CN102234265A - Lansoprazole compound - Google Patents
Lansoprazole compound Download PDFInfo
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- CN102234265A CN102234265A CN2011102247467A CN201110224746A CN102234265A CN 102234265 A CN102234265 A CN 102234265A CN 2011102247467 A CN2011102247467 A CN 2011102247467A CN 201110224746 A CN201110224746 A CN 201110224746A CN 102234265 A CN102234265 A CN 102234265A
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- lansoprazole
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- 0 *C*c1ccnc(C(Cc2nc3ccccc3[n]2)C=O)c1* Chemical compound *C*c1ccnc(C(Cc2nc3ccccc3[n]2)C=O)c1* 0.000 description 1
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to a dexlansoprazole compound and a preparation method thereof. The compound comprises 2.5 crystal water molecules, and has the advantages that: the chemical purity is 99.95 percent, the highest content of impurities is less than 0.1 percent, the optical purity is 99.99 percent ee, and the stability is high. The invention also relates to application of a composition of the compound in preparation of medicines for treating stomach burning caused by non-erosive gastro-oesophageal reflux and erosive esophagitis.
Description
Technical field
The invention belongs to medical technical field, be specifically related to R-lansoprazole compound and preparation method thereof, the invention still further relates to the composition manufacturing of using this hydrate and treat the stomach burning sensation that non-erosive gastroesophageal reflux causes, the application in the erosive esophagitis medicine.
Background technology
Lansoprazole is after omeprazole, the proton pump inhibitor of second listing.Owing to introduced fluorine, make its character be different from omeprazole, thermodynamics and oxidative stability increase, and have improved biological activity greatly.Be used for the treatment of stomach ulcer, duodenal ulcer and reflux esophagitis, and be used for eliminating pylorus.
Lansoprazole has a chiral centre sulphur atom, therefore has two optical isomers.The lansoprazole drug effect that studies show that (R)-configuration obviously is better than the lansoprazole raceme, and optically active blue rope azoles toxic side effect is lower than raceme.
R-lansoprazole controlled release capsule (dexlansoprazole) listing of FDA approval Tap Pharmaceutical Products (US) is used for the treatment of the treatment of keeping of stomach burning sensation, erosive esophagitis and erosive esophagitis that non-erosive gastroesophageal reflux causes.28 all randomized, double-blind comparative studies by a definite date contrast the curative effect that this product and lansoprazole are used for the treatment of erosive esophagitis respectively.The result shows that during 8 weeks, this product (60 mg) group curative ratio is than lansoprazole group height, and patient tolerability is good.
R-lansoprazole (delansoprazole), molecular formula: C
16H
14F
3N
3O
2S, structural formula is as follows:
The R-lansoprazole structural formula
R-lansoprazole has multiple crystal formation, as WO2009113696A1, and WO2009088857A1, WO2009087672A1, United States Patent (USP) 20110009637A1, WO2011004387A2, EP2216333A2, WO2010039885A2 or the like discloses numerous different crystal formations.
In research process, repeat the method for above-mentioned patent documentation, the impurity number that obtains R-lansoprazole is more, and total impurities is higher, and optical purity is low.The R-lansoprazole that the present invention obtains, contain two hypocrystalline water, the advantage that has: chemical purity height, maximum contaminant be less than 1 ‰, the optical purity height; Good stability.
Summary of the invention
One object of the present invention discloses two semihydrates of a kind of R-lansoprazole.
Another object of the present invention discloses the preparation method of two semihydrates of R-lansoprazole.
Another purpose of the present invention discloses the pharmaceutical composition that comprises two semihydrates of R-lansoprazole.
The invention also discloses the application of two semihydrates of R-lansoprazole in making medicines such as stomach burning sensation that treatment stomach ulcer, non-erosive gastroesophageal reflux causes, erosive esophagitis.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The invention provides two semihydrates of a kind of R-lansoprazole (shown in the formula I)
（Ⅰ）
Karl Fischer method (Karl Fischer method) is in a kind of all kinds of chemical processes of measuring moisture in the material, and, the most accurately method the most single-minded to water has been listed in the standard method of moisture determination in many materials, organic compound especially, reliable results.
Through 8 batches of mensuration, the moisture that described invention compound contains is between 10.78%-10.95% (weight percent).The theoretical content of water is 10.87% in two semihydrates of R-lansoprazole, can assert that the invention compound contains two hypocrystalline water.
Two semihydrate crystal of this R-lansoprazole adopt D/Max-2500.9161 type x-ray diffractometer to measure condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value are as follows, see Fig. 1.
| Peak number | 2 θ angles (°) measured value | D() measured value | I/ |
| 1 | 5.700 | 15.4919 | 18 |
| 2 | 9.860 | 8.9632 | 33 |
| 3 | 10.900 | 8.1102 | 9 |
| 4 | 11.400 | 7.7556 | 61 |
| 5 | 12.440 | 7.1094 | 78 |
| 6 | 13.980 | 6.3295 | 13 |
| 7 | 14.900 | 5.9407 | 32 |
| 8 | 16.100 | 5.5005 | 22 |
| 9 | 17.080 | 5.1871 | 61 |
| 10 | 17.280 | 5.1275 | 32 |
| 11 | 18.140 | 4.8863 | 7 |
| 12 | 18.860 | 4.7014 | 100 |
| 13 | 19.840 | 4.4713 | 33 |
| 14 | 20.420 | 4.3456 | 30 |
| 15 | 21.920 | 4.0515 | 11 |
| 16 | 23.080 | 3.8504 | 19 |
| 17 | 23.620 | 3.7636 | 88 |
| 18 | 24.480 | 3.6333 | 43 |
| 19 | 25.040 | 3.5533 | 21 |
| 20 | 26.140 | 3.4062 | 18 |
| 21 | 26.360 | 3.3783 | 22 |
| 22 | 27.040 | 3.2948 | 6 |
| 23 | 27.400 | 3.2524 | 36 |
| 24 | 28.300 | 3.1509 | 6 |
| 25 | 28.760 | 3.1016 | 18 |
| 26 | 29.000 | 3.0764 | 91 |
| 27 | 30.000 | 2.9761 | 11 |
| 28 | 30.500 | 2.9285 | 6 |
| 29 | 32.620 | 2.7428 | 5 |
| 30 | 33.360 | 2.6837 | 6 |
| 31 | 35.140 | 2.5517 | 4 |
| 32 | 37.060 | 2.4238 | 7 |
| 33 | 38.000 | 2.3660 | 8 |
| 34 | 39.440 | 2.2828 | 5 |
| 35 | 39.760 | 2.2652 | 6 |
| 36 | 31.540 | 2.1721 | 5 |
| 37 | 42.680 | 2.1167 | 5 |
| 38 | 43.240 | 2.0906 | 5 |
| 39 | 44.380 | 2.0395 | 10 |
| 40 | 48.340 | 1.8813 | 7 |
The mensuration of 2 θ values is used light source among the present invention, and precision is ± 0.2 °, therefore represents above-mentioned value of getting to allow certain reasonably limit of error, and its limit of error is ± 0.2 °.
The correction polystyrene film of instrument when infrared spectrogram is measured meets the regulation of Chinese Pharmacopoeia.
This crystal formation infrared spectrogram (KBr pressed disc method mensuration) is at 3340 ± 5cm
-13375 ± 5cm
-13190 ± 5cm
-13340 ± 5cm
-12970 ± 5cm
-12907 ± 5cm
-12837 ± 5cm
-11597 ± 2cm
-11154 ± 2cm
-1There is characteristic peak at the place.
Another object of the present invention discloses two semihydrate crystalline of R-lansoprazole preparation method, by with R-lansoprazole in the dissolving of Virahol-acetate-heated in water solution, naturally cool to room temperature, be incubated for some time again to obtain.
Comprise the following steps: that specifically R-lansoprazole adds in the mixed solution of 5-6 times of (weight or measurement (WM) ratio) Virahol-acetate-water=5-6:1-2:3-4, is heated to 68 ℃-72 ℃, filtered while hot, naturally cool to room temperature, be incubated 5-7 hour again, separate out crystallization, filter, drying obtains.
Used R-lansoprazole, the method that reference US6462058 provides is synthetic, and the synthetic R-lansoprazole shows the feature of unformed powder, and its chemical structure proves that through determination of elemental analysis chemical structure is correct.
Another purpose of the present invention provides the composition that comprises two semihydrates of R-lansoprazole that the pharmaceutically acceptable carrier of two semihydrate crystal of R-lansoprazole and one or more forms.
Preparation of pharmaceutical compositions of the present invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Said composition is used to prepare oral preparations, injection.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can be according to patient's the state of an illness, specific being applied of situation of diagnosis, the amount of used compound or concentration are regulated in the scope of a broad, and the weight range of active compound is 1%～30%(weight of composition).
The present invention also provides the application in making medicines such as stomach burning sensation that treatment stomach ulcer, non-erosive gastroesophageal reflux causes, erosive esophagitis of R-lansoprazole two semihydrate crystal.
Through animal (male rat) test, give alcohol induced gastric mucosa injury rats and irritate stomach, experimental result shows: learn through stomach-tissue and observe the visible a large amount of downright bad materials in damage model group rat ulcer bottom, neutrophil infiltration is obvious in the surrounding tissue; Neutrophil infiltration all obviously reduces than damage model group in the unformed powder group ulcer downright bad material in bottom of crystal formation of the present invention and R-lansoprazole and the surrounding tissue; the rat stomach mucosa injury is had provide protection, and the difference between two medication groups does not have significance (P〉0.05).
Stability test
The contriver studies the chemical stability of crystal formation of the present invention, and the investigation condition is a high temperature (60 ℃ ± 2 ℃), (4500Lx ± 500lx), (92.5%, RH) investigate index is outward appearance, content and related substance to high humidity to strong illumination.
The result: under high light, high temperature, super-humid conditions from 0-15 days, outward appearance, related substance, content do not change, and illustrates that chemical stability is good, the manufacturing and the standing storage of suitable pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), the mensuration of moisture in two semihydrate crystal of R-lansoprazole: 10.78%-10.95%.
The result: at 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), it is constant that moisture keeps, and explanation has good stability, and is fit to the manufacturing and the standing storage of pharmaceutical preparation.
Figure of description:
Fig. 1, two semihydrate X-ray diffraction in crystals of R-lansoprazole figure;
Fig. 2, two semihydrate crystalline of R-lansoprazole infrared spectrogram;
Embodiment:
The present invention is described further below in conjunction with embodiment, makes this area professional and technical personnel better understand the present invention.Embodiment only is indicative, means that never it limits the scope of the invention by any way.
Used R-lansoprazole among the present invention, the method that reference US6462058 provides is synthetic, the synthetic R-lansoprazole shows the feature of unformed powder, purity 98.5% (HPLC normalization method), optical purity 99.6%ee, its chemical structure proves that through determination of elemental analysis chemical structure is correct.
Results of elemental analyses:
Measured value (calculated value), C:52.10 (52.03), H:3.80 (3.82), N:11.30 (11.38),
S:8.75(8.68),F:15.51(15.43)；
The proof chemical structure is correct.
In the 1000ml reaction flask of stirring, thermometer, condenser is housed, in the mixed solution of Virahol-acetate-water=5-6:1-2:3-4 of adding 80 gram R-lansoprazoles and 400ml, start stirring, be heated to 70 ℃-72 ℃, filtered while hot naturally cools to room temperature, be incubated 5 hours again, separate out crystallization, filter, obtain white crystals 72.7 grams through indoor seasoning.Measure through the karl Fischer method, contain the moisture of 10.88% (weight percent).Purity 99.95% (HPLC normalization method), optical purity 99.99%ee.
Results of elemental analyses:
Measured value (calculated value), C:46.28 (46.37), H:4.60 (4.62), N:10.20 (10.14),
S:7.79(7.74),F:13.81(13.75)。
This crystalline X-ray diffractogram is seen Fig. 1.Instrument model and condition determination: Japanese D/max 2500 type diffractometers of science; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°
This crystalline infrared spectrogram is seen Fig. 2, uses the KBr compressing tablet during mensuration.
Embodiment 2
The capsule that contains two semihydrates of R-lansoprazole
Prescription: two semihydrates of R-lansoprazole, 60 grams, propylene glycol 5ml, starch 150 grams are made 1000.
Technology: two semihydrates of R-lansoprazole, starch is wetting with 15% aqueous solution of propylene glycol, the granulation of sieving behind the mixing, 60 ℃ of dryings, whole grain, filled capsules.
Embodiment 3
The tablet that contains two semihydrates of R-lansoprazole
Prescription: two semihydrates of R-lansoprazole, 30 grams, lactose 200 grams, 30 gram PEG-4000, Magnesium Stearate 11 grams, 27 gram 30 POVIDONE K 30 BP/USPs 30, croscarmellose sodium 50 grams, distilled water is an amount of, makes 1000.
Two semihydrates of technology: PEG-4000 and R-lansoprazole are pulverized jointly, cross 80 mesh sieves, with behind other material mixing with distilled water system softwood, 16 mesh sieve system particles are put in the loft drier in 40-45 ℃ of drying, the whole grain of 16 mesh sieves, Magnesium Stearate adds mixing in the dried particle, compressing tablet.
Claims (7)
1. the hydrate of R-lansoprazole compound shown in the formula I,
（Ⅰ）
Measure with the karl Fischer method, described hydrate contains the moisture of 10.78%-10.95% (weight percent);
The crystal of described R-lansoprazole hydrate, as in the characteristic X-ray powder mensuration, its collection of illustrative plates has following 2 θ diffraction angle and D value with the CuKa ray,
The error of 2 θ diffraction angle is ± 0.2.
2. the described R-lansoprazole hydrate crystal of claim 1, infrared spectrogram, pellet technique is measured, at 3340 ± 5cm
-13375 ± 5cm
-13190 ± 5cm
-13340 ± 5cm
-12970 ± 5cm
-12907 ± 5cm
-12837 ± 5cm
-11597 ± 2cm
-11154 ± 2cm
-1There is characteristic peak at the place.
3. the preparation method of the described R-lansoprazole hydrate crystal of claim 1, by with R-lansoprazole in Virahol-acetate-heated in water solution dissolving, naturally cool to room temperature, be incubated for some time again to obtain.
4. according to the method for claim 3, it is characterized in that comprising the following steps: that R-lansoprazole adds in the mixed solution of 5-6 times of (weight or measurement (WM) ratio) Virahol-acetate-water=5-6:1-2:3-4, be heated to 68 ℃-72 ℃, filtered while hot, naturally cool to room temperature, be incubated 5-7 hour again, separate out crystallization, filter, drying obtains.
5. one kind contains the hydrate crystal of the described R-lansoprazole of claim 1 and the composition of the R-lansoprazole hydrate that one or more pharmaceutically acceptable carriers are formed.
6. right requires 5 described compositions, it is characterized in that said composition is used to prepare oral preparations, injection.
7. the described R-lansoprazole hydrate of claim 1 is being made the stomach burning sensation for the treatment of non-erosive gastroesophageal reflux and causing, the application in the erosive esophagitis medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102247467A CN102234265B (en) | 2011-08-08 | 2011-08-08 | Lansoprazole compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102247467A CN102234265B (en) | 2011-08-08 | 2011-08-08 | Lansoprazole compound |
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| Publication Number | Publication Date |
|---|---|
| CN102234265A true CN102234265A (en) | 2011-11-09 |
| CN102234265B CN102234265B (en) | 2013-11-20 |
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|---|---|---|---|
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012176140A1 (en) * | 2011-06-21 | 2012-12-27 | Ranbaxy Laboratories Limited | Process for the preparation of dexlansoprazole |
| CN104177333A (en) * | 2013-05-24 | 2014-12-03 | 四川海思科制药有限公司 | (R)-2-[[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl) methyl] sulfinyl]-1 H-benzimidazole with stabile physical and chemical properties |
| CN104447695A (en) * | 2013-11-22 | 2015-03-25 | 广东东阳光药业有限公司 | Benzimidazole compound hydrate |
| CN104844576A (en) * | 2015-04-28 | 2015-08-19 | 山东罗欣药业集团股份有限公司 | Lansoprazole or dextral lansoprazole crystal type compound and preparation method thereof |
| CN107011329A (en) * | 2017-05-05 | 2017-08-04 | 广州大光制药有限公司 | Lansoprazole monohydrate crystal form and its crystallization preparation method |
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| WO2001087874A1 (en) * | 2000-05-15 | 2001-11-22 | Takeda Chemical Industries, Ltd. | Process for producing crystal |
| CN1355798A (en) * | 1999-06-17 | 2002-06-26 | 武田药品工业株式会社 | Benzimidazole compound crystal |
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| CN102399212A (en) * | 2010-08-23 | 2012-04-04 | 江苏豪森医药集团有限公司 | Dexlansoprazole crystal form and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012176140A1 (en) * | 2011-06-21 | 2012-12-27 | Ranbaxy Laboratories Limited | Process for the preparation of dexlansoprazole |
| CN104177333A (en) * | 2013-05-24 | 2014-12-03 | 四川海思科制药有限公司 | (R)-2-[[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl) methyl] sulfinyl]-1 H-benzimidazole with stabile physical and chemical properties |
| CN104447695A (en) * | 2013-11-22 | 2015-03-25 | 广东东阳光药业有限公司 | Benzimidazole compound hydrate |
| CN104844576A (en) * | 2015-04-28 | 2015-08-19 | 山东罗欣药业集团股份有限公司 | Lansoprazole or dextral lansoprazole crystal type compound and preparation method thereof |
| CN107011329A (en) * | 2017-05-05 | 2017-08-04 | 广州大光制药有限公司 | Lansoprazole monohydrate crystal form and its crystallization preparation method |
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| CN102234265B (en) | 2013-11-20 |
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