MXPA06007435A - Crystal form of quinoline compound and process for its production - Google Patents
Crystal form of quinoline compound and process for its productionInfo
- Publication number
- MXPA06007435A MXPA06007435A MXPA/A/2006/007435A MXPA06007435A MXPA06007435A MX PA06007435 A MXPA06007435 A MX PA06007435A MX PA06007435 A MXPA06007435 A MX PA06007435A MX PA06007435 A MXPA06007435 A MX PA06007435A
- Authority
- MX
- Mexico
- Prior art keywords
- crystal form
- crystal
- compound
- water
- formula
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims description 7
- -1 quinoline compound Chemical class 0.000 title description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 14
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 229910016523 CuKa Inorganic materials 0.000 claims description 3
- 150000001674 calcium compounds Chemical class 0.000 claims description 3
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 2
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 abstract description 3
- 229960003296 pitavastatin calcium Drugs 0.000 abstract 2
- VGYFMXBACGZSIL-MCBHFWOFSA-N Pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 229960002797 pitavastatin Drugs 0.000 description 15
- 229940079593 drugs Drugs 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 239000011575 calcium Substances 0.000 description 6
- 230000005712 crystallization Effects 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
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- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229940116362 Tragacanth Drugs 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
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- 238000002347 injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-Phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L Calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 240000008528 Hevea brasiliensis Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010062060 Hyperlipidaemia Diseases 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N Isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 229940039717 Lanolin Drugs 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- AQLLBJAXUCIJSR-UHFFFAOYSA-N OC(=O)C[Na] Chemical class OC(=O)C[Na] AQLLBJAXUCIJSR-UHFFFAOYSA-N 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- 229940051841 POLYOXYETHYLENE ETHER Drugs 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229950008882 Polysorbate Drugs 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M Sodium laurate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 Sodium laurate Drugs 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
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- 230000001058 adult Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000001315 anti-hyperlipaemic Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- 230000037396 body weight Effects 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
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- 239000003937 drug carrier Chemical class 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
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- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
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- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
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- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940035429 isobutyl alcohol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
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- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
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- 235000013772 propylene glycol Nutrition 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
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- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
A method for producing a drug substance of crystalline pitavastatin calcium excellent in stability, is presented. In the production of a compound (pitavastatin calcium) represented by the formula (1):The water content is adjusted to a level of from 5 to 15%, and the crystal form is controlled to be crystal form A, thereby to obtain a drug substance excellent in stability.
Description
FORM OF CRYSTAL OF THE COMPOUND QUINOLINE AND PROCEDURE FOR ITS PRODUCTION
TECHNICAL FIELD
The present invention relates to a crystal form of pitavastatin calcica known by a chemical name bis [(3R, 5S, 6E) -7- (2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl) -3, 5-dihydroxy-6-heptenoate] monocalcium, which is useful for the treatment of hyperlipemia, as an HMG-CoA reductase inhibitor, to a process for its production and to a pharmaceutical composition comprising this compound and a pharmaceutically acceptable carrier. Particularly, it refers to crystallized pitavastatin in crystal form, which is characterized in that it contains from 5 to 15% (w / w) of water and which is useful as a drug substance for pharmaceutical products, from the point of view of stability, etc., to a process for its production and to a pharmaceutical composition that contains it.
PREVIOUS TECHNIQUE
Calcium pitavastatin (see patent documents 1, 2 and 3) is commercially available as an antihyperlipidemic treatment agent, and has already been reported about its production method, optical resolution method employing optically active α-methylbenzylamine (cf. patent document 4 and non-patent document 1).
Known as methods for producing the compound of the formula (3) as the starting material are: • column chromatographic separation employing a column of optical isomer separation (see patent document 5), • asymmetric synthesis (see patent documents 6 and 7),
• method of subjecting to chemical synthesis reduction a compound of formula (4) that can be produced using chiral synthon
(see patent document 8) • method of subjecting a compound of formula (4) to reduction of biological synthesis (see patent document 9), and • optical resolution using an enzyme (see patent document 10) .
wherein R is a C1-4 alkyl group.
wherein R is an alkyl group of C -? - 4. Patent Document 1: JP-A-1 -279866 Patent Document 2: EP304063A Patent Document 3: US Patent. No. 5,011, 930
Patent Document 4: JP-A-5-148237 Patent Document 5: WO95 / 23125 Patent Document 6: WO03 / 042180 Patent Document 7: JP-A-8-092217 Patent Document 8: JP-A-8 -127585 Patent Document 9: JP-A-2002-300897 Patent Document 10: JP-A-13-352996 Non-Patent Document 1: Bioorganic & Medicinal Chemistry Letters, 9 (1999), p. 2977
BRIEF DESCRIPTION OF THE INVENTION
A drug substance for pharmaceuticals having high quality and a stable crystal form is needed from the storage point of view and it is further required to be durable for large scale production. However, in the conventional method for producing calcitic pitavastatin, no reference has been made to the water content or the crystal form. It has been found that if the calcium pitavastatin (crystal form A) is subjected to drying in the usual manner, the crystallinity will decrease to a state close to the amorphous state, as shown in Figure 2, when the water content turns out to be a as much as 4%, even with one that shows X-ray diffraction through powder, as shown in figure 1, before drying. In addition, it has been found that calcium pitavastatin that has become amorphous has very poor stability during storage, as shown in table 1.
TABLE 1 Stability data of the drug substance (influence of water content)
It is an object of the present invention to provide a crystalline pitavastatin crystalline drug substance, which is stable, even if it is not stored under special storage conditions and also to enable mass industrial production. The present inventors have carried out an extensive study on the interrelation between the moisture and the stability of the drug substance and as a result have found that the stability of the calcitic pitavastatin can be markedly improved., controlling the water content in the drug substance within a specific range. In addition, it has been found that there are three types of crystal form that have the same water content and, among them, the crystal (crystal form A) characterized by X-ray diffraction through powder, which is measured using lightning CuKa, is very preferred as a drug substance for pharmaceutical products. The present invention has been carried out on the basis of these discoveries. Specifically, the present invention provides: 1. The crystal (crystal form A) of a compound of the formula d):
which contains 5 to 15% water and which shows, in its X-ray powder diffraction, which is measured using CuKa radiation, a peak that has a relative intensity of more than 25% at an angle of diffraction (2T) of 30.16 °. 2. A process for producing the crystal (crystal form A) as defined in article 1, which comprises adding a calcium compound to a compound of the formula (2):
wherein M + represents an alkali metal ion, dissolved in water or in a C1-4 alcohol containing at least 60% water. 3. A method for producing a drug substance of the crystal (crystal form A) as defined in article 1, which comprises adjusting the water content to a level of 5 to 15%. 4. A pharmaceutical composition containing the crystal (crystal form A) as defined in article 1. The two types of crystal forms other than the crystal form A are represented by the crystal forms B and C, but none of them shows peaks at the diffraction angles of 10.40 °, 13.20 ° and 30.16 ° characteristic of the crystal form A, thus indicating that they are crystal polymorphs. It was evident that they are deficient in filtration capacity, require strict drying conditions (which are likely to experience a change in the crystal form during drying), are likely to include an inorganic substance, such as NaCl, and are not necessarily able to maintain the ability to reproduce in the control of the crystal form. Thus, there are many drawbacks from the point of view of the industrial production method and the crystal form A is the best as a drug substance for pharmaceutical products.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a powder X-ray diffraction pattern of the crystal form A, in which the water content is 8.78%. Figure 2 is a powder X-ray diffraction pattern; when the crystals are used in figure 1, they are dried to make the water content of 3.76%.
BEST MODE FOR CARRYING OUT THE INVENTION
Now, the present invention will be described in detail. The crystallized pitavastatin, which is in the form of crystal A, is characterized by its powder X-ray diffraction pattern. Diffraction Angle (29) (") Grid distribution d Relative intensity (> 25%) 4.96 17.7999 35.9 6.72 13.1423 55.1 9.08 9.7314 33.3 10.40 8.4991 34.8 10.88 8.1248 27.3 13.20 6.7020 27.8 13.60 6.5053 48.8 13.96 6.3387 60.0 18.32 4.8386 56.7 20.68 4.2915 100.0 21.52 4.1259 57.4 23.64 3.7604 41.3 24.12 3.6866 45.0 27.00 3.2996 28.5 30.16 2.9607 30.6 Apparatus Powder X-ray diffraction measurement equipment: MXLabo (manufactured by MacScience) Light source: Cu, wavelength: 1.54056A, goniometer: vertical goniometer Monochrome: used, auxiliary means: None, X-ray tube voltage: 50.0 KV, tube current: 30.0 mA.
Measurement method Before the measurement, the alignment of the X-ray tube is tested, using silicon (usual substance). Approximately 100 mg of a sample is placed on a glass plate for the sample and flattened, followed by measurement under the following conditions. Data interval: from 3.0400 to 40.0000 degrees. Number of data points: 925. Scan axis: 2T / T, axis angle?: No adjustment. Sampling interval: 0.0400 degrees. Scan speed: 4,800 degrees / minute. The present invention also provides a production method for controlling the calcitic pitavastatin to have the crystal form A.
The starting material is an alkali metal salt of pitavastatin shown by formula (2) and the alkali metal can be, for example, lithium, sodium or potassium, preferably sodium. As the calcium compound, calcium chloride or calcium acetate may be preferred and its amount is within a range of 0.3 to 3 moles, preferably 0.5 to 2 moles, per mole of the compound of the formula (2). The alkaline metal salt of pitavastatin of the formula (2) should not necessarily be isolated. For example, the Ca salt can be produced, as a result of the hydrolyzing reaction, for example a compound of the formula (3).
As the solvent to be used, water or C1-4 alcohol containing at least 60% water is preferred. The alcohol of C -? - can be, for example, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or tert-butyl alcohol. The amount of solvent to be used is usually within a range of 3 to 100 times by mass, preferably within the range of 5 to 30 times by mass, to the amount of the compound of formula (2). The crystallization temperature is not particularly limited, but is usually within a range of -10 to 70 ° C, preferably within a range of -5 to 40 ° C, more preferably within a range of 0 to 20 ° C. The crystallization time is not particularly limited, but a crystallization time of about 30 minutes to 15 hours is usually sufficient. As the crystallization method, there may be mentioned, for example, a method of carrying out crystallization in a state of rest or a method of carrying out crystallization with stirring. However, it is preferred to carry out the crystallization with stirring. In addition, seed crystals of the crystal form A can be used, as the case requires. Then the precipitated crystals will be filtered and dried. In the present invention, it is very important to adjust the water content. The drying temperature is not particularly limited, but is preferably within a range of 15 to 40 ° C.
The water content is adjusted, so that it is finally within a range of 5 to 15% (w / w), preferably within a range of 7 to 15% (w / w), more preferably within a range of 7 to 13% (w / w), most preferably within a range of 9 to 13% (w / w). The obtained calcium pitavastatin will be pulverized and then used as a drug substance for pharmaceutical products. The administration of the compound of the present invention can be, for example, parenteral administration in the form of injection drug (subcutaneous, intravenous, intramuscular or intraperitoneal injection), an ointment, a suppository, an aerosol or the like, or oral administration in the form of tablets, capsules, granules, pills, a drug in syrup, a liquid drug, an emulsion drug or a suspension drug. A pharmaceutical or veterinary medicine composition containing the compound of the present invention contains from about 0.001 to 30%, preferably from about 0.01 to 10% of the compound of the present invention, based on the weight of the total composition. In addition to the compound of the present invention or the composition containing such compound, other pharmaceutically active compounds or those of veterinary medicine may be incorporated. The clinical dosage of the compound of the present invention may vary, depending for example on age, body weight, sensitivity of the patient or severity of the symptom: However, the effective dosage is usually at a level of 0.03 to 100 mg, preferably from 0.01 to 10 mg, per day for an adult. However, if necessary, a dosage outside this range can be used. The compound of the present invention can be formulated for administration according to a common method for the preparation of medicines. Specifically, tablets, capsules, granules or pills can be formulated for oral administration, using, for example, an excipient, such as sucrose, lactose, glucose, starch or mannitol; a binder, such as hydroxypropylcellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose or polyvinylpyrrolidone; a disintegrant, such as starch, carboxymethylcellulose, or its calcium salt, fine crystal cellulose, or polyethylene glycol; a lubricant, such as talc, magnesium or calcium stearate, or silica; a lubricating agent, such as sodium laurate or glycerol. An injection drug, a liquid drug, an emulsion drug, a suspension drug, a syrup drug or an aerosol drug can be prepared using, for example, a solvent for the active ingredient, such as water, ethyl alcohol , isopropyl alcohol, propylene glycol, 1,3-butylene glycol or polyethylene glycol; a surfactant, such as a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene ether of hydrogenated castor oil or lecithin; a suspending agent, such as carboxymethyl sodium salt, or a cellulose derivative, such as methylcellulose, tragacanth, a natural rubber, such as gum arabic; a preservative, such as p-hydroxybenzoate, benzalkonium chloride or a salt of sorbic acid.
For an ointment which is a percutaneous absorption type formulation, for example, white petrolatum, liquid paraffin, a higher alcohol, macrogol ointment, hydrophilic ointment or an aqueous gel base material can be used. A suppository can be prepared, using for example cocoa butter, polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil or polysorbate. Now, the present invention will be described in greater detail with reference to an example. However, it should be understood that the present invention is not restricted in any way to the specific example. The compound (5) used in the example was prepared according to the method disclosed in W095 / 23125.
EXAMPLE 1
2.71 kg (6.03 mol) of the compound (5) was dissolved in 50 kg of ethanol with stirring and, after confirming that the solution was a uniform solution, 58.5 kg of water was added. After cooling to -3 to 3 ° C, 3.37 liters of an aqueous solution of sodium hydroxide at 2 moles / liter was added dropwise thereto, followed by stirring at the same temperature for 3 hours to complete the reaction hydrolytic In order to introduce the entire amount of the aqueous solution of sodium hydroxide to the reaction system, 4.70 kg of water was used. The reaction mixture was distilled under reduced pressure to remove the solvent and, after removing 52.2 kg of ethanol / water, the internal temperature was adjusted to 10 and up to 20 ° C. To the obtained concentrated solution was added dropwise an aqueous solution of calcium chloride prepared separately (95% CaCl 2 775 g / water 39.3 kg, 5.53 moles) over a period of 2 hours. In order to introduce the entire amount of the aqueous solution of calcium chloride into the reaction system, 4.70 kg of water was used. After completion of the dropwise addition, stirring was continued at the same temperature for 12 hours, after which the precipitated crystals were collected by filtration. The crystals were washed with 72.3 kg of water and then dried under reduced pressure in a dryer at 40 ° C, while paying attention to the temperature of the product, until the water content was converted to 10%, to obtain 2.80 kg (yield: 95%) of calcium pitavastatin as white crystals. X-ray diffraction was measured through powder to confirm that the crystals were of crystal form A.
INDUSTRIAL APPLICABILITY According to the present invention, an industrial method for producing a crystalline pitavastatin crystalline drug substance of excellent stability has been established.
Claims (4)
1. - A crystal (crystal form A) of a compound of the formula (1): which contains 5 to 15% water and which shows, in its X-ray powder diffraction, which is measured using CuKa radiation, a peak that has a relative intensity of more than 25% at an angle of diffraction (2T) of 30.16 °.
2. A process for producing a crystal (crystal form A) as claimed in claim 1, characterized in that it comprises adding a calcium compound to a compound of the formula (2): wherein M + represents an alkali metal ion, dissolved in water or a C1- alcohol containing at least 60% water.
3. A method for producing a drug substance of a crystal (crystal form A) as claimed in claim 1, characterized in that it comprises adjusting the water content at a level of 5 to 15%.
4. A pharmaceutical composition, characterized in that it contains a crystal (crystal form A) as claimed in claim 1.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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JP2003-431788 | 2003-12-26 |
Publications (1)
Publication Number | Publication Date |
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MXPA06007435A true MXPA06007435A (en) | 2007-04-20 |
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