CN104370827B - Rosuvastatin calcium compound - Google Patents
Rosuvastatin calcium compound Download PDFInfo
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- CN104370827B CN104370827B CN201310349194.1A CN201310349194A CN104370827B CN 104370827 B CN104370827 B CN 104370827B CN 201310349194 A CN201310349194 A CN 201310349194A CN 104370827 B CN104370827 B CN 104370827B
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- calcium
- hydrate
- rosuvastatin
- rosuvastain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention belongs to pharmaceutical technology field, it is specifically related to Rosuvastatin hydrate of calcium and preparation method thereof, the Rosuvastatin hydrate of calcium that the present invention obtains, containing a hypocrystalline water, have the advantage that: purity is high, good stability, the invention still further relates to use Rosuvastatin hydrate of calcium manufacture treatment primary hypercholesterolemia or the application of Combination dyslipidaemia medicine.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to Rosuvastatin hydrate of calcium and preparation method thereof, the present invention
Further relate to use the composition of this hydrate, and manufacture treatment primary hypercholesterolemia or Combination dyslipidaemia
Application in medicine.
Background technology
It is new for 3-hydroxyl-3-that AstraZeneca company develops in the world wide in addition to the East Asian countries such as Japan
Methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, listed in Canada first in February, 2003, general entitled
Rosuvastatin calcium, Chinese entitled rosuvastain calcium, trade name Crestor.This product have reduction LDC-C,
Raising the effect of HDL-C, be better than other statinses listed, tolerance is good with security, is described as " superstatin ".
Recently, the rosuvastain calcium of AstraZeneea company obtains the indication that FDA approval is new, can be used for reducing patient's cerebral apoplexy, the heart
Room fibrillation (atrial fibrillation) and the risk of arteries regeneration.The sale in the rosuvastain calcium whole world in 2009 has reached 6,200,000,000 dollars,
There is the growth of 32% upper one year, had become as the object falling over each other to carry out copying both at home and abroad.
Rosuvastain calcium is a kind of selective HMG-CoA reductase inhibitor.HMG-CoA reductase inhibitor is to change
3-hydroxy-3-methylglutaryl-coenzyme A is the rate-limiting enzyme of the precursor of first valerate cholesterol.The Main Function of Rosuvastatin
Position is the target organs that liver reduces cholesterol.Rosuvastatin adds liver LDL cell surface receptor number, promotes LDL
Absorption and catabolism, it is suppressed that VLDL liver synthesis, thus reduce VLDL and LDL particulate sum.
Rosuvastain calcium reaches maximal plasma concentration in 5 hours after oral administration, absolute bioavailability about 20%.
It is extensively absorbed by liver, and distribution volume is about 134L, and about 90% is combined with plasma protein.It occurs limited in vivo
Metabolism (about 10%), predominantly N-demethyl metabolin and lactone metabolin.The Rosuvastatin of about 90% passes through with original shape
Ight soil is drained, and remainder passes through urine drains.Plasma elimination half life is about 19 hours.
Rosuvastain calcium (rosuvastatin calcium, 1), chemistry entitled [S-[R, S-(E)]]-7-[4-
(4-fluorophenyl)-6-isopropyl-2-(N-methylmethanesulfonamide base)-5-pyrimidine radicals]-3,5-dihydroxy-6-enanthic acid
Calcium (2:1).
Molecular formula: 2(C22H27FN3O6S) Ca
Molecular weight: 1001.15
Its structural formula is:
The preparation method of rosuvastain calcium is more, J.Org.Chem., 1994,59 (25), 7849-7854；
US5260440(1993-11-09)； Bioorg.Med.Chem.,1997,5(2):437-444； WO2008096257；Etc..
In research process, the method repeating document, the Rosuvastatin calcium impurities number obtained is more, and total impurities is relatively
High.The rosuvastain calcium that the present invention obtains, containing a hypocrystalline water, has the advantage that: purity is high, and maximum contaminant is less than
0.5‰；Good stability.
Summary of the invention
One object of the present invention, discloses a kind of Rosuvastatin hydrate of calcium.
Another object of the present invention, discloses the preparation method of Rosuvastatin hydrate of calcium.
A further object of the present invention, discloses the pharmaceutical composition comprising Rosuvastatin hydrate of calcium.
The invention also discloses Rosuvastatin hydrate of calcium and manufacture treatment primary hypercholesterolemia or Combination
Application in dyslipidaemia medicine.
In conjunction with the purpose of the present invention, present invention is specifically described.
The invention provides a kind of Rosuvastatin hydrate of calcium (shown in formula I),
(I)
Karl_Fischer method (Karl Fischer method) is a kind of to measure in material in all kinds of chemical methodes of moisture, to water
For single-minded, method the most accurately, it is listed in the standard method of determination of moisture in many materials, especially organic compound,
Reliable results.
After sample constant weight, measuring through continuous 4 batches, the moisture that described invention compound contains is 2.51% 2.75%
Between (percentage by weight).In rosuvastain calcium times semihydrate, the theoretical content of water is 2.63%, it can be assumed that invention chemical combination
Thing contains a hypocrystalline water.
| Batch | Moisture (%) | Batch | Moisture (%) |
| 1 | 2.62 | 2 | 2.51 |
| 3 | 2.75 | 4 | 2.67 |
Rosuvastain calcium times hemi-hydrate crystalline, uses D/Max-2500.9161 type x-ray diffractometer to measure, measures
Condition: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak (2 θ), d value and relative intensity
As follows, see Fig. 1.
| Spectral line number | 2 θ (spend) | Interplanar distance (d) | I/I0 |
| 1 | 7.040 | 12.5459 | 85 |
| 2 | 14.420 | 6.1374 | 100 |
| 3 | 19.640 | 4.5164 | 8 |
| 4 | 21.860 | 4.0625 | 50 |
| 5 | 24.180 | 3.6777 | 1 |
| 6 | 26.060 | 3.4165 | 2 |
| 7 | 27.240 | 3.2711 | 4 |
| 8 | 27.960 | 3.1885 | 2 |
| 9 | 28.300 | 3.1509 | 1 |
| 10 | 29.240 | 3.0517 | 2 |
| 11 | 30.860 | 2.8915 | 2 |
| 12 | 32.360 | 2.7643 | 1 |
| 13 | 32.800 | 2.7282 | 1 |
| 14 | 33.640 | 2.6620 | 1 |
| 15 | 35.120 | 2.5531 | 1 |
| 16 | 37.020 | 2.4263 | 19 |
| 17 | 40.020 | 2.2511 | 1 |
| 18 | 40.580 | 2.2213 | 2 |
| 19 | 42.180 | 2.1407 | 1 |
| 20 | 43.320 | 2.0869 | 1 |
| 21 | 44.860 | 2.0188 | 6 |
| 22 | 45.700 | 1.9836 | 3 |
| 23 | 46.780 | 1.9403 | 2 |
| 24 | 47.960 | 1.8953 | 1 |
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, therefore represents above-mentioned taken value and has allowed one
Fixed rational error range, its error range is ± 0.2 °.
Fusing point test: measure Rosuvastain according to Pharmacopoeia of People's Republic of China (2010 editions, two) annex VI C the first method
The fusing point of spit of fland calcium times hemi-hydrate crystalline, the fusing point recorded is 153.3 DEG C 154.1 DEG C.
Another object of the present invention, the preparation method of rosuvastain calcium times hemi-hydrate crystalline.
Document is reported, rosuvastain calcium has multiple preparation method, although process for purification is different, fusing point be about 161 DEG C-
162℃.The present inventor by substantial amounts of experiment, explores refining solvent and includes water, acetonitrile, benzene, toluene, chlorobenzene, ethyl acetate, and two
NMF, acetone, oxolane, methyl alcohol, ethanol, isopropanol, isopropyl ether, the one such as methyl tertiary butyl ether(MTBE), two kinds or three
Kind mixed liquor and the relation of different process conditions and the rosuvastain calcium crystal obtained, the wherein number of impurity
Amount with each impurity.Eventually through by rosuvastain calcium heating for dissolving in distilled water-isopropanol-tetrahydrofuran solution,
Lower the temperature the most stage by stage, obtain rosuvastain calcium hydrate crystal of the present invention.
Specifically include the following step: rosuvastain calcium adds 10-11 times of (w/v) water-isopropanol-tetrahydrochysene
In the mixed liquor of furans=9:0.5-1:0.5-1, it is heated to 78 DEG C-83 DEG C, filters while hot, be cooled to 50 DEG C, 47 DEG C-50 DEG C, protect
Temperature stirring 4-5 hour；Then, it is cooled to 25 DEG C, 23 DEG C-25 DEG C, is incubated 5-6 hour, separate out crystallization, filter, through room temperature in vacuo
It is dried to constant weight, obtains high-purity above-mentioned rosuvastain calcium hydrate crystal.
The method is reproducible, is amplified to pilot-scale, purity and crystal formation and all can reappear very well.
Rosuvastain calcium used can be prepared easily according to document, such as J.Org.Chem., and 1994,59
(25),7849-7854；US5260440 (1993-11-09) etc., it is possible to be commercially available by commercial sources.
A further object of the present invention, it is provided that comprise rosuvastain calcium hydrate crystal with one or more pharmaceutically
The composition of the Rosuvastatin hydrate of calcium of acceptable carrier composition.
The pharmaceutical composition preparation of the present invention is as follows: uses standard and conventional technique, makes the compounds of this invention and preparation
On, acceptable solid or liquid-carrier combine, and are allowed at random acceptable adjuvant and excipient with on galenic pharmacy
In conjunction with being prepared as particulate or microballoon.Said composition is used for preparing oral formulations.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form can be according to patient
The state of an illness, the situation of diagnosis be specifically applied, the amount of compound used or concentration are in a wider scope
Regulation, the weight range of reactive compound is 0.5%～20%(weight of composition).
Present invention also offers the application in manufacturing treatment hyperlipidemia of the Rosuvastatin hydrate of calcium.
Stability test
The chemical stability of the Rosuvastatin hydrate of calcium of the present invention is studied by inventor, and the condition of investigation is high
Temperature (60 DEG C ± 2 DEG C), strong illumination (4500Lx ± 500lx), high humidity (92.5%, RH) inspection target is outward appearance, content and relevant
Material.
Result: from 0 10 days under high light, high temperature, super-humid conditions, outward appearance, there are related substance, content not to change, explanation
Chemical stability is good, is suitable for manufacture and the long term storage of pharmaceutical preparation.
At 40 DEG C, under different relative humidity (RH) conditions (75%, 92.5%), the survey of moisture in hydrate crystal of the present invention
Fixed:
Result: at 40 DEG C, under different relative humidity (RH) conditions (75%, 92.5%), water tariff collection is constant, and stability is described
Well, manufacture and the long term storage of pharmaceutical preparation it are suitable for.
Figure of description:
Fig. 1 is the X-ray diffractogram of rosuvastain calcium times hemi-hydrate crystalline；
Detailed description of the invention:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field be better understood from this
Invention.Embodiment is only explanatory, is in no way intended to it and limits the scope of the present invention by any way.
In the present invention, rosuvastain calcium used can be prepared easily according to document, such as J.Org.Chem., and 1994,59
(25), 7849-7854, optical purity 97.7% (HPLC normalization method), fusing point is 160.6 DEG C-161.9 DEG C.Its chemical constitution
Through proton nmr spectra, elementary analysis, high resolution mass spectrometry confirmation, it was demonstrated that chemical constitution is correct.
The moisture recorded with Karl_Fischer method is 0.11%.
Embodiment 1
Equipped with stirring, thermometer, condenser 5L reaction bulb in, add 350 grams of rosuvastain calciums and 3500ml
Water-isopropanol-oxolane (9:0.5:0.5) mixed liquor, is heated to 78 DEG C-83 DEG C, filters while hot, is cooled to 50 DEG C, 47 DEG C-
50 DEG C, insulated and stirred 4 hours；Then, it is cooled to 25 DEG C, 23 DEG C-25 DEG C, is incubated 5 hours, separate out crystallization, filter, true through room temperature
Sky is dried to constant weight, obtains high-purity above-mentioned rosuvastain calcium hydrate crystal 322.3 grams, and fusing point is 153.3 DEG C 154.1
℃.Optical purity 99.97%.Dissolvent residual detection meets the requirements.
Measure through Karl_Fischer method, containing the moisture of 2.62% (percentage by weight).
The X-ray diffractogram of this crystallization is shown in Fig. 1.INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffraction
Instrument； CuKa 40Kv 100mA;2 θ sweep limits: 0-50°。
Embodiment 2
Equipped with stirring, thermometer, condenser 5L reaction bulb in, add 320 grams of rosuvastain calciums and 3520ml
Water-isopropanol-oxolane (9:0.8:0.7) mixed liquor, is heated to 78 DEG C-83 DEG C, filters while hot, is cooled to 50 DEG C, 47 DEG C-
50 DEG C, insulated and stirred 5 hours；Then, it is cooled to 25 DEG C, 23 DEG C-25 DEG C, is incubated 6 hours, separate out crystallization, filter, true through room temperature
Sky is dried to constant weight, obtains high-purity above-mentioned rosuvastain calcium hydrate crystal 288.9 grams, and fusing point is 153.3 DEG C 154.0
DEG C, optical purity 99.95%.Dissolvent residual detection meets the requirements.
Measure through Karl_Fischer method, containing the moisture of 2.51% (percentage by weight).
Embodiment 3
Equipped with stirring, thermometer, condenser 5L reaction bulb in, add 320 grams of rosuvastain calciums and 3360ml
Water-isopropanol-oxolane (9:1:1) mixed liquor, is heated to 78 DEG C-83 DEG C, filters while hot, is cooled to 50 DEG C, 47 DEG C-50
DEG C, insulated and stirred 4.5 hours；Then, it is cooled to 25 DEG C, 23 DEG C-25 DEG C, is incubated 5.5 hours, separate out crystallization, filter, through room temperature
Being dried under vacuum to constant weight, obtain high-purity above-mentioned rosuvastain calcium hydrate crystal 300.8 grams, fusing point is 153.3 DEG C
154.1 DEG C, optical purity 99.96%.Dissolvent residual detection meets the requirements.
Measure through Karl_Fischer method, containing the moisture of 2.75% (percentage by weight).
Embodiment 4
Equipped with stirring, thermometer, condenser 5L reaction bulb in, add 300 grams of rosuvastain calciums and 3100ml
Water-isopropanol-oxolane (9:0.9:0.6) mixed liquor, is heated to 78 DEG C-83 DEG C, filters while hot, is cooled to 50 DEG C, 47 DEG C-
50 DEG C, insulated and stirred 5 hours；Then, it is cooled to 25 DEG C, 23 DEG C-25 DEG C, is incubated 5 hours, separate out crystallization, filter, true through room temperature
Sky is dried to constant weight, obtains high-purity above-mentioned rosuvastain calcium hydrate crystal 277.3 grams, and fusing point is 153.4 DEG C 154.1
DEG C, optical purity 99.97%.Dissolvent residual detection meets the requirements.
Measure through Karl_Fischer method, containing the moisture of 2.67% (percentage by weight).
Use standard and conventional technique, make the compounds of this invention and acceptable solid on galenic pharmacy or liquid-carrier knot
Close, and be allowed at random on galenic pharmacy acceptable adjuvant and excipient be combined and be prepared as particulate or microballoon.This combination
Thing is used for preparing oral formulations.Only citing is illustrated, and is in no way intended to it and limits the scope of the present invention by any way.
Embodiment 5
Tablet containing Rosuvastatin hydrate of calcium
Prescription: rosuvastain calcium times semihydrate 51.4 grams, N-METHYL-ALPHA-L-GLUCOSAMINE 4 grams, polyvinylpyrrolidone 16 grams,
Microcrystalline cellulose 250 grams, taurine 20 grams, sodium carboxymethyl starch 185 grams, magnesium stearate 10 grams, distilled water is appropriate, makes
10000.
Technique: rosuvastain calcium times semihydrate and excipient are dissolved in 80 DEG C of distilled water containing taurine, add
One of percentage entering microcrystalline cellulose is measured, and mixing final vacuum dry, pulverize, and crosses 100 mesh sieves, compressing tablet after mixing with other material.
Embodiment 6
Capsule containing Rosuvastatin hydrate of calcium
Prescription: rosuvastain calcium times semihydrate 102.8 grams, Celluloasun Microcrystallisatum 300 grams, pregelatinized starch 250 grams, poly-
Vinylpyrrolidone 35 grams, magnesium stearate 22 grams, make 10000.
Technique: rosuvastain calcium times semihydrate, Celluloasun Microcrystallisatum are sieved, be sufficiently mixed, adds polyvinyl pyrrole
Alkanone solution, is sufficiently mixed, softwood processed, sieves, and pelletizes, and 55 DEG C-60 DEG C are dried, magnesium stearate and talcum powder are sieved, and add
In above-mentioned particle, encapsulated and get final product.
Claims (6)
1. the hydrate of rosuvastain calcium shown in formula I,
(I)
Measuring with Karl_Fischer method, described hydrate contains the moisture of 2.51% 2.75%；
Described Rosuvastatin hydrate of calcium, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ
The angle of diffraction, interplanar distance:
Described Rosuvastatin hydrate of calcium, fusing point is 153.3 DEG C 154.1 DEG C.
2. the preparation method of Rosuvastatin hydrate of calcium described in claim 1, by by rosuvastain calcium at distilled water-different
Heating for dissolving in propyl alcohol-tetrahydrofuran solution, lowers the temperature the most stage by stage, obtains Rosuvastatin hydrate of calcium.
3. the method for claim 2, it is characterised in that comprise the following steps: that rosuvastain calcium adds 10-11 times of weighing body
In the long-pending mixed liquor than water-isopropanol-oxolane=9:0.5-1:0.5-1, it is heated to 78 DEG C-83 DEG C, filters while hot, cooling
To 50 DEG C, 47 DEG C-50 DEG C, insulated and stirred 4-5 hour；Then, it is cooled to 25 DEG C, 23 DEG C-25 DEG C, is incubated 5-6 hour, separate out knot
Crystalline substance, filters, is dried through room temperature in vacuo, obtains above-mentioned Rosuvastatin hydrate of calcium.
4. the Rosuvastatin hydrate of calcium contained described in claim 1 and one or more pharmaceutically acceptable carriers
The composition of the Rosuvastatin hydrate of calcium of composition.
5. the composition of the Rosuvastatin hydrate of calcium described in claim 4, it is characterised in that said composition is used for preparing mouth
Formulation.
6. Rosuvastatin hydrate of calcium described in claim 1 is manufacturing treatment primary hypercholesterolemia or Combination piarhemia
Application in disorder remedies.
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| CN201310349194.1A CN104370827B (en) | 2013-08-13 | 2013-08-13 | Rosuvastatin calcium compound |
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|---|---|---|---|
| CN201310349194.1A CN104370827B (en) | 2013-08-13 | 2013-08-13 | Rosuvastatin calcium compound |
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| CN104370827A CN104370827A (en) | 2015-02-25 |
| CN104370827B true CN104370827B (en) | 2016-09-07 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1807418A (en) * | 2005-01-19 | 2006-07-26 | 安徽省庆云医药化工有限公司 | Rosuvastatin calcium synthesis method |
| CN101203496A (en) * | 2005-06-24 | 2008-06-18 | 力奇制药公司 | Process for preparing pure amorphous rosuvastatin calcium |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012176218A1 (en) * | 2011-06-24 | 2012-12-27 | Ind-Swift Laboratories Limited | Process for preparing rosuvastatin calcium through novel amine salt |
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2013
- 2013-08-13 CN CN201310349194.1A patent/CN104370827B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1807418A (en) * | 2005-01-19 | 2006-07-26 | 安徽省庆云医药化工有限公司 | Rosuvastatin calcium synthesis method |
| CN101203496A (en) * | 2005-06-24 | 2008-06-18 | 力奇制药公司 | Process for preparing pure amorphous rosuvastatin calcium |
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