CN101195603A - Novel crystal system of pitavastatin calcium and method for producing the same - Google Patents
Novel crystal system of pitavastatin calcium and method for producing the same Download PDFInfo
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- CN101195603A CN101195603A CNA2007100930119A CN200710093011A CN101195603A CN 101195603 A CN101195603 A CN 101195603A CN A2007100930119 A CNA2007100930119 A CN A2007100930119A CN 200710093011 A CN200710093011 A CN 200710093011A CN 101195603 A CN101195603 A CN 101195603A
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Abstract
The invention relates to organic chemical and pharmacy technical field, which provides a new crystal form of (3R, 5R)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-group]-3, 5-dihydroxy-6(E)-semi-calcium heptanoate (pitavastatin calcium) for treating hypercholesterolemia or atherosclerosis, and a relative preparation method. The 2-theta value relative to the characteristic diffracted ray in X-powder diffracted pattern of the crystal form is 4.3 and 5.2, while the positions of 2-theta as 6.6, 8.6, 11.0, and 13.1 are existed with relative diffracted rays, and the water content of the crystal form is 0.5-3%.
Description
Technical field
The present invention relates to organic chemistry filed and pharmaceutical field, be specifically related to the HMG-CoA reductase inhibitor two-[(3R, 5S, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-6-heptenoic acid] calcium salt (formula I compound, general Pitavastatin Calcium by name, Pitavastatin Calcium) a kind of new crystal and preparation method thereof, and the pharmaceutical composition that contains this new crystal.
Background technology
Pitavastatin Calcium (Pitavastatin Calcium, formula I compound) is first complete synthesis HMG-CoA reductase inhibitor of developing by daily output chemical company and Kowa company Ltd, the powerful lipopenicillinase that shows in its clinical trial is renderd a service and is described as " super he spit of fland ", data presentation Pitavastatin Calcium lipid-lowering effect according to report is very good, is the most potent up to now fat-reducing medicament.The mechanism of action of statins is 3-hydroxyl-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, can suppress the activity of HMG-CoA reductase enzyme competitively.Nearest research finds that also statins is blood fat reducing obviously, and protects the effect of cardio and vascular function in addition.
Reported that at present Pitavastatin Calcium has multiple crystal formation.WO2004072040 discloses A, B, C, D, E, F and non-crystalline state, and B, C, D, E, F crystal formation are to obtain under differing temps and solvent condition by the A crystal formation; US2005209259 discloses the anhydrous non-crystalline state of Pitavastatin Calcium, it provides two kinds of preparation methods, a kind of method is in tetrahydrofuran (THF) and hexanaphthene, the solid that obtains was 50 ℃ of vacuum-dryings 15 hours, another kind is in ethanol and Virahol, and the solid that obtains obtains non-crystalline state in room temperature vacuum-drying; The crystal formation that WO2005063711 provides obtains at 40 ℃ of drying under reduced pressure by the Pitavastatin Calcium that reaction is obtained, and its water content is 5%～15%.In research process to the Pitavastatin Calcium crystal formation, the discovery that we are pleasantly surprised a kind of new crystal of Pitavastatin Calcium, its X-ray powder diffraction feature obviously is different from existing crystal formation, and the steady quality of this crystal formation, the preparation method is simpler.
Summary of the invention
The object of the present invention is to provide a kind of steady quality, the better simply Pitavastatin Calcium new crystal of preparation method and preparation method thereof; Another object of the present invention is to this Pitavastatin Calcium new crystal is used to prepare medicine.
In order to realize this purpose, the invention provides a kind of two-[(3R with certain X-ray powder diffraction, 5S, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-6-heptenoic acid] calcium salt (Pitavastatin Calcium, formula I compound) new crystal, 2 θ values of feature diffracted ray correspondence are 4.3,5.2 in this collection of illustrative plates; Be that places such as 6.6,8.6,11.0,13.1 also have corresponding diffracted ray in 2 θ values in addition, more than the measuring error of 2 θ be ± 0.2, under envrionment temperature and ambient moisture, use copper gamma ray source is measured and is obtained.
Contain a certain amount of water in the Pitavastatin Calcium new crystal of the present invention, its water content ranges is 0.5～3%.
The invention provides the method that a kind of preparation has the Pitavastatin Calcium new crystal of above X-ray powder diffraction feature, comprise Pitavastatin Calcium is crystallized out from the aqueous solution that comprises Pitavastatin Calcium or from the water that comprises Pitavastatin Calcium and the mixing solutions that mixes water-soluble organic solvent, crystallizing out, then the Pitavastatin Calcium that crystallizes out is dried to water content 0.5～3%.
The invention provides a kind of pharmaceutical composition, comprise Pitavastatin Calcium new crystal of the present invention and pharmaceutical excipient.
The present invention also provides Pitavastatin Calcium new crystal of the present invention to be used for the treatment of utilization in hypercholesterolemia, familial hypercholesterolemia or the atherosclerotic medicine in preparation.
The X-ray powder diffraction analysis of Pitavastatin Calcium new crystal of the present invention is under envrionment temperature and ambient moisture, measure through the CuK α source (α=1.54056 ) of Philips X ' Pert Pro MPD X-ray powder diffraction instrument and to finish, 2 θ value measuring error are ± 0.2.This Pitavastatin Calcium new crystal typical X-ray powder diffraction as shown in drawings.
It generally is 0～40 ℃ that the present invention carries out Pitavastatin Calcium new crystal form X-ray powder diffraction survey periodic " envrionment temperature "; " ambient moisture " generally is 30%～80% relative humidity.
(3R involved in the present invention, 5S, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, the multiple preparation method of 5-dihydroxyl-6-heptenoic acid (pitavastatin) or its salt is at EP304063, EP520406, EP1099694, Tetrahedronletters, 1993,34:8267-8270., Bull.Chem.Soc.Jpn.1995,68:2649-2656, Boorganic ﹠amp; MedicinalChemistry Letters, 1999, open in the documents such as 9:2977-2982..The preparation method of Pitavastatin Calcium new crystal provided by the invention specifically may further comprise the steps:
(1), in the aqueous solution or in water and the mixing solutions that mixes water-soluble organic solvent, forms and crystallization goes out Pitavastatin Calcium;
(2), isolate Pitavastatin Calcium, it is 0.5～3% that drying makes its water content.
" mix water-soluble organic solvent " in the step (1) and comprise methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile or their mixed solvent etc., wherein preferred alcohol, acetone.
The method of " forming also, crystallization goes out Pitavastatin Calcium " comprises that the water-soluble salt (as lithium salts, sodium salt, sylvite, ammonium salt etc.) with pitavastatin forms Pitavastatin Calcium with water miscible calcium salt (as calcium chloride, Calcium Bromide, calcium iodide, calcium acetate, calcium lactate etc.) reaction in the step (1), and crystallization is separated out.Wherein the mole number that feeds intake of water-soluble Ca salt is generally 0.4～1 times of water-soluble salt of pitavastatin, preferred 0.5～0.7 times.
" separation " method comprises and filtering or centrifugal etc. in the step (2).
" drying " comprises constant pressure and dry, drying under reduced pressure or their mixed form in the step (2); Wherein the straight reciprocal of duty cycle of drying under reduced pressure is generally 0.050～0.098MPa, preferred 0.085～0.095MPa.Drying temperature generally is 20～150 ℃, preferred 30～100 ℃; Drying temperature can keep constant in drying process, also can use different drying temperatures at different drying stages.
The mensuration of water content is carried out with Ka Shi moisture determination method in the step (2).
Pitavastatin Calcium new crystal provided by the invention shows that through stability study it is stable and controllable for quality, and 40 ℃ of accelerated test data of this crystal formation are as shown in table 1.
The main test result of the accelerated test of table 1 Pitavastatin Calcium new crystal
| 0 month | June | |
| Proterties related substance moisture content IR collection of illustrative plates X-ray powder diffraction | White crystalline powder 0.63% 0.9% | White crystalline powder 0.68% 1.1% consistent with 0 month with 0 month unanimity |
Generally speaking, Pitavastatin Calcium new crystal provided by the invention has the X-ray powder diffraction feature that obviously is different from existing crystal formation, it is stable and controllable for quality, and preparation method's controllability is strong, easy and simple to handle, favorable reproducibility is all used conventional equipment, be easy to suitability for industrialized production, therefore Pitavastatin Calcium new crystal provided by the invention is a kind of new crystal with practical value of Pitavastatin Calcium.
Pitavastatin Calcium new crystal of the present invention can be used as active constituent and is used for preparation treatment hypercholesterolemia, familial hypercholesterolemia or atherosclerotic medicine.Generally be that treatment this crystallization of significant quantity or this crystal formation and one or more pharmaceutical carriers or vehicle are made pharmaceutical preparation or composition, this pharmaceutical preparation or composition are to be prepared in the mode of knowing in the pharmacy field.Carrier or vehicle can be solid, semisolid or liquid substance, and they are as the carrier or the medium of active constituent, and suitable carriers or vehicle are to know in this area.That this pharmaceutical preparation or composition go for is oral, intravenous injection (quiet notes), intramuscular injection (intramuscular injection), subcutaneous injection (subcutaneous), sublingual administration (hypogloeeis), rectal perfusion (rectal administration), eye drip, nasal spray, mouth spray or local skin (surface) or whole body (through skin) medication.The formulation of this pharmaceutical preparation or composition includes but not limited to tablet, capsule, granule, pill, pulvis, aerosol, suppository, gelifying agent, injection, pharmaceutical solutions, tincture etc.Wherein preferred tablet, capsule.
Tablet (comprises ordinary tablet, coating tablet, dispersible tablets etc.) carrier or vehicle generally comprise and in the capsule: weighting agent or expanding material are (as starch, lactose, glucose, N.F,USP MANNITOL and silicon-dioxide etc.), tackiness agent is (as carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, alginate, gelatin, Povidone etc.), wetting Agent for Printing Inks (as glycerine etc.), disintegrating agent is (as agar, lime carbonate and sodium bicarbonate etc.), the dissolving retarding agent (as paraffin etc.), absorption enhancer (as quaternary ammonium salt etc.), treating compound is (as hexadecyl alcohol, glyceryl monostearate etc.), sorbent material is (as kaolin, wilkinites etc.), lubricant is (as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol etc.); Also can comprise tinting material, sanitas, sweetener etc. in addition.Coating material comprises the multipolymer etc. of multipolymer, methacrylic acid and the methyl methacrylate of phthalic ester cellulose ethanoate, hydroxypropylmethylcellulose phthalate, polyethylene phthalic ester, carboxymethylethylcellulose, vinylbenzene and toxilic acid, if needed, they can use with suitable manufacturing methods and/or extender.Capsule material comprises gelatin or other conventional lapping.
Can also contain other suitable activeconstituentss in the pharmaceutical preparation of Pitavastatin Calcium new crystal of the present invention or the composition.
The pharmaceutical preparation of Pitavastatin Calcium new crystal of the present invention or the unitary dose of composition are generally 0.1-50mg, preferred 0.5-10mg, for example 0.5mg, 1mg, 2mg, 5mg or 10mg etc.
Pharmaceutical preparation or composition with Pitavastatin Calcium new crystal of the present invention are used for the treatment of hypercholesterolemia, familial hypercholesterolemia or atherosclerosis, wherein preferred hypercholesterolemia or familial hypercholesterolemia.
Description of drawings
The X-ray powder diffraction of Pitavastatin Calcium new crystal.
Embodiment
The invention will be further described below in conjunction with embodiment, can make this area professional and technical personnel more fully understand the present invention, but the scope that does not limit the present invention in any way.Term that uses among the embodiment and abbreviation have common implication.
Reference example
The preparation of pitavastatin sodium
In 1000 milliliters of there-necked flasks, add (3R, 5S, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-6-heptenoic acid-Alpha-Methyl benzylamine salt (is pressed document Boorganic ﹠amp; Medicinal Chemistry Letters, 1999,9:2977-2982. preparation) 50g and purified water are 500 milliliters, logical nitrogen stirred 30 minutes, got muddy milk sap, splash into 101 milliliters of 1 mol aqueous sodium hydroxide solutions, stir and got homogeneous transparent solution in 30 minutes, with 500 milliliters of washings of methyl tert-butyl ether, water layer is the aqueous solution of pitavastatin sodium.
Embodiment 1
The preparation of Pitavastatin Calcium new crystal
In 1000 milliliters of there-necked flasks, add the pitavastatin sodium water solution that makes by the reference example method, under nitrogen protection, splash into 12 gram crystallization calcium chloride (CaCl
2.6H
2O) 200 milliliters of purification of aqueous solutions have dropwised continuation and had stirred 3 hours, suction filtration, and filter cake washs with an amount of purified water, and (vacuum tightness 0.090～0.095MPa) drying got the Pitavastatin Calcium new crystal in 10 hours 55～60 ℃ of decompressions down.Measuring its water content is 1.5%, and the X-ray powder diffraction is consistent with accompanying drawing.
Embodiment 2
The preparation of Pitavastatin Calcium new crystal
In 1000 milliliters of there-necked flasks, add Pitavastatin Calcium sodium water solution and the 100 milliliters of ethanol that make by embodiment 1 method, under nitrogen protection, splash into 13 gram crystallization calcium chloride (CaCl
2.6H
2O) 200 milliliters of purification of aqueous solutions have dropwised and have continued to stir 3 hours, suction filtration, and filter cake washs with an amount of purified water, and (vacuum tightness 0.090～0.095MPa) drying 12 hours gets the Pitavastatin Calcium new crystal 35～40 ℃ of decompressions.Measuring its water content is 2.7%, and the X-ray powder diffraction is consistent with accompanying drawing.
Embodiment 3
The preparation of Pitavastatin Calcium new crystal
In 1000 milliliters of there-necked flasks, add Pitavastatin Calcium sodium water solution and the 100 milliliters of acetone that make by embodiment 1 method; under nitrogen protection, splash into 150 milliliters of purification of aqueous solutions of 10 gram calcium acetates; dropwised and continued to stir 2 hours; suction filtration; filter cake washs with an amount of purified water; (vacuum tightness 0.085～0.090MPa) drying 15 hours gets the Pitavastatin Calcium new crystal 75～80 ℃ of decompressions.Measuring its water content is 0.6%, and the X-ray powder diffraction is consistent with accompanying drawing.
Embodiment 4
Pitavastatin Calcium tablet with the preparation of Pitavastatin Calcium new crystal
Prescription:
Pitavastatin Calcium new crystal 1.0g
Lactose 74.2g
Low-substituted hydroxypropyl cellulose 4.0g
Magnesium Stearate 0.8g
Make 1000
Preparation technology:
The Pitavastatin Calcium new crystal is crossed 100 mesh sieves, adopt the equivalent incremental method to mix, added the low-substituted hydroxypropyl cellulose of 80 mesh sieves, mix with lactose; Aqueous ethanolic solution 30 mesh sieves with 50% are granulated; 50 ℃ of oven for drying, the whole grain of 30 mesh sieves; Add Magnesium Stearate, mix; Measure granule content, it is heavy to calculate sheet; Compressing tablet.
The front has been described the present invention in detail, comprises its embodiment preferred.But, should be understood that and consider content disclosed by the invention that those skilled in the art can change the present invention and/or improve, and also belong to scope of the present invention in spirit (essence of the present invention) scope of claims.
Claims (10)
1. a Pitavastatin Calcium (formula I) new crystal, it is characterized in that: 2 θ values of the feature diffracted ray correspondence of the X-ray powder diffraction of this crystal formation are 4.3,5.2.
2. the Pitavastatin Calcium new crystal of claim 1, its water content is 0.5～3%.
3. method for preparing the Pitavastatin Calcium new crystal described in claim 1 or 2, comprise Pitavastatin Calcium is crystallized out from the aqueous solution that comprises Pitavastatin Calcium or from the water that comprises Pitavastatin Calcium and the mixing solutions that mixes water-soluble organic solvent, crystallizing out, then the Pitavastatin Calcium that crystallizes out is dried to water content 0.5～3%.
4. the method for claim 3, wherein said Pitavastatin Calcium is formed by pitavastatin water-soluble salt and the reaction of water miscible calcium salt.
5. the method for claim 3, wherein drying temperature is 20～150 ℃, preferred 30～100 ℃.
6. the method for claim 4, said pitavastatin water-soluble salt is lithium salts, sodium salt, sylvite or ammonium salt, said water-soluble Ca salt is calcium chloride, Calcium Bromide, calcium iodide, calcium acetate or calcium lactate.
7. the method for claim 3, wherein said to mix water-soluble organic solvent be methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile or their mixed solvent, preferred alcohol, acetone.
8. medicinal compositions comprises the Pitavastatin Calcium new crystal and the pharmaceutical excipient of claim 1 or 2.
9. the composition of claim 8, wherein dosage form is tablet, capsule.
10. claim 1 or 2 Pitavastatin Calcium new crystal are used for the treatment of utilization in hypercholesterolemia, familial hypercholesterolemia or the atherosclerotic medicine in preparation.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007100930119A CN101195603A (en) | 2007-11-21 | 2007-11-21 | Novel crystal system of pitavastatin calcium and method for producing the same |
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| CNA2007100930119A CN101195603A (en) | 2007-11-21 | 2007-11-21 | Novel crystal system of pitavastatin calcium and method for producing the same |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012025939A1 (en) * | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Pitavastatin calcium and process for its preparation |
| CN102432533A (en) * | 2011-12-20 | 2012-05-02 | 浙江国邦药业有限公司 | Method for preparing high-optical purity pitavastatin calcium |
| CN102653523A (en) * | 2011-12-17 | 2012-09-05 | 东莞达信生物技术有限公司 | Preparation method of pitavastatin calcium by recrystallization |
| WO2013037838A1 (en) | 2011-09-12 | 2013-03-21 | Farma Grs, D.O.O. | Polymorphic form of pitavastatin calcium |
| WO2013098773A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Crystalline forms of pitavastatin calcium |
| CN104860882A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug pitavastatin calcium composition for treating hyperlipidemia |
| EP3178812A1 (en) * | 2010-11-12 | 2017-06-14 | Hetero Research Foundation | Novel polymorphs of pitavastatin calcium |
| CN109053568A (en) * | 2018-08-29 | 2018-12-21 | 南京卓康医药科技有限公司 | A kind of high-purity Pitavastatin Calcium novel crystal forms and preparation method thereof |
| CN111053742A (en) * | 2018-10-16 | 2020-04-24 | 南京卓康医药科技有限公司 | Pitavastatin calcium oral spray and preparation and use method thereof |
-
2007
- 2007-11-21 CN CNA2007100930119A patent/CN101195603A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012025939A1 (en) * | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Pitavastatin calcium and process for its preparation |
| JP2013536219A (en) * | 2010-08-25 | 2013-09-19 | カディラ・ヘルスケア・リミテッド | Pitavastatin calcium and method for preparing the same |
| US9034901B2 (en) | 2010-08-25 | 2015-05-19 | Cadila Healthcare Limited | Pitavastatin calcium and process for its preparation |
| EP3178812A1 (en) * | 2010-11-12 | 2017-06-14 | Hetero Research Foundation | Novel polymorphs of pitavastatin calcium |
| WO2013037838A1 (en) | 2011-09-12 | 2013-03-21 | Farma Grs, D.O.O. | Polymorphic form of pitavastatin calcium |
| EA024991B1 (en) * | 2011-09-12 | 2016-11-30 | ФАРМА ДжРС, Д.О.О. | Polymorphic form of pitavastatin calcium |
| CN102653523A (en) * | 2011-12-17 | 2012-09-05 | 东莞达信生物技术有限公司 | Preparation method of pitavastatin calcium by recrystallization |
| CN102432533A (en) * | 2011-12-20 | 2012-05-02 | 浙江国邦药业有限公司 | Method for preparing high-optical purity pitavastatin calcium |
| WO2013098773A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Crystalline forms of pitavastatin calcium |
| CN104860882A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug pitavastatin calcium composition for treating hyperlipidemia |
| CN109053568A (en) * | 2018-08-29 | 2018-12-21 | 南京卓康医药科技有限公司 | A kind of high-purity Pitavastatin Calcium novel crystal forms and preparation method thereof |
| CN111053742A (en) * | 2018-10-16 | 2020-04-24 | 南京卓康医药科技有限公司 | Pitavastatin calcium oral spray and preparation and use method thereof |
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Application publication date: 20080611 |