U.S. patent application number 15/700734 was filed with the patent office on 2018-01-11 for novel forms of [r-(r*,r*)]-2-(4-fluorophenyl)-beta, gamma-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-p- yrrole-1-heptanoic acid calcium salt (2:1).
The applicant listed for this patent is Warner-Lambert Company LLC. Invention is credited to Joseph Francis Krzyzaniak, George Michael Laurence, Aeri Park, Kevin Quackenbush, Marie Louise Reynolds, Peter Robert Rose, Timothy Andrew Woods.
Application Number | 20180009748 15/700734 |
Document ID | / |
Family ID | 35462253 |
Filed Date | 2018-01-11 |
United States Patent
Application |
20180009748 |
Kind Code |
A1 |
Krzyzaniak; Joseph Francis ;
et al. |
January 11, 2018 |
Novel Forms of [R-(R*,R*)]-2-(4-Fluorophenyl)-Beta,
Gamma-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)carbonyl]-1H-P-
yrrole-1-Heptanoic Acid Calcium Salt (2:1)
Abstract
Novel forms of
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-
-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptatonic acid
hemi calcium salt designated Form XX, Form XXI, Form XXII, Form
XXIII, Form XXIV, Form XXV, Form XXVI, Form XXVII, Form XXVIII,
Form XXIX, and Form XXX, 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, benign
prostatic hyperplasia (BPH) and Alzheimer's disease.
Inventors: |
Krzyzaniak; Joseph Francis;
(Pawcatuck, CT) ; Laurence; George Michael; (West
Lafayette, IN) ; Park; Aeri; (Lansdale, PA) ;
Quackenbush; Kevin; (Groton, CT) ; Reynolds; Marie
Louise; (Lebanon, CT) ; Rose; Peter Robert;
(Ledyard, CT) ; Woods; Timothy Andrew; (Edinburgh,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Warner-Lambert Company LLC |
New York |
NY |
US |
|
|
Family ID: |
35462253 |
Appl. No.: |
15/700734 |
Filed: |
September 11, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15285037 |
Oct 4, 2016 |
9790177 |
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15700734 |
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14924011 |
Oct 27, 2015 |
9481647 |
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15285037 |
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14520742 |
Oct 22, 2014 |
9199932 |
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14924011 |
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14021151 |
Sep 9, 2013 |
8895758 |
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14520742 |
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13214559 |
Aug 22, 2011 |
8563750 |
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14021151 |
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11572333 |
Aug 19, 2008 |
8026376 |
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PCT/IB2005/002181 |
Jul 11, 2005 |
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13214559 |
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60589485 |
Jul 20, 2004 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 3/06 20180101; C07D 207/34 20130101; A61P 43/00 20180101; A61P
13/08 20180101; A61P 19/10 20180101 |
International
Class: |
C07D 207/34 20060101
C07D207/34 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4. A Form XXIV atorvastatin calcium having an X-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation: 2.9, 7.4, 7.8, 8.7, 9.5, 10.0, 12.2, 18.0,
18.6, 19.0, and 22.7.
5. (canceled)
6. (canceled)
7. (canceled)
8. A Form XXVIII atorvastatin calcium having an X-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation: 7.6, 9.5, 12.2, 16.5, 17.0, 18.0, 20.5, 21.5,
and 22.3.
9. (canceled)
10. A Form XXX atorvastatin calcium having an X-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation: 3.1, 9.0, 9.7, 12.0, 16.5, 17.0, 20.9, 21.6,
22.5, and 24.3.
11. (canceled)
12. (canceled)
13. (canceled)
14. A Form XXVIII atorvastatin calcium having an X-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation: 7.6, 9.5, 20.5, and 22.3, and a solid state
.sup.19F nuclear magnetic resonance having the following chemical
shifts expressed in parts per million: -116.4, -117.1, and
-119.2.
15. A Form XXX atorvastatin calcium having an X-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation: 3.1, 9.0, and 21.6, and a solid state .sup.19F
nuclear magnetic resonance having the following chemical shifts
expressed in parts per million: -116.7 and -118.6.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel forms of atorvastatin
calcium 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-heptatonic 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, benign prostatic hyperplasia,
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*)]-2-4fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]- 1H-pyrrole-1-heptatonic acid
calcium salt (2:1) trihydrate and the formula
##STR00001##
[0004] 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.
[0005] A number of patents have issued disclosing atorvastatin,
formulations of atorvastatin, as well as processes and key
intermediates for preparing atorvastatin. These include: U.S. Pat.
Nos. 4,681,893; 5,273,995; 5,003,080; 5,097,045; 5,103,024;
5,124,482; 5,149,837; 5,155,251; 5,261,174; 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; 5,686,104; 5,998,633; 6,087,522;
6,236,972; 6,433,213; and 6,476,235, which are herein incorporated
by reference.
[0006] Additionally, a number of published International Patent
Applications and patents have disclosed crystalline forms of
atorvastatin, we well as processes for preparing amorphous
atorvastatin. These include: U.S. Pat. No. 5,969,156; U.S. Pat. No.
6,605,729; WO 07/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO
02/41734; WO 02/43667; WO 02/43732; WO 02/051804; WO 01/057228; WO
02/057229; WO 02/057274; WO 02/059087; WO 02/072073; WO 02/083637;
WO 02/083638; WO 03/050085; WO 03/070702; and WO 04/02053.
[0007] Atorvastatin is prepared as its calcium salt, i.e.,
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-6-(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, tables,
capsules, lozenges, powders, and the like for oral
administration.
[0008] The process by which atorvastatin calcium 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.
[0009] Furthermore, it has been disclosed that the amorphous forms
in a number of drugs exhibit different dissolution characteristics,
and in some cases different bioavailability patterns compared to
the crystalline forms (Konno T., Chem. Pharm. Bull., 1990; 38;
2003-2007). For some therapeutic indications, one bioavailability
pattern may be favored over another.
[0010] In the course of drug development, it is generally assumed
to be important to discover the most stable crystalline form of the
drug. This most stable crystalline form is the form which is likely
to have the best chemical stability, and thus the longest
shelf-like in a formulation. However, it is also advantageous to
have multiple forms of a drug, e.g. salts, hydrates, polymorphs,
crystalline, and noncrystalline forms. There is no one ideal
physical form of a drug because different physical forms provide
different advantages. The search for the most stable form and for
such other forms is arduous and the outcome is unpredictable.
[0011] The successful development of a drug requires that it meet
certain requirements to be a therapeutically effective treatment
for patients. These requirements fall into two categories: (1)
requirements for successful manufacture of dosage forms, and (2)
requirements for successful drug delivery and disposition after the
drug formulation has been administered to the patient.
[0012] There are many kinds of drug formulations for administration
by various routes, and the optimum drug form for different
formulations is likely to be different. As mentioned above, a drug
formulation must have sufficient shelf-life to allow successful
distribution to patients in need of treatment. In addition, a drug
formulation must provide the drug in a form which will dissolve in
the patient's gastrointestinal tract when orally dosed. For oral
dosing in an immediate release dosage form, such as an immediate
release tablet, capsule, suspension, or sachet, it is generally
desirable to have a drug salt of drug form which has high
solubility, in order to assure complete dissolution of the dose and
optimal bioavailability. For some drugs particularly low solubility
drugs or poorly wetting drugs. It may be advantageous to utilize a
noncrystalline drug form, which will generally have a higher
initial solubility then a crystalline form when administered into
the gastrointestinal tract. A noncrystalline form of a drug is
frequently less chemically stable than a crystalline form. Thus it
is advantageous to identify noncrystalline drug forms which are
sufficiently chemically stable to provide a practical product which
is stable enough to maintain its potency for enough time to permit
dosage form manufacture, packaging storage, and distribution to
patients around the world.
[0013] On the other hand, there are dosage forms which operate
better if the drug form is less soluble. For example, a chewable
tablet or a suspension or a sachet dosage form exposes the tongue
to the drug directly. For such dosage forms, it is desirable to
minimize the solubility of the drug in the mouth, in order to keep
a portion of the drug in the solid state, minimizing bad taste. For
such dosage forms, it is often desirable to use a low solubility
salt or crystalline form.
[0014] For controlled release oral or injectable, e.g. subcutaneous
or intramuscular, dosage forms, the desired drug solubility is a
complex function of delivery route, dose, dosage form design, and
desired duration of release. For a drug which has high solubility,
it may be desirable to utilize a lower solubility crystalline salt
or polymorph for a controlled release dosage form, to aid in
achievement of slow release through slow dissolution. For a drug
which has low solubility, it may be necessary to utilize a higher
solubility crystalline salt or polymorph, or a noncrystalline form,
in order to achieve a sufficient dissolution rate to support the
desired drug release rate from the controlled release dosage
form.
[0015] In soft gelatin capsule dosage forms ("soft-gels"), the drug
is dissolved in a small quantity of a solvent or vehicle such as a
triglyceride oil or polyethylene glycol, and encapsulated in a
gelatin capsule. An optimal drug form for this dosage form is one
which has a high solubility in an appropriate soft-gel vehicle. In
general, a drug form which is more soluble in a triglyceride oil
will be less soluble in water. Identification of an appropriate
drug form for a soft-gel dosage form requires study of various
salts, polymorphs, crystalline, and noncrystalline forms.
[0016] Thus, it can e seen that the desired solubility of a drug
form depends on the intended use, and not all forms are
equivalent.
[0017] For a drug form to be practically useful for human or animal
therapy, it is desirable that the drug form exhibit minimal
hygroscopicity. Dosage forms containing highly hygroscopic drugs
require protective packaging, and may exhibit altered dissolution
if stored in a humid environment. Thus, it is desirable to identify
nonhygroscopic crystalline salts and polymorphs of a drug. If a
drug is noncrystalline, or if a noncrystalline form is desired to
improve solubility and dissolution rate, then it is desirable to
identify a noncrystalline salt or form which has a low
hygroscopicity relative to other noncrystalline salts or forms.
[0018] A drug, crystalline of noncrystalline, may exist in an
anhydrous form, or as a hydrate or solvate or hydrate/solvate. The
hydration state and solvation state of a drug affects its
solubility and dissolution behavior.
[0019] The melting point of a drug may vary for different salts,
polymorphs, crystalline, and noncrystalline forms. In order to
permit manufacture of tablets on commercial tablet presses, it is
desirable that the drug melting point be greater than around
60.degree. C., preferable greater than 100.degree. C. to prevent
drug melting during tablet manufacture. A preferred drug form in
this instance is one that has the highest melting point. In
addition, it is desirable to have a high melting point to assure
chemical stability of a solid drug in a solid dosage form at high
environmental storage temperatures which occur in direct sunlight
and in geographic areas such as near the equator, if a soft-gel
dosage form is desired, it is preferred to have a drug form which
has a low melting point, to minimize crystallization of the drug in
the dosage form. Thus, it can be seen that the desired melting
point of a drug depends on the intended use, and not all drug forms
are equivalent.
[0020] When a drug's dose is high, or if a small dosage form is
dosage form is desired, the selection of a salt, hydrate, or
solvate affects the potency per unit weight. For example, a drug
salt with a higher molecular weight counterion will have a lower
drug potency per gram than will a drug salt with a lower molecular
weight counterion. It is desirable to choose a drug form which has
the highest potency per unit weight.
[0021] The method of preparation of different crystalline
polymorphs and noncrystalline forms varies widely from drug to
drug. It is desirable that minimally toxic solvents be used in
these methods, particularly for the last synthetic step, and
particularly if the drug has a tendency to exist as a solvate with
the solvent utilized in the last step, and synthesis. Preferred
drug forms are those which utilize less toxic solvents in their
synthesis.
[0022] The ability of a drug to form good tablets at commercial
scale depends upon a variety of drug physical properties, such as
the Tableting indices described in Hiestand H, Smith D. Indices of
tableting performance. Powder Technology, 1984;38:145-159. These
indices may be used to identify forms of a drug, e.g. of
atorvastatin calcium, which have superior tableting performance.
Ona such index is the Brittle Fracture Index (BFI), which reflects
brittleness, and ranges from 0 (good-low brittleness) to 1
(poor-high brittleness). Other useful indices or measures of
mechanical properties, flow properties, and tableting performance
include compression stress, absolute density, solid fraction,
dynamic indentation hardness, ductility, elastic modulus, reduced
elastic modulus, quasistatic indentation hardness, shear modulus,
tensile strength, compromised tensile strength, best case bonding
index, worst case bonding index, brittle/viscoelastic bonding
index, strain index, viscoelastic number, effective angle of
internal friction (from a shear cell test), cohesivity (from a
powder avalanche test) and flow variability. A number of these
measures are obtained on drug compacts, preferably prepared using a
triaxial hydraulic press. Many of these measures are further
described in Hancock B, Carlson G, Ladipo D, Langdon B, and
Mullarney M. Comparison of the Mechanical Properties of the
Crystalline and Amorphous Forms of a Drug Substance, International
Journal of Pharmaceutics, 2002;241:73-85.
[0023] Drug form properties which affect flow are important and not
just for tablet dosage form manufacture, but also for manufacture
of capsules, suspensions, and sachets.
[0024] The particle size distribution of a drug powder can also
have large effects on manufacturing processes, particularly through
effects on powder flow. Different drug forms have different
characteristic particle size distributions.
[0025] From the above discussion, it is apparent that there is no
one drug form which is ideal for all therapeutic applications. Thus
it is important to seek a variety of unique drug forms, e.g. salts,
polymorphs, noncrystalline forms, which, may be used in various
formulations. The selection of a drug form for a specific
formulation or therapeutic application requires consideration of a
variety of properties, as described above, and the best form for a
particular application may be one which has one specific important
good property while other properties may be acceptable or
marginally acceptable.
[0026] We have now surprisingly and unexpectedly found novel forms
of atorvastatin calcium. Thus the present invention provides news
forms of atorvastatin calcium designated Forms XX, XXI, XXII,
XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX. The new forms of
atorvastatin are purer, more stable, or have advantageous
manufacturing and/or physical properties compared to forms of
atorvastatin previously described.
[0027] In general, the new forms of atorvastatin calcium disclosed
in the present application have high water solubility and high
dissolution rates. This is an advantage for immediate release
dosage forms since such forms need to be fully dissolved in the
stomach before passing into the digestive tract. Additionally, some
of the new forms can be prepared using solvents which are nontoxic.
This avoids any residual solvents and their toxicity. Furthermore,
some of the new forms have low hygroscopicity which, as explained
above, is desirable from a packaging or handling aspect. Also, some
of the new forms have advantageous tableting properties and can be
conveniently made into a tablet. Additionally, some of the new
forms can be easily and directly prepared, which provide a cost
advantage. Also, some of the new forms see physically stable and
not easily converted into other forms.
SUMMARY OF THE INVENTION
[0028] Accordingly, the present invention is directed to Form XX
atorvastatin calcium characterized by the following x-ray powder
diffraction (XRPD) pattern expressed in terms of degree 2.theta.
and relative intensities with a relative intensity of >10% and
relative peak width measured on a Shimadzu diffractometer with
CuK.sub.a radiation:
TABLE-US-00001 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 7.5-9.0 m vb 17.5-26.0 s vb .sup.as = strong; m =
medium .sup.bvb = very broad (>1 degrees 2.theta. peak
width)
[0029] In a second aspect, the present invention is directed to
Form XXI atorvastatin calcium characterized by the following x-ray
powder diffraction (XRPD) pattern expressed in terms of degree
2.theta. and relative intensities with a relative intensity of
>10% and relative peak width measured on a Shimadzu
diffractometer with CuK.sub.a radiation:
TABLE-US-00002 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 3.1 w b 4.1 w b 5.0 w b 6.3 w b 7.6 s b 8.6 m b,
sh 9.2 w b, sh 10.1 w b 12.2 w b 16.7 m vb 18.2 m vb 19.2 m vb 20.1
m vb 20.5 w vb 23.1 m vb, sh 29.6 w vb .sup.as = strong; m =
medium; w = weak .sup.bb = broad, sh = shoulder, vb = very broad
(>1 degrees 2.theta. peak width)
[0030] In a third aspect, the present invention is directed to Form
XXII atorvastatin calcium characterized by the following x-ray
powder diffraction (XRPD) pattern expressed in terms of degree
2.theta. and relative intensities with a relative intensity of
>10% and relative peak width measured on a Shimadzu
diffractometer with CuK.sub.a radiation:
TABLE-US-00003 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 4.0 m b 4.9 w b 8.0 m b 10.0 s b 11.1 w b 11.7 w b
12.2 w b 13.1 w b, sh 13.5 m b 14.0 w b 14.8 w b, sh 16.1 m b 16.4
m b, sh 17.0 m b 17.4 m b, sh 17.7 m b, sh 19.2 w b 20.0 m b 20.3 m
b 21.3 w b 22.6 w b 24.5 w vb 27.0 w b 28.1 w b 28.9 w vb 29.4 w vb
.sup.as = strong; m = medium; w = weak .sup.bb = broad, sh =
shoulder, vb = very broad (>1 degrees 2.theta. peak width)
[0031] In a fourth aspect, the present invention is directed to
Form XXIII atorvastatin calcium characterized by the following
x-ray powder diffraction (XRPD) pattern expressed in terms of
degree 2.theta. and relative intensities with a relative intensity
of >10% and relative peak width measured on a Shimadzu
diffractometer with CuK.sub.a radiation:
TABLE-US-00004 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 3.2 w b 4.1 w b 5.0 w b 6.3 w b 7.2 w b, sh 7.7 s
b 8.1 m b 8.5 m b 9.1 w b 10.1 w b 10.5 w b 12.1 w b 12.8 w b 13.3
w b 16.7 m vb 18.4 m vb 19.1 m b 20.2 m vb 21.0 w b 21.4 m b 23.2 m
vb 24.3 w b 25.2 w b 29.3 w b .sup.as = strong; m = medium; w =
weak .sup.bb = broad, sh = shoulder, vb = very broad (>1 degrees
2.theta. peak width)
[0032] In a fifth aspect, the present invention is directed to Form
XXIV atorvastatin calcium characterized by the following x-ray
powder diffraction (XRPD) pattern expressed in terms of degree
2.theta. and relative intensities with a relative intensity of
>10% and relative peak width measured on a Shimadzu
diffractometer with CuK.sub.a radiation:
TABLE-US-00005 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 2.9 m b 4.6 w b 5.2 w b 7.4 m b, sh 7.8 s b 8.7 m
b 9.5 s b 10.0 w b 12.2 w vb 12.5 w b 13.4 w b 13.9 w b 17.3 w vb
18.0 m b 18.6 m b 19.0 m b 20.6 w b 21.2 w vb 22.3 w vb 22.7 s b
23.2 m b, sh 24.2 w b 24.5 w vb 25.0 w vb 26.4 w vb 28.8 w vb 31.8
w b .sup.as = strong; m = medium; w = weak .sup.bb = broad, sh =
shoulder, vb = very broad (>1 degrees 2.theta. peak width)
[0033] In a sixth aspect, the present invention is directed to Form
XXV atorvastatin calcium characterized by the following x-ray
powder diffraction (XRPD) pattern expressed in terms of degree
2.theta. and relative intensities with a relative intensity of
>10% and relative peak width measured on a Shimadzu
diffractometer with CuK.sub.a radiation:
TABLE-US-00006 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 3.1 w b 5.2 w vb 6.4 w sh, b 7.4 s vb 7.9 w sh, vb
8.7 m vb 10.4 w vb 12.0 w vb 12.7 w vb 16.6 m vb 18.1 m vb 19.2 m
vb 20.0 m b 20.7 m b 22.8 m vb 23.2 m vb 24.4 m vb 25.6 w vb 26.5 w
vb 29.3 w vb .sup.as = strong; m = medium; w = weak .sup.bb =
broad, sh = shoulder, vb = very broad (>1 degrees 2.theta. peak
width)
[0034] In a seventh aspect, the present invention is directed to
Form XXVI atorvastatin calcium characterized by the following x-ray
powder diffraction (XRPD) pattern expressed in terms of degree
2.theta. and relative intensities with a relative intensity of
>10% and relative peak width measured on a Shimadzu
diffractometer with CuK.sub.a radiation:
TABLE-US-00007 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 3.7 w b 7.3 w b, sh 8.4 s b 9.0 s b 12.2 w b 16.0
w vb 17.1 m vb 17.7 m vb 18.7 m b 20.1 s b 20.7 m b, sh 22.3 m vb
23.0 m vb 25.2 m vb 28.7 w vb .sup.as = strong; m = medium; w =
weak .sup.bb = broad, sh = shoulder, vb = very broad (>1 degrees
2.theta. peak width)
[0035] In a eighth aspect, the present invention is directed to
Form XXVII atorvastatin calcium characterized by the following
x-ray powder diffraction (XRPD) pattern expressed in terms of
degree 2.theta. and relative intensities with a relative intensity
of >10% and relative peak width measured on a Shimadzu
diffractometer with CuK.sub.a radiation:
TABLE-US-00008 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 3.5 w b, sh 3.9 m b 4.6 w b 7.1 w vb, sh 7.5 s b
7.9 m vb, sh 9.6 m b 9.9 m b 10.6 w b 11.8 w b 13.0 w vb 15.3 w b
16.6 w vb 17.2 w vb 18.7 s b 22.6 w vb 23.8 w b 25.1 w b .sup.as =
strong; m = medium; w = weak .sup.bb = broad, sh = shoulder, vb =
very broad (>1 degrees 2.theta. peak width)
[0036] In a ninth aspect, the present invention is directed to Form
XXVIII atorvastatin calcium characterized by the following x-ray
powder diffraction (XRPD) pattern expressed in terms of degree
2.theta. and relative intensities with a relative intensity of
>10% and relative peak width measured on a Bruker diffractometer
with CuK.sub.a radiation:
TABLE-US-00009 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 7.6 s b 9.5 m b 12.2 w b 16.5 m b 17.0 m b 18.0 w
b 19.2 w b 19.5 w b, sh 20.5 m b 20.9 w b 21.5 w b 21.8 w b, sh
22.3 m vb 23.3 w b 23.8 w b .sup.as = strong; m = medium; w = weak
.sup.bb = broad, sh = shoulder, vb = very broad (>1 degrees
2.theta. peak width)
[0037] In a tenth aspect, the present invention is directed to Form
XXIX atorvastatin calcium characterized by the following x-ray
powder diffraction (XRPD) pattern expressed in terms of degree
2.theta. and relative intensities with a relative intensity of
>10% and relative peak width measured on a Bruker diffractometer
with CuK.sub.a radiation:
TABLE-US-00010 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 8.0 m b 10.2 w b 11.5 m b 14.5 w b 15.3 w b 16.2 m
vb 18.0 m b 19.6 m b 20.2 m b 20.6 w b 21.4 w b 22.3 m b 23.0 m b
23.9 w b 24.2 m b 24.9 s b 25.9 w vb 26.9 w b 28.6 w b 29.1 w b
30.4 w b 30.9 w b .sup.as = strong; m = medium; w = weak .sup.bb =
broad, sh = shoulder, vb = very broad (>1 degrees 2.theta. peak
width)
[0038] In an eleventh aspect, the present invention is directed to
Form XXX atorvastatin calcium characterized by the following x-ray
powder diffraction (XRPD) pattern expressed in terms of degree
2.theta. and relative intensities with a relative intensity of
>10% and relative peak width measured on a Shimadzu
diffractometer with CuK.sub.a radiation:
TABLE-US-00011 degree 2.theta. Relative Intensity.sup.a Relative
Peak Width.sup.b 3.1 s b 9.0 m b 9.7 w b 10.5 w b 12.0 w b 16.5 w b
17.0 m b 19.0 m b 19.3 w b, sh 19.9 w b 20.9 m b 21.1 w b 21.6 s b
22.5 m vb 24.3 m b 26.7 w b 27.0 w b 27.6 w b 29.6 w b 31.8 w b
.sup.as = strong; m = medium; w = weak .sup.bb = broad, sh =
shoulder, vb = very broad (>1 degrees 2.theta. peak width)
[0039] As inhibitors of HMG-CoA reductase, the novel forms of
atorvastatin calcium are useful as hypolipidemic and
hypocholesterolemic agents as well as agents in the treatment of
osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's
disease.
[0040] A still further embodiment of the present invention is a
pharmaceutical composition for administering an effective amount of
Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV, Form
XXVI, Form XXVII, Form XXVIII, Form XXIX, or Form XXX atorvastatin
calcium in unit dosage form in the treatment methods mentioned
above. Finally, the present invention is directed to methods for
production of Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV,
Form XXV, Form XXVI, Form XXVII, Form XXVIII, Form XXIX, or Form
XXX atorvastatin calcium.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] The invention is further described by the following
nonlimiting examples which refer to the accompanying Forms XX, XXI,
XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVII, XXIX, and XXX, short
particulars of which are given below.
[0042] FIG. 1 Diffractogram of Form XX atorvastatin calcium carried
out on a Shimadzu XRD-6000 diffractometer.
[0043] FIG. 2 Diffractogram of Form XXI atorvastatin calcium
carried out on a Shimadzu XRD-6000 diffractometer.
[0044] FIG. 3 Diffractogram of Form XXII atorvastatin calcium
carried out on a Shimadzu XRD-6000 diffractometer.
[0045] FIG. 4 Diffractogram of Form XXIII atorvastatin calcium
carried out on a Shimadzu XRD-6000 diffractometer.
[0046] FIG. 5 Diffractogram of Form XXIV atorvastatin calcium
carried out on a Shimadzu XRD-6000 diffractometer.
[0047] FIG. 6 Diffractogram of Form XXV atorvastatin calcium
carried out on a Shimadzu XRD-6000 diffractometer.
[0048] FIG. 7 Diffractogram of Form XXVI atorvastatin calcium
carried out on a Shimadzu XRD-6000 diffractometer.
[0049] FIG. 8 Diffractogram of Form XXVII atorvastatin calcium
carried out on a Shimadzu XRD-6000 diffractometer.
[0050] FIG. 9 Diffractogram of Form XXVIII atorvastatin calcium
carried out on a Bruker diffractometer.
[0051] FIG. 10 Diffractogram of Form XXIX atorvastatin calcium
carried out on a Bruker diffractometer.
[0052] FIG. 11 Diffractogram of Form XXX atorvastatin calcium
carried out on a Shimadzu XRD-6000 diffractometer.
[0053] FIG. 12 Small angle diffractogram of Form XX atorvastatin
calcium.
[0054] FIG. 13 Small angle diffractogram of Form XXII atorvastatin
calcium.
[0055] FIG. 14 Small angle diffractogram of Form XXIV atorvastatin
calcium.
[0056] FIG. 15 Small angle diffractogram of Form XXV atorvastatin
calcium.
[0057] FIG. 16 Small angle diffractogram of Form XXVII atorvastatin
calcium.
[0058] FIG. 17 Small angle diffractogram of Form XXX atorvastatin
calcium.
[0059] FIG. 18 Raman spectrum of Form XX atorvastatin calcium.
[0060] FIG. 19 Raman spectrum of Form XXII atorvastatin
calcium.
[0061] FIG. 20 Raman spectrum of Form XXIV atorvastatin
calcium.
[0062] FIG. 21 Raman spectrum of Form XXV atorvastatin calcium.
[0063] FIG. 22 Raman spectrum of Form XXVII atorvastatin
calcium.
[0064] FIG. 23 Raman spectrum of Form XXVIII atorvastatin
calcium.
[0065] FIG. 24 Solid state .sup.13C nuclear magnetic resonance
spectrum of Form XX atorvastatin calcium.
[0066] FIG. 25 Solid state .sup.13C nuclear magnetic resonance
spectrum of Form XXII atorvastatin calcium.
[0067] FIG. 26 Solid state .sup.13C nuclear magnetic resonance
spectrum of Form XXIV atorvastatin calcium.
[0068] FIG. 27 Solid state .sup.13C nuclear magnetic resonance
spectrum of Form XXV atorvastatin calcium.
[0069] FIG. 28 Solid state .sup.13C nuclear magnetic resonance
spectrum of Form XXVII atorvastatin calcium.
[0070] FIG. 29 Solid state .sup.13C nuclear magnetic resonance
spectrum of Form XXVIII atorvastatin calcium.
[0071] FIG. 30 Solid state .sup.13C nuclear magnetic resonance
spectrum of Form XXX atorvastatin calcium.
[0072] FIG. 31 Solid state .sup.19F nuclear magnetic resonance
spectrum of Form XX atorvastatin calcium.
[0073] FIG. 32 Solid state .sup.19F nuclear magnetic resonance
spectrum of Form XXII atorvastatin calcium.
[0074] FIG. 33 Solid state .sup.19F nuclear magnetic resonance
spectrum of Form XXIV atorvastatin calcium.
[0075] FIG. 34 Solid state .sup.19F nuclear magnetic resonance
spectrum of Form XXV atorvastatin calcium.
[0076] FIG. 35 Solid state .sup.19F nuclear magnetic resonance
spectrum of Form XXVII atorvastatin calcium.
[0077] FIG. 36 Solid state .sup.19F nuclear magnetic resonance
spectrum of Form XXVIII atorvastatin calcium.
[0078] FIG. 37 Solid state .sup.19F nuclear magnetic resonance
spectrum of Form XXX atorvastatin calcium.
DETAILED DESCRIPTION OF THE INVENTION
[0079] Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form
XXV, Form XXVI, Form XXVII, Form XXVIII, Form XXIX, or Form XXX
atorvastatin calcium may be characterized by x-ray powder
diffraction patterns, by itself solid stale nuclear magnetic
resonance spectra (NMR), and/or their Raman spectra.
[0080] The "forms" of atorvastatin calcium disclosed in the present
invention may exist as disordered crystals, liquid crystal, plastic
crystals, mesophases, and the like. Forms that are related through
disorder will have essentially the same major peak positions but
the disordering process will cause broadening of these peaks. For
many of the weaker peaks, the broadening may be so severe that they
are no longer visible above the background. The peak broadening
caused by disorder may in addition cause errors in the location of
the exact peak position.
X-ray Powder Diffraction
[0081] Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form
XXV, Form XXVI, Form XXVII, Form XXVIII, Form XXIX, or Form XXX
atorvastatin calcium may be characterized by X-ray powder
diffraction patterns. Thus, the X-ray powder distraction patters of
Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, and XXX were
carried out on a Shimadzu XRD-6000 X-ray diffractometer using
CuK.sub.a radiation. This instrument is equipped with a fine focus
X-ray tube. The tube voltage and amperage were set to 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. Diffraction
radiation was detected by a Nal scintillation detector. A theta-two
theta continuous scan at 3.degree. C./min (0.4 sec/0.0220 step)
from 2.5 to 40.degree. 2.theta. was used. A silicon standard was
analyzed each day to check the instrument alignment. Data were
collected and analyzed using XRD-6000 V. 4.1. Samples were prepared
for analysis by placing them in an aluminum holder.
[0082] The X-ray powder diffraction patterns of Forms XXVIII and
XXIX were carried out on a Bruker D5000 diffractometer using
CuK.sub.a radiation. The instrument was equipped with a fine focus
X-ray tube. The tube voltage and amperage were set to 40 kV and 40
mA, respectively. The divergence and scattering slits were set at 1
mm, and the receiving slit was set at 0.6 mm. Diffracted radiation
was detected by a Kevex PSI detector. A theta two theta continuous
scan at 2.4.degree./min (1 sec/0.4.degree. step) from 3.0 to
40.degree. 2.theta. was used. An alumina standard was analyzed to
check the instrument alignment. Data were collected and analyzed
using Bruker axs software Version 7.0. Samples were prepared for
analysis by placing them in a quartz holder. It should be noted
that Bruker Instruments purchased Siemens; thus, a Bruker D5000
instrument is essentially the same as a Siemens D5000.
[0083] To perform an X-ray diffraction measurement on a
Bragg-Brentano instrument like the Shimadzu system or the Bruker
system 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 a proper sample height. The sample holder is then
placed into the Shimadzu instrument. The incident X-ray beam is
directed at the sample, initially at a small angle relative to the
plane of the holder, and then 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) the nature of the material
(e.g. preferred orientation and transparency errors. Calibration
errors and sample height errors often result in a shift of all the
peaks in the same direction. Small differences in sample height
when using a flat holder will 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
difference of 1 mm lead 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. 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
measured peak positions from the Shimadzu or Bruker into agreement
with the expected peak positions and may be in the range of 0 to
0.2.degree.2.theta..
[0084] Tables 1-11 list peak positions in degrees 2.theta.,
relative intensities, and relative peak widths for X-ray powder
diffraction patterns of each form of atorvastatin calcium disclosed
in the present application. The relatively narrow peak positions
were picked by the Shimadzu software using default settings. X-ray
powder diffraction patterns were processed by the Shimadzu XRD-6000
version 2.6 software to automatically find peak positions The "peak
position" means the maximum intensity of a peaked intensity
profile. To maximize accuracy and precision, the entire intensity
profile is considered when selecting peak positions. Intensity
spikes from large crystals and the expected intensity fluctuations
from noise were considered in picking the position of a peak.
[0085] The following processes were used with the Shimadzu XRD-6000
"Basic Process" version 2.6 algorithm:
1. Smoothing was done on all patterns. [0086] 2. The background was
subtracted to find the net, relative intensity of the peaks. [0087]
3. A peak from CuK.sub.a alpha2 (1.5444 .ANG.) wavelength was
subtracted from the peak generated by CuK.sub.a alpha1 (1.5406
.ANG.) peak at 50% intensity for all patterns.
[0088] Default values of the software were used in picking the
peaks and all peak positions were rounded to 1/10.sup.th. Some of
the XRPD patterns displayed very diffuse and very noisy patterns
and the peak positions were determined manually, and expressed as a
range of degree 2 theta (from the beginning of the broad peak to
the end of the broad peak). All peak positions were rounded to
0.1.degree. 2.theta.. The following abbreviations are used to
describe the peak intensity (s=strong; m=medium; w=weak) and the
peal width (b=broad (where broad refers to peak widths of between
0.2 and 1.0 degrees 2.theta., sh=shoulder, vb=very broad (where
very broad refers to peaks with >1 degrees 2.theta. peak
width)).
TABLE-US-00012 TABLE 1 XPRD Peak List for Form XX degree 2.theta.
Relative Intensity.sup.a Relative Peak Width.sup.b 7.5-9.0 m vb
17.5-26.0 s vb .sup.as = strong; m = medium; w = weak .sup.bb =
broad; sh = shoulder; vb = very broad (>1 degrees 2.theta. peak
width)
TABLE-US-00013 TABLE 2 XPRD Peak List for Form XXI degree 2.theta.
Relative Intensity.sup.a Relative Peak Width.sup.b 3.1 w b 4.1 w b
5.0 w b 6.3 w b 7.6 s b 8.6 m b, sh 9.2 w b, sh 10.1 w b 12.2 w b
16.7 m vb 18.2 m vb 19.2 m vb 20.1 m vb 20.5 w vb 23.1 m vb, sh
29.6 w vb .sup.as = strong; m = medium; w = weak .sup.bb = broad;
sh = shoulder; vb = very broad (>1 degrees 2.theta. peak
width)
TABLE-US-00014 TABLE 3 XPRD Peak List for Form XXII degree 2.theta.
Relative Intensity.sup.a Relative Peak Width.sup.b 4.0 m b 4.9 w b
8.0 m b 10.0 s b 11.1 w b 11.7 w b 12.2 w b 13.1 w b, sh 13.5 m b
14.0 w b 14.8 w b, sh 16.1 m b 16.4 m b, sh 17.0 m b 17.4 m b, sh
17.7 m b, sh 19.2 w b 20.0 m b 20.3 m b 21.3 w b 22.6 w b 24.5 w vb
27.0 w b 28.1 w b 28.9 w vb 29.4 w vb .sup.as = strong; m = medium;
w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1
degrees 2.theta. peak width)
TABLE-US-00015 TABLE 4 XPRD Peak List for Form XXIII degree
2.theta. Relative Intensity.sup.a Relative Peak Width.sup.b 3.2 w b
4.1 w b 5.0 w b 6.3 w b 7.2 w b, sh 7.7 s b 8.1 m b 8.5 m b 9.1 w b
10.1 w b 10.5 w b 12.1 w b 12.8 w b 13.3 w b 16.7 m vb 18.4 m vb
19.1 m b 20.2 m vb 21.0 w b 21.4 m b 23.2 m vb 24.3 w b 25.2 w b
29.3 w b .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh
= shoulder; vb = very broad (>1 degrees 2.theta. peak width)
TABLE-US-00016 TABLE 5 XPRD Peak List for Form XXIV degree 2.theta.
Relative Intensity.sup.a Relative Peak Width.sup.b 2.9 m b 4.6 w b
5.2 w b 7.4 m b, sh 7.8 s b 8.7 m b 9.5 s b 10.0 w b 12.2 w vb 12.5
w b 13.4 w b 13.9 w b 17.3 w vb 18.0 m b 18.6 m b 19.0 m vb 20.6 w
b 21.2 w vb 22.3 w vb 22.7 s b 23.2 m b, sh 24.2 w b 24.5 w vb 25.0
w vb 26.4 w vb 28.8 w vb 31.8 w b .sup.as = strong; m = medium; w =
weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees
2.theta. peak width)
TABLE-US-00017 TABLE 6 XPRD Peak List for Form XXV degree 2.theta.
Relative Intensity.sup.a Relative Peak Width.sup.b 3.1 w b 5.2 w vb
6.4 w sh, b 7.4 s vb 7.9 w sh, vb 8.7 m vb 10.4 w vb 12.0 w vb 12.7
w vb 16.6 m vb 18.1 m vb 19.2 m vb 20.0 m b 20.7 m b 22.8 m vb 23.2
m vb 24.4 m vb 25.6 w vb 26.5 w vb 29.3 w vb .sup.as = strong; m =
medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad
(>1 degrees 2.theta. peak width)
TABLE-US-00018 TABLE 7 XPRD Peak List for Form XXVI degree 2.theta.
Relative Intensity.sup.a Relative Peak Width.sup.b 3.7 w b 7.3 w b,
sh 8.4 s b 9.0 s b 12.2 w b 16.0 w vb 17.1 m vb 17.7 m vb 18.7 m b
20.1 s b 20.7 m b, sh 22.3 m vb 23.0 m vb 25.2 m vb 28.7 w vb
.sup.as = strong; m = medium; w = weak .sup.bb = broad; sh =
shoulder; vb = very broad (>1 degrees 2.theta. peak width)
TABLE-US-00019 TABLE 8 XPRD Peak List for Form XXVII degree
2.theta. Relative Intensity.sup.a Relative Peak Width.sup.b 3.5 w
b, sh 3.9 m b 4.6 w b 7.1 w vb, sh 7.5 s b 7.9 m vb, sh 9.6 m b 9.9
m b 10.6 w b 11.8 w b 13.0 w vb 15.3 w b 16.6 w vb 17.2 w b 18.7 s
b 22.6 w vb 23.8 w b 25.1 w b .sup.as = strong; m = medium; w =
weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees
2.theta. peak width)
TABLE-US-00020 TABLE 9 XPRD Peak List for Form XXVIII degree
2.theta. Relative Intensity.sup.a Relative Peak Width.sup.b 7.6 s b
9.5 m b 12.2 w b 16.5 m b 17.0 m b 18.0 w b 19.2 w b 19.5 w b, sh
20.5 m b 20.9 w b 21.5 w b 21.8 w b, sh 22.3 m vb 23.3 w b 23.8 w b
.sup.as = strong; m = medium; w = weak .sup.bb = broad; sh =
shoulder; vb = very broad (>1 degrees 2.theta. peak width)
TABLE-US-00021 TABLE 10 XPRD Peak List for Form XXIX degree
2.theta. Relative Intensity.sup.a Relative Peak Width.sup.b 8.0 m b
10.2 w b 11.5 m b 14.5 w b 15.3 w b 16.2 m vb 18.0 m b 19.6 m b
20.2 m b 20.6 w b 21.4 w b 22.3 m b 23.0 m b 23.9 w b 24.2 m b 24.9
s b 25.9 w vb 26.9 w b 28.6 w b 29.1 w b 30.4 w b 30.9 w b .sup.as
= strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb =
very broad (>1 degrees 2.theta. peak width)
TABLE-US-00022 TABLE 11 XPRD Peak List for Form XXX degree 2.theta.
Relative Intensity.sup.a Relative Peak Width.sup.b 3.1 s b 9.0 m b
9.7 w b 10.5 w b 12.0 w b 16.5 w b 17.0 m b 19.0 m b 19.3 w b, sh
19.9 w b 20.9 m b 21.1 w b 21.6 s b 22.5 m vb 24.3 m b 26.7 w b
27.0 w b 27.6 w b 29.6 w b 31.8 w b .sup.as = strong; m = medium; w
= weak .sup.bb = broad; sh = shoulder; vb = very broad (>1
degrees 2.theta. peak width)
[0089] Table 12 lists combination of 2.theta. peaks for Forms XXI,
XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX
atorvastatin calcium, i.e., a set of x-ray diffraction lines that
are unique to each form.
TABLE-US-00023 TABLE 12 Forms XXI, XXII, XXIII, XXIV, XXV, XXVI,
XXVII, XXVIII, XXIX, and XXX. Form degree 2.theta. XXI 3.1 4.1 5.0
7.6 16.7 18.2 19.2 20.1 20.5 23.1 XXII 4.0 8.0 10.0 13.5 16.1 16.4
17.0 17.4 19.2 20.0 20.3 XXIII 4.1 5.0 6.3 7.7 8.5 9.1 10.5 16.7
18.4 20.2 21.4 XXIV 2.9 7.4 7.8 8.7 9.5 10.0 12.2 18.0 18.6 19.0
22.7 XXV 3.1 5.2 7.4 8.7 10.4 12.7 16.6 18.1 19.2 20.0 20.7 23.2
24.4 XXVI 3.7 8.4 9.0 17.1 17.7 18.7 20.1 22.3 23.0 XXVII 3.9 4.5
7.1 7.5 9.6 10.6 11.8 13.0 15.3 18.7 XXVIII 7.6 9.5 12.2 16.5 17.0
18.0 20.5 21.5 22.3 XXIX 8.0 10.2 11.5 14.5 15.3 18.0 19.6 20.2
22.3 24.9 XXX 3.1 9.0 9.7 12.0 16.5 17.0 20.9 21.6 22.5 24.3
[0090] Further, Table 13 lists additional combinations of 2.theta.
peaks for Forms XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII,
XXIX, and XXX atorvastatin calcium, i.e., an additional set of
x-ray diffraction lines that are unique to each form.
TABLE-US-00024 TABLE 13 Forms XX, XXI, XXII, XXIII, XXIV, XXV,
XXVI, XXVII, XXVIII, XXIX, and XXX Form Degree 2.theta. Form XXI
3.1 4.1 5.0 7.6 16.7 18.2 19.2 23.1 Form XXII 4.0 10.0 13.5 17.0
19.2 20.3 Form XXIII 4.1 5.0 6.3 7.7 8.5 9.1 10.5 16.7 21.4 Form
XXIV 2.9 7.4 7.8 8.7 9.5 12.2 18.6 19.0 22.7 Form XXV 3.1 5.2 7.4
8.7 23.2 24.4 Form XXVI 3.7 8.4 9.0 17.1 18.7 20.1 23.0 Form XXVII
3.9 4.5 7.5 9.6 10.6 13.0 15.3 18.7 Form XXVIII 7.6 9.5 12.2 16.5
17.0 18.0 21.5 22.3 Form XXX 9.0 9.7 12.0 16.5 17.0 21.6 22.5
24.3
Small Angle Powder X-Ray Diffraction
Methodology
[0091] Powder materials of different lots of atorvastatin calcium
were packed in either glass or quartz x-ray capillaries with
diameter of 1 to 2 mm. Small-Angle X-Ray Diffraction (SAXD)
experiments were performed at the beamline ID2. European
Synchrotron Radiation Facility (ESRF) Grenoble, France. The
radiation wavelength was 0.996 .ANG. (silicon channel-cut
monochromator). The 2-dimensional SAXD images were recorded using
image-intensified change coupled device (CCD) detector and the data
was expressed as reciprocal spacing q in nm.sup.-5 units. The
exposure time was adjusted to use the maximum dynamic of the
detectors for every particular sample and was less than 1s in the
majority of cases. The 2-dimensional images were normalized to an
absolute intensity scale after performing the standard detector
corrections and azimuthally integrated to obtain the corresponding
1-dimensional x-ray diffraction curves. Peaks positions were
measured using Gaussian fit using single peak analysis. The SAXD
and (wide angle x-ray diffraction) WAXD q-scales were calibrated
with silver behenate and silicon powders, respectively.
[0092] Table 14 shows the SAXRD peaks for Forms XX, XXII, XXIV,
XXV, XXVII and XXX atorvastatin calcium.
TABLE-US-00025 TABLE 14 SAXRD Data Form Position of peaks, q,
nm.sup.-1 XX 2.11 3.93 XXII 2.85 3.48 4.16 XXIV 2.09 2.24 2.84 3.33
3.54 3.69 4.50 5.23 XXV 2.22 2.86 3.62 4.46 5.28 XXVII 2.19 2.76
2.86 3.27 3.33 4.00 4.69 4.97 XXX 2.13 4.26
Raman Spectroscopy
Methodology
[0093] 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 6 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. Peak
tables were generated using the Nicolet software with default
threshold and sensitivity settings. The spectrometer was calibrated
(wavelength) with sulfur and cyclohexane at the time of use.
[0094] Table 15 shows the Raman spectra for Forms XX, XXII, XXIV,
XXV, XXVII and XXVIII atorvastatin calcium.
TABLE-US-00026 TABLE 15 Raman Peak Listing Peak Positions in
Wavenumbers (cm.sup.-1) Form cm.sup.-1 XX 618 818 855 892 999 1034
1158 1178 1244 1412 1480 1528 1558 1604 1649 3059 XXII 618 820 855
998 1033 1157 1243 1364 1410 1526 1603 1671 3059 XXIV 133 217 247
298 422 500 617 643 697 789 811 825 857 900 925 961 1000 1034 1056
1112 1160 1179 1240 1301 1370 1398 1413 1473 1527 1603 1651 2263
2555 2922 2972 3062 XXV 138 224 245 300 422 495 617 644 697 726 825
859 901 1001 1034 1058 1112 1159 1181 1243 1320 1368 1397 1412 1477
1528 1604 1654 2257 2933 3063 XXVII 130 288 366 512 581 618 634 736
821 858 898 998 1034 1112 1158 1240 1314 1368 1411 1481 1527 1559
1578 1604 1658 2927 3063 XXVIII 148 248 296 341 405 522 478 617 642
699 755 824 863 999 1034 1062 1090 1159 1180 1242 1298 1316 1369
1412 1468 1525 1603 1640 2882 2940 3060 3376
Solid State Nuclear Magnetic Resonance (NMR)
Methodology
[0095] Solid-state .sup.13C NMR and .sup.19F NMR spectra were
obtained at 293 K on 500 MHz NMR spectrometer. Approximately 80 mg
of sample were tightly packed into a 4 mm ZrO spinner for analysis.
The one-dimensional solid state spectra were collected at ambient
pressure and 293 K on a wide-bore Bruker-Biospin Avance DSX 500 MHz
NMR spectrometer using a Bruker 4 mm HFX BL cross-polarization
magic angle spinning (CPMAS) probe. To minimize the spinning side
bands, spinning speed was set to 15.0 kHz, the maximum specified
spinning speed for the 4 mm HFX BL probe. .sup.13C CPMAS and
.sup.19F MAS peaks were peak-picked using Bruker-Biospin TOPSPIN
1.3 software, by suitably setting the spectral window and the peak
picking threshold intensity to eliminate peak picking of spinning
side bands. The detection sensitivity parameter (PC) was typically
set to 0.5.
.sup.13C CPMAS
[0096] The one-dimensional .sup.13C spectra were collected using
.sup.1H-.sup.13C cross-polarization magic angle spinning (CPMAS).
To optimize the signal sensitivity, the cross-polarization contact
time was adjusted to 2.3 ms, and the decoupling power was set to 80
kHz. The carbon spectra were acquired with approximately 1,100
scans with a recycle delay of 8 seconds. They were referenced using
an external sample of adamantane, setting its upfield resonance to
29.5 ppm.
.sup.19F MAS
[0097] The one-dimensional .sup.19F spectra were collected using
magic angle spinning (MAS) with proton decoupling. The decoupling
field was set to approximately 65 kHz. .sup.19F detected .sup.1H T1
relaxation times were calculated based on inversion recovery
experiments. For all samples, the probe background was reduced by
subtracting signal from interleaved scans, during which a .sup.19F
presaturation pulse was applied. The spectra were acquired with
approximately 64 scans with a recycle delay of 10 seconds. The
samples were referenced using an external sample of trifluoroacetic
acid (diluted to 50% V/V by H.sub.2O), setting its resonance to
-76.54 ppm.
[0098] Table 16 shows the .sup.13C solid state NMR spectrum for
Forms XX, XXII, XXIV, XXV, XXVII, XXVIII, and XXX atorvastatin
calcium. Table 17 shows the .sup.19F solid state NMR spectrum for
Forms XX, XXII, XXIV, XXV, XXVII, XXVIII, and XXX atorvastatin
calcium.
TABLE-US-00027 TABLE 16 CPMAS .sup.13C Data Form Solid State
Chemical Shift.sup.a [ppm] XX 180.7 166.8 162.9 161.0 134.7 128.5
122.5 118.6 69.8 41.8 26.1 21.7 XXII 182.1 166.6 164.1 161.8 143.7
139.4 136.1 134.2 129.1 123.4 119.7 115.7 68.7 45.1 43.9 39.1 37.4
26.8 22.7 20.6 18.3 XXIV 187.5 185.2 184.2 180.5 179.0 178.4 177.4
166.8 162.7 160.9 138.7 138.2 133.7 128.7 124.4 122.4 121.2 120.5
118.0 115.7 69.8 67.4 65.7 46.4 44.3 43.5 40.6 26.7 25.5 21.8 19.6
0.0 XXV 186.3 185.0 182.5 177.0 167.0 166.2 162.8 160.9 138.6 136.1
133.4 129.2 128.5 126.0 124.0 121.5 120.7 118.0 116.8 116.0 69.9
68.0 46.4 43.3 40.9 25.7 25.2 21.3 20.0 0.6 XXVII 179.7 166.0 163.6
161.7 140.7 133.8 128.8 122.4 115.3 72.5 70.9 66.6 41.8 27.3 22.0
XXVIII 184.1 183.4 181.2 180.9 165.8 162.5 160.5 138.1 137.5 135.3
134.5 132.8 131.4 131.1 130.0 129.6 127.7 123.9 123.1 121.4 120.6
118.4 117.6 113.1 73.7 73.1 71.7 66.8 65.9 63.9 46.7 43.0 26.5 24.7
23.8 21.4 21.0 XXX 181.0 177.2 167.2 162.5 160.5 137.8 137.1 135.4
134.4 132.3 131.2 129.9 128.2 127.4 123.7 123.1 121.8 120.9 118.6
117.8 113.9 67.9 65.4 63.9 47.5 47.0 46.2 43.3 41.5 40.5 26.2 25.5
24.9 21.8 21.4 .sup.aReferenced using an external standard of
crystalline adamantane, setting its upfield resonance to 29.5
ppm.
TABLE-US-00028 TABLE 17 MAS .sup.19F Data Form Fluorine chemical
shift.sup.a [ppm] XX -113.9 XXII -112.0 -114.8 -118.9 XXIV -114.0
-116.8 -117.9 XXV -113.2 -116.3 -118.4 XXVII -112.2 -113.0 -117.2
XXVIII -116.4 -117.1 -119.2 XXX -116.7 -118.6 .sup.aReferenced
using an external standard of trifluoroacetic acid (diluted to 50%
V/V by H.sub.2O), setting its resonance to -76.54 ppm.
[0099] Additionally Forms XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII,
XXVIII, XXIX, and XXX atorvastatin calcium may be characterized by
an x-ray powder diffraction and a solid state .sup.19F nuclear
magnetic resonance spectrum. For example:
[0100] A Form XXII atorvastatin calcium having an x-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation; 10.0, 16.1, and 19.2, and a solid state
.sup.19F nuclear magnetic resonance having the following chemical
shifts expressed in parts per million: -112.0 -114.8, and
-118.9.
[0101] A Form XXIV atorvastatin calcium having an X-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation: 7.4, 9.5 and 12.2, and a solid state .sup.19F
nuclear magnetic resonance having the following chemical shifts
expressed in parts per million: -114.0, -116.8, and -117.9.
[0102] A Form XXV atorvastatin calcium having an x-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation: 7.4, 8.7, 19.2, and 20.0, and a solid state
.sup.19F nuclear magnetic resonance having the following chemical
shifts expressed in parts per million: -133.2, -116.3, and
-118.4.
[0103] A Form XXVII atorvastatin calcium having an x-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation 3.9, 7.5, and 18.7, and a solid state .sup.19F
nuclear magnetic resonance having the following chemical shifts
expressed in parts per million: -112.2, -113.0, and -117.2.
[0104] A Form XXVIII atorvastatin calcium having an x-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation: 7.6, 9.5, 20.5, and 22.3. and a solid state
.sup.19F nuclear magnetic resonance having the following chemical
shifts expressed in parts per million: -116.4, -117.1 and
-119.2.
[0105] A Form XXX atorvastatin calcium having an x-ray powder
diffraction containing the following 2.theta. values measured using
CuK.sub.a radiation: 3.1, 9.0, and 21.6, and a solid state .sup.19F
nuclear magnetic resonance having the following chemical shifts
expressed in parts per million: -116.7 and -118.6.
[0106] The forms of atorvastatin calcium described in the present
invention may exist in anhydrous forms as well as containing
various amounts of water and/or solvents. In general, these forms
are equivalent to the anhydrous forms and are intended to be
encompassed within the scope of the present invention.
[0107] The forms of atorvastatin calcium of the present invention,
regardless of the extent of water and/or solvent having equivalent
x-ray powder diffractograms are within the scope of the present
invention.
[0108] The new forms of atorvastatin calcium described in the
present application have advantageous properties.
[0109] The ability of a material to form good tablets at commercial
scale depends upon a variety of physical properties of the drug,
such as, for example, 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).
[0110] The present invention provides a process for the preparation
of Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII,
XXIX, and XXX atorvastatin calcium which comprises forming
atorvastatin calcium from a solution or slurry in solvents under
conditions which yield Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI,
XXVII, XXVIII, XXIX, and XXX atorvastatin calcium.
[0111] The precise conditions under which Forms XX, XXI, XXII,
XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin
calcium 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.
[0112] 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 trasdermally. It will be obvious to those skilled in
the art that the following dosage forms may comprise as the active
component a compound of the present invention.
[0113] For preparing pharmaceutical compositions for 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 encapsulation material.
[0114] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component.
[0115] 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.
[0116] The powders and tablets preferably contain from two or ten
to about seventy percent of the active compound. Suitable carriers
are magnesium carbonate, methylcellulose, sodium
carboxymethycellulose, 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.
[0117] 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 homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] The quantity of active component in a unit dosage
preparation may be varied or adjusted from 0.5 mg to 100 mg,
preferably 2.5 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.
[0124] In therapeutic use as hypolipidermic and/or
hypocholesterolemic agents and agents to treat BPH, osteoporosis,
and Alzheimer's disease, the Forms XX, XXI, XXII, XXIII, XXIV, XXV,
XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium 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.
[0125] The following nonlimiting examples illustrate the inventors'
preferred methods for preparing the compounds of the invention:
EXAMPLE 1
[0126]
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methyl-
ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic
acid hemi calcium salt (Forms XX, XXI, XXII, XXIII, XXIV, XXV,
XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium).
Form XX Atorvastatin Calcium
Method A
[0127] A 12.2 g sample of Form I atorvastatin calcium (U.S. Pat.
No. 5,969,156, which is herein incorporated by reference) was
suspended in 300 mL of methanol (MeOH): H.sub.2O (95:5, v:v) and
sonicated. The resulting suspension was filtered into a 1 L flask.
The sample was evaporated on a rotary evaporator with an unheated
water bath and the vacuum provided with an aspirator. The solid
obtained was dried under vacuum at ambient temperature overnight to
afford Form XX atorvastatin calcium.
Method B
[0128] A 24 mg sample of Form I atorvastatin calcium (U.S. Pat. No.
5,969,156) was dissolved in 7 mL of ethanol (EtOH):H.sub.2O (4:1,
v:v) and filtered through a 0.2 .mu.m nylon filter. The resulting
solution was evaporated in an open vial to dryness to afford Form
XX atorvastatin calcium.
Form XXI Atorvastatin Calcium
[0129] A 3.6 g sample of Form I atorvastatin calcium (U.S. Pat. No.
5,969,156) was dissolved in 10 mL of tetrahydrofuran;water (9:1,
v/v) at 43.degree. C. A 1-mL aliquot was filtered into a vial and
approximately 1 mL of pre-warmed acetonitrile (ACN) was added
drop-wise. The clear solution was placed in a refrigerator. Solids
formed within 1 day, recovered with vacuum filtration, and
air-dried at ambient temperature to afford Form XXI atorvastatin
calcium.
Method B
[0130] A 10.5 g sample of Form I (U.S. Pat. No. 5,969,156) was
slurried in 450 mL of isopropyl alcohol (IPA)/50 mL H.sub.2O (9:1)
at room temperature for 20 days. The sample was then vacuum
filtered. The sample was then slurried in 450 mL of ACN/50 mL
H.sub.2O (9:1) overnight. The sample was vacuum filtered for 5
hours to afford Form XXI atorvastatin calcium.
Form XXII Atorvastatin Calcium
[0131] An 11.5 g sample of Form XX atorvastatin calcium (prepared
as described above) was mixed with 29 mL of MeOH and stirred on an
a ambient temperature orbital shaker for 1 day. The sample was then
vacuum dried at ambient temperature for 1 day. The recovered solid
was mixed with 29 ml of MeOH and slurried on an ambient temperature
orbital shaker for less than 1 hour. The gel that formed was then
mixed with an additional 40 mL of MeOH and slurried on the ambient
temperature orbital shaker for 3 days. The solids were vacuum dried
at ambient temperature for 1 day to afford Form XXII atorvastatin
calcium.
Form XXIII Atorvastatin Calcium
Method A
[0132] A 1.5 g sample of Form I atorvastatin calcium (U.S. Pat. No.
5,969,156) was slurried with approximately 75 mL of ACN:water
(9:1,v/v) in a flask and placed on an ambient temperature orbital
shaker block for 1 day. The sample was divided into four portions
and centrifuged and the supernatant decanted and discarded. The
recovered solids were returned to the shaker block for 1 hour. The
samples were air dried for less than 1 day. The four portions were
recombined and the sample was further air-dried at ambient
conditions for 3 hours to afford Form XXIII atorvastatin
calcium.
Method B
[0133] A 11.0 g sample of Form I atorvastatin calcium (U.S. Pat.
No. 5,969,156) was slurried with approximately 430 mL of ACN:water
(9:1, v/v) on an ambient temperature magnetic stir plate at 500 rpm
for 2 days. The sample was vacuum filtered through a 0.22-.mu.m
nylon membrane filter and the filtered solids were air dried at
ambient conditions for 1 day to afford Form XXIII atorvastatin
calcium.
Form XXIV Atorvastatin Calcium
[0134] A 1.0 g sample containing a mixture of amorphous
atorvastatin calcium (U.S. Pat. No. 6,087,511, which is herein
incorporated by reference) and Form XX atorvastatin calcium
(prepared as described above) was slurried with 195 mL of ACN:water
(9:1, v/v) in a flask and placed on a magnetic stir plate set at
55% and 500 rpm for 1 day. The sample was vacuum filtered using a
0.22-.mu.m nylon membrane filter and the solids were slurried with
195 mL of the fresh solvent at the same conditions for 1 day.
Again, the sample was vacuum filtered using 0.22-.mu.m nylon
membrane filter and the solids were slurried with 195 mL of the
fresh solvent at the same conditions for 1 day. The solids were
isolated by vacuum filtration and were air dried in petri dish at
ambient conditions for 4 days to afford Form XXIV atorvastatin
calcium.
Form XXV Atorvastatin Calcium
[0135] A 58 mg sample of Form XX atorvastatin calcium (prepared as
described above) was slurried in 2 mL of ACN:water (9:1) on a
magnetic stir plate for 5 days and then filtered to afford Form XXV
atorvastatin calcium.
Form XXVI Atorvastatin Calcium
Method A
[0136] A 2.0 g sample of Form I atorvastatin calcium (U.S. Pat. No.
5,969,156) was slurried with 0.57 mL at water in a vial, 5.1 mL of
MeOH added, and the sample was placed on an orbital shaker block at
58 to 60.degree. C. for 3 days. The resulting sample was vacuum
dried between 70-75.degree. C. for 3 days to afford Form XXVI
atorvastatin calcium.
Method B
[0137] A 5.0 g sample of Form I atorvastatin calcium (U.S. Pat. No.
5,969,156) was dissolved in 200 mL of 80:20 (v/v) water/MeOH at
60.degree. C. After forming a solution, a slurry resumed while
stirring at 60.degree. C. The slurry was isolated via vacuum
filtration after 2.5 hours. The material was vacuum dried at
45.degree. C. overnight to afford Form XXVI atorvastatin
calcium.
Form XXVII Atorvastatin Calcium
Method A
[0138] A sample of Form VIII atorvastatin calcium (U.S. Pat. No.
6,605,729) which is herein incorporated by reference) was heatad on
a sample holder in a Variable Temperature X-ray powder diffraction
unit at 5.degree. C./minute ramp rate. The temperature was held at
35.degree., 80.degree., 100.degree., 115.degree., and 140.degree.
C. for approximately 15 minutes. before reaching 165.degree. C. to
afford Form XXVII atorvastatin calcium. The Form XXVII atorvastatin
calcium remained unchanged upon cooling to 40.degree. C.
Method B
[0139] A sample of Form VIII atorvastatin calcium (U.S. Pat. No.
6,605,729) was heated using a variable temperature XRPD with
humidity conditions remaining uncontrolled throughout the
experiment. The sample was heated in a series of 4 steps beginning
at 35.degree. C., it continued up to 135.degree. C. (holding for
13.5 min) and then on to 148.degree. C. (holding for 15.5 min)
before returning to 35.degree. C. (holding for 15.5 min) to afford
Form XXVII atorvastatin calcium. Form XXVII atorvastatin calcium
was obtained at 148.degree. C. and remained unchanged upon cooling
to 35.degree. C.
Form XXVIII Atorvastatin Calcium
[0140] A 0.3 g sample of amorphous atorvastatin calcium (U.S. Pat.
No. 6,087,151) was slurried with 1 mL of ethylene glycol at
50.degree. C. for 24 hours. The solids were isolates by vacuum
filtration at ambient conditions to afford Form XXVIII atorvastatin
calcium.
Form XXIX Atorvastatin Calcium
[0141] A 1.0 g sample of amorphous atorvastatin calcium (U.S. Pat.
No. 6,087,151) was slurried with 8 mL of water tetrahydrofuran
(4:1, v/v) at ambient temperature. The mixture was seeded with
atorvastatin calcium Form XII (U.S. Pat. No. 6,605,729) and stirred
at ambient conditions for 5 hours. The solids were isolated by
vacuum filtration to afford Form XXIX atorvastatin calcium.
Form XXVIII Atorvastatin Calcium
Method A
[0142] A slurry containing 0.3 g of amorphous atorvastatin calcium
(U.S. Pat. No. 6,087,151) and 24 mL of ethylene glycol was shaken
on an ambient temperature orbital shaker block for about 1 day. The
slurry was vacuum filtered and the solids were air dried at ambient
temperature for 6 days to afford Form XXX atorvastatin calcium.
Method B
[0143] A 200 mg sample of Form I atorvastatin calcium (U.S. Pat.
No. 5,969,156) was exposed to ACN vapor at ambient temperature
inside a sealed chamber for two months to afford Form XXX
atorvastatin calcium.
* * * * *