U.S. patent application number 11/441268 was filed with the patent office on 2006-10-26 for crystalline forms of [r-(r*.r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-p- henyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid calcium salt (2:1).
Invention is credited to Aeri Park.
Application Number | 20060241169 11/441268 |
Document ID | / |
Family ID | 23166039 |
Filed Date | 2006-10-26 |
United States Patent
Application |
20060241169 |
Kind Code |
A1 |
Park; Aeri |
October 26, 2006 |
Crystalline forms of
[R-(R*.R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-p-
henyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium
salt (2:1)
Abstract
Novel crystalline forms of
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-
-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid
hemi calcium salt designated Form V, Form VI, Form VII, Form VIII.
Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV,
Form XVI, Form XVII, Form XVIII, and Form XIX are characterized by
their X-ray powder diffraction, solid-state NMR, and/or Raman
spectroscopy are described, as well as methods for the preparation
and pharmaceutical composition of the same, which are useful as
agents for treating hyperlipidemia, hypercholesterolemia,
osteoporosis, and Alzheimer's disease.
Inventors: |
Park; Aeri; (West Lafayette,
IN) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
23166039 |
Appl. No.: |
11/441268 |
Filed: |
May 25, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10456046 |
Jun 6, 2003 |
|
|
|
11441268 |
May 25, 2006 |
|
|
|
10184669 |
Jun 28, 2002 |
6605729 |
|
|
10456046 |
Jun 6, 2003 |
|
|
|
60302049 |
Jun 29, 2001 |
|
|
|
Current U.S.
Class: |
514/423 ;
548/537 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 3/06 20180101; C07D 207/34 20130101; A61P 19/10 20180101; A61K
31/401 20130101 |
Class at
Publication: |
514/423 ;
548/537 |
International
Class: |
A61K 31/401 20060101
A61K031/401 |
Claims
1-15. (canceled)
16. A solid pharmaceutical composition comprising crystalline Form
X atorvastatin or a hydrate thereof having an X-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub..alpha. radiation: 4.7, 5.2, 5.8, 6.9, 7.9, 9.2, 9.5, 10.3
(broad), 11.8, 16.1, 16.9, 19.1, 19.8, 21.4, 22.3 (broad), 23.7
(broad), 24.4, and 28.7, and at least one pharmaceutically
acceptable excipient, diluent or carrier.
17. A solid pharmaceutical composition comprising crystalline Form
X atorvastatin or a hydrate thereof characterized by solid state
.sup.13C nuclear magnetic resonance having the following chemical
shifts expressed in parts per million: 18.3, 20.3, 25.3, 26.4,
40.9, 43.7, 71.1, 119.9, 123.2, 127.9, 129.4, 134.8, 137.9, 159.4,
165.5, 179.5, and 187.0, and at least one pharmaceutically
acceptable excipient, diluent or carrier.
18. A solid pharmaceutical composition comprising crystalline Form
X atorvastatin or a hydrate thereof characterized by Raman
spectroscopy having the following peaks expressed in cm.sup.-1:
116, 824, 999, 1034, 1158, 1240, 1369, 1411, 1478, 1525, 1603,
1650, 2911, and 3062, and at least one pharmaceutically acceptable
excipient, diluent or carrier.
19. A method of treating hyperlipidemia, hypercholesterolemia,
osteoporosis or Alzheimer's Disease comprising administering to a
host suffering therefrom a therapeutically effective amount of
crystalline Form X or a hydrate thereof having an X-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub..alpha. radiation: 4.7, 5.2, 5.8, 6.9, 7.9, 9.2, 9.5, 10.3
(broad), 11.8, 16.1, 16.9, 19.1, 19.8, 21.4, 22.3 (broad), 23.7
(broad), 24.4, and 28.7, in solid unit dosage form.
20. A method of treating hyperlipidemia, hypercholesterolemia,
osteoporosis or Alzheimer's Disease comprising administering to a
host suffering therefrom a therapeutically effective amount of
crystalline Form X or a hydrate thereof characterized by solid
state .sup.13C nuclear magnetic resonance having the following
chemical shifts expressed in parts per million: 18.3, 20.3, 25.3,
26.4, 40.9, 43.7, 71.1, 119.9, 123.2, 127.9, 129.4, 134.8, 137.9,
159.4, 165.5, 179.5, and 187.0, in solid unit dosage form.
21. A method of treating hyperlipidemia, hypercholesterolemia,
osteoporosis or Alzheimer's Disease comprising administering to a
host suffering therefrom a therapeutically effective amount of
crystalline Form X or a hydrate thereof characterized by Raman
spectroscopy having the following peaks expressed in cm.sup.-1:
116, 284, 999, 1034, 1158, 1240, 1369, 1411, 1478, 1525, 1603,
1650, 2911, and 3062, in solid unit dosage form.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel crystalline forms of
atorvastatin which is known by the chemical name
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-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
[0002] 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.
[0003] Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995,
which is incorporated herein by reference, is currently sold as
Lipitor.RTM. having the chemical name
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-
-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid
calcium salt (2:1) trihydrate and the formula ##STR1## 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.
[0004] 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-pyrro-
le-3-carboxamide.
[0005] 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-pyrro-
le-3-carboxamide, ie,
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-di
hydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole--
1-heptanoic acid which is atorvastatin.
[0006] 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.
[0007] 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.
[0008] International Published Patent Application Number WO
01/36384 allegedly discloses a polymorphic form of atorvastatin
calcium.
[0009] Stable oral formulations of atorvastatin calcium are
disclosed in U.S. Pat. Nos. 5,686,104 and 6,126,971.
[0010] Atorvastatin is prepared as its calcium salt, ie,
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-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.
[0011] 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.
[0012] 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
[0013] 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.theta. and relative intensities with a relative
intensity of >10% measured on a Shimadzu diffractometer with
CuK.sub..alpha. radiation: TABLE-US-00001 Relative Intensity
2.theta. (>10%).sup.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 .sup.aRelative intensity
of 4.9 (broad) 2.theta. is 9.
[0014] Additionally, the following X-ray powder diffraction pattern
of crystalline Form V atorvastatin expressed in terms of the
2.theta. values was measured on an Inel (capillary) diffractometer:
TABLE-US-00002 2.theta. 5.0 6.1 7.5 8.4 (broad) 8.7 (broad) 9.9
16.7 19.0 21.2
[0015] Further, the present invention is directed to crystalline
Form V atorvastatin and hydrates thereof characterized by the
following solid-state .sup.13C nuclear magnetic resonance (ssNMR)
spectrum wherein chemical shift is expressed in parts per million:
TABLE-US-00003 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
[0016] 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.sup.-1: TABLE-US-00004 3062 1652 1604 1528 1478 1440 1413 1397
1368 1158 1034 1001 825 245 224 130
[0017] In a preferred embodiment of the first aspect of the
invention, crystalline Form V atorvastatin is a trihydrate.
[0018] 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.theta. and relative intensities with a relative
intensity of >10% measured on a Shimadzu diffractometer with
CuK.sub..alpha. radiation: TABLE-US-00005 Relative Intensity
2.theta. (>10%).sup.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 .sup.aRelative
intensity of 13.8 (broad) 2.theta. is 9.
[0019] Additionally, the following X-ray powder diffraction pattern
of crystalline Form VI atorvastatin expressed in terms of the
2.theta. values was measured on an Inel (capillary) diffractometer:
TABLE-US-00006 2.theta. 7.3 8.5 11.2 12.7 14.0 17.1 (broad) 18.7
19.9 21.1 (broad) 25.2 (broad)
[0020] Further, the present invention is directed to crystalline
Form VI atorvastatin and hydrates thereof characterized by the
following solid-state .sup.13C nuclear magnetic resonance spectrum
wherein chemical shift is expressed in parts per million:
TABLE-US-00007 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
[0021] 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.theta. and relative intensities with a
relative intensity of >10% measured on a Shimadzu diffractometer
with CuK.sub..alpha. radiation: TABLE-US-00008 Relative Intensity
2.theta. (>10%) 8.6 76 10.2 70 12.4 (broad) 12 12.8 (broad) 15
17.6 20 18.3 (broad) 43 19.3 100 22.2 (broad) 14 23.4 (broad) 23
23.8 (broad) 26 25.5 (broad) 16
[0022] Additionally, the following X-ray powder diffraction pattern
of crystalline Form VII atorvastatin expressed in terms of the
2.theta. values was measured on an Inel (capillary) diffractometer:
TABLE-US-00009 2.theta. 8.7 10.2 12.4 12.9 17.6 18.4 19.4 22.2 23.5
23.9 25.6
[0023] Further, the present invention is directed to crystalline
Form VII atorvastatin and hydrates thereof characterized by the
following solid-state .sup.13C nuclear magnetic resonance spectrum
wherein chemical shift is expressed in parts per million:
TABLE-US-00010 Assignment Chemical Shift C12 or C25 186.5 C12 or
C25 183.3 C12 or C25 176.8 C16 166.5 159.2 Aromatic Carbons 137.6
C2-C5, C13-C18, 128.3 C19-C24, C27-C32 122.3 119.2 C8, C10 74.5 C8,
C10 70.3 C8, C10 68.3 C8, C10 66.2 Methylene Carbons 43.5 C6, C7,
C9, C11 40.3 C33, C34 26.3 C33, C34 24.9 C33, C34 20.2
[0024] Additionally, the present invention is directed to
crystalline Form VII atorvastatin and hydrates thereof
characterized by the following Raman spectrum having peaks
expressed in cm.sup.-1: TABLE-US-00011 Raman Spectrum 3060 2927
1649 1603 1524 1476 1412 1397 1368 1159 1034 998 824 114
[0025] In a preferred embodiment of the third aspect of the
invention, crystalline Form VII atorvastatin is a
sesquihydrate.
[0026] In a fourth aspect, the present invention is directed to
crystalline Form VIII atorvastatin and hydrates thereof
characterized by the following X-ray powder diffraction pattern
expressed in terms of the 2.theta. and relative intensities with a
relative intensity of >10% measured on a Shimadzu diffractometer
with CuK.sub..alpha. radiation: TABLE-US-00012 Relative Intensity
2.theta. (>10%).sup.a 7.5 61 9.2 29 10.0 16 12.1 10 12.8 6 13.8
4 15.1 13 16.7 (broad) 64 18.6 (broad) 100 20.3 (broad) 79 21.2 24
21.9 30 22.4 19 25.8 33 26.5 20 27.4 (broad) 38 30.5 20
.sup.aRelative intensity of 12.8 2.theta. is 6 and 13.8 2.theta. is
4.
[0027] Additionally, the following X-ray powder diffraction pattern
of crystalline Form VIII atorvastatin expressed in terms of the
2.theta. values was measured on an Inel (capillary) diffractometer:
TABLE-US-00013 2.theta. 7.5 9.3 10.1 12.2 12.8 13.8 15.1 16.6-169.9
18.5-18.9 20.2-20.6 21.3 22.0 22.5 25.9 26.5 27.4 (broad) 30.6
[0028] Further, the present invention is directed to crystalline
Form VIII atorvastatin and hydrates thereof characterized by the
following solid-state .sup.13C nuclear magnetic resonance spectrum
wherein chemical shift is expressed in parts per million:
TABLE-US-00014 Assignment Chemical Shift C12 or C25 186.1 C12 or
C25 179.5 C16 167.9 C16 161.0 Aromatic Carbons 139.4 C2-C5,
C13-C18, 132.9 C19-C24, C27-C32 128.7 124.7 121.8 116.6 C8, C10
67.0 Methylene Carbons 43.3 C6, C7, C9, C11 C33, C34 26.7 C33, C34
24.7 C33, C34 20.9 C33, C34 20.1
[0029] Additionally, the present invention is directed to
crystalline Form VIII atorvastatin and hydrates thereof
characterized by the following Raman spectrum having peaks
expressed in cm.sup.-1: TABLE-US-00015 Raman Spectrum 3065 2923
1658 1603 1531 1510 1481 1413 997 121
[0030] In a preferred embodiment of the fourth aspect of the
invention, crystalline Form VIII atorvastatin is a dihydrate.
[0031] In a fifth aspect, the present invention is directed to
crystalline Form IX atorvastatin and hydrates thereof characterized
by the following X-ray powder diffraction pattern expressed in
terms of the 2.theta. and relative intensities with a relative
intensity of >10% measured on a Shimadzu diffractometer with
CuK.sub..alpha. radiation: TABLE-US-00016 Relative Intensity
2.theta. (>10%) 8.8 50 9.4 (broad) 32 11.2-11.7 (broad) 26 16.7
59 17.5 (broad) 33 19.3 (broad) 55 21.4 (broad) 100 22.4 (broad) 33
23.2 (broad) 63 29.0 (broad) 15
[0032] Additionally, the following X-ray powder diffraction pattern
of crystalline Form IX atorvastatin expressed in terms of the
2.theta. values was measured on an Inel (capillary) diffractometer:
TABLE-US-00017 2.theta. 9.0 9.4 10.0-10.5 (broad) 11.8-12.0 (broad)
16.9 17.5 (broad) 19.4 (broad) 21.6 (broad) 22.6 (broad) 23.2
(broad) 29.4 (broad)
[0033] In a sixth aspect, the present invention is directed to
crystalline Form X atorvastatin and hydrates thereof characterized
by the following X-ray powder diffraction pattern expressed in
terms of the 2.theta. and relative intensities with a relative
intensity of >10% measured on a Shimadzu diffractometer with
CuK.sub..alpha. radiation: TABLE-US-00018 Relative Intensity
2.theta. (>10%) 4.7 35 5.2 24 5.8 11 6.9 13 7.9 53 9.2 56 9.5 50
10.3 (broad) 13 11.8 20 16.1 13 16.9 39 19.1 100 19.8 71 21.4 49
22.3 (broad) 36 23.7 (broad) 37 24.4 15 28.7 31
[0034] Additionally, the following X-ray powder diffraction pattern
of crystalline Form X atorvastatin expressed in terms of the
2.theta. values was measured on an Inel (capillary) diffractometer:
TABLE-US-00019 2.theta. 4.7 5.2 5.8 6.9 7.9 9.2 9.6 10.2-10.4 11.9
16.2 16.9 19.1 19.9 21.5 22.3-22.6 23.7-24.0 (broad) 24.5 28.8
[0035] Further, the present invention is directed to crystalline
Form X atorvastatin and hydrates thereof characterized by the
following solid-state .sup.13C nuclear magnetic resonance spectrum
wherein chemical shift is expressed in parts per million:
TABLE-US-00020 Assignment Chemical Shift C12 or C25 187.0 C12 or
C25 179.5 C16 165.5 C16 159.4 Aromatic Carbons 137.9 C2-C5,
C13-C18, 134.8 C19-C24, C27-C32 129.4 129.4 127.9 123.2 119.9 C8,
C10 71.1 Methylene Carbons 43.7 C6, C7, C9, C11 40.9 C33 26.4 25.3
C34 20.3 18.3
[0036] Additionally, the present invention is directed crystalline
Form X atorvastatin and hydrates thereof characterized by the
following Raman spectrum having peaks expressed in cm.sup.-1:
TABLE-US-00021 Raman Spectrum 3062 2911 1650 1603 1525 1478 1411
1369 1240 1158 1034 999 824 116
[0037] In a preferred embodiment of the sixth aspect of the
invention. crystalline Form X atorvastatin is a trihydrate.
[0038] In a seventh aspect, the present invention is directed to
crystalline Form XI atorvastatin and hydrates thereof characterized
by the following X-ray powder diffraction pattern expressed in
terms of the 2.theta. and relative intensities with a relative
intensity of >10% measured on a Shimadzu diffractometer with
CuK.sub..alpha. radiation: TABLE-US-00022 Relative Intensity
2.theta. (>10%) 10.8 (broad) 58 12.0 12 13.5 11 16.5 52
17.6-18.0 (broad) 35 19.7 82 22.3 100 23.2 26 24.4 28 25.8 17 26.5
30 27.3 31 28.7 19 29.5 12 30.9 (broad) 17 32.8 (broad) 11 33.6
(broad) 15 36.0 (broad) 15 38.5 (broad) 14
[0039] In an eighth aspect, the present invention is directed to
crystalline Form XII atorvastatin and hydrates thereof
characterized by the following X-ray powder diffraction pattern
expressed in terms of the 2.theta. and relative intensities with a
relative intensity of >10% measured on a Shimadzu diffractometer
with CuK.sub..alpha. radiation: TABLE-US-00023 Relative Intensity
2.theta. (>10%).sup.a 5.4 11 7.7 24 8.0 25 8.6 42 8.9 25 9.9 36
10.4 (broad) 24 12.5 18 13.9 (broad) 9 16.2 10 17.8 70 19.4 100
20.8 51 21.7 13 22.4-22.6 (broad) 18 24.3 19 25.5 24 26.2 11 27.1 8
.sup.aRelative intensity of 13.9 (broad) 2.theta. is 9 and 27.1
2.theta. is 8.
[0040] Additionally, the following X-ray powder diffraction pattern
of crystalline Form XII atorvastatin expressed in terms of the
2.theta. values was measured on an Inel (capillary) diffractometer:
TABLE-US-00024 2.theta. 5.4 7.7 8.1 8.6 8.9 10.0 10.5 12.6 14.0
(broad) 16.2 17.9 19.4 20.9 21.8 22.5-22.8 (broad) 24.4 25.6 26.4
27.2
[0041] Additionally, the present invention is directed crystalline
Form XII atorvastatin and hydrates thereof characterized by the
following Raman spectrum having peaks expressed in cm.sup.-1:
TABLE-US-00025 Raman Spectrum 3064 2973 2926 1652 1603 1527 1470
1410 1367 1240 1159 1034 1002 823
[0042] In a ninth aspect, the present invention is directed to
crystalline Form XIII atorvastatin and hydrates thereof
characterized by the following X-ray powder diffraction pattern
expressed in terms of the 2.theta. and relative intensities with a
relative intensity of >10% measured on a Shimadzu diffractometer
with CuK.sub..alpha. radiation: TABLE-US-00026 Relative Intensity
2.theta. (>10%) 8.4 100 8.9 82 15.7 (broad) 45 16.4 (broad) 46
17.6 (broad) 57 18.1 (broad) 62 19.7 (broad) 58 20.8 (broad) 91
23.8 (broad 57
[0043] In a tenth aspect, the present invention is directed to
crystalline Form XIV atorvastatin and hydrates thereof
characterized by the following X-ray powder diffraction pattern
expressed in terms of the 2.theta. and relative intensities with a
relative intensity of >10% measured on a Bruker D5000
diffractometer with CuK.sub..alpha. radiation: TABLE-US-00027
Relative Intensity 2.theta. (>10%) 5.4 41 6.7 31 7.7 100 8.1 35
9.0 65 16.5 (broad) 15 17.6 (broad) 17 18.0-18.7 (broad) 21 19.5
(broad) 18
[0044] In an eleventh aspect, the present invention is directed to
crystalline Form XV atorvastatin and hydrates thereof characterized
by the following X-ray powder diffraction pattern expressed in
terms of the 2.theta. and relative intensities with a relative
intensity of >10% measured on a Bruker D5000 diffractometer with
CuK.sub..alpha. radiation: TABLE-US-00028 Relative Intensity
2.theta. (>10%) 5.7 26 6.1 21 6.8 18 7.5 39 8.1 39 8.5 42 9.5 33
10.5 (broad) 18 19.1-19.6 (broad) 32
[0045] In a twelfth aspect, the present invention is directed to
crystalline Form XVI atorvastatin and hydrates thereof
characterized by the following X-ray powder diffraction pattern
expressed in terms of the 2.theta. and relative intensities with a
relative intensity of >10% measured on a Bruker D5000
diffractometer with CuK.sub..alpha. radiation: TABLE-US-00029
Relative Intensity 2.theta. (>10%) 5.2 37 6.4 34 7.5 100 8.7 79
10.5 (broad) 19 12.0 (broad) 10 12.7 (broad) 17 16.7 26 18.3
(broad) 27 19.5 23 20.1-20.4 (broad) 37 21.2-21.9 (broad) 32
22.9-23.3 (broad) 38 24.4-25.0 (broad) 35
[0046] Additionally, the following X-ray powder diffraction pattern
of crystalline Form XVI atorvastatin expressed in terms of the
2.theta. values was measured on a Shimadzu diffractometer with
CuK.sub..alpha. radiation: TABLE-US-00030 2.theta. 7.6 8.8 10.2
12.5 16.8 18.2 19.3 20.5 23.0 24.8
[0047] In addition, the following X-ray powder diffraction pattern
of crystalline Form XVI atorvastatin expressed in terms of the
2.theta. values was measured on an Inel (capillary) diffractometer:
TABLE-US-00031 2.theta. 5.1 6.2 7.3 8.7 10.2 (broad) 12.0 (broad)
12.7 (broad) 16.7 18.0 (broad) 19.5 (broad) 20.0-20.5 (broad)
21.5-21.6 (broad) 22.9-23.3 (broad) 24.0-25.0 (broad)
[0048] In a thirteenth aspect, the present invention is directed to
crystalline Form XVII atorvastatin and hydrates thereof
characterized by the following X-ray powder diffraction pattern
expressed in terms of the 2.theta. and relative intensities with a
relative intensity of >10% measured on a Bruker D5000
diffractometer with CuK.sub..alpha. radiation: TABLE-US-00032
Relative Intensity 2.theta. (>10%) 5.0 27 6.1 33 7.3 100 7.9 30
8.5 29 9.1 22 10.0 45 12.1 (broad) 24 14.8 17 16.0-16.5 (broad) 20
17.5 (broad) 28 19.0 (broad) 46 19.5 65 20.2 (broad) 47 21.3 64
21.6 55 22.0 45
[0049] In a fourteenth aspect, the present invention is directed to
crystalline Form XVIII atorvastatin and hydrates thereof
characterized by the following X-ray powder diffraction pattern
expressed in terms of the 2.theta. and relative intensities with a
relative intensity of >10% measured on a Bruker D5000
diffractometer with CuK.sub..alpha. radiation: TABLE-US-00033
Relative Intensity 2.theta. (>10%) 8.0 100 9.2 (broad) 52 9.7
(broad) 40 12.1 24 16.6 (broad) 48 18.5 67
[0050] Additionally, the following X-ray powder diffraction pattern
of crystalline Form XVIII atorvastatin expressed in terms of the
2.theta. values was measured on a Shimadzu diffractometer with
CuK.sub..alpha. radiation: TABLE-US-00034 2.theta. 7.7 9.3 9.9 12.2
16.8 18.5
[0051] In addition, the following X-ray powder diffraction pattern
of crystalline Form XVIII atorvastatin expressed in terms of the
2.theta. values was measured on an Inel (capillary) diffractometer:
TABLE-US-00035 2.theta. 7.9 9.2 (broad) 9.8 (broad) 12.2 (broad)
16.7 (broad) 18.5
[0052] In a fifteenth aspect, the present invention is directed to
crystalline Form XIX atorvastatin and hydrates thereof
characterized by the following X-ray powder diffraction pattern
expressed in terms of the 2.theta. and relative intensities with a
relative intensity of >10% measured on a Bruker D5000
diffractometer with CuK.sub..alpha. radiation: TABLE-US-00036
Relative Intensity 2.theta. (>10%) 5.2 32 6.3 28 7.0 100 8.6 74
10.5 34 11.6 (broad) 26 12.7 (broad) 35 14.0 15 16.7 (broad) 30
18.9 86 20.8 94 23.6 (broad) 38 25.5 (broad) 32
[0053] As inhibitors of HMG-CoA reductase, the novel crystalline
forms of atorvastatin are useful hypolipidemic and
hypocholesterolemic agents as well as agents in the treatment of
osteoporosis and Alzheimer's disease.
[0054] A still further embodiment of the present invention is a
pharmaceutical composition for administering an effective amount of
crystalline Form V, Form VI, Form VII, Form VIII, Form IX, Form X,
Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form
XVII, Form XVIII, or Form XIX atorvastatin in unit dosage form in
the treatment methods mentioned above. Finally, the present
invention is directed to methods for production of Form V, Form VI,
Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII,
Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, or Form XIX
atorvastatin.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] The invention is further described by the following
nonlimiting examples which refer to the accompanying FIGS. 1 to 35,
short particulars of which are given below.
[0056] FIG. 1
[0057] Diffractogram of Form V atorvastatin carried out on Shimadzu
XRD-6000 diffractometer.
[0058] FIG. 2
[0059] Diffractogram of Form VI atorvastatin carried out on
Shimadzu XRD-6000 diffractometer.
[0060] FIG. 3
[0061] Diffractogram of Form VII atorvastatin carried out on
Shimadzu XRD-6000 diffractometer.
[0062] FIG. 4
[0063] Diffractogram of Form VIII atorvastatin carried out on
Shimadzu XRD-6000 diffractometer.
[0064] FIG. 5
[0065] Diffractogram of Form IX atorvastatin carried out on
Shimadzu XRD-6000 diffractometer.
[0066] FIG. 6
[0067] Diffractogram of Form X atorvastatin carried out on Shimadzu
XRD-6000 diffractometer.
[0068] FIG. 7
[0069] Diffractogram of Form XI atorvastatin carried out on
Shimadzu XRD-6000 diffractometer.
[0070] FIG. 8
[0071] Diffractogram of Form XII atorvastatin carried out on
Shimadzu XRD-6000 diffractometer.
[0072] FIG. 9
[0073] Diffractogram of Form XIII atorvastatin carried out on
Shimadzu XRD-6000 diffractometer.
[0074] FIG. 10
[0075] Diffractogram of Form XIV atorvastatin carried out on Bruker
D 5000 diffractometer.
[0076] FIG. 11
[0077] Diffractogram of Form XV atorvastatin carried out on Bruker
D 5000 diffractometer.
[0078] FIG. 12
[0079] Diffractogram of Form XVI atorvastatin carried out on Bruker
D 5000 diffractometer.
[0080] FIG. 13
[0081] Diffractogram of Form XVII atorvastatin carried out on
Bruker D 5000 diffractometer.
[0082] FIG. 14
[0083] Diffractogram of Form XVIII atorvastatin carried out on
Bruker D 5000 diffractometer.
[0084] FIG. 15
[0085] Diffractogram of Form XIX atorvastatin carried out on Bruker
D 5000 diffractometer.
[0086] FIG. 16
[0087] Diffractogram of Form V atorvastatin carried out on Inel
XRG-3000 diffractometer.
[0088] FIG. 17
[0089] Diffractogram of Form VI atorvastatin carried out on Inel
XRG-3000 diffractometer.
[0090] FIG. 18
[0091] Diffractogram of Form VII atorvastatin carried out on Inel
XRG-3000 diffractometer.
[0092] FIG. 19
[0093] Diffractogram of Form VIII atorvastatin carried out on Inel
XRG-3000 diffractometer.
[0094] FIG. 20
[0095] Diffractogram of Form IX atorvastatin carried out on Inel
XRG-3000 diffractometer.
[0096] FIG. 21
[0097] Diffractogram of Form X atorvastatin carried out on Inel
XRG-3000 diffractometer.
[0098] FIG. 22
[0099] Diffractogram of Form XII atorvastatin carried out on Inel
XRG-3000 diffractometer.
[0100] FIG. 23
[0101] Diffractogram of Form XVI atorvastatin carried out on Inel
XRG-3000 diffractometer.
[0102] FIG. 24
[0103] Diffractogram of Form XVIII atorvastatin carried out on Inel
XRG-3000 diffractometer.
[0104] FIG. 25
[0105] Solid-state .sup.13C nuclear magnetic resonance spectrum
with spinning side bands identified by an asterisk of Form V
atorvastatin.
[0106] FIG. 26
[0107] Solid-state .sup.13C nuclear magnetic resonance spectrum
with spinning side bands identified by an asterisk of Form VI
atorvastatin.
[0108] FIG. 27
[0109] Solid-state .sup.13C nuclear magnetic resonance spectrum
with spinning side bands identified by an asterisk of Form VII
atorvastatin.
[0110] FIG. 28
[0111] Solid-state .sup.13C nuclear magnetic resonance spectrum
with spinning side bands identified by an asterisk of Form VIII
atorvastatin.
[0112] FIG. 29
[0113] Solid-state .sup.13C nuclear magnetic resonance spectrum of
Form X atorvastatin.
[0114] FIG. 30
[0115] Raman spectrum of Form V.
[0116] FIG. 31
[0117] Raman spectrum of Form VI.
[0118] FIG. 32
[0119] Raman spectrum of Form VII.
[0120] FIG. 33
[0121] Raman spectrum of Form VIII.
[0122] FIG. 34
[0123] Raman spectrum of Form X.
[0124] FIG. 35
[0125] Raman spectrum of Form XII.
DETAILED DESCRIPTION OF THE INVENTION
[0126] Crystalline Form V, Form VI, Form VII, Form VIII, Form IX,
Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI,
Form XVII, Form XVIII, and Form XIX atorvastatin may be
characterized by their X-ray powder diffraction patterns, by their
solid state nuclear magnetic resonance spectra (NMR), and/or their
Raman spectra.
X-Ray Powder Diffraction
Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII,
XVIII, and XIX
[0127] Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI,
XVII, XVIII, or XIX atorvastatin were characterized by their X-ray
powder diffraction pattern. Thus, the X-ray diffraction patterns of
Forms V, VI, VII, VIII, IX, X, XI, XII, or Form XIII atorvastatin
were carried out on a Shimadzu XRD-6000 X-ray powder diffractometer
using CuK.sub..alpha. radiation. The instrument is equipped with a
fine-focus X-ray tube. The tube voltage and amperage were set at 40
kV and 40 mA, respectively. The divergence and scattering slits
were set at 1.degree., and the receiving slit was set at 0.15 mm.
Diffracted radiation was detected by a NaI scintillation detector.
A theta-two theta continuous scan at 3'/min (0.4 sec/0.02.degree.
step) from 2.5 to 40.degree. 2.theta. was used. A silicon standard
was analyzed each day to check the instrument alignment. The X-ray
diffraction patterns of Forms XIV, XV, XVI, XVII, XVIII, and XIX
were carried out on a Bruker D5000 diffractometer using copper
radiation, fixed slits (1.0, 1.0, 0.6 mm), and a Kevex solid slate
detector. Data was collected from 3.0 to 40.0 degrees in 2.theta.
using a step size of 0.04 degrees and a step time of 1.0 seconds.
It should be noted that Bruker Instruments purchased Siemans; thus,
a Bruker D 5000 instrument is essentially the same as a Siemans D
5000.
[0128] The X-ray diffraction patterns of Forms V, VI, VII, VIII,
IX, X, XII, XVI, and XVIII were also carried out on an Inel
diffractometer. X-ray diffraction analyses were carried out on an
Inel XRG-3000 diffractometer, equipped with a Curved Position
Sensitive (CPS) detector with a 2.theta. range of 120 degrees. Real
time data were collected using CuK.sub..alpha. radiation starting
at approximately 4.degree.2.theta. at a resolution of
0.03.degree.2.theta.. The tube voltage and amperage were set to 40
kV and 30 mA, respectively. Samples were prepared for analysis by
packing them into thin-walled glass capillaries. Each capillary was
mounted onto a goniometer head that is motorized to permit spinning
of the capillary during data acquisition. Instrument calibration
was performed daily using a silicon reference standard. The Inel
diffractograms for the available forms are shown in the figures
without baseline subtraction. Calculating the intensities from
these diffractograms is within the skill of the art and involves
using baseline subtraction to account for background scattering
(e.g., scattering from the capillary).
[0129] To perform an X-ray powder diffraction measurement on a
Shimadzu or Bruker instrument like the ones used for measurements
reported herein, the sample is typically placed into a holder which
has a cavity. The sample powder is pressed by a glass slide or
equivalent to ensure a random surface and proper sample height. The
sample holder is then placed into the instrument (Shimadzu or
Bruker). The source of the X-ray beam is positioned over the
sample, initially at a small angle relative to the plane of the
holder, and moved through an arc that continuously increases the
angle between the incident beam and the plane of the holder.
Measurement differences associated with such X-ray powder analyses
result from a variety of factors including: (a) errors in sample
preparation (e.g., sample height), (b) instrument errors (e.g.,
flat sample errors), (c) calibration errors, (d) operator errors
(including those errors present when determining the peak
locations), and (e) preferred orientation. Calibration errors and
sample height errors often result in a shift of all the peaks in
the same direction and by the same amount. Small differences in
sample height on a flat holder lead to large displacements in XRPD
peak positions. A systematic study showed that, using a Shimadzu
XRD-6000 in the typical Bragg-Brentano configuration, sample height
differences of 1 mm led to peak shifts as high as 1.degree.2.theta.
(Chen, et al., J. Pharmaceutical and Biomedical Analysis,
2001;26:63). These shifts can be identified from the X-ray
diffractogram and can be eliminated by compensating for the shift
(applying a systematic correction factor to all peak position
values) or recalibrating the instrument. In contrast, the Inel
instrument used herein places the sample in a capillary which is
positioned at the center of the instrument. This minimizes sample
height errors (a) and preferred orientation (e). Since, when using
capillaries, the sample height is not established manually, the
peak locations from the Inel measurements are typically more
accurate than those from the Shimadzu or the Bruker instrument. As
mentioned above, it is possible to rectify measurements from the
various machines by applying a systematic correction factor to
bring the peak positions into agreement. In general, this
correction factor will bring the peak positions from the Shimadzu
and Bruker into agreement with the Inel and will be in the range of
0 to 0.2.degree.2.theta..
[0130] Table 1 lists the 2.theta. and relative intensities of all
lines in the sample with a relative intensity of >10% for
crystalline Forms V-XIX atorvastatin. The numbers listed in this
table are rounded numbers. TABLE-US-00037 TABLE 1 Intensities and
Peak Locations of All Diffraction Lines With Relative Intensity
Greater Than 10%.sup.a for Forms V to XIX (Measured on Shimadzu
Diffractometer) Form XII Form V Form VI Form VII Form VIII Form IX
Form X Form XI Relative Relative Relative Relative Relative
Relative Relative Relative Inten- Intensity Intensity Intensity
Intensity Intensity Intensity Intensity sity 2.theta. (>10%)
2.theta. (>10%) 2.theta. (>10%) 2.theta. (>10%) 2.theta.
(>10%) 2.theta. (>10%) 2.theta. (>10%) 2.theta. (>10%)
4.9* 9 7.2 11 8.6 76 7.5 61 8.8 50 4.7 35 10.8* 58 5.4 11 6.0 15
8.3 77 10.2 70 9.2 29 9.4* 32 5.2 24 12.0 12 7.7 24 7.0 100 11.0 20
12.4* 12 10.0 16 11.2- 26 5.8 11 13.5 11 8.0 25 11.7* 8.0* 20 12.4
11 12.8* 15 12.1 10 16.7 59 6.9 13 16.5 52 8.6 42 8.6 57 13.8 9
17.6 20 12.8 6 17.5* 33 7.9 53 17.6- 35 8.9 25 18.0* 9.9 22 16.8 14
18.3* 43 13.8 4 19.3* 55 9.2 56 19.7 82 9.9 36 16.6 42 18.5 100
19.3 100 15.1 13 21.4* 100 9.5 50 22.3 100 10.4* 24 19.0 27 19.7*
22 22.2* 14 16.7* 64 22.4* 33 10.3* 13 23.2 26 12.5 18 21.1 35 20.9
14 23.4* 23 18.6* 100 23.2* 63 11.8 20 24.4 28 13.9* 9 25.0* 15
23.8* 26 20.3* 79 29.0* 15 16.1 13 25.8 17 16.2 10 25.5* 16 21.2 24
16.9 39 26.5 30 17.8 70 21.9 30 22.4 19 19.1 100 27.3 31 25.8 33
19.8 71 28.7 19 19.4 100 26.5 20 21.4 49 29.5 12 20.8 51 27.4* 38
22.3* 36 30.9* 17 21.7 13 30.5 20 23.7* 37 32.8* 11 22.4- 18 22.6*
24.4 15 33.6* 15 24.3 19 28.7 31 36.0* 15 25.5 24 38.5* 14 26.2 11
27.1 8 Form XV Form XVI Form XVII Form XVIII Form XIX Form XIII
Form XIV Relative Relative Relative Relative Relative Relative
Relative Inten- Inten- Inten- Inten- Inten- Intensity Intensity
sity sity sity sity sity 2.theta. (>10%) 2.theta. (>10%)
2.theta. (>10%) 2.theta. (>10%) 2.theta. (>10%) 2.theta.
(>10%) 2.theta. (>10%) 8.4 100 5.4 41 5.7 26 5.2 37 5.0 27
8.0 100 5.2 32 8.9 82 6.7 31 6.1 21 6.4 34 6.1 33 9.2* 52 6.3 28
15.7* 45 7.7 100 6.8 18 7.5 100 7.3 100 9.7* 40 7.0 100 16.4* 46
8.1 35 7.5 39 8.7 79 7.9 30 12.1 24 8.6 74 17.6* 57 9.0 65 8.1 39
10.5* 19 8.5 29 16.6* 48 10.5 34 18.1* 62 16.5* 15 8.5 42 12.0* 10
9.1 22 18.5 67 11.6* 26 19.7* 58 17.6* 17 9.5 33 12.7* 17 10.0 45
12.7* 35 20.8* 91 18.0-18.7* 21 10.5* 18 16.7 26 12.1* 24 14.0 15
23.8* 57 19.5* 18 19.1-19.6* 32 18.3* 27 14.8 17 16.7* 30 19.5 23
16.0-16.5* 20 18.9 86 20.1-20.4* 37 17.5* 28 20.8 94 21.2-21.9* 32
19.0* 46 23.6* 38 22.9-23.3* 38 19.5 65 25.5* 32 24.4-25.0* 35
20.2* 47 21.3 64 21.6 55 22.0 45 *Broad Forms XIV, XV, XVI, XVII,
XVIII, and XIX were measured on Brucker D-5000 Diffractometer.
.sup.aRelative intensity for Form V 4.9 (broad) 2.theta. is 9; Form
VI 13.8 2.theta. is 9; Form VIII 12.8 2.theta. is 6 and 13.8
2.theta. is 4; and Form XII 13.9 (broad) 2.theta. is 9 and 27.1
2.theta. is 8.
[0131] Because only 19 crystalline forms of atorvastatin are known,
each form can be identified and distinguished from the other
crystalline forms by either a combination of lines or a pattern
that is different from the X-ray powder diffraction of the other
forms.
[0132] For example, Table 2 lists combination of 2.theta. peaks for
Forms V to XIX atorvastatin, i.e., a set of X-ray diffraction lines
that are unique to each form. Forms I to IV atorvastatin disclosed
in U.S. Pat. Nos. 5,969,156 and 6,121,461 are included for
comparison. TABLE-US-00038 TABLE 2 Forms I to XIX Unique
Combination of 2.theta. Peaks Form I Form II Form III Form IV Form
V Form VI Form VII Form VIII Form IX Form X 9.0 8.5 8.3 4.7 6.0 7.2
8.6 7.5 8.8 4.7 9.3 9.0 16.4 5.2 7.0 8.3 10.2 9.2 9.4* 6.9 10.1
17.1-17.4 19.9 7.7 8.0* 11.0 12.8* 10.0 16.7 7.9 10.4 20.5 24.2 9.4
9.9 18.5 17.6 16.7* 17.5* 9.2 11.7 10.1 16.6 18.3* 18.6* 19.3* 9.5
12.0 19.3 20.3* 21.4* 19.1 16.8 29.0* 19.8 30.0 Form XI Form XII
Form XIII Form XIV Form XV Form XVI Form XVII Form XVIII Form XIX
10.8* 7.7 8.4 5.4 5.7 5.2 6.1 8.0 5.5 16.5 8.0 8.9 6.7 6.1 6.4 7.3
9.2* 7.0 19.7 8.6 20.8* 7.7 7.5 7.5 7.9 16.6* 8.6 22.3 8.9 23.8*
8.1 8.1 8.7 10.0 18.5 10.5 9.9 9.0 8.5 16.7 19.0* 12.7* 17.8 9.5
20.1-20.4* 19.5 18.9 19.4 19.1-19.6* 22.9-23.3* 21.3 20.8 21.6
*Broad Forms I to XIII were measured on Shimadzu XRD-6000
diffractometer. Forms XIV to XIX were measured on Bruker D 50001
diffractometer. Form II 2.theta. peaks from US Patent Number
5,969,156.
Solid State Nuclear Magnetic Resonance (NMR)
Methodology
[0133] Solid-state .sup.13C NMR spectra were obtained at 270 or 360
MHz Tecmag instruments. High-power proton decoupling and
cross-polarization with magic-angle spinning at approximately 4.7
and 4.2 kHz or 4.6 and 4.0 kHz were used for 68 MHz (.sup.13C
frequency) data acquisition, 4.9 and 4.4 kHz were used for 91 MHz
(.sup.13C frequency) data acquisition. The magic angle was adjusted
using the Br signal of KBr by detecting the side bands. A sample
was packed into a 7 mm Doty rotor and used for each experiment. The
chemical shifts were referenced externally to adamantine except for
Form X where the chemical shifts are arbitrary.
[0134] Table 3 shows the solid-state NMR spectrum for crystalline
Forms V, VI, VII, VIII, and X atorvastatin. ##STR2## TABLE-US-00039
TABLE 3 Chemical Shifts for Forms V, VI, VII, VIII, and X
Atorvastatin Chemical Shift V VI VII VIII X 185.7 186.5 186.1 187.0
183.3 179.5 176.8 176.5 176.8 179.5 166.9 168.2 166.5 167.9 165.5
163.1 161.0 159.8 159.2 159.4 138.7 136.8 137.6 139.4 137.9 136.3
132.9 134.8 133.0 129.4 128.4 127.8 128.3 128.7 127.9 124.7 123.2
122.0 122.3 122.3 121.8 118.8 119.2 119.9 117.0 116.3 116.6 113.7
88.2 74.5 79.3 70.5 70.3 71.1 68.0 68.3 67.0 66.2 43.1 43.3 43.5
43.3 43.7 40.3 36.9 40.9 31.9 25.6 25.9 26.3 26.7 26.4 24.9 24.7
25.3 22.5 20.2 20.9 20.3 19.9 20.1 18.3
Forms V, VI, VII, VIII, and X: Relative peak intensity over 20 are
shown here (4.5, 4.6, 4.7, or 4.9 kHz CPMAS). Spectra were obtained
using two different magic-angle spinning rates to determine
spinning sidebands. Form X: Relative peak intensity over 20 are
shown here (5.0 kHz CPMAS).
[0135] Table 4 shows unique solid-state NMR peaks for Forms V, VI,
VII, VIII and X atorvastatin, ie, peaks within .+-.1.0 ppm. Forms I
to IV atorvastatin are included for comparison. TABLE-US-00040
TABLE 4 Forms I to VIII and X Unique Solid-State NMR Peaks Form I
Form II Form III Form IV Form V Form VI Form VII Form VIII Form X
182.8 181.0 161.0 181.4 176.8 163.1 183.3 132.9 18.3 131.1 163.0
140.1 63.5 36.9 176.8 73.1 161.0 131.8 17.9 31.9 74.5 64.9 140.5
69.8 35.4
Raman Spectroscopy
Methodology
[0136] The Raman spectrum was obtained on a Raman accessory
interfaced to a Nicolet Magna 860 Fourier transform infrared
spectrometer. The accessory utilizes an excitation wavelength of
1064 nm and approximately 0.45 W of neodymium-doped yttrium
aluminum garnet (Nd:YAG) laser power. The spectrum represents 64 or
128 co-added scans acquired at 4 cm.sup.-1 resolution. The sample
was prepared for analysis by placing a portion into a 5-mm diameter
glass tube and positioning this tube in the spectrometer. The
spectrometer was calibrated (wavelength) with sulfur and
cyclohexane at the time of use.
[0137] Table 5 shows the Raman spectra for Forms V, VI, VII, VIII,
X, and XII atorvastatin. TABLE-US-00041 TABLE 5 Raman Peak Listing
for Forms V, VI, VII, VIII, X and XII Atorvastatin Form V Form VI
Form VII Form VIII Form X Form XI 3062 3058 3060 3065 3062 3064
2973 2935 2927 2923 2911 2926 1652 1651 1649 1658 1650 1652 1604
1603 1603 1603 1603 1603 1528 1556 1524 1531 1525 1527 1525 1510
1481 1478 1478 1476 1478 1470 1440 1413 1412 1412 1413 1411 1410
1397 1397 1368 1368 1369 1367 1240 1240 1158 1157 1159 1158 1159
1034 1034 1034 1034 1001 997 998 997 999 1002 825 824 824 823 245
224 130 114 121 116 Relative peak intensity over 20 are shown.
[0138] Table 6 lists unique Raman peaks for Forms V, VI, VII, VIII.
X, and XII atorvastatin, ie, only one other form has a peak with
.+-.4 cm.sup.-1. In the case of Forms VI and X, it is a unique
combination of peaks. Forms I to IV atorvastatin are included for
comparison. TABLE-US-00042 TABLE 6 Forms I to VIII, X and XII
Unique Raman Peaks Form I Form II Form III Form IV Form V Form VI*
Form VII Form VIII Form X* Form XII 3080 1663 2938 423 1440 3058
1397 1510 3062 2973 1512 359 1660 215 1397 2935 1481 2911 1439 1510
132 130 1556 1413 1525 142 1481 1525 121 1240 1427 1182 859 *Unique
combination of Raman peaks
[0139] Crystalline Forms V to XIX atorvastatin of the present
invention may exist in anhydrous forms as well as hydrated and
solvated forms. In general, the hydrated forms are equivalent to
unhydrated forms and are intended to be encompassed within the
scope of the present invention. Crystalline Form XIV contains about
6 mol of water. Preferably, Form XIV contains 6 mol of water.
Crystalline Forms V, X, and XV atorvastatin contain about 3 mol of
water. Preferably, Forms V, X, and XV atorvastatin contain 3 mol of
water.
[0140] Crystalline Form VII contains about 1.5 mol of water.
Preferably, Form VII atorvastatin contains 1.5 mol of water.
Crystalline Form VIII contains about 2 mol of water. Preferably,
Form VIII atorvastatin contains 2 mol of water.
[0141] Crystalline Forms XVI-XIX may exist as a solvate.
[0142] Crystalline forms of atorvastatin of the present invention,
regardless of the extent of hydration and/or solvation having
equivalent x-ray powder diffractograms, ssNMR, or Raman spectra are
within the scope of the present invention.
[0143] Crystalline forms, in general, can have advantageous
properties. A polymorph, solvate, or hydrate is defined by its
crystal structure and properties. The crystal structure can be
obtained from X-ray data or approximated from other data. The
properties are determined by testing. The chemical formula and
chemical structure does not describe or suggest the crystal
structure of any particular polymorphic or crystalline hydrate
form. One cannot ascertain any particular crystalline form from the
chemical formula, nor does the chemical formula tell one how to
identify any particular crystalline solid form or describe its
properties. Whereas a chemical compound can exist in three
states--solid, solution, and gas-crystalline solid forms exist only
in the solid state. Once a chemical compound is dissolved or
melted, the crystalline solid form is destroyed and no longer
exists (Wells J. I., Aulton M. E. Pharmaceutics. The Science of
Dosage Form Design. Reformulation, Aulton M. E. ed., Churchill
Livingstone, 1988,13:237).
[0144] The new crystalline forms of atorvastatin described herein
have advantageous properties. Form VII has good chemical stability,
which is comparable to Form I (disclosed in U.S. Pat. No.
5,969,156). Since noncrystalline forms of atorvastatin are not
chemically stable, this is a significant advantage, which would
translate into enhanced shelf life and longer expiration dating.
Form VII can be prepared from acetone/water. whereas Form I is
prepared from the more toxic methanol/water system. Form VII is the
sesquihydrate and contains less water, meaning that a unit weight
of Form VII contains more atorvastatin molecules, meaning it is of
higher potency.
[0145] The ability of a material to form good tablets at commercial
scale depends upon a variety of drug physical properties, such as
the Tableting Indices described in Hiestand H. and Smith D.,
Indices of Tableting Performance, Powder Technology,
1984;38:145-159. These indices may be used to identify forms of
atorvastatin calcium which have superior tableting performance. One
such index is the Brittle Fracture Index (BFI), which reflects
brittleness, and ranges from 0 (good--low brittleness) to 1
(poor-high brittleness). For example, Form VII has a BFI value
0.09, while Form I has a BFI value 0.81. Thus, Form VII is less
brittle than Form I. This lower brittleness indicates greater ease
of manufacture of tablets.+
[0146] Form VIII also has less water than Form I (dihydrate vs
trihydrate) and thus a gram of Form VIII contains more atorvastatin
molecules.
[0147] Form X is advantageous in that it can be prepared from the
less toxic isopropanol (IPA):water system, thus avoiding the more
toxic methanol:water system.
[0148] Form XII has the highest melting point (210.6). Since high
melting point correlates with stability at high temperature, this
means this form is most stable at temperatures near the melting
point. High melting forms can be advantageous when process methods
involving high temperatures are used. Form XII is also prepared
from the less toxic tetrahydrofuran (THF) water system.
[0149] Form XIV is prepared using the less toxic THF/water
system.
[0150] The present invention provides a process for the preparation
of crystalline Forms V to XIX atorvastatin which comprises
crystallizing atorvastatin from a solution in solvents under
conditions which yield crystalline Forms V to XIX atorvastatin.
[0151] The precise conditions under which crystalline Forms V to
XIX atorvastatin are formed may be empirically determined, and it
is only possible to give a number of methods which have been found
to be suitable in practice.
[0152] The compounds of the present invention can be prepared and
administered in a wide variety of oral and parenteral dosage forms.
Thus, the compounds of the present invention can be administered by
injection, that is, intravenously, intramuscularly,
intracutaneously, subcutaneously, intraduodenally, or
intraperitoneally. Also, the compounds of the present invention can
be administered by inhalation, for example, intranasally.
Additionally, the compounds of the present invention can be
administered transdermally. It will be obvious to those skilled in
the an that the following dosage forms may comprise as the active
component, either compounds or a corresponding pharmaceutically
acceptable salt of a compound of the present invention.
[0153] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0154] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component.
[0155] In tablets, the active component is mixed with the carrier
having the necessary binding properties in suitable proportions and
compacted in the shape and size desired.
[0156] The powders and tablets preferably contain from two or ten
to about seventy percent of the active compound. Suitable carriers
are magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter, and
the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as a
carrier providing a capsule in which the active component, with or
without other carriers, is surrounded by a carrier, which is thus
in association with it. Similarly, cachets and lozenges are
included. Tablets, powders, capsules, pills, cachets, and lozenges
can be used as solid dosage forms suitable for oral
administration.
[0157] For preparing suppositories, a low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[0158] Liquid form preparations include solutions, suspensions,
retention enemas, and emulsions, for example water or water
propylene glycol solutions. For parenteral injection, liquid
preparations can be formulated in solution in aqueous polyethylene
glycol solution.
[0159] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavors, stabilizing, and thickening agents as
desired.
[0160] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other
well-known suspending agents.
[0161] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0162] The pharmaceutical preparation is preferably in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsule, tablet, cachet, or lozenge itself, or it can
be the appropriate number of any of these in packaged form.
[0163] The quantity of active component in a unit dose preparation
may be varied or adjusted from 0.5 mg to 100 mg, preferably 2.5 mg
to 80 mg according to the particular application and the potency of
the active component. The composition can, if desired, also contain
other compatible therapeutic agents.
[0164] In therapeutic use as hypolipidemic and/or
hypocholesterolemic agents and agents to treat osteoporosis and
Alzheimer's disease, the crystalline Forms V to XIX atorvastatin
utilized in the pharmaceutical method of this invention are
administered at the initial dosage of about 2.5 mg to about 80 mg
daily. A daily dose range of about 2.5 mg to about 20 mg is
preferred. The dosages, however, may be varied depending upon the
requirements of the patient, the severity of the condition being
treated, and the compound being employed. Determination of the
proper dosage for a particular situation is within the skill of the
art. Generally, treatment is initiated with smaller dosages which
are less than the optimum dose of the compound. Thereafter, the
dosage is increased by small increments until the optimum effect
under the circumstance is reached. For convenience, the total daily
dosage may be divided and administered in portions during the day
if desired.
[0165] The following nonlimiting examples illustrate the inventors'
preferred methods for preparing the compounds of the invention.
EXAMPLE 1
[R-(R*,R*)]-2-(4-Fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)--
3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi
calcium salt
(Forms V-XIX Atorvastatin)
Form V Atorvastatin
Method A
[0166] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) was
slurried in a mixture of acetonitrile/water (9:1) to afford
crystalline Form V atorvastatin.
Method B
[0167] Crystalline Form I atorvastatin calcium (U.S. Pat. No.
5,969,156) was slurried in a mixture of acetonitrile/water (9:1) at
60.degree. C. overnight, filtered, and air dried to afford
crystalline Form V atorvastatin.
Method C
[0168] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) was
stressed under vapors of acetonitrile/water (9:1) to afford
crystalline Form V atorvastatin.
Method D
[0169] Acetonitrile was added to a solution of amorphous
atorvastatin calcium (U.S. Pat. No. 5,273,995) in
tetrahydrofuran/water (9:1) and cooled to afford crystalline Form V
atorvastatin.
Method E
[0170] Acetonitrile was added to a solution of amorphous
atorvastatin calcium (U.S. Pat. No. 5,273,995) in
dimethylformamide/water and fast evaporation affords crystalline
Form V atorvastatin.
Method F
[0171] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995)
diffused in a vapor of acetonitrile/water (9:1) to afford
crystalline Form V atorvastatin.
Crystalline Form V atorvastatin, mp 171.4.degree. C.,
trihydrate
Karl Fischer 4.88% (3 mol of water).
Form VI Atorvastatin
Method A
[0172] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) was
placed into a vapor jar containing dimethylformamide/water (9:1)
for 20 days to afford crystalline Form VI atorvastatin.
Method B
[0173] Fast evaporation of a dimethylformamide/water solution of
amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) afforded
crystalline Form VI atorvastatin.
Method C
[0174] Fast evaporation of a dimethylformamide/water (saturated)
solution of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) seeded with crystalline Form VI afforded crystalline
Form VI atorvastatin.
Crystalline Form VI atorvastatin, mp 145.9.degree. C.
Form VII Atorvastatin
Method A
[0175] A solution of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) in acetone/water (1:1) (5.8 mg/mL) was stirred
overnight. A solid formed which was filtered to afford crystalline
Form VII atorvastatin.
Method B
[0176] A solution of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) in acetone/water (1:1) was evaporated at 50.degree. C.
to afford crystalline Form VII atorvastatin.
Method C
[0177] A saturated solution of amorphous atorvastatin calcium (U.S.
Pat. No. 5,273,995) in acetone/water (1:1) was seeded with
crystalline Form VII atorvastatin to afford crystalline Form VII
atorvastatin.
Method D
[0178] Fast evaporation of a saturated solution of amorphous
atorvastatin calcium (U.S. Pat. No. 5,273,995) in acetone/water
(1:1) was seeded with crystalline Form VII to afford crystalline
Form VII atorvastatin.
Crystalline Form VU atorvastatin, mp 195.9.degree. C., 1.5
hydrate
Karl Fischer 2.34% (1.5 mol of water).
Form VIII Atorvastatin
Method A
[0179] A solution of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) in dimethylformamide/water (saturated) (9:1), was seeded
with crystalline Form VII and evaporated to afford crystalline Form
VIII atorvastatin.
Method B
[0180] Fast evaporation of a solution of amorphous atorvastatin
calcium (U.S. Pat. No. 5,273,995) in dimethylformamide/water (9:1)
affords crystalline Form VIII atorvastatin.
Crystalline Form VIII atorvastatin, mp 151.degree. C.,
dihydrate
Karl Fischer 2.98% (2 mol of water).
Form IX Atorvastatin
Method A
[0181] A solution of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) in acetone/water (6:4) (3.4 mg/mL) was evaporated on a
rotary evaporator to afford crystalline Form IX atorvastatin.
Method B
[0182] A solution of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) in acetone/water (6:4) was filtered, seeded with
crystalline Form IX evaporated on a rotary evaporator to afford
crystalline Form IX atorvastatin.
Method C
[0183] A solution of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) in acetone/water (6:4) was stirred for 0.5 hours,
filtered, evaporated on rotary evaporator to concentrate the
solution, and dried in a vacuum oven to afford crystalline Form IX
atorvastatin.
Form X Atorvastatin
Method A
[0184] A slurry of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) in isopropanol/water (9:1) was stirred for a few days,
filtered, and air dried to afford crystalline Form X
atorvastatin.
Method B
[0185] A slurry of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) in isopropanol/water (9:1) was stirred for 5 days,
filtered, and air dried to afford crystalline Form X
atorvastatin.
Method C
[0186] A saturated solution of amorphous atorvastatin calcium (U.S.
Pat. No. 5,273,995) in isopropanol/water (9:1) was stirred for 2
days, filtered, and air dried to afford crystalline Form X
atorvastatin.
Crystalline Form X atorvastatin, mp 180.1.degree. C.,
trihydrate
Karl Fischer 5.5% (3.5 mol of water).
Form XI Atorvastatin
[0187] A solution of amorphous atorvastatin calcium (U.S. Pat. No.
5,273,995) in acetonitrile/water (9:1) was filtered and allowed to
evaporate slowly to afford crystalline Form XI atorvastatin.
Form XII Atorvastatin
[0188] Crystalline Form I atorvastatin calcium (U.S. Pat. No.
5,969,156) was slurried in tetrahydrofuran/water (2:8) at
90.degree. C. for 5 days, filtered, and air dried to afford
crystalline Form XII atorvastatin.
Crystalline Form XII atorvastatin, mp 210.6.degree. C.
Form XIII Atorvastatin
[0189] Crystalline Form I atorvastatin calcium (U.S. Pat. No.
5,969,156) was added to 10 mL 2:8 water:methanol to leave a layer
of solid on the bottom of a vial. The slurry was heated to about
70.degree. C. for 5 days. The supernatant was removed, and the
solid air dried to afford crystalline Form XIII atorvastatin.
Form XIV Atorvastatin
[0190] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 1
g, was slurried for 3 weeks in 45 mL of isopropyl alcohol/5 mL of
water (9:1) at ambient temperature. The mixture was filtered to
afford crystalline Form XIV atorvastatin after drying at ambient
temperature.
[0191] Differential scanning calorimetry (DSC) indicates a low
desolvation event at about 60.degree. C. (peak) followed by a melt
at about 150.degree. C. Combustion analysis indicates that the
compound is a hexahydrate. Thermographic infrared spectroscopy
(TG-1R) shows the compound contains water. Karl Fischer shows the
compound contains 5.8% water.
Form XV Atorvastatin
[0192] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 1
g, was slurried for 3 weeks in 45 mL acetonitrile/5 mL of water
(9:1) at ambient temperature. The mixture was filtered to afford
crystalline Form XV atorvastatin after drying at ambient
temperature. DSC indicates a low desolvation event at about
78.degree. C. (peak) followed by a melt at about 165.degree. C.
Combustion analysis indicates that the compound is a trihydrate.
TG-IR shows the compound contains water.
Form XVI Atorvastatin
[0193] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 1
g, was slurried for about 1 day in 9:1 acetonitrile/water at room
temperature. The mixture was filtered to afford crystalline Form
XVI atorvastatin after drying at ambient temperature. DSC indicates
a broad endotherm at peak temperature of 72.degree. C. and an
endotherm with onset temperature of 164.degree. C. The weight loss
profile by thermographic analysis (TGA) indicates a total weight
loss of about 7% at 30.degree. C. to 160.degree. C. Combustion
analysis indicates that TGA and Karl Fischer analysis (shows 7.1%
water) indicates the compound is a tetrahydrate/acetonitrile
solvate.
Form XVII Atorvastatin
[0194] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995),
0.5 g, was slurried for about 2 days in 5 mL of 9:1
dimethylformamide (DMF)/water containing 25 mL of acetonitrile at
room temperature. The mixture was filtered to afford crystalline
Form XVII atorvastatin after drying at ambient temperature. DSC
showed multiple broad endotherms indicating the compound was a
solvate.
Form XVIII Atorvastatin
[0195] Crystalline Form XVI atorvastatin, 0.5 g. was dried for
about 1 day at room temperature to afford crystalline Form XVIII
atorvastatin. DSC showed a broad endotherm at low temperature
indicating the compound was a solvate. Karl Fischer analysis showed
the compound contained 4.4% water.
Form XIX Atorvastatin
[0196] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995),
0.4 g, was slurried for about 7 days in 4 mL methyl ethyl ketone at
room temperature. The mixture was filtered to afford crystalline
Form XIX atorvastatin after drying at ambient temperature. DSC
indicated a low desolvation event at about 50.degree. C. (peak)
followed by a melt at about 125.degree. C. TGA analysis indicates
that the compound is a solvate that desolvates at low
temperature.
* * * * *