U.S. patent application number 11/977387 was filed with the patent office on 2008-09-04 for novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel process for preparing other forms.
Invention is credited to Judith Aronhime, Ramy Lidor-Hadas, Revital Lifshitz, Valerie Niddam, Shlomit Wizel.
Application Number | 20080214650 11/977387 |
Document ID | / |
Family ID | 27540285 |
Filed Date | 2008-09-04 |
United States Patent
Application |
20080214650 |
Kind Code |
A1 |
Aronhime; Judith ; et
al. |
September 4, 2008 |
Novel crystal forms of atorvastatin hemi-calcium and processes for
their preparation as well as novel process for preparing other
forms
Abstract
The present invention provides novel forms of atorvastatin
designated Forms VI, VIII, IX, X, XI and XII and novel processes
for their preparation as well as processes for preparing
atorvastatin Forms I, II, IV, V and amorphous atorvastatin.
Inventors: |
Aronhime; Judith; (Rehovot,
IL) ; Lidor-Hadas; Ramy; (Kfar Saba, IL) ;
Niddam; Valerie; (Even-Yeouda, IL) ; Lifshitz;
Revital; (Herzlia, IL) ; Wizel; Shlomit;
(Petah Tiqva, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
27540285 |
Appl. No.: |
11/977387 |
Filed: |
October 23, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11257808 |
Oct 24, 2005 |
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11977387 |
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10994142 |
Nov 19, 2004 |
7144916 |
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11257808 |
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09997126 |
Nov 29, 2001 |
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10994142 |
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60250072 |
Nov 30, 2000 |
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60267897 |
Feb 9, 2001 |
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60281872 |
Apr 5, 2001 |
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60312144 |
Aug 13, 2001 |
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60326529 |
Oct 1, 2001 |
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Current U.S.
Class: |
514/423 ;
548/537 |
Current CPC
Class: |
A61K 9/282 20130101;
A61K 9/5021 20130101; C07D 405/06 20130101; A61P 9/00 20180101;
C07D 207/34 20130101; A61P 3/06 20180101 |
Class at
Publication: |
514/423 ;
548/537 |
International
Class: |
A61K 31/401 20060101
A61K031/401; C07D 207/34 20060101 C07D207/34 |
Claims
1. A process for preparing atorvastatin hemi-calcium Form XII
characterized by a powder X-ray diffraction pattern having peaks at
8.0, 8.4, 11.8, 18.2, and 19.0.+-.0.2 degrees 2.theta. comprising
the steps of: a) suspending
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester in ethanol, b) deprotecting the
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester by adding hydrochloric acid to the suspension, thereby
forming a solution of atorvastatin ester derivatives in ethanol, c)
adding calcium hydroxide to the solution, thereby forming a
solution of atorvastatin hemi-calcium in ethanol, d) optionally
removing any excess calcium hydroxide, and e) precipitating
atorvastatin hemi-calcium from the solution as Form XII
characterized by a powder X-ray diffraction pattern having peaks at
8.0, 8.4, 11.8, 18.2, 19.0.+-.0.2 degrees 2.theta..
2. A pharmaceutical composition comprising solid atorvastatin
hemi-calcium Form XII characterized by a powder X-ray diffraction
pattern having peaks at 8.0, 8.4, 11.8, 18.2, 19.0.+-.0.2 degrees
2.theta. and a pharmaceutically acceptable excipient.
3. A pharmaceutical dosage form comprising solid atorvastatin
hemi-calcium Form XII characterized by a powder X-ray diffraction
pattern having peaks at 8.0, 8.4, 11.8, 18.2, 19.0.+-.0.2 degrees
2.theta..
4. The pharmaceutical dosage form of claim 7 which contains 2.5 mg
to 80 mg of atorvastatin hemi-calcium Form XII characterized by a
powder X-ray diffraction pattern having peaks at 8.0, 8.4, 11.8,
18.2, 19.0.+-.0.2 degrees 2.theta..
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of application Ser. No.
11/257,808, filed Oct. 24, 2005, which is a divisional application
of application Ser. No. 10/994,142, now U.S. Pat. No. 7,144,916,
filed Nov. 19, 2004, which is a divisional application of
application Ser. No. 09/997,126, filed Nov. 29, 2001, and claims
the benefit of provisional application Ser. Nos. 60/250,072, filed
Nov. 30, 2000; 60/267,897, filed Feb. 9, 2001; 60/281,872, filed
Apr. 5, 2001; 60/312,144, filed Aug. 13, 2001 and 60/326,529, filed
Oct. 1, 2001, all of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to crystalline polymorphic
forms of atorvastatin hemi-calcium, novel processes for preparing
crystalline forms of atorvastatin hemi-calcium and crystalline
atorvastatin hemi-calcium with a small particle size
distribution
BACKGROUND OF THE INVENTION
[0003] Atorvastatin,
([R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl-
)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid),
depicted in lactone form in formula (I) and its calcium salt
trihydrate of formula (II) are well known in the art, and
described, inter alia, in U.S. Pat. Nos. 4,681,893, 5,273,995, and
in copending U.S. Ser. No. 60/166,153, filed Nov. 17, 2000, all of
which are herein incorporated by reference.
##STR00001##
[0004] 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 linked 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.
[0005] 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.
[0006] 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. Pat. No. 4,681,893. The
hemi-calcium salt depicted in formula (II) is disclosed in U.S.
Pat. 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 CaCl.sub.2 and
further purified by recrystallization from a 5:3 mixture of ethyl
acetate and hexane.
[0007] 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.
[0008] Crystalline Forms I, II, III and IV of atorvastatin
hemi-calcium are the subjects of U.S. Pat. Nos. 5,959,156 and
6,121,461 assigned to Warner-Lambert and crystalline atorvastatin
hemi-calcium Form V is disclosed in commonly-owned 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. 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
[0009] FIG. 1 is a characteristic powder X-ray diffraction pattern
of atorvastatin hemi-calcium Form VI obtained using a conventional
X-ray generator with a copper anode.
[0010] FIG. 2 is a characteristic powder X-ray diffraction pattern
of atorvastatin hemi-calcium Form VII obtained using a conventional
X-ray generator with a copper anode.
[0011] FIG. 3 is a characteristic powder X-ray diffraction pattern
of atorvastatin hemi-calcium Form VIII obtained using a
conventional X-ray generator with a copper anode.
[0012] FIG. 4 is a characteristic powder X-ray diffraction pattern
of atorvastatin hemi-calcium Form VIII obtained using a synchrotron
X-ray source.
[0013] FIG. 5 is a characteristic solid state .sup.13C NMR spectrum
of atorvastatin Form VIII.
[0014] FIG. 6 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.
[0015] FIG. 7 is a characteristic powder X-ray diffraction pattern
of atorvastatin hemi-calcium Form IX obtained using a synchrotron
X-ray source.
[0016] FIG. 8 is a characteristic solid state .sup.13C NMR spectrum
of atorvastatin Form IX.
[0017] FIG. 9 is a characteristic powder X-ray diffraction pattern
of atorvastatin hemi-calcium Form X obtained using a conventional
X-ray generator with a copper anode.
[0018] FIG. 10 is a characteristic powder X-ray diffraction pattern
of atorvastatin hemi-calcium Form X obtained using a synchrotron
X-ray source.
[0019] FIG. 11 is a characteristic solid state .sup.13C NMR
spectrum of atorvastatin hemi-calcium Form X.
[0020] FIG. 12 is a characteristic powder X-ray diffraction pattern
of atorvastatin hemi-calcium Form XI obtained using a conventional
X-ray generator with a copper anode.
[0021] FIG. 13 is an overlay of typical powder X-ray diffraction
patterns of atorvastatin hemi-calcium Form XII obtained using a
conventional X-ray generator with a copper anode.
SUMMARY OF THE INVENTION
[0022] The present invention provides new atorvastatin hemi-calcium
solvates and hydrates.
[0023] The present invention provides a novel crystalline form of
atorvastatin hemi-calcium denominated Form VI and novel processes
for its preparation.
[0024] In another aspect, the present invention provides a novel
crystalline form of atorvastatin hemi-calcium denominated Form VIII
and novel processes for its preparation.
[0025] In another aspect, the present invention provides a novel
crystalline form of atorvastatin hemi-calcium denominated Form IX
and novel processes for its preparation.
[0026] In another aspect, the present invention provides a novel
crystalline form of atorvastatin hemi-calcium denominated Form X
and novel processes for its preparation.
[0027] In another aspect, the present invention provides a novel
crystalline form of atorvastatin hemi-calcium denominated Form XI
and novel processes for its preparation.
[0028] In another aspect, the present invention provides a novel
crystalline form of atorvastatin hemi-calcium denominated Form XII
and novel processes for its preparation.
[0029] In another aspect, the present invention provides novel
processes for preparing atorvastatin hemi-calcium Form I.
[0030] In another aspect, the present invention provides novel
processes for preparing atorvastatin hemi-calcium Form II.
[0031] In another aspect, the present invention provides novel
processes for preparing atorvastatin hemi-calcium Form IV.
[0032] In another aspect, the present invention provides novel
processes for preparing atorvastatin hemi-calcium Form V.
[0033] In another aspect, the present invention provides novel
processes for preparing amorphous atorvastatin hemi-calcium
[0034] In another aspect, the invention provides compositions and
dosage forms comprising atorvastatin hemi-calcium Forms VI, VII,
VIII, IX, X, XI and their mixtures.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0035] 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.
[0036] Powder X-ray diffraction ("PXRD") analysis employing
conventional CuK.sub..alpha. 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
.lamda.=1.5418 .ANG. was used. Measurement range: 2-40 degrees
2.theta.. 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.
[0037] PXRD analysis using a synchrotron X-ray source was performed
at the National Synchrotron Light Source of the Brookhaven National
Laboratory (diffractometer station X3B1). Samples were loosely
packed into thin-walled glass capillaries. X-ray radiation was
approximately 1.15 .ANG.. Since the wavelength of incident light
does correspond to the wavelength most commonly used in
conventional PXRD analysis, X-ray peak positions in the diffraction
patterns obtained from the synchrotron source are expressed in
terms of d spacings, which are invariant with changes in wavelength
of the X-radiation used to produce the pattern. The scan width was
from 1 to 20 degrees 2.theta.. The resolution of the spectra is in
the range of 0.01 to 0.03 degrees full width at half maximum. The
positions of well resolved peaks are accurate to within 0.003 to
0.01 degrees.
[0038] The CP/MAS .sup.13C NMR measurements were made at 125.76 MHz
and were performed on a Bruker DMX-500 digital FT NMR spectrometer
equipped with a BL-4 CP/MAS probehead and a High Resolution/High
Performance .sup.1H preamplifier for solids: spin rate 5.0 kHz,
pulse sequence SELTICS, sample holder: Zirconia rotor 4 mm
diameter.
[0039] Atorvastatin hemi-calcium Form VI is characterized by a
powder X-ray diffraction pattern (FIG. 1) with peaks at 3.5, 5.1,
7.7, 8.2, 8.7, 10.0, 12.5, 13.8, 16.2, 17.2, 17.9 18.3, 19.5, 20.4,
20.9, 21.7, 22.4, 23.2, 24.3, 25.5.+-.0.2 degrees two-theta. The
most characteristic peak is observed at 19.5.+-.0.2 degrees
two-theta. The PXRD pattern of Form VI was taken using a Phylips
diffractometer similar to the SCINTAG instrumentation described
above.
[0040] Atorvastatin hemi-calcium Form VI may be obtained by
dissolving any other form of atorvastatin hemi-calcium, preferably
Form I, in acetone and then precipitating Form VI by addition of an
anti-solvent, preferably water.
[0041] Atorvastatin hemi-calcium Form VII is characterized by a
powder X-ray diffraction pattern (FIG. 2) having two broad peaks,
one in the range 18.5-21.8 and the other in the range of 21.8-25.0
degrees 2.theta., and other additional broad peaks at 4.7, 7.8,
9.3, 12.0, 17.1, 18.2.+-.0.2 degrees 2.theta.. Samples of Form VII
may contain up to 12% water.
[0042] Form VII is readily distinguished from known forms of
atorvastatin hemi-calcium by the broad peaks at 7.8 and 9.3.+-.0.2
degrees 2.theta.. For instance, Form I has peaks at 9.2, 9.5, 10.3,
10.6, 11.0 and 12.2 degrees 2.theta. according to the information
provided in U.S. Pat. No. 5,969,156. In this region, Form II has
two sharp peaks at 8.5 and 9.0 degrees 2.theta. and Form IV has one
strong peak at 8.0 degrees 2.theta.. The other broad peaks in the
region of 15-25 degrees 2.theta. distinguish Form VII from all
other forms. Forms I, III and IV all have sharp peaks in this
region.
[0043] Atorvastatin hemi-calcium Form VII may be prepared by
treating atorvastatin calcium Forms I or V with ethanol, preferably
absolute ethanol, at room temperature to reflux temperature for a
period of from about 1 h to about 24 h, preferably 2.5-16 h. If the
process is carried out in refluxing EtOH, the conversion is
complete in about 2.5 h. If the process is carried out at room
temperature a longer period is required.
[0044] Atorvastatin hemi-calcium Form VIII is characterized by a
powder X-ray diffraction pattern (FIG. 3) obtained using
conventional CuK.sub..alpha. radiation having peaks 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. The most characteristic peaks are 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 26.5.+-.0.2 degrees 2.theta.. Samples of atorvastatin
hemi-calcium Form VIII were found to contain up to 7% water by Karl
Fisher. Form VIII is readily distinguished from Forms I-IV by its
characteristic sharp peaks at 9.3 and 9.6 degrees 2.theta..
According to the information provided in U.S. Pat. No. 5,969,156,
Form I has one medium peak at 6.9 and sharp peaks at 9.2, 9.5,
10.3, 10.6, 11.0 and 12.2.+-.0.2 degrees 2.theta.. Form IV is said
to have two peaks at 8.0 and 9.7 degrees 2.theta.. Form II is said
to have in this region two sharp peaks at 8.5 and 9.0 degrees
2.theta.. Form III has in this region one strong sharp peak at 8.7
degrees 2.theta. according to the information provided in U.S. Pat.
No. 6,121,461. The features are not observed in the Form VIII PXRD
pattern. Further, there is in the PXRD pattern of Form VIII one
sharp, medium intensity peak at 7.0 which is well distinguished
from other peaks in the region. A comparison of the PXRD pattern of
Form VIII with the patterns of Forms I-IV reveals that this feature
of the Form VIII pattern is distinctive.
[0045] Other peaks in the Form VIII pattern that are unique to this
form are the two strong and sharp peaks at 19.2 and 20.0 degrees
2.theta.. In this region, Form I has sharp peaks at 21.6, 22.7,
23.3 and 23.7 degrees 2.theta. according to the information
provided in the 156 patent. Form IV is said to have peaks at 18.4
and 19.6 degrees 2.theta., while Form II has two main peaks at 17.0
and 20.5 and Form III has peaks at 17.7, 18.2, 18.9, 20.0 and
20.3.+-.0.2 degrees 2.theta..
[0046] Synchrotron X-ray powder diffraction analysis was performed
on Form VIII to determine its crystal system and unit cell
dimensions. Form VIII has a monoclinic unit cell with lattice
dimensions: a=18.55-18.7 .ANG., b=5.52-5.53 .ANG., c=31.0-31.2
.ANG. and angle .beta. between the a and c axes of
97.5-99.5.degree.. The unit cell parameters were determined using
the Le Bail method.
[0047] The diffractogram of FIG. 4 obtained using a synchrotron
X-ray source has many sharp well resolved peaks. The d-spacings of
some of the more prominent peaks are listed in Table 1, along with
the positions in units of two-theta that the peaks would have using
CuK.sub..alpha. radiation of 1.5418 .ANG..
TABLE-US-00001 TABLE 1 d (.ANG.) 2.theta..sup.a 30.81 2.87 18.46
4.79 16.96 5.21 15.39 5.74 14.90 5.93 12.78 6.92 11.05 8.00 9.58
9.23 9.22 9.59 7.42 11.93 6.15 14.40 5.43 16.32 4.62 19.21 4.44
20.00 3.98 22.34 .sup.aCalculated from d for CuK.sub..alpha.
radiation
[0048] Because of the natural variation between independent samples
and measurements, the peak positions may deviate from the reported
positions by as much as 0.5% of the d values. There may be larger
shifts if the material undergoes size reduction as
micronization.
[0049] Atorvastatin hemi-calcium Form VIII produced the solid-state
.sup.13C NMR spectrum shown in FIG. 5. Form VIII is characterized
by the following solid-state .sup.13C nuclear magnetic resonance
chemical shifts in ppm: 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. Form VIII is characterized by a
solid-state .sup.13C 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. The chemical shifts reported
for Form VIII are averaged from spectra taken of four samples of
Form VIII. Characteristic parts of the pattern are found at 24-26
ppm (aliphatic range), 119-140 ppm (aromatic range) and other
regions. The shift values are accurate to within .+-.0.1 ppm,
except for the carbonyl peak at 178.8 ppm which has a fluctuation
of .+-.0.4 ppm.
[0050] Atorvastatin hemi-calcium Form VIII can exist as an ethanol
solvate containing up to about 3% ethanol by weight.
[0051] The following methods have been found suitable for
generating Form VIII. This form may, however, also be accessible by
empirical development and by routine modification of these
procedures.
[0052] 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.degree. C.
The slurrying procedure may be incorporated into the last step of a
process for preparing atorvastatin hemi-calcium, which typically is
generation of the hemi-calcium salt from the atorvastatin free acid
or lactone by treatment with a source of calcium ion. In such a
combined procedure the salt is generated in a solvent system
comprising ethanol and water. Conveniently, after precipitation of
the atorvastatin hemi-calcium salt by an additional amount of
water, the salt may be slurried in the reaction mixture for a
period of several hours, preferably from about 6 to about 16 hours
to obtain atorvastatin hemi-calcium Form VIII.
[0053] Form VIII also may be obtained starting from Form V by
treating Form V with a mixture of EtOH:H.sub.2O, preferably in the
ratio of about 5:1 at an elevated temperature below reflux,
preferably 78-80.degree. C. An especially preferred EtOH:H.sub.2O
mixture contains about 4% by volume water in ethanol. During the
heating, atorvastatin Form V gradually dissolves and at the point
of 78-80.degree. C. turbidity, with or without seeding, is
observed. At this point the suspension is immediately cooled to
room temperature.
[0054] 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.
[0055] The quantity of EtOH or mixture thereof with water is
preferably in the range of from about 10 to about 100 ml g.sup.-1,
more preferably about 20 to about 80 ml g.sup.-1.
[0056] We have discovered that atorvastatin hemi-calcium that
contains greater than 0.1% des-fluoro atorvastatin hemi-calcium
and/or greater than 1% trans atorvastatin hemi-calcium may be
purified by suspending in a solution of about 96% ethanol and about
4% water at elevated temperature, preferably at reflux temperature.
Typically, atorvastatin hemi-calcium is recovered with less than
0.07% contamination with des-fluoro atorvastatin hemi-calcium and
less than 0.6% contamination with trans atorvastatin
hemi-calcium.
[0057] 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.
[0058] Atorvastatin hemi-calcium Form IX is characterized by a
powder X-ray diffraction pattern (FIG. 5) with 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, 30.0.+-.0.2 degrees
two-theta. The most characteristic peaks of Form IX are at 6.9,
17.0, 17.4, 18.2, 18.6, 19.1, 19.9, 21.4, 22.5 and 23.5.+-.0.2
degrees two-theta. Form IX may contain up to 7% water. Form IX also
can exist as a butanol solvate containing up to about 5%
butanol.
[0059] Form IX is readily distinguished by its characteristic sharp
peaks at 18.6, 19.1, 19.9, 21.4, 22.5, 23.5 degrees 2.theta.. For
comparison, Form I has sharp peaks at 21.6, 22.7, 23.3 and 23.7
degrees 2.theta., while Form IV has in this region sharp peaks at
18.4 and 19.6 degrees 2.theta. and Form II has two main peaks at
17.0 and 20.5 degrees 2.theta., according to information in the
'156 patent. Form III has in this region peaks at 17.7, 18.3, 18.9,
20.0 and 20.3 degrees 2.theta.. Also, there is in the PXRD pattern
of Form IX, as there is in the pattern of Form VIII, a sharp, well
distinguished medium intensity peak at 7.0 degrees 2.theta..
[0060] The crystal system and unit cell dimension of Form IX were
determined using synchrotron X-ray powder diffraction analysis.
Form IX has a monoclinic crystal lattice with lattice dimensions:
a=18.75-18.85 .ANG., b=5.525-5.54 .ANG., c=30.9-31.15 .ANG. and
angle .beta. between the a and c axes of 96.5-97.5.degree..
[0061] The d-spacings of some of the more prominent peaks in the
synchrotron X-ray powder diffractogram of FIG. 7 are listed in
Table 2, along with the positions in units of two-theta that the
peaks would have using CuK.sub..alpha. radiation.
TABLE-US-00002 TABLE 2 d (.ANG.) 2.theta..sup.a 30.86 2.86 18.67
4.73 16.91 5.23 15.17 5.83 12.66 6.98 11.20 7.89 9.50 9.31 9.28
9.53 8.63 10.25 7.69 11.51 7.38 11.99 6.51 13.60 5.45 16.26 5.26
16.86 5.20 17.05 5.12 17.32 4.87 18.22 4.76 18.64 4.63 19.17 4.47
19.86 4.14 21.46 4.08 21.78 3.78 23.54 3.73 23.86 3.62 24.59 3.58
24.87 .sup.aCalculated from for CuK.sub..alpha. radiation
[0062] Because of the natural variation between independent samples
and measurements, the peak positions may deviate from the reported
positions by as much as 0.5% of the d values. There may be larger
shifts if the material undergoes size reduction as
micronization.
[0063] Atorvastatin hemi-calcium Form IX produced the solid-state
.sup.13C NMR spectrum shown in FIG. 8. Form IX is characterized by
the following solid-state .sup.13C nuclear resonance chemical
shifts in ppm: 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. Form
IX is characterized by a solid-state .sup.13C nuclear resonance
having the following chemical shifts differences between the lowest
ppm resonance and other resonances: 2.4, 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. Characteristic parts of the pattern are found at 24-26 ppm
(aliphatic range), 119-140 ppm (aromatic range) and other regions.
The chemical shifts of Form IX are an average taken from spectra on
two samples of Form IX. The shift values are accurate to within
.+-.0.1 ppm.
[0064] Form IX may be prepared by the following processes though
this form may be accessed by empirical development and by routine
modification of these procedures.
[0065] Atorvastatin hemi-calcium 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.degree. 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
n-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.
[0066] 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.
[0067] 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.
[0068] Atorvastatin hemi-calcium Form X is characterized by a
powder X-ray diffraction pattern (FIG. 7) having peaks at 4.8, 5.3,
5.9, 9.6, 10.3, 11.5, 12.0, a double peak at 16.1 and 16.3, 16.9,
17.4, 18.2, 19.2, 19.4, 20.0, 20.8, 21.6, 22.0, 22.8, 23.6, 24.6,
25.0, 25.5, 26.2, 26.8, 27.4, 28.0, 30.3.+-.0.2 degrees 2.theta..
The most characteristic peaks are two peaks at 20.0 and 20.8.+-.0.2
degrees 2.theta. and other peaks at 19.1, 19.4, 22.8, 23.6, 25.0,
28.0, 30.3.+-.0.2 degrees 2.theta.. Form X contains up to 2%
ethanol and may contain up to 4% water.
[0069] Form X is distinguished from that of Form IV by having
characteristic peaks at 7.0, 19.9, 20.7, 24.1, 25.0, 28.0 and
30.3.+-.0.2 degrees 2.theta.. These features are clearly
distinguished from those appearing the corresponding regions of the
PXRD patterns of Forms I-IV which have been previously
described.
[0070] The crystal system and unit cell dimension of Form X were
determined using synchrotron X-ray powder diffraction analysis.
Form X has a monoclinic crystal lattice with lattice dimensions:
a=18.55-18.65 .ANG., b=5.52-5.53 .ANG., c=30.7-30.85 .ANG. and
angle .beta. between the a and c axes of 95.7-96.7.degree..
[0071] The d-spacings of some of the more prominent peaks in the
synchrotron X-ray powder diffractogram of FIG. 10 are listed in
Table 3, along with the positions in units of two-theta that the
peaks would have using CuK.sub..alpha. radiation.
TABLE-US-00003 TABLE 3 d (.ANG.) 2.theta..sup.a 30.63 2.88 18.49
4.78 16.66 5.30 15.12 5.85 12.49 7.08 11.19 7.90 10.20 8.67 9.38
9.43 9.24 9.57 9.13 9.69 8.58 10.31 7.64 11.58 7.36 12.02 7.26
12.19 6.81 13.00 6.50 13.62 6.16 14.38 5.91 14.99 5.24 16.92 5.19
17.08 5.06 17.53 4.86 18.25 4.74 18.72 4.65 19.09 4.61 19.25 4.56
19.47 4.12 21.57 4.10 21.95 3.93 22.62 3.90 22.80 3.77 23.60
.sup.aCalculated from for CuK.sub..alpha. radiation
[0072] Because of the natural variation between independent samples
and measurements, the peak positions may deviate from the reported
positions by as much as 0.5%. There may be larger shifts if the
material undergoes size reduction as micronization.
[0073] Atorvastatin hemi-calcium Form X produced the solid-state
.sup.13C NMR spectrum shown in FIG. 11. Form X is characterized by
the following solid-state .sup.13C nuclear resonance chemical
shifts in ppm: 17.7, 18.7, 19.6, 20.6, 24.9, 43.4, 63.1, 66.2,
67.5, 71.1, 115.9, 119.5, 122.4, 126.7, 128.9, 134.5, 138.0, 159.4,
166.2, 179.3, 181.1, 184.3, 186.1. Form X is characterized by a
solid-state .sup.13C nuclear magnetic resonance having the
following chemical shifts differences between the lowest ppm
resonance and other resonances: 1.0, 1.9, 2.9, 7.2, 25.7, 45.4,
48.5, 49.8, 53.4, 98.2, 101.8, 104.7, 109.0, 111.2, 116.8, 120.3,
141.7, 148.5, 161.6, 163.4, 166.6, 168.4. Characteristic parts of
the pattern are found at 24-26 ppm (aliphatic range), 119-140 ppm
(aromatic range) and other regions. The chemical shifts of Form X
are averaged from three spectra taken of three samples of Form X.
The values reported are within .+-.0.1 ppm, except for the carbonyl
peak at 179. 3 ppm that is accurate within .+-.0.4 ppm.
[0074] Atorvastatin hemi-calcium Form X may be prepared by treating
crystalline atorvastatin hemi-calcium, preferably Form V or Form I
or mixtures thereof, or amorphous atorvastatin hemi-calcium with a
mixture of ethanol and water, preferably in a ratio of about 5:1,
at elevated temperature, preferably at reflux temperature, for a
period of from about half an hour to a few hours, preferably about
1 h. The starting material may be added to the EtOH:water mixture
at room temperature, followed by gradual heating of the suspension
to reflux. Alternatively, the starting form of atorvastatin
hemi-calcium may be added to the refluxing solvent mixture. In
either case, the atorvastatin hemi-calcium should be observed to
dissolve in the mixture and then reprecipitate in Form X. The ratio
of atorvastatin hemi-calcium to the EtOH:water mixture preferably
ranges from about 1:16 to about 1:25 (g:ml), more preferably from
about 1:16 to about 1:21 (g:ml) and most preferably about 1:16
(g:ml). Form X may be collected by filtration shortly after cooling
to room temperature or the suspension may be stirred for an
addition period of from about 1 to about 20 hours, more preferably
from about 3 to about 16 hours, before collecting the Form X.
[0075] Atorvastatin hemi-calcium Form XI is characterized by a
powder X-ray diffraction pattern (FIG. 9) having peaks at 3.2, 3.7,
5.1, 6.3, 7.8, 8.6, 9.8, 11.2, 11.8, 12.4, 15.4, 18.7, 19.9, 20.5,
24.0.+-.0.2 degrees two-theta.
[0076] Form XI may be obtained by suspending atorvastatin
hemi-calcium Form V in methyl ethyl ketone ("MEK") at room
temperature for a period of time sufficient to cause the conversion
of Form V into Form XI.
[0077] Form XI also may be obtained by preparing a gel containing
atorvastatin hemi-calcium in isopropyl alcohol and then drying the
gel. The gel is best prepared by saturating isopropyl alcohol with
atorvastatin hemi-calcium at reflux temperature and then cooling to
room temperature. Extensive stirring at room temperature, as long
as or more than 20 h, may be required in order for the gel to form.
In the gel state, the solution is detectably more resistant to
stirring and does not pour smoothly. The gel remains flowable in
the sense that it can be stirred if sufficient force is applied and
would not tear under such force.
[0078] Atorvastatin hemi-calcium Form XII is characterized by a
powder X-ray diffraction pattern having peaks at 2.7, 8.0, 8.4,
11.8, 18.2, 19.0, 19.8, 20.7.+-.0.2 degrees two-theta, and a halo
that indicates the presence of amorphous material. Typical X-ray
powder diffraction patterns of atorvastatin hemi-calcium Form XII
are shown in FIG. 10.
[0079] Form XII may be prepared directly from the following
compound
##STR00002##
whose systematic chemical name is
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.gamma.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester, and which will hereafter be referred to as pyrrole acetonide
ester or PAE. Form XII is prepared by first subjecting PAE to
conditions that cleave the acetonide and tert-butyl ester group.
Preferred conditions employ aqueous hydrochloric acid, more
preferably about 1.5% aqueous hydrochloric acid. The solution of
atorvastatin, in either free acid or lactone form, or mixture
thereof, is then treated with calcium hydroxide, preferably a
modest excess thereof, more preferably about 1.5 equivalents with
respect to the PAE. After association of the atorvastatin with
dissolved calcium derived from the added hydroxide salt, any excess
calcium hydroxide may be separated by filtration. One important
feature of this process is the subsequent manipulation of the
filtrate. Water is slowly added to the reaction mixture at mildly
elevated temperature, preferably about 65.degree. C., until
atorvastatin hemi-calcium precipitates. At that point the
temperature is increased until a clear solution is once again
attained. The mixture is then allowed to cool resulting in the
precipitation of atorvastatin hemi-calcium. The isolated
precipitate is atorvastatin hemi-calcium Form XII.
[0080] The present invention also provides novel processes for
preparing known forms of atorvastatin hemi-calcium.
[0081] Form I may be obtained by treating any form of atorvastatin
hemi-calcium with water at room temperature to 100.degree. C. for a
period between a few to about 25 hours, preferably about 16 hours.
Preferred starting materials are Forms V, VII, VIII, IX and X of
atorvastatin hemi-calcium.
[0082] Form I also may be prepared by sonicating a suspension of
atorvastatin hemi-calcium in ethanol, preferably absolute ethanol
or in water, at between room temperature and the reflux temperature
of the solvent for a period of a few minutes. Preferably between 1
and 3 minutes. Atorvastatin hemi-calcium Form VII is a preferred
starting material though other forms may be used as well.
[0083] Form II may be prepared directly from
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester (PAE) according to Example 31.
[0084] Atorvastatin hemi-calcium Form IV may be prepared by
suspending Form I or Form V in 1-butanol for a period of time
sufficient to complete the conversion of Form I or Form V to Form
IV and then isolating Form IV from the mixture. The conversion may
require a prolonged period depending on temperature and other
conditions. The conversion typically takes about 24-72 hours at
room temperature.
[0085] Form IV also may be obtained by suspending Form V in
EtOH/H.sub.2O at 50.degree. C. for a period of time sufficient to
cause the conversion of Form V to Form IV and then recovering Form
IV from the suspensions. Preferred EtOH/H.sub.2O mixtures contain
about 15% H.sub.2O.
[0086] Form IV also may be obtained by suspending atorvastatin
hemi-calcium Form V in methanol for a period of time sufficient to
cause the conversion of Form V to Form IV. The rate of conversion
is sensitive to temperature and may take from about 1 to about 25
hours under typical laboratory conditions. The conversion requires
about 16 hours, at room temperature. The conversion may be
conducted at elevated temperature up to the reflux temperature of
the solvent.
[0087] Form V may be prepared from PAE according to the process
described with reference to the preparation of atorvastatin
hemi-calcium Form XII. Form V may be obtained by drying Form XII at
about 65.degree. C. for about 24 hours. The atorvastatin
hemi-calcium Form V obtained in this manner is of high purity.
However, it may be further purified by suspending in a mixture of
about 10% water and about 90% ethanol and recovering form V from
the mixture in greater purity.
[0088] Amorphous atorvastatin hemi-calcium may be prepared by
treating any other form of atorvastatin hemi-calcium with acetone
at room temperature to reflux temperature for between a few hours
and 25 hours, preferably about 16 hours. A preferred starting
material is Form V.
[0089] Amorphous atorvastatin hemi-calcium also may be prepared by
sonicating any form of atorvastatin hemi-calcium in acetonitrile at
any temperature between room temperature and the reflux temperature
of acetonitrile. Sonicating for a few minutes, preferably from 1 to
3 minutes, is sufficient to transform the starting material into
amorphous atorvastatin hemi-calcium. Preferred starting forms of
atorvastatin hemi-calcium are Forms VII and I.
[0090] Amorphous atorvastatin hemi-calcium also may be prepared by
ball milling of any crystalline form of atorvastatin
hemi-calcium.
[0091] A further aspect of the present invention is a
pharmaceutical composition and dosage form containing the novel
forms of atorvastatin hemi-calcium.
[0092] The compositions of the invention include powders,
granulates, aggregates and other solid compositions comprising
novel Forms VI, VII, VIII, IX, X, XI and XII of atorvastatin
hemi-calcium. In addition, Forms VI, VII, VIII, IX, X, XI and XII
solid compositions that are contemplated by the present invention
may further include diluents, such as cellulose-derived materials
like powdered cellulose, microcrystalline cellulose, microfine
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.
[0093] 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. Excipients that also may be present in a solid
composition of Forms VI, VII, VIII, IX, X, XI and XII 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.
[0094] 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.
[0095] 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.
[0096] 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,
carboxymethylethylcellulose, a copolymer of styrene and maleic
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.
[0097] Preferred unit dosages of the pharmaceutical compositions of
this invention typically contain from 0.5 to 100 mg of the novel
atorvastatin hemi-calcium Forms VI, VII, VIII, IX, X, XI and XII 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.
[0098] 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
General
[0099] Absolute ethanol containing less than 0.2% water was
purchased from Biolab.RTM.. Other reagents were reagent grade and
were used as received.
[0100] Ball milling was performed using a Retsch centrifugal
ball-mill S-100 equipped with a 250 ml stainless steal milling
chamber and twenty seven 10 mm diameter stainless steal balls as
milling media.
Preparation of Atorvastatin Hemi-Calcium Form VI
Example 1
[0101] Atorvastatin hemi-calcium Form I (1 g) was dissolved in
acetone (9 ml) at room temperature and stirred for 2.5 hours. Then,
water (8.5 ml) was added to get a precipitation and the mixture was
then stirred for another 2.5 hours. The white solid was then
filtered and dried at 50.degree. C. for 5 hrs to obtain
atorvastatin hemi-calcium Form VI (0.88 g, 88%).
Preparation of Atorvastatin Hemi-Calcium Form VII
Example 2
[0102] Atorvastatin hemi-calcium Form V (1.00 g) was stirred in
absolute EtOH (400 ml) at room temperature for 16 h. The solid was
collected by filtration and dried at 65.degree. C. for 24 h to give
atorvastatin hemi-calcium Form VII (40 mg, 40%).
Example 3
[0103] Atorvastatin hemi-calcium Form I (75 mg) was stirred in
absolute EtOH (30 ml) at room temperature for 16 h. The solid was
collected by filtration and dried at 65.degree. C. for 24 h to give
atorvastatin hemi-calcium Form VII (0.60 g, 80%).
Preparation of Atorvastatin Hemi-Calcium Form VIII
Example 4
[0104] To a flask equipped with a magnetic stirrer 1.0 g
(1.59.times.10.sup.-3 mole) of
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester were put in suspension in a 90% aqueous solution of acetic
acid (10 ml). The reaction mixture was heated to 50.degree. C. for
three hours and then stirred at room temperature until the reaction
was complete as determined by HPLC. The solvent was evaporated and
the traces of acetic acid were removed by azeotropic distillation
with toluene (3.times.100 ml) to obtain an oil with some toluene.
This oil was dissolved in EtOH (10 ml) and water (2 ml). Then 5.5
eq (8.4.times.10.sup.-3 mole, 622 mg) of Ca(OH).sub.2 and
tetrabutyl ammonium bromide (5%, 0.05 g) were added. The reaction
mixture was heated at 50.degree. C. for 5 hours until the reaction
was complete according to HPLC. Then a hot filtration was done
under vacuum to remove the excess of Ca(OH).sub.2. The reaction
mixture was then cooled to room temperature. To this solution water
(50 ml) was added while stirring. The white precipitate was stirred
at RT overnight, filtered under vacuum and dried at 65.degree. C.
for 18 hours to give 145 mg (16%) of atorvastatin hemi-calcium salt
Form VIII.
Example 5
[0105] Atorvastatin hemi-calcium Form I (1 g) was slurried in
absolute EtOH (80 ml), under reflux, for 24 hrs. The white solid
was then filtered and dried at 65.degree. C. for 20 hrs to obtain
atorvastatin hemi-calcium Form VIII (0.85 g, 85%).
Example 6
[0106] Atorvastatin hemi-calcium Form I (1 g) was poured in boiling
absolute EtOH (40 ml). The compound began first to get soluble and
then precipitate again. To this mixture was added MeOH (20 ml). The
white solid was then filtered and dried at 50.degree. C. for 20 hrs
in a vacuum oven to obtain atorvastatin hemi-calcium Form VIII (188
mg, 19%).
Example 7
[0107] A suspension of 1.0 g of Atorvastatin hemi-calcium salt Form
V in 1-Butanol (4 ml) and H.sub.2O (16 ml) was heated to reflux
temperature for 1 hr. The mixture was then cooled to room
temperature and stirred at this temperature for additional 16 hrs.
The solid was filtered and dried at 50.degree. C. in a vacuum oven
for 16 hrs to give 0.9 g (91%) of Atorvastatin hemi-calcium salt
Form VIII.
Example 8
[0108] 5.0 g of Atorvastatin hemi-calcium salt Form V were added to
a boiled solution of Ethanol 96% (150 ml). The mixture was refluxed
for 2.5 hrs. Then it was cooled to 20.degree. C. during 1.5 hrs,
and stirred at this temperature for additional 16 hrs. The solid
was filtered, washed with Ethanol 96% (2.times.25 ml) and dried at
65.degree. C. for 20 hrs to give 4.4 g (88%) of Atorvastatin
hemi-calcium salt Form VIII. During this process chemical
purification occurs, so this process is good also for
purification.
Example 9
[0109] 5.0 g of Atorvastatin hemi calcium salt Form V, with a level
of 0.12% of Des-fluoro Atorvastatin, were added to a boiled
solution of Ethanol 96% (150 ml). The mixture was refluxed for 2.5
hrs. Then it was cooled to 20.degree. C. during 1.5 hrs and stirred
at this temperature for additional 16 hrs. The solid was filtered,
washed with Ethanol 96% (2.times.25 ml) and dried at 65.degree. C.
for 20 hrs to give 4.4 g (88%) of Atorvastatin hemi calcium salt
with a level of 0.06% of Des-fluoro Atorvastatin. Atorvastatin is
obtained in Form VIII by this procedure.
Example 10
[0110] Atorvastatin hemi-calcium Form V (5 g) in absolute EtOH (35
ml) was refluxed for 2.5 h. The reaction mixture was then cooled to
room temperature and stirred for an additional 16 h. Absolute
ethanol (15 ml) was then added and the suspension was filtered and
the collected solids were dried at 65.degree. C. for 20 h to yield
atorvastatin hemi-calcium Form VIII (4.7 g, 94%).
Preparation of Atorvastatin Hemi-Calcium Form IX
Example 11
[0111] Atorvastatin hemi-calcium Form I (1 g) was slurried in
1-butanol (20 ml) under reflux for 30 minutes. The mixture was then
cooled to room temperature. The white solid was then filtered and
dried at 50.degree. C. under vacuum for 20 hrs to yield
atorvastatin hemi-calcium Form IX (0.94 g, 94%). KF=0.9.
Example 12
[0112] Atorvastatin hemi-calcium Form I (1 g) was slurried in
1-butanol (20 ml) under reflux for 30 minute. Then n-hexane (40 ml)
was added for further precipitation and the reaction mixture was
stirred at room temperature for 2 hours. The white solid was then
filtered and dried at 50.degree. C. in a vacuum oven for 20 hrs to
yield atorvastatin Form IX (0.96 g, 96%).
Example 13
[0113] Atorvastatin hemi-calcium Form I (1 g) was slurried in
1-butanol (20 ml) under reflux for 30 minute. Then, IPA (40 ml) was
added for further precipitation and the reaction mixture was
stirred at room temperature for 2 hours. The white solid was then
filtered and dried at 50.degree. C. for 20 hrs in a vacuum oven to
yield atorvastatin hemi-calcium Form IX (0.94 g, 94%) containing
0.9% water by Karl Fisher analysis.
Example 14
[0114] Atorvastatin hemi-calcium Form VIII (800 mg) was stirred in
absolute EtOH (320 ml) at room temperature for 16 h. The solid was
collected by filtration and dried at 65.degree. C. for 24 hours to
give atorvastatin hemi-calcium Form IX (630 mg, 79%).
Example 15
[0115] A mixture of atorvastatin hemi-calcium Form V (2.00 g) and
1-butanol (40 ml) was refluxed at 118.degree. C. for half an hour.
The mixture was then cooled to room temperature and stirred for an
additional 3 hours. The solid was then collected by filtration and
dried at 65.degree. C. for 24 hours to give atorvastatin
hemi-calcium Form IX (1.83 g, 92%).
Example 16
[0116] Atorvastatin hemi-calcium Form VIII was stored under 100%
relative humidity at room temperature for nine days. The resulting
solid was identified as Form IX by powder X-ray diffraction
analysis.
Example 17
[0117] 1 g of Atorvastatin hemi-calcium salt form V in 1-BuOH (10
ml) and H.sub.2O (10 ml) 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.degree. C. for
24 hrs gave 0.79 g (79%) of Atorvastatin hemi-calcium salt form
IX.
Example 18
[0118] 1 g of Atorvastatin hemi-calcium salt form V in 1-BuOH (10
ml) and EtOH (10 ml) 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.degree. C. for 24
hrs gave 0.98 g (98%) of Atorvastatin. hemi-calcium salt form
IX.
Preparation of Atorvastatin Hemi-Calcium Form X
Example 19
[0119] Atorvastatin hemi-calcium Form V (10.00 g) was suspended in
a mixture of EtOH (135 ml) and water (24 ml) and heated to reflux
for 1 h. The mixture was then cooled to room temperature and
stirred for an addition 16 h. The solid was collected by filtration
and dried at 65.degree. C. for 24 h to give atorvastatin
hemi-calcium Form X (8.26 g, 83%).
Example 20
[0120] Atorvastatin hemi-calcium Form V (1.00 g) in a mixture of
EtOH (9 ml) and water (1.6 ml) was refluxed for 1 h. The mixture
was cooled to room temperature and then stirred an additional 3 h.
The solid was collected by filtration and dried at 65.degree. C.
for 24 h to give atorvastatin hemi-calcium Form X (0.80 g,
80%).
Preparation of Atorvastatin Hemi-Calcium Form XI
Example 21
[0121] 1.0 g of Atorvastatin hemi-calcium salt Form V was stirred
in Methylethyl ketone ("MEK") (5 ml) at room temperature for 24
hrs. The solid was then filtered, washed with MEK (2 ml) and dried
at 65.degree. C. for 20 hrs to give 0.5 g (50%) of Atorvastatin
hemi-calcium salt Form XI.
Example 22
[0122] A suspension of 1.0 g of Atorvastatin hemi-calcium salt Form
V in Iso-propyl alcohol ("IPA") (7 ml) was heated to reflux
temperature for 1 hr. The mixture was then cooled to room
temperature and stirred at this temperature for additional 20 hrs.
A gelatinous product was obtained. After addition of IPA (3 ml) the
gel was filtered and dried at 65.degree. C. for 20 hrs to give 0.8
g (80%) of Atorvastatin hemi-calcium salt Form XI.
Preparation of Atorvastatin Hemi-Calcium Form XII
Example 23
[0123] To a cylindrical reactor equipped with a distillation
apparatus and a mechanical stirrer, 20 g (30.6 mmole) of
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester (=pyrrole acetonide ester=PAE) were put in suspension in 250
ml of absolute Ethanol and 50 ml of aqueous 1.5% Hydrochloric acid.
The reaction mixture was heated to 40.degree. C. for 9-11 hrs,
while a continuous distillation of a mixture of Ethanol, Acetone
and water, under reduced pressure (500-600 mbar), was performed.
Make-up of absolute Ethanol was done every hour (35-40 ml.). After
9-11 hours there was a reduction in the level of PAE to below 0.1%
(according to HPLC). Without any further treatment, Ca(OH).sub.2
(1.5 eq., 3.4 g) were added. The reaction mixture was heated to
70.degree. C. for 4-5 hrs. Then the excess of Ca(OH).sub.2 was
collected by filtration. To the hot filtrate (65.degree. C.), 350
ml of water were added slowly (using a dosing pump) during 3/4-1
hour at 65.degree. C. During the addition of water Atorvastatin
hemi-calcium salt precipitated. After the addition of water the
reaction mixture was heated to reflux (84.degree. C.) till a clear
solution was obtained. Then the mixture was cooled to 20.degree. C.
during 3 hrs and was stirred at this temperature for an additional
12-16 hrs. The solid was then filtered to give 45.0 g of wet cake
of Atorvastatin hemi-calcium salt crystal form XII.
Preparation of Known Atorvastatin Hemi-Calcium Form I
Example 24
[0124] Atorvastatin hemi-calcium Form V (1.00 g) was stirred in
water (400 ml) at room temperature for 16 h. The solid was
collected by filtration and dried at 65.degree. C. for 24 hours to
yield atorvastatin hemi-calcium Form I (0.7 g, 70%).
Example 25
[0125] A mixture of atorvastatin hemi-calcium Form VII (10.00 g) in
water (100 ml) was refluxed for 2 h. The mixture was cooled to room
temperature and stirred for an additional hour. The solid was
collected by filtration and dried at 65.degree. C. for 24 h to
yield atorvastatin hemi-calcium Form I (9.64 g, 96%).
Example 26
[0126] Atorvastatin hemi-calcium Form VIII (800 mg) was stirred in
water (320 ml) at room temperature for 16 h. The solid was
collected by filtration and dried at 65.degree. C. for 24 h to
yield atorvastatin hemi-calcium Form I (350 mg, 44%).
Example 27
[0127] Atorvastatin hemi-calcium Form X (1.0 g) was stirred in
water (400 ml) at room temperature for 24 h. The solid was
collected by filtration and dried at 65.degree. C. for 24 h to
yield atorvastatin hemi-calcium Form I (720 mg, 72%).
Example 28
[0128] Atorvastatin hemi-calcium Form IX (750 mg) was stirred in
water (300 ml) at room temperature for 24 h. The solid was
collected and dried at 65.degree. C. for 20 h to give atorvastatin
calcium Form I (420 mg, 56%).
Example 29
[0129] Atorvastatin hemi-calcium Form VII (1.00 g) was stirred in
absolute EtOH (20 ml) at room temperature. The slurry was then
placed into a sonicator for 1.5 min (energy=235 kJ, Amp.=50%) to
obtain a clear solution. After addition of water (14 ml), a
precipitate formed and the slurry was put in the sonicator for
another 2 min. (energy=3.16 kJ, Amp.=50%) which caused the slurry
to gel The gel was dried at 65.degree. C. for 20 h to give
atorvastatin hemi-calcium Form I (0.50 g, 50%).
Example 30
[0130] Atorvastatin hemi-calcium Form VII (1.00 g) was stirred in
water (200 ml) at room temperature. The slurry was then placed into
a sonicator for 2 min. (energy=3.0 kJ, Amp.=50%) which caused the
slurry to gel. The gel was dried at 65.degree. C. for 20 h to yield
atorvastatin hemi-calcium Form I (0.92 g, 92%).
Preparation of Known Atorvastatin Hemi-Calcium Form II
Example 31
[0131] To a cylindrical reactor equipped with a distillation
apparatus and a mechanical stirrer, 20 g (30.6 mmole) of
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester (=pyrrole acetonide ester=PAE) were put in suspension in 135
ml of Methanol and 7.6 ml of aqueous 10% Hydrochloric acid. The
reaction mixture was heated to 35.degree. C. for 3 hrs, while a
continuous distillation of a mixture of Methanol, Acetone and water
under reduced pressure (820 mbar) was performed. Make-up of
Methanol was done every 1/2 hour (35 ml). After 3 hrs the level of
PAE reduced below 0.1% (according to HPLC). Without any further
treatment, Ca(OH).sub.2 (1.5 eq., 3.4 g), water (5 ml) and Methanol
(45 ml) were added. The reaction mixture was heated to 70.degree.
C. for 2 hrs. Then the excess of Ca(OH).sub.2 was collected by
filtration and the Ca(OH).sub.2 cake was washed with Methanol
(2.times.10 ml). To the filtrate, 300 ml of water were added slowly
(using a dosing pump) during 3/4 hour at 65.degree. C. During the
addition of water Atorvastatin hemi-calcium salt precipitated.
After the addition of water the reaction mixture was heated to
reflux temperature (78.degree. C.) for % hour. Then the mixture was
cooled to 20.degree. C. during 3 hrs and was stirred at this
temperature for additional 20 hrs. The solid was then filtered and
dried at 65.degree. C. for 48 hrs to give 16.9 g (96%) Atorvastatin
hemi-calcium salt crystal form II.
KF=3.2%
Preparation of Known Atorvastatin Hemi-Calcium Form IV
Example 32
[0132] Atorvastatin hemi-calcium salt Form I (1.0 g) was stirred in
9 ml of 1-butanol at room temperature for 24 hours. The white solid
was then filtered and dried at 50.degree. C. in a vacuum oven for
16 hours to obtain 0.83 g (83%) of atorvastatin hemi-calcium salt
Form IV.
Example 33
[0133] Atorvastatin hemi-calcium salt Form V (1.0 g) was stirred in
20 ml of 1-butanol at room temperature for 72 hours. The white
solid was then filtered and dried at 65.degree. C. in an oven for
20 hours to obtain 0.82 g (82%) of atorvastatin hemi-calcium salt
Form IV.
Example 34
[0134] Atorvastatin hemi-calcium salt form V (2.0 g) was stirred in
a mixture of EtOH (18 ml) and water (3.2 ml) at 50.degree. C. for 1
hour. The precipitate was then filtered and dried at 65.degree. C.
for 20 hours to obtain 1.60 g (80%) of atorvastatin hemi-calcium
salt form IV.
Example 35
[0135] A mixture of atorvastatin hemi-calcium Form V (2.00 g) and
methanol (20 ml) was refluxed for 1 hour. The mixture was cooled to
room temperature and stirred for an additional 16 hours. The solid
was collected by filtration and dried at 65.degree. C. for 24 to
give atorvastatin calcium Form IV (1.37 g, 56%).
Example 36
[0136] A mixture of atorvastatin hemi-calcium Form V (1.00 g) in
methanol (10 ml) was stirred at room temperature for 20 hours. The
solid was collected by filtration and dried at 65.degree. C. for 24
hours to give atorvastatin hemi-calcium Form IV (0.25 g, 25%).
Preparation of Atorvastatin Hemi-Calcium Form V
Example 37
[0137] To a cylindrical reactor equipped with a distillation
apparatus and a mechanical stirrer, 20 g (30.6 mmole) of
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester (pyrrole acetonide ester=PAE) were put in suspension in 250
ml of absolute Ethanol and 50 ml of aqueous 1.5% Hydrochloric acid.
The reaction mixture was heated to 40.degree. C. for 9-11 hrs,
while a continuous distillation of a mixture of Ethanol, Acetone
and water, under reduced pressure (500-600 mbar), was performed.
Make-up of absolute Ethanol was done every hour (35-40 ml.). After
9-11 hours there was a reduction in the level of PAE to below 0.1%
(according to HPLC). Without any further treatment, Ca(OH).sub.2
(1.5 eq., 3.4 g) were added. The reaction mixture was heated to
70.degree. C. for 4-5 hrs. Then the excess of Ca(OH).sub.2 was
collected by filtration. To the hot filtrate (65.degree. C.), 350
ml of water were added slowly (using a dosing pump) during 3/4-1
hour at 65.degree. C. During the addition of water Atorvastatin
hemi-calcium salt precipitated. After the addition of water the
reaction mixture was heated to reflux (84.degree. C.) till a clear
solution was obtained. Then the mixture was cooled to 20.degree. C.
during 3 hrs and was stirred at this temperature for an additional
20 hrs. The solid was then filtered to give 45.0 g of wet cake of
Atorvastatin hemi-calcium salt crystal form XII. This solid was
dried at 65.degree. C. for 24 hrs to give 16.7 g (95%) Atorvastatin
hemi-calcium salt crystal form V.
KF=2.8%-6.6%.
Process for Purifying Atorvastatin Hemi-calcium Form V
Example 38
[0138] 5.0 g of Atorvastatin hemi-calcium salt Form V were added to
a boiled aqueous solution of Ethanol 90% (150 ml). The mixture was
refluxed for 2.5 hrs. Then it was cooled to 20.degree. C. during
1.5 hrs and stirred at this temperature for additional 16 hrs. The
solid was then filtered, washed with Ethanol 90% (2.times.25 ml)
and dried at 65.degree. C. for 20 hrs to give 3.4 g (68%) of
Atorvastatin hemi-calcium salt Form V.
Preparation of Known Amorphous Atorvastatin Hemi-Calcium
Example 39
[0139] Atorvastatin hemi-calcium Form V (2.00 g) was stirred in
acetone (14 ml) at room temperature in a closed flask for 16 h.
After 2 hours, the mixture clarified. While continuing to stir at
room temperature, a solid precipitated. The acetone was decanted
and the solid was collected with a spatula and transferred to a
drying oven and dried at 65.degree. C. for 20 h to give amorphous
atorvastatin hemi-calcium (1.85 g, 93%).
Example 40
[0140] Atorvastatin hemi-calcium Form VII (1.00 g) was stirred in
acetonitrile (20 ml) at room temperature. The slurry was then
sonicated for 2 min. (energy=2.5 kJ, Amp.=50%). After decantation
the acetonitrile, the solid was dried at 65.degree. C. for 20 h to
give amorphous atorvastatin hemi-calcium (0.71 g, 71%).
Example 41
[0141] Atorvastatin hemi-calcium Form I (1.00 g) was stirred in
acetonitrile (20 ml) at room temperature. The slurry was then
placed into a sonicator for 2 min. (energy=2.5 kJ, Amp.=50%). After
decanting the acetonitrile, the solid was dried at 65.degree. C.
for 20 h to give amorphous atorvastatin hemi-calcium (0.71 g,
71%).
Example 42
[0142] Atorvastatin hemi-calcium (108 g) and twenty seven 10 mm
diameter stainless steel milling balls were loaded into the milling
chamber of the ball mill. The chamber was weighed and the mill was
balanced according to the weight. The mill was operated at 500 rpm
with the mill's reversing system on for 0.5 hr. The build-up
material was scraped from the chamber walls into the bulk, and the
mill was again operated for 4 hr, with cleaning of build-up every
15 min. finally, the material was separated from the balls by
sieving with 300 .mu.m screen. The resulting material was analyzed
by PXRD and found to be amorphous. The process was repeated using
atorvastatin Forms I, V and VIII and in each instance amorphous
atorvastatin hemi-calcium was obtained.
[0143] 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.
decanted and the solid was collected with a spatula and transferred
to a drying oven and dried at 65.degree. C. for 20 h to give
amorphous atorvastatin hemi-calcium (1.85 g, 93%).
Example 40
[0144] Atorvastatin hemi-calcium Form VII (1.00 g) was stirred in
acetonitrile (20 ml) at room temperature. The slurry was then
sonicated for 2 min. (energy=2.5 kJ, Amp.=50%). After decantation
the acetonitrile, the solid was dried at 65.degree. C. for 20 h to
give amorphous atorvastatin hemi-calcium (0.71 g, 71%).
Example 41
[0145] Atorvastatin hemi-calcium Form I (1.00 g) was stirred in
acetonitrile (20 ml) at room temperature. The slurry was then
placed into a sonicator for 2 min. (energy=2.5 kJ, Amp.=50%). After
decanting the acetonitrile, the solid was dried at 65.degree. C.
for 20 h to give amorphous atorvastatin hemi-calcium (0.71 g,
71%).
Example 42
[0146] Atorvastatin hemi-calcium (108 g) and twenty seven 10 mm
diameter stainless steel milling balls were loaded into the milling
chamber of the ball mill. The chamber was weighed and the mill was
balanced according to the weight. The mill was operated at 500 rpm
with the mill's reversing system on for 0.5 hr. The build-up
material was scraped from the chamber walls into the bulk, and the
mill was again operated for 4 hr, with cleaning of build-up every
15 min. finally, the material was separated from the balls by
sieving with 300 .mu.m screen. The resulting material was analyzed
by PXRD and found to be amorphous. The process was repeated using
atorvastatin Forms I, V and VIII and in each instance amorphous
atorvastatin hemi-calcium was obtained.
[0147] 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.
* * * * *