Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-28
2003-08-12
Powers, Fiona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06605729
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel crystalline forms of atorvastatin which is known by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt useful as pharmaceutical agents, to methods for their production and isolation, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, as well as methods of using such compositions to treat subjects, including human subjects, suffering from hyperlipidemia, hypercholesterolemia, osteoporosis, and Alzheimer's disease.
BACKGROUND OF THE INVENTION
The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents.
Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, which is incorporated herein by reference, is currently sold as Lipitor® having the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate and the formula
Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase. As such, atorvastatin calcium is a potent lipid lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent.
U.S. Pat. No. 4,681,893, which is incorporated herein by reference, discloses certain trans-6-[2-(3- or 4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-ones including trans (±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
U.S. Pat. No. 5,273,995, which is herein incorporated by reference, discloses the enantiomer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, ie, [R-(R*,R*)]-2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid which is atorvastatin.
U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,998,633; and 6,087,511, which are herein incorporated by reference, disclose various processes and key intermediates for preparing amorphous atorvastatin. Amorphous atorvastatin has unsuitable filtration and drying characteristics for large-scale production and must be protected from heat, light, oxygen, and moisture.
Crystalline forms of atorvastatin calcium are disclosed in U.S. Pat. Nos. 5,969,156 and 6,121,461 which are herein incorporated by reference.
International Published Patent Application Number WO 01/36384 allegedly discloses a polymorphic form of atorvastatin calcium.
Stable oral formulations of atorvastatin calcium are disclosed in U.S. Pat. Nos. 5,686,104 and 6,126,971.
Atorvastatin is prepared as its calcium salt, ie, [R-(R*,R*)]-2-(4-fluorophenyl)-&bgr;, &dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1). The calcium salt is desirable since it enables atorvastatin to be conveniently formulated in, for example, tablets, capsules, lozenges, powders, and the like for oral administration. Additionally, there is a need to produce atorvastatin in a pure and crystalline form to enable formulations to meet exacting pharmaceutical requirements and specifications.
Furthermore, the process by which atorvastatin is produced needs to be one which is amenable to large-scale production. Additionally, it is desirable that the product should be in a form that is readily filterable and easily dried. Finally, it is economically desirable that the product be stable for extended periods of time without the need for specialized storage conditions.
We have now surprisingly and unexpectedly found novel crystalline forms of atorvastatin. Thus, the present invention provides atorvastatin in new crystalline forms designated Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX. The new crystalline forms of atorvastatin are purer, more stable, or have advantageous manufacturing properties than the amorphous product.
SUMMARY OF THE INVENTION
Accordingly, the present invention is directed to crystalline Form V atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2&thgr; and relative intensities with a relative intensity of >10% measured on a Shimadzu diffractometer with CuK
&agr;
radiation:
Relative Intensity
2&thgr;
(>10%)
a
4.9 (broad)
9
6.0
15
7.0
100
8.0 (broad)
20
8.6
57
9.9
22
16.6
42
19.0
27
21.1
35
a
Relative intensity of 4.9 (broad) 2&thgr; is 9.
Additionally, the following X-ray powder diffraction pattern of crystalline Form V atorvastatin expressed in terms of the 2&thgr; values was measured on an Inel (capillary) diffractometer:
2&thgr;
5.0
6.1
7.5
8.4 (broad)
8.7 (broad)
9.9
16.7
19.0
21.2
Further, the present invention is directed to crystalline Form V atorvastatin and hydrates thereof characterized by the following solid-state
13
C nuclear magnetic resonance (ssNMR) spectrum wherein chemical shift is expressed in parts per million:
Assignment
Chemical Shift
C12 or C25
185.7
C12 or C25
176.8
C16
166.9
Aromatic Carbons
138.7
C2-C5, C13-C18,
136.3
C19-C24, C27-C32
133.0
128.4
122.0
117.0
116.3
C8, C10
68.0
Methylene Carbons
43.1
C6, C7, C9, C11
C33
25.6
C34
19.9
Additionally, the present invention is directed to crystalline Form V atorvastatin and hydrates thereof characterized by the following Raman spectrum having peaks expressed in cm-
−1
:
3062
1652
1604
1528
1478
1440
1413
1397
1368
1158
1034
1001
825
245
224
130
In a preferred embodiment of the first aspect of the invention, crystalline Form V atorvastatin is a trihydrate.
In a second aspect, the present invention is directed to crystalline Form VI atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2&thgr; and relative intensities with a relative intensity of >10% measured on a Shimadzu diffractometer with CuK
&agr;
radiation:
Relative Intensity
2&thgr;
(>10%)
a
7.2
11
8.3
77
11.0
20
12.4
11
13.8
9
16.8
14
18.5
100
19.7 (broad)
22
20.9
14
25.0 (broad)
15
a
Relative intensity of 13.8 (broad) 2&thgr; is 9.
Additionally, the following X-ray powder diffraction pattern of crystalline Form VI atorvastatin expressed in terms of the 2&thgr; values was measured on an Inel (capillary) diffractometer:
2&thgr;
7.3
8.5
11.2
12.7
14.0
17.1 (broad)
18.7
19.9
21.1 (broad)
25.2 (broad)
Further, the present invention is directed to crystalline Form VI atorvastatin and hydrates thereof characterized by the following solid-state
13
C nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million:
Assignment
Chemical Shift
C12 or C25
176.5
C16 or C12 or C25
168.2
C16 or C12 or C25
163.1
C16 or C12 or C25
159.8
Aromatic Carbons
136.8
C2-C5, C13-C18,
127.8
C19-C24, C27-C32
122.3
118.8
113.7
C8, C10
88.2
C8, C10
79.3
70.5
Methylene Carbons
43.3
C6, C7, C9, C11
36.9
31.9
C33, C34
25.9
C33, C34
22.5
In a third aspect, the present invention is directed to crystalline Form VII atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2&thgr; and relative intensities with a relative intensity of >10% measured on a Shimadzu diffractometer with CuK
&agr;
radiation:
Relative Intensity
2&thgr;
(>10%)
8.6
76
10.2
70
12.4 (broad)
12
12.8 (broad)
15
17.6
20
18.3 (broad)
43
19.
Byrn Stephen Robert
Coates David Andrew
Gushurst Karen Sue
Krzyzaniak Joseph Francis
Li Zheng Jane
Powers Fiona T.
Tinney Francis J.
Warner-Lambert & Company
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