CA2546894C - Reference standard for characterization of rosuvastatin - Google Patents
Reference standard for characterization of rosuvastatin Download PDFInfo
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- CA2546894C CA2546894C CA002546894A CA2546894A CA2546894C CA 2546894 C CA2546894 C CA 2546894C CA 002546894 A CA002546894 A CA 002546894A CA 2546894 A CA2546894 A CA 2546894A CA 2546894 C CA2546894 C CA 2546894C
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- rosuvastatin
- degradation product
- lactone
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- calcium
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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
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
Abstract
Provided are rosuvastatin degradation products and their use as a reference standard (including reference marker) for analysis of rosuvastatin.
Description
REFERENCE STANDARD FOR CHARACTERIZATION OF
ROSUVASTATIN
FIELD OF THE INVENTION
The present invention relates to rosuvastatin degradation products and their use as a reference standard for analysis of rosuvastatin.
BACKGROUND OF THE INVENTION
Statins are currently the most therapeutically effective drugs available for reducing low-density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Thus, statins are used in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. A high level of LDL in the bloodstream has been linked to the formation of coronary lesions that obstruct the flow of blood and can rupture and promote throinbosis. Goodman and Gilman, The Pharinacological Basis of Therapeutics, page 879 (9th Ed. 1996).
Statins inhibit cholesterol biosynthesis in humans by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A("HMG-CoA") reductase enzyme. HMG-CoA
reductase catalyzes the conversion of HMG to mevalonate, which is the rate-determining step in the biosynthesis of cholesterol. Decreased production of cholesterol causes an increase in the number of LDL receptors and corresponding reduction in the concentration of LDL particles in the bloodstream. Reduction in the LDL level in the bloodstream reduces the risk of coronary artery disease. JA.M.A. 1984, 251, 351-74.
Currently available statins include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin. Lovastatin (disclosed in U.S. Pat. No.
4,231,938) and simvastatin (disclosed in U.S. Pat. No. 4,444,784) are administered in the lactone form.
After absorption, the lactone ring is opened in the liver by chemical or enzyrnatic hydrolysis, and the active hydroxy acid is generated.
Pravastatin (disclosed in U.S. Pat. No. 4,346,227) is administered as the sodium salt. Fluvastatin (disclosed in U.S. Pat. No. 4,739,073) and cerivastatin (disclosed in U.S.
Pat. Nos. 5,006,530 and 5,177,080), also administered as the sodium salt, are entirely synthetic compounds that are in part structurally distinct from the fungal derivatives of this class that contain a hexahydronaphthalene ring. Atorvastatin and two new "superstatins,"
rosuvastatin and pitavastatin, are administered as calcium salts.
Rosuvastatin calcium (monocalcium bis (+) 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoate) is an HMG-CoA reductase inhibitor, developed by Shionogi for the once daily oral treatinent of hyperlipidaemia (Ann Rep, Shionogi, 1996; Direct communications, Shionogi, 8 Feb 1999 & 25 Feb 2000). Rosuvastatin calcium is a superstatin, which can lower LDL-cholesterol and triglycerides more effectively than first generation drugs. Rosuvastatin calcium has the following chemical formula:
F
4"
5,I 3~.
1" 7 4' 6 3' N~ 5- g 4 3 2 1 O 1/2 Ca2+
9 N2' N 8 S '
ROSUVASTATIN
FIELD OF THE INVENTION
The present invention relates to rosuvastatin degradation products and their use as a reference standard for analysis of rosuvastatin.
BACKGROUND OF THE INVENTION
Statins are currently the most therapeutically effective drugs available for reducing low-density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Thus, statins are used in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. A high level of LDL in the bloodstream has been linked to the formation of coronary lesions that obstruct the flow of blood and can rupture and promote throinbosis. Goodman and Gilman, The Pharinacological Basis of Therapeutics, page 879 (9th Ed. 1996).
Statins inhibit cholesterol biosynthesis in humans by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A("HMG-CoA") reductase enzyme. HMG-CoA
reductase catalyzes the conversion of HMG to mevalonate, which is the rate-determining step in the biosynthesis of cholesterol. Decreased production of cholesterol causes an increase in the number of LDL receptors and corresponding reduction in the concentration of LDL particles in the bloodstream. Reduction in the LDL level in the bloodstream reduces the risk of coronary artery disease. JA.M.A. 1984, 251, 351-74.
Currently available statins include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin. Lovastatin (disclosed in U.S. Pat. No.
4,231,938) and simvastatin (disclosed in U.S. Pat. No. 4,444,784) are administered in the lactone form.
After absorption, the lactone ring is opened in the liver by chemical or enzyrnatic hydrolysis, and the active hydroxy acid is generated.
Pravastatin (disclosed in U.S. Pat. No. 4,346,227) is administered as the sodium salt. Fluvastatin (disclosed in U.S. Pat. No. 4,739,073) and cerivastatin (disclosed in U.S.
Pat. Nos. 5,006,530 and 5,177,080), also administered as the sodium salt, are entirely synthetic compounds that are in part structurally distinct from the fungal derivatives of this class that contain a hexahydronaphthalene ring. Atorvastatin and two new "superstatins,"
rosuvastatin and pitavastatin, are administered as calcium salts.
Rosuvastatin calcium (monocalcium bis (+) 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoate) is an HMG-CoA reductase inhibitor, developed by Shionogi for the once daily oral treatinent of hyperlipidaemia (Ann Rep, Shionogi, 1996; Direct communications, Shionogi, 8 Feb 1999 & 25 Feb 2000). Rosuvastatin calcium is a superstatin, which can lower LDL-cholesterol and triglycerides more effectively than first generation drugs. Rosuvastatin calcium has the following chemical formula:
F
4"
5,I 3~.
1" 7 4' 6 3' N~ 5- g 4 3 2 1 O 1/2 Ca2+
9 N2' N 8 S '
2\
10' Rosuvastatin calcium is marketed under the name CRESTORO for treatment of a mammal such as a human. According to the maker of CRESTOR , it is administered in a daily dose of from about 5mg to about 40 mg. For patients requiring less aggressive LDL-C reductions or who have pre-disposing factors for myopathy, the 5mg dose is recommended, while 10 mg dose is recommended for the average patient, 20 mg dose for patients with marked hyper-cholesterolemia and aggressive lipid targets (>190 mg/dL), and the 40 mg dose for patients who have not been responsive to lower doses.
U.S. Pat. No. 5,260,440 discloses and claims rosuvastatin, its calcium salt (2:1), and its lactone form. The process of the `440 patent prepares rosuvastatin by reacting 4-(4-fluorophenyl)-6-i sopropyl-2-(N-methyl-N-methylsulfonylamino)-5 -pyrimidinecarbaldehyde with methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenyiphosphoranylidene hexanate in acetonitrile under reflux. The silyl group is then cleaved with hydrogen fluoride, followed by reduction with NaBH4 and diethylmethoxyborane in THF to obtain a methyl ester of rosuvastatin.
The ester is then hydrolyzed with sodium hydroxide in ethanol at room temperature, followed by removal of ethanol and addition of ether, to obtain the sodium salt of rosuvastatin.
The sodium salt is then converted to the calcium salt. The sodium salt is dissolved in water and maintained under a nitrogen atmosphere. Calcium chloride is then added to the solution, resulting in precipitation of rosuvastatin calcium (2:1). The process for preparation of the intermediates disclosed in the `440 patent.
U.S. Pat. No. 6,316,460 discloses a pharmaceutical composition of rosuvastatin. The pharmaceutical compositions contain rosuvastatin or its salt and a multivalent tribasic phosphate salt.
The product mixture of a reaction rarely is a single compound pure enough to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, be present. At certain stages during processing of the rosuvastatin contained in the product mixture into an active pharmaceutical ingredient ("API"), the rosuvastatin must be analyzed for purity, typically by HPLC or GC
analysis, to determine if it is suitable for continued processing or ultimately for use in a pharmaceutical product. The rosuvastatin does not need to be absolutely pure. Absolute purity is a theoretical ideal that is unattainable. Rather, there are purity standards intended to ensure that an API is not made less safe for clinical use because of the presence of impurities. In the United States, the Food and Drug Administration guidelines recommend that applicants limit some impurities to below 0.1 %.
Generally, side products, byproducts and adjunct reagents (collectively "impurities") are identified spectroscopically and by other physical methods and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). (Strobel p.
953) (Strobel, H.A.; Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3"d dd.
(Wiley &
Sons: New York 1989)). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the "retention
10' Rosuvastatin calcium is marketed under the name CRESTORO for treatment of a mammal such as a human. According to the maker of CRESTOR , it is administered in a daily dose of from about 5mg to about 40 mg. For patients requiring less aggressive LDL-C reductions or who have pre-disposing factors for myopathy, the 5mg dose is recommended, while 10 mg dose is recommended for the average patient, 20 mg dose for patients with marked hyper-cholesterolemia and aggressive lipid targets (>190 mg/dL), and the 40 mg dose for patients who have not been responsive to lower doses.
U.S. Pat. No. 5,260,440 discloses and claims rosuvastatin, its calcium salt (2:1), and its lactone form. The process of the `440 patent prepares rosuvastatin by reacting 4-(4-fluorophenyl)-6-i sopropyl-2-(N-methyl-N-methylsulfonylamino)-5 -pyrimidinecarbaldehyde with methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenyiphosphoranylidene hexanate in acetonitrile under reflux. The silyl group is then cleaved with hydrogen fluoride, followed by reduction with NaBH4 and diethylmethoxyborane in THF to obtain a methyl ester of rosuvastatin.
The ester is then hydrolyzed with sodium hydroxide in ethanol at room temperature, followed by removal of ethanol and addition of ether, to obtain the sodium salt of rosuvastatin.
The sodium salt is then converted to the calcium salt. The sodium salt is dissolved in water and maintained under a nitrogen atmosphere. Calcium chloride is then added to the solution, resulting in precipitation of rosuvastatin calcium (2:1). The process for preparation of the intermediates disclosed in the `440 patent.
U.S. Pat. No. 6,316,460 discloses a pharmaceutical composition of rosuvastatin. The pharmaceutical compositions contain rosuvastatin or its salt and a multivalent tribasic phosphate salt.
The product mixture of a reaction rarely is a single compound pure enough to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, be present. At certain stages during processing of the rosuvastatin contained in the product mixture into an active pharmaceutical ingredient ("API"), the rosuvastatin must be analyzed for purity, typically by HPLC or GC
analysis, to determine if it is suitable for continued processing or ultimately for use in a pharmaceutical product. The rosuvastatin does not need to be absolutely pure. Absolute purity is a theoretical ideal that is unattainable. Rather, there are purity standards intended to ensure that an API is not made less safe for clinical use because of the presence of impurities. In the United States, the Food and Drug Administration guidelines recommend that applicants limit some impurities to below 0.1 %.
Generally, side products, byproducts and adjunct reagents (collectively "impurities") are identified spectroscopically and by other physical methods and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). (Strobel p.
953) (Strobel, H.A.; Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3"d dd.
(Wiley &
Sons: New York 1989)). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the "retention
-3-time." This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use "relative retention time" ("RRT") to identify impurities. (Strobel p.
922). The RRT of an impurity is its retention time divided by the retention time of some reference marker. In theory, rosuvastatin itself could be used as the reference marker, but as a practical matter it is present in such overwhelming proportion in the mixture that it tends to saturate the column, leading to irreproducible retention times, i.e., the maximum of the peak corresponding to rosuvastatin tends to wander (Strobel Fig. 24.8(b) p. 879, contains an illustration of the sort of asymmetric peak that is observed when a column is overloaded). Thus, it is sometimes desirable to select an alternative compound that is added to, or is present in, the mixture in an amount significant enough to be detectable and sufficiently low as not to saturate the column and to use that compound as the reference marker.
Researchers and developers in drug manufacturing understand that a compound in a relatively pure state can be used as a "reference standard" (a "reference marker" is similar to a reference standard but it is used for qualitative analysis) to quantify the amount of the compound in an unknown mixture. When the compound is used as an "external standard," a solution of a known concentration of the compound is analyzed by the same technique as the unknown mixture. (Strobel p. 924, Snyder p. 549) (Snyder, L.R.; Kirkland, J.J.
Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response. See also USP 6,333,198.
The reference standard compound also can be used to quantify the amount of another compound in the mixture if the "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined.
(Strobel p. 894). For this purpose, the reference standard compound may be added directly to the mixture, in which case it is called an "internal standard." (Strobel p. 925, Snyder p. 552).
The reference standard compound can even be used as an internal standard when the unknown mixture contains some of the reference standard compound by using a technique called "standard addition," wherein at least two samples are prepared by adding known and differing amounts of the internal standard. (Strobel
922). The RRT of an impurity is its retention time divided by the retention time of some reference marker. In theory, rosuvastatin itself could be used as the reference marker, but as a practical matter it is present in such overwhelming proportion in the mixture that it tends to saturate the column, leading to irreproducible retention times, i.e., the maximum of the peak corresponding to rosuvastatin tends to wander (Strobel Fig. 24.8(b) p. 879, contains an illustration of the sort of asymmetric peak that is observed when a column is overloaded). Thus, it is sometimes desirable to select an alternative compound that is added to, or is present in, the mixture in an amount significant enough to be detectable and sufficiently low as not to saturate the column and to use that compound as the reference marker.
Researchers and developers in drug manufacturing understand that a compound in a relatively pure state can be used as a "reference standard" (a "reference marker" is similar to a reference standard but it is used for qualitative analysis) to quantify the amount of the compound in an unknown mixture. When the compound is used as an "external standard," a solution of a known concentration of the compound is analyzed by the same technique as the unknown mixture. (Strobel p. 924, Snyder p. 549) (Snyder, L.R.; Kirkland, J.J.
Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response. See also USP 6,333,198.
The reference standard compound also can be used to quantify the amount of another compound in the mixture if the "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined.
(Strobel p. 894). For this purpose, the reference standard compound may be added directly to the mixture, in which case it is called an "internal standard." (Strobel p. 925, Snyder p. 552).
The reference standard compound can even be used as an internal standard when the unknown mixture contains some of the reference standard compound by using a technique called "standard addition," wherein at least two samples are prepared by adding known and differing amounts of the internal standard. (Strobel
-4-pp. 391-393, Snyder pp. 571, 572). The proportion of detector response due to the reference standard compound that is originally in the mixture can be determined by extrapolation of a plot of detector response versus the amount of the reference standard compound that was added to each of the samples to zero. (e.g. Strobel, Fig. 11.4 p. 392).
The present invention provides a rosuvastatin degradation product that can be used as a reference standard for analysis of rosuvastatin.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a rosuvastatin degradation product having the following structure:
F
4"
The present invention provides a rosuvastatin degradation product that can be used as a reference standard for analysis of rosuvastatin.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a rosuvastatin degradation product having the following structure:
F
4"
5" HOH OH 0
6"
6 5 4 3 2~ OH
3'N~4 7 N2'~'N 6, 7 8, ,.
$02 10' In another aspect, the present invention provides a rosuvastatin degradation product having the following structure:
F
4"
5" ~ 3" H OH OH 0 ., :
.g 5 4 3 2~ OH
6 5 4 3 2~ OH
3'N~4 7 N2'~'N 6, 7 8, ,.
$02 10' In another aspect, the present invention provides a rosuvastatin degradation product having the following structure:
F
4"
5" ~ 3" H OH OH 0 ., :
.g 5 4 3 2~ OH
7 I 5' ~
~
N 6, 7~ 8, ,, 10' In another aspect, the present invention provides a rosuvastatin degradation product having the following structure:
F
4"
õ
3'N 7 ' 9. N 5 2 N 6 7' g 110, wherein M is an alkali or alkaline earth metal.
In another aspect, the present invention provides a rosuvastatin degradation product having the following structure:
F
4"
5" 3" H OH OH O
6"I ' -6 5 4 3 2 ~ OM
3'N ~4 7 5' ~
~
NN6,7' 8, I 1, 110, wherein M is an alkali or alkaline earth metal. Preferably M is calcium. The calcium salt may be converted to lactone form by combining acetonitrile, hydrochloric acid and the calcium salt to obtain the lactone; or to free acid comprising dissolving the calcium salt in a mixture of acetonitrile and water, and contacting the calcium salt with a silica colunm.
In another aspect the present invention provides a lactone form of a rosuvastatin degradation product having the following structure:
F
4"
3"H OH OH 0 6"I
iõ 6 5 4 3 2 1 OH
3'N~4 7 5' 9.N 6, 7' 8 1' SOZ
5 110' In another aspect, the present invention provides a lactone form of a rosuvastatin degradation product having the following structure:
F
4"
s" rH
"0 6,~ OH
3'4 ~
~NN
1' sOz 10' In another aspect, the present invention provides a process for converting the lactone to a calcium salt comprising hydrolyzing the lactone under aqueous basic conditions, and reacting the hydrolyzed lactone with a source of calcium.
In another aspect, the present invention provides a process for converting the lactone to free acid form comprising hydrolyzing the lactone under aqueous basic conditions to obtain a metal salt and contacting the metal salt with a silica column.
Preferably the degradation product is about 95% free % area by HPLC by weight of its corresponding stereoisomer at position 6. The rosuvastatin degradation product may be isolated or purified.
In another aspect, the present invention provides a method for analyzing a sample of rosuvastatin comprising the steps of:
a) performing chromatography on the sample to obtain data; and b) comparing the data with the chromatography data of the degradation product.
In another aspect the present invention provides a process for preparing the degradation product comprising the step of irradiating with visible light rosuvastatin acid, rosuvastatin alkali or alkaline earth metal salt or rosuvastatin lactone.
In another aspect, the present invention provides a method for determining the retention time of a chromatography column for rosuvastatin, comprising the steps of carrying out chromatography with the following compound as a standard, F
4f 5It 3~~ ORl OR2 O
s 'N
9~N/~ 6, 7 s s SOZ--, wherein Rl and R2 are independently hydrogen or a hydrolyzable protecting group;
R3 is hydrogen, a C, to C4 alkyl group, or an alkali or alkaline earth metal;
or wherein C' and C5 form a lactone.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is an HPLC chromatogram of Compound VI.
Figure 2 is an HPLC chromatogram of Compound VII.
Figure 3 is an HPLC chromatogram of a mixture of rosuvastatin, Compound VI, and Compound VII.
Figure 4 is a chromatogram of purity of Compound VI.
Figure 5 is a chromatogram of purity of Compound VII.
Figure 6 is a chromatogram of mixture of rosuvastatin Ca, Compound VI and Compound VII.
Figure 7 is a chromatogram of rosuvastatin Ca spiked with Compound VI and Compound VII
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "reference standard" refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. For example, the retention time of the compound in HPLC allows for setting a relative retention time, thus making qualitative analysis possible.
The concentration of the compound in solution before injection into an HPLC column allows for comparison of the areas under the peaks in an HPLC chromatogram, thus making quantitative analysis possible.
~
N 6, 7~ 8, ,, 10' In another aspect, the present invention provides a rosuvastatin degradation product having the following structure:
F
4"
õ
3'N 7 ' 9. N 5 2 N 6 7' g 110, wherein M is an alkali or alkaline earth metal.
In another aspect, the present invention provides a rosuvastatin degradation product having the following structure:
F
4"
5" 3" H OH OH O
6"I ' -6 5 4 3 2 ~ OM
3'N ~4 7 5' ~
~
NN6,7' 8, I 1, 110, wherein M is an alkali or alkaline earth metal. Preferably M is calcium. The calcium salt may be converted to lactone form by combining acetonitrile, hydrochloric acid and the calcium salt to obtain the lactone; or to free acid comprising dissolving the calcium salt in a mixture of acetonitrile and water, and contacting the calcium salt with a silica colunm.
In another aspect the present invention provides a lactone form of a rosuvastatin degradation product having the following structure:
F
4"
3"H OH OH 0 6"I
iõ 6 5 4 3 2 1 OH
3'N~4 7 5' 9.N 6, 7' 8 1' SOZ
5 110' In another aspect, the present invention provides a lactone form of a rosuvastatin degradation product having the following structure:
F
4"
s" rH
"0 6,~ OH
3'4 ~
~NN
1' sOz 10' In another aspect, the present invention provides a process for converting the lactone to a calcium salt comprising hydrolyzing the lactone under aqueous basic conditions, and reacting the hydrolyzed lactone with a source of calcium.
In another aspect, the present invention provides a process for converting the lactone to free acid form comprising hydrolyzing the lactone under aqueous basic conditions to obtain a metal salt and contacting the metal salt with a silica column.
Preferably the degradation product is about 95% free % area by HPLC by weight of its corresponding stereoisomer at position 6. The rosuvastatin degradation product may be isolated or purified.
In another aspect, the present invention provides a method for analyzing a sample of rosuvastatin comprising the steps of:
a) performing chromatography on the sample to obtain data; and b) comparing the data with the chromatography data of the degradation product.
In another aspect the present invention provides a process for preparing the degradation product comprising the step of irradiating with visible light rosuvastatin acid, rosuvastatin alkali or alkaline earth metal salt or rosuvastatin lactone.
In another aspect, the present invention provides a method for determining the retention time of a chromatography column for rosuvastatin, comprising the steps of carrying out chromatography with the following compound as a standard, F
4f 5It 3~~ ORl OR2 O
s 'N
9~N/~ 6, 7 s s SOZ--, wherein Rl and R2 are independently hydrogen or a hydrolyzable protecting group;
R3 is hydrogen, a C, to C4 alkyl group, or an alkali or alkaline earth metal;
or wherein C' and C5 form a lactone.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is an HPLC chromatogram of Compound VI.
Figure 2 is an HPLC chromatogram of Compound VII.
Figure 3 is an HPLC chromatogram of a mixture of rosuvastatin, Compound VI, and Compound VII.
Figure 4 is a chromatogram of purity of Compound VI.
Figure 5 is a chromatogram of purity of Compound VII.
Figure 6 is a chromatogram of mixture of rosuvastatin Ca, Compound VI and Compound VII.
Figure 7 is a chromatogram of rosuvastatin Ca spiked with Compound VI and Compound VII
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "reference standard" refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. For example, the retention time of the compound in HPLC allows for setting a relative retention time, thus making qualitative analysis possible.
The concentration of the compound in solution before injection into an HPLC column allows for comparison of the areas under the peaks in an HPLC chromatogram, thus making quantitative analysis possible.
8 AMENDED SHEET
A "reference marker" is used in qualitative analysis to identify components of a mixture based upon their position, e.g. in a chromatogram or on a Thin Layer Chromatography (TLC) plate (Strobel pp. 921, 922, 953). For this purpose, the compound does not necessarily have to be added to the mixture if it is present in the mixture. A "reference marker" is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.
Although some of the knowledge of those in the art regarding reference standards has been described in general terms up to this point, those skilled in the art also understand that the detector response can be, for example, the peak heights or integrated peak areas of a chromatogram obtained, e.g. by UV or refractive index detection, from the eluent of an HPLC system or, e.g. flame ionization detection or thermal conductivity detection, from the eluent of a gas chromatograph, or other detector response, e.g. the UV absorbence, of spots on a fluorescent TLC
plate. The position of the reference standard may be used to calculate the relative retention time for rosuvastatin and other impurities.
When rosuvastatin calcium is exposed to visible light irradiation, degradation products of rosuvastatin are obtained, which can be used as a reference standard. The two degradation products are diastereomeric cyclic products (II) and (III) with the creation of an additional asymmetric center in position 6 as follows:
F
4"
611I 2~~
1*65 4 3 2 k1O-31 N 517 1/2 Ca2+
9t NN
61 71 $1 O
S 2N, 10' In addition to rosuvastatin calciuni, other forms of rosuvastatin may be irradiated, including the lactone, free acid and salts such as sodium salt.
The irradiation may be performed in solution or in solid state. When irradiating a solution, the irradiation may be performed at preferably from about room
A "reference marker" is used in qualitative analysis to identify components of a mixture based upon their position, e.g. in a chromatogram or on a Thin Layer Chromatography (TLC) plate (Strobel pp. 921, 922, 953). For this purpose, the compound does not necessarily have to be added to the mixture if it is present in the mixture. A "reference marker" is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.
Although some of the knowledge of those in the art regarding reference standards has been described in general terms up to this point, those skilled in the art also understand that the detector response can be, for example, the peak heights or integrated peak areas of a chromatogram obtained, e.g. by UV or refractive index detection, from the eluent of an HPLC system or, e.g. flame ionization detection or thermal conductivity detection, from the eluent of a gas chromatograph, or other detector response, e.g. the UV absorbence, of spots on a fluorescent TLC
plate. The position of the reference standard may be used to calculate the relative retention time for rosuvastatin and other impurities.
When rosuvastatin calcium is exposed to visible light irradiation, degradation products of rosuvastatin are obtained, which can be used as a reference standard. The two degradation products are diastereomeric cyclic products (II) and (III) with the creation of an additional asymmetric center in position 6 as follows:
F
4"
611I 2~~
1*65 4 3 2 k1O-31 N 517 1/2 Ca2+
9t NN
61 71 $1 O
S 2N, 10' In addition to rosuvastatin calciuni, other forms of rosuvastatin may be irradiated, including the lactone, free acid and salts such as sodium salt.
The irradiation may be performed in solution or in solid state. When irradiating a solution, the irradiation may be performed at preferably from about room
9 temperature up to about reflux temperature. The organic solvent used for dissolution may be either polar protonic (Cl to C4 alcohol such as methanol or ethanol) or aprotonic (acetonitrile, tetrahydrofuran) in a mixture with water. Visible light irradiation of about 750w at about 35 C of aqueous acetonitrile solution of rosuvastatin calcium for about 7 hours gives a mixture of compounds (II and III) in the ratio 1:1. When irradiating in the solid state, the temperature is preferably from about 20EC to about 100EC. One of skill in the art may yet choose a narrow spectrum within these spectrums or a mixture of various spectrums. Based on the structural guidance provided herein of the various degradation products, one of skill in the art may prepare a synthetic route to obtain the degradation products.
In another embodiment, the corresponding lactone is obtained, either by irradiating the lactone form of rosuvastatin or by preparing the lactone from Compounds II and III to obtain the corresponding Compounds N and V which can be used as a reference standard. Compound IV has the following_1H NMR (300MHz, CDC13) 8 (ppm): 1.24, 1.34, 1.68, 2.47, 2.53, 2.64, 3.15, 3.35, 3.46, 3.56, 3.60, 4.28, 4.45, 6.99, 7.14, 8.31; 13C NMR (75MHz, CDC13) 6(ppm): 20.87, 21.26, 23.29, 31.41, 33.26, 34.03, 38.23, 42.07, 43.00, 62.23, 74.53, 115.61, 116.08 (J=26Hz), 116.25 (J=22Hz), 129.08, 128.91 (J=91-Iz), 139.28 (J=8Hz), 157.64, 157.86, 163.96 (J=253Hz), 169.47, 174.48; FAB+m/z (MH+): 464. Compound V has the following 1H NMR (300MHz, CDC13) S(ppm): 1.24, 1.29, 1.52, 1.70, 2.58, 3.02, 3.21, 3.27, 3.41, 3.55, 3.60, 4.26, 4.78, 7.05, 7.12, 8.34; FAB+m/z (MH+): 464.
The preparation of the corresponding lactone compounds IV and V from compound II and III includes dissolving compound II and III in a suitable solvent and forming a lactone ring for example with aqueous hydrochloric acid. Other acids may be used to form a lactone. A suitable solvent for preparation of the lactone from Compound II or III is dichloromethane, chloroform, acetonitrile or tetrahydrofuran.
Preferably, the suitable solvent is acetonitrile. To recover the product, the solvent may be removed by any conventional process, such as evaporation. Obtained compounds N and V can be separated by methods such as column chromatography and crystallization.
The preparation of the corresponding lactone compounds IV and V from rosuvastatin lactone may also be performed by visible light irradiation in the same solvents. The irradiation characteristics are as described above. The lactone compounds IV and V may be hydrolyzed with an equivalent amount of an aqueous base such as sodium or calcium hydroxide to obtain the corresponding salts in the presence of a solvent. Preferably, the solvent is acetonitrile. In one embodiment, the lactones are hydrolyzed with an aqueous solution of sodium hydroxide in acetonitrile, followed by removal of acetonitrile and addition of a source of calcium such as calcium chloride.
The lactone forms IV and V can be hydrolyzed with a base to obtain salts and thereafter converted to acid forms VI and VII, respectively, which can be used as a reference standard. The conversion of the lactones to salts may be carried out by using a basic aqueous solution. In one embodiment, the lactone is dissolved in a mixture of acetonitrile and an aqueous NaOH solution. The acetonitrile is then removed and a source of calcium such as calcium chloride is added to precipitate the calcium salt.
The acid forms are obtained after purifying the salt products by column chromatography on silica gel (as described in example 1). It is believed that the acidity of the silica column is responsible for the conversion. Compound VI
has the following 'H NMR (600MHz, CDC13+CD3OD 5:1) S(ppm): 1.25, 1.33,1.39, 1.58, 2.22, 2.80, 2.89, 3.36, 3.52, 3.58, 3.61, 3.95, 7.01, 7.09, 8.26; 13C NMR
(150MHz, CDC13+CD3OD 5:1) 3 (ppm): 21.14, 21.31, 23.32, 31.56, 33.47, 40.15, 42.16, 42.97, 44.62, 68.99, 71.45, 115.17 (J=21 Hz), 116.32 (J=22Hz), 117.77, 128.87 (J=9Hz), 129.20,142.34 (J=8Hz), 157.71, 158.57, 164.26 (J=251Hz), 174.30; Cl+m/z (MH+):
482. Compound VII has the following 'H NMR (600MHz, CDCI3+CD3OD 5:1) 8 (ppm): 1.24, 1.31, 1.43, 2.25, 2.95, 3.05, 3.19, 3.30, 3.56, 3.60, 3.85, 4.03, 7.02, 7.08, 7.31;13C NMR (150MHz, CDC13+CD3OD 5:1) S(ppm): 21.15, 21.23, 22.98, 31.22, 33.36, 38.83, 42.08, 43.45, 68.82, 73.86, 114.95 (J=2lHz), 116.31 (J=21Hz), 117.41, 128.56 (J=8Hz), 128.91, 142.02 (J=8Hz), 157.58, 158.45, 164.28 (J=252Hz), -173.19, 178; Cl+m/z(1VIH+): 482.
The various forms of the degradation product may be purified so that only one stereoisomer is present. The R stereoisomer at position 6 is preferably at least about 95% free of the S stereoisomer % area by HPLC. Conversely, the S stereoisomer at position 6 is preferably at least about 95% free of the R stereoisomer % area by HPLC. Purification may be performed by column chromatography, TLC, HPLC, or other known purification methods.
AMENDED SHEET
Instruments For chromatography, aluminum oxide or, preferably, silica gel may be used for packing. As for the eluent, different organic solvents or mixtures thereof may be used. Ethyl acetate is preferred.
Compounds II and III, isolated as corresponding, acids (VI and VII), lactones (IV and V) can be investigated with 1H NMR, 13C NMR, COSY NMR and mass spectroscopic analyses to determine their structures.
EXAMPLES
Example 1. Preparation of rosuvastatin degradation products by irradiation of rosuvastatin (Ca salt).
1. Rosuvastatin (Ca-salt) (4.0g) was dissolved in a mixture acetonitrile-water (380ml-140m1) and irradiated with visible light (750w, 35 C) for 7 hours.
Acetonitrile and water were evaporated under vacuum.
2. The obtained solid was dissolved in 40m1 of acetonitrile and 40ml of 1N
hydrochloric acid was added. The mixture was stirred at room temperature overnight.
After evaporation of acetonitrile and water, and drying under vacuum, the obtained products,were separated by column chromatography on silica gel (eluent hexane-ethyl acetate 1:2), giving lactone IV (0.8g) and lactone V (0.6g). TLC on silica gel, eluent hexane-ethyl acetate (1:2) Rf=0.30 for Compound IV, Rt=0.25 for Compound V.
Compound IV
Number atom 'H NMR 13C NMR
(CDC13) (CDC13) A -A J(Hz) 1 169.47 2 2.53, 2.64 38.23 3 4.28 62.23 4 1.68 34.03 4.45 74.53 6 3.15 43.00 7 2.47, 3.46 23.29 2' 157.64 4' 157.86 5' 115.61 6' 174.48 7' 3.35 31.41 8' 1.24, 1.34 21.36, 20.87 9' 3.60 33.26
In another embodiment, the corresponding lactone is obtained, either by irradiating the lactone form of rosuvastatin or by preparing the lactone from Compounds II and III to obtain the corresponding Compounds N and V which can be used as a reference standard. Compound IV has the following_1H NMR (300MHz, CDC13) 8 (ppm): 1.24, 1.34, 1.68, 2.47, 2.53, 2.64, 3.15, 3.35, 3.46, 3.56, 3.60, 4.28, 4.45, 6.99, 7.14, 8.31; 13C NMR (75MHz, CDC13) 6(ppm): 20.87, 21.26, 23.29, 31.41, 33.26, 34.03, 38.23, 42.07, 43.00, 62.23, 74.53, 115.61, 116.08 (J=26Hz), 116.25 (J=22Hz), 129.08, 128.91 (J=91-Iz), 139.28 (J=8Hz), 157.64, 157.86, 163.96 (J=253Hz), 169.47, 174.48; FAB+m/z (MH+): 464. Compound V has the following 1H NMR (300MHz, CDC13) S(ppm): 1.24, 1.29, 1.52, 1.70, 2.58, 3.02, 3.21, 3.27, 3.41, 3.55, 3.60, 4.26, 4.78, 7.05, 7.12, 8.34; FAB+m/z (MH+): 464.
The preparation of the corresponding lactone compounds IV and V from compound II and III includes dissolving compound II and III in a suitable solvent and forming a lactone ring for example with aqueous hydrochloric acid. Other acids may be used to form a lactone. A suitable solvent for preparation of the lactone from Compound II or III is dichloromethane, chloroform, acetonitrile or tetrahydrofuran.
Preferably, the suitable solvent is acetonitrile. To recover the product, the solvent may be removed by any conventional process, such as evaporation. Obtained compounds N and V can be separated by methods such as column chromatography and crystallization.
The preparation of the corresponding lactone compounds IV and V from rosuvastatin lactone may also be performed by visible light irradiation in the same solvents. The irradiation characteristics are as described above. The lactone compounds IV and V may be hydrolyzed with an equivalent amount of an aqueous base such as sodium or calcium hydroxide to obtain the corresponding salts in the presence of a solvent. Preferably, the solvent is acetonitrile. In one embodiment, the lactones are hydrolyzed with an aqueous solution of sodium hydroxide in acetonitrile, followed by removal of acetonitrile and addition of a source of calcium such as calcium chloride.
The lactone forms IV and V can be hydrolyzed with a base to obtain salts and thereafter converted to acid forms VI and VII, respectively, which can be used as a reference standard. The conversion of the lactones to salts may be carried out by using a basic aqueous solution. In one embodiment, the lactone is dissolved in a mixture of acetonitrile and an aqueous NaOH solution. The acetonitrile is then removed and a source of calcium such as calcium chloride is added to precipitate the calcium salt.
The acid forms are obtained after purifying the salt products by column chromatography on silica gel (as described in example 1). It is believed that the acidity of the silica column is responsible for the conversion. Compound VI
has the following 'H NMR (600MHz, CDC13+CD3OD 5:1) S(ppm): 1.25, 1.33,1.39, 1.58, 2.22, 2.80, 2.89, 3.36, 3.52, 3.58, 3.61, 3.95, 7.01, 7.09, 8.26; 13C NMR
(150MHz, CDC13+CD3OD 5:1) 3 (ppm): 21.14, 21.31, 23.32, 31.56, 33.47, 40.15, 42.16, 42.97, 44.62, 68.99, 71.45, 115.17 (J=21 Hz), 116.32 (J=22Hz), 117.77, 128.87 (J=9Hz), 129.20,142.34 (J=8Hz), 157.71, 158.57, 164.26 (J=251Hz), 174.30; Cl+m/z (MH+):
482. Compound VII has the following 'H NMR (600MHz, CDCI3+CD3OD 5:1) 8 (ppm): 1.24, 1.31, 1.43, 2.25, 2.95, 3.05, 3.19, 3.30, 3.56, 3.60, 3.85, 4.03, 7.02, 7.08, 7.31;13C NMR (150MHz, CDC13+CD3OD 5:1) S(ppm): 21.15, 21.23, 22.98, 31.22, 33.36, 38.83, 42.08, 43.45, 68.82, 73.86, 114.95 (J=2lHz), 116.31 (J=21Hz), 117.41, 128.56 (J=8Hz), 128.91, 142.02 (J=8Hz), 157.58, 158.45, 164.28 (J=252Hz), -173.19, 178; Cl+m/z(1VIH+): 482.
The various forms of the degradation product may be purified so that only one stereoisomer is present. The R stereoisomer at position 6 is preferably at least about 95% free of the S stereoisomer % area by HPLC. Conversely, the S stereoisomer at position 6 is preferably at least about 95% free of the R stereoisomer % area by HPLC. Purification may be performed by column chromatography, TLC, HPLC, or other known purification methods.
AMENDED SHEET
Instruments For chromatography, aluminum oxide or, preferably, silica gel may be used for packing. As for the eluent, different organic solvents or mixtures thereof may be used. Ethyl acetate is preferred.
Compounds II and III, isolated as corresponding, acids (VI and VII), lactones (IV and V) can be investigated with 1H NMR, 13C NMR, COSY NMR and mass spectroscopic analyses to determine their structures.
EXAMPLES
Example 1. Preparation of rosuvastatin degradation products by irradiation of rosuvastatin (Ca salt).
1. Rosuvastatin (Ca-salt) (4.0g) was dissolved in a mixture acetonitrile-water (380ml-140m1) and irradiated with visible light (750w, 35 C) for 7 hours.
Acetonitrile and water were evaporated under vacuum.
2. The obtained solid was dissolved in 40m1 of acetonitrile and 40ml of 1N
hydrochloric acid was added. The mixture was stirred at room temperature overnight.
After evaporation of acetonitrile and water, and drying under vacuum, the obtained products,were separated by column chromatography on silica gel (eluent hexane-ethyl acetate 1:2), giving lactone IV (0.8g) and lactone V (0.6g). TLC on silica gel, eluent hexane-ethyl acetate (1:2) Rf=0.30 for Compound IV, Rt=0.25 for Compound V.
Compound IV
Number atom 'H NMR 13C NMR
(CDC13) (CDC13) A -A J(Hz) 1 169.47 2 2.53, 2.64 38.23 3 4.28 62.23 4 1.68 34.03 4.45 74.53 6 3.15 43.00 7 2.47, 3.46 23.29 2' 157.64 4' 157.86 5' 115.61 6' 174.48 7' 3.35 31.41 8' 1.24, 1.34 21.36, 20.87 9' 3.60 33.26
10' 3.56 42.07 1" 129.08 2" 139.28 8 3" 6.99 116.25 22 4" 163.96 253 5" 7.14 116.08 26 6" 8.31 128.91 9 Compound V
Number atom 1H N1VIR (CDCI3) __õ.,..., A;.
2 2.58 3 4.26 4 1.52, 1.70 5 4.78 6 3.41 7 3.02, 3.21 7' 3.27 8' 1.24, 1.29 9' 3.60 10' 3.55 3" 7.05 4"
5" 7.12 6" 8.34 3. Lactone IV (0.8g) was dissolved in acetonitrile, and 1N aqueous sodium hydroxide (4m1) was added. The mixture was stirred at room temperature overnight. After evaporation of acetonitrile and water, and drying under vacuum, the obtained product was purified by coluinn chromatography on silica gel (eluent dichloromethane-methano165m1: l Om1), giving pure Compound VI (0.4g).
Compound VI (Corresponding acid of Compound IV) Number atom 'H NMR ' C NMR
(CDC13fCD30 (CDC13+C1330D 5:1) b 5:1 A A J(HZ) 2 2.22 42.97 3 3.95 68.99 4 1.39/1.58 40.15 5 3.58 71.45 6 2.89 44.62 7 2.80/3.52 23.32 2' 157.71 4' 158.57 5' 117.77 6' 174.30 7' 3.36 31.56 8' 1.25/1.33 21.14/21.31 9' 3.61 33.47 10' 3.58 42.16 1" 129.20 2" 142.34 8 3" 7.01 116.32 22 4" 164.26 251 5" 7.09 115.17 21 6" 8.26 128.87 9 4. Analogously, Compound VII (0.3g) was obtained from lactone V.
Compound VII (Corresponding acid of Compound V) Number atom 'H NMR 3C NMR
(CDCI3+CD30D (CDCI3+CD3OD 5:1) 5:1) A A J(Hz) 2 2.25 42.08 3 4.03 68.82 4 1.43 38.83 5 3.85 73.86 6 3.05 43.45 7 2.95/3.19 22.98 2' 157.58 41 158.45 5' 117.41 6' 173.19 7' 3.30 31.22 8' 1.24/1.31 21.15/21.23 9' 3.60 33.36 10' 3.56 42.08 1" 128.91 2" 142.02 8 3" 7.02 116.31 21 4" 164.28 252 5" 7.08 114.95 21 6" 8.31 128.56 8 Example 2. Preparation of rosuvastatin degradation products by irradiation of rosuvastatin lactone 1. Rosuvastatin lactone (2.0g) was dissolved in 200m1 of acetonitrile and irradiated with visible light (750w, 35 C) for 7 hours. After evaporation of the acetonitrile, and drying under vacuum, the obtained products were separated by column chromatography on silica gel (eluent hexane-ethyl acetate 1:2), giving lactone IV
(1.1g) and lactone V (0.6g).
2. Lactone IV (1.0g) was dissolved in 5m1 of acetonitrile and 2ml of 1N
aqueous NaOH was added. The mixture was stirred at room temperature for 4 hours. After evaporation of acetonitrile, lml of 2N aqueous CaC12 was added, and the mixture was stirred for 1 hour at room temperature. The precipitate was filtered and dried under vacuum giving Compound II.
3. Analogously, Compound III was obtained from lactone V.
Example 3. HPLC impurity profile determination of rosuvastatin calcium The purity of Compounds IV, V, VI and VII is determined by HPLC analysis.
HPLC
Colunm: C 18 Eluent: Gradient of Formate buffer and Acetonitrile Flow: 1 ml/min Detector:245nm Sample volume: l0ul Diluent: Acetonitrile: Water = 50:50 Mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
Sample Preparation About 10mg of rosuvastatin calcium sample is weighed in a 20m1 amber volumetric flask. The sample is dissolved with l Oml acetonitrile and diluted to volume with water.
Standard Preparation About 10mg of each Compounds IV, V, VI and VII are weighed in a 20rn1 amber volumetric flask, dissolved with 10m1 acetonitrile and diluted to volume with water. lml of prepared solution is diluted to 100m1 with diluent.
Method The freshly prepared sample solutions are injected into the chromatograph, and the chromatogram of the sample is continued up to the end of the gradient.
The areas for each peak in each solution is determined using a suitable integrator.
Having thus described the invention with reference to particular preferred embodiments and illustrated it with Examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods.
Number atom 1H N1VIR (CDCI3) __õ.,..., A;.
2 2.58 3 4.26 4 1.52, 1.70 5 4.78 6 3.41 7 3.02, 3.21 7' 3.27 8' 1.24, 1.29 9' 3.60 10' 3.55 3" 7.05 4"
5" 7.12 6" 8.34 3. Lactone IV (0.8g) was dissolved in acetonitrile, and 1N aqueous sodium hydroxide (4m1) was added. The mixture was stirred at room temperature overnight. After evaporation of acetonitrile and water, and drying under vacuum, the obtained product was purified by coluinn chromatography on silica gel (eluent dichloromethane-methano165m1: l Om1), giving pure Compound VI (0.4g).
Compound VI (Corresponding acid of Compound IV) Number atom 'H NMR ' C NMR
(CDC13fCD30 (CDC13+C1330D 5:1) b 5:1 A A J(HZ) 2 2.22 42.97 3 3.95 68.99 4 1.39/1.58 40.15 5 3.58 71.45 6 2.89 44.62 7 2.80/3.52 23.32 2' 157.71 4' 158.57 5' 117.77 6' 174.30 7' 3.36 31.56 8' 1.25/1.33 21.14/21.31 9' 3.61 33.47 10' 3.58 42.16 1" 129.20 2" 142.34 8 3" 7.01 116.32 22 4" 164.26 251 5" 7.09 115.17 21 6" 8.26 128.87 9 4. Analogously, Compound VII (0.3g) was obtained from lactone V.
Compound VII (Corresponding acid of Compound V) Number atom 'H NMR 3C NMR
(CDCI3+CD30D (CDCI3+CD3OD 5:1) 5:1) A A J(Hz) 2 2.25 42.08 3 4.03 68.82 4 1.43 38.83 5 3.85 73.86 6 3.05 43.45 7 2.95/3.19 22.98 2' 157.58 41 158.45 5' 117.41 6' 173.19 7' 3.30 31.22 8' 1.24/1.31 21.15/21.23 9' 3.60 33.36 10' 3.56 42.08 1" 128.91 2" 142.02 8 3" 7.02 116.31 21 4" 164.28 252 5" 7.08 114.95 21 6" 8.31 128.56 8 Example 2. Preparation of rosuvastatin degradation products by irradiation of rosuvastatin lactone 1. Rosuvastatin lactone (2.0g) was dissolved in 200m1 of acetonitrile and irradiated with visible light (750w, 35 C) for 7 hours. After evaporation of the acetonitrile, and drying under vacuum, the obtained products were separated by column chromatography on silica gel (eluent hexane-ethyl acetate 1:2), giving lactone IV
(1.1g) and lactone V (0.6g).
2. Lactone IV (1.0g) was dissolved in 5m1 of acetonitrile and 2ml of 1N
aqueous NaOH was added. The mixture was stirred at room temperature for 4 hours. After evaporation of acetonitrile, lml of 2N aqueous CaC12 was added, and the mixture was stirred for 1 hour at room temperature. The precipitate was filtered and dried under vacuum giving Compound II.
3. Analogously, Compound III was obtained from lactone V.
Example 3. HPLC impurity profile determination of rosuvastatin calcium The purity of Compounds IV, V, VI and VII is determined by HPLC analysis.
HPLC
Colunm: C 18 Eluent: Gradient of Formate buffer and Acetonitrile Flow: 1 ml/min Detector:245nm Sample volume: l0ul Diluent: Acetonitrile: Water = 50:50 Mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
Sample Preparation About 10mg of rosuvastatin calcium sample is weighed in a 20m1 amber volumetric flask. The sample is dissolved with l Oml acetonitrile and diluted to volume with water.
Standard Preparation About 10mg of each Compounds IV, V, VI and VII are weighed in a 20rn1 amber volumetric flask, dissolved with 10m1 acetonitrile and diluted to volume with water. lml of prepared solution is diluted to 100m1 with diluent.
Method The freshly prepared sample solutions are injected into the chromatograph, and the chromatogram of the sample is continued up to the end of the gradient.
The areas for each peak in each solution is determined using a suitable integrator.
Having thus described the invention with reference to particular preferred embodiments and illustrated it with Examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods.
Claims (38)
1. A rosuvastatin degradation product having the following structure:
2. A rosuvastatin degradation product having the following structure:
3. A rosuvastatin degradation product having the following structure:
wherein M is an alkali or alkaline earth metal.
wherein M is an alkali or alkaline earth metal.
4. A rosuvastatin degradation product having the following structure:
wherein M is an alkali or alkaline earth metal.
wherein M is an alkali or alkaline earth metal.
5. The rosuvastatin degradation product of claim 3 or 4, wherein M is calcium.
6. A process for converting the calcium salt of claim 5 to lactone form comprising combining acetonitrile, hydrochloric acid and the calcium salt to obtain the lactone.
7. A process for converting the calcium salt of claim 5 to a free acid comprising dissolving the calcium salt in a mixture of acetonitrile and water to obtain a solution, and contacting the solution with a silica column.
8. The process of claim 7, further comprising obtaining the free acid from the silica column.
9. A lactone form of a rosuvastatin degradation product having the following structure:
wherein in the lactone form, C1 and C5 form an ester derivative of formula:
wherein R4 is a hydrogen and R represents the rest of the structure of the rosuvastatin degradation product.
wherein in the lactone form, C1 and C5 form an ester derivative of formula:
wherein R4 is a hydrogen and R represents the rest of the structure of the rosuvastatin degradation product.
10. A lactone form of a rosuvastatin degradation product having the following structure:
wherein in the lactone form, C1 and C5 form an ester derivative of formula:
wherein R4 is a hydrogen and R represents the rest of the structure of the rosuvastatin degradation product.
wherein in the lactone form, C1 and C5 form an ester derivative of formula:
wherein R4 is a hydrogen and R represents the rest of the structure of the rosuvastatin degradation product.
11. A process for converting the lactone of claim 9 or 10 to a calcium salt comprising hydrolyzing the lactone under aqueous basic conditions, and reacting the hydrolyzed lactone with a source of calcium.
12. The process of claim 11, wherein a basic aqueous solution is combined with a solution of the lactone in acetonitrile, followed by removal of acetonitrile and addition of a source of calcium, and recovery of the calcium salt.
13. The process of claim 12, wherein the process comprises dissolving the lactone in a mixture of acetonitrile and aqueous sodium hydroxide, evaporating the acetonitrile, adding calcium chloride to the remaining water to precipitate the calcium salt.
14. A process for converting the lactone of claim 9 or 10 to free acid form comprising hydrolyzing the lactone under aqueous basic conditions to obtain a salt and contacting the salt with a silica column to obtain the free acid.
15. The rosuvastatin degradation product of claim 1, 2, 3, 4, 9 or 10, wherein the degradation product is about 95% free of its corresponding stereoisomer at position 6, according to % area by HPLC.
16. The rosuvastatin degradation product of claim 1, 2, 3, 4, 9 or 10, wherein the rosuvastatin degradation product is isolated or purified.
17. A method for analyzing a sample of rosuvastatin comprising the steps of:
a) performing chromatography on the sample to obtain data; and b) comparing the data with the chromatography data of the degradation product of claim 1, 2, 3, 4, 9 or 10.
a) performing chromatography on the sample to obtain data; and b) comparing the data with the chromatography data of the degradation product of claim 1, 2, 3, 4, 9 or 10.
18. The method of Claim 17, wherein the method comprises the following steps:
(a) preparing a solution of rosuvastatin containing the degradation product;
(b) subjecting the solution to a high pressure liquid chromatography to obtain a chromatogram; and (c) comparing a peak obtained in the chromatogram to a peak resulting from the degradation product.
(a) preparing a solution of rosuvastatin containing the degradation product;
(b) subjecting the solution to a high pressure liquid chromatography to obtain a chromatogram; and (c) comparing a peak obtained in the chromatogram to a peak resulting from the degradation product.
19. The method of Claim 17, wherein the method comprises the following steps:
(a) preparing a solution of rosuvastatin containing the degradation product;
(b) subjecting the solution to thin layer chromatography to obtain a chromatogram; and (c) comparing a band or spot obtained in the chromatogram to a peak or band resulting from the degradation product.
(a) preparing a solution of rosuvastatin containing the degradation product;
(b) subjecting the solution to thin layer chromatography to obtain a chromatogram; and (c) comparing a band or spot obtained in the chromatogram to a peak or band resulting from the degradation product.
20. A process for preparing the degradation product of claim 1, 2, 3, 4, 9 or comprising the step of irradiating with visible light rosuvastatin acid, rosuvastatin alkali or alkaline earth metal salt or rosuvastatin lactone.
21. A process for preparing the compound:
or wherein M is calcium, comprising irradiating with visible light rosuvastatin calcium in solution in a mixture of an organic solvent and water.
or wherein M is calcium, comprising irradiating with visible light rosuvastatin calcium in solution in a mixture of an organic solvent and water.
22. The process of claim 21, wherein the organic solvent is acetonitrile.
23. The process of claim 21, wherein the visible light radiation is of about 750 w at about 35°C.
24. A process for preparing a lactone form of a rosuvastatin degradation product having the following structure:
wherein in the lactone form, C1 and C5 form an ester derivative of formula:
wherein R4 is a hydrogen and R represents the rest of the structure of the rosuvastatin degradation product;
or lactone form of a rosuvastatin degradation product having the following structure:
wherein in the lactone form, C1 and C5 form an ester derivative of formula:
wherein R4 is a hydrogen and R represents the rest of the structure of the rosuvastatin degradation product;
comprising irradiating with visible light rosuvastatin lactone in a solvent.
wherein in the lactone form, C1 and C5 form an ester derivative of formula:
wherein R4 is a hydrogen and R represents the rest of the structure of the rosuvastatin degradation product;
or lactone form of a rosuvastatin degradation product having the following structure:
wherein in the lactone form, C1 and C5 form an ester derivative of formula:
wherein R4 is a hydrogen and R represents the rest of the structure of the rosuvastatin degradation product;
comprising irradiating with visible light rosuvastatin lactone in a solvent.
25. The process of claim 24, wherein the visible light radiation is at about 20°C to about 100°C.
26. The process of claim 24, wherein the solvent is acetonitrile.
27. A method for determining the retention time of a chromatography column for rosuvastatin, comprising the steps of carrying out chromatography with the following compound as a standard, wherein R1 and R2 are independently hydrogen or a hydrolyzable protecting group; R3 is hydrogen, a C1 to C4 alkyl group, or an alkali or alkaline earth metal; or wherein C1 and C5 form a lactone.
28. The process of claim 27, wherein the reference standard is a reference marker.
29. The process of claim 27, wherein the standard is the degradation product of claim 1, 2, 3, 4, 9, or 10.
30. A process for preparing the rosuvastatin degradation product of claim 1 or comprising the steps of:
(a) irradiating with visible light rosuvastatin calcium in a mixture of an organic solvent and water to obtain the rosuvastatin degradation product having the following structure wherein M is calcium;
(b) recovering the product obtained in step (a);
(c) dissolving the compound obtained in step (b) in a suitable solvent and combining the solution with aqueous hydrochloric acid;
(d) recovering the product of step (c);
(e) hydrolyzing the product recovered in step (d) under aqueous basic conditions and reacting the hydrolyzed product with a source of calcium to precipitate a solid;
(f) recovering the solid precipitated in step (e); and (g) dissolving the product recovered in step (f) in a mixture of acetonitrile and water, and contacting the solution with a silica column to obtain a free acid.
(a) irradiating with visible light rosuvastatin calcium in a mixture of an organic solvent and water to obtain the rosuvastatin degradation product having the following structure wherein M is calcium;
(b) recovering the product obtained in step (a);
(c) dissolving the compound obtained in step (b) in a suitable solvent and combining the solution with aqueous hydrochloric acid;
(d) recovering the product of step (c);
(e) hydrolyzing the product recovered in step (d) under aqueous basic conditions and reacting the hydrolyzed product with a source of calcium to precipitate a solid;
(f) recovering the solid precipitated in step (e); and (g) dissolving the product recovered in step (f) in a mixture of acetonitrile and water, and contacting the solution with a silica column to obtain a free acid.
31. A process for preparing the rosuvastatin degradation product of claim 1 or comprising the steps of:
(a) irradiating with visible light rosuvastatin lactone in a mixture of an organic solvent and water to obtain the rosuvastatin degradation product having the following structure:
or (b) recovering the product obtained in step (a);
(c) hydrolyzing the product recovered in step (b) under aqueous basic conditions and reacting the hydrolyzed product with a source of calcium to precipitate a solid, (d) recovering the solid precipitated in step (c); and (e) dissolving the product recovered in step (d) in a mixture of acetonitrile and water, and contacting the solution with a silica column to obtain a free acid.
(a) irradiating with visible light rosuvastatin lactone in a mixture of an organic solvent and water to obtain the rosuvastatin degradation product having the following structure:
or (b) recovering the product obtained in step (a);
(c) hydrolyzing the product recovered in step (b) under aqueous basic conditions and reacting the hydrolyzed product with a source of calcium to precipitate a solid, (d) recovering the solid precipitated in step (c); and (e) dissolving the product recovered in step (d) in a mixture of acetonitrile and water, and contacting the solution with a silica column to obtain a free acid.
32. A rosuvastatin degradation product having the following structure:
wherein R1 and R2 are independently hydrogen or a hydrolyzable protecting group; R3 is a C1 to C4 alkyl group.
wherein R1 and R2 are independently hydrogen or a hydrolyzable protecting group; R3 is a C1 to C4 alkyl group.
33. The rosuvastatin degradation product of claim 32, wherein R1 and R2 are independently hydrogen.
34. The rosuvastatin degradation product of claim 32, wherein R3 is methyl.
35. The rosuvastatin degradation product of claim 32, wherein the hydrogen at carbon position 6 is in the R configuration.
36. The rosuvastatin degradation product of claim 32, the hydrogen at carbon position 6 is in the S configuration.
37. A mixture comprising rosuvastatin degradation product I
and rosuvastatin degradation product II
wherein rosuvastatin product II is less than 5% by HPLC in relation to product I
in the mixture.
and rosuvastatin degradation product II
wherein rosuvastatin product II is less than 5% by HPLC in relation to product I
in the mixture.
38. The rosuvastatin degradation product of claim 32, wherein the rosuvastatin degradation product is isolated or purified.
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| US60/526,449 | 2003-12-02 | ||
| PCT/US2004/040329 WO2005056534A1 (en) | 2003-12-02 | 2004-12-02 | Reference standard for characterization of rosuvastatin |
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| EP (1) | EP1689723B1 (en) |
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| CN109020902A (en) * | 2018-07-23 | 2018-12-18 | 唯智医药科技（北京）有限公司 | A kind of Rosuvastatin calcium impurities and preparation method thereof and purposes |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0218781D0 (en) | 2002-08-13 | 2002-09-18 | Astrazeneca Ab | Chemical process |
| GB0312896D0 (en) | 2003-06-05 | 2003-07-09 | Astrazeneca Ab | Chemical process |
| GB0324791D0 (en) | 2003-10-24 | 2003-11-26 | Astrazeneca Ab | Chemical process |
| ATE507209T1 (en) * | 2003-12-02 | 2011-05-15 | Teva Pharma | REFERENCE STANDARD FOR CHARACTERIZATION OF ROSUVASTATIN |
| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
| PL1851206T3 (en) * | 2005-02-22 | 2013-01-31 | Teva Pharma | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
| CA2630704C (en) * | 2005-12-20 | 2014-08-19 | Lek Pharmaceuticals D.D. | Pharmaceutical composition |
| BRPI0803085A2 (en) * | 2007-03-13 | 2011-08-30 | Teva Pharma | rosuvastatin triol form |
| EP2189456A1 (en) * | 2008-11-14 | 2010-05-26 | LEK Pharmaceuticals d.d. | New compounds prepared from omeprazole |
| TWI461410B (en) | 2008-12-30 | 2014-11-21 | Arqule Inc | Substituted 5,6-dihydro-6-phenylbenzo[f]isoquinolin-2-amine compounds |
| CN103454352B (en) * | 2013-07-30 | 2015-07-15 | 广东先强药业有限公司 | Method for determining content of rosuvastatin calcium and related substances thereof by employing HPLC (high performance liquid chromatography) method |
| CN103776939A (en) * | 2014-02-11 | 2014-05-07 | 润泽制药(苏州)有限公司 | Preparation detection method for substances related to rosuvastatin calcium preparation |
| CN108398501A (en) * | 2018-03-02 | 2018-08-14 | 海南通用三洋药业有限公司 | A method of the related substance of detection rosuvastain calcium |
| CN114280181A (en) * | 2021-12-23 | 2022-04-05 | 浙江海翔川南药业有限公司 | Detection method of rosuvastatin intermediate and related substances thereof |
Family Cites Families (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US37314A (en) * | 1863-01-06 | Improved composition for lemonade | ||
| US633198A (en) * | 1899-02-08 | 1899-09-19 | Wilhelm Magnus Hoekerstedt | Automatic-lighting torch. |
| US4231938A (en) * | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
| US4444784A (en) * | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| DK149080C (en) * | 1980-06-06 | 1986-07-28 | Sankyo Co | METHOD FOR PREPARING ML-236B CARBOXYLIC ACID DERIVATIVES |
| US4739073A (en) * | 1983-11-04 | 1988-04-19 | Sandoz Pharmaceuticals Corp. | Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof |
| NO177005C (en) * | 1988-01-20 | 1995-07-05 | Bayer Ag | Analogous process for the preparation of substituted pyridines, as well as intermediates for use in the preparation |
| US5177080A (en) * | 1990-12-14 | 1993-01-05 | Bayer Aktiengesellschaft | Substituted pyridyl-dihydroxy-heptenoic acid and its salts |
| US5354879A (en) * | 1991-06-19 | 1994-10-11 | Shionogi Seiyaku Kabushiki Kaisha | Optically active intermediate and method for production thereof |
| JP2648897B2 (en) | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | Pyrimidine derivatives |
| GB9626746D0 (en) | 1996-12-23 | 1997-02-12 | Knoll Ag | Process |
| GB9812413D0 (en) * | 1998-06-10 | 1998-08-05 | Glaxo Group Ltd | Compound and its use |
| SI20070A (en) | 1998-09-18 | 2000-04-30 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | NOVEL SALTS OF INHIBITORS OF HMG-CoA REDUCTASE |
| GB9903472D0 (en) | 1999-02-17 | 1999-04-07 | Zeneca Ltd | Chemical process |
| GB0001621D0 (en) * | 2000-01-26 | 2000-03-15 | Astrazeneca Ab | Pharmaceutical compositions |
| GB0003305D0 (en) | 2000-02-15 | 2000-04-05 | Zeneca Ltd | Pyrimidine derivatives |
| US6777552B2 (en) * | 2001-08-16 | 2004-08-17 | Teva Pharmaceutical Industries, Ltd. | Processes for preparing calcium salt forms of statins |
| GB0028429D0 (en) * | 2000-11-22 | 2001-01-10 | Astrazeneca Ab | Therapy |
| HUP0500616A3 (en) * | 2001-08-16 | 2011-07-28 | Teva Pharma | Processes for preparing calcium salt forms of statins |
| SE0103509D0 (en) | 2001-10-19 | 2001-10-19 | Astrazeneca Ab | Rosuvastatin in pre-demented states |
| KR100511533B1 (en) | 2002-04-09 | 2005-08-31 | 임광민 | CHIRAL INTERMEDIATE, PROCESS FOR THE PRODUCTION THEREOF, AND PROCESS FOR THE PRODUCTION OF HMG-CoA REDUCTASE INHIBITOR |
| AR039836A1 (en) * | 2002-05-21 | 2005-03-02 | Ranbaxy Lab Ltd | PROCESS FOR THE PREPARATION OF A PIRIMIDINE ALDEHIDO USEFUL FOR THE PREPARATION OF ROSUVASTATIN |
| GB0218781D0 (en) | 2002-08-13 | 2002-09-18 | Astrazeneca Ab | Chemical process |
| HUP0500851A3 (en) | 2002-12-10 | 2008-02-28 | Ranbaxy Lab Ltd | Process for the preparation of rosuvastatin |
| WO2005021511A1 (en) | 2003-08-27 | 2005-03-10 | Hetero Drugs Limited | A novel process for amorphous rosuvastatin calcium |
| EP1678148A1 (en) | 2003-10-22 | 2006-07-12 | Ranbaxy Laboratories Limited | Process for the preparation of amorphous rosuvastatin calcium |
| CA2546701C (en) * | 2003-11-24 | 2010-07-27 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
| ATE507209T1 (en) * | 2003-12-02 | 2011-05-15 | Teva Pharma | REFERENCE STANDARD FOR CHARACTERIZATION OF ROSUVASTATIN |
| US20080234302A1 (en) | 2004-09-27 | 2008-09-25 | Mohammad Rafeeq | Novel Processes for Preparing Amorphous Rosuvastatin Calcium and a Novel Polymorphic Form of Rosuvastatin Sodium |
| WO2006079611A1 (en) | 2005-01-31 | 2006-08-03 | Ciba Specialty Chemicals Holding Inc. | Crystalline forms of rosuvastatin calcium salt |
| EP1863773A1 (en) | 2005-03-22 | 2007-12-12 | Unichem Laboratories Limited | Process for preparation of rosuvastatin |
| EP1869005A1 (en) | 2005-04-04 | 2007-12-26 | Unichem Laboratories Limited | Process for preparation of calcium salt of rosuvastatin |
| EP2508514B1 (en) | 2005-06-24 | 2017-10-18 | LEK Pharmaceuticals d.d. | Process for preparing amorphous rosuvastatin calcium free of impurities |
| WO2006136408A2 (en) | 2005-06-24 | 2006-12-28 | Lek Pharmaceuticals D.D. | Process for preparing pure amorphous rosuvastatin calcium |
| GB0514078D0 (en) | 2005-07-08 | 2005-08-17 | Astrazeneca Uk Ltd | Chemical process |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109020902A (en) * | 2018-07-23 | 2018-12-18 | 唯智医药科技（北京）有限公司 | A kind of Rosuvastatin calcium impurities and preparation method thereof and purposes |
| CN109020902B (en) * | 2018-07-23 | 2020-06-02 | 唯智医药科技（北京）有限公司 | Rosuvastatin calcium impurity, and preparation method and application thereof |
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| US20070255059A1 (en) | 2007-11-01 |
| TWI351958B (en) | 2011-11-11 |
| ATE507209T1 (en) | 2011-05-15 |
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| US20070244321A1 (en) | 2007-10-18 |
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| CN1894221B (en) | 2012-08-08 |
| PT1689723E (en) | 2011-07-06 |
| EP1689723B1 (en) | 2011-04-27 |
| US7244844B2 (en) | 2007-07-17 |
| CN1894221A (en) | 2007-01-10 |
| ES2364143T3 (en) | 2011-08-25 |
| US20070249830A1 (en) | 2007-10-25 |
| WO2005056534A1 (en) | 2005-06-23 |
| TW200522959A (en) | 2005-07-16 |
| DE602004032465D1 (en) | 2011-06-09 |
| IL175511A (en) | 2011-11-30 |
| US20090188305A1 (en) | 2009-07-30 |
| US7692009B2 (en) | 2010-04-06 |
| US7692010B2 (en) | 2010-04-06 |
| JP4733047B2 (en) | 2011-07-27 |
| US7741482B2 (en) | 2010-06-22 |
| US20050187234A1 (en) | 2005-08-25 |
| KR100887264B1 (en) | 2009-03-06 |
| US7692008B2 (en) | 2010-04-06 |
| IL175511A0 (en) | 2006-09-05 |
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