Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL CRUDE AND CRYSTALLINE FORMS OF LERCANIDIPINE
HYDROCHLORIDE
FIELD OF THE INVENTION
The invention is directed to novel crude forms, crystalline forms, and solvate
of
lercanidipine hydrochloride, and to processes for the preparation of these
forms.
Pharmaceutical compositions comprising the novel crystalline forms are also
contemplated.
BACKGROUND OF THE INVENTION
Lercanidipine (methyl 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-
dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate) is a highly
lipophilic
dihydropyridine calcium antagonist with long duration of action and high
vascular
selectivity. Its mechanism of antihypertensive activity is attributed to a
direct relaxant
effect on vascular smooth muscle, which lowers total peripheral resistance.
The
recommended starting dose of lercanidipine as monotherapy is 10 mg daily by
oral route,
with a drug titration as necessary to 20 mg daily. Lercanidipine is rapidly
absorbed
following oral administration with peak plasma levels occurring 2-3 hours
following
dosing. Elimination is essentially via the hepatic route.
By virtue of its high lipophilicity and high membrane coefficient,
lercanidipine
combines a short plasma half life with a long duration of action. In fact, the
preferential
distribution of the drug into membranes of smooth muscle cells results in
membrane-
controlled pharmacokinetics characterized by a prolonged pharmacological
effect. In
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comparison to other calcium antagonists, lercanidipine is characterized by
gradual onset
and long-lasting duration of action despite decreasing plasma levels. In vitro
studies
show that isolated rat aorta response to high K+ may be attenuated by
lercanidipine, even
after the drug has been removed from the environment of the aortic tissue for
6 hours.
Lercanidipine is commercially available from Recordati S.p.A. (Milan, Italy)
and
has been described along with methods for making it and resolving it into
individual
enantiomers in U.S. Patents 4,705,797; 5,767,136; 4,968,832; 5,912,351; and
5,696,139.
A process for preparing lercanidipine described in U.S. Patent No. 4,705,797
involves the following scheme:
Ph
/~Ph CH3 (1) ~/^\`~
H3C\
+CI/~ C
N Ph Ph
OH CH3
CH3
NOb\~- O O CH3 Ph 0
(zh h H
0 CH3 O-~ N Ph ON
(2) I I (3)
CH3 CH3
0 H2N
N02 CH33 ^ Ph
O-I N' v 'Ph OOCH3
CH3 CH3
O CH3
(4)
0 Lercanidipine
(1): xylene at reflux; (2): toluene, 85 C; (3) HCI +CHa3; 0 C; (4) HO-CH(CH3)2
at reflux
Crude lercanidipine is an oily residue that must be purified by flash
chromatography
using chloroform, containing increasing amounts of acetone, as the eluant. The
solvent
is then evaporated to dryness and remaining residue is dissolved in methanol
adding a
small excess of hydrochloric acid in ethanol. After evaporation of the
solvent, the hemi-
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hydrated hydrochloride salt is prepared by treatment with diluted hydrochloric
acid in the
presence of sodium chloride.
A major disadvantage of the process of preparing lercanidipine, as it is
described
in U.S. Patent No. 4,705,797, is that the disclosed cyclization reaction
generates several
by-products, which results in a lower yield for the desired product. Moreover,
the
purification and isolation of lercanidipine from the reaction mixture is quite
complex,
since it requires numerous treatments with different solvents. Finally, the
purification
and isolation steps are difficult to perform on an industrial scale because of
the necessity
of purifying the product by column chromatography.
U.S. Patent 5,912,351 describes a simpler process for the preparation of
lercanidipine hydrochloride. It involves reaction of 1,4-dihydro-2,6-dimethyl-
5-
methoxycarbonyl-4- (3-nitrophenyl) pyridine-3-carboxylic acid with thionyl
chloride in
dichloromethane and dimethylformamide at a temperature between -4 and +1 C
and
subsequent esterification of the obtained acid chloride with 2, N-dimethyl-N-
(3,3-
diphenylpropyl)-1-amino-2-propyl alcohol at a temperature between -10 and 0 C.
The
process yields lercanidipine hydrochloride in an anhydrous non-hygroscopic
crystalline
form, and avoids the formation of unwanted by-products and the subsequent
purification
on chromatography columns.
However, the isolation of lercanidipine hydrochloride in crystalline form is
again
quite complex. After evaporating the solvent from the reaction mixture and
dissolving
the residue thus obtained in ethyl acetate, the solution is washed first with
brine, then
washed further five times with a 10% solution of sodium carbonate, five times
with IN
hydrochloric acid, and eventually once again with brine.
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Therefore, there is a need in the art for a process for the preparation of
lercanidipine hydrochloride in crystalline form which avoids one more of the
disadvantages of the currently used processes.
In addition, it was observed that lercanidipine, as produced by the second-
described process above, displayed batch-to-batch variability despite careful
process
control and even observation of the melting point believed to be
characteristic of the
solid product obtained by the process of Example 3 of USP 5,767,136 of 186-
188EC.
This variability was manifest in seemingly unpredictably appearing (and
disappearing)
differences in one or more of product appearance (e.g., color), melting point
and
solubility. This raised issues as to whether assurances of purity and/or
reproducibility
can be made (e.g., to regulatory authorities) that the product is always the
same.
Further research by the present inventors revealed batch-to-batch differences
in
bioavailability in animals, and differences in crystal size. In the course of
researching
the causes of the variability problem, the inventors surprisingly discovered
novel
lercanidipine hydrochloride polymorphs. They also discovered more suitable
processes
for the preparation and isolation of crystalline lercanidipine hydrochloride
products from
the reaction mixture. It was surprisingly determined that lercanidipine
hydrochloride
shows polymorphic features and crystallizes into different crystalline forms
depending
on the process followed and on the solvents used. Furthermore, the isolation
of each of
individual crystalline polymorphs has become possible, thus decreasing the
possibility of
batch to batch variability of lercanidipine, which the present inventors
determined was
due to mixtures of different solid forms being present by the same batch and
to such
mixtures of different composition having melting points within the same narrow
range as
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the individual forms. As a result, more reproducible batches of lercanidipine
more
suitable for large scale manufacture and quality control were needed.
Accordingly, herein Applicants disclose crude lercanidipine Forms (A) and (B)
and two crystalline forms formed therefrom, as well as two additional novel
crystalline
forms which are formed from novel solvate forms of lercanidipine.
SUMMARY OF THE INVENTION
The present invention provides novel crude forms, crystalline forms and
solvates
of lercanidipine hydrochloride and processes for making them.
In one embodiment, the invention provides novel crude lercanidipine
hydrochloride Form (A), which has a melting point of about 150-152EC (DSC
peak) and
comprises about 3-4% (w/w) ethyl acetate.
In another embodiment, the invention provides novel crude lercanidipine
hydrochloride Form (B) which has a melting point of about 131-135EC (DSC peak)
and
comprises about 0.3-0.7% (w/w) ethyl acetate.
Methods are provided for the independent syntheses of crude lercanidipine
hydrochloride Form (A) and crude lercanidipine hydrochloride Form (B), making
possible to obtain each crude form in isolated form.
In a further embodiment, isolated lercanidipine hydrochloride crystalline Form
(I)
is provided which has the following X-ray diffraction pattern, at wavelength
Ka wherein
distances between peaks (D in X), relative intensity ratios (1/lo) ratios, and
angles of
significant peaks (20) are:
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dLA) Relative intensity (1/lo) 2 0 angle
16.3 83 5.4
6.2 47 14.2
4.78 29 18.6
4.10 63 21.7
4.06 36 21.9
3.90 100 22.8
The lercanidipine hydrochloride crystalline Form (I) has a melting point of
about
197-201 EC, when said melting point is determined as DSC peak.
In an alternative embodiment, isolated lercanidipine hydrochloride crystalline
Form (II) is provided, which has the following X-ray diffraction pattern, at
wavelength
Ka, as shown wherein distances, (1/lo) ratios, and 2 0 angles of significant
peaks are:
d(A) Relative intensity (1/lo) 2 0 angle
9.3 35 9.5
6.0 45 14.7
5.49 65 16.1
4.65 52 19.1
4.27 74 20.8
3.81 41 23.4
3.77 100 23.6
3.58 44 24.8
3.54 29 25.2
The lercanidipine hydrochloride crystalline Form (II) has a melting point of
about
207-211EC, when said melting point is determined as DSC peak.
The present invention thus permits obtaining mixtures of Form I and Form II
having a predetermined and reproducible content of each form, and optionally,
also other
forms of lercanidipine, such as amorphous.
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Also provided are methods of syntheses in which each of isolated lercanidipine
hydrochloride crystalline Form (I) and Form (II) may be obtained,
independently, from
the starting material of lercanidipine hydrochloride crude Form (A) or crude
Form (B).
Also provided are pharmaceutical compositions comprising (1) crystalline
lercanidipine hydrochloride and optionally other forms of lercanidipine, such
as
amorphous, wherein the crystalline lercanidipine hydrochloride is selected
from the
group consisting of lercanidipine hydrochloride crystalline Form (I),
lercanidipine
hydrochloride crystalline Form (II), and combinations thereof comprising a
predetermined content of each crystalline form, and (2) at least one component
selected
from the group consisting of a pharmaceutically acceptable carrier or diluent,
a flavorant,
a sweetener, a preservative, a dye, a binder, a suspending agent, a dispersing
agent, a
colorant, a disintegrant, an excipient, a lubricant, a plasticizer, and an
edible oil.
In certain embodiments the aforementioned pharmaceutical compositions are
provided as a dosage form comprising lercanidipine hydrochloride crystalline
Form (I) or
Form (II) or a combination thereof having a predetermined formulation of each
crystalline Form.
In further embodiments, the invention also provides for methods of treating a
subject with arterial hypertension, the method comprising administering a
therapeutically
effective amount of lercanidipine hydrochloride crystalline Form (I),
lercanidipine
hydrochloride crystalline Form (II), or combinations thereof comprising a
predetermined
content of each form to a subject in need of such treatment.
In other embodiments, a method of treating or preventing atherosclerotic
lesions
in arteries of a subject is provided, the method comprising administering a
therapeutically effective amount of lercanidipine hydrochloride crystalline
Form (I),
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lercanidipine hydrochloride crystalline Form (II), or combinations thereof
comprising a
predetermined amount of each form, to a subject in need of such treatment. In
preferred
aspect, a subject in need of treatment is a mammal. Most preferably the
subject in need
of treatment is a human.
In certain embodiments, the invention provides solvates of lercanidipine
hydrochloride comprising lercanidipine hydrochloride and an organic solvent.
In
preferred embodiments, the solvent is selected from the group consisting of
methylene
chloride, acetone, anisole, tetrahydrofuran, terbutyl methyl ether,
isopropanol, 2-butanol,
heptane, methyl ethyl ketone, and ethyl acetate.
In one embodiment, the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is methylene chloride, the lercanidipine
hydrochloride-methylene chloride content is 1:1 (mole/mole), and the solvate
has, at
wavelength Ka, an X-ray diffraction image expressed by the following Table:
4-CA
~ Relative intensity (1/lo) 2 0 angle
6.6 40 13.4
5.87 42 15.1
5.04 39 17.6
4.00 96 22.2
3.90 29 22.8
3.86 34 23.0
3.67 100 24.2
2.04 31 44.4
In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is anisole, the lercanidipine hydrochloride-
anisole
content is 1:0.4 (mole/mole), and the solvate (a) form has, at wavelength Ka,
an X-ray
diffraction image expressed by the following Table:
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d(A) Relative intensity (%) Angle ( 20)
17.4 62 5.1
7.6 34 11.6
5.71 43 15.5
5.57 58 15.9 -
4.99 47 17.7
4.62 40 19.2
4.44 29 20.0
4.28 98 20.8
4.04 100 22.0
3.19 43 27.9
2.92 36 30.6
2.86 42 31.3
In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is anisole, the lercanidipine hydrochloride-
anisole
content is 1:0.4 (mole/mole), and the solvate (b) form has, at wavelength Ka,
an X-ray
diffraction image expressed by the following Table:
d(A) Relative intensity (%) Angle ( 20)
6.9 49 12.8
6.7 63 13.3
5.82 86 15.2
5.27 41 16.8
5.15 53 17.2
4.00 47 22.2
3.89 46 22.8
3.66 100 24.3
In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is acetone, the lercanidipine hydrochloride-
acetone
content is 1:1.2 (mole/mole), and the solvate has, at wavelength Ka, an X-ray
diffraction
image expressed by the following Table:
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d(A) Relative intensit(1/lo) 2 0 angle
10.1 42 8.8
7.3 100 12.1
5.87 31 15.1
4.07 41 21.8
3.96 52 22.4
3.79 49 23.5
3.71 37 24.0
3.34 33 26.7
In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is ethyl acetate, the lercanidipine
hydrochloride-ethyl
acetate content is 1:1 (mole/mole), and the solvate has, at wavelength Ka, an
X-ray
diffraction image expressed by the following Table:
d (A) Relative intensit(1/lo) 2 0 angle
6.9 100 12.8
6.3 29 14.0
5.80 45 15.3
5.65 31 15.7
5.43 44 16.3
4.74 53 18.7
4.53 49 19.6
4.00 84 22.2
3.91 91 22.7
3.67 77 24.2
3.60 34 24.7
3.53 34 25.2
3.49 43 25.5
In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is terbutyl methyl ether, the lercanidipine
hydrochloride- terbutyl methyl ether content is 1:0.8 (mole/mole), and the
solvate has, at
wavelength Ku, an X-ray diffraction image expressed by the following Table:
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d (A) Relative intensity (1/lo) 2 0 angle
6.2 77 14.2
4.88 29 18.2
4.52 64 19.6
4.02 48 22.1
3.93 100 22.6
3.43 46 26.0
In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is isopropanol, the lercanidipine
hydrochloride-
isopropanol content is 1:1 (mole/mole), and the solvate has, at wavelength Ka,
an X-ray
diffraction image expressed by the following Table:
d (A) Relative intensity (1/lo) 2 0 angle
6.6 35 13.5
5.85 48 15.1
5.06 41 17.5
4.04 64 22.0
3.90 39 22.8
3.72 37 23.9
3.67 100 24.2
In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is 2-butanol, the lercanidipine
hydrochloride-2-
butanol content is 1:0.8 (mole/mole), and the solvate has, at wavelength Ka,
an X-ray
diffraction image expressed by the following Table:
d (A) Relative intensity (1/lo) 2 0 angle
6.8 34 13.1
5.86 36 15.1
5.13 42 17.3
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4.03 51 22.0
3.90 36 22.8
3.67 100 24.2
In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is heptane, the lercanidipine hydrochloride-
heptane
content is 1:0.9 (mole/mole), and the solvate has, at wavelength Ka, an X-ray
diffraction
image expressed by the following Table:
d (A) Relative intensity (1/lo) 2 0 angle
7.3 54 12.2
6.0 44 14.7
4.03 85 22.0
3.85 100 23.1
3.76 93 23.6
3.63 67 24.5
3.38 39 26.4
3.01 47 29.6
In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is methyl ethyl ketone, the lercanidipine
hydrochloride-methyl ethyl ketone content is 1:0.7 (mole/mole), and the
solvate has, at
wavelength Ka, an X-ray diffraction image expressed by the following Table:
Relative intensity (1/lo) 2 0 angle
6.8 50 13.1
6.1 43 14.5
5.87 47 15.1
5.10 53 17.4
3.99 100 22.2
3.87 48 22.9
3.74 36 23.8
3.69 65 24.1
3.61 70 24.6
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In another embodiment the invention provides a solvate of lercanidipine
hydrochloride wherein the solvent is tetrahydrofuran, the lercanidipine
hydrochloride-
tetrahydrofuran content is 1:0.9 (mole/mole), and the solvate has, at
wavelength Ka, an
X-ray diffraction image expressed by the following Table:
Relative intensity (1/lo) 2 0 angle
6.6 100 13.5
5.88 32 15.1
5.12 56 17.3
4.25 38 20.9
4.06 50 21.9
3.92 42 22.7
3.75 44 23.7
3.70 90 24.0
3.64 31 24.4
In yet another embodiment, the invention provides isolated lercanidipine
hydrochloride crystalline form (III), having a melting point in the range of
137-150 C
and having an X-ray diffraction image, at wavelength Ka, expressed by the
following
Table:
d (A) Relative intensity (1/lo) 2 0 angle
11.5 39 7.7
9.1 38 9.7
9.0 37 9.8
8.0 50 11.0
6.6 48 13.5
5.58 57 15.9
5.49 34 16.1
5.13 43 17.3
4.09 63 21.7
3.92 43 22.7
3.72 100 23.9
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3.60 85 24.7
3.47 31 25.6
In another embodiment, the invention provides crystalline form (IV), having a
melting point in the range of 116-135 C and having an X-ray diffraction image,
at
wavelength Ka, expressed by the following Table:
d (A) Relative intensity (1/lo) 2 0 angle
7.9 71 11.2
6.9 53 12.7
5.21 57 17.0
5.13 46 17.3
4.73 66 18.8
4.69 95 18.9
4.53 53 19.6
4.40 81 20.2
4.34 43 20.4
3.99 44 22.2
3.89 52 22.8
3.77 100 23.6
3.69 35 24.1
Also provided are pharmaceutical compositions comprising (1) lercanidipine
hydrochloride crystalline Form (III) or lercanidipine hydrochloride
crystalline Form
(IV), and combinations thereof, comprising a predetermined content of each
crystalline
form, and optionally including other forms of lercanidipine, such as,
amorphous
lercanidipine, lercanidipine hydrochloride crystalline Form (I) or
lercanidipine
hydrochloride crystalline Form (II), and (2) at least one component selected
from the
group consisting of a pharmaceutically acceptable carrier or diluent, a
flavorant, a
sweetener, a preservative, a dye, a binder, a suspending agent, a dispersing
agent, a
colorant, a disintegrant, an excipient, a lubricant, a plasticizer, and an
edible oil.
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In certain embodiments the aforementioned pharmaceutical compositions are
provided as a dosage form comprising lercanidipine hydrochloride crystalline
Form (III)
or Form (IV) or a combination thereof having a predetermined formulation of
each
crystalline Form, optionally including other forms of lercanidipine, such
those set forth
above.
In further embodiments, the invention provides lercanidipine hydrochloride
crystalline forms (III) or (IV) or mixtures thereof, including the dosage
forms set forth
above, wherein said crystalline forms are in micronized form, preferably with
an average
size of D(50%) 2-8 m, D(90%) < 15 m.
In another embodiment, a method is provided for treating a subject with
arterial
hypertension, the method comprising administering a therapeutically effective
amount of
lercanidipine hydrochloride crystalline Form (III), lercanidipine
hydrochloride crystalline
form (IV), or combinations thereof to a subject in need of such treatment.
In another embodiment, the invention provides a method of treating or
preventing
atherosclerotic lesions in arteries in a subject, which comprises
administering a
therapeutically effective amount of lercanidipine hydrochloride crystalline
Form (III),
lercanidipine hydrochloride crystalline Form (IV), or combinations thereof
having a
predetermined content in each of said Form (III) and (IV) to a subject in need
of such
treatment.
In other embodiments, the invention provides an antihypertensive composition
comprising predetermined amounts of lercanidipine hydrochloride crystalline
Form (III)
and lercanidipine hydrochloride crystalline Form (IV). In certain embodiments,
the ratio
of Form (III) : Form (IV) is between about 1:9 to 9:1. e.g., wherein the ratio
of Form (III)
Form (IV) is selected from the group consisting of 9:1, 7:3, 1:1, 3:7 and 1:9.
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Also provided are methods of making a lercanidipine hydrochloride-methylene
chloride solvate or a lercanidipine hydrochloride-methyl ethyl ketone solvate
from the
starting material of lercanidipine hydrochloride crystalline Form I, methods
for
preparing lercanidipine hydrochloride crystalline Form (III) by the removal of
solvent
from a lercanidipine hydrochloride solvate by evaporation under vacuum or in
nitrogen stream to form said crystalline Form (III) and a method for preparing
lercanidipine hydrochloride crystalline Form (IV) by removal of acetone from a
lercanidipine hydrochloride-acetone solvate by evaporation under vacuum or in
a
nitrogen stream.
According to one aspect of the present invention, there is provided
isolated lercanidipine hydrochloride crystalline Form (I), which has the X-ray
diffraction pattern, at wavelength Ka, wherein distances, (1/l0) ratios, and
angles of significant peaks are:
D (A) Relative intensity (1/l0) 20 angle
15 16.3 83 5.4
6.2 47 14.2
4.78 29 18.6
4.10 63 21.7
4.06 36 21.9
20 3.90 100 22.8
According to another aspect of the present invention, there is provided
a method of producing lercanidipine hydrochloride crystalline Form (I), which
has an
X-ray diffraction pattern, at wavelength Ka, wherein distances, (1/l0) ratios,
and 20 angles of significant peaks are:
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D (A) Relative intensity (1/l0) 20 angle
16.3 83 5.4
6.2 47 14.2
4.78 29 18.6
4.10 63 21.7
4.06 36 21.9
3.90 100 22.8
which comprises: d) adding a C1-C5 alcohol solvent containing a maximum of 5%
water (v/v) to a crude lercanidipine hydrochloride Form and heating under
reflux and
with stirring to produce a clear solution; e) cooling the solution of step d)
and stirring
until the concentration of lercanidipine hydrochloride dissolved in the
crystallization
solvent is <_2% by weight; and f) recovering the solid obtained from step e),
and drying
said solid to produce the lercanidipine hydrochloride crystalline Form (I).
According to still another aspect of the present invention, there is
provided a method of producing lercanidipine hydrochloride crystalline Form
(I),
which has an X-ray diffraction pattern, at wavelength Ka, wherein distances,
(1/l0) ratios, and 20 angles of significant peaks are:
D (A) Relative intensity (1/l0) 20 angle
16.3 83 5.4
6.2 47 14.2
4.78 29 18.6
4.10 63 21.7
4.06 36 21.9
3.90 100 22.8
which comprises: d') providing a mixture of ethanol and lercanidipine
hydrochloride,
refluxing under stirring and cooling and adding crystalline seeds of Form (I);
e') further
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cooling the seeded mixture of step d') and stirring until the concentration of
lercanidipine hydrochloride dissolved in the crystallization solvent is <_2%
by weight;
and f') recovering the solid of step e') to form lercanidipine hydrochloride
Form (I).
According to yet another aspect of the present invention, there is
provided an anti hypertensive pharmaceutical composition comprising (1)
crystalline
lercanidipine hydrochloride and optionally other forms of lercanidipine,
wherein the
crystalline lercanidipine hydrochloride is lercanidipine hydrochloride
crystalline
Form (I), comprising a predetermined content of each crystalline form, and (2)
at least
one component selected from the group consisting of a pharmaceutically
acceptable
carrier or diluent, a flavorant, a sweetener, a preservative, a dye, a binder,
a
suspending agent, a dispersing agent, a colorant, a disintegrant, an
excipient, a
lubricant, a plasticizer, and an edible oil.
According to a further aspect of the present invention, there is provided
a unit dosage form comprising the anti hypertensive pharmaceutical composition
described herein.
According to yet a further aspect of the present invention, there is
provided a use of lercanidipine hydrochloride crystalline Form (I) for
treating
hypertension, coronary heart disease or congestive heart failure in a subject
in need
thereof.
According to still a further aspect of the present invention, there is
provided a use of lercanidipine hydrochloride crystalline Form (I) for
treating or
preventing atherosclerotic lesions in arteries in a subject in need thereof.
According to another aspect of the present invention, there is provided
a use of lercanidipine hydrochloride crystalline Form (I) for treating or
preventing
heart failure in a subject in need thereof.
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According to yet another aspect of the present invention, there is
provided an anti hypertensive composition comprising lercanidipine
hydrochloride
crystalline Form (I) and lercanidipine hydrochloride crystalline Form (II).
These and other aspects of the present invention will be apparent to
those of ordinary skill in the art in light of the present description, claims
and figures.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph of DSC analysis carried out on crystalline Form (I),
according to the working conditions described in Example 12. The ordinate
indicates
heat flow in mW and the abscissa temperature in C.
Figure 2 is a graph of DSC analysis carried out on crystalline Form (II),
according to the working conditions described in Example 12. The ordinate
indicates
heat flow in mW and the abscissa temperature in C.
Figure 3 is a graph of the results of the thermogravimetric tests carried
out on Form (I) and Form (II), respectively, as described in Example 13. The
abscissa indicates temperature in C and the ordinate indicates percent mass
variation.
Figure 4 is a graph of solubility at 25 C of Forms (I) and (II) in ethanol
at increasing water concentrations. The experiments are described in Example
15.
The
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ordinate indicates % solubility expressed as w/w and the abscissa % by weight
of water
in ethanol.
Figure 5 is a graph of solubility at 40 C of Forms (I) and (II) in ethanol at
increasing water concentrations. The tests are described in Example 15. The
ordinate
indicates % solubility expressed as w/w and the abscissa % by weight of water
in
ethanol.
Figure 6 shows 13C NMR spectra in solid phase of crystalline Form (I). The
signals and attributes of the corresponding carbon atoms can be found in Table
4.
Figure 7 shows 13C NMR spectra in solid phase of crystalline Form (II). The
signals and attributes of the corresponding carbon atoms can be found in Table
5.
Figure 8 shows IR spectra of Form (I). The signal and corresponding attributes
can be found in Table 6.
Figure 9 shows IR spectra of Form (II). The signal and corresponding
attributes
can be found in Table 7.
Figure 10 represents percent average concentration of lercanidipine
hydrochloride in dog plasma after administration of crystalline Form (I) and
of
crystalline Form (II) in an amount of 3 mg/kg, in the form of a hard gelatin
capsule. The
ordinate indicates the mean value of concentration in plasma and the abscissa
indicates
time (in minutes).
Figures 11 and 12 show X-ray diffraction spectra at wavelength Ka of
crystalline
Forms (I) and (II), respectively. The distances (d) in X, the (1/lo) ratios
and values of 20
angles of the most significant peaks can be found in Tables 1 and 2 below. The
ordinate
indicates the number of counts/sec and the abscissa shows the values of 20
angles.
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Figures 13 and 14 are plots of percent mass change as a function of time in
hygroscopicity tests carried out on Forms (I) and (II) of lercanidipine
hydrochloride,
respectively. The ordinate on the left indicates percent mass changes and the
ordinate on
the right percent relative humidity; the abscissa indicates time in minutes.
The protocol
for the hygroscopicity tests are described in Example 14.
Figures 15 and 16 show X-ray diffraction spectra at wavelength Ka of crude
lercanidipine hydrochloride Form (A) and of crude lercanidipine hydrochloride
Form
(B), respectively.
Figures 17 and 18 show Raman spectra of crude lercanidipine hydrochloride
Form (A) and of crude lercanidipine hydrochloride Form (B), respectively,
where the
ordinate represents Raman units and the abscissa represents wave number (cm-1
).
Figures 19 and 20 show the results of the thermogravimetric analysis carried
out
on crude lercanidipine hydrochloride Form (A) and on crude lercanidipine
hydrochloride
Form (B), respectively. In these figures, the abscissa indicates temperature
(in C) and
the ordinate indicates percent mass variation.
Figure 21 shows the X-ray diffraction spectrum at wavelength Ka of the solvate
of lercanidipine hydrochloride with methylene chloride having a lercanidipine
hydrochloride-methylene chloride content of 1:1 (mole/mole). The ordinate
indicates the
number of counts per second and the abscissa represents the values of 20
angles.
Figure 22 shows the X-ray diffraction spectrum at wavelength Ka of crystalline
form (III) of lercanidipine hydrochloride.
Figures 23 and 24 show plots referring to the solvate of lercanidipine
hydrochloride with methylene chloride having a lercanidipine hydrochloride-
methylene
chloride content of 1:1 (mole/mole)and of lercanidipine hydrochloride
crystalline form
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(III) and the thermogravimetric analysis carried out according to the
operating modes
described in Example 36B. The ordinate indicates % mass variation and the
abscissa the
temperature.
Figures 25 and 26 show Raman spectrums referring to the solvate of
lercanidipine hydrochloride with methylene chloride having a lercanidipine
hydrochloride-methylene chloride content of 1:1 (mole/mole) and of
lercanidipine
hydrochloride crystalline form (III), respectively. The ordinate indicates
Raman units
and the abscissa represents wave number (in cm I).
Figure 27 shows the X-ray diffraction spectrum of lercanidipine hydrochloride
crystalline form (IV).
Figure 28 shows the X-ray diffraction spectrum of the solvate lercanidipine
hydrochloride-acetone having a lercanidipine hydrochloride-acetone content of
1:1.2(mole/mole).
Figure 29 shows the X-ray diffraction spectrum of the solvate lercanidipine
hydrochloride-ethyl acetate having a lercanidipine hydrochloride-ethyl acetate
content of
1:1 (mole/mole).
Figure 30 shows the X-ray diffraction spectrum of the solvate lercanidipine
hydrochloride-tetrahydrofuran having a lercanidipine hydrochloride-
tetrahydrofuran
content of 1:0.9(mole/mole).
Figure 31 shows the X-ray diffraction spectrum of the solvate lercanidipine
hydrochloride-terbutyl methyl ether having a lercanidipine hydrochloride-
terbutyl methyl
ether content of 1:0.8 (mole/mole).
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Figure 32 shows the X-ray diffraction spectrum of the solvate lercanidipine
hydrochloride-anisole (a) form having a lercanidipine hydrochloride- anisole
content of
1:0.4 (mole/mole).
Figure 33 shows the X-ray diffraction spectrum of the solvate lercanidipine
hydrochloride-anisole (b) form having a lercanidipine hydrochloride-anisole
content of
1:0.4 (mole/mole).
Figure 34 shows the X-ray diffraction spectrum of the solvate lercanidipine
hydrochloride-isopropanol having a lercanidipine hydrochloride-isopropanol
content of
1:1 (mole/mole).
Figure 35 shows the X-ray diffraction spectrum of the solvate lercanidipine
hydrochloride-isobutanol having a lercanidipine hydrochloride-isobutanol
content of
1:0.8 (mole/mole).
Figure 36 shows the X-ray diffraction spectrum of the solvate lercanidipine
hydrochloride-heptane having a lercanidipine hydrochloride-heptane content of
1:0.9
(mole/mole).
Figure 37 shows the Raman spectrum of lercanidipine hydrochloride crystalline
form (IV).
Figure 38 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
acetone having a lercanidipine hydrochloride-acetone content of
1:1.2(mole/mole).
Figure 39 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
ethyl acetate having a lercanidipine hydrochloride-ethyl acetate content of
1:1
(mole/mole).
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Figure 40 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
tetrahydrofuran having a lercanidipine hydrochloride-tetrahydrofuran content
of 1:0.9
(mole/mole).
Figure 41 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
terbutyl methyl ether having a lercanidipine hydrochloride-terbutyl methyl
ether content
of 1:0.8 (mole/mole).
Figure 42 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
anisole (a) form having a lercanidipine hydrochloride-anisole content of
1:0.4(mole/mole).
Figure 43 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
anisole (b) form having a lercanidipine hydrochloride-anisole content of
1:0.4(mole/mole).
Figure 44 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
isopropanol having a lercanidipine hydrochloride-isopropanol content of 1:1
(mole/mole).
Figure 45 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
isobutanol having a lercanidipine hydrochloride-isobutanol content of 1:0.8
(mole/mole).
Figure 46 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
heptane having a lercanidipine hydrochloride-heptane content of 1:0.9
(mole/mole).
Figure 47 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-anisole (b) form having a lercanidipine
hydrochloride-anisole content of 1:0.4 (mole/mole).
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Figure 48 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-ethyl acetate having a lercanidipine
hydrochloride-
ethyl acetate content of 1:1 (mole/mole).
Figure 49 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-acetone having a lercanidipine
hydrochloride-
acetone content of 1:1.2 (mole/mole).
Figure 50 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-tetrahydrofuran having a lercanidipine
hydrochloride-tetrahydrofuran content of 1:0.9 (mole/mole).
Figure 51 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-anisole (a) form having a lercanidipine
hydrochloride-anisole content of 1:0.4 (mole/mole).
Figure 52 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-terbutyl methyl ether having a
lercanidipine
hydrochloride-terbutyl methyl ether content of 1:0.8 (mole/mole).
Figure 53 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-isopropanol having a lercanidipine
hydrochloride-
isopropanol content of 1:1 (mole/mole).
Figure 54 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-isobutanol having a lercanidipine
hydrochloride-
isobutanol content of 1:0.8 (mole/mole).
Figure 55 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-heptane having a lercanidipine
hydrochloride-
heptane content of 1:0.9 (mole/mole).
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Figure 56 shows the results of the thermogravimetric analysis carried out on
lercanidipine hydrochloride crystalline form (IV).
Figure 57 shows the results of the thermogravimetric analysis carried out on
the
solvate lercanidipine hydrochloride-methyl ethyl ketone having a lercanidipine
hydrochloride-methyl ethyl ketone content of 1:0.7 (mole/mole).
Figure 58 shows the X-ray spectrum of the solvate lercanidipine hydrochloride-
methyl ethyl ketone having a lercanidipine hydrochloride-methyl ethyl ketone
content of
1:0.7 (mole/mole).
Figure 59 shows the Raman spectrum of the solvate lercanidipine hydrochloride-
methyl ethyl ketone having a lercanidipine hydrochloride-methyl ethyl ketone
content of
1:0.7 (mole/mole).
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided isolated
lercanidipine hydrochloride crystalline Form (I), which has the X-ray
diffraction pattern,
at wavelength Ka, as shown in Figure 11.
According to another aspect of the present invention, there is provided a
method
of producing lercanidipine hydrochloride crystalline Form (I), which has an X-
ray
diffraction pattern, at wavelength Ka, as shown in Figure 11, which comprises:
d) adding
a C 1-C5 alcohol solvent containing a maximum of 5% water (v/v) to a crude
lercanidipine hydrochloride Form and heating under reflux and with stirring to
produce a
clear solution; e) cooling the solution of step d) and stirring until the
concentration of
lercanidipine hydrochloride dissolved in the crystallization solvent is <2%;
and f)
recovering the solid obtained from step e), and drying said solid to produce
the
lercanidipine hydrochloride crystalline Form (I).
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According to still another aspect of the present invention, there is provided
a
method of producing lercanidipine hydrochloride crystalline Form (1), which
has an x-
ray diffraction pattern, at wavelength Ka, as shown in Figure 12, which
comprises: d')
providing a mixture of ethanol and lercanidipine hydrochloride, refluxing
under stirring
and cooling and adding crystalline seeds of Form (I); e') further cooling the
seeded
mixture of step d') and stirring until the concentration of lercanidipine
hydrochloride
dissolved in the crystallization solvent is <2%; and f) recovering the solid
of step e') to
form lercanidipine hydrochloride Form (I).
According to yet another aspect of the present invention, there is provided an
antihypertensive pharmaceutical composition comprising (1) crystalline
lercanidipine
hydrochloride and optionally other forms of lercanidipine, wherein the
crystalline
lercanidipine hydrochloride is lercanidipine hydrochloride crystalline Form
(I), and (2) at
least one component selected from the group consisting of a pharmaceutically
acceptable
carrier or diluent, a flavorant, a sweetener, a preservative, a dye, a binder,
a suspending
agent, a dispersing agent, a colorant, a disintegrant, an excipient, a
lubricant, a
plasticizer, and an edible oil.
According to a further aspect of the present invention, there is provided a
unit
dosage form comprising the antihypertensive pharmaceutical composition
described
herein.
According to yet a further aspect of the present invention, there is provided
a use
of lercanidipine hydrochloride crystalline Form (I) for treating hypertension,
coronary
heart disease or congestive heart failure in a subject in need thereof.
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According to still a further aspect of the present invention, there is
provided a use
of lercanidipine hydrochloride crystalline Form (I) for treating or preventing
atherosclerotic lesions in arteries in a subject in need thereof.
According to another aspect of the present invention, there is provided a use
of
lercanidipine hydrochloride crystalline Form (I) for treating or preventing
heart failure in
a subject in need thereof.
According to yet another aspect of the present invention, there is provided an
antihypertensive composition comprising lercanidipine hydrochloride
crystalline Form
(I) and lercanidipine hydrochloride crystalline Form (II).
The present invention discloses novel crude forms and crystalline forms and
novel solvate forms of lercanidipine hydrochloride and processes for making
them.
Applicants have determined that lercanidipine hydrochloride exhibits
polymorphism and
crystallizes in different forms depending on the process followed and on the
solvents
used, especially for crystallization. Additionally, the various novel forms
have distinct
chemical and physical properties and bioavailability profiles in animals,
including man,
as discussed herein.
The novel methods for preparation of crude of lercanidipine hydrochloride are
suitable for highly reproducible commercial scale production of reproducible
solid
compositions of lercanidipine hydrochloride. The methods advantageously
produce
novel crude Forms (A) and (B) of lercanidipine hydrochloride which also
exhibit
characteristics desirable for industrial applications. Crude Forms (A) and
(B), e.g.,
exhibit higher solubility and faster drying rates compared to other crude
forms of
lercanidipine hydrochloride that have previously been reported. Crude Forms
(A) and
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(B) further allow simplified crystallization procedures to be used for
production of novel
isolated crystalline forms of lercanidipine hydrochloride.
The novel isolated crystalline forms of lercanidipine hydrochloride of the
present
invention can be obtained from lercanidipine hydrochloride crude Forms (A) and
(B) and
are termed lercanidipine hydrochloride crystalline Form (I) and Form (II).
Either of
isolated Form (I) or isolated Form (II) may be reproducibly obtained from the
(A) and
(B) intermediates by varying the crystallization conditions as described
below. Forms (I)
and (II) may also be obtained using other starting materials. Both of Forms
(I) and (II)
may be obtained using, for example, crude lercanidipine Form (C) as starting
material, as
described herein. Form (II) may also be obtained using Form (I) as starting
material, as
described herein.
Both lercanidipine hydrochloride crystalline Forms (I) and (II) exhibit good
stability. Form (1) is characterized by a paler yellow color, smaller crystal
size, higher
solubility in aqueous media (all compared to Form (II)), and a melting point
(DSC peak)
within the rage of about 197EC to about 201 EC, more specifically, about
198.7EC, and
the X-ray diffraction pattern set forth, supra.
Form (II) is characterized by a more pronounced yellow color, larger crystal
size,
slightly lower solubility in aqueous media (all compared to Form (I)), and a
melting
point (DSC peak) within the range of about 207-211 EC, more specifically about
209.3EC.
Both Form (I) and Form (II) are stable. Form II exhibited higher
bioavailability
in the dog, and was also non equivalent to form I in man, showing a higher
plasma
concentration (AUCo-t) and a delayed time of maximum concentration (tmax),
compared
to Form (I).
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Methods known in the art for producing crystalline lercanidipine hydrochloride
were inconsistent in producing lercanidipine hydrochloride with predictable
physical and
chemical characteristics. Hence, prior art methods had the undesirable
property of
producing lercanidipine hydrochloride that varied, e.g., in physico-chemical
properties,
from batch to batch, even among batches produced by the same process and under
the
same conditions. The present inventors have discovered that the source of
inconsistency
exhibited by the prior art methods of producing lercanidipine hydrochloride is
the
presence of varying and unpredictable amounts of crystalline lercanidipine
hydrochloride
Form (II). In contrast to prior art methods of producing lercanidipine
hydrochloride, the
invention provides the novel crystalline Forms (I) and (II) that represent
crystalline
forms of lercanidipine hydrochloride of a purity and uniformity that has not
been
obtained with previously achieved solid forms of lercanidipine hydrochloride.
The purity and uniformity of Forms (I) and (II) allow for increased ease in
production of lercanidipine dosage forms, due to, e.g., more precisely defined
physico-
chemical characteristics, such as, for example, increased uniformity of
particle size
following micronization and more reproducible solubility. Forms (I) and (II)
also
provide dosage forms with more precisely defined pharmacological
characteristics, e.g.,
bioavailability, compared to previously achieved dosage forms that varied from
batch-to-
batch in their physico-chemical characteristics.
In a human study in man, where the plasma levels of lercanidipine were
assessed
after administration of a single dose of either lercanidipine hydrochloride
Form (I) or
(II), Form (I) had shorter time in obtaining the maximum concentration in
plasma,
relative to Form (II). Hence, Form (I) is more suited for immediate release
formulations
and dosage forms. From the same study, Form (II) showed a higher
bioavailability,
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relative to Form (I), and is thus suited for use in controlled release
formulations and
dosage forms. Accordingly, the availability of pure Forms (I) and (II)
provides for the
ability to blend the two polymorphs into dosage forms with novel controlled
characteristics, e.g., a dosage form with both a rapid onset and sustained
biological
action.
The novel methods for preparation of solvates of lercanidipine hydrochloride
described herein are suitable for highly reproducible commercial scale
production of
reproducible solid compositions of lercanidipine hydrochloride. The methods
advantageously produce novel solvates and crystalline forms starting with
crude Forms
(A) or (B) of lercanidipine hydrochloride or crystalline Forms (I) and (II)
that are
disclosed in Italian patent application no. MI 2001A 001726, filed August 6,
2001, and
which exhibit characteristics desirable for industrial applications. Methods
of preparing
crude Forms (A) and (B) are described herein, infra. Crude Forms (A) and (B),
e.g.,
exhibit higher solubility and faster drying rates compared to other crude
forms of
lercanidipine hydrochloride that have previously been reported. Hence, it is
desirable to
produce crystalline forms of lercanidipine hydrochloride using crude Form (A)
or (B) as
starting material. The solvates and crystalline forms of the present invention
may also be
produced using other forms of lercanidine, such as, for example and without
limitation,
amorphous lercanidipine and lercanidipine crude Form (C). As used herein, the
term
"crude form" refers to precipitated solid forms comprising crystals of a
compound that
have not been washed and/or recrystallized to remove impurities (including but
not
limited to solvent) that may be present and which lack, e.g., melting point
and x-ray
spectra characteristic of crystalline forms. In the present specification, the
crude forms
are referred to as Forms (A) and (B) of lercanidipine hydrochloride.
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As used herein, the term "crystalline form" refers to crystals of a compound
that
have been crystallized and treated to remove impurities, e.g., a form obtained
after
evaporation of solvent from a solvate, or having melting point and x-ray
spectra
characteristic of crystalline forms. Crystalline Forms (I) and (II) of
lercanidipine
hydrochloride are disclosed herein and in Italian patent application no. MI
2001A
001726, filed August 6, 2001. These crystalline forms have an HPLC purity El
99.5 %
and residual solvents content of < 3000 ppm. Lercanidipine hydrochloride
crystalline
Forms (III) and (IV) are described by their X-ray structure, Raman spectra and
melting
points, which are discussed below. Alternatively, these crystalline forms can
be
described by a process that yields them, e.g., removal of solvent from a
solvate under
specified conditions. These crystalline forms have an HPLC purity of > 99 %
and
residual solvents content of :5 3000 ppm. These additional lercanidipine
hydrochloride
crystalline forms, i.e., lercanidipine hydrochloride crystalline Forms (III)
and (IV) are
described in Italian patent application no. MI 2001 A 001727, filed August 6,
2001, and
the attached Appendix I, application of Leonardi et al., for " NOVEL SOLVATE
AND
CRYSTALLINE FORMS OF LERCANIDIPINE HYDROCHLORIDE," filed August 6,
2002.
As used herein, the term "polymorphism" refers to a property of a compound to
crystallize in two or more forms with distinct structures. The different
crystalline forms
can be detected directly by crystallographic techniques or indirectly by
assessment of
differences in physical and/or chemical properties associated with each
particular
polymorph.
As used herein, a "subject in need of treatment" is a mammalian (e.g., human)
subject suffering from or at risk of developing the particular condition to be
treated, e.g.,
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essential hypertension, secondary hypertension, isolated systolic
hypertension, coronary
heart disease (e.g., chronic stable angina, myocardial infarction), congestive
heart failure.
A subject in need of treatment for arterial hypertension may be identified
using methods
well known in the art such as, for example, by direct measurement of blood
pressure
using, for example, a manual sphygmomanometer, automatic/electronic devices or
ambulatory blood pressure monitoring.
As used herein, a "therapeutically effective amount" of an agent is an amount
sufficient to ameliorate at least one symptom associated with a pathological,
abnormal or
otherwise undesirable condition, an amount sufficient to prevent or lessen the
probability
that such a condition will occur or re-occur, or an amount sufficient to delay
worsening
of such a condition. An amount sufficient to lower blood pressure to values
lower than
140/90 is recommended. Recent World Health Organization guidelines recommended
a
diastolic blood pressure lower than 85 mm Hg and a systolic blood pressure
lower than
130 mm Hg in younger patients and in diabetic patients. Treatment of other
pathologies,
such as heart failure or artherosclerois is also specifically contemplated as
per, e.g., U.S.
Patent No. 5,696,139 and 5,767,136.
The present invention contemplates any method that may be used to produce the
novel crude forms of lercanidipine hydrochloride described herein. These forms
have
different physico-chemical properties, e.g., melting points (which can be
determined by
DSC analysis), than the crude form of lercanidipine hydrochloride produced by
other
known methods, e.g., by the method described in U.S. Patent No. 5,912,351;
termed
Form (C). Form (A) has a melting point of about 150EC to about 152EC (DSC
peak),
Form (B) has a melting point of about 131EC to about 135EC (DSC peak), and
Form (C)
has a melting point of about 186EC to about 192EC (DSC peak). Additionally,
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thermogravimetric studies show that Form (A) comprises 3 - 4 % residual ethyl
acetate
and Form (B) comprises 0.3-0.7 % residual ethyl acetate, by weight.
Comparatively, the
residual solvent present in Form (C) has been determined to be 0-0.1 %.
Aspects of the invention are directed to processes for the preparation of
lercanidipine hydrochloride, each resulting in a different crude form of the
product. The
first two steps in producing either crude form are identical and are:
(a) reacting 2, 6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3-carboxylic acid (prepared as described in German patent DE
2847
237) with thionyl chloride or oxalyl chloride in a mixture of an aprotic
dipolar solvent
and of an aprotic polar solvent to yield a chloride compound, and
(b) in-situ reaction of the chloride obtained from the above step with 2, N-
dimethyl-N-(3,3 -diphenylpropyl)- 1 -amino-2-propyl alcohol, at a temperature
preferably
between -5 and +5 C, in a mixture of an aprotic dipolar solvent and of an
aprotic polar
solvent.
In a preferred embodiment, the mixture of an aprotic dipolar solvent and of an
aprotic polar solvent is ethyl acetate and dimethylformamide used at a ratio
of 4:1.
After the in-situ reaction, the lercanidipine hydrochloride is isolated and
recovered from the mixture. The method of isolation used determines the crude
form of
lercanidipine hydrochloride obtained. Following the protocol below (a
protocol) yields
Form (A):
i) washing the mixture of step (b), preferably with water,
ii) removing water from the reaction mixture of step i), preferably by
azeotropic distillation under vacuum at 200-300 mmHg at a temperature below
about 60 C (preferably at 40-50 C);
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iii) concentrating the mixture of step ii) preferably to about 1/3 of the
initial
volume at the same temperature and pressure as in step (ii), adding fresh
solvent
(e.g., ethyl acetate) preferably to obtain the initial volume, thus obtaining
a
suspension with a water content, as determined according to Karl Fischer (U.S.
Pharmacopoeia 25, Method 921) preferably between 0.10 and 0.15%;
iv) cooling the suspension of step iii) preferably to 0-5 C;
v) filtering the solid of step iv);
vi) re-suspending the solid of step v) preferably in ethyl acetate and
stirring
preferably at 60-65 C for about 1 hour; and
vii) cooling to 5-10 C, filtering and drying the obtained solid (e.g., in an
oven
at about 70 C).
The second process ((3 protocol; used to prepare Form (B)) is performed using
the
following steps:
i') washing the mixture of step (b) preferably with water,
ii') removing the water from step i') preferably by azeotropically refluxing
the product of step i') with a Dean Stark apparatus until a water content of
about 2%,
measured according to Karl Fischer, is obtained;
iii') concentrating the mixture of step ii') to preferably 3/4 of the initial
volume
and adding fresh solvent (ethyl acetate) to the mixture preferably until (1)
the initial
volume is achieved and (2) a water content, measured according to Karl
Fischer, between
0.9 and 1.1 % is obtained;
iv') cooling the solution of step iii') preferably to 0-5 C to obtain a solid;
v') filtering the solid of step iv');
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vi') re-suspending the solid of step v') preferably in ethyl acetate and
stirring
at preferably 60-65 C for about 1 hour; and
vii') cooling the suspension of step vi') preferably to 5-10 C , filtering and
drying the solid obtained, preferably in an oven at about 70 C.
The temperature of step vii') should be carcfully controlled at 5-10 C to
maximize yield.
These novel crude forms of lercanidipine hydrochloride present the advantage
of
higher solubility and faster drying rate compared to Form (C) and make a
simplified
further crystallization process possible (which can advantageously be used to
prepare
Form (I) or Form (II)). Compared to the crude form produced by the method of
U.S.
Patent No. 5,912,351, these forms permit use of less solvent to recrystallize
the
compound. This also increases yield by reducing loss of compound.
Additionally, the
methods used to produce these crude forms are more adaptable to use in a large
scale
setting and commercial setting.
It has been surprisingly found that each of crude lercanidipine hydrochloride
Form (A) and Form (B), when undergoing different purification treatments,
result in two
novel and different crystalline forms of lercanidipine hydrochloride. Studies
indicate
that these novel crystalline forms have different physical and chemical
properties. DSC
analysis of crystalline Form (I) indicates that it has a melting peak of about
197EC to
about 201EC, specifically about 198.7EC. DSC analysis of crystalline Form (II)
indicates that it has a melting peak of about 207EC to about 211EC,
specifically about
209.3EC.
One purification process (y process), that leads to formation of one of the
novel
crystalline forms (Form (I)) comprises the following steps:
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Process for Making Form (I)
d) adding isopropanol to crude lercanidipine hydrochloride (Form (A) or
Form (B)) and heating under reflux with stirring to produce a solution (if the
solution is
not clear, it should be filtered hot);
e) cooling the solution of step d) preferably to a temperature between 30 and
40 C and stirring for a period of time preferably between 12 and 48 hours to
produce a
solid; and
f) filtering the solid obtained from step e), washing the solid with
isopropanol, re-filtering the solid, and drying the solid (e.g., in an oven)
at preferably
70 C for a period of time preferably between 12-48 hours.
Crude Form (C) may be also be used as starting material in step d). In such
case,
however, there is the risk of decreased yield of product because the solution
should be
filtered hot, resulting in the increased loss of lercanidipine hydrochloride
in step d). In
step e), crystallization is considered complete when the content of the
solution is #2%
lercanidipine HCI. Other alcohols may also be used as the solvent in step d).
An
alternatively preferred solvent is a C1-C5 alcohol containing a maximum of 5%
water,
e.g., anhydrous ethanol. Crystalline Form (I) may be added in step (e) as
seeds to further
promote crystal formation.
Alternative Process for Making Form (I)
The present application also contemplates an alternative method of producing
lercanidipine hydrochloride having crystalline Form (I) which comprises the
steps of:
d') adding ethanol to crude lercanidipine hydrochloride, preferably at a
weight/volume ratio of lercanidipine hydrochloride solvent of 1:4 to 1:6, most
preferably
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1:4, refluxing under stirring in order to obtain a solution (if the solution
is not clear it
should preferably be filtered hot), cooling under stirring, preferably to 20
C, and adding
crystalline seeds of Form (I);
e') cooling the seeded mixture of step d'), preferably to a temperature
between 10 and 15 C, and stirring at this temperature for a period of time
preferably
between 24 and 96 hours to form a solid; and
f) filtering and drying the solid of step e'), it preferably in an oven at
preferably 70 C to obtain lercanidipine hydrochloride Form (I).
In step e'), crystallization is considered complete when the content of the
solution
is # 2% lercanidipine hydrochloride. Crystalline seeds of Form (I) may also be
added to
steps e') to further promote crystal formation .
Process for Making Form (II)
The second purification process (b process), which yields crystalline Form
(II),
comprises the steps of.
d") adding acetonitrile to crude lercanidipine hydrochloride (Form (A) or
Form (B)) and heating the mixture under reflux and stirring,
e") cooling of the mixture of step d") to room temperature and stirring
preferably for 24 hours to form a solid,
f") filtering the solid obtained from step e") and drying it preferably in an
oven.
In step e"), crystallization is considered complete when the content of the
solution is # 2% lercanidipine HCI.
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The present application also contemplates two additional methods for producing
Form (II).
First Alternative Process for Making Form (II)
The first alternative method comprises the steps of-
d"') adding isopropanol or ethanol, preferably ethanol, with a water content
preferably between 5 to 10% by weight to lercanidipine hydrochloride,
refluxing with
stirring to produce a solution;
e"') cooling the mixture to a temperature preferably between 20 and 40 C and
stirring for a period preferably between 24 and 96 hours to form a solid;
f") filtering the solid and drying (e.g., in an oven) at preferably 70 C for
12-
18 hours to produce lercanidipine hydrochloride Form (II).
In step e"'), crystallization is considered complete when the content of the
solution is # 2% lercanidipine HCI.
Second Alternative Method for Making Form II
The second alternative method of obtaining the Form (II) polymorph comprises
the steps of:
d"") dissolving crude lercanidipine hydrochloride or its crystalline Form (I)
in
a protic polar or an aprotic dipolar solvents preferably containing up to 50%
by weight of
water at a temperature preferably between 20 and 70 C to produce a solution;
e"") stirring the solution of step d"") at a temperature preferably between 20
and 25 C to produce a solid;
f"') filtering the solid of step e"") and drying (e.g., in an oven) at
preferably
70 C for preferably 12-18 hours.
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The second alternative method may optionally comprise the step of adding up to
60% water to the solution of step d"") prior to step e""). The second
alternative method
may further comprise irradiating with ultrasound and/or adding preferably
authentic
crystalline seeds of Form (II) to step e""). In step e""), crystallization is
considered
complete when the content of the solution is #2% lercanidipine HCI. In a
preferred
embodiment, the protic polar solvent is an alcohol solvent such as, but not
limited to,
methanol, ethanol, n-propanol, isopropanol. In another preferred embodiment,
the
aprotic dipolar solvent is N-methylpyrrolidone.
The preferred process for preparing Form (I) is the y process and the
preferred
process for preparing Form (II) is the 6 process. Applicants have determined
that Form
(I) can be quantitatively obtained by use of C1-C5 anhydrous alcohol
(preferably
anhydrous ethanol or isopropanol) or C1-C5 alcohol containing up to 5% water
under
controlled conditions d'-f). In fact, the foregoing processes, especially the
y and 6
processes can be used to produce the desired polymorph reproducibly and
consistently.
In addition to differences in melting point, the two crystalline forms exhibit
differences in x-ray structure, solubility, and bioavailability. Solubility
studies show that
Form (I) is more soluble than Form (II) in water, ethanol, and mixtures
thereof (See
Tables 2 & 3). Bioavailability studies in dogs and humans indicate that Form
(II) is
more bioavailable than Form (I). The study in humans also indicates, however,
that
Form (I) has a shorter time to maximum concentration attainable and is thus
suitable for
use in immediate release formulations and dosage forms. Finally, x-ray
diffraction
studies show that these two forms have different diffraction patterns (see
Figures 11 and
12 and Example 20). Form I has a smaller crystal and hence particle size
before
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micronization and so is easier and faster to process than Form II, which
presents with
larger crystals.
The present application further discloses pharmaceutical formulations and unit
dosage forms that comprise one of the isolated polymorphs of the present
invention or a
mixture thereof of predetermined polymorph content.
The present invention is also directed to a method of treating a subject with
hypertension (e.g., essential hypertension, secondary hypertension or isolated
systolic
hypertension), coronary heart disease (e.g., chronic stable angina, myocardial
infarction)
or congestive heart failure the method comprising administering a
therapeutically
effective amount of isolated lercanidipine hydrochloride crystalline Form (I),
lercanidipine hydrochloride crystalline Form (II), or combinations thereof of
predetermined polymorph content (optionally with other form of lercanidipine,
such as
amorphous form) to a subject in need of such treatment.
The invention also contemplates a method of treating and preventing
atherosclerotic lesions in arteries of a subject, the method comprising
administering a
therapeutically effective amount of isolated lercanidipine hydrochloride
crystalline Form
(I), isolated lercanidipine hydrochloride crystalline Form (II), or
combinations thereof to
a subject in need of such treatment.
Subjects suffering from and in need of treatment of hypertension and the other
conditions mentioned above can be treated by the administering a
therapeutically
effective amount of isolated lercanidipine hydrochloride crystalline Form
(III),
lercanidipine hydrochloride crystalline Form (IV), or combinations thereof, of
predetermined polymorph content (optionally with one or more other form of
lercanidipine, such as, for example, lercanidipine hydrochloride crystalline
Form (I),
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lercanidipine hydrochloride crystalline Form (II) or amorphous form)
formulated
according to, for example and without limitation, the compositions and dosage
forms
described herein.
The invention also contemplates a method of treating and preventing
atherosclerotic lesions in arteries of a subject, the method comprising
administering a
therapeutically effective amount of isolated lercanidipine hydrochloride
crystalline Form
(III), isolated lercanidipine hydrochloride crystalline Form (IV), or
combinations thereof
to a subject in need of such treatment (optionally with other form of
lercanidipine, such
as, for example, lercanidipine hydrochloride crystalline Form (I),
lercanidipine
hydrochloride crystalline Form (II) or amorphous form).
Pharmaceutical Compositions
The present invention contemplates novel solvates of lercanidipine
hydrochoride.
The solvates of the present invention include, but are not limited to,
lercanidipine in
combination with methylene chloride, methyl ethyl ketone, acetone, anisole,
ethyl
acetate, tetrahydrofuran, terbutyl methyl ether, isopropanol, 2-butanol, or
heptane. These
solvates are advantageous because they can be obtained under defined
conditions.
The present application contemplates any method that produces the solvates of
the present invention. These solvates are defined by specific X-ray
diffraction patterns
(see Figures 8-16 and 38), Raman spectra (see Figures 18-26 and 39), and
thermogravimetric results (see Figures 27-35 and 37). Specific methods of
producing
the solvates of the invention are disclosed herein.
A lercanidipine hydrochloride-methylene chloride solvate can be prepared with
a
method comprising the steps of:
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(i) suspending crystalline Form (I) of lercanidipine hydrochloride in
methylene chloride to produce a mixture;
(ii) placing the mixture of step (i) in a closed vessel and stirring under
mild
conditions, e.g., at a temperature between about 20 to 50 C to produce a
solid; and
(iii) isolating the solid produced in step (ii), e.g., by filtration.
In step (ii), stirring is typically performed for eight days. Similar results
may be
obtained, however, with longer or shorter times. The methods can also be
practiced
using lercanidipine crude form (C) as starting materia.
A lercanidipine hydrochloride-methyl ethyl ketone solvate can be prepared by:
(i') dissolving lercanidipine hydrochloride crystalline Form (I) in methyl
ethyl ketone
to produce a solution;
(ii') cooling the solution of step (i') to preferably 20-25 C while stirring
and
keeping the solution at the temperature for preferably at least two days to
produce a
solid; and
(iii') filtering the solid and drying.
Step (i') is preferably performed, for example, at 80 C. Also preferred is
where
the lercanidipine hydrochloride-methyl ethyl ketone solution of step (i')
comprises 0 to
5% (v/v) water.
Independent preferences for step (ii') are cooling the solution to room
temperature
and stirring for at least two days. Further preferred are simultaneous
preferences where
the solution in step (ii') is cooled to room temperature and stirred at room
temperature for
at least two days.
The preferred conditions for drying in step (iii') are in an oven at 60 C for
24
hours under vacuum.
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The other solvates of the present invention can be obtained by suspending a
lercanidipine hydrochloride-methylene chloride solvate prepared, for example
and
without limitation by the method in steps (i) - (iii), with a solvent selected
from the
group consisting of acetone, anisole, ethyl acetate, tetrahydrofuran, terbutyl
methyl ether,
isopropanol, 2-butanol, and heptane, at a temperature between 20 and 50 C for
114 to
420 hours to produce a solid. The solid produced by this method is a novel
solvate
comprising lercanidipine hydrochloride with the solvent used in the reaction.
Therefore,
if heptane is used as the solvent then the final solvate would be
lercanidipine
hydrochloride-heptane.
It has been determined that when anisole is used as the solvate, that two
different
forms of the solvate may be produced ((a) and (b) forms). The differences
between these
forms are clear from their x-ray spectra. When using the method disclosed
above
lercanidipine hydrochloride-anisole (b) form is produced.
As an alternative method, the solvates can be prepared by suspending
lercanidipine hydrochloride crystalline Form (III), which is described in
further detail
below, in a solvent selected from the group consisting of anisole, ethyl
acetate,
tetrahydrofuran, terbutyl methyl ether, or acetone to produce a solution. The
solution
that is prepared is kept under mild stirring in a closed vessel at a
temperature between 20
and 50 C for 114 to 420 hours to produce a solid. The solid that is formed is
then
filtered. When anisole is used as the solvent with this method, lercanidipine
hydrochloride-anisole (a) form solvate is produced. In a preferred embodiment,
the
temperature is 20-50 C and the solution is stirred from 114 to 420 hours.
In another alternative embodiment, the solvates of the present invention can
be
prepared by suspending crude lercanidipine hydrochloride Form (A) or (B) in a
solvent
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selected from the group consisting of anisole, ethyl acetate, tetrahydrofuran,
terbutyl
methyl ether, acetone, or methylene chloride to produce a suspension. The
suspension is
maintained under mild stirring in a closed vessel at a temperature between 20
and 50 C
for 114 to 420 hours. The solid that is produced is then filtered to give the
final product.
When anisole is used as the solvent in this method, lercandipine hydrochloride-
anisole
(a) form solvate is produced. In a preferred embodiment, the temperature is 20-
50 C and
the solution is stirred for 114 to 420 hours.
The preparation of the these solvates, both starting from the solvate of
lercanidipine hydrochloride or from the crude (A) or (B) or (C) forms, may be
preferably
carried out at room temperature. Alternatively, the method may include a
series of
thermal cycles performed after the solvent is added to lercanidipine. The
length and
number of the cooling and heating steps, as well as the temperatures, may be
determined
by one of ordinary skill in the art. In a preferred embodiment, the steps are
about 3 hours
each. In another embodiment, the heating step is performed at 35 C and the
cooling step
is performed at 25 C. In a most preferred embodiment, the thermal cycle is
composed of
a cooling step at 25 C, heating step at 35 C, and a cooling step at 25 C
(written as 25 C-
35 C-25 C), where each step is about 3 hours. The number of cycles can
preferably
range from 10 to 20. Preferably, after completion of the final cycle the
sample is stirred
at a temperature of 25 C for a period of time of 24 -240 h.
Crystalline Forms III and IV
Under specific conditions, removal of the solvents from the solvates disclosed
above produces novel crystalline forms. These forms have been termed
lercanidipine
hydrochloride crystalline Form (III) and (IV).
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The present application contemplates any and all methods that may be used to
prepare the forms described herein. In the present application, preferred
methods of
preparing these forms are described.
In one method, evaporation of solvent from a solvate, under a nitrogen stream
or
under vacuum, produces lerecanidipine hydrochloride crystalline Form (III). A
preferred
set of conditions for evaporation is, without limitation, a vacuum of 1-0.01
mbarr for 20-
30 hours at a temperature of 50-90 C. Preferably, the solvent is selected from
the group
consisting of methylene chloride, tetrahydrofuran, heptane, anisole, ethyl
acetate,
isopropanol and 2-butanol. In one embodiment, the solvate is selected from any
of the
solvates described herein, except lercanidipine hydrochloride-anisole (a) form
that was
described previously.
To prepare lercanidipine hydrochloride crystalline form (IV), acetone is
removed
from a lercanidipine hydrochloride-acetone solvate, under a nitrogen stream or
under
vacuum. A preferred set of conditions for acetone removal is, without
limitation, a
vacuum of 1-0.01 mbar for 20-30 hours at a temperature of 50-90 C.
The compounds and polymorphs of the present invention may be formulated into
a pharmaceutical composition. The pharmaceutical composition may also include
optional additives, such as a pharmaceutically acceptable carrier or diluent,
a flavorant, a
sweetener, a preservative, a dye, a binder, a suspending agent, a dispersing
agent, a
colorant, a disintegrant, an excipient, a film forming agent, a lubricant, a
plasticizer, an
edible oil or any combination of two or more of the foregoing.
The crystalline forms can undergo micronization, using any method known in the
art. The average size of particle produced by this method are preferably
D(50%)2-8 m,
D(90%)<15 m.
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Suitable pharmaceutically acceptable carriers or diluents include, but are not
limited to, ethanol; water; glycerol; propylene glycol, aloe vera gel;
allantoin; glycerin;
vitamin A and E oils; mineral oil; PPG2 myristyl propionate; magnesium
carbonate;
potassium phosphate; vegetable oil; animal oil; and solketal.
Suitable binders include, but are not limited to, starch; gelatin; natural
sugars,
such as glucose, sucrose and lactose; corn sweeteners; natural and synthetic
gums, such
as acacia, tragacanth, vegetable gum, and sodium alginate;
carboxymethylcellulose;
hydroxypropylmethylcellulose; polyethylene glycol; povidone; waxes; and the
like.
Suitable disintegrants include, but are not limited to, starch, e.g., corn
starch,
methyl cellulose, agar, bentonite, xanthan gum, sodium starch glycolate,
crosspovidone
and the like.
Suitable lubricants include, but are not limited to, sodium oleate, sodium
stearate,
sodium stearyl fumarate, magnesium stearate, sodium benzoate, sodium acetate,
sodium
chloride and the like.
A suitable suspending agent is, but is not limited to, bentonite, ethoxylated
isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline
cellulose, aluminum metahydroxide, agar-agar and tragacanth, or mixtures of
two or
more of these substances, and the like.
Suitable dispersing and suspending agents include, but are not limited to,
synthetic and natural gums, such as vegetable gum, tragacanth, acacia,
alginate, dextran,
sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone and
gelatin.
Suitable film forming agents include, but are not limited to,
hydroxypropylmethylcellulose, ethylcellulose and polymethacrylates.
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Suitable plasticizers include, but are not limited to, polyethylene glycols of
different molecular weights (e.g., 200-8000 Da) and propylene glycol.
Suitable colorants include, but are not limited to, ferric oxide(s), titanium
dioxide
and natural and synthetic lakes.
Suitable edible oils include, but are not limited to, cottonseed oil, sesame
oil,
coconut oil and peanut oil.
Examples of additional additives include, but are not limited to, sorbitol,
talc,
stearic acid, dicalcium phosphate and polydextrose.
Unit Dosage Forms
The pharmaceutical composition may be formulated as unit dosage forms, such
as tablets, pills, capsules, caplets, boluses, powders, granules, sterile
parenteral solutions,
sterile parenteral suspensions, sterile parenteral emulsions, elixirs,
tinctures, metered
aerosol or liquid sprays, drops, ampoules, autoinjector devices or
suppositories. Unit
dosage forms may be used for oral, parenteral, intranasal, sublingual or
rectal
administration, or for administration by inhalation or insufflation,
transdermal patches,
and a lyophilized composition. In general, any delivery of active ingredients
that results
in systemic availability of them can be used. Preferably the unit dosage form
is an oral
dosage form, most preferably a solid oral dosage form, therefore the preferred
dosage
forms are tablets, pills, caplets and capsules. Parenteral preparations (e.g.,
injectable
preparations and preparations for powder jet systems) also are preferred.
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Solid unit dosage forms may be prepared by mixing an active agent of the
present
invention with a pharmaceutically acceptable carrier and any other desired
additives as
described above. The mixture is typically mixed until a homogeneous mixture of
the
active agents of the present invention and the carrier and any other desired
additives is
formed, i.e., until the active agent is dispersed evenly throughout the
composition. In
this case, the compositions can be formed as dry or moist granules.
Dosage forms with predetermined amounts of lercanidipine hydrochloride may
be formulated starting with compositions with known quantities of
lercanidipine
hydrochloride using methods well known in the art. In a preferred embodiment a
dosage
form is obtained by mixing compositions comprising known quantities of
crystalline
lercanidipine hydrochloride, e.g., Form (I) or (II), optionally including non-
crystalline
lercanidipine hydrochloride. Further preferred is where a dosage form with
predetermined amounts of crystalline lercanidipine hydrochloride is formulated
by
mixing compositions comprising essentially pure crystalline lercanidipine
hydrochloride
are mixed to form dosage forms comprising a predetermined ratio of
crystalline, e.g.,
Forms (I) and (II).
Dosage forms can be formulated as, for example, "immediate release" dosage
forms. "Immediate release" dosage forms are typically formulated as tablets
that release
at least 70%-90% of the active ingredient within 30-60 min when tested in a
drug
dissolution test, e.g., U.S. Pharmacopeia standard <711>. In a preferred
embodiment,
immediate dosage forms release at 75% of active ingredient in 45 min.
Dosage forms can also be formulated as, for example, "controlled release"
dosage
forms. "Controlled," "sustained," "extended" or "time release" dosage forms
are
equivalent terms that describe the type of active agent delivery that occurs
when the
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active agent is released from a delivery vehicle at an ascertainable and
manipulatable rate
over a period of time, which is generally on the order of minutes, hours or
days, typically
ranging from about sixty minutes to about 3 days, rather than being dispersed
immediately upon entry into the digestive tract or upon contact with gastric
fluid. A
controlled release rate can vary as a function of a multiplicity of factors.
Factors
influencing the rate of delivery in controlled release include the particle
size,
composition, porosity, charge structure, and degree of hydration of the
delivery vehicle
and the active ingredient(s), the acidity of the environment (either internal
or external to
the delivery vehicle), and the solubility of the active agent in the
physiological
environment, i.e., the particular location along the digestive tract. Typical
parameters for
dissolution test of controlled release forms are found in U.S. Pharmacopeia
standard
<724>.
Dosage forms can also be formulated to deliver active agent in multiphasic
stages
whereby a first fraction of an active ingredient is released at a first rate
and at least a
second fractions of active ingredient is released at a second rate. In a
preferred
embodiment, a dosage form can be formulated to deliver active agent in a
biphasic
manner, comprising a first "immediate release phase", wherein a fraction of
active
ingredient is delivered at a rate set forth above for immediate release dosage
forms, and a
second "controlled release phase," wherein the remainder of the active
ingredient is
released in a controlled release manner, as set forth above for controlled
release dosage
forms.
Tablets or pills can be coated or otherwise compounded to form a unit dosage
form which has delayed and/or prolonged action, such as time release and
controlled
release unit dosage forms. For example, the tablet or pill can comprise an
inner dosage
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and an outer dosage component, the latter being in the form of a layer or
envelope over
the former. The two components can be separated by an enteric layer which
serves to
resist disintegration in the stomach and permits the inner component to pass
intact into
the duodenum or to be delayed in release.
Biodegradable polymers for controlling the release of the active agents,
include,
but are not limited to, polylactic acid, polyepsilon caprolactone, polyhydroxy
butyric
acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and
cross-
linked or amphipathic block copolymers of hydrogels.
For liquid dosage forms, the active substances or their physiologically
acceptable
salts are brought into solution, suspension or emulsion, optionally with the
usually
employed substances such as solubilizers, emulsifiers or other auxiliaries.
Solvents for
the active combinations and the corresponding physiologically acceptable
salts, can
include water, physiological salt solutions or alcohols, e.g. ethanol, propane-
diol or
glycerol. Additionally, sugar solutions such as glucose or mannitol solutions
may be
used. A mixture of the various solvents mentioned may further be used in the
present
invention.
A transdermal dosage form also is contemplated by the present invention.
Transdermal forms may be a diffusion-driven transdermal system (transdermal
patch)
using either a fluid reservoir or a drug-in-adhesive matrix system. Other
transdermal
dosage forms include, but are not limited to, topical gels, lotions,
ointments,
transmucosal systems and devices, and iontohoretic (electrical diffusion)
delivery
system. Transdermal dosage forms may be used for timed release and controlled
release
of the active agents of the present invention.
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Pharmaceutical compositions and unit dosage forms of the present invention for
administration parenterally, and in particular by injection, typically include
a
pharmaceutically acceptable carrier, as described above. A preferred liquid
carrier is
vegetable oil. Injection may be, for example, intravenous, intrathecal,
intramuscular,
intraruminal, intratracheal, or subcutaneous.
The active agent also can be administered in the form of liposome delivery
systems, such as small unilamellar vesicles, large unilamellar vesicles and
multilamellar
vesicles. Liposomes can be formed from a variety of phospholipids, such as
cholesterol,
stearylamine or phosphatidylcholines.
The polymorphs of the present invention also may be coupled with soluble
polymers as targetable drug carriers. Such polymers include, but are not
limited to,
polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl-
amidephenol,
polyhydroxy-ethylaspartamidephenol, and polyethyl-eneoxideopolylysine
substituted
with palmitoyl residues.
The present application further discloses pharmaceutical formulations and unit
dosage forms that comprise one of the isolated polymorphs of the present
invention or a
mixture thereof of predetermined polymorph content. Dosage forms with
predetermined
amounts of lercanidipine hydrochloride may be formulated starting with
compositions
with known quantities of lercanidipine hydrochloride using methods well known
in the
art. In a preferred embodiment a dosage form is obtained by mixing
compositions
comprising known quantities of crystalline lercanidipine hydrochloride, e.g.,
Form (III)
or (IV), optionally including other forms of crystalline lercanidipine
hydrochloride, e.g.,
Form (I) or (II), or non-crystalline forms or lercanidipine hydrochloride,
e.g., amorphous.
Further preferred is where a dosage form with predetermined amounts of
crystalline
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lercanidipine hydrochloride is formulated by mixing compositions comprising
essentially
pure crystalline lercanidipine hydrochloride are mixed to form dosage forms
comprising
a predetermined ratio of crystalline Forms (III) and (IV).
Dosage forms preferably comprise a predetermined amount of any one of
crystalline lercanidipine hydrochloride Form (I), (II), (III) or (IV). Also
preferred are
dosage forms that simultaneously comprise predetermined amounts of at least
two
crystalline lercanidipine hydrochloride Forms, e.g., Forms (I) and (II), Forms
(I) and
(III), Forms (I) and (IV), Forms (II) and (III), Forms (II) and (IV), or Forms
(III) and
(IV). Also preferred are dosage forms that simultaneously comprise
predetermined
amounts of at least three crystalline lercanidipine hydrochloride Forms, e.g.,
Forms (I),
(II) and (III), Forms (I), (II) and (IV), Forms (I), (III) and (IV), or Forms
(II), (III) and
(IV). Also preferred are dosage forms that simultaneously comprise
predetermined
amounts of at least four crystalline lercanidipine hydrochloride Forms, e.g.,
Forms (I),
(II), (III) and (IV). Each of the aforementioned may optionally include other
forms of
lercanidipine such as, for example and without limitation, indeterminate or
amounts of
crystalline lercanidipine hydrochloride, e.g., Forms (I), (II), (III) and
(IV), that have not
been predetermined, or other forms of lercanidipine, e.g., crude or amorphous.
Administration
The pharmaceutical composition or unit dosage forms of the present invention
may be administered by a variety of routes such as intravenous, intratracheal,
subcutaneous, oral, mucosal parenteral, buccal, sublingual, ophthalmic,
pulmonary,
transmucosal, transdermal, and intramuscular. Unit dosage forms also can be
administered in intranasal form via topical use of suitable intranasal
vehicles, or via
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transdermal routes, using those forms of transdermal skin patches known to
those of
ordinary skill in the art. Oral administration is preferred.
The pharmaceutical composition or unit dosage forms of the present invention
may be administered to an animal, preferably a human being, in need of
antihypertensive
treatment. The pharmaceutical composition or unit dosage form of the present
invention
may be administered according to a dosage and administration regimen defined
by
routine testing in light of the guidelines given above in order to obtain
optimal
antihypertensive activity and a decreased in blood pressure while minimizing
toxicity or
side-effects for a particular patient. However, such fine turning of the
therapeutic
regimen is routine in light of the guidelines given herein.
The dosage of the composition containing polymorphs or mixtures of the present
invention may vary according to a variety of factors such as underlying
disease state, the
individual's condition, weight, sex and age and the mode of administration.
For oral
administration, the pharmaceutical compositions can be provided in the form of
scored or
unscored solid unit dosage forms.
A pharmaceutical composition comprising (1) lercanidipine hydrochloride, where
the lercanidipine hydrochloride is selected from the group consisting of
isolated
lercanidipine hydrochloride crystalline Form (I), isolated lercanidipine
hydrochloride
crystalline Form (II), or combinations thereof of predetermined polymorph
composition;
and (2) at least one component selected from the group consisting of a
pharmaceutically
acceptable carrier or diluent, a flavorant, a sweetener, a preservative, a
dye, a binder, a
suspending agent, a dispersing agent, a colorant, a disintegrant, an
excipient, a diluent, a
lubricant, a plasticizer, and an edible oil. In a preferred embodiment, the
pharmaceutical
composition or dosage form comprises 0.1 to 400 mg lercanidipine
hydrochloride.
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Preferably, the composition or dosage form comprises 1 to 200 mg lercanidipine
hydrochloride, for all uses disclosed herein. More preferably, the composition
or dosage
form comprises 5 to 40 mg lercanidipine hydrochloride. Smaller amounts may be
selected when a preferred enantiomer having higher activity for a particular
therapeutic
goal is used.
A pharmaceutical composition comprising (1) lercanidipine hydrochloride, where
the lercanidipine hydrochloride is selected from the group consisting of
isolated
lercanidipine hydrochloride crystalline Form (III), isolated lercanidipine
hydrochloride
crystalline Form (IV), or combinations thereof of predetermined polymorph
composition; and (2) at least one component selected from the group consisting
of a
pharmaceutically acceptable carrier or diluent, a flavorant, a sweetener, a
preservative, a
dye, a binder, a suspending agent, a dispersing agent, a colorant, a
disintegrant, an
excipient, a diluent, a lubricant, a plasticizer, and an edible oil. In a
preferred
embodiment, the pharmaceutical composition or dosage form comprises 0.1 to 400
mg
lercanidipine hydrochloride, for all uses disclosed herein. Preferably, the
composition or
dosage form comprises 1 to 200 mg lercanidipine hydrochloride. More
preferably, the
composition or dosage form comprises 5 to 40 mg lercanidipine hydrochloride.
Smaller
amounts may be selected when a preferred enantiomer having a higher activity
for a
particular therapeutic goal is used.
The pharmaceutical composition or unit dosage form may be administered in a
single daily dose, or the total daily dosage may be administered in divided
doses. In
addition, co-administration or sequential administration of other active
agents may be
desirable. The polymorphs and mixtures thereof of the invention may be
combined with
any known drug therapy, preferably for treatment of hypertension. For example,
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bimodal therapy involving in addition a diuretic, a (3-receptor blocker, an
ACE inhibitor
or an angiotensin II receptor antagonist is contemplated by the present
invention (see,
e.g., U.S. Provisional Application No. 60/344,601, filed October 23, 2001 and
Italian
Application No. MI 2001 A 002136 filed October 16, 2001).
For combination therapy the compounds may initially be provided as separate
dosage forms until an optimum dosage combination and administration regimen is
achieved. Therefore, the patient may be titrated to the appropriate dosages
for his/her
particular hypertensive condition. After the appropriate dosage of each of the
compounds is determined to achieve a decrease of the blood pressure without
untoward
side effects, the patient then may be switched to a single dosage form
containing the
appropriate dosages of each of the active agents, or may continue with a dual
dosage
form.
The exact dosage and administration regimen utilizing the combination therapy
of the present invention is selected in accordance with a variety of factors
including type,
species, age, weight, sex and medical condition of the patient; the severity
and etiology
of the hypertension to be treated; the route of administration; the renal and
hepatic
function of the patient; the treatment history of the patient; and the
responsiveness of the
patient. Optimal precision in achieving concentrations of compounds within the
range
that yields efficacy without toxicity requires a regimen based on the kinetics
of the
drug's availability to target sites. This involves a consideration of the
absorption,
distribution, metabolism, excretion of a drug, and responsiveness of the
patient to the
dosage regimen. However, such fine tuning of the therapeutic regimen is
routine in light
of the guidelines given herein.
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A pharmaceutical composition for parenteral administration contains not below
0.1%, preferably from about 0.5% to about 30%, by weight of a polymorph or
mixture of
the present invention, based upon the total weight of the pharmaceutical
composition.
Individual isolated polymorphs are preferred for parenteral administration.
Generally, transdermal dosage forms contain from about 0.01% to about 100% by
weight of the active agents, based upon 100% total weight of the dosage.
In a preferred embodiment of the present invention, the composition is
administered daily to the patient. In a further preferred embodiment, the
pharmaceutical
composition or dosage form 0.1 to 400 mg lercanidipine hydrochloride.
Preferably, the
composition or dosage form comprises 1 to 200 mg lercanidipine hydrochloride.
More
preferably, the composition or dosage form comprises 5 to 40 mg lercanidipine
hydrochloride.
EXAMPLES
The following examples of preparation of lercanidipine hydrochloride crude
Forms (A) and (B) and crystalline Forms (I) and (II) are now disclosed for
illustrative
non-limiting purposes, together with the results of DSC analysis and
solubility, stability
and hygroscopicity tests; the bioavailability tests for the new crystalline
forms are also
disclosed.
EXAMPLE 1 Initial preparation
Thionyl chloride (36 g) diluted in ethyl acetate (25 g) was slowly added to a
solution of 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3-
carboxylic acid (90 g) prepared, e.g., as disclosed in German patent DE 2847
237, in
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dimethylformamide (115 g) and ethyl acetate (396 g), keeping temperature
between -1
and +1 C. A solution of 2, N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-
propanol (84
g) in ethyl acetate (72 g) was slowly added to the mixture thus obtained. The
whole was
kept under stirring at the same temperature for 3 hours. The mixture was then
heated to
20-25 C and kept under stirring for 12 hours. Water (340 ml) was then added,
the whole
was stirred for 30 min and after settling the aqueous phase was discarded. The
organic
phase was washed again with water (340 ml).
EXAMPLE 2 Crude lercanidipine hydrochloride Form (A)
The organic phase obtained from Example 1 was then subjected to azeotropic
distillation under vacuum at about 250 mmHg, without going above a temperature
of
60 C. After removing about 50 ml of water, the solution was concentrated to
about 1/3
of the initial volume in the same conditions of temperature and pressure and
then brought
to its initial volume with fresh ethyl acetate until the K.F. value (Karl
Fisher value) was
about 0.10-0.15%. The final suspension was cooled to 0-5 C. The solid was
filtered,
suspended in ethyl acetate (350 g) and stirred at 60-65 C for 1 hour. The
whole was
cooled to 5-10 C and then filtered. The solid was dried in an oven at 70 C.
133 g of dry
raw lercanidipine hydrochloride Form (A) was obtained (75% yield), DSC peak
150-
152 C.
EXAMPLE 3 Crude lercanidipine hydrochloride Form (B)
The organic phase obtained at the end of Example 1 was heated under reflux (70-
75 C) and the water contained in the solution was removed with a Dean Stark
apparatus
(Spaziani Rolando, Nettuno, Rome, Italy) until a K.F. value of about 2% was
obtained.
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The whole was then distilled at atmospheric pressure to reach 3/4 of initial
volume. The
solution was brought to its initial volume by adding fresh ethyl acetate. The
K.F. value at
the end of this operation was 0.9-1.1%. The final solution was cooled to 0-5
C. A solid
slowly precipitates which was filtered. The solid thus obtained was suspended
in ethyl
acetate (350 g) and stirred at 60-65 C for 1 hour. The whole was cooled to 5-
10 C, then
filtered and dried in an oven at 70 C, thus obtaining 133 g of crude
lercanidipine
hydrochloride Form (B), DSC peak 131-135 C; 75% yield.
EXAMPLE 3A Crude lercanidipine hydrochloride Form (B)
The organic phase obtained at the end of Example 1 was heated under reflux (70-
75 C) and the water contained in the solution was removed with a Dean Stark
apparatus
until a K.F. value of about 2% was obtained. The whole was then distilled at
atmospheric pressure to reach 3/4 of initial volume. The solution was brought
to its initial
volume by adding fresh ethyl acetate. The K.F. value at the end of this
operation was
0.9-1.1%. The final solution was cooled to 20 C, seeded with 0.1% of crude
lercanidipine hydrochloride Form (B) and cooled to 0-5 C. A solid slowly
precipitated
and was then filtered. The solid thus obtained was suspended in ethyl acetate
(350 g)
and stirred at 60-65 C for 1 hour. The whole was cooled at 5-10 C, then
filtered and
dried in an oven at 70 C for 24 hours, thus obtaining 133 g of crude
lercanidipine
hydrochloride Form (B), DSC peak 131-135 C; 75% yield.
EXAMPLE 4 Preparation of lercanidipine hydrochloride crystalline Form (I)
In separate representative experiments, 100 g of crude lercanidipine
hydrochloride Form (A), (B), or (C) was loaded into a reactor, followed by 400
ml of 2-
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propanol. The mixture was heated under strong reflux and under stirring, thus
obtaining
an almost complete dissolution of the crude substance. The mixture was hot
filtered to
eliminate a slight opalescence and the clear solution kept under stirring was
cooled to
40 C. Temperature was then set at 35 C. The whole was kept for 24 hours under
stirring
at 35 C, then temperature was set at 30 C, and stirring was continued at said
temperature
for another 24 hours. The solid was filtered at 30 C and washed with 50 ml of
2-
propanol, then dried in an oven at 70 C under vacuum for 24 hours. Weight of
dry
product in each case was (lercanidipine HCI (I)) 90 g (HPLC purity of the
product in
Form (I) > 99.5%).
EXAMPLE 4A Preparation of lercanidipine hydrochloride crystalline Form (I)
In separate representative experiments, 100 g of crude lercanidipine
hydrochloride Form (A), (B), or (C) was loaded into a reactor, followed by 400
ml of 2-
propanol. The mixture was heated under strong reflux and under stirring, thus
obtaining
an almost complete dissolution of the crude substance. The mixture was hot
filtered to
eliminate a slight opalescence and the clear solution kept under stirring is
slowly cooled
to 40 C. Precipitation was then triggered with 100 mg of lercanidipine
hydrochloride
Form (I) and temperature was set at 35 C, keeping the mixture under stirring.
The whole
was kept for 24 hours under stirring at 35 C, then temperature was set at 30
C, keeping
under stirring at said temperature for another 24 hours. The solid was
filtered at 30 C
and washed with 50 ml of 2-propanol, then dried in an oven at 70 C under
vacuum for 24
hours. Weight of dry product (lercanidipine HC1(I)) was 90 g (HPLC purity of
the
product in Form (I) > 99.5%).
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EXAMPLE 5 Preparation of lercanidipine hydrochloride crystalline Form (I)
In independent preparations, 25 kg of crude lercanidipine hydrochloride, Form
(A) or (B), and then 100 mL of 95% ethanol were loaded and brought to strong
reflux
under stirring. The solution was cooled under stirring at 20 C and then seeded
with
crystalline Form (I). The whole was then cooled to a temperature between 10
and 15 C,
keeping the reaction mixture under stirring for 4 days. The solid thus
obtained was
filtered and washed with 95% ethanol, the precipitate was filtered and dried
in an oven
under vacuum at 70 C for 24 hours. 20.2 kg of product was obtained,
corresponding to a
yield of 81%; HPLC purity in Form (I) > 99.5%. Comparable results are obtained
with
Form (C) as starting material.
EXAMPLE 6 Preparation of lercanidipine hydrochloride crystalline Form (II)
100 g of crude lercanidipine hydrochloride Form (C) and then 200 ml of
acetonitrile was loaded into a reactor. The mixture was heated under strong
reflux and
under stirring, thus obtaining a complete dissolution. The mixture was brought
to 20-
30 C under slight stirring and kept at said temperature for 24 hours. The
precipitate was
filtered and dried in an oven at 70 C for 24 hours. 95 g of dry product was
obtained,
corresponding to a 95% yield; HPLC purity > 99.5% in lercanidipine
hydrochloride
Form (II). Comparable results are obtained when lercanidipine hydrochloride
Form (A)
or (B) is used as starting material.
EXAMPLE 7 Preparation of lercanidipine hydrochloride crystalline Form (II)
In separate representative experiments, 100 g of crude lercanidipine
hydrochloride Form (A), (B), or (C) in 200 ml of 95% ethanol was loaded into a
reactor,
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the mixture thus obtained was heated under stirring and under strong reflux
and then
cooled at 25 C always under stirring. The solution was kept at said
temperature for 24
hours under stirring. The precipitate thus obtained was then filtered and
dried in an oven
at 70 C for 24 hours. 90 g of Form (II), HPLC purity > 99.5% was obtained.
-
EXAMPLE 7A Preparation of lercanidipine hydrochloride crystalline Form (II)
25 g of lercanidipine HCl crude substance or Form (C) was dissolved at 60 C in
100 ml of a mixture ethanol-H2O (8:2). The whole was filtered by gravity to
eliminate
the possible insoluble portion and diluted with 100 ml of H2O. The solution
thus
obtained was stirred at 25 C as such, or it was added with 0.1 g of
lercanidipine
hydrochloride Form (II) or it was sonicated for 6 seconds at 20 kHz and 100
Watts,
always at 25 C. Whatever the choice, after 48 hours under stirring the
precipitate thus
formed was collected and dried in an oven at 70 C for 24 hours, obtaining a 80-
85%
yield of Form (II). Comparable results are obtained using crude Forms (A) or
(B) or
lercanidipine hydrochloride crystalline Form (I) as starting material.
As an alternative, the initial clear solution is diluted with 100 ml of
ethanol and
seeded with lercanidipine hydrochloride Form (II) (0.1 g). After 48 hours with
stirring at
C, 80% yield with respect to stoichiometric lercanidipine hydrochloride Form
(II) is
obtained.
EXAMPLE 8 Preparation of lercanidipine hydrochloride crystalline Form (II) in
aqueous methanol
In representative independent examples, 40 g of lercanidipine hydrochloride
crude Form (C) or crystalline Form (I) was dissolved in 100 ml of methanol at
30 C.
The whole was filtered by gravity to eliminate the possible insoluble portion
and 25 ml
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of water was added. The solution thus obtained was stirred at 25 C as such, or
was
mixed with 0.1 g of lercanidipine hydrochloride Form (II), or was sonicated
for 6
seconds at 20 kHz and 100 Watts, always at 25 C. Whichever the choice, after
48 hours
under stirring the precipitate thus formed was collected and dried, with
yields of 80-85%
with respect to stoichiometric lercanidipine hydrochloride Form (II).
Comparable results
are obtained using crude Form (A) or (B).
EXAMPLE 9 Preparation of lercanidipine hydrochloride crystalline Form (II) in
aqueous 1-propanol
60 g of lercanidipine HC1 crude Form (C) was dissolved at 60 C in 100 ml of 1-
propanol-H20 (8:2). After filtering by gravity the possible insoluble portion
the solution
was cooled in two hours to 25 C and stirred for 120 hours at said temperature,
with or
without sonication for 6 seconds at 20 kHz and 100 Watts. The precipitate thus
formed
was collected, obtaining 90% yield with respect to stoichiometric
lercanidipine
hydrochloride Form (II) after a drying step. Comparable results are obtained
using crude
Forms (A) or (B) or lercanidipine hydrochloride crystalline Form (I) as
starting material.
EXAMPLE 10 Preparation of lercanidipine hydrochloride crystalline Form (II) in
aqueous 2-propanol
30 g of lercanidipine hydrochloride crude Form (C) was dissolved at 60 C in
100
ml of 2-propanol-H20 (8:2). After filtering by gravity the possible insoluble
portion the
solution was cooled in two hours to 25 C and stirred for 72 hours at said
temperature,
with or without sonication for 6 seconds at 20 kHz and 100 Watts. The
precipitate thus
formed was collected, obtaining 85% yield with respect to stoichiometric
lercanidipine
hydrochloride Form (II) after a drying step. The same result is obtained by
stirring for
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168 hours at 10 C. Comparable results are obtained using crude Forms (A) or
(B) or
lercanidipine hydrochloride crystalline Form (I) as starting material.
EXAMPLE 11 Preparation of lercanidipine hydrochloride crystalline Form (II) in
aqueous N-methylpyrrolidone
A suspension of 50 g of lercanidipine hydrochloride crude Form (C) in 30 ml of
N-methylpyrrolidone/water (1:1) was stirred at 20-25 C for 12 days. The solid
thus
formed was collected by filtration and dried, yielding 40 g of lercanidipine
hydrochloride
Form (II). Comparable results are obtained using crude Forms (A) or (B) or
lercanidipine hydrochloride crystalline Form (I) as starting material.
EXAMPLE 12 DSC analysis of lercanidipine hydrochloride crystalline Forms (I)
and (II)
DSC analysis measures changes that occur in a given sample with heating,
wherein the changes identify transition phases. Enthalpy variations taking
place in a
transition phase are calculated on the basis of the area under the curve. The
most
common transition phases are melting and sublimation. The temperature at which
transition starts, onset T, is given by the point in which the curve starts to
deviate from
the base line (flex point).
DSC of Form (I): 3.8 mg of Form (I) was placed in a golden pan of the
apparatus
Perkin Elmer DSC7. The heating speed during the test was 10 C/min.
DSC Form (II): 4.6 mg of Form (II) was placed in a golden pan of the apparatus
Perkin Elmer DSC7. The heating speed during the test was 10 C/min.
The data are shown in Figures 1 and 2 and the characteristic points of the
figures
are briefly summarized in the following Table 1.
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Table 1.
Compound Melting T (Tpeak) [ Cl Onset T [ C]
Form (I) 198.7 179.8
Form (II) 209.3 169.0
Immediately after melting of Form (I) or (II) an exothermic event due to salt
decomposition can be observed.
EXAMPLE 13 Thermogravimetry
A gravimetric analysis associated with an IR analysis was carried out on both
crystalline Forms (I) and (II), and also on crude lercanidipine hydrochloride
Form (A)
and on crude lercanidipine hydrochloride Form (B), using a Netsch
Thermomicrobalance 209 in combination with a spectrometer FTIR Bruker Vector
22.
The tests were carried out according to the following working conditions: 2-5
mg
of sample was heated in a steel crucible in nitrogen atmosphere, with a
heating speed of
I0 C/min. The results obtained with crystalline Forms (I) and (II) are shown
in Figure 3,
from which it can be inferred that in both crystalline forms no weight loss
can be
observed up to their melting point (i.e., until about 190-200 C).
During degradation, which takes places as indicated above after melting, a CO2
loss can be observed.
The results obtained with crude lercanidipine hydrochloride Form (A) are shown
in Figure 19, where a weight loss of 3.4% can be observed in the temperature
range 25-
153 C. The volatile compound has been identified by its corresponding IR
spectrum and
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is ethyl acetate. During degradation (T > 170 C) a small amount of ethyl
acetate in gas
phase could be observed.
The results obtained with crude lercanidipine hydrochloride Form (B) are shown
in Figure 20, where a weight loss of 0.5% in temperature range 25-153 C can be
observed. The volatile compound identified with its corresponding IR spectrum
is ethyl
acetate (0.4%) and water (0.1%). During degradation (T > 170 C) a small amount
of
ethyl acetate in gas phase can be observed.
EXAMPLE 14 Hygroscopicity of crystalline Forms (I) and (II)
The hygroscopicity of both crystalline Forms (I) and (II) was measured with
DVS
analysis by means of a water absorption analyzer (SURFACE MEASUREMENT
SYSTEM, Marion, Buckinghamshire, UK) according to the following working
conditions:
10-15 mg of Form (I) and (II) respectively were placed in a quartz sample-
holder,
placed in its turn on a microbalance, and the sample underwent humidity cycles
between
0 and 95%, starting from 50% of relative humidity (25 C, relative humidity
(RH): 50-95-
0-95-0-50% at RH/h:5%).
The results of the tests are shown in the diagrams of Figures 13 and 14.
14-1 Results obtained with crystalline Form (I)
The exposure of Form (I) to humidity in the DVS analyzer results in a mass
change of +0.15% at 95% RH, and of -0.3% at 0% RH, with almost no hysteresis
during
mass increase and loss. These slight variations are probably due to a
reversible surface
absorption of water.
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14-2 Results obtained with crystalline Form (II)
The exposure of Form (II) to humidity in DVS causes a negligible mass
variation
(< 0.05%) in the whole RH range tested.
EXAMPLE 15 Solubility of crystalline Forms (I) and (II)
15.1 Solubility in water and in ethanol at room temperature
The solubility at 23 C of both crystalline Forms (I) and (II) was evaluated by
UV-
Visible spectroscopy in bi-distilled water (at the pH value spontaneously
reached by the
system) and in absolute ethanol. The molar absorptivity had been previously
determined
in acetonitrile. The same molar absorptivity was considered for the
determination in
water and in ethanol. Solubility in water certainly depends on pH. The
residual solid
obtained by filtration of the suspension was immediately analyzed with Raman
spectroscopy. The results are shown in the following Tables 2 and 3.
TABLE 2. Solubility in water (about 40 mg/ml as initial condition).
Starting material Time min Solubility [mil Residual material
Form (I) 5/25/45/990 0.4/0.5/0.5/0.5 Form (I)
Form (II) 5/25/45/990 0.2/0.2/0.3/0.3 Form (II)
TABLE 3. Solubility in ethanol (100 mg/ml as initial condition)
Starting material Time min Solubility [mg/ml] Residual material
Form (I) 15/45/120 28/27/27 Form (I)
Form (II) 15/45/120 11/12/12 Form (II)
Form (II) is less soluble than Form (I) in both solvents.
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15.2 Solubility in mixtures of water-ethanol at 25 C and at 40 C, with
increasing water
concentrations
Figures 4 and 5 show solubility in water-ethanol at 25 C and at 40 C of Form
(I)
and of Form (II). The maximum solubility is reached for both forms, at both
temperatures, when water concentration is of 20%. Also in this case the
solubility of
crystalline Form (I) is higher than that of crystalline Form (II).
EXAMPLE 16 Solid phase 13C-NMR studies
The high resolution 13C-NMR solid phase spectra were carried out with the
Bruker, ASX300 Instrument equipped with a 7 mm Rotor accessory, using several
combined techniques:
Magic angle spinning (MAS). About 300 mg of the sample was placed in the
rotor spinning at 4.3 kHz around an axis oriented at the magic angle (54 70')
to the
magnetic field to overcome the dipolar bradening caused by CSA (Chemical Shift
Anisotropy). The experiments were conducted at room temerature.
Dipolar Coupling. Since much of line broadening in 13C spectra of organic
solids
is due to coupling to protons, it was removed by heteronuclear decoupling
(decoupling
power level was almost 1 Kilowatt).
Cross polarization (CP). Cross polarization allowed carbon magnetization from
larger proton magnetization via the dipolar coupling to increase signal
intensity.
Total suppression of sidebands (TOSS). TOSS was performed using spin-echoes
synchronized with the rotation of the sample to cause phase alteration of the
spinning
sidebands, resulting in cancellation when successive spectra were added
together.
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Crystalline Forms (I) and (II) show different 13C-NMR spectra in solid phase.
The signals (chemical shift ) and attribution of the corresponding carbon
atoms (as
numbered in the formula of lercanidipine hydrochloride shown below) are
represented in
the following Tables 4 and 5, respectively.
35 INO2 2
23
36 34 II
li\ 3I 0 13 16 20 \ 24 1-1 10 II 3I (I I15~ I /17\ /19 \25
,,,- 941112 N 18
H3CO 5 3 \ I + //26\
(I II 14 H 3T 27
s 6N
H 7 CI- 3 02 8
\\/
29
Table 4. Lercanidipine hydrochloride crystalline Form (I)
Chemical shift (8, ppm) Attribution of carbon atoms
168.7; 167.7 9; 11 or 11; 9
150.1 to 120.4 2; 6 and 20 to 37
104.3; 100.9 3; 5 or 5; 3
79.7 12
63.0; 60.1 (weak) 15; 17 or 17;15
48.6 10
47.7 16
45.4 19
41.1 4
31.6 18
27.7; 26.4 13; 14 or 14; 13
19.6; 18.0 7; 8 or 8; 7
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Table 5. Lercanidipine hydrochloride crystalline Form (II)
Chemical shift (S, ppm) Attribution of carbon atoms
168.1; 166.6 9; 11 or 11; 9
151.9 to 121.9 2; 6 and from 20 to 37
104.0; 102.8 3; 5 or 5; 3
79.0 12
66.0; 58.0 (weak) 15; 17 or 17;15
49.7 10
48.8 16
44.3 19
40.5 4
29.8 18
27.6; 23.5 13; 14 or 14; 13
19.6; 18.3 7; 8 or 8; 7
EXAMPLE 17 IR Studies
The IR (infrared) spectra were recorded in KBr powder by Diffuse Reflectance
Technique using a Perkin Elmer Spectrum-one instrument. IR spectra, whose wave
lengths and corresponding attribution are shown in the following Tables 6 and
7, are
clearly different for the new Forms (I) and (II).
Table 6. IR spectrum in KBr powder of lercanidipine hydrochloride Form (I)
Wavelength (cm -t) Attribution
3186 NH stretching
3100-2800 Alkyl and phenyl stretching
2565 N+H stretching
1673 C=O stretching
1525; 1348 Asymmetric and symmetric stretching of NO2
group
1405; 1386 Bending of geminal methyl groups
785-685 Out-of-plane bending of 5 and 3 adjacent
hydrogens on aromatic rings
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Table 7. IR spectrum in KBr powder of lercanidipine hydrochloride Form (II)
Wavelength (cm -1) Attribution
3183 NH stretching
3100-2800 Alkyl and phenyl stretching
2684 N+H stretching
1705;1675 C=O stretching
1526; 1350 Asymmetric and symmetric stretching of NO2
group
1402; 1380 Bending of geminal methyl groups
800-680 Out-of-plane bending of 5 and 3 adjacent
hydrogens on aromatic rings
EXAMPLE 18: Raman Spectra
A Bruker FT-Raman RFS 100 Spectrophotometer was utilized under the
following typical conditions: about 10 mg sample (without any previous
treatment), 64
scans 2 cm -1 resolution, 100 mW laser power, Ge-detector.
The following Tables 8 and 9 show the most significant peaks of Raman spectra
of Form (I) and Form (II), respectively.
Table 8. Raman spectrum of crystalline Form (I)
Wave number (cm-1 Z Peak intensity
3054 M
3040 M
2981 M
2941 M
1675 S
1646 M
1583 M
1489 M
1349 Vs
1236 M
1005 S
821 M
174 M
98 S
73 Vs
* M= moderate; S= strong, Vs =very strong
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Table 9. Raman spectrum of crystalline Form (II)
Wave number (cm-1 ) Peak intensity
3074 M
3064 M
3055 M
3048 M
3030 M
2973 M
2940 M
1675 S
1647 S
1630 M
1584 M
1489 M
1351 Vs
1005 M
995 M
103 Vs
85 S
* M= moderate; S= strong, Vs =very strong
EXAMPLE 19 Bioavailability of crystalline Forms (I) and (II)
19a-Dog
A study was carried out on six Beagle dogs to evaluate the bioavailability of
crystalline Forms (I) and (II).
The products, in micronized form, were administered orally by hard gelatin
capsules filled up with the active agent, Form (I) and (II), at a dosage of 3
mg/kg,
administered once in the morning of the day of the experiment.
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Blood samples were taken at given times and plasma concentrations of
lercanidipine were determined with a stereoselective analytical method HPLC-
MS/MS,
according to the following working conditions;
Lercanidipine was extracted from dog plasma by means of a liquid-liquid
extraction with a mixture of n-hexane and ethyl ether. The dry residue of the
organic
phase was taken up with a mixture of methanol and water and a liquid-phase
chromatographic separation (LC) was carried out; the two enantiomers of
lercanidipine
were separated on a CHIROBIOTIC V column (Vancomycin) (particle size 5 m,
column
size 150 x 4.6 mm (ASTEC, NJ, USA)) and were detected with a mass spectrometer
(MS/MS) by using an electrospray technique.
The analytical method was validated in a concentration range between 0.1 and
20
ng/ml of plasma for both enantiomers. The method has shown to be specific with
an
accuracy of 15%. The average concentrations of lercanidipine in the tables
represent the
sum of both enantiomers.
The profiles referring to the average concentrations of lercanidipine for both
forms are shown in Figure 10. The following Tables 10 and 11 show single
values
referring to AUC, Tmax, C,,,ax and to plasma concentrations.
TABLE 10. Mean values (n=5) of AUC0_t, Cmax and Tma,c of lercanidipine
hydrochloride
(S+R) crystalline Form (I) and crystalline Form (II), in dogs, after oral
administration at
a dosage of 3 mg/kg.
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Form (I)
Parameter Dog Dog 2* Dog 3 Dog 4 Dog 5 Dog 6 Mean SD
1
AUCo_t 15.41 263.83 27.544 46.57 70.39 28.72 37.73 19.12
ng/h/ml
Tmax (h) 2.00 4.00 6.00 3.00 3.00 6.00 4.00 1.67
Cmax 8.29 128.87 11.62 27.17 22.58 17.83 17.50 6.91
(ng/ml)
Form (II)
Parameter Dog Dog 2* Dog 3 Dog 4 Dog 5 Dog 6 Mean SD
1
AUC0 _t 54.59 119.77 75.62 173.82 142.34 61.91 104.68 43.99
ng/h/ml
Tmax (h) 3.00 1.50 1.50 4.00 2.00 6.00 3.00 1.61
Cniax 18.46 52.19 19.78 52.64 55.38 18.56 36.17 17.27
(ng/ml)
* not included in the calculation of mean value
Table 11. Average concentration in plasma of lercanidipine hydrochloride (S+R)
crystalline Form (I) and crystalline Form (II), in dogs, after oral
administration at a
dosage of 3 mg/kg.
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Form (I)
Time (h) Dog 1 Dog 2* Dog 3 Dog 4 Dog 5 Dog 6 Mean SD
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
0.5 0.1 0.20 0.00 0.00 0.00 0.00 0.00 0.02
1 0.59 0.29 0.00 0.00 0.00 0.00 0.12 0.22
1.5 1.83 1.06 0.32 0.00 1.33 0.00 0.70 0.73
2 8.29 8.94 0.94 0.35 17.11 0.28 5.39 6.34
3 4.44 36.39 0.92 27.17 22.58 1.29 11.28 11.11
4 1.81 128.87 9.42 11.07 16.39 6.26 8.99 5.56
6 0.80 26.65 11.62 2.53 9.73 17.83 8.50 6.50
Form (II)
Time (h) Dog 1 Dog 2* Dog 3 Dog 4 Dog 5 Dog 6 Mean SD
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
0.5 0.00 22.67 6.99 0.00 0.00 0.00 1.40 2.61
1 0.00 52.13 16.61 5.50 3.28 0.00 5.08 5.91
1.5 0.23 52.19 19.78 35.43 32.69 3.49 18.32 14.88
2 7.63 35.45 17.81 38.10 55.38 10.19 25.82 19.23
3 18.46 17.43 15.80 28.36 40.57 14.10 23.46 12.56
4 14.83 5.17 14.10 52.64 23.66 13.24 23.69 16.26
6 8.05 4.50 3.62 17.46 6.76 18.56 10.89 6.82
* not included in the calculation of mean value
The formulation containing Form (II) is more bioavailable than the one
containing crystalline Form (I) in 5 animals out of 6.
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To simplify the comparison, dog 2 was excluded from the evaluation, since
after
the administration of Form (I) dog 2 shows a plasma AUC of 264 ng/h/ml versus
a mean
value of 38 + 19 (SD) of the other 5 dogs. On the other hand, its AUC after
administration of Form (I) is similar to that of the other animals, the value
being 120
versus 105 + 44 ng/h/ml.
The bioavailability of lercanidipine hydrochloride (Form (II)), expressed as
increase in the AUC of lercanidipine (R+S) obtained after administration of
Form (II), is
about 3 times higher than that obtained with Form (I). The average profile of
plasma
concentrations for both crystalline forms is shown in Figure 10.
The analysis of these results shows that the amount of lercanidipine (S+R)
absorbed after administration of crystalline Form (II) is 3 times higher that
of Form (I),
whereas the absorption speed, expressed as Tm., is practically unchanged.
Plasma concentrations 6 hours after administration (last sampling time) are
similar, the concentrations being of 8.5 6.5 ng/ml after administration of
Form (I) and
of 10.9 6.8 ng/ml after administration of Form (II).
19b-Man
A study was carried out on 16 healty volunteers to assess the relative
bioavailability of lercanidipine hydrochloride Form (I) and Form (II). Form
(I) was
represented by a tablet of ZanedipR corresponding to 10 mg of lercanidipine
hydrochloride (Reference -R). Form (II) was administered in form of a 10 mg
tablet
prepared exactly in the same way and with the same composition of ZanedipR
10mg,
starting from micronized Form (II) having the same particle size of Form I
(Test-T).
Blood samples were taken at 15 points from time 0 to 24 h post-dosing and
plasma
concentrations of lercanidipine were determined with a stereoselective
analytical method
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HPLC-MS/MS as described in Example 19a, as validated for man at the same
concentration intervals.
The pharmacokinetic parameters obtained are given in the following table
Form (I) Form (II) Point Estimate 90%C.I.
geom. least geom. least square (T/R)
square mean mean
AUC o_t 8.82 10.36 1.17 0.93 -1.48
n -h/mL)
Cmax 3.18 3.22 1.01 0.73 -1.42
n /mL)
tmax 1.50* 2.50* 0.75** 0.00-1.25
(h)
Cmax/AUC 0.386^ 0.329^ 0.85 0.69-1.02
* median
** median difference
A least square mean
The obtained results indicated that lercanidipine hdyrochloride Form (II) was
not
bioequivalent to Form I, with Form (II) obtaining higher plasma levels, that
lercanidipine
hydrochloride Form (I) has a tm that is shorter than that of Form (II),
suggesting its use
in immediate release formulations.
EXAMPLE 20 X-ray diffraction studies
Philips PW 1710 and Philips X pert PW 3040 powder diffractometer (Copper Ka
radiation) were used, under the following typical conditions: about 5-70 mg
sample
(without any previous treatment) with application of a slight pressure to
obtain a flat
surface. Ambient air atmosphere. 0.02 20 stepsize, 2 sec step-1, 2-50 20.
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The obtained spectra are given in Figures 11 and 12 and the corresponding main
peaks are described in Tables 12 and 13. The data are clearly different for
new isolated
Forms (I) and (II).
Table 12. X RD spectrum of lercanidipine hydrochloride Form (I).
d -(A) Relative intensity (I/Io) 2 0 angle
16.3 83 5.4
6.2 47 14.2
4.78 29 18.6
4.10 63 21.7
4.06 36 21.9
3.90 100 22.8
Table 13. X RD spectrum of lercanidipine hydrochloride Form (II).
d (A) Relative intensity((1/lo) 2 0 angle
9.3 35 9.5
6.0 45 14.7
5.49 65 16.1
4.65 52 19.1
4.27 74 20.8
3.81 41 23.4
3.77 100 23.6
3.58 44 24.8
3.54 29 25.2
EXAMPLE 21 Melting point determination of various mixtures of lercanidipine
hydrochloride crystalline Forms (I) and (II)
The melting points of compositions consisting of known ratios of lercanidipine
hydrochloride crystalline Forms (I) and (II) were determined manually.
Conditions
consisted of using a set point of 177 C and introducing the capillary into the
instrument
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(Melting Point Apparatus model 535, BO chi Labortechnik AG, Flawil,
Switzerland) at
approximately 5 C below the melting point. Results are shown in Table 14.
Table 14. Melting points of compositions consisting of known ratios of
lercanidipine
hydrochloride crystalline Forms (I) and (II). Samples in Series A and Series B
were
heated at a gradient of 1 C/min and 0.5 C/min, respectively. Results are given
in C.
Ratio lercanidipine hydrochloride crystalline
Sample Pure Form (1): Form (II) Pure Form
Form (I) 9:1 7:3 1:1 3:7 1:9 (II)
Series A 186.8 188.0 189.5 190.0 192.2 194.2 194.3
Series B 185.9- 184.4- 184.5- 186.7- 186.5- 188.7- 190.6-192.9
186.8 186.1 187.0 187.4 189.4 190.5
U.S. Patent No. 5,767,136 discloses crystalline lercanidipine hydrochloride as
having a melting point of 186-188 C. Table 14 shows that this melting point is
exhibited
by mixtures of Form (I) and Form(II) in which the ratio of Form (I):Form (II)
varies
between 9:1 to 3:7. Bianchi et al. (Drugs of the Future, 1987, 12:1113-1115)
report a
melting point of 186-188EC (non DSC) for a lercanidipine product they
characterize as
"crystals". Hence, the melting point of a preparation of lercanidipine
hydrochloride is
not sufficient by itself to distinguish the particular form or forms present
therein, and
many mixtures of different compositions have the same melting point range.
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EXAMPLE 22. Micronization of lercanidipine hydrochloride.
Micronization is carried out by a jet-mill process using a MICRONETTE M300
from the firm NUOVA GUSEO (Villanova sull'Arda -PC- Italy). Parameters are as
follows: Injection pressure, 5 Kg/cmq; micronization pressure, 9 Kg/cmq; and
cyclone
pressure, 2.5 Kg/cmq. Capacity of micronization is 16 Kg/h. Particle size is
determined
by laser light scattering using a GALAI CIS 1 laser instrument (GALAI, Haifa,
Israel).
Micronization is performed to obtain an average particle size of D (50%) 2-8
m and D
(90%) < 15 m.
EXAMPLE 23
Preparation of the solvate of lercanidipine hydrochloride with methylene
chloride
Lercanidipine hydrochloride Form (I) (5.34 g), prepared as described supra,
was
combined with 20 ml of methylene chloride in a closed vessel, the suspension
was kept
under mild stirring for 192 hours at 20-25 C to produce a solid. The solid was
then
filtered with a glass filter G4 and washed with fresh methylene chloride. A
product of
7.4 g of lercanidipine hydrochloride-methylene chloride solvate (1:1 mol/mol)
was
obtained.
EXAMPLE 24
Preparation lercanidipine hydrochloride form (III)
3.9 g of solvate of lercanidipine hydrochloride with methylene chloride
solvate,
prepared by the method of Example 1, was placed in a glove hood under constant
nitrogen stream (25 1/h) at ambient temperature. The sample was then dried at
90 C and
1 millibar, then placed in a stoppered flask and isolated with parafilm.
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EXAMPLES 25-49 describe preparation of solvates of lercanidipine hydrochloride
with
solvents other than methylene chloride
EXAMPLES 25-28
Preparation of solvates of lercanidipine hydrochloride with anisole, ethyl
acetate
and terbutyl methyl ether
The solvate of lercanidipine hydrochloride with methylene chloride prepared as
described in Example 1, the lercanidipine hydrochloride crystalline form (III)
obtained as
described in Example 2, or the lercanidipine crude (A) or (B) forms prepared
as
described supra, were introduced in a closed vessel together with a solvent
chosen from
the group consisting of anisole, ethyl acetate and terbutyl methyl ether,
under mild
stirring, with 10-20 thermal cycles: 25 C-35 C-25 C (3 hours each). After
these thermal
cycles the samples were kept at 25 C for 24-240 hours. The solvate was then
isolated by
filtration. The solvent used, the concentration of the starting product in the
solvation
solvent, and the solvate stoichiometry are shown in Table 1.
EXAMPLES 29-31
Preparation of solvates of lercanidipine hydrochloride with isopropanol, 2-
butanol,
heptane
The solvate of lercanidipine hydrochloride with methylene chloride prepared as
described in Example 1 was placed in a closed vessel together with a solvent
chosen
from the group consisting of isopropanol, 2-butanol and heptane, kept under
mild stirring
and subjected to 10-20 thermal cycles 25 C-35 C-25 C (heating step 3 hours,
cooling
step 3 hours). After these thermal cycles the sample was kept at 25 C for 24-
240 hours
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and then filtered. The solvent used, the concentrations of the starting
product in the
solvation solvent and the solvate stoichiometry are shown in Table 1.
EXAMPLES 32-33
Preparation of solvates of lercanidipine hydrochloride with acetone and
tetrahydrofuran
The solvate of lercanidipine hydrochloride with methylene chloride, prepared
as
described in Example 1, and a solvent chosen from the group consisting of
acetone and
tetrahydrofuran were placed in a closed vessel, kept under mild stirring and
subjected to
10-20 thermal cycles: 25 C-35 C-25 C (heating step 3 hours, cooling step 3
hours).
After these thermal cycles the samples were kept at 25 C for 24-240 hours and
then
filtered. The solvent used, the concentrations of the starting product in the
solvation
solvent and the solvate stoichiometry are shown in Table 1.
TABLE 15
SOLID SOLVATE
EXAMPLE CONCENTRATION SOLVENT OBTAINED
(mg/ml) [content of solvent:lercanidipine
hydrochloride (mole/mole)]
lercanidipine hydrochloride-
3 500 Anisole anisole (b) form
[0.4]
lercanidipine hydrochloride-
4 508 Ethyl acetate ethyl acetate
[1]
lercanidipine hydrochloride-
5 164 Anisole anisole (a) form
[0.4]
6 229 Terbutyl methyl lercanidipine hydrochloride-
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ether terbutyl methyl ether
[0.8]
lercanidipine hydrochloride-
7 447 Isopropanol isopropanol
[1]
lercanidipine hydrochloride-2-
8 390 2-butanol butanol
[0.8]
lercanidipine hydrochloride-
9 348 Heptane heptane
[0.9]
lercanidipine hydrochloride-
297 Acetone acetone
[1.2]
lercanidipine hydrochloride-
11 308 Tetrahydrofuran tetrahydrofuran
[0.9]
EXAMPLES 34-41
Preparation of solvates of lercanidipine hydrochloride with 2-propanol, 2-
butanol,
tetrahydrofuran, terbutyl methyl ether, anisole, acetone, ethyl acetate,
heptane,
5 using lercanidipine-hydrochloride-methylene chloride
The solvate of lercanidipine hydrochloride with methylene chloride, obtained
as
described in Example 1, was suspended in a closed vessel in a solvent chosen
from the
group consisting of 2-propanol, 2-butanol, tetrahydrofuran, terbutyl methyl
ether,
anisole, acetone, ethyl acetate and heptane. The suspension that was produced
was
10 stirred at 20-50 C for 114-420 hours to produce the solvates. The solvates
were then
filtered. The solvent used, the concentration of the starting product in the
solvation
solvent, and the solvate obtained are shown in Table 2.
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TABLE 16
EXAMPLE CONCENTRATION SOLVENT SOLID SOLVATE
(mg/ml) OBTAINED
lercanidipine
12 320 2-propanol hydrochloride-
2-propanol
lercanidipine
13 323 2-butanol hydrochloride-
2-butanol
lercanidipine
14 323 Tetrahydrofuran hydrochloride-
tetrahydrofuran
Terbutyl methyl lercanidipine
15 306 ether hydrochloride-terbutyl
methyl ether
lercanidipine
16 306 Anisole hydrochloride-anisole (b)
form
17 320 Acetone lercanidipine
hydrochloride-acetone
lercanidipine
18 320 Ethyl acetate hydrochloride-
ethyl acetate
19 330 Heptane lercanidipine
hydrochloride-heptane
EXAMPLES 42-46
Preparation of solvates of lercanidipine hydrochloride with the following
solvents
chosen in the group comprising: tetrahydrofuran, terbutyl methyl ether,
anisole,
acetone, ethyl acetate
Lercanidipine hydrochloride crystalline form (III), obtained as described in
Example 2, was suspended in a solvent chosen from the group consisting of
tetrahydrofuran, terbutyl methyl ether, anisole, acetone and ethyl acetate.
The
suspension then was stirred at 20-50 C for 114-240 hours. The solvent used,
the
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concentration of the starting product in the solvent and the solvate obtained
are shown in
the following Table 3.
TABLE 17
EXAMPLE CONCENTRATION SOLVENT SOLID OBTAINED
(mg/ml)
20 317 Tetrahydrofuran lercanidipine hydrochloride-
tetrahydrofuran
21 313 Terbutyl methyl lercanidipine hydrochloride-
ether terbutyl methyl ether
22 317 Anisole lercanidipine hydrochloride-
anisole (a) form
23 313 Acetone lercanidipine hydrochloride-
acetone
24 327 Ethyl acetate lercanidipine hydrochloride-
ethyl acetate
EXAMPLES 47-55
De-solvation of the solvates obtained in Examples 3-11
The solvent was removed from the solvates by heating under vacuum. The
starting solvate (also indicated with the number of the preparation example),
the
operating conditions applied in the removal of the inclusion solvent and the
crystalline
form of lercanidipine hydrochloride obtained are shown in Table 4.
TABLE 18
STARTING SOLVENT CRYSTALLINE
Ex. STARTING SOLVATE SOLVATE REMOVAL LERCANIDIPINE
PREPARATION CONDITIONS HCl FORM
OBTAINED*
lercanidipine 90 C/<1 mbar/
25 hydrochloride-anisole Example 3 24 hours Form (III)
(b form)
lercanidipine 90 C/<1 mbar/
26 hydrochloride-ethyl Example 4 Form (III)
acetate 24 hours
27 lercanidipine Example 5 50 C/<1 mbar/ Form (I)
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hydrochloride- anisole 24 hours
(a form)
lercanidipine
28 hydrochloride-terbutyl Example 6 90 C/<1 mbar/ Form (I)
methyl ether 24 hours
29 lercanidipine Example 10 90 C/<1 mbar/ Form (IV)
hydrochloride-acetone 24 hours
lercanidipine
30 hydrochloride- Example 11 90 C/<1 mbar/ Form (III)
tetrahydrofurane 24 hours
lercanidipine
31 hydrochloride- Example 7 90 C/<1 mbar/ Form (III)
isopropanol 22 hours
32 lercanidipine Example 8 90 C/<l mbar/ Form (III)
hydrochloride-2-butanol 22 hours
33 lercanidipine Example 9 90 C/<l mbar/ Form (III)
hydrochloride-heptane 22 hours
*determined by Raman spectroscopy and X-ray diffraction
EXAMPLE 56
Preparation of the solvate lercanidipine hydrochloride-methyl ethyl ketone
100 g of lercanidipine hydrochloride crystalline Form (I) was suspended in 250
ml of methyl ethyl ketone/water (95/5) and heated at 80 C until complete
dissolution.
The solution was cooled under stirring, kept at room temperature, and then
filtered. The
product was dried in an oven at 60 C under vacuum (about 200 mmHg). 93 g of
product
was obtained having a lercanidipine hydrochloride-methyl ethyl ketone content
of 1:0.7
(mole/mole).
EXAMPLE 57
X-ray diffraction
The new crystalline forms are hereinafter identified by their X-ray spectrums.
Philips PW 1710 and Philips X pert PW 3040 powder diffractometer (Copper Ka
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radiation) were used, under the following typical conditions: about 5-70 mg
sample
(without any previous treatment) with application of a slight pressure to
obtain a flat
surface. Ambient air atmosphere. 0.02 20 stepsize, 2 sec step-1, 2-50 20.
Lercanidipine hydrochloride crystalline form (III) showed an X-ray diffraction
image at wavelength Ka as expressed in Table 5 and shown in Figure 2.
TABLE 19
d (A) Relative intensity (1/lo) 2 0 angle
11.5 39 7.7
9.1 38 9.7
9.0 37 9.8
8.0 50 11.0
6.6 48 13.5
5.58 57 15.9
5.49 34 16.1
5.13 43 17.3
4.09 63 21.7
3.92 43 22.7
3.72 100 23.9
3.60 85 24.7
3.47 31 25.6
Lercanidipine hydrochloride crystalline form (IV) showed an X-ray diffraction
image, at wavelength Ka as expressed in Table 6 and shown in Figure 7.
TABLE 20
d (A) Relative intensity (1/lo) 2 0 angle
7.9 71 11.2
6.9 53 12.7
5.21 57 17.0
5.13 46 17.3
4.73 66 18.8
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4.69 95 18.9
4.53 53 19.6
4.40 81 20.2
4.34 43 20.4
3.99 44 22.2
3.89 52 22.8
3.77 100 23.6
3.69 35 24.1
The solvate of lercanidipine hydrochloride with methylene chloride showed an
X-ray diffraction image, at wavelength Ku as expressed in Table 7 and shown in
Figure
1.
TABLE 21
d(A) Relative intensity (1/lo) 2 0 angle
6.6 40 13.4
5.87 42 15.1
5.04 39 17.6
4.00 96 22.2
3.90 29 22.8
3.86 34 23.0
3.67 100 24.2
2.04 31 44.4
The solvate of lercanidipine hydrochloride with anisole (a) form showed an X-
ray
diffraction image, at wavelength Ku as expressed in Table 8 and shown in
Figure 12.
TABLE 22
d (A) Relative intensity (1/lo) 2 0 angle
17.4 62 5.1
7.6 34 11.6
5.71 43 15.5
5.57 58 15.9
4.99 47 17.7
4.62 40 19.2
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4.44 29 20.0
4.28 98 20.8
4.04 100 22.0
3.19 43 27.9
2.92 36 30.6
2.86 42 31.3
The solvate of lercanidipine hydrochloride with anisole (b) form showed an X-
ray diffraction image, at wavelength Ka expressed in Table 9 and shown in
Figure 13.
TABLE 23
d(A) Relative intensity (1/lo) 2 0 angle
6.9 49 12.8
6.7 63 13.3
5.82 86 15.2
5.27 41 16.8
5.15 53 17.2
4.00 47 22.2
3.89 46 22.8
3.66 100 24.3
The solvate of lercanidipine hydrochloride with acetone showed an X-ray
diffraction image, at wavelength Ka as expressed in Table 10 and shown in
Figure 8.
TABLE 24
d (A) Relative intensity (1/Io) 2 0 angle
10.1 42 8.8
7.3 100 12.1
5.87 31 15.1
4.07 41 21.8
3.96 52 22.4
3.79 49 23.5
3.71 37 24.0
3.34 33 26.7
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The solvate of lercanidipine hydrochloride with ethyl acetate showed an X-ray
diffraction image, at wavelength Ka as expressed in Table 11 and shown in
Figure 9.
TABLE 25
d (A) Relative intensity (1/lo) 2 0 angle
6.9 100 12.8
6.3 29 14.0
5.80 45 15.3
5.65 31 15.7
5.43 44 16.3
4.74 53 18.7
4.53 49 19.6
4.00 84 22.2
3.91 91 22.7
3.67 77 24.2
3.60 34 24.7
3.53 34 25.2
3.49 43 25.5
The solvate of lercanidipine hydrochloride with terbutyl methyl ether showed
an
X-ray diffraction image, at wavelength Ka, as expressed in Table 12 and shown
in
Figure 11.
TABLE 26
d (A) Relative intensity (I/Io) 2 0 angle
6.2 77 14.2
4.88 29 18.2
4.52 64 19.6
4.02 48 22.1
3.93 100 22.6
3.43 46 26.0
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The solvate of lercanidipine hydrochloride with isopropanol showed an X-ray
diffraction image, at wavelength Ka as expressed in Table 13 and shown in
Figure 14.
TABLE 27
d (A) Relative intensity (1/lo) 2 0 angle
6.6 35 13.5
5.85 48 15.1
5.06 41 17.5
4.04 64 22.0
3.90 39 22.8
3.72 37 23.9
3.67 100 24.2
The solvate of lercanidipine hydrochloride with 2-butanol showed an X-ray
diffraction image, at wavelength Ka the image as expressed in Table 14 and
shown in
Figure 15.
TABLE 28
d (A) Relative intensity (1/lo) 2 0 angle
6.8 34 13.1
5.86 36 15.1
5.13 42 17.3
4.03 51 22.0
3.90 36 22.8
3.67 100 24.2
The solvate of lercanidipine hydrochloride with heptane showed an X-ray
diffraction image, at wavelength Ka as expressed in Table 15 and shown in
Figure 16.
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TABLE 29
d (A) Relative intensity (I/Io) 2 0 angle
7.3 54 12.2
6.0 44 14.7
4.03 85 22.0
3.85 100 23.1
3.76 93 23.6
3.63 67 24.5
3.38 39 26.4
3.01 47 29.6
The solvate of lercanidipine hydrochloride with tetrahydrofuran showed an X-
ray
diffraction image, at wavelength Ka as expressed in Table 16 and shown in
Figure 10.
TABLE 30
d (A) Relative intensity (I/Ion 2 0 angle
6.6 100 13.5
5.88 32 15.1
5.12 56 17.3
4.25 38 20.9
4.06 50 21.9
3.92 42 22.7
3.75 44 23.7
3.70 90 24.0
3.64 31 24.4
The solvate of lercanidipine hydrochloride with methyl ethyl ketone showed an
X-ray diffraction image, at wavelength Ka as expressed in Table 17 and shown
in Figure
38.
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TABLE 31
d (A) Relative intensity (1/lo) 2 0 angle
6.8 50 13.1
6.1 43 14.5
5.87 47 15.1
5.10 53 17.4
3.99 100 22.2
3.87 48 22.9
3.74 36 23.8
3.69 65 24.1
3.61 70 24.6
EXAMPLE 58
Description of the crystals and their thermal characterization
EXAMPLE 58 A Thermomicroscopic analysis
A few mg of each sample were placed on a microscope slide provided with cover
slip and placed on a Mettler model FP82 hotplate (Mettler, Volketswil,
Switzerland) with
a heating speed of 10 C/min, and analyzed with a Leitz Orthoplan Pol light
microscope
(Wild Leitz, Zurich, Switzerland) The sample was not hermetically sealed. The
analysis
provided the following results.
Solvate of lercanidipine hydrochloride with methylene chloride prepared
according to Example 23: The sample consisted of irregular striated
birefringent crystals
(examined with a crossed polarizer). The heating of the solvate resulted in
the melting of
the powder in a range between 138 and 150 C. No other transition phase was
visible.
Lercanidipine hydrochloride crystalline Form (III) obtained as described in
Example 24: The sample consisted of small and very small birefringent crystals
(examined with a crossed polarizer) with an irregular shape and having breaks
and
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cracks. The heating of the crystalline Form (III) resulted in a melting in a
range of 137-
150 C. No other transition phase was visible.
Solvate lercanidipine hydrochloride-anisole (b) form obtained as described in
Example 25: The sample consisted of small birefringent cylinders (examined
with a
crossed polarizer), having breaks and cracks. No transition phase was observed
up to the
melting temperature of 144-146 C.
Solvate lercanidipine hydrochloride-ethyl acetate obtained as described in
Example 26: The sample consisted of small birefringent cylinders (examined
with a
crossed polarizer), having breaks and cracks. Some small drops built up at 106
C. No
transition phase was observed up to the melting temperature of 135-145 C.
Solvate lercanidipine hydrochloride-anisole (a) form obtained as described in
Example 27: The sample consisted of birefringent crystals (examined with a
crossed
polarizer). Formation of microdrops together with the presence of several
microcrystals
was observed at 95 C; no other transformation was seen by heating to melting
at 188 C.
Solvate lercanidipine hydrochloride-terbutyl methyl ether obtained as
described
in Example 28: The sample consisted of non-birefringent crystals (examined
with a
crossed polarizer). Some small drops built up upon pressing the sample with a
spatula.
No transition phase was observed up to the melting temperature of 172-190 C.
Solvate lercanidipine hydrochloride-isopropanol (Example 29): The sample
consisted of small birefringent cylinders (with a crossed polarizer) without
breaks or
cracks. From a range of 135-148 C the crystals de-solvate and remained bathed
in the
liquid. The crystals melted at 177-200 C.
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Solvate lercanidipine hydrochloride-2-butanol (Example 30): The sample
consisted of birefringent cylinders (with a crossed polarizer) having several
breaks and
cracks. No transition phase was observed when the crystals were heated up to
their
melting temperature of 125-145 C.
Solvate lercanidipine hydrochloride-heptane (Example 31): The sample
consisted of small irregular birefringent crystals (with a crossed polarizer).
No transition
phase was observed when the crystals were heated up to their melting point at
125-
150 C.
Solvate lercanidipine hydrochloride-acetone (Example 32): The sample
consisted of large irregular birefringent crystals (with a crossed polarizer).
No transition
phase was observed when the crystals were heated up to their melting
temperature at
125-135 C.
Solvate lercanidipine hydrochloride-tetrahydrofuran (Example 33): The sample
consisted of irregular crystals having breaks and cracks, which were
birefringent
(examined with a crossed polarizer). No transition phase was observed if the
crystals
were heated up to their melting point of 125-160 C.
Lercanidipine hydrochloride crystalline Form IV (Example 51): The sample
consisted of large crystals having several breaks and cracks that were
practically non
birefringent (examined with a crossed polarizer). No transition phase was
observed
when the crystals were heated up to their melting temperature of 116-135 C. A
few
crystals kept their solid form and melted only at 195 C.
Solvate lercanidipine hydrochloride-methyl ethyl ketone (Example 55): The
sample consisted of small cylinder-shaped birefringent crystals (with a
crossed polarizer)
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having breaks and cracks. No transition phase was observed when the sample was
heated up to the melting temperature (135-155 C).
EXAMPLE 58B Thermogravimetric analysis (TG and TGFTIR)
Each sample weighing 2 to 5 mg was placed in an aluminum crucible of an
apparatus PERKIN ELMER TGS-2 Thermogravimetric System (Perkin-Elmer
International, Inc., Rotkreuz, Switzerland) and heated in nitrogen stream at a
rate of
C/min. The thermogravimetric analysis together with an IR analysis in Fourier
transform was carried out according to the following operating modes. Each
sample
10 weighing 2 to 5 mg was placed in an aluminum crucible of an apparatus
Netzsch
Thermomicrobalance TG209 (Netzsch Geratebau, Selb, Germany) coupled with a
spectrometer in Fourier transform BRUKER FTIR Vector 22 (Spectrospin,
Fallanden,
Switzerland) and heated in nitrogen stream at a rate of 10 C/min.
The thermogravimetric analyses gave the following results:
Solvate of lercanidipine hydrochloride with methylene chloride prepared
according to Example 23: A weight loss of 10.1 % was observed in the
temperature
range between 25 and 150 C. (Fig. 3).
The volatile compound was identified by the corresponding IR spectrum and was
found to be methylene chloride. The stoichiometric compound monosolvate
corresponded to a weight loss of 11.6%. Since methylene chloride has a high
vapor
pressure and since the sample already lost small amounts of dichloromethane at
25 C, it
can be inferred that the product obtained in Example I corresponded to a
solvate of
lercanidipine hydrochloride with 1 molecule of methylene chloride.
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Lercanidipine hydrochloride crystalline Form (III) obtained as described in
Example 24: A weight loss of 0.3% corresponding to the presence of
dichloromethane,
as identified by the corresponding IR spectrum, was observed in the
temperature range
25-165 C (See Fig. 4).
Solvate lercanidipine hydrochloride-anisole (b) form obtained as described in
Example 25: A weight loss of 6.1% was observed in the range 25-170 C (Fig.
27).
Anisole was mainly present in the gas phase.
Solvate lercanidipine hydrochloride-ethyl acetate obtained as described in
Example 26: A weight loss of 11.4% was observed in the temperature range
between 25
and 160 C (Fig. 28). The volatile compound, as identified by the IR spectrum,
was found
to be ethyl acetate.
Solvate lercanidipine hydrochloride-anisole (a) form obtained as described in
Example 27: A weight loss of 5.9% was observed in the temperature range
between 25
and 175 C (Fig. 31). The volatile compound was found to be anisole.
Solvate lercanidipine hydrochloride-terbutyl methyl ether obtained as
described
in Example 28: A weight loss of 10% was observed in the temperature range
between 25
and 130 C (Fig. 32). The volatile compound, as identified by the IR spectrum,
was
found to be terbutyl methyl ether. Degradation was observed at a temperature
above
180 C (only CO2 is present).
Solvate lercanidipine hydrochloride-isopropanol obtained as described in
Example 29: A weight loss of 8.4% is observed in the temperature range between
25 and
160 C (Fig. 33). The volatile component is found to be isopropanol.
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Solvate lercanidipine hydrochloride-2-butanol obtained as described in Example
30: A weight loss of 8.6% was observed in the temperature range 25-155 C (Fig.
34).
The volatile component was found to consist of 2-butanol.
Solvate lercanidipine hydrochloride-heptane obtained as described in Example
31: A weight loss of 12.4% was observed in the temperature range 25-160 C
(Fig. 35).
Solvate lercanidipine hydrochloride-acetone obtained as described in Example
32: A weight loss of 10.1% was observed in the temperature range 25-175 C
(Fig. 29).
Solvate lercanidipine hydrochloride-methyl ethyl ketone obtained as described
in
Example 55: A weight loss of 7.4% was observed in the temperature range 25-160
C,
(Fig. 37). The volatile compound identified was found to be methyl ethyl
ketone.
Solvate lercanidipine hydrochloride-tetrahydrofuran (Example 33): A weight
loss of 9.3% was observed at 25-180 C. The volatile component was found to be
THE
(Fig. 35).
Lercanidipine hydrochloride Form (IV) (Example 51): A weight loss of 0.3%
was observed between 25 and 140 C; the volatile component was water (Fig. 36).
For some samples, mass loss did not correspond to stoichiometric values, which
can be
due to the presence of inclusion complexes.
The present invention is not to be limited in scope by the specific
embodiments
described herein. Indeed, various modifications of the invention in addition
to those
described herein will become apparent to those skilled in the art from the
foregoing
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description and the accompanying figures. Such modifications are intended to
fall within
the scope of the appended claims.
It is further to be understood that values are approximate, and are provided
for
description.
