, and with 10% gastric soluable Opadry, 80% aqueous ethanolic solution bag barrier gown, the control inlet temperature is 36～38 ℃, and air outlet temperature is 33～35 ℃, until ball core weightening finish 3%, gets final product.
(3) enteric coated
Above-mentioned ball core is put in the fluidized-bed, and enteric coated with 10% enteric solubility Opadry, 88% aqueous ethanolic solution, the control inlet temperature is 36～38 ℃, and air outlet temperature is 33～35 ℃, until ball core weightening finish 8%, gets final product.
(4) can
Above-mentioned micropill is after quality inspection is qualified, and can is to hard capsule case, and packing gets final product.
Claims (6)
1, a kind of S-Pantoprazole Sodium; it is characterized in that general (the S)-5-difluoro-methoxy-2-[(3 by name of chemistry; 4-dimethoxy-2-pyridyl) methyl] solid form of sulfinyl-1H-benzimidazolyl sodium, described solid form is amorphous, its contained humidity is 0.1%～1.9%.
2. the preparation method of the described S-Pantoprazole Sodium of claim 1 comprises the steps:
(a) the S-pantoprazole is mixed stirring with tetrahydrofuran (THF), add the sodium hydride reaction, the sodium hydride of adding and S-pantoprazole mol ratio are 1: 1, and the tetrahydrofuran (THF) volume of adding is 2～50 times of S-pantoprazole weight;
(b) add ether in last step reaction solution and separate out the S-Pantoprazole Sodium, the amount that adds ether is 1～10 times of tetrahydrofuran (THF) volume;
(c) the crystallization liquid that will go up step gained S-Pantoprazole Sodium filters, and vacuum-drying gets unbodied S-Pantoprazole Sodium, and drying temperature is 20～50 ℃.
3. the preparation method of S-Pantoprazole Sodium according to claim 2 is characterized in that the tetrahydrofuran (THF) volume that adds is 5～20 times of S-pantoprazole weight.
4. the preparation method of S-Pantoprazole Sodium according to claim 2, the amount that it is characterized in that adding ether is 2～5 times of tetrahydrofuran (THF) volume.
5. the preparation method of S-Pantoprazole Sodium according to claim 2 is characterized in that the exsiccant temperature is 30～45 ℃.
6. the application of the described amorphous S-pantoprazole sodium of claim 1 in preparation treatment gastrointestinal illness pharmaceutical preparation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7915423B2 (en) | 2002-12-19 | 2011-03-29 | Teva Pharmaceutical Industries, Ltd. | Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates |
| CN103467451A (en) * | 2012-06-07 | 2013-12-25 | 上海汇伦生命科技有限公司 | Preparation method for S-pantoprazole sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994024867A1 (en) * | 1993-04-27 | 1994-11-10 | Sepracor, Inc. | Methods and compositions for treating gastric disorders using optically pure (-) pantoprazole |
| WO2005074932A1 (en) * | 2004-01-28 | 2005-08-18 | Altana Pharma Ag | The use of (s) - pantoprazole magnesium for the treatment of airway disorders |
| WO2005074931A1 (en) * | 2004-01-28 | 2005-08-18 | Altana Pharma Ag | Pharmaceutical combinations comprising (s) -pantoprazole |
-
2008
- 2008-03-26 CN CN 200810024533 patent/CN101250181B/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7915423B2 (en) | 2002-12-19 | 2011-03-29 | Teva Pharmaceutical Industries, Ltd. | Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates |
| CN103467451A (en) * | 2012-06-07 | 2013-12-25 | 上海汇伦生命科技有限公司 | Preparation method for S-pantoprazole sodium |
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| CN101250181B (en) | 2011-04-27 |
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