CN102234265B - Lansoprazole compound - Google Patents
Lansoprazole compound Download PDFInfo
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- CN102234265B CN102234265B CN2011102247467A CN201110224746A CN102234265B CN 102234265 B CN102234265 B CN 102234265B CN 2011102247467 A CN2011102247467 A CN 2011102247467A CN 201110224746 A CN201110224746 A CN 201110224746A CN 102234265 B CN102234265 B CN 102234265B
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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 scorching hot sense that the composition manufacture treatment Non-erosive gastroesophageal reflux that uses this hydrate causes, the application in the erosive esophagitis medicine.
Background technology
Lansoprazole is after omeprazole, the proton pump inhibitor of second listing.Owing to having introduced fluorine, make its character be different from omeprazole, thermodynamics and oxidative stability increase, and have greatly improved biological activity.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.Research shows that the lansoprazole drug effect of (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), be used for the treatment of the treatment of remaining of scorching hot sense, erosive esophagitis and erosive esophagitis that Non-erosive gastroesophageal reflux causes.28 all double-blind, randomized controlled clinical study :s researchs by a definite date, the curative effect of respectively this product and lansoprazole being treated for erosive esophagitis contrasts.The result demonstration, during 8 week, this product (60 mg) group curative ratio is high than the lansoprazole group, 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 etc., disclose 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, and have advantages of: chemical purity is high, and maximum contaminant is less than 1 ‰, and optical purity is high; Good stability.
Summary of the invention
One object of the present invention, disclose two semihydrates of a kind of R-lansoprazole.
Another object of the present invention, disclose the preparation method of two semihydrates of R-lansoprazole.
Another purpose of the present invention, disclose the pharmaceutical composition that comprises two semihydrates of R-lansoprazole.
The invention also discloses the application of two semihydrates of R-lansoprazole in manufacturing the medicines such as scorching hot sense that treatment stomach ulcer, Non-erosive gastroesophageal reflux causes, erosive esophagitis.
Now in conjunction with purpose of the present invention, content of the present invention is specifically described.
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 material, and, the most accurately method the most single-minded to water, be 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).In two semihydrates of R-lansoprazole, the theoretical content of water is 10.87%, 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 |
In the present invention, the mensuration of 2 θ values is used light source, and precision is ± 0.2 °, represents that therefore above-mentioned value of getting has allowed certain reasonably limit of error, and its limit of error is ± 0.2 °.
The correction polystyrene film of instrument when infrared spectrogram is measured, meet the regulation of Chinese Pharmacopoeia.
This crystal formation infrared spectrogram (KBr pressed disc method mensuration), at 3340 ± 5cm
-13375 ± 5cm
-13190 ± 5cm
-13340 ± 5cm
-12970 ± 5cm
-12907 ± 5cm
-12837 ± 5cm
-11597 ± 2cm
-11154 ± 2cm
-1There is characteristic peak at place.
Another object of the present invention, disclose the preparation method of two semihydrate crystal of R-lansoprazole, by R-lansoprazole is dissolved in Virahol-acetic acid-heated in water solution, naturally cools to room temperature, then be incubated for some time and 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-acetic acid-water=5-6:1-2:3-4, is heated to 68 ℃-72 ℃, filtered while hot, naturally cool to room temperature, then be incubated 5-7 hour, crystallization, filter, drying obtains.
R-lansoprazole used, the method that reference US6462058 provides is synthetic, and synthetic R-lansoprazole shows the feature of unformed powder, and its chemical structure, through determination of elemental analysis, proves that chemical structure is correct.
Another purpose of the present invention, provide the composition that comprises two semihydrates of R-lansoprazole that two semihydrate crystal of R-lansoprazole and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: Application standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.
The amount of the active ingredient that contains in pharmaceutical composition and unit dosage form (the compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, the amount of compound used or concentration are regulated in a wider scope, the weight range of active compound is 1%～30%(weight of composition).
The present invention also provides the application in manufacturing the medicines such as scorching hot sense that treatment stomach ulcer, Non-erosive gastroesophageal reflux causes, erosive esophagitis of R-lansoprazole two semihydrate crystal.
Through animal (male rat) test, give the ethanol-induced gastric lesion rat oral gavage, experimental result shows: through stomach-tissue, learn and observe the visible a large amount of downright bad materials in damage model group rat ulcer bottom, in surrounding tissue, neutrophil infiltration is obvious; In the unformed powder group ulcer downright bad material in bottom of crystal formation of the present invention and R-lansoprazole and surrounding tissue, neutrophil infiltration all obviously reduces than damage model group; damage has provide protection to gastric mucosa, the no significant difference between two medication groups (P > 0.05).
Stability test
The contriver is studied the chemical stability of crystal formation of the present invention, and the investigation condition is high temperature (60 ℃ ± 2 ℃), (4500Lx ± 500lx), (92.5%, RH) investigate index is outward appearance to high humidity to strong illumination, content and related substance.
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, manufacture and the standing storage of suitable pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in two semihydrate crystal of R-lansoprazole: 10.78%-10.95%.
Result: at 40 ℃, under different relative humidity (RH) condition (75%, 92.5%), it is constant that moisture keeps, and explanation has good stability, and is suitable for manufacture and the standing storage of pharmaceutical preparation.
Figure of description:
Fig. 1, the X-ray diffractogram of two semihydrate crystal of R-lansoprazole;
Fig. 2, the infrared spectrogram of two semihydrate crystal of R-lansoprazole;
Embodiment:
The present invention is described further below in conjunction with embodiment, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, means that never it limits the scope of the invention by any way.
R-lansoprazole used in the present invention, the method that reference US6462058 provides is synthetic, synthetic R-lansoprazole shows the feature of unformed powder, purity 98.5% (HPLC normalization method), optical purity 99.6%ee, its chemical structure, through determination of elemental analysis, proves that 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, add in the mixed solution of Virahol-acetic acid of 80 gram R-lansoprazoles and 400ml-water=5-6:1-2:3-4, start stirring, be heated to 70 ℃-72 ℃, filtered while hot, naturally cool to room temperature, be incubated again 5 hours, crystallization, filter, and through indoor seasoning, obtains white crystals 72.7 grams.Through the karl Fischer method, measure, 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)。
The X-ray diffractogram of this crystallization is shown in Fig. 1.Instrument model and condition determination: Rigaku D/max 2500 type diffractometers; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°
The infrared spectrogram of this crystallization is shown in Fig. 2, during mensuration, uses the KBr compressing tablet.
Embodiment 2
The capsule that contains two semihydrates of R-lansoprazole
Prescription: two semihydrate 60 grams of R-lansoprazole, propylene glycol 5ml, starch 150 grams, make 1000.
Technique: by two semihydrates of R-lansoprazole, starch, wetting with 15% aqueous solution of propylene glycol, the granulation of sieving after mixing, 60 ℃ of dryings, whole grain, filled capsules.
Embodiment 3
The tablet that contains two semihydrates of R-lansoprazole
Prescription: two semihydrate 30 grams of R-lansoprazole, lactose 200 grams, 30 gram PEG-4000, Magnesium Stearate 11 grams, 27 gram PVP K30s, croscarmellose sodium 50 grams, distilled water is appropriate, makes 1000.
Two semihydrates of technique: PEG-4000 and R-lansoprazole are pulverized jointly, cross 80 mesh sieves, with other material, mix rear with distilled water softwood processed, 16 mesh sieve particle processed, put in loft drier in 40-45 ℃ of drying, the whole grain of 16 mesh sieves, Magnesium Stearate adds in dried particle and mixes, compressing tablet.
Claims (5)
1. the crystal of the hydrate of R-lansoprazole compound shown in the formula I,
（Ⅰ）
With the karl Fischer method, measure, described hydrate contains the moisture of 10.78wt%-10.95wt%;
The crystal of described R-lansoprazole hydrate, in the CuKa ray, as the characteristic X-ray powder, measuring, its collection of illustrative plates has following 2 θ diffraction angle and D value,
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of the described R-lansoprazole hydrate crystal of claim 1, it is characterized in that comprising the following steps: R-lansoprazole by weight, by volume, a R-lansoprazole adds in the mixed solution of the Virahol-acetic acid of 5-6 part-water=5-6:1-2:3-4 Virahol-acetic acid-water, is heated to 68 ℃-72 ℃, filtered while hot, naturally cool to room temperature, then be incubated 5-7 hour, crystallization, filter, drying obtains.
3. 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 form.
4. composition claimed in claim 3, is characterized in that said composition is for the preparation of oral preparations, injection.
5. the crystal of the described R-lansoprazole hydrate of claim 1 is being manufactured the scorching hot sense 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 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102247467A CN102234265B (en) | 2011-08-08 | 2011-08-08 | Lansoprazole compound |
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| CN102234265B true CN102234265B (en) | 2013-11-20 |
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Families Citing this family (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 |
| CN104844576B (en) * | 2015-04-28 | 2017-03-08 | 山东罗欣药业集团股份有限公司 | A kind of Lansoprazole or Dexlansoprazole crystal-form 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN1478086A (en) * | 2000-12-01 | 2004-02-25 | ����ҩƷ��ҵ��ʽ���� | Process for crystallization of(R)-or(S)-lansoprazole |
| WO2009088857A1 (en) * | 2007-12-31 | 2009-07-16 | Takeda Pharmaceutical Company Limited | Crystalline solvated forms of (r) -2- [ [ [3-methyl-4- (2, 2, 2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1h-benz imidazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110028518A1 (en) * | 2008-03-18 | 2011-02-03 | Dr. Reddy's Laboratories Ltd. | Dexlansoprazole process and polymorphs |
| WO2011042910A2 (en) * | 2009-10-09 | 2011-04-14 | Hetero Research Foundation | Optical resolution of substituted 2-(2- pyridinylmethylsulphinyl)-1h-benzimidazoles |
| CN102399212B (en) * | 2010-08-23 | 2014-07-16 | 江苏豪森医药集团有限公司 | Dexlansoprazole crystal form and preparation method thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355798A (en) * | 1999-06-17 | 2002-06-26 | 武田药品工业株式会社 | Benzimidazole compound crystal |
| WO2004083200A1 (en) * | 1999-06-17 | 2004-09-30 | Akira Fujishima | Crystalline form of (r)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1h-benzimidazole |
| WO2001087874A1 (en) * | 2000-05-15 | 2001-11-22 | Takeda Chemical Industries, Ltd. | Process for producing crystal |
| CN1478086A (en) * | 2000-12-01 | 2004-02-25 | ����ҩƷ��ҵ��ʽ���� | Process for crystallization of(R)-or(S)-lansoprazole |
| WO2009088857A1 (en) * | 2007-12-31 | 2009-07-16 | Takeda Pharmaceutical Company Limited | Crystalline solvated forms of (r) -2- [ [ [3-methyl-4- (2, 2, 2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1h-benz imidazole |
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