Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL CRYSTAL FORMS OF ATORVASTATIN HEMI-CALCIUM AND
PROCESSES FOR THEIR PREPARATION, AS WELL AS NOVEL PROCESSES
FOR PREPARING ATORVASTATIN HEMI-CALCIUM FORMS I, VIII AND IX
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit of U.S. provisional applications Serial
Numbers
60/357,181, filed February 15, 2002 and 60/425,325, filed November 12, 2002,
both of
which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to crystalline polymorphic forms of atorvastatin
hemi-
calcium and novel processes for preparing crystalline forms of atorvastatin
hemi-calcium.
BACKGROUND OF THE INVENTION
Atorvastatin, ([R-(R*,R*)]-2-(4-fluorophenyl)-~3,8-dihydroxy-5-(1-methylethyl)-
3-
phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid), depicted in
lactone form
in formula (>] and its calcium salt of formula (I>] are well lmown in the art,
and described,
ihte~ alia, in U.S. Patents Nos. 4,681,893, 5,273,995, and in copending USSN
60/166,153,
filed November 17, 2000, all of which are herein incorporated by reference.
O OH OH O
N ~ N O' .,+
(1) H Ca'
F
Processes for preparing atorvastatin and its hemi-calcium salt are also
disclosed in
U.S. Patent Application Publication No. 2002/0099224; U.S. Patents Nos.
5,273,995;
5,298,627; 5,003,080; 5,097,045; 5,124,482; 5,149,837; 5,216,174; 5,245,047,
5,280,126;
Baumann, K.L. et al. Tet. Lett. 1992, 33, 2283-2284., which are hereby
incorporated by
reference in their entirety and in particular for their teachings related to
the preparation of
atorvastatin and atorvastatin hemi-calcium.
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Atorvastatin is a member of the class of drugs called statins. Statin drugs
are
currently the most therapeutically effective drugs available for reducing low
density
lipoprotein (LDL) particle concentration in the blood stream of patients at
risk for
cardiovascular disease. A high level of LDL in the bloodstream has been
linlced to the
formation of coronary lesions which obstruct the flow of blood and can rupture
and
promote thrombosis. Goodman and Gilman, The Pharmacological Basis of
Therapeutics
879 (9th ed. 1996). Reducing plasma LDL levels has been shown to reduce the
risk of
clinical events in patients with cardiovascular disease and patients who are
free of
cardiovascular disease but who have hypercholesterolemia. Scandinavian
Simvastatin
Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.
The mechanism of action of statin drugs has been elucidated in some detail.
They
interfere with the synthesis of cholesterol and other sterols in the liver by
competitively
inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme ("HMG-
CoA
reductase"). HMG-CoA reductase catalyzes the conversion HMG to mevalonate,
which is
the rate determining step in the biosynthesis of cholesterol, and so, its
inhibition leads to a
reduction in the concentration of cholesterol in the liver. Very low density
lipoprotein
(VLDL) is the biological vehicle for transporting cholesterol and
triglycerides from the
liver to peripheral cells. VLDL is catabolized in the peripheral cells which
releases fatty
acids which may be stored in adopcytes or oxidized by muscle. The VLDL is
converted to
intermediate density lipoprotein (IDL), which is either removed by an LDL
receptor, or is
converted to LDL. Decreased production of cholesterol leads to an increase in
the number
of LDL receptors and corresponding reduction in the production of LDL
particles by
metabolism of IDL.
Atorvastatin hemi-calcium salt trihydrate is marketed under the name LIPITOR
by
Warner-Lambert Co. Atorvastatin was first disclosed to the public and claimed
in U.S.
Patent No. 4,681,893. The hemi-calcium salt depicted in formula (II) is
disclosed in U.S.
Patent No. 5,273,995. The '995 patent teaches that the hemi-calcium salt is
obtained by
crystallization from a brine solution resulting from the transposition of the
sodium salt
with CaCl2 and further purified by recrystallization from a 5:3 mixture of
ethyl acetate and
hexane.
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The present invention provides new crystal forms of atorvastatin hemi-calcium
in
both solvated and hydrated states. The occurrence of different crystal forms
(polymorphism) is a property of some molecules and molecular complexes. A
single
molecule, like the atorvastatin in formula (I) or the salt complex of formula
(II), may give
rise to a variety of solids having distinct physical properties like melting
point, X-ray
diffraction pattern, infrared absorption fingerprint and NMR spectrum. The
differences in
the physical properties of polymorphs result from the orientation and
intermolecular
interactions of adjacent molecules (complexes) in the bulk solid. Accordingly,
polymorphs
are distinct solids sharing the same molecular formula yet having distinct
advantageous
and/or disadvantageous physical properties compared to other forms in the
polymorph
family. One of the most important physical properties of pharmaceutical
polymorphs is
their solubility in aqueous solution, particularly their solubility in the
gastric juices of a
patient. For example, where absorption through the gastrointestinal tract is
slow, it is often
desirable for a drug that is unstable to conditions in the patient's stomach
or intestine to
dissolve slowly so that it does not accumulate in a deleterious environment.
On the other
hand, where the effectiveness of a drug correlates with peak bloodstream
levels of the
drug, a property shared by statin drugs, and provided the drug is rapidly
absorbed by the GI
system, then a more rapidly dissolving form is likely to exhibit increased
effectiveness
over a comparable amount of a more slowly dissolving form.
Crystalline Forms I, II, III and IV of atorvastatin hemi-calcium are the
subjects of
U.S. Patents Nos. 5,959,156 and 6,121,461 assigned to Warner-Lambert and
crystalline
atorvastatin hemi-calcium Form V is disclosed in conunonly-owned International
Publication No. WO 01/36384 (PCT Application No. PCT/US00/31555). There is an
assertion in the '156 patent that Form I possesses more favorable filtration
and drying
characteristics than the known amorphous form of atorvastatin hemi-calcium.
According
to the '156 patent, Form I is characterized by powder X-ray diffraction
pattern having
peaks at 9.150, 9.470, 10.266, 10.560, 11.853, 12.195, 17.075, 19.485, 21.626,
21.960,
22.748, 23.335, 23.734, 24.438, 28.915 and 29.234 degrees two-theta.
Commonly owned, co-pending U.S. Patent Application No. 2002/0115709
discloses atorvastatin hemi-calcium Form VII, processes for preparing it and
pharmaceutical compositions containing it.
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Commonly owned co-pending U.S. Patent Application No. 200210183378 discloses
Forms VI, VIII, IX, X, XI and XII atorvastatin hemi-calcium, processes for
preparing them
and pharmaceutical compositions containing them.
According to the '378 publication, atorvastatin hemi-calcium Form VIII
produces a
powder X-ray diffraction pattern using conventional CuKa radiation having
peaks at 6.9,
9.3, 9.6, 16.3, 17.1, 19.2, 20.0, 21.6, 22.4, 23,9, 24.7, 25.6, and 26.50.2
degrees 20.
Additional peaks have been observed at 4.8, 5.2, 5.9, 7.0, 8.0, 9.3, 9.6,
10.4, 11.9, 16.3,
17.1(broad), 17.9, 18.6, 19.2, 20.0, 20.8, 21.1, 21.6, 22.4, 22.8, 23.9, 24.7,
25.6, 26.5,
29.0 0.2 degrees two-theta.
Synchrotron X-ray powder diffraction analysis was performed on Form VIII to
determine its crystal system and unit cell dimensions. Form VIII was found to
have a
monoclinic unit cell with lattice dimensions: a =18.55-18.71, b = 5.52-5.53 ~,
c = 31.0-
31.2 l~ and angle (3 between the a and c axes of 97.5-99.5 °.
Atorvastatin hemi-calcium Form VIII produces a cross-polarization, magic angle
spinning solid-state'3C NMR spectrum with resonances at the following chemical
shift
positions:: 17.8, 20.0, 24.8, 25.2, 26.1, 40.3, 40.8, 41.5, 43.4, 44.1, 46.1,
70.8, 73.3, 114.1,
116.0, 119.5, 120.1, 121.8, 122.8, 126.6, 128.8, 129.2, 134.2 , 135.1, 137.0,
138.3, 139.8,
159.8, 166.4, 178.8, 186.5 ppm. Form VIII is characterized by a solid-state'3C
nuclear
magnetic resonance having the following chemical shifts differences between
the lowest
ppm resonance and other resonances: 2.2, 7.0, 7.4, 8.3, 22.5, 23.0, 23.7,
25.6, 26.3, 28.3,
53.0, 55.5, 96.3, 98.2, 101.7, 102.3, 104.0, 105.0, 108.8, 111.0, 111.4,
116.4, 117.3, 119.2,
120.5, 122.0, 142.0, 148.6, 161.0 and 168.7.
Atorvastatin hemi-calcium Form VIII can exist as an ethanol solvate containing
up
to about 3 % ethanol by weight. Samples of atorvastatin hemi-calcium Form VIII
also can
contain up to 7% water as determined by Karl Fisher analysis.
The '378 application teaches that atorvastatin hemi-calcium Form VIII may be
obtained by slurrying atorvastatin hemi-calcium in a mixture of ethanol and
water at
elevated temperature, preferably about 78-80°C.
It also teaches that Form VIII may be obtained starting from Form V by
treating
Form V with a mixture of EtOH:H2O, preferably in the ratio of about 5:1 at an
elevated
temperature below reflux, preferably 78-80°C. An especially preferred
EtOH:HzO mixture
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for that process contains about 4 % by volume water in ethanol. During the
heating,
atorvastatin Form V gradually dissolves and at the point of 78-80°C
turbidity, with or
without seeding, is observed. At this point the suspension is immediately
cooled to room
temperature.
Yet further, the '378 publication teaches that Form VIII may be obtained by
treating atorvastatin hemi-calcium in EtOH, preferably absolute EtOH, at
elevated
temperature, preferably boiling EtOH. Under these conditions, the atorvastatin
dissolves
and reprecipitates. MeOH may be added at reflux. Added MeOH may adversely
affect the
yield, but may improve the chemical purity of the product. Starting materials
for preparing
Form VIII by this process can be crystalline forms of atorvastatin hemi-
calcium, preferably
Forms I and V and mixtures thereof or amorphous atorvastatin hemi-calcium. The
quantity of EtOH or mixture thereof with water is preferably in the range of
from about 10
to about 100 ml g 1, more preferably about 20 to about 80 ml g'.
Form VIII also may be prepared by suspending atorvastatin hemi-calcium in
certain
1-butanol/water and ethanol/water mixtures for a period of time sufficient to
cause the
conversion of the atorvastatin hemi-calcium to Form VIII. 1-Butanol/water
mixtures
should contain about 20% 1-butanol by volume at elevated temperature,
preferably at
reflux temperature.
According to the '378 publication, atorvastatin hemi-calcium Form IX produces
a
powder X-ray diffraction pattern using conventional CuKa radiation having
peaks at 4.7,
5.2, 5.7, 7.0, 7.9, 9.4, 10.2, 12.0, 17.0, 17.4, 18.2, 19.1, 19.9, 21.4, 22.5,
23.5, 24.8 (broad),
26.1, 28.7, 30.00.2 degrees two-theta. The crystal system and unit cell
dimension of
Form IX were determined using synchrotron X-ray powder diffraction analysis.
Fonn IX
has a monoclinic crystal lattice with lattice dimensions: a = 18.75-18.851, b
= 5.525-5.54
~, c= 30.9-31.151 and angle j3 between the a and c axes of 96.5-97.5 °.
Atorvastatin hemi-calcium Form IX produces a cross-polarization, magic angle
spinning solid-state'3C NMR spectrum with resonances at the following chemical
shift
positions: 18.0, 20.4, 24.9, 26.1, 40.4, 46.4, 71.0, 73.4, 114.3, 116.0,
119.5, 120.2, 121.7,
122.8, 126.7, 128.6, 129.4, 134.3, 135.1, 136.8, 138.3, 139.4, 159.9, 166.3,
178.4, 186.6
ppm. Form IX is characterized by a solid-state 13C nuclear resonance having
the following
chemical shifts differences between the lowest ppm resonance and other
resonances: 2.4,
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6.9, 8.1, 22.4, 28.4, 53.0, 55.4, 96.3, 98.0, 101.5, 102.2, 103.7, 104.8,
108.7, 110.6, 111.4,
116.3, 117.1, 118.8, 120.3, 121.4, 141.9, 148.3, 160.4, 168.6.
The '378 publication discloses that Form IX may be prepared by slurrying
atorvastatin hemi-calcium in butanol and isolating Form IX by, for example,
filtration or
decantation of the butanol, preferably by filtration. Preferred temperature
ranges for the
slurrying are from 78 °C to the reflux temperature of the solvent.
Recovery of atorvastatin
hemi-calcium salt from the slurry can be enhanced by addition of an anti-
solvent to the
slurry before isolating Form IX. Preferred anti-solvents include isopropanol
and ~r-hexane.
Starting materials for preparing Form IX by this process can be crystalline or
amorphous
atorvastatin hemi-calcium, preferably Forms I and V and mixtures thereof.
The '378 publication further teaches that Form IX may be prepared by
suspending
Form VIII in ethanol, preferably absolute ethanol, at room temperature for a
period of time
sufficient to convert form VIII to Form IX, which may range from a few hours
to 24 hours
and typically requires about 16 hours. Thereafter, Form IX is recovered from
the
suspension. Form IX also may be prepared by maintaining Form VIII under a
humid
atmosphere.
Yet further, the '378 patent teaches that Form IX also may be prepared by
suspending atorvastatin hemi-calcium Form V in mixtures of 1-butanol and
either ethanol
or water at reflux temperature for a period of time sufficient to convert Form
V into Form
IX and recovering Form IX from the suspension. Preferably the mixtures contain
about 50
volume percent of each component.
Although Form I remedies some of the deficiencies of the amorphous material in
terms of manufacturability, there remains a need for yet further improvement
in these
properties as well as improvements in other properties such as flowability,
vapor
impermeability and solubility. Further, the discovery of new crystalline
polymorphic
forms of a drug enlarges the repertoire of materials that a formulation
scientist has with
which to design a pharmaceutical dosage form of a drug with a targeted release
profile or
other desired characteristic.
BRIEF DESCRIPTION OF THE FIGURES
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Fig. 1 is a characteristic powder X-ray diffraction pattern of atorvastatin
hemi-
calcium Form IX obtained using a conventional X-ray generator with a copper
anode.
Fig. 2 is a characteristic powder X-ray diffraction pattern of atorvastatin
hemi-
calcium Form IXa obtained using a conventional X-ray generator with a copper
anode.
Fig. 3 is a characteristic powder X-ray diffraction pattern of atorvastatin
hemi-
calcium Form XIV obtained using a conventional X-ray generator with a copper
anode.
Fig. 4 is a characteristic powder X-ray diffraction pattern of atorvastatin
hemi-
calcium Form XVI obtained using a conventional X-ray generator with a copper
anode.
Fig. 5 is a characteristic powder X-ray diffraction pattern of atorvastatin
hemi-
calcium Forni XVII.
SUMMARY OF THE INVENTION
The present invention provides new solid crystalline forms of atorvastatin
hemi-
calcium, and solvates and hydrates thereof.
More particularly, the present invention provides novel solid crystalline
atorvastatin hemi-calcium characterized by a powder X-ray diffraction pattern
obtained
using conventional CuKa radiation having peaks at 9.3 and 9.5 X0.2 degrees two-
theta. In
addition, small peaks are observed at15.7, 20.5, 21.1, 22.8, 23.8, 24.0, 25.3,
26.4, 26.8,
27.2, 29.2, 31.60.2 degrees two-theta.
In another aspect, the present invention provides novel solid crystalline
atorvastatin
hemi-calcium characterized by a powder X-ray diffraction pattern obtained
using
conventional CuKa radiation having peaks at 7.6, 9.8, 16.5, 29.4 ~ 0.2 degrees
two-theta
and novel processes for its preparation.
In another aspect, the present invention provides a novel crystalline form of
atorvastatin hemi-calcium characterized by a powder X-ray diffraction pattern
obtained
using conventional CuI~a radiation having peaks at 16.5, 21.9, 29.5 ~ 0.2
degrees two-theta
and novel processes for its preparation.
In another aspect, the present invention provides a novel crystalline form of
atorvastatin hemi-calcium characterized by a powder X-ray diffraction pattern
obtained
using conventional CuKa radiation by typical X-Ray peaks at 7.8, 9.5, 10.2,
18.2, 19.1,
25.3, 26.2, 30.10.2 degrees two-theta and novel processes for its preparation.
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In another aspect, the present invention provides a novel process for
preparing
atorvastatin hemi-calcium Form VIII.
In another aspect, the present invention provides a novel process for
preparing
atorvastatin hemi-calcium Form IX.
In another aspect, the invention provides compositions and dosage forms
comprising the novel solid crystalline atorvastatin hemi-calcium and their
mixtures along
with a pharmaceutically acceptable carrier, as well as methods of treating
hyperlipidemia
with the new forms.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Some crystalline forms of atorvastatin hemi-calcium of the present invention
exist
in a solvated state and hydrated state. Hydrates have been analyzed by Karl-
Fisher and
thermogravimetric analysis.
Powder X-ray diffraction ("PXRD") analysis employing conventional CuKa
radiation was performed by methods known in the art using a SCINTAG powder X-
ray
diffractometer model X'TRA equipped with a solid-state detector. Copper
radiation of ~.
= 1.5418 A was used. Measurement range: 2-40 degrees 28. The sample was
introduced
using a round standard aluminum sample holder with round zero background
quartz plate
in the bottom. Powdered samples were gently ground and filled in the round
cavity of the
sample holder by pressing with a glass plate.
As previously discussed, commonly assigned, co-pending U.S. Patent Application
Publication No. 2002/0183378 teaches that atorvastatin hemi-calcium Form IX
can be
produced using mixtures of 1-butanol and either ethanol or water. It has now
been found
that suspending atorvastatin hemi-calcium Form V in mixtures of 1-butanol and
water,
wherein one or the other diluent is predominant in the mixture, will yield a
more highly
pure and crystalline atorvastatin hemi-calcium product. This product has been
denominated Form IXa. Atomastatin hemi-calcium Form IXa is characterized by
its
PXRD pattern (Fig. 2), which is similar in some respects to that of Form IX
described in
the '378 publication whose PXRD pattern is reproduced here as Fig. 1. However,
there are
differences between the two patterns. The most predominant difference is at
about 9.5
degrees two-theta. There, a single strong peak is observed in the PXRD pattern
of Form
8
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IX whereas two strong peaks are observed 9.3 and 9.5 degrees two-theta in the
Form IXa
pattern. In addition, there are small peaks at 15.7, 20.5, 21.1, 22.8, 23.8,
24.0, 25.3, 26.4,
26.8, 27.2, 29.2 and 31.60.2 degrees two-theta in the PXRD pattern of Form
IXa.
Atorvastatin hemi-calcium Form IXa is considered to be an especially
crystalline,
filterable and pure material having similar internal structure to Form IX,
hence the
designation Form IXa. Form IXa can be prepared by suspending atorvastatin hemi-
calcium Form V in mixtures of 1-butanol and water in which either the 1-
butanol or water
constitutes from about 85% to about 95%, more preferably about 90%, of the
mixture. The
suspension can be heated to accelerate conversion of Form V to Form IXa.
Sixteen hours
at about 85 °C is generally sufficient. Under these conditions, yields
as high as 95% can be
obtained and the impurity level of the material can be significantly reduced.
The impurity
content of the starting atorvastatin hemi-calcium can be reduced by about 50%
or more.
For example, Form IX can be obtained in about 0.7% chemical purity when
starting with
Form V of about 1.3% chemical purity. Chemical purity was measured by high
performance liquid chromatography ("HPLC"). HPLC was performed on a
Spherisorb~
S5, C8 column, 250x4.6 mm with gradient elution: Solvent A O.OSM I~H3P04
adjusted
to pH 5 with 1N KOH:acetonitrile: methanol:THF (62:26:8:4); Solvent B:
methanol. The
HPLC system was equipped with Waters' pumps and a UV detector set to detect at
254
mn.
Among the specific procedures that can be used, there may be mentioned the
following. Form V is suspended in a mixture of 90% 1-butanol and 10% water
(v/v). The
mixture is used in an amount of about 20 milliliters per gram of Form V. The
suspension
is refluxed at 90°C for about 16 hours, after which time Form V is
transformed into Form
IX, which is then be recovered from the suspension by conventional means, like
filtration.
According to another specific procedure, Form V is suspended in a mixture of
10%
1-butanol and 90% water (v/v). The mixture is used in an amount of about 20
milliliters
per gram of Form V. The suspension is refluxed for about 16 hours, after which
time
Form V is transformed into Form IX, which is then recovered by conventional
means.
The present invention further provides a novel polyrnorph of atorvastatin hemi-
calcium that has been denominated Form XIV. Atorvastatin hemi-calcium Form XIV
is
characterized by a powder X-ray diffraction pattern obtained using
conventional CuI~a
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radiation (FIG. 3) having peaks at 7.6, 9.8, 16.5, 18.1, 20.0, 20.4, 21.9,
22.4, 23.6, 29.4 ~
0.2 degrees two-theta. The most characteristic peaks are those at 7.6, 9.8,
16.5, 29.4 ~ 0.2
degrees two-theta.
In general terms, Form XIV can be obtained from a suspension of atorvastatin
hemi-calcium in water. According to U.S. Patent No. 5,969,156, atorvastatin
hemi-
calcium Form I precipitates when calcium acetate is added to a solution of
atorvastatin
sodium in water. It is also said that Form I can be prepared by suspending
amorphous
atorvastatin hemi-calcium in water. In the specific example provided, Example
1, a
mixture formed from atorvastatin sodium and calcium acetate in water was
seeded with
Form I shortly after addition of the calcium acetate solution and, thereafter,
Form I was
obtained.
We have found that suspending atorvastatin hemi-calcium in or precipitating
atorvastatin hemi-calcium from water does not invariably lead to the
production of Form I
as might be expected after studying the '156 patent. On the contrary, in our
hands,
suspensions of atorvastatin hemi-calcium in water yield a previously unknown
polymorph
that we have denominated Form XIV. Form XIV is readily distinguishable from
Form I
(which is also obtained by precipitation from water, but with seeding with
Form I' by the
peaks at 7.6, 16.5, 20.0 and 19.4 degrees two-theta, which peaks are absent
from the
PXRD pattern of Form I.
It should be noted that in Example 3, below, the suspension is not stirred or
seeded
with a crystal of Form I. Atorvastatin hemi-calcium Form XIV can be prepared
by
suspending atorvastatin hemi-calcium in water until a fine suspension forms
and then
allowing the suspension to stand undisturbed until the fine crystals transform
substantially
into white flakes. The flakes can be separated from the suspension by
conventional means,
like decanting or filtering (either with or without suction and they do not
clog the filter)
and washing the crystals. The crystals of the fine suspension are very small
giving the
suspension the appearance of an emulsion. The transformation from fine
suspension to
flakes is readily apparent from visual inspection of the suspension. Preferred
process
parameters are as follows. The preferred starting material is atorvastatin
hemi-calcium
Form V. The fine suspension typically forms over a period of from about 2 to
about 10
hours, on average about 5 hours. The fine suspension transforms into white
flakes over
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about one to about five days, with longer time periods being preferred for
more complete
conversion and a more easily filterable product. Other conditions which lead
to the
production of Form XIV may be discovered but presently the best method known
is by
suspending atorvastatin hemi-calcium in water that is not agitated and has not
been seeded
with a different polymorph of atorvastatin. Form XIV has been obtained in our
laboratory
without seeding of any kind.
Form XIV crystals can be transformed into another crystal form without contact
with solvent. This new form has been denominated Form XVI. Form XVI is
characterized
by a powder X-ray diffraction pattern obtained using conventional CuI~a
radiation (FIG. 4)
having peaks at 7.7, 9.9, 16.5, 17.7, 18.3, 20.0, 21.9, 29.5 ~ 0.2 degrees two-
theta. The
most characteristic peaks are at 16.5, 21.9, 29.5 ~ 0.2 degrees two-theta.
Form XVI may be produced by maintaining Form XIV at from about 20
° C to
about 50°C, preferably about 22°C or room temperature, and
preferably exposed to air.
Preferably, Form XIV is maintained under these conditions for about three
hours. Other
conditions under which Fonn XVI is formed may be empirically determined. It is
only
possible to give methods which have so far been found suitable for producing
it.
The present invention further provides a hydrated form of atorvastatin hemi-
calcium that has been denominated Form XVII. Fornn XVII has been isolated as
the
immediate product obtained by precipitation from wet ethanol. As taught by
U.S. Patent
Application Publication No. 2992/0183378 (alternatively, see International
Publication No.
WO 01/36384 of PCT application number PCT/US00/31555), Fonn VIII can be
prepared
from a dispersion of Form V in a mixture of 96% ethanol/water at a temperature
of about
70°C. By using this procedure in scales of at least 1 liter or more,
the precipitated
material, prior to being dried, is obtained in Form XVII.
Atorvastatin hemi-calcium Form XVII is characterized by a powder X-ray
diffraction pattern obtained using conventional CuI~ radiation by typical X-
Ray peaks at
19.1, 20.6, 21.4 and 23.60.2 degrees two-theta. Additional peaks are observed
at 7.8, 9.5,
10.2, 18.2, 19.1, 25.3, 26.2, 30.10.2 degrees two-theta. Form XVII is also
characterized
by the typical X-Ray powder diffraction pattern of FIG. 5. Form XVII is
distinguishable
from Form VIII (the material obtained by complete drying of material obtained
by
precipitation from 96% ethanol/4% water) by the peak pattern in the range of 9-
10, 18-25
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degrees two-theta. In particular, Form VIII exhibits two strong peaks at 19.2
and 20.00.2
degrees 28, while Form XVII has one strong peak at 19.10.2 degrees 2A, but no
comparably strong peak at 200.2 degrees 20.
Atorvastatin hemi-calcium Form XVII may be produced by suspending atorvastatin
hemi-calcium Form V in a mixture of 96% ethanol and 4% water (v/v) and heating
to
about 78-80°C, followed by cooling. Form XVII can be isolated
immediately after the
material starts to precipitate in the mixture at reflux temperature, or after
all the material is
precipitated, after the material is cooled down to room temperature, or after
all the solid is
isolated from the mother liquor (for instance by filtration). Although there
may be other
ways to obtain Form XVII, the best way presently known is to suspend
atorvastatin hemi-
calcium Form V in at least about 500 milliliters or more of a mixture of about
96% ethanol
and about 4% water (v/v) and refluxing the suspension, followed by cooling.
The solids
are then recovered by conventional means such as filtering or decanting as
Form XVII.
Additional experimental details are provided in Example 6. The volume of the
reactor
should be at least about 1 liter.
The present invention also provides novel processes for preparing known forms
of
atorvastatin hemi-calcium.
Atorvastatin hemi-calcium Form I may be produced by heating Form XIV to about
50° C or above, preferably about 65 °C. Preferably, Form X1V is
maintained at elevated
temperature for about 15 hours.
It will be appreciated from the foregoing disclosure that conventional drying
of
Form XVII transforms it into Form VIII. By conventional drying it is meant the
methods
of drying routinely used by those skilled in the art in the pharmaceutical
industry. Any
drying type of equipment conventionally used in the pharmaceutical industry is
suitable for
this purpose. A drying temperature in the range of about 40-70°C (in
temperature steps or
in one temperature only) is preferred. The amount of time required to convert
Form XVII
to Form VIII depends on the quantity of material employed. Vacuum may be
preferably
used to convert Form XVII to Form VIII by drying. Preparation of Form VIB also
may be
achieved by drying Form XVII at temperatures lower than 40 ° C, down to
room
temperature.
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It has been found that atorvastatin hemi-calcium Form IX can be prepared by
suspending Form V in a mixture of 50% 1-butanol and 50% of another organic
solvents)
like acetone, 2-propanol, tetrahydrofuran, 1-propanol and methyl t-butyl
ether. The
mixture is used in an amount of about 20 milliliters per gram of Form V. The
suspension
is heated to reflux temperature for about 16 hours, after which time Form V is
transformed
into Form IX, which can then be recovered from the suspension by conventional
means.
Atorvastatin hemi-calcium Forms IXa, XIV, XVI and XVII are useful for reducing
the plasma low density lipoprotein level of a patient suffering from or
susceptible to
hypercholesterolemia. For this purpose, it will typically be administered to
human patients
in a unit dose of from about 0.5 mg to about 100 mg. For most patients, a dose
of from
about 2.5 to about 80 mg per day, more particularly from about 2.5 to about 20
mg per day,
causes a lowering of the plasma low density lipoprotein level in human
patients. Whether
such lowering is sufficient or whether the dose or dose frequency should be
increased is a
determination that is within the skill level of appropriately trained medical
personnel.
A further aspect of the present invention is a pharmaceutical composition and
dosage form containing the novel forms of atorvastatin hemi-calcium.
The compositions of the invention include powders, granulates, aggregates and
other solid compositions comprising novel Forms IXa, XIV, XVI and XVII of
atorvastatin
hemi-calcium. In addition, Forms IXa, XIV, XVI and XVII solid compositions
that are
contemplated by the present invention may further include diluents, such as
cellulose-
derived materials like powdered cellulose, microcrystalline cellulose,
microfme cellulose,
methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other
substituted and
unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents
like calcium
carbonate and calcium diphosphate and other diluents known to the
pharmaceutical
industry. Yet other suitable diluents include waxes, sugars and sugar alcohols
like
mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin,
dextrin and
gelatin.
Further excipients that are within the contemplation of the present invention
include binders, such as acacia gum, pregelatinized starch, sodium alginate,
glucose and
other binders used in wet and dry granulation and direct compression tableting
processes.
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Excipients that also may be present in a solid composition of Fortes IXa, XIV,
XVI and
XVII atorvastatin hemi-calcium further include disintegrants like sodium
starch glycolate,
crospovidone, low-substituted hydroxypropyl cellulose and others. In addition,
excipients
may include tableting lubricants like magnesium and calcium stearate and
sodium stearyl
fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable
dyes and
glidants such as silicon dioxide.
The dosages include dosages suitable for oral, buccal, rectal, parenteral
(including
subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic
administration.
Although the most suitable route in any given case will depend on the nature
and severity
of the condition being treated, the most preferred route of the present
invention is oral. The
Dosages may be conveniently presented in unit dosage form and prepared by any
of the
methods well-known in the art of pharmacy.
Dosage forms include solid dosage forms, like tablets, powders, capsules,
suppositories, sachets, troches and losenges as well as liquid suspensions and
elixirs.
While the description is not intended to be limiting, the invention is also
not intended to
pertain to true solutions of atorvastatin hemi-calcium whereupon the
properties that
distinguish the solid forms of atorvastatin hemi-calcium are lost. However,
the use of the
novel forms to prepare such solutions (e.g. so as to deliver, in addition to
atorvastatin, a
solvate to said solution in a certain ratio with a solvate) is considered to
be within the
contemplation of the invention.
Capsule dosages, of course, will contain the solid composition within a
capsule
which may be made of gelatin or other conventional encapsulating material.
Tablets and
powders may be coated. Tablets and powders may be coated with an enteric
coating. The
enteric coated powder forms may have coatings comprising phthalic acid
cellulose acetate,
hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate,
carboxyrnethylethylcellulose, a copolymer of styrene and malefic acid, a
copolymer of
methacrylic acid and methyl methacrylate, and like materials, and if desired,
they may be
employed with suitable plasticizers and/or extending agents. A coated tablet
may have a
coating on the surface of the tablet or may be a tablet comprising a powder or
granules
with an enteric-coating.
Preferred unit dosages of the pharmaceutical compositions of this invention
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typically contain from 0.5 to 100 mg of the novel atorvastatin hemi-calcium
Forms IXa,
XIV, XVI and XVII or mixtures thereof with each other or other forms of
atorvastatin
hemi-calcium. More usually, the combined weight of the atorvastatin hemi-
calcium forms
of a unit dosage are from 2.5 mg. to 80 mg.
Having thus described the various aspects of the present invention, the
following
examples are provided to illustrate specific embodiments of the present
invention. They
are not intended to be limiting in any way.
EXAMPLES
(Preparation of Atorvastatin Hemi-Calcium Form IXa)
Example 1
Atomastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-
butanol (90m1) and water (lOml) at reflux temperature (85°C) for 16
hours. The mixture
was then cooled to room temperature and then to 0°C using an ice-bath.
The product was
isolated by filtration and dried at 65°C in a vacuum oven for 24 hours
to give 4.738 (95%)
of Atorvastatin hemi-calcium crystalline Fonn IXa.
Example 2
Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-
butanol (1 Oml) and water (90m1) at reflux temperature for 16 hours. The
mixture was then
cooled to room temperature and then to 0°C using an ice-bath. The
product was isolated by
filtration and dried at 65°C in a vacuum oven for 24 hours to give
atorvastatin hemi-
calcium crystalline Form IXa.
(Preparation of Atorvastatin Hemi-Calcium Form XIV)
Exarnzale 3
Atorvastatin hemi-calcium Form V (1 g) was introduced into a 500 ml beaker.
Water (240 ml) was added. The suspension was mixed for 5 hours. A fine
suspension
appeared. It was left standing undisturbed for three days. After three days
white flakes
formed in the suspension. The suspension was then filtered and analyzed by
X1ZD as is.
The resulting form is novel atorvastatin hemi-calcium Form XIV.
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(Preparation of Atorvastatin Hemi-Calcium Form XVI)
Example 4
A small aliquot of form XIV was exposed to the air at room temperature for
three
hours, and then analyzed by XRD. The resulting form is Form XVI.
(Preparation of Atorvastatin Hemi-Calcium Form XVII)
Example 5
Wet Atoravstatin hemi-calcium salt Form V (53 g) was added to a hot solution
(about 70°C) of ethanol (about 485 ml). The resulting quantity of water
in ethanol should
be about 4%. The mixture was refluxed for about 2 hours. The mixture was
cooled to
15-20 degrees. The solid was filtered, washed with ethanol 96%. The material
was then
analysed by X-Ray powder diffraction and found to contain Form XVII.
Conventional
drying (40-70) degrees produced atorvastatin hemi-calcium Form VIII.
Example 6
About 20 kg of Atorvastatin hemi-calcium Form V was added to a hot solution
(about 70 ° C) of ethanol (about 600 liters). The resulting quantity of
water in ethanol
should be about 4% , and it is adjusted according to the initial moisture
level of Form V.
The mixture was refluxed for about 2.5 hours. The mixture was cooled to 15-20
° C and
stirred at this temperature for at least 3 hours. The solid was filtered,
washed with 96%
ethanol. The material was then analyzed by powder X-Ray diffraction and found
to
contain form XVII. Conventional drying at 40-70°C produced atorvastatin
hemi-calcium
form VIII.
(Preparation of Atorvastatin Hemi-Calcium Form IX)
Example 7
Atorvastatin hemi-calcium salt Form V (1 g) in 1-BuOH (10m1) and EtOH (lOml)
was heated to reflux for 1 h. The mixture was then cooled to room temperature
and stirred
at this temperature for additional 16 hrs. Filtration and drying at 65
°C for 24 hrs gave
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0.988 (98%) of atorvastatin hemi-calcium Form IX.
Exa~le ~
Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-
butanol (SOml) and Acetone (SOml) at reflux temperature (71°C) for 17
hours. The mixture
was then cooled to room temperature and then to 0°C using an ice-bath.
The product was
isolated by filtration and dried at 65°C in a vacuum oven for 24 hours
to give 4.6g (93%)
of Atorvastatin hemi-calcium salt Form IX.
Exan~le 9
Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-
butanol (SOml) and 11'A (SOml) at reflux temperature (91.5°C) for 15
hours. The mixture
was then cooled to room temperature and then to 0°C using an ice-bath.
The product was
isolated by filtration and dried at 65°C in a vacuum oven for 24 hours
to give 4.7g (94%)
of Atorvastatin hemi-calcium salt Form IX.
Exa ale 10
Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-
butanol (SOml) and THF (SOmI) at reflux temperature (80°C) for 15
hours. The mixture
was then cooled to room temperature and then to 0°C using an ice-bath.
The product was
isolated by filtration and dried at 65°C in a vacuum oven for 24 hours
to give 2.4g (48%)
of Atorvastatin hemi-calcium salt Form IX.
Exassa~le 11
Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-
butanol (SOml) and 1-propanol (SOml) at reflux temperature (95°C) for
16 hours. The
mixture was then cooled to room temperature and then to 0°C using an
ice-bath. The
product was isolated by filtration and dried at 65°C in a vacuum oven
for 24 hours to give
4.8g (96%) of Atorvastatin hemi-calcium salt Form IX.
Example 12
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Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-
butanol (SOmI) and MTBE (50m1) at reflux temperature (73°C) for 16
hours. The mixture
was then cooled to room temperature and then to 0°C using an ice-bath.
The product was
isolated by filtration and dried at 65°C in a vacuum oven for 24 hours
to give 4.8g (97%)
of Atorvastatin hemi-calcium salt Form IX.
Having thus described the invention with reference to particular preferred
embodiments and illustrated it with examples, those in the art may appreciate
modifications to the invention as described and illustrated that do not depart
from the spirit
and scope of the invention as defined by the claims which follow.
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