CN102249978A - KY crystal form of Atorvastatin calcium and preparation method thereof - Google Patents
KY crystal form of Atorvastatin calcium and preparation method thereof Download PDFInfo
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- CN102249978A CN102249978A CN2011101546599A CN201110154659A CN102249978A CN 102249978 A CN102249978 A CN 102249978A CN 2011101546599 A CN2011101546599 A CN 2011101546599A CN 201110154659 A CN201110154659 A CN 201110154659A CN 102249978 A CN102249978 A CN 102249978A
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- atorvastatincalcuim
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Abstract
The invention relates to a new crystal form of Atorvastatin calcium, namely KY crystal form. Expressed in interplanar distance (d), the characteristic peak of the crystal under X-ray powder diffraction conditions is 3.03; or the crystal is (2theta) 5.389 degrees, 8.799 degrees, 11.573 degrees, 18.892 degrees and 28.116 degrees under X-ray powder diffraction conditions. In the differential thermal analysis map (DSC map) of the crystal, characteristic endothermic peaks are arranged at about 44.0 DEG C, 148.6 DEG C, 166.8 DEG C and 252.9 DEG C. The invention also relates to a method for preparing the crystal form and a medical composition containing the crystal form.
Description
Technical field
The invention belongs to medical technical field, relate to crystal formation, its preparation method of atorvastatincalcuim (Atorvastatin) and contain the lipidemia pharmaceutical composition of these crystal formations.
Background of invention
Atorvastatincalcuim can be used as enzyme 3-methylglutaryl CoA-reductase (HMG-CoA reductase enzyme) inhibitor effectively, so this material can be used as hypolipidemic and anticholesteremic (hypocholesterolemicagent).
Atorvastatincalcuim is for having crystal water form and no crystal water form, and it has the crystal water structural formula as follows:
Atorvastatincalcuim can be used as enzyme 3-methylglutaryl CoA-reductase (HMG-CoA reductase enzyme) inhibitor effectively, so this material can be used as hypolipidemic and anticholesteremic (hypocholesterolemicagent).
United States Patent (USP) the 5th, 273,995; 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; With 5,342,952 have disclosed the various methods that prepare atorvastatincalcuim and intermediate thereof.In following patent, also reported the preparation method of the various crystal formations of some preparation atorvastatincalcuims: United States Patent (USP) the 6th, 528,660; 6,613,916; 6,646,133 and 2002/183378; 2003/109569; 2004/063969 and international monopoly WO01/2899; WO02/57228; WO02/83637; WO02/83638 and Chinese patent 1157374C; 1942939A; 101092385A; 101468963A; 1487921A; 1260213C; 1876629A etc.
Above-mentioned patent can be divided into following a few class: 1, method of enrichment according to the difference of employing method; 2, reaction precipitation method; 3, spray method etc.First method is that method is simple, but atorvastatincalcuim foams difficult operation easily; Second kind of difficult control of condition, poor reproducibility; The third method is simple to operate, but yield is not high, and high temperature destroys down easily, and impurity increases.
United States Patent (USP) discloses three kinds of atorvastatincalcuim polymorphic forms that are denoted as crystal formation I, II, IV by the contriver for No. 5969156, Chinese patent CN1423634 provides the new crystal V of atorvastatincalcuim, but the disclosed stable crystal form of prior art is bad, poor solubility is so influenced the curative effect of medicine.
Summary of the invention
The purpose of this invention is to provide a kind of new crystal, its preparation method of atorvastatincalcuim and contain the pharmaceutical composition of these crystal formations, the crystal formation of the brand-new atorvastatincalcuim that obtains, yield height, good stability, solubleness is good, lifting evident in efficacy, and perhaps side effect obviously reduces.
For achieving the above object, adopt following technical scheme:
The KY crystal formation of atorvastatincalcuim is using Cu-K α radiation condition
Powder x-ray diffraction when 2 θ angles are 0-50 ° in Prague has following characteristic peak, and (d) is expressed as with spacing
Or this crystallization under the X-ray diffraction of powder (2 θ) 5.389 °, 8.799 °, 11.573 °, 18.892 °, 28.116 °); Its crystalline differential thermal analysis collection of illustrative plates (DSC figure) is at about 44.0 ℃, and 148.6 ℃, 166.8 ℃, 252.9 ℃ have the feature endotherm(ic)peak.
Further, the KY crystal formation of atorvastatincalcuim of the present invention is surveyed infrared absorption spectrum at about 617.59cm with the KCl pressed disc method
-1700.08cm
-1753.76cm
-1844.43cm
-11111.45cm
-11158.31cm
-11223.71cm
-11316.70cm
-11438.96cm
-11481.23cm
-11531.57cm
-11561.60cm
-11599.12cm
-11651.85cm
-12364.69cm
-12956.08cm
-13281.21cm
-1There is absorption peak at the place.
The present invention also provides a kind of KY crystal formation for preparing atorvastatincalcuim, and is simple, is suitable for suitability for industrialized production, and generates crystal formation yield height, and this preparation method comprises the steps:
(1) atorvastatincalcuim that will not have the crystal water thing or contain the crystal water thing is dissolved in acetone, butanone, or in the mixed solvent of acetone, butanone and water, the solvent load that needs of every g atorvastatincalcuim is 5～50ml;
(2) be heated to 40～65 ℃ of dissolvings after, under this temperature, add ether or isopropyl ether, the consumption of ether or isopropyl ether is that every 1g atorvastatincalcuim adds 20～100ml ether or isopropyl ether, or adds crystal seed behind the cool to room temperature;
(3) be cooled to below 0 ℃, stirring and crystallizing, the temperature of crystallization are-15～0 ℃, filter, 50 ℃ dry 4-6 hour, collect crystallisate.
Another object of the present invention provides a kind of pharmaceutical composition, and it contains the KY crystal formation and at least a pharmaceutically acceptable carrier of the atorvastatincalcuim of significant quantity.
The atorvastatincalcuim of existing market is the white film garment piece, but this medicine often causes gastrointestinal discomfort, also has headache, fash, dizziness, the dimness of vision and dysgeusia.
Atorvastatincalcuim crystallization of the present invention has definite structure, crystallized form is highly stable, tap density is good, sealing was preserved more than half a year in 40 ℃ of accelerated tests and 50% humidity environment, crystal formation is constant substantially, content does not reduce, can be in lucifuge, prolonged preservation under cool place and the drying conditions, be suitable for preparing oral administered dosage form, the atorvastatincalcuim crystalline pharmaceutical composition that contains disclosed in this invention, it can be that tablet is (as enteric coated tablet, coating tablet, film coated tablet, coated tablet, the medicinal extract sheet, dispersible tablet, cut sheet etc.), hard capsule, soft capsule (capsule and pill), enteric coated capsule, the sustained-release and controlled release formulation, slow releasing tablet, sustained release coating and other are any to be fit to oral formulation.The carrier that the pharmacy that is fit to can go up acceptance can be starch, Mierocrystalline cellulose, talcum, sugar (lactose, glucose, sucrose etc.), dextrin, lime carbonate, magnesium oxide, N.F,USP MANNITOL, poly-methyl acrylate, Repone K, sodium-chlor, sorbyl alcohol, secondary calcium phosphate, croscarmellose sodium, Natvosol, gelatin, hydroxypropylcellulose, sodium alginate, carboxymethyl cellulose, carboxyethyl cellulose, colloid silica, Magnesium Stearate, hydrogenated vegetable oil, polyoxyethylene glycol, palmitostearate, citric acid, wherein one or more such as neusilin.In final pharmaceutical composition, atorvastatincalcuim crystalline content is 6%-8%, preferred 7.0%-7.5%.
Compared to existing technology, atorvastatincalcuim crystallization preparation method technology of the present invention is simple, easy to operate, and yield is higher, and the atorvastatincalcuim crystallization-stable that obtains is good, and solubleness is good, the lifting evident in efficacy of preparation, and perhaps side effect obviously reduces.
Description of drawings
Accompanying drawing 2 is the embodiment of the invention 2 atorvastatincalcuim crystalline powder x-ray diffraction spectrograms;
Accompanying drawing 3 is the embodiment of the invention 1 atorvastatincalcuim crystalline infrared absorption patterns;
Accompanying drawing 4 is infrared absorption patterns of the embodiment of the invention 2 atorvastatincalcuim crystalline;
Accompanying drawing 5 is DSC and DTG collection of illustrative plates of the embodiment of the invention 1 atorvastatincalcuim crystalline.
Embodiment
Come the present invention is further specified below in conjunction with specific embodiment, but do not limit the invention to these embodiments.One skilled in the art would recognize that the present invention contained in claims scope all alternativess, improvement project and the equivalents that may comprise.
In having the 2000ml four-hole bottle of mechanical stirring and heating unit, add the 50g atorvastatincalcuim, add 270ml acetone and 30ml water then, be heated to and make dissolving fully about 50 ℃, under this temperature, add the 1250ml ether, stirring is cooled to room temperature, and then is cooled to 0 ℃ of following stirred crystallization 2 hours.Filtration, filter cake is filtered and is done with the washing of 50ml ether, and drying under reduced pressure below 50 ℃ got the atorvastatincalcuim of 46.1g Ky type in 8 hours, and it is 99.75% that HPLC detects purity.
The X-diffractogram of pressing the prepared atorvastatincalcuim of present embodiment as shown in Figure 1, Fig. 3 is the embodiment of the invention 1 an atorvastatincalcuim crystalline infrared absorption pattern.
In having the 1000ml four-hole bottle of mechanical stirring and heating unit, add the 50g atorvastatincalcuim, add 500ml acetone then, be heated to make about 50 ℃ and dissolve fully, under this temperature, add and 300ml water.Stirring is cooled to 20～30 ℃, adds 2g the foregoing description 1 resulting crystal seed, and then is cooled to 0 ℃ of following stirred crystallization 2 hours.Filter, filter cake 50ml water washing, filter is done, and filter cake got the atorvastatincalcuim of 47.3g Ky type in 12 hours at drying under reduced pressure below 50 ℃.
The X-diffractogram of pressing the prepared atorvastatincalcuim of present embodiment as shown in Figure 2.The infrared absorption pattern of present embodiment atorvastatincalcuim crystalline is seen Fig. 4.
Embodiment 3
In having the 2000ml four-hole bottle of mechanical stirring and heating unit, add the 50g atorvastatincalcuim, the water that adds 300ml acetone and 50ml then, be heated to and make dissolving fully about 50 ℃, stirring is cooled to 20～30 ℃, from dropping funnel, drip the 1500ml ether, and then be cooled to 0 ℃ of following stirred crystallization 2 hours.Filtration, filter cake is filtered and is done with the washing of 50ml ether, and filter cake got the atorvastatincalcuim of 46.5gKy type in 8 hours at drying under reduced pressure below 50 ℃.
Embodiment 4
In having the 2000ml four-hole bottle of mechanical stirring and heating unit, add the 50g atorvastatincalcuim, add 400ml butanone and 30ml water then, be heated to and make dissolving fully about 50 ℃, under this temperature, add the 1200ml ether, stirring is cooled to room temperature, and then is cooled to 0 ℃ of following stirred crystallization 2 hours.Filtration, filter cake is filtered and is done with the washing of 50ml ether, and drying under reduced pressure below 50 ℃ got the atorvastatincalcuim of 45.0g Ky type in 8 hours.
Embodiment 5
In having the 1000ml four-hole bottle of mechanical stirring and heating unit, add the 50g atorvastatincalcuim, add the 600ml butanone then, be heated to make about 50 ℃ and dissolve fully, under this temperature, add and 300ml water.Stirring is cooled to 20～30 ℃, adds 2g the foregoing description 1 resulting crystal seed, and then is cooled to 0 ℃ of following stirred crystallization 2 hours.Filter, filter cake 50ml water washing, filter is done, and filter cake got the atorvastatincalcuim of 46.2g Ky type in 12 hours at drying under reduced pressure below 50 ℃.
Embodiment 6
In having the 2000ml four-hole bottle of mechanical stirring and heating unit, add the 50g atorvastatincalcuim, add 270ml acetone and 30ml water then, be heated to and make dissolving fully about 50 ℃, under this temperature, add the 1500ml isopropyl ether, stirring is cooled to room temperature, and then is cooled to 0 ℃ of following stirred crystallization 2 hours.Filtration, filter cake is filtered and is done with the washing of 50ml isopropyl ether, and drying under reduced pressure below 50 ℃ got the atorvastatincalcuim of 46.1g Ky type in 8 hours.
Embodiment 7
The crystallisate powder of getting embodiment 1 preparation carries out X ray diffracting spectrum to be measured, and described A crystal formation is using Cu-K α radiation condition
X-ray diffractogram of powder spectrum data when 2 θ angles are 0-50 ° in Prague are as shown in table 1, and wherein 2Tetha is 2 θ angles, and d is a spacing, I/I
0Represent relative intensity, the per-cent that accounts for area under the intense line with area under a certain spectral line is represented.Characteristic peak as shown in Figure 1, its characteristic peak is expressed as with spacing d (round up and get hundredths)
These crystal formation x-ray diffractogram of powder spectrum data of table 1
| 2-Theta | d | I(％) |
| 5.389 | 16.8853 | 13.9 |
| 8.799 | 10.4097 | 19.2 |
| 11.573 | 8.1583 | 2.3 |
| 18.892 | 4.7630 | 15.1 |
| 28.116 | 3.0309 | 1.7 |
Embodiment 7
The KY crystal formation infrared absorption spectrum of atorvastatincalcuim
With the KCl pressed disc method KY crystal formation of atorvastatincalcuim is measured infrared absorption spectrum, the KY crystal formation is at about 617.59cm
-1700.08cm
-1753.76cm
-1844.43cm
-11111.45cm
-11158.31cm
-11223.71cm
-11316.70cm
-11438.96cm
-11481.23cm
-11531.57cm
-11561.60cm
-11599.12cm
-11651.85cm
-12364.69cm
-12956.08cm
-13281.21cm
-1There is absorption peak at the place.
Embodiment 8 differential thermal analysis (DSC)
Adopt Perkin Elmer Diamond Differential Scanning Calorimeter Autosample equipment that the KY crystal formation of atorvastatincalcuim is carried out calorimetric analysis, temperature range is 20.0 ℃-300.0 ℃, its crystalline differential thermal analysis collection of illustrative plates (DSC figure) is at about 44.0 ℃, 148.6 ℃, 166.8 ℃, 252.9 ℃ have the feature endotherm(ic)peak.Fig. 5 is atorvastatincalcuim KY crystal formation DSC and DTG collection of illustrative plates.
The preparation of embodiment 9 atorvastatincalcuim KY crystal formation tablets
A kind of tablet, wherein atorvastatincalcuim KY crystal formation crystalline content is 7.2%, and the microcrystalline cellulose cellulose content is 28.1%, and lime carbonate is 26.7%, and lactose-content is 28%, Magnesium Stearate content is 1%.Every tablet of medicament contains the about 10.8mg of atorvastatincalcuim KY crystal formation crystallization.
The capsular preparation of embodiment 11 atorvastatincalcuim KY crystal formation crystallizations
A kind of capsule, wherein atorvastatincalcuim KY crystal formation type crystalline content is 7.5%, and lactose hydrous content is 28%, and the microcrystalline cellulose cellulose content is 27.5%, and croscarmellose sodium content is 5%, Magnesium Stearate content is 1.2%.Every capsules contains atorvastatincalcuim KY crystal formation 10mg.
Claims (5)
1. the KY crystal formation of atorvastatincalcuim, it is characterized in that: this crystallization has following characteristic peak at the X-ray diffraction of powder: (d) is expressed as with spacing
Or this crystallization under the X-ray diffraction of powder (2 θ) 5.389 °, 8.799 °, 11.573 °, 18.892 °, 28.116 °); Its crystalline differential thermal analysis collection of illustrative plates (DSC figure) is at about 44.0 ℃, and 148.6 ℃, 166.8 ℃, 252.9 ℃ have the feature endotherm(ic)peak.
2. the KY crystal formation of atorvastatincalcuim according to claim 1, it is characterized in that: described KY crystal formation infrared absorption spectrum is at about 617.59cm
-1700.08cm
-1753.76cm
-1844.43cm
-11111.45cm
-11158.31cm
-11223.71cm
-11316.70cm
-11438.96cm
-11481.23cm
-11531.57cm
-11561.60cm
-11599.12cm
-11651.85cm
-12364.69cm
-12956.08cm
-13281.21cm
-1There is absorption peak at the place.
3. prepare the KY crystal formation of atorvastatincalcuim as claimed in claim 1, comprise the steps:
(1) atorvastatincalcuim that will not have the crystal water thing or contain the crystal water thing is dissolved in acetone, butanone, or in the mixed solvent of acetone, butanone and water, the solvent load that needs of every g atorvastatincalcuim is 5～50ml;
(2) be heated to 40～65 ℃ of dissolvings after, under this temperature, add ether or isopropyl ether, the consumption of ether or isopropyl ether is that every 1g atorvastatincalcuim adds 20～100ml ether or isopropyl ether, or adds crystal seed behind the cool to room temperature;
(3) be cooled to below 0 ℃, stirring and crystallizing, the temperature of crystallization are-15～0 ℃, filter, 50 ℃ dry 4-6 hour, collect crystallisate.
4. pharmaceutical composition, it contains the KY crystal formation and at least a pharmaceutically acceptable carrier of the atorvastatincalcuim of significant quantity.
5. pharmaceutical composition according to claim 4 is characterized in that: to be that tablet, hard capsule, soft capsule, enteric coated capsule, sustained-release and controlled release formulation, slow releasing tablet, sustained release coating and other are any be fit to oral formulation to the formulation of described pharmaceutical composition.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101546599A CN102249978A (en) | 2011-06-09 | 2011-06-09 | KY crystal form of Atorvastatin calcium and preparation method thereof |
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| CN2011101546599A CN102249978A (en) | 2011-06-09 | 2011-06-09 | KY crystal form of Atorvastatin calcium and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061285A (en) * | 2015-07-23 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Atorvastatin calcium drug compound for treating coronary heart disease and preparation method therefor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001044181A1 (en) * | 1999-12-17 | 2001-06-21 | Warner Lambert Research And Development Ireland Limited | A process for producing crystalline atorvastatin calcium |
| CN1423634A (en) * | 1999-11-17 | 2003-06-11 | 特瓦制药工业有限公司 | Polymorphic form of atorvastain calcium |
| CN101684090A (en) * | 2008-09-27 | 2010-03-31 | 广东东阳光药业有限公司 | Method for preparing amorphous atorvastatin calcium |
-
2011
- 2011-06-09 CN CN2011101546599A patent/CN102249978A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1423634A (en) * | 1999-11-17 | 2003-06-11 | 特瓦制药工业有限公司 | Polymorphic form of atorvastain calcium |
| WO2001044181A1 (en) * | 1999-12-17 | 2001-06-21 | Warner Lambert Research And Development Ireland Limited | A process for producing crystalline atorvastatin calcium |
| CN101684090A (en) * | 2008-09-27 | 2010-03-31 | 广东东阳光药业有限公司 | Method for preparing amorphous atorvastatin calcium |
Non-Patent Citations (2)
| Title |
|---|
| 《Archives of Pharmacal Research》 20091231 Su-Gyeong An et al. "Crystal Forms of Atorvastatin" 第933-936页 1-5 第32卷, 第6期 * |
| SU-GYEONG AN ET AL.: ""Crystal Forms of Atorvastatin"", 《ARCHIVES OF PHARMACAL RESEARCH》, vol. 32, no. 6, 31 December 2009 (2009-12-31), pages 933 - 936 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061285A (en) * | 2015-07-23 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Atorvastatin calcium drug compound for treating coronary heart disease and preparation method therefor |
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Application publication date: 20111123 |