Note: Descriptions are shown in the official language in which they were submitted.
CA 02465565 2004-04-29
PC25685A
-1-
PHARMACEUTICAL COMPOSTTIONS OF ATORVASTATIN
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. Provisional Patent Application No.
60/478,119 filed June 12, 2003.
FIELD OF THE INVENTION
This invention relates to pharmaceutical compositions comprising atorvastatin
and pharmaceutically acceptable salts thereof and a process for the
preparation of the
same, kits containing such compositions, as well as methods of using such
compositions
to treat subjects suffering from hypercholesterolemia and/or hyperlipidemia,
as well as
osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer s disease.
BACKGROUND OF THE INVENTION
The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to
mevalonate is an early and rate-limiting step in the cholesterol biosynthetic
pathway.
This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-
CoA
reductase from catalyzing this conversion. As such, statins are collectively
potent lipid
lowering agents.
Atorvastatin calcium, disclosed in United States Patent No. 5,273,995 which is
incorporated herein by reference, is currently sold as Lipitor having the
chemical name
[R-(R*,R*)]-2-(4-fluorophenyl)-(3,8-dihydroxy-5-( 1-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
trihydrate and
the formula
CA 02465565 2004-04-29
-2-
Ca2+
2
Atorvastatin and pharmaceutically acceptable salts thereof are selective,
competitive inhibitors of HMG-CoA reductase. As such, atorvastatin calcium is
a potent
lipid-lowering compound and is thus useful as a hypolipidemic and/or
hypocholesterolemic agent, as well as in the treatment of osteoporosis, benign
prostatic
hyperplasia (BPH), and Alzheimer s disease.
A number of patents have issued disclosing atorvastatin, formulations of
atorvastatin, as well as processes and key intermediates for preparing
atorvastatin. These
include: United States Patent Numbers 4,681,893; 5,273,995; 5,003,080,
5,097,045;
5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793;
5,280,126;
5,397,792; 5,342,952; 5,298,62?; 5,446,054; 5,470,981; 5,489,690; 5,489,691;
5,510,488;
5,686,104; 5,998,633; 6,087,511; 6,126,971; 6,433,213; and 6,476,235, which
are herein
incorporated by reference.
Atorvastatin can exist in crystalline, liquid crystalline and non-crystalline
and
amorphous forms.
Crystalline forms of atorvastatin calcium are disclosed in United States
Patent
Numbers 5,969,156 and 6,121,461, which are herein incorporated by reference.
Further
crystalline forms of atorvastatin are disclosed United States Patent 6,605,729
which is
herein incorporated by reference.
Additionally, a number of published International Patent Applications have
disclosed crystalline forms of atorvastatin, as well as processes for
preparing amorphous
atorvastatin. These include: WO 00/71116; WO 01/28999; WO 01/36384; WO
01/42209; WO 02141834; WO 02/43667; WO 02143732; WO 021051804; WO
02/057228; WO 02/057229; WO 02/057274; WO 02/059087; WO 02/083637; WO
021083638; WO 03/011826; WO 03/050085; WO 03/070702; and WO 04/022053.
CA 02465565 2004-04-29
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It has been disclosed that the amorphous forms in a number of drugs exhibit
different dissolution characteristics and in some cases different
bioavailability patterns
compared to the crystalline form (Konno, T., Chem. Pharm. Bull., 1990;38:2003-
2007).
For some therapeutic indications one bioavailability pattern may be favored
over another.
Variations in dissolution rates can make it advantageous to produce
atorvastatin
formulations in either crystalline or amorphous forms. For example, for some
potential
uses of atorvastatin (e.g., acute treatment of patients having strokes as
described in
Takemoto, M.; Node, K.; Nakagami, H.; Liao, Y.; Crnmm, M.; Takemoto, Y.;
Kitakaze,
M.; Liao, J.K., Journal of Clinical Investigation, 2001; 108(10): 1429-1437) a
rapid onset
of activity may be highly beneficial in improving the efficacy of the drug.
The preparation of solid formulations of atorvastatin is described in United
States
Patent Numbers 5,686,104 and 6,126,971. In the process described therein,
atorvastatin is
combined with a stabilizing additive, such as, an alkaline earth metal salt,
and excipients
and subjected to wet granulation using a combination of water and a surfactant
(Tween~
80). Because alkaline earth metal salt additives can affect atorvastatin
bioavailability,
there remains a need to provide atorvastatin in a wet granulated composition
wherein said
composition is substantially free of an alkaline earth metal salt additive.
Similarly, it can
be desirable to minimize the use of any alkalizing agent additives in a
composition of
atorvastatin to avoid potential bioavailability issues and avoid interactions
when the drug
is used in combination dosage forms with other drugs.
Concurrently filed United States Patent Applications, commonly owned, attorney
case number PC25684, Serial Number dislcoses a unit dosage form comprising
atrovastatin or a pharmaceutically acceptable salt thereof prepared without a
granulation
step and attorney case number PC25686 discloses a dry-granulated
pharmaceutical
composition comprising atorvastatin or a pharmaceutically acceptable salt
thereof.
In preparation and storage of dosage forms of atorvastatin, it is important to
provide the active drug in a pure form. Moreover, it is desirable to achieve
this high
purity and stability with as simple a formulation as possible. There remains a
need to
provide simple formulations and processes for preparation of unit dosage forms
of
atorvastatin that have low levels of impurities. Moreover, there remains a
need to provide
atorvastatin formulations suitable for unit dosage forms whereby adequate drug
purity,
stability, and desired dissolution rate and bioavailability is provided with
minimal
addition of alkalizing agents.
One preferred unit dosage form for atorvastatin is a tablet. For active drugs
in
tablets to be rapidly absorbed once swallowed, it is generally important for
the tablet to
disintegrate rapidly once exposed to fluids in the gastrointestinal tract. At
the same time,
CA 02465565 2004-04-29
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it is important that the tablets be sufficiently hard that they do not
fracture or chip during
manufacturing, handling or storage. These seemingly contradictory needs can be
met by
addition of disintegrants to the composition. A number of disintegrants for
compositions
of atorvastatin have been disclosed in the prior art including calcium
carboxymethylcellulose, starch and croscarmellose sodium (see US Patent
numbers
5686014 and 6126971). When using atorvastatin with minimal levels of an
alkalizing
additive or an alkaline earth metal salt additive, we have unexpectedly found
that with the
standard wet granulation process, only certain disintegrants provide for
tablets of
atorvastatin with acceptable purity. This is especially unexpected since the
disintegrant
used in commercial formulations (croscarmellose sodium) was found to be
unacceptable
for wet granulations of amorphous atorvastatin with minimal levels of added
alkalizing
additives or alkaline earth metal salt additives. Moreover, this stability is
unexpectedly
maintained even when the atorvastatin is in an amorphous form. In addition to
formulation improvements, we have developed wet granulation processes for
incorporation of disintegrants into formulations that provide atorvastatin
with high purity,
even for disintegrants that provide poor stability with the standard process.
We have further found that when using a wet granulation of atorvastatin
(especially non-crystalline atorvastatin), purity of the drug can be improved
by addition of
volatile bases to the granulation solvent. These volatile bases provide for
improved purity
of the drug in the dosage form, yet are not themselves present in the final
dosage form,
and as such cannot affect the bioavailability.
Therefore, it is an object of the present invention to provide a stable dosage
form
of atorvastatin having a good disintegration rate and bioavailability. It is a
further object
of the present invention to provide a stable and pure composition of
atorvastatin with
minimal levels of alkaline earth metal salt additives or other added
alkalizing agents in
the composition.
SUMMARY OF THE INVENTION
Accordingly, the first aspect of the present invention is a wet granulated
pharmaceutical composition of atorvastatin with less than about 5 weight% of
an alkaline
earth metal salt additive comprising:
(a) atorvastatin or a pharmaceutically acceptable salt thereof; and
(b) a disintegrant or combination of disintegrants> wherein said wet
granulated pharmaceutical composition contains not more than about 3%
atorvastatin lactone based on the ratio of lactone peak area compared to
the total drug-related peak integrated areas using HPLC.
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A second aspect of the present invention is a wet granulated pharmaceutical
composition of atorvastatin with less than about 5 weight% of an alkaline
earth metal salt
additive comprising:
(a) atorvastatin or a pharmaceutical) acceptable salt thereof in combination
with at least one active drug; and
(b) a disintegrant or combination of disintegrants, wherein said wet
granulated pharmaceutical composition contains not more than about 3%
atorvastatin lactone based on the ratio of lactone peak area compared to
the total drug-related peak integrated areas using HPLC.
A third aspect of the present invention is a method for preparing a wet-
granulated
composition of atorvastatin comprising:
(a) combining atorvastatin or a pharmaceutically acceptable salt thereof with
sodium starch glycolate, starch, sodium alginate, powdered cellulose,
hydroxypropylcellulose, magnesium aluminum silicate or polacrilin
potassium or combinations thereof, and optionally other excipients;
(b) adding sufficient water, isopropanol, ethanol, or a mixture thereof to the
atorvastatin blend from step (a) under shear to generate granules;
(c) optionally milling or sieving said wet granules;
(d) drying said granules;
(e) optionally milling, grinding or sieving said granules;
(f) optionally mixing in other excipients; and
(g) optionally, forming the composition into unit dosage forms.
A fourth aspect of the present invention is a method for preparing a wet
granulated
composition of atorvastatin comprising:
(a) combining atorvastatin or a pharmaceutically salt thereof with a diluent
with
less than 2 weight °~O of a disintegrant;
(b) adding sufficient water, isopropanol, ethanol, or a mixture thereof to the
atorvastatin blend from step (a) under shear to generate granules;
(c) optionally milling, grinding or sieving said wet granules;
(d) drying said granules;
(e) optionally milling, grinding or sieving said granules;
(f) mixing in a disintegrant and optionally other excipients; and
(g) optionally, forming the composition into unit dosage forms.
A fifth aspect of the present invention is a method for preparing a wet
granulated
composition of atorvastatin comprising:
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(a) combining atorvastatin or a pharmaceutically acceptable salt thereof and
one
or more excipients;
(b) adding, under shear, a sufficient amount of a solution of a volatile base
dissolved in water, isopropanol or ethanol or a mixture thereof, to generate
granules;
(c) optionally milling, grinding or sieving said wet granules;
(d) drying said granules;
(e) optionally milling, grinding or sieving said granules;
(f) optionally mixing in other excipients as needed to make the final
composition; and
(g) optionally, forming said composition into unit dosage forms.
A sixth aspect of the present invention is a method for preparing a wet-
granulated
composition of atorvastatin comprising:
(a) combining atorvastatin or a pharmaceutically acceptable salt thereof in
combination with at least one active drug with sodium starch glycolate,
starch, sodium alginate, powdered cellulose, hydroxypropylcellulose,
magnesium aluminum silicate or polacrilin potassium or combinations
thereof, and optionally other excipients;
(b) adding sufficient water, isopropanol, ethanol, or a mixture thereof to the
atorvastatin blend from step (a) under shear to generate granules;
(c) optionally milling or sieving said wet granules;
(d) drying said granules;
(e) optionally milling, grinding or sieving said granules;
(f) optionally mixing in other exciptients; and
(g) optionally, forming the composition into unit dosage forms.
A seventh aspect of the present invention is a method for preparing a wet
granulated composition of atorvastatin comprising:
(a) combining atorvastatin or a pharmaceutically acceptable salt thereof in
combination with at least one active drug with a diluent with less than 2
weight% of a disintegrant;
(b) adding sufficient water, isopropanol, ethanol, or a mixture thereof to the
atorvastatin blend from step (a) under shear to generate granules;
(c) optionally milling, grinding or sieving said wet granules;
(d) drying said granules;
(e) optionally milling, grinding or sieving said granules;
(fj mixing in a disintegrant and optionally other excipients; and
CA 02465565 2004-04-29
(g) optionally, forming the composition into unit dosage forms.
An eighth aspect of the present invention is a method for preparing a wet
granulated composition of atorvastatin comprising:
(a) combining atorvastatin or a pharmaceutically acceptable salt thereof in
combination with at least one active drug and one or more excipients;
(b) adding, under shear, a sufficient amount of a solution of a volatile base
dissolved in water, isopropanol or ethanol or a mixture thereof, to
generate granules;
(c) optionally milling, grinding or sieving said wet granules;
(d) drying said granules;
(e) optionally milling, grinding or sieving said granules;
(f) optionally mixing in other excipients as needed to make the final
composition; and
(g) optionally, forming said composition into unit dosage forms.
A ninth aspect of the present invention is a kit for achieving a therapeutic
effect
in a mammal comprising a therapeutically effective amount of tablets or
capsules
prepared from a wet granulated composition of atorvastatin prepared in the
form of unit
dosage forms from said compositions and a container for containing said dosage
forms.
An tenth aspect of the present invention is a method of using the
pharmaceutical
composition to treat subjects suffering from hypercholesterolemia and/or
hyperlipidemia,
osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
DETAILED DESCRIPTION OF THE INVENTION
Atorvastatin can readily be prepared as described in United States Patent
Numbers 4,681,893, 5,273,995 and 5,969,156, which are incorporated herein by
reference. The hemicalcium salt of atorvastatin is currently sold as
Lipitor°.
Atorvastatin exists in a number of morphological forms ranging from highly
crystalline forms to forms with varying degrees of disorder. Some of these
disordered
forms still possess some structure as indicated by powder x-ray patterns. For
the purpose
of the present invention, all forms of atorvastatin benefit from the invention
and are
included in the scope of the invention. Less ordered forms of atorvastatin,
especially
amorphous or predominantly amorphous forms, particularly benefit from the
invention.
Such forms can be prepared, for example, from the crystalline material using
procedures
disclosed in United States Patent Number 6,087,511, which is incorporated
herein by reference.
CA 02465565 2004-04-29
_g_
Alternatively, amorphous atorvastatin material can be prepared according to
the processes
disclosed in United States Patent Application, commonly owned, attorney's case
number PC-
25825 (Serial Number ). For the practice of the present invention, non-
crystalline and
crystalline atorvastatin can be prepared by any method known in the art. The
following is a non-
exclusive list of patents and published patent applications disclosing
preferred forms of
atorvastatin for the present invention: United States Patent 5,969,156; United
States Patent
6,121,461; United States Patent 6,605,729; International Patent Application WO
01136384;
International Patent Application WO 02/41834; International Patent Application
WO 02/43732;
International Patent Application WO 02/051804; International Patent
Application WO 02/057229;
International Patent Application WO 03/011826; International Patent
Application WO 03/050085;
International Patent Application WO 03/070?02; and International Patent
Application WO
04!022053. All the above patents and applications are incorporated herein by
reference.
The atorvastatin can be used in the form it is prepared, or it can be
subjected to a process
which changes the physical nature of the particles. Fox example, the material
can be milled by
any process known in the art. Non-exclusive examples of such processes include
mechanical
milling and jet milling. The particles produced either directly from the
process of forming non-
crystalline atorvastatin or after a milling operation preferably provide
average particle diameters
in the range of 1-200 pm; more preferably between 5 and 150 ~,m.
Pharmaceutically acceptable base addition salts of atorvastatin are formed
with
metals or amines, such as alkaline and alkaline earth metals or organic
amines. Examples
of metals used as cations are sodium, potassium, magnesium, calcium, and the
like.
Examples of suitable amines are N,N~-dibenzylethylenediamine, chloroprocaine,
choline,
diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and
procaine
(see, for example, Berge, S.M., et al., "Pharmaceutical Salts", 3. Pharm.
Sci., 1977; 66:1).
The base addition salts of atorvastatin are prepared by contacting the free
acid
form with a sufficient amount of the desired base to produce the salt in the
conventional
manner. The free acid form may be regenerated by contacting the salt form with
an acid
and isolating the free acid in the conventional manner. The free acid forms
differ from
their respective salt forms somewhat in certain physical properties such as
solubility in
polar solvents, but otherwise the salts are equivalent to their respective
free acid for
purposes of the present invention.
Additionally, atorvastatin can exist in unsolvated forms as well as solvated
forms,
including hydrated forms. In general, the solvated forms, including hydrated
forms, are
intended to be encompassed within the scope of the present invention.
Forms of atorvastatin that are at least somewhat disordered or a mixture of
CA 02465565 2004-04-29
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crystalline and disordered forms of atorvastatin benefit most significantly
from the
present invention. By somewhat disordered, it is meant that the line width
(peak width at
half the height of the peak) of any of the peaks measured using powder x-ray
diffraction
(PXRD) have 2 theta values greater than about 2°. Amorphous or
predominantly
amorphous forms of atorvastatin, which especially benefit from the present
invention, are
characterized by having very broad, featureless peaks. It should be noted that
combinations of crystalline and at least somewhat disordered forms of
atorvastatin will
show both sharp (i.e., less than 2° values for 2 theta) and broad peaks
(i.e., greater than
2°), and such combinations of forms benefit from the present invention.
IO Atorvastatin has been found to be an effective drug even at relatively low
doses.
In fact, by keeping the dose low for a given patient, it is possible to
minimize side-effects
while still maintaining drug efficacy. It is therefore desirable to provide
atorvastatin in a
form capable of providing a low dose to the patient. For the purposes of the
present
invention, the dose provided by the final dosage form of atorvastatin is
preferably
I5 between 0.5 and 120 mgA (where mgA means milligrams of active drug based on
the free
acid); more preferably between 5 and 80 mgA.
For convenience and ease of patient compliance, most drugs are delivered in
the
form of unit dosage forms. For solid drug substances, these unit dosage forms
are
generally in the form of tablets and capsules. In the present invention, the
dosage form is
20 preferably in the form of a capsule or tablet; most preferably in the form
of a tablet. The
preparation of these forms involves a necessary step of filling a die or
capsule with
powder. In order for the unit dosages to have the same potency within
allowable margins
(relative standard deviation, RSD, of less than 6% to meet Stage I, and less
than
7.8% to meet Stage II of the United States Pharmacopoeia, USP, guidelines),
there
25 must not be any significant segregation of formulation components. For this
reason, it
can be desirable to granulate atorvastatin, especially when the drug is used
at low doses.
Wet granulations bind the drug with excipients and thereby minimize any
segregation
tendency.
The present invention discloses wet granulation processes and formulations
that
30 provide atorvastatin in a pure and stable form. The term "impurities"
describes materials
in the drug substance present from the synthesis and purification process and
any drug-
based materials formed in the preparation of the unit dosage form. The term
"degradants"
refers to any drug-based materials generated after the preparation of the unit
dosage form
(during the shelf life of the dosage form). Analysis of impurities and
degradants is done
35 using reverse phase high performance liquid chromatography, HPLC,
techniques on
CA 02465565 2004-04-29
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extracted samples as is known in the art. Calculations of the amount of
impurities and
degradants is expressed as the integrated area percent of all peaks other than
the drug
peak divided by the integrated area percent of all peaks, or where possible,
based on a
response factor for integration of peaks from samples of authentic materials.
In the formulation of atorvastatin with a wet granulation, combinations of
diluents, binders, disintegrants, lubricants and other additives known in the
art are used to
provide the properties needed for the unit dosage form as is known in the art.
For
example, for preparation of tablets, the combination provides for adequate
tablet hardness
upon compression while providing rapid disintegration in vivo. Although there
is a wide
degree of latitude in formulating atorvastatin to meet these conditions,
typically such
tablet formulations contain about 1-40% weight:weight (w:w) drug, about 1-
15010
disintegrant, about 0-10% binder and about 0.5-2010 lubricant, with the bulk
comprising a
diluent and/or other components. Preferred binders include
carboxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum,
hydroxypropyl methylcellulose, maltodextrin, methylcellulose, polyethylene
oxide,
polymethacrylates and sodium alginate; a particularly preferred binder is
hydroxypropylcellulose. A preferred lubricant is magnesium stearate. Preferred
diluents
include calcium phosphate, calcium sulfate, cellulose acetate, dextrates,
dextrin, dextrose,
fructose, kaolin, lactitol, lactose, maltitol, maltodextrin, maltose,
microcrystalline
cellulose, polymethacrylates, powdered cellulose, silicified microcrystalline
cellulose,
sodium chloride, sorbitol, sucrose and talc.
In the practice of the present invention, the level of alkaline earth metal
salt
additives in the composition is preferably about 0-5% (w:w); more preferably,
about 0-
3%; most preferably about 0-2%. It is also preferred that the level of other
alkalizing
agent additives in the composition be about 0-5% (w:w); more preferably, about
0-3%;
most preferably about 0-2%. It is also preferred that amine polymers and amide
polymers
be less than about 0-5% (w:w); more preferably, about 0-3%; most preferably
about 0-2%
of the formulation. Examples of such polymers are disclosed in International
Patent
Application WO Ol/76566AI.
Alkalizing agents are additives or excipients that have the property of
increasing
the pH of a formulation, when such formulations are added to water. Examples
of
alkalizing agents include inorganic and organic bases (buffers). Examples of
inorganic
alkalizing agents include sodium or potassium citrate, carbonate, bicarbonate,
phosphate,
sulfate, benzoate and ascorbate, and calcium carbonate and magnesium
carbonate. The
latter two examples also represent alkaline earth metal salts. Examples of
organic
alkalizing agents include amines. Specific examples of amines include N-
CA 02465565 2004-04-29
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methylglucamine, guanine and arginine.
In preparation of atorvastatin compositions by wet granulation, any technique
known in the art for wet granulation can be used for the purposes of the
present invention.
An important element to these processes is that the granulation solution is
added to the
atorvastatin composition while the powder blend is under shear. The shear
serves to
break up incipient clumps and thereby provide a more uniform granulation. Non-
limiting
examples of shearing processes include high shear wet granulations, fluid-bed
granulations, extrusion granulations and low shear wet granulations (such as
stirrers,
mixers and blenders, including bin blenders). The amount of wet granulation
solvent
added is determined based on adequate wetting to bind the majority of the fine
particles.
The wet granulation solvent addition can be carried out using any technique
known in the
art. For example, the liquid can be added in single or multiple rapid
additions, sprayed
onto a stirring powder bed, pumped directly onto the powder or introduced into
fluidizing
gas. Mixing times with the liquid are generally optimized such that the
majority of fine
particles are bound in granules, yet the granules themselves are not over-
hardened.
Once the granules are formed, it is sometimes advantageous to mill, grind or
sieve the material while it is wet (softened), as is known in the art. The wet
composition
is preferably dried before use in formation of unit dosage forms. Such drying
can be
accomplished using any method known in the art. Non-limiting examples of these
methods include air drying, fluid bed drying, microwave drying, oven drying,
radio
frequency drying vacuum oven drying and convection oven drying. We have found
that
the drying temperature is important to control to provide low levels of
atorvastatin
impurities. Preferably the drying temperature does not exceed about
60°C; more
preferably, the temperature does not exceed about 50°C; most
preferably, the temperature
does not exceed about 40°C. Once the granules are dry, it is sometimes
desirable to
reduce the particle size by milling, grinding or sieving, as is known in the
art. After this
point, a lubricant is typically added followed by a short (about 1-10 minute)
mixing
period, typically carried out in a low shear blender such as a tumbling
blender, Examples
of said tumbling blenders include bin-blenders, V-blenders and Turbula~
blenders. The
preferred lubricant is magnesium stearate. Once the blend is made, unit dosage
forms are
prepared by procedures known in the art. Preferable the unit dosage forms
include tablets
or capsules. Tablets are made by filling a die with the atorvastatin
containing
composition, then pressing with a matching punch. Capsules are prepared by
filling
shaped capsule shells then sealing. Such operations are preferably carried out
using a
rotary tablet press or commercial capsule-filling machine. Non-exclusive
examples of
commercial rotary tablet presses include those produced by Niro Pharma Systems
CA 02465565 2004-04-29
-12-
(Columbia, MD), Kilian and Company (Horsham, PA), Korsch (Berline, Germany)
and
Elizabet-Hata International (North Huntingdon, PA). Non-exclusive examples of
commercial capsule filling equipment include those made by Capsugel (Moms
Plains,
NJ) and CapPlus Technologies (Phoenix, AZ). Tablets thus prepared can then
optionally
be coated with a film designed to provide ease of swallowing, a proprietary or
identification appearance andlor protection of the dosage form. The final unit
dosage
form is then packaged using procedures known in the art. For the present
invention, the
packaging is preferably in the form of foil-foil cold form blisters, plastic
blisters or sealed
bottles containing desiccants. Optionally, the packaging can contain active
oxygen
absorbing materials as is disclosed in EP1243524A2 or EP1241110A1, which are
incorporated herein by reference.
Atorvastatin undergoes two major degradation pathways: lactonization and
oxidation. The lactone is formed by internal condensation (loss of water) of
the alcohol
and carboxylic acid to form a six-membered ring. This is the major degradant
of
atorvastatin found upon wet granulation and tablet formation, especially in
the absence of
alkaline earth metal salts. We have found that the level of the lactone in
tablets prepared
by wet granulation with less than 5% (w:w) of an alkaline earth metal salt
additive can be
significantly reduced by a combination of the choice of excipients and the wet
granulation
process.
When atorvastatin is prepared in the form of a tablet, a disintegrant is
desirable to
provide for rapid disintegration of the tablet in the gastrointestinal tract
and thereby assure
that the drug is rapidly available for absorption. A large number of
disintegrants are
disclosed in the prior art for use with atorvastatin. For example, the
following list of
disintegrants is disclosed in International Patent Publication Number
W003/011283A1 in
combination with an alkalizing agent and a second active pharmaceutical
ingredient:
calcium carboxymethylcellulose, sodium carboxymethylcellulose, silica,
croscarmellose
sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose,
polacrilin potassium, cellulose, pregelatinized starch, sodium alginate,
sodium starch
glycolate and starch. In a number of patents, the examples have focused on use
of
croscarmellose sodium (see for example U.S. Patent Numbers 5686014, 6126971,
65315078 1, and Published European Patent Application EP1336405A1). This
disintegrant is also used in the commercial product Lipitor°. While
many of these
disintegrants provide for adequate disintegration properties, in wet
granulations of
atorvastatin with less than 5°l0 (w:w) alkalizing agent additives, we
have unexpectedly
determined that only some of the many possible disintegrants provide for
adequate drug
purity. In fact, the disintegrant used in the majority of examples
(croscarmellose sodium),
CA 02465565 2004-04-29
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was unexpectedly found to provide poor drug purity.
Preferred disintegrants provide atorvastatin formulations with a level of
atorvastatin lactone less than about 3% (based on area percent of the lactone
peak
compared to all drug-related peaks by HPLC integration) after wet granulation
and
drying; more preferred disintegrants provide lactone levels less than about 1
%; and still
more preferred disintegrants provide lactone levels less than about 0.5%.
Disintegrants suitable for the current invention also provide for
disintegration
times of tablets produced therein of preferably less than 30 minutes; still
more preferably
less than 15 minutes; and still more preferably less than 8 minutes.
Disintegration times
are measured using pH 6.8 phosphate buffer solutions with commercially
available
disintegration measurement devices.
Preferred disintegrants for compositions useful for wet granulation of
atorvastatin
with less than about 5 weight% alkalizing agent additives or alkaline earth
metal salts
include starches, sodium starch glycolate, sodium alginate, powdered
cellulose,
hydroxypropylcellulose, magnesium aluminum silicate and polacrilin potassium.
Particularly preferred starches include cornstarch and pregelatinized starch.
These
disintegrants are preferably used in compositions of atorvastatin at levels
between about 1
and about 10% (w:w) of the overall formulation; more preferably between about
3 and
about 8% (w:w).
Preferred wet granulation solvents have the property of inducing adhesion
between particles without significant dissolution of the atorvastatin, which
could cause
the drug to change morphological forms. In addition, it is preferable that
such solvents be
volatile and of low toxicity such that any trace amount remaining will not be
harmful. As
such, preferred granulation solvents for atorvastatin are water and alcohols.
Particularly
preferred alcohols are ethanol and isopropanol. In many cases, combinations of
solvents
can be advantageous. Preferably such combinations involve water with ethanol
or
isopropanol. In addition, it can be advantageous to add ingredients to the
granulation
solvent, as is known in the art. For example, binding agents, wetting agents
and
stabilizers can be incorporated as part of the granulation solvent and are
within the scope
of the present invention.
We have found that a particular additive to the granulation solvent, the
wetting
agent Tween~ 80 (polysorbate 80) is detrimental to the stability of the
atorvastatin. This
is surprising since this additive is commonly used in most prior art
formulations of
atovastatin (see for example, US Patent numbers 5,686,104 and 6,126,971 ).
Therefore, it
is preferable that the level of Tween 80 used in wet granulated compositions
of
atorvastatin be less than 0.5% (w:w); more preferably less than 0.2%; and
still more
CA 02465565 2004-04-29
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preferably, less than 0.1 %.
Preferred processes for preparing a wet granulation of atorvastatin with less
than
about 5 weight% alkalizing agent additives or alkaline earth metal salts with
preferred
disintegrants comprise the following steps:
(a) blending of the atorvastatin with a preferred disintegrant and optionally
some or all of the remaining excipients needed for the final composition.
These other excipients can include diluents, binders and other such
materials necessary for processing, flow, stability or formation of unit
dosage forms;
(b) adding a granulation solvent while the material from step (a) is under
shear. Preferred granulation solvents include, water, ethanol, isopropanol
and combinations thereof. Other ingredients can be added to the
granulation solvent as is known in the art. Examples of such additives
are binders, wetting agents, stabilizers and buffers. The solvent can be
applied by any technique known in the art. Preferred methods of
applying the solvent while imparting shear include high shear
granulation, low shear granulation, fluid bed granulation and extrusion
granulation;
(c) optionally, the material from step (b) can be milled, ground or sieved.
This wet material is then dried, preferably using air drying, fluid bed
drying, oven drying or microwave drying. The drying is preferably
carned out such that the drying temperature does not exceed about 60°C;
more preferably, the temperature does not exceed about 50°C; most
preferably, the temperature does not exceed about 40°C;
(d) optionally this material is then milled or sieved;
(e) the material is then blended with additional excipients; and
(f) the composition is optionally formed into a unit dosage form, preferably
a tablet or a capsule.
We have also found that even when using disintegrants that induce
lactonization
of the drug (in the absence of base) during a wet granulation, it is possible
to incorporate
such excipients by a change in the process for addition of the disintegrant.
More
specifically, we have found that adding disintegrants to the composition
subsequent to the
wet granulation step, that is, in an extragranular addition, provides for
unexpected
improvement in the drug stability. The preferred steps in this process
comprise:
(a) blending of the atorvastatin with at least some of the excipients needed
for the final composition, but with no significant amount of a
CA 02465565 2004-04-29
-15-
disintegrant. A significant amount of disintegrant is considered greater
than about 2% (w:w) of the formulation. Other excipients can include
diluents, binders and other such materials necessary for processing, flow,
stability or formation of unit dosage forms;
(b) adding a granulation solvent while the material from step (a) is under
shear. Preferred granulation solvents include water, ethanol and
isopropanol and combinations thereof. Other ingredients can be added to
the granulation solvent as is known in the art. Examples of such
additives are binders, wetting agents, stabilizers and buffers. The liquid
can be applied by any technique known in the art. Preferred methods of
applying the liquid while imparting shear include high shear granulation,
low shear granulation, fluid bed granulation and extrusion granulation;
(c) optionally, the material from step (b) can be milled, ground or sieved.
This wet material is then dried, preferably using air drying, fluid bed
drying, oven drying or microwave drying; such drying is preferably
carned out such that the drying temperature does not exceed about 60°C;
more preferably, the temperature does not exceed about 50°C; most
preferably, the temperature does not exceed about 40°C;
(d) optionally this material is then milled, ground or sieved;
(e) this composition is then blended with one or more disintegrants and
optionally additional excipients, preferably including a lubricant, and
(f) the final composition is optionally formed into a unit dosage form,
preferably a tablet or a capsule.
We have also found another process for improving drug purity for a wet
granulation of atorvastatin, even in the presence of disintegrants showing
poor drug
purity. More specifically, we have unexpectedly found that having a base
present in a
composition only during the wet granulation and drying processes provides for
stabilization of atorvastatin against lactonization, even though the base is
not present in
the final product. In particular, volatile bases were found to provide wet
granulations of
atorvastatin in the absence of other added bases with a higher degree of
purity than in the
absence of such volatile bases. Examples of such preferred volatile bases
include
ammonium hydroxide, tetraalkylammonium hydroxides, secondary and tertiary
alkyl and
aryl amines, diethanolamine and monoethanolamine. Particularly preferred
volatile bases
include ammonium hydroxide and tetrabutyl ammonium hydroxide. These bases can
be
added with the granulation solvent (preferably water, isopropanol, ethanol, or
combination thereof) at a level selected to be effective at providing good
purity and
CA 02465565 2004-04-29
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stability for the final atorvastatin dosage form without themselves inducing
drug
degradation or discoloration of the formulation. We have found that the
concentration of
volatile base used in the granulation water preferably ranges between about
0.001 and
about 50% (w:w); more preferably, between about 0.1 and about 40% (w:w). The
amount
of granulation solution of base added to the granulation preferably is between
about 40
and about 100% (w:w) of the solid material.
The present invention provides for compositions of atorvastatin which are
particularly well suited for combination products with other drug substances
because of
the greater atorvastatin stability imparted by the disintegrants of the
present invention.
This is especially true when the second drug (with its associated excipients)
can
destabilize atorvastatin. Non-limiting examples of drugs which may benefit
from
combinations with the inventive atorvastatin compositions and processes
include
torcetrapib and amlodipine and its pharmaceutically acceptable salts.
Compositions of atorvastatin according to the present invention can be
combined
with a least one other active drug to form unit dosage forms. Preferred unit
dosage forms
include tablets and capsules. In the combination of the atorvastatin
composition with at
least one other active drug to form a unit dosage form, the following non-
limiting list
describes options for such unit dosage forms: (a) a blend of wet-granulated
atorvastatin
with the other active drug itself (i.e., extragranular addition of the other
drug to the wet
granulated atorvastatin), as a blend with excipients (i.e., extragranular
addition of the
other drug plus excipients to the wet granulated atorvastatin), or as a
granulation (i.e.,
combination of the other drug granulation with the wet granulated
atovastatin), formed
into tablets or capsules; (b) a single wet granulation of atorvastatin with
the other drug,
formed into tablets of capsules; (c) a bilayer tablet comprising wet
granulated atorvastatin
in one layer and the other drug and optional excipients in the other layer.
The present invention relates to the treatment of diseases and conditions in a
subject, such as, hyperlipidemia and/or hypercholesterolemia, osteoporosis,
benign
prostatic hyperplasia (BPS, and Alzheimer's disease with atorvastatin or a
pharmaceutically acceptable salt thereof as described above that may be
administered in a
unit dosage form having low levels of degradation products and/or impurities
contained in
a therapeutic package or kit. The kit includes the unit dosage form and a
container.
Typically, the kit includes directions for administration of the dosage form.
The container
can be in any conventional shape or form as known in the art, for example, a
paper box, a
glass or plastic bottle, or a blister pack with individual dosage forms
pressing out of the
back according to a therapeutic schedule.
The following non-limiting examples illustrate the inventors' preferred
methods
CA 02465565 2004-04-29
-I7-
for preparing and using the pharmaceutical compositions of the present
invention.
EXAMPLE 1
GENERAL METHOD FOR PREPARATION OF AMORPHOUS
ATORVASTATIN
Amorphous atorvastatin, an example of disordered atorvastatin as previously
described and used in the following examples was prepared according to the
process
disclosed in concurrently filed U.S. Patent Application, commonly owned,
attorney case
number PC-25825, serial number , by first dissolving atorvastatin calcium
(U.S.
Patent No. 5,273,995) in methanol to make a 5% (w:w) solution. This solution
was
sprayed into a Niro PSD-1 spray dryer at a rate of 170 gram/minute (g/min)
using
nitrogen as the atomizing gas. The inlet temperature was 195°C and the
outlet
temperature was 60°C. After spray drying, the powder was tray-dried in
an oven at 40°C
IS for 12 hrs to afford amorphous atorvastatin.
EXAMPLE 2
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM TABLETS
USING A WET GRANULATION WITHOUT A DISINTEGRANT
Amorphous atorvastatin calcium, prepared as described in Example 1 (1.3 g),
39.0 g of microcrystalline cellulose (Avicel PH102~, FMC Biopolymer,
Philadelphia,
PA), 50.7 g of lactose, hydrous (Foremost Farms USA, Rothschild,WI), and 2.0 g
of
hydroxypropyl cellulose (Klucel EXF"''i, Hercules Incorporated, Aqualon
Division,
Wilmington, DE) were combined in a 500-cc bottle and mixed for 10 min. using a
Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel,
Switzerland).
The formulation was then granulated using a Pro-C~pT Mi Mi Pro high shear wet
granulator (Pro-C-epT n.v., B- 9060 Zelzate, Belgium) using a 0.9 L bowl. The
formulation was dry-mixed for 2 min. at an impeller speed of 400 revolutions
per minute
(rpm) and chopper speed of 1000 rpm. Wet mixing was done at a 600-rpm impeller
speed
and 1000-rpm chopper speed. Water was added in increments of 10-30 g at 20-30
g/min.
for a total of 45 g using a standard 60-cc syringe. The material was wet-mixed
for a total
of 2.5 min. The granulation was wet sieved through a #10 mesh sieve by hand to
achieve
a more uniform granule size before drying. The granulation was tray-dried
overnight at
50°C for 16 hrs. in a forced hot air dryer (Gruenberg Forced Hot Air
Oven, Gruenberg
Oven Co., Williamsport, PA). The granulation was then milled using a
Fitzpatrick L1A
CA 02465565 2004-04-29
-18-
mill (Fitzpatrick Co., Elmhurst, IL) with a 0.040" Conidur rasping plate at
500 rpm.
Material was analyzed for the level of atorvastatin lactone (based on the
ratio of lactone
peak integration compared to the total peak integrated areas using HPLC) by
adding 400
mg of the granulation to 50 mL of l:1 (v:v) of O.OSM ammonium citrate buffer
(pH
7.4):acetonitrile and shaking for 20 min. The material was then filtered using
a Gelman
Acrodisc polytetrafluoroethylene membrane (0.45 ~m pore size), and analyzed
using
high-pressure liquid chromatography (HPLC) (Phenomenex, Ultremex C18 column, 5
~.m
particle size, 25.0 cm x 4.6 mm, HPLC Waters 2690D, Waters Corp., Milford, MA,
20 pl
injection volume, flow of 1.5 mL/min; mobile phase of 53:27:20 (v:v:v) 0.05M
ammonium citrate (pH 4.0):acetonitrileaetrahydrofuran; detection using a
Waters 2487
detector at 244 nm). Results are reported in Table 1. Tablets were made under
manual
power using a single station Manesty F-Press (Manesty, Liverpool, United
Kingdom). A
13132" standard round concave (SRC) punch and die was used to produce tablets
with
weights of 450 mg each. The target tablet hardness was 12 kP with a range of
10-14 kP
(tablet hardness was tested using a Schleuniger Tablet Hardness Tester, Dr.
Schleuniger
Pharmatron AG, Solothurn, Switzerland).
EXAMPLE 3
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM USING A
WET GRANULATION WITH CROSCARMELLOSE SODIUM
Amorphous atorvastatin calcium, prepared as described in Example 1 ( 1.3 g),
39.0 g of microcrystalline cellulose (Avicel PH102~, FMC Biopolymer,
Philadelphia,
PA), 50.7 g of lactose, hydrous (Foremost Farms USA, Rothschild,WI), 3.0 g of
croscarmellose sodium (Ac-Di-Sol"~', FMC Biopolymer, Philadelphia, PA) and 2.0
g of
hydroxypropyl cellulose (Klucel EXF~, Hercules Incorporated, Aqualon Division,
Wilmington, DE) were combined in a 500-cc bottle and mixed for 10 min. using a
Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel,
Switzerland).
The formulation was then granulated using a Pro-C-epT Mi Mi Pro high shear wet
granulator (Pro-C-epT n.v., B- 9060 Zelzate, Belgium) using a 0.9 L bowl. The
formulation was dry-mixed for 2 min. at an impeller speed of 400 rpm and
chopper speed
of 1000 rpm. Wet mixing was done at a 600-rpm impeller speed and 1000-rpm
chopper
speed. Water was added in increments of 10-30 g at 20-30 glmin. for a total of
60 g using
a standard 60-cc syringe. The material was wet-mixed for a total of 5.5 min.
The
granulation was wet sieved through a #10 mesh sieve by hand to achieve a more
uniform
CA 02465565 2004-04-29
-19-
granule size before drying. The granulation was tray-dried overnight at
50°C for 16 hrs. in
a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co.,
Williamsport, PA). The granulation was then milled using a Fitzpatrick L1A
mill with a
0.040" Conidur rasping plate at 500 rpm. Material was analyzed as described in
Example
2, and results are reported in Table 1.
EXAMPLE 4
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM USING
A WET GRANULATION WITH SODIUM STARCH GLYCOLATE
Amorphous atorvastatin calcium, prepared as described in Example 1 ( 1.3 g),
39.0 g of microcrystalline cellulose (Avicel PH102~, FMC Biopolymer,
Philadelphia,
PA), 50.7 g of lactose, hydrous (Foremost Farms USA, Rothschild,WI), 3.0 g of
sodium
starch glycolate, (Explotab'~, Penwest Pharmaceuticals Co., Cedar Rapids, IA)
and 2.0 g
of hydroxypropyl cellulose (Klucel EXF~, Hercules Incorporated, Aqualon
Division,
Wilmington, DE) were combined in a 500-cc bottle and mixed for 10 min. using a
Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel,
Switzerland).
The formulation was then granulated using a Pro-C-epT Mi Mi Pro high shear wet
granulator (Pro-C-epT n.v., B- 9060 Zelzate, Belgium) using a 0.9 L bowl. The
formulation was dry-mixed for 2 min. at an impeller speed of 400 rpm and
chopper speed
of 1000 rpm. Wet mixing was done at a 600-rpm impeller speed and 1000-rpm
chopper
speed. Water was added in increments of 10-30 g at 20-30 glmin. for a total of
55 g using
a standard 60-cc syringe. The material was wet-mixed for a total of 5.5 min.
The
granulation was wet sieved through a #10 mesh sieve by hand to achieve a more
uniform
granule size before drying. The granulation was tray-dried overnight at
50°C for 16 hrs. in
a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co.,
Williamsport, PA). The granulation was then milled using a Fitzpatrick LlA
mill with a
0.040" Conidur rasping plate at 500 rpm. Material was analyzed as described in
Example
2, and results are reported in Table 1.
EXAMPLE 5
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM USING
A WET GRANULATION WITH CORN STARCH
Amorphous atorvastatin calcium, prepared as described Example 1 (1.3 g), 39.0
g
of microcrystalline cellulose (Avicel PH102~, FMC Biopolymer, Philadelphia,
PA), 50.7
CA 02465565 2004-04-29
-20-
g of lactose, hydrous (Foremost Farms USA, Rothschild,WI), 3.0 g of corn
starch - Purity
21 (National Starch and Chemical Corp., Bridgewater, NJ) and 2.0 g of
hydroxypropyl
cellulose (Klucel EXF'~, Hercules Incorporated, Aqualon Division, Wilmington,
DE)
were combined in a 500-cc bottle and mixed for 10 min. using a Turbula Shaker
Mixer
(Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The formulation
was then
granulated using a Pro-C-epT Mi Mi Pro high shear wet granulator (Pro-C-epT
n.v., 8-
9060 Zelzate, Belgium) using a 0.9 L bowl. The formulation was dry-mixed for 2
min. at
an impeller speed of 400 rpm and chopper speed of 1000 rpm. Wet mixing was
done at a
600-rpm impeller speed and 1000-rpm chopper speed. Water was added in
increments of
10-30 g at 20-30 g/min. for a total of 45 g using a standard 60-cc syringe.
The material
was wet-mixed for a total of 2.5 min. The granulation was wet sieved through a
#8 mesh
sieve by hand to achieve a more uniform granule size before drying. The
granulation was
tray-dried overnight at 50°C for 16 hrs, in a forced hot air dryer
(Gruenberg Forced Hot
Air Oven, Gruenberg Oven Co., Williamsport, PA). The granulation was then
milled
using a Fitzpatrick L1A mill with a 0.040" Conidur rasping plate at 500 rpm.
Material
was analyzed as described in Example 2, and results are reported in Table 1.
EXAMPLE 6
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM USING
A WET GRANULATION WITH PREGELATINZED STARCH
Amorphous atorvastatin calcium, prepared as described in Example 1 (1.3 g),
39.0 g of microcrystalline cellulose (Avicel PH102"~, FMC Biopolymer,
Philadelphia,
PA), 50.? g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 3.0 g of
pregelatinized starch (Starch 1500, Colorcon, West Point, PA) and 2.0 g of
hydroxypropyl cellulose (Klucel EXF'~''~, Hercules Incorporated, Aqualon
Division,
Wilmington, DE) were combined in a 500-cc bottle and mixed for 10 min. using a
Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel,
Switzerland).
The formulation was then granulated using a Pro-C-epT Mi Mi Pro high shear wet
granulator (Pro-C-epT n.v., B- 9060 Zelzate, Belgium) using a 0.9 L bowl. The
formulation was dry-mixed for 2 min. at an impeller speed of 400 rpm and
chopper speed
of 1000 rpm. Wet mixing was done at a 600-rpm impeller speed and 1000-rpm
chopper
speed. Water was added in increments of 10-30 g at 20-30 glmin. for a total of
40 g using
a standard 60-cc syringe. The material was wet-mixed for a total of 3 min. The
granulation was wet sieved through a #8 mesh sieve by hand to achieve a more
uniform
granule size before drying. The granulation was tray-dried overnight at
50°C for 16 hrs. in
CA 02465565 2004-04-29
-21-
a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co.,
Williamsport, PA). The granulation was then milled using a Fitzpatrick L1A
mill with a
0.040" Conidur rasping plate at 500 rpm. Material was analyzed as described in
Example
2, and results are reported in Table 1.
EXAMPLE 7
PREPARATION OF AMORPHOUS ATORVASTATIN USING
A WET GRANULATION WITH SODIUM ALGINATE
Amorphous atorvastatin calcium, prepared as described in Example 1 (40.5 mg),
1.22 g of microcrystalline cellulose (Avicel PH102'~'', FMC Biopolymer,
Philadelphia,
PA), 1.58 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg
of
sodium alginate (Protanal~, FMC BioPolymer, Philadelphia, PA) and 62.4 mg of
hydroxypropyl cellulose (Klucel EXF~, Hercules Incorporated, Aqualon Division,
Wilmington, DE) were combined in a 30-cc bottle and mixed for 10 min. using a
Turbula
Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The
mixture
was then granulated in the 30-cc bottle, using a bent micro-spatula impeller
with a 1/2"
blade on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron
Precision
Engineering Co., Sonora, CA 95370). Prior to use, the blade was bent to an
angle
sufficient to sweep the material being granulated, and to allow a portion of
this material to
flow over the top of the blade. The blade was bent to an angle about
30° from vertical.
The granulating fluid was pipetted in 1.0 to 0.5 mL increments, wet mixing for
2.5 min.
until a suitable granulation was formed based upon visual observations (total
of 1.5 mL
added). The granulation was tray-dried for 16 hrs at 50°C in a forced
hot air dryer
(Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA).
Material was
analyzed as described in Example 2, and results are reported in Table 1.
EXAMPLE 8
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM USING
A WET GRANULATION WITH ALGINIC ACID
Amorphous atorvastatin calcium, prepared as described in Example 1 (40.5 mg),
1.22 g of microcrystalline cellulose (Avicel PH102~, FMC Biopolymer,
Philadelphia,
PA), 1.58 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg
of
CA 02465565 2004-04-29
-22-
alginic acid (Protacid"~, FMC BioPolymer, Philadelphia, PA) and 62.4 mg of
hydroxypropyl cellulose (Klucel EXF~, Hercules Incorporated, Aqualon Division,
Wilmington, DE) were combined in a 30-cc bottle and mixed for 10 min. using a
Turbula
Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The
mixture
was then granulated in the 30-cc bottle, using a bent micro-spatula impeller
with a 1/2"
blade on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron
Precision
Engineering Co., Sonora, CA 95370). Prior to use, the blade was bent to an
angle
sufficient to sweep the material being granulated, and to allow a portion of
this material to
flow over the top of the blade. The blade was bent to an angle about
30° from vertical.
The granulating fluid was pipetted in 1.0 to 0.5 mL increments, wet mixing for
2.5 min.
until a suitable granulation was formed based upon visual observations (total
of 1.5 mL
added). The granulation was tray-dried for 16 hrs at 50°C in a forced
hot air dryer
(Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA).
Material was
analyzed as described in Example 2, and results are reported in Table 1.
EXAMPLE 9
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM USING
A WET GRANULATION WITH POWDERED CELLULOSE
Amorphous atorvastatin calcium, prepared as described in Example 1 (40.5 mg),
1.22 g of microcrystalline cellulose (Avicel PH102~, FMC Biopolymer,
Philadelphia,
PA), 1.5$ g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg
of
powdered cellulose (Solka-Floc 40NF~,International Fiber Corp., North
Tonawanda,
NY) and 62.4 mg of hydroxypropyl cellulose (Klucel EXF~, Hercules
Incorporated,
Aqualon Division, Wilmington, DE) were combined in a 30-cc bottle and mixed
for 10
min. using a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik,
Basel,
Switzerland). The mixture was then granulated in the 30-cc bottle, using a
bent micro-
spatula impeller with a ll2" blade on a variable speed mini-drill press (Micro-
Drill model
164C-7, Cameron Precision Engineering Co., Sonora, CA 95370). Prior to use,
the blade
was bent to an angle sufficient to sweep the material being granulated, and to
allow a
portion of this material to flow over the top of the blade. The blade was bent
to an angle
about 30° from vertical. The granulating fluid was pipetted in 1.0 to
0.5 mL increments,
wet mixing for 2.5 min. until a suitable granulation was formed based upon
visual
observations (total of 1.5 mL added). The granulation was tray-dried for 16
hrs at 50°C
in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co.,
CA 02465565 2004-04-29
-23-
Williamsport, PA). Material was analyzed as described in Example 2, and
results are
reported in Table I.
EXAMPLE 10
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM USING
A WET GRANULATION WITH HYDROXYPROPYLCELLULOSE
Amorphous atorvastatin calcium, prepared as described in Example 1 (40.5 mg),
1.22 g of microcrystalline cellulose (Avicel PH102~, FMC Biopolymer,
Philadelphia,
PA), 1.58 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg
of
hydroxypropylcellulose (low substitution grade, Shin-Etsu Chemical Co., Tokyo,
Japan)
and 62.4 mg of hydroxypropyl cellulose (Klucel EXF""I, Hercules Incorporated,
Aqualon
Division, Wilmington, DE) were combined in a 30-cc bottle and mixed for 10
min. using
a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel,
Switzerland).
The mixture was then granulated in the 30-cc bottle, using a bent micro-
spatula impeller
with a ll2" blade on a variable speed mini-drill press (Micro-Drill model 164C-
7,
Cameron Precision Engineering Co., Sonora, CA 95370). Prior to use, the blade
was bent
to an angle sufficient to sweep the material being granulated, and to allow a
portion of
this material to flow over the top of the blade. The blade was bent to an
angle about 30°
from vertical. The granulating fluid was pipetted in 1.0 to 0.5 mL increments,
wet mixing
for 2.5 min. until a suitable granulation was formed based upon visual
observations (total
of 1.5 mL added). The granulation was tray-dried for 16 hrs at 50°C in
a forced hot air
dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA).
Material was analyzed as described in Example 2, and results are reported in
Table 1.
EXAMPLE 11
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM USING
A WET GRANULATION WITH MAGNESIUM ALUMINUM SILICATE
Amorphous atorvastatin calcium, prepared as described in Example 1 (40.5 mg),
1.22 g of microcrystalline cellulose (Avicel PH102~, FMC Biopolymer,
Philadelphia,
PA), 1.58 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg
of
magnesium aluminum silicate (Veegum F~'~'', R.T. Vanderbilt Co., Norwalk, CT)
and 62.4
mg of hydroxypropyl cellulose (Klucel EXF~, Hercules Incorporated, Aqualon
Division,
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Wilmington, DE) were combined in a 30-cc bottle and mixed for 10 min. using a
Turbula
Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The
mixture
was then granulated in the 34-cc bottle, using a bent micro-spatula impeller
with a 1/2"
blade on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron
Precision
Engineering Co., Sonora, CA 95370). Prior to use, the blade was bent to an
angle
sufficient to sweep the material being granulated, and to allow a portion of
this material to
flow over the top of the blade. The blade was bent to an angle about
30° from vertical.
The granulating fluid was pipetted in 1.0 to 0.5 mL, increments, wet mixing
for 2.5 min.
until a suitable granulation was formed based upon visual observations (total
of 1.5 mL
added). The granulation was tray-dried for 16 hrs at 50°C in a forced
hot air dryer
(Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA).
Material was
analyzed as described in Example 2, and results are reported in Table 1.
EXAMPLE 12
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM USING
A WET GRANULATION WITH POLACRILIN POTASSIUM
Amorphous atorvastatin calcium, prepared as described in Example 1 (40.5 mg),
1.22 g of microcrystalline cellulose (Avicel PH102~, FMC Biopolymer,
Philadelphia,
PA), 1.58 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg
of
polacrilin potassium (Amberlite IRP88'~~'', Rohm and Haas Co., Philadelphia,
PA) and
62.4 mg of hydroxypropyl cellulose (Klucel EXF~, Hercules Incorporated,
Aqualon
Division, Wilmington, DE) were combined in a 30-cc bottle and mixed for 10
min. using
a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel,
Switzerland).
The mixture was then granulated in the 30-cc bottle, using a bent micro-
spatula impeller
with a 1/2" blade on a variable speed mini-drill press (Micro-Drill model 164C-
7,
Cameron Precision Engineering Co., Sonora, CA 95370). Prior to use, the blade
was bent
to an angle sufficient to sweep the material being granulated, and to allow a
portion of
this material to flow over the top of the blade. The blade was bent to an
angle about 30°
from vertical. The granulating fluid was pipetted in 1.0 to 0.5 mL increments,
wet mixing
for 2.5 min. until a suitable granulation was formed based upon visual
observations (total
of 1.5 mL added). The granulation was tray-dried for 16 hrs at 50°C in
a forced hot air
dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA).
Material was analyzed as described in Example 2, and results are reported in
Table 1.
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Table 1 Effect on drug purity of material formed by wet granulations of
atorvastatin with intragranular disintegrants.
ExampleDisintegrant % Atorvastatin Lactone
No. (as
determined by HPLC)
2 control (no disintegrant)0.21
3 croscarmellose sodium5.47
4 sodium starch glycolate0.41
corn starch 0.25
6 pregelatinized starch0.20
7 sodium alginate 0.52
8 alginic acid 15.71
9 powdered cellulose 0.41
hydroxypropylcellulose0.38
11 magnesium aluminum 0.12
silicate
12 polacrilin potassium 0.29
5
EXAMPLE 13
PREPARATION OF WET GRANULATIONS OF ATORVASTATIN AND
TABLETS THEREOF WITH PROCESS PROVIDING PURE ATORVASTATIN
WITH RANGE OF DISINTEGRANTS
To 13.30 g of material prepared in Example 2 was added 0.858 g of one of the
following disintegrants: (a) sodium starch glycolate; (b) croscarmellose
sodium; (c) corn
starch, or (d) pregelatinized starch in a 60-cc bottle. The blends were mixed
for 5 min.
using a Turbula Shaker Mixer. To this blend was added, in each case, 0.143 g
of
magnesium stearate (Mallinckrodt Co., St. Louis, MO). The formulations were
then
blended 3 min. using a Turbula Shaker Mixer. Material was analyzed for the
level of
lactone as described in Example 2 and results are reported in Table 2. Tablets
were made
under manual power using a single station Manesty F-Press (Manesty, Liverpool,
United
Kingdom). A 13/32" SRC punch and die was used to produce tablets with weights
of 450
mg each. The target tablet hardness was 12 kP with a range of 10-14 kP (tablet
hardness
was tested using a Schleuniger Tablet Hardness Tester, Dr. Schleuniger
Pharmatron AG,
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Solothurn, Switzerland). Material was analyzed a described in Example 2 and
results are
reported in Table 2.
Table 2 Unexpected beneficial effect on drug purity for wet granulations of
atorvastatin with extragranular disintegrants.
ExampleDisintegrant % Atorvastatin Lactone
(as
determined by HPLC)
2 control, no disintegrant0.21
13a sodium starch glycolate0.25
13b croscarmellose sodium 0.24
13c corn starch 0.24
13d pregelatinized starch 0.24
EXAMPLE 14
CONTROL OF WET GRANULATION OF ATORVASTATIN WITH NO
VOLATILE BASE
Amorphous atorvastatin calcium prepared as described in Example 1 (62.1
mg), 1772.1 mg of microcrystalline cellulose (Avicel PH102~, FMC
Biopolymer, Philadelphia, PA), 1010.4 mg of lactose, hydrous (Foremost Farms
USA, Rothschild,WI), 62.1mg of hydroxypropyl cellulose (Klucel EXF~,
Hercules Incorporated, Aqualon Division, Wilmington, DE), and 93.3 mg of
croscarmellose sodium (Ac-Di-Sol~, FMC Biopolymer, Philadelphia, PA) were
placed in a 30-cc glass bottle. The combined dry components were mixed for 10
min. using a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik,
Basel, Switzerland). The mixture was then granulated in the 30-cc bottle,
using a
bent micro-spatula impeller with a 1/2" blade on a variable speed mini-drill
press
(Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA
95370). Prior to use, the blade was bent to an angle sufficient to sweep the
material being granulated, and to allow a portion of this material to flow
over the
top of the blade. The blade was bent to an angle about 30° from
vertical. The
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granulating fluid was pipetted in 0.5 to 1.0 mL increments, wet mixing for 4
min.
until a suitable granulation was formed based upon visual observations (total
of
2.5 mL added). The wet granulation was dried overnight at 50°C for 16
hr. in a
forced hot air tray dryer. Material was analyzed for the level of lactone as
S described in Example 2, with the modification of using 275 mg granulation
instead of 400 mg. Results are reported in Table 3.
EXAMPLE 15
PREPARATION OF WET GRANULATIONS OF AMORPHOUS
ATORVASTATIN WITH VOLATILE BASES
Amorphous atorvastatin calcium prepared as described in Example 1 (62.1 mg),
1772.1 mg of microcrystalline cellulose (Avicel PH102'~, FMC Biopolymer,
Philadelphia, PA), 1010.4 mg of lactose, hydrous (Foremost Farms USA,
Rothschild,Wn, 62.1mg of hydroxypropyl cellulose (Klucel EXF~, Hercules
Incorporated, Aqualon Division, Wilmington, DE), and 93.3 mg of croscarmellose
sodium (Ac-Di-Sol"'~, FMC Biopolymer, Philadelphia, PA) were placed in a 30-cc
glass
bottle. The combined dry components were mixed for 10 min. using a Turbula
Shaker
Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The mixture
was
then granulated as described in the control above using volatile base
solutions for the
tests: (a) 2.5 mL of 30% ammonium hydroxide (J. T. Baker Co.), (b) 2.5 mL of
3%
ammonium hydroxide, (c) 2.5 mI. of 0.00012% ammonium hydroxide, (d) 2.0 mL of
40%
tetrabutylammonium hydroxide (Mallinckrodt Co.). The wet granulations were
dried
overnight at 50°C for 16 hr. in a forced hot air tray dryer. For each
sample, material was
analyzed for the level of lactone as described in Example 2, with the
modification of
using 150 mg of the granulation and the extraction volume of 30 mL. Results
are reported
in Table 3.
Table 3 Unexpected beneficial effect on drug purity for wet granulations of
atorvastatin with added volatile bases.
ExampleVolatile Base % Atorvastatin Lactone
(as
determined by HPLC)
14 control, no base 4.35
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15a 30% ammonium hydroxide 0.47
15b 3% ammonium hydroxide 0.46
15c 0.00012% ammonium hydroxide2.75
15d 40% tetrabutylammonium hydroxidebelow limit of quantification
(<0.1 %)
EXAMPLE 16
PREPARATION OF WET GRANULATIONS OF AMORPHOUS
ATORVASTATIN WITH DRYING AT DIFFERENT TEMPERATURES
Amorphous atorvastatin calcium as prepared in Example 1 (40.5 mg), 1218.8 mg
of microcrystalline cellulose (Avicel PH102~'~'', FMC Biopolymer,
Philadelphia, PA),
1572.1 mg of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 62.5mg of
hydroxypropyl cellulose (Klucel EXF~, Hercules Incorporated, Aqualon Division,
Wilmington, DE), and 93.8 mg of sodium starch glycolate (Explotab"~ , Penwest
Pharmaceuticals Co., Cedar Rapids, IA) were placed in a 30-cc glass bottle.
The
combined dry components were mixed for 10 min. using a Turbula Shaker Mixer
(Willy
A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The granulating liquid,
made in
excess, was made by combining 99g of H20 with lg of polysorbate 80 (Tween
80'x'',
Spectrum Chemicals & Lab Products, Gardena, CA) in a 125 mL flask and mixing.
The
powder mixture was then granulated as described in Example 1 using 2.5 mL of
the
granulating liquid, wet mixing for 4 min. The wet granulation was then divided
into three
approximately equal portions. Each portion was dried under the following
conditions for
16 hr.: (a) 30°C vacuum oven, (b) 50°C convection oven, and (c)
70°C vacuum oven. For
each sample, material was analyzed for the level of lactone (based on the
ratio of lactone
peak integration compared to the total peak integrated areas using HPLC) by
adding 300
mg of material to 1:2:2 (v:v:v) of 0.05M ammonium acetate buffer (pH
7.4):acetonitrileaetrahydrofuran and shaking for 20 minutes. This mixture was
filtered
using a disposable 0.45 ~tm polytetrafluoroethylene membrane (Whatman) and
analyzed
using an HPLC (HP 1100, Zorbax SB-C8 5 pm particle size, 25.0 cm x 4.6 mm
column,
thermostated to 35°C; injection volume 20 pL,; flow rate 1.5 mL/min.;
244 nm detection).
The elution used a linear gradient starting from a 67:21:12 (v:v:v) and
switching to
54:34:12 (v:v:v) of 0.05M ammonium acetate buffer (pH
S.0):acetonitrileaetrahydrofuran
after 40 minutes (100% of the latter mixture after 55 minutes).Results
reported in Table 4.
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Table 4 Unexpected beneficial effect on drug purity for wet granulations of
atorvastatin when dried at lower temperatures.
Example Drying Conditions% Atorvastatin Lactone (as determined
by
HPLC)
16a 30C vacuum oven0.25
16b 50C convection 1.18
oven
16c ?0C vacuum oven4.36
