U.S. patent application number 11/048647 was filed with the patent office on 2005-10-27 for novel crude and crystalline forms of lercanidipine hydrochloride.
This patent application is currently assigned to Recordati Ireland Limited. Invention is credited to Bonifacio, Fausto, Campana, Francesco, Iasi, Gianluca De, Leonardi, Amedeo.
Application Number | 20050239847 11/048647 |
Document ID | / |
Family ID | 27453070 |
Filed Date | 2005-10-27 |
United States Patent
Application |
20050239847 |
Kind Code |
A1 |
Bonifacio, Fausto ; et
al. |
October 27, 2005 |
Novel crude and crystalline forms of lercanidipine
hydrochloride
Abstract
The invention describes novel lercanidipine crude Forms (A) and
(B), novel lercanidipine hydrochloride crystalline Forms (I) and
(II) obtained from said crude Forms, pharmaceutical,
antihypertensive compositions containing as active agent at least
one of the lercanidipine hydrochloride crystalline Forms (I) and
(II) and methods of use thereof.
Inventors: |
Bonifacio, Fausto; (Latina,
IT) ; Campana, Francesco; (Rocca Priora, IT) ;
Iasi, Gianluca De; (Aprilia, IT) ; Leonardi,
Amedeo; (Milan, IT) |
Correspondence
Address: |
DARBY & DARBY P.C.
P. O. BOX 5257
NEW YORK
NY
10150-5257
US
|
Assignee: |
Recordati Ireland Limited
Ringaskiddy
IE
|
Family ID: |
27453070 |
Appl. No.: |
11/048647 |
Filed: |
January 31, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11048647 |
Jan 31, 2005 |
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10214386 |
Aug 6, 2002 |
|
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6852737 |
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60367789 |
Mar 26, 2002 |
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Current U.S.
Class: |
514/355 ;
546/315 |
Current CPC
Class: |
C07D 211/90
20130101 |
Class at
Publication: |
514/355 ;
546/315 |
International
Class: |
A61K 031/455; C07D
211/82 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 6, 2001 |
IT |
MI 2001A 0001726 |
Aug 6, 2001 |
IT |
MI 2001A 0001727 |
Claims
1-84. (canceled)
85. A crystalline lercanidipine hydrochloride Form I having at
least one significant X-ray powder diffraction pattern peak at a
2.theta. value selected from the group consisting of 5.4, 14.2,
18.6, 21.7, 21.9, and 22.8.
86. The crystalline lercanidipine hydrchloride Form I of claim 85
having at least three significant X-ray powder diffraction pattern
peaks at 20 values selected from the group consisting of 5.4, 14.2,
18.6, 21.7, 21.9, and 22.8.
87. The crystalline lercanidipine hydrochloride Form I of claim 86
having significant X-ray powder diffraction pattern peaks at 20
values of 5.4, 14.2, 18.6, 21.7, 21.9, and 22.8.
88. The crystalline lercanidipine hydrochloride Form I of claim 85
having a melting point of about 197-201.degree. C. as determined by
DSC.
89. The crystalline lercanidipine hydrochloride Form I of claim 85,
said crystalline lercanidipine hydrochloride Form I being
substantially free of crystalline lercanidipine hydrochloride Form
II having at least one significant X-ray powder diffraction peak at
a 2.theta. value selected from the group consisting of 9.5, 14.7,
16.1, 19.1, 20.8, 23.4, 23.6, 24.8 and 25.2.
90. An antihypertensive composition comprising the crystalline
lercanidipine hydrochloride Form I of claim 85 and amorphous
lercanidipine hydrochloride.
91. The antihypertensive composition of claim 90 wherein the
composition is substantially free of crystalline lercanidipine
hydrochloride Form II having at least one significant X-ray powder
diffraction peak at a 2.theta. value selected from the group
consisting of 9.5, 14.7, 16.1, 19.1, 20.8, 23.4, 23.6, 24.8 and
25.2.
92. The antihypertensive composition of claim 90 further comprising
a pharmaceutically acceptable excipient.
93. An antihypertensive composition comprising the crystalline
lercanidipine hydrochloride Form I of claim 86 and amorphous
lercanidipine hydrochloride.
94. The antihypertensive composition of claim 93 wherein the
composition is substantially free of crystalline lercanidipine
hydrochloride Form II having at least one significant X-ray powder
diffraction peak at a 2.theta. value selected from the group
consisting of 9.5, 14.7, 16.1, 19.1, 20.8, 23.4, 23.6, 24.8 and
25.2.
95. The antihypertensive composition of claim 93 further comprising
a pharmaceutically acceptable excipient.
96. An antihypertensive composition comprising the crystalline
lercanidipine hydrochloride Form I of claim 87 and amorphous
lercanidipine hydrochloride.
97. The antihypertensive composition of claim 96 wherein the
composition is substantially free of crystalline lercanidipine
hydrochloride Form II having at least one significant X-ray powder
diffraction peak at a 2.theta. value selected from the group
consisting of 9.5, 14.7, 16.1, 19.1, 20.8, 23.4, 23.6, 24.8 and
25.2.
98. The antihypertensive composition of claim 96 further comprising
a pharmaceutically acceptable excipient.
99. A lercanidipine hydrochloride preparation comprising a
crystalline lercanidipine hydrochloride Form I having at least one
significant X-ray powder diffraction pattern peak at a 2.theta.
value selected from the group consisting of 5.4, 14.2, 18.6, 21.7,
21.9, and 22.8 subjected to micronization.
100. The lercanidipine hydrochloride preparation of claim 99
comprising a crystalline lercanidipine hydrochloride Form I having
at least three significant X-ray powder diffraction pattern peaks
at 2.theta. values selected from the group consisting of 5.4, 14.2,
18.6, 21.7, 21.9, and 22.8 subjected to micronization.
101. The lercanidipine hydrochloride preparation of claim 100
comprising a crystalline lercanidipine hydrochloride Form I having
significant X-ray powder diffraction pattern peaks at 2.theta.
values of 5.4, 14.2, 18.6, 21.7, 21.9, and 22.8 subjected to
micronization.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation application of and
claims the benefit of priority under 35 U.S.C. .sctn. 121 of prior
application Ser. No. 10/214,386, filed Aug. 6, 2002, and claims
priority under 35 U.S.C. 119 (e) of U.S. provisional application
60/367,789, filed Mar. 26, 2002 and priority under 35 U.S.C. 119
(a)-(d) of Italian patent applications MI 2001A 001726 and MI 2001A
001727, both filed Aug. 6, 2001. Each of the aforementioned
applications is hereby incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The invention is directed to novel crude forms and
crystalline forms 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
[0003] Lercanidipine (methyl
1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-amin- oethyl
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylat-
e) 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.
[0004] 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 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.sup.+ may
be attenuated by lercanidipine, even after the drug has been
removed from the environment of the aortic tissue for 6 hours.
[0005] 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. Pat.
Nos. 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. Pat. No.
4,705,797 involves the following scheme: 1
[0006] 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-hydrated hydrochloride salt is prepared by
treatment with diluted hydrochloric acid in the presence of sodium
chloride.
[0007] A major disadvantage of the process of preparing
lercanidipine, as it is described in U.S. Pat. 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.
[0008] U.S. Pat. No. 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.degree. 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.degree. 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.
[0009] 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 1N hydrochloric acid, and eventually
once again with brine.
[0010] 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.
[0011] 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 U.S. Pat. No.
5,767,136 of 186-188.degree. C. 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.
[0012] 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
the individual forms. As a result, more reproducible batches of
lercanidipine more suitable for large scale manufacture and quality
control were needed.
SUMMARY OF THE INVENTION
[0013] The present invention provides novel crude forms and
crystalline forms of lercanidipine hydrochloride and processes for
making them.
[0014] In one embodiment, the invention provides novel crude
lercanidipine hydrochloride Form (A), which has a melting point of
about 150-152.degree. C. (DSC peak) and comprises about 3-4% (w/w)
ethyl acetate.
[0015] In another embodiment, the invention provides novel crude
lercanidipine hydrochloride Form (B) which has a melting point of
about 131-135.degree. C. (DSC peak) and comprises about 0.3-0.7%
(w/w) ethyl acetate.
[0016] 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.
[0017] In a further embodiment, isolated lercanidipine
hydrochloride crystalline Form (I) is provided which has the
following X-ray diffraction pattern, at wavelength K.alpha. wherein
distances between peaks (D in .ANG.), relative intensity ratios
(I/Io) ratios, and angles of significant peaks (2.theta.) are:
1 D (.ANG.) Relative intensity (I/Io) 2 .theta. 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
[0018] The lercanidipine hydrochloride crystalline Form (I) has a
melting point of about 197-201.degree. C., when said melting point
is determined as DSC peak.
[0019] In an alternative embodiment, isolated lercanidipine
hydrochloride crystalline Form (II) is provided, which has the
following X-ray diffraction pattern, at wavelength K.alpha., as
shown wherein distances, (I/Io) ratios, and 2 .theta. angles of
significant peaks are:
2 D (.ANG.) Relative intensity (I/Io) 2 .theta. 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
[0020] The lercanidipine hydrochloride crystalline Form (II) has a
melting point of about 207-211.degree. C., when said melting point
is determined as DSC peak.
[0021] 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.
[0022] 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).
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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), 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.
[0027] 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
[0028] FIG. 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 .degree. C.
[0029] FIG. 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 .degree. C.
[0030] FIG. 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
.degree. C. and the ordinate indicates percent mass variation.
[0031] FIG. 4 is a graph of solubility at 25.degree. C. of Forms
(I) and (II) in ethanol at increasing water concentrations. The
experiments are described in Example 15. The ordinate indicates %
solubility expressed as w/w and the abscissa % by weight of water
in ethanol.
[0032] FIG. 5 is a graph of solubility at 40.degree. 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.
[0033] FIG. 6 shows .sup.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.
[0034] FIG. 7 shows .sup.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.
[0035] FIG. 8 shows IR spectra of Form (I). The signal and
corresponding attributes can be found in Table 6.
[0036] FIG. 9 shows IR spectra of Form (II). The signal and
corresponding attributes can be found in Table 7.
[0037] FIG. 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).
[0038] FIGS. 11 and 12 show X-ray diffraction spectra at wavelength
K.alpha. of crystalline Forms (I) and (II), respectively. The
distances (d) in .ANG., the (I/Io) ratios and values of 2.theta.
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 2.theta. angles.
[0039] FIGS. 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.
[0040] FIGS. 15 and 16 show X-ray diffraction spectra at wavelength
K.alpha. of crude lercanidipine hydrochloride Form (A) and of crude
lercanidipine hydrochloride Form (B), respectively.
[0041] FIGS. 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.sup.-1).
[0042] FIGS. 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 .degree. C.)
and the ordinate indicates percent mass variation.
DETAILED DESCRIPTION OF THE INVENTION
[0043] The present invention discloses novel crude forms and
crystalline 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.
[0044] 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 (B) further
allow simplified crystallization procedures to be used for
production of novel isolated crystalline forms of lercanidipine
hydrochloride.
[0045] 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.
[0046] Both lercanidipine hydrochloride crystalline Forms (I) and
(II) exhibit good stability. Form (I) 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 197.degree. C. to about 201.degree. C.,
more specifically, about 198.7.degree. C., and the X-ray
diffraction pattern set forth, supra.
[0047] 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.degree. C., more specifically
about 209.3.degree. C.
[0048] 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).
[0049] 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.
[0050] 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.
[0051] 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, 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.
[0052] 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.
[0053] As used herein, the term "crystalline form" refers to
crystals of a compound that have been washed and recrystallized to
remove impurities, or having melting point and x-ray spectra
characteristic of crystalline forms. In the present invention,
unless specifically stated otherwise, the term crystalline forms
refers to Forms (I) and (II) of lercanidipine hydrochloride. These
crystalline forms have an HPLC purity .gtoreq.99.5% and residual
solvents content of <3000 ppm. Additional lercanidipine
hydrochloride crystalline forms, i.e., lercanidipine hydrochloride
crystalline Forms (III) and (IV) are described in Italian patent
application no. MI 2001A 001727, filed Aug. 6, 2001, and in
co-pending U.S. application Ser. No. ______ of Leonardi et al., for
"NOVEL SOLVATE AND CRYSTALLINE FORMS OF LERCANIDIPINE
HYDROCHLORIDE" (Docket no.: 4266/0J960-USO), filed Aug. 6,
2002.
[0054] 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.
[0055] 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., 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.
[0056] 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. Pat. Nos. 5,696,139 and 5,767,136.
[0057] 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. Pat. No. 5,912,351; termed Form (C). Form (A) has
a melting point of about 150.degree. C. to about 152.degree. C.
(DSC peak), Form (B) has a melting point of about 131.degree. C. to
about 135.degree. C. (DSC peak), and Form (C) has a melting point
of about 186.degree. C. to about 192.degree. C. (DSC peak).
Additionally, 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%.
[0058] 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:
[0059] (a) reacting
2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-d-
ihydropyridine-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
[0060] (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.degree. C.,
in a mixture of an aprotic dipolar solvent and of an aprotic polar
solvent.
[0061] 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.
[0062] 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):
[0063] i) washing the mixture of step (b), preferably with
water,
[0064] 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.degree. C. (preferably at
40-50.degree. C.);
[0065] 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%;
[0066] iv) cooling the suspension of step iii) preferably to
0-5.degree. C.;
[0067] v) filtering the solid of step iv);
[0068] vi) re-suspending the solid of step v) preferably in ethyl
acetate and stirring preferably at 60-65.degree. C. for about 1
hour; and
[0069] vii) cooling to 5-10.degree. C., filtering and drying the
obtained solid (e.g., in an oven at about 70.degree. C.).
[0070] The second process (p protocol; used to prepare Form (B)) is
performed using the following steps:
[0071] i') washing the mixture of step (b) preferably with
water,
[0072] 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;
[0073] 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;
[0074] iv') cooling the solution of step iii') preferably to
0-5.degree. C. to obtain a solid;
[0075] v') filtering the solid of step iv');
[0076] vi') re-suspending the solid of step v') preferably in ethyl
acetate and stirring at preferably 60-65.degree. C. for about 1
hour; and
[0077] vii') cooling the suspension of step vi') preferably to
5-10.degree. C., filtering and drying the solid obtained,
preferably in an oven at about 70.degree. C.
[0078] The temperature of step vii') should be carefully controlled
at 5-10.degree. C. to maximize yield.
[0079] 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. Pat. 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.
[0080] 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 197.degree. C. to
about 201.degree. C., specifically about 198.7.degree. C. DSC
analysis of crystalline Form (II) indicates that it has a melting
peak of about 207.degree. C. to about 211.degree. C., specifically
about 209.3.degree. C.
[0081] One purification process (.gamma. process), that leads to
formation of one of the novel crystalline forms (Form (I))
comprises the following steps:
Process for Making Form (I)
[0082] 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);
[0083] e) cooling the solution of step d) preferably to a
temperature between 30 and 40.degree. C. and stirring for a period
of time preferably between 12 and 48 hours to produce a solid;
and
[0084] 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.degree. C. for a period
of time preferably between 12-48 hours.
[0085] 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 .ltoreq.2% lercanidipine HCl. Other
alcohols may also be used as the solvent in step d). An
alternatively preferred solvent is a C.sub.1-C.sub.5 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)
[0086] The present application also contemplates an alternative
method of producing lercanidipine hydrochloride having crystalline
Form (I) which comprises the steps of:
[0087] 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 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.degree. C., and adding crystalline seeds
of Form (I);
[0088] e') cooling the seeded mixture of step d'), preferably to a
temperature between 10 and 15.degree. C., and stirring at this
temperature for a period of time preferably between 24 and 96 hours
to form a solid; and
[0089] f') filtering and drying the solid of step e'), it
preferably in an oven at preferably 70.degree. C. to obtain
lercanidipine hydrochloride Form (I).
[0090] In step e'), crystallization is considered complete when the
content of the solution is .ltoreq.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)
[0091] The second purification process (6 process), which yields
crystalline Form (II), comprises the steps of:
[0092] d") adding acetonitrile to crude lercanidipine hydrochloride
(Form (A) or Form (B)) and heating the mixture under reflux and
stirring,
[0093] e") cooling of the mixture of step d") to room temperature
and stirring preferably for 24 hours to form a solid,
[0094] f") filtering the solid obtained from step e") and drying it
preferably in an oven.
[0095] In step e"), crystallization is considered complete when the
content of the solution is .ltoreq.2% lercanidipine HCl.
[0096] The present application also contemplates two additional
methods for producing Form (II).
[0097] First Alternative Process for Making Form (II)
[0098] The first alternative method comprises the steps of:
[0099] 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;
[0100] e'") cooling the mixture to a temperature preferably between
20 and 40.degree. C. and stirring for a period preferably between
24 and 96 hours to form a solid;
[0101] f'") filtering the solid and drying (e.g., in an oven) at
preferably 70.degree. C. for 12-18 hours to produce lercanidipine
hydrochloride Form (II).
[0102] In step e'"), crystallization is considered complete when
the content of the solution is .ltoreq.2% lercanidipine HCl.
[0103] Second Alternative Method for Making Form II
[0104] The second alternative method of obtaining the Form (II)
polymorph comprises the steps of:
[0105] 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.degree. C. to produce a
solution;
[0106] e"") stirring the solution of step d" ") at a temperature
preferably between 20 and 25.degree. C. to produce a solid;
[0107] f"") filtering the solid of step e"") and drying (e.g., in
an oven) at preferably 70.degree. C. for preferably 12-18
hours.
[0108] 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 .ltoreq.2% lercanidipine HCl. 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.
[0109] The preferred process for preparing Form (I) is the .gamma.
process and the preferred process for preparing Form (II) is the
.delta. process. Applicants have determined that Form (I) can be
quantitatively obtained by use of C.sub.1-C.sub.5 anhydrous alcohol
(preferably anhydrous ethanol or isopropanol) or C.sub.1-C.sub.5
alcohol containing up to 5% water under controlled conditions
d'-f'). In fact, the foregoing processes, especially the .gamma.
and .delta. processes can be used to produce the desired polymorph
reproducibly and consistently.
[0110] 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 FIGS. 11 and 12 and
Example 20). Form I has a smaller crystal and hence particle size
before micronization and so is easier and faster to process than
Form II, which presents with larger crystals.
[0111] 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.
[0112] 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.
[0113] 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.
Pharmaceutical Compositions
[0114] 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.
[0115] Both 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%).sub.2-8 .mu.m, D(90%)<15
.mu.m.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] Suitable film forming agents include, but are not limited
to, hydroxypropylmethylcellulose, ethylcellulose and
polymethacrylates.
[0123] Suitable plasticizers include, but are not limited to,
polyethylene glycols of different molecular weights (e.g., 200-8000
Da) and propylene glycol.
[0124] Suitable colorants include, but are not limited to, ferric
oxide(s), titanium dioxide and natural and synthetic lakes.
[0125] Suitable edible oils include, but are not limited to,
cottonseed oil, sesame oil, coconut oil and peanut oil.
[0126] Examples of additional additives include, but are not
limited to, sorbitol, talc, stearic acid, dicalcium phosphate and
polydextrose.
Unit Dosage Forms
[0127] 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.
[0128] 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.
[0129] 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 Forms (I) and (II).
[0130] 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.
[0131] 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
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>.
[0132] 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.
[0133] 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 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.
[0134] 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.
[0135] 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.
[0136] 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.
[0137] 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.
[0138] 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.
[0139] 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-ethylaspartamidepheno- l, and
polyethyl-eneoxideopolylysine substituted with palmitoyl
residues.
Administration
[0140] 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 transdermal routes, using
those forms of transdermal skin patches known to those of ordinary
skill in the art. Oral administration is preferred.
[0141] 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.
[0142] 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.
[0143] 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.
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.
[0144] 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, bimodal therapy involving in addition a
diuretic, a .beta.-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 Oct. 23, 2001 and Italian Application No. MI 2001 A 002136
filed Oct. 16, 2001).
[0145] 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.
[0146] 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.
[0147] 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.
[0148] 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.
[0149] 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
[0150] 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
[0151] 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 dimethylformamide (115
g) and ethyl acetate (396 g), keeping temperature between -1 and
+1.degree. 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.degree. 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)
[0152] 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.degree. 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.degree. C. The solid was
filtered, suspended in ethyl acetate (350 g) and stirred at
60-65.degree. C. for 1 hour. The whole was cooled to 5-10.degree.
C. and then filtered. The solid was dried in an oven at 70.degree.
C. 133 g of dry raw lercanidipine hydrochloride Form (A) was
obtained (75% yield), DSC peak 150-152.degree. C.
Example 3
Crude Lercanidipine Hydrochloride Form (B)
[0153] The organic phase obtained at the end of Example 1 was
heated under reflux (70-75.degree. 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. 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.degree. C. A solid slowly precipitates which was filtered.
The solid thus obtained was suspended in ethyl acetate (350 g) and
stirred at 60-65.degree. C. for 1 hour. The whole was cooled to
5-10.degree. C., then filtered and dried in an oven at 70.degree.
C., thus obtaining 133 g of crude lercanidipine hydrochloride Form
(B), DSC peak 131-135.degree. C.; 75% yield.
Example 3A
Crude Lercanidipine Hydrochloride Form (B)
[0154] The organic phase obtained at the end of Example 1 was
heated under reflux (70-75.degree. 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.degree. C., seeded with 0.1% of crude
lercanidipine hydrochloride Form (B) and cooled to 0-5.degree. 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.degree. C. for 1 hour. The whole was cooled at 5-10.degree.
C., then filtered and dried in an oven at 70.degree. C. for 24
hours, thus obtaining 133 g of crude lercanidipine hydrochloride
Form (B), DSC peak 131-135.degree. C.; 75% yield.
Example 4
Preparation of Lercanidipine Hydrochloride Crystalline Form (I)
[0155] 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 was cooled to 40.degree. C. Temperature was
then set at 35.degree. C. The whole was kept for 24 hours under
stirring at 35.degree. C., then temperature was set at 30.degree.
C., and stirring was continued at said temperature for another 24
hours. The solid was filtered at 30.degree. C. and washed with 50
ml of 2-propanol, then dried in an oven at 70.degree. C. under
vacuum for 24 hours. Weight of dry product in each case was
(lercanidipine HCl (I)) 90 g (HPLC purity of the product in Form
(I)>99.5%).
Example 4A
Preparation of Lercanidipine Hydrochloride Crystalline Form (I)
[0156] 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.degree. C. Precipitation
was then triggered with 100 mg of lercanidipine hydrochloride Form
(I) and temperature was set at 35.degree. C., keeping the mixture
under stirring. The whole was kept for 24 hours under stirring at
35.degree. C., then temperature was set at 30.degree. C., keeping
under stirring at said temperature for another 24 hours. The solid
was filtered at 30.degree. C. and washed with 50 ml of 2-propanol,
then dried in an oven at 70.degree. C. under vacuum for 24 hours.
Weight of dry product (lercanidipine HCl (I)) was 90 g (HPLC purity
of the product in Form (I)>99.5%).
Example 5
Preparation of Lercanidipine Hydrochloride Crystalline Form (I)
[0157] 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.degree. C. and then seeded with
crystalline Form (I). The whole was then cooled to a temperature
between 10 and 15.degree. 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.degree. 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)
[0158] 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.degree. C.
under slight stirring and kept at said temperature for 24 hours.
The precipitate was filtered and dried in an oven at 70.degree. 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)
[0159] 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, the mixture thus obtained was
heated under stirring and under strong reflux and then cooled at
25.degree. 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.degree. C.
for 24 hours. 90 g of Form (II), HPLC purity >99.5% was
obtained.
Example 7A
Preparation of Lercanidipine Hydrochloride Crystalline Form
(II)
[0160] 25 g of lercanidipine HCl crude substance or Form (C) was
dissolved at 60.degree. C. in 100 ml of a mixture ethanol-H.sub.2O
(8:2). The whole was filtered by gravity to eliminate the possible
insoluble portion and diluted with 100 ml of H.sub.2O. The solution
thus obtained was stirred at 25.degree. 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.degree. C. Whatever the choice, after 48 hours under stirring
the precipitate thus formed was collected and dried in an oven at
70.degree. 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.
[0161] 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 25.degree. 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
[0162] In representative independent examples, 40 g of
lercanidipine hydrochloride crude 20 Form (C) or crystalline Form
(I) was dissolved in 100 ml of methanol at 30.degree. C. The whole
was filtered by gravity to eliminate the possible insoluble portion
and 25 ml of water was added. The solution thus obtained was
stirred at 25.degree. 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.degree. 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
[0163] 60 g of lercanidipine HCl crude Form (C) was dissolved at
60.degree. C. in 100 ml of 1-propanol-H.sub.2O (8:2). After
filtering by gravity the possible insoluble portion the solution
was cooled in two hours to 25.degree. 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
[0164] 30 g of lercanidipine hydrochloride crude Form (C) was
dissolved at 60.degree. C. in 100 ml of 2-propanol-H.sub.2O (8:2).
After filtering by gravity the possible insoluble portion the
solution was cooled in two hours to 25.degree. 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 168 hours at 10.degree. 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
[0165] 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.degree. 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)
[0166] 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).
[0167] 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.degree. C./min.
[0168] 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.degree. C./min.
[0169] The data are shown in FIGS. 1 and 2 and the characteristic
points of the figures are briefly summarized in the following Table
1.
3 TABLE 1 Compound Melting T (Tpeak) [.degree. C.] Onset T
[.degree. C.] Form (I) 198.7 179.8 Form (II) 209.3 169.0
[0170] Immediately after melting of Form (I) or (II) an exothermic
event due to salt decomposition can be observed.
Example 13
Thermogravimetry
[0171] 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.
[0172] 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 10.degree. C./min.
The results obtained with crystalline Forms (I) and (II) are shown
in FIG. 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.degree. C.).
[0173] During degradation, which takes places as indicated above
after melting, a CO.sub.2 loss can be observed.
[0174] The results obtained with crude lercanidipine hydrochloride
Form (A) are shown in FIG. 19, where a weight loss of 3.4% can be
observed in the temperature range 25-153.degree. C. The volatile
compound has been identified by its corresponding IR spectrum and
is ethyl acetate. During degradation (T>170.degree. C.) a small
amount of ethyl acetate in gas phase could be observed.
[0175] The results obtained with crude lercanidipine hydrochloride
Form (B) are shown in FIG. 20, where a weight loss of 0.5% in
temperature range 25-153.degree. 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.degree. C.) a small amount of ethyl acetate in gas phase
can be observed.
Example 14
Hygroscopicity of Crystalline Forms (I) and (II)
[0176] 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:
[0177] 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.degree. C., relative humidity (RH):
50-95-O-95-0-50% at RH/h:5%).
[0178] The results of the tests are shown in the diagrams of FIGS.
13 and 14.
[0179] 14-1 Results obtained with Crystalline Form (I)
[0180] 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.
[0181] 14-2 Results obtained with Crystalline Form (II)
[0182] 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)
[0183] 15.1 Solubility in Water and in Ethanol at Room
Temperature
[0184] The solubility at 23.degree. 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.
4TABLE 2 Solubility in water (about 40 mg/ml as initial condition).
Starting material Time [min] Solubility [mg/ml] 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)
[0185]
5TABLE 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)
[0186] Form (II) is less soluble than Form (I) in both
solvents.
[0187] 15.2 Solubility in Mixtures of Water-Ethanol at 25.degree.
c. and at 40.degree. c., with Increasing Water Concentrations
[0188] FIGS. 4 and 5 show solubility in water-ethanol at 25.degree.
C. and at 40.degree. 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 .sup.13C-NMR Studies
[0189] The high resolution .sup.13C-NMR solid phase spectra were
carried out with the Bruker, ASX300 Instrument equipped with a 7 mm
Rotor accessory, using several combined techniques:
[0190] 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.degree. 70') to the magnetic field to overcome
the dipolar bradening caused by CSA (Chemical Shift Anisotropy).
The experiments were conducted at room temerature.
[0191] Dipolar Coupling. Since much of line broadening in .sup.13C
spectra of organic solids is due to coupling to protons, it was
removed by heteronuclear decoupling (decoupling power level was
almost 1 Kilowatt).
[0192] Cross polarization (CP). Cross polarization allowed carbon
magnetization from larger proton magnetization via the dipolar
coupling to increase signal intensity.
[0193] 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.
[0194] Crystalline Forms (I) and (II) show different .sup.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. 2
6TABLE 4 Lercanidipine hydrochloride crystalline Form (I) Chemical
shift (.delta., 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
[0195]
7TABLE 5 Lercanidipine hydrochloride crystalline Form (II) Chemical
shift (.delta., 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
[0196] 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).
8TABLE 6 IR spectrum in KBr powder of lercanidipine hydrochloride
Form (I) Wavelength (cm.sup.-1) Attribution 3186 NH stretching
3100-2800 Alkyl and phenyl stretching 2565 N.sup.+H stretching 1673
C.dbd.O stretching 1525; 1348 Asymmetric and symmetric stretching
of NO.sub.2 group 1405; 1386 Bending of geminal methyl groups
785-685 Out-of-plane bending of 5 and 3 adjacent hydrogens on
aromatic rings
[0197]
9TABLE 7 IR spectrum in KBr powder of lercanidipine hydrochloride
Form (II) Wavelength (cm.sup.-1) Attribution 3183 NH stretching
3100-2800 Alkyl and phenyl stretching 2684 N.sup.+H stretching
1705; 1675 C.dbd.O stretching 1526; 1350 Asymmetric and symmetric
stretching of NO.sub.2 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
[0198] A Bruker FT-Raman RFS100 Spectrophotometer was utilized
under the following typical conditions: about 10 mg sample (without
any previous treatment), 64 scans 2 cm.sup.-1 resolution, 100 mW
laser power, Ge-detector.
[0199] The following Tables 8 and 9 show the most significant peaks
of Raman spectra of Form (I) and Form (II), respectively.
10TABLE 8 Raman spectrum of crystalline Form (I) Wave number
(cm.sup.-1) 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
[0200]
11TABLE 9 Raman spectrum of crystalline Form (II) Wave number
(cm.sup.-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)
[0201] 19a-Dog
[0202] A study was carried out on six Beagle dogs to evaluate the
bioavailability of crystalline Forms (I) and (II).
[0203] 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.
[0204] 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;
[0205] 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.times.4.6 mm (ASTEC, NJ, USA))
and were detected with a mass spectrometer (MS/MS) by using an
electrospray technique.
[0206] 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.
[0207] The profiles referring to the average concentrations of
lercanidipine for both forms are shown in FIG. 10. The following
Tables 10 and 111 show single values referring to AUC, Tmax,
C.sub.max and to plasma concentrations.
12TABLE 10 Mean values (n = 5) of AUC.sub.0-t, C.sub.max and
T.sub.max of lercanidipine hydrochloride (S + R) crystalline Form
(I) and crystalline Form (II), in dogs, after oral administration
at a dosage of 3 mg/kg. Parameter Dog 1 Dog 2* Dog 3 Dog 4 Dog 5
Dog 6 Mean SD Form (I) AUC.sub.0-t 15.41 263.83 27.544 46.57 70.39
28.72 37.73 19.12 ng/h/ml T.sub.max (h) 2.00 4.00 6.00 3.00 3.00
6.00 4.00 1.67 C.sub.max 8.29 128.87 11.62 27.17 22.58 17.83 17.50
6.91 (ng/ml) Form (II) AUC.sub.0-t 54.59 119.77 75.62 173.82 142.34
61.91 104.68 43.99 ng/h/ml T.sub.max (h) 3.00 1.50 1.50 4.00 2.00
6.00 3.00 1.61 C.sub.max 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
[0208]
13TABLE 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.
Time (h) Dog 1 Dog 2* Dog 3 Dog 4 Dog 5 Dog 6 Mean SD Form (I) 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) 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 Z16.26 6 8.05 4.50 3.62 17.46 6.76 18.56
Z10.89 6.82 *not included in the calculation of mean value
[0209] The formulation containing Form (II) is more bioavailable
than the one containing crystalline Form (I) in 5 animals out of
6.
[0210] 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.
[0211] 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 FIG. 10.
[0212] 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 T.sub.max, is practically
unchanged.
[0213] 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).
[0214] 19b-Man
[0215] 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
Zanedip.sup.R 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 Zanedip.sup.R 10 mg, 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 HPLC-MS/MS as described in
Example 19a, as validated for man at the same concentration
intervals.
14 Form (I) Form (II) Point geom. least geom. least square Estimate
square mean mean (T/R) 90% C.I. AUC.sub.0-t 8.82 10.36 1.17
0.93-1.48 (ng .multidot. h/mL) C.sub.max 3.18 3.22 1.01 0.73-1.42
(ng/mL) t.sub.max 1.50* 2.50* 0.75** 0.00-1.25 (h) C.sub.max/AUC
0.386{circumflex over ( )} 0.329{circumflex over ( )} 0.85
0.69-1.02 *median **median difference {circumflex over ( )}least
square mean
[0216] 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 t.sub.max that is shorter than that of
Form (II), suggesting its use in immediate release
formulations.
Example 20
X-ray Diffraction Studies
[0217] Philips PW 1710 and Philips X pert PW 3040 powder
diffractometer (Copper K.alpha. 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.degree.
2.theta.stepsize, 2 sec step-1,2-50 2.theta..
[0218] The obtained spectra are given in FIGS. 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).
15TABLE 12 X RD spectrum of lercanidipine hydrochloride Form (I). D
(.ANG.) Relative intensity (I/Io) 2 .theta. 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
[0219]
16TABLE 13 X RD spectrum of lercanidipine hydrochloride Form (II).
D (.ANG.) Relative intensity (I/Io) 2 .theta. 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)
[0220] 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.degree. C. and introducing the capillary into the
instrument (Melting Point Apparatus model 535, Buchi Labortechnik
AG, Flawil, Switzerland) at approximately 5.degree. C. below the
melting point. Results are shown in Table 14.
17TABLE 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.degree. C./min and 0.5.degree. C./min, respectively. Results are
given in .degree. C. Ratio lercanidipine hydrochloride crystalline
Pure Form (I):Form (II) Pure Form Sample 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 185.9-186.8 184.4-186.1 184.5-187.0 186.7-187.4 186.5-189.4
188.7-190.5 190.6-192.9
[0221] U.S. Pat. No. 5,767,136 discloses crystalline lercanidipine
hydrochloride as having a melting point of 186-188.degree. 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 186-188.degree. C. (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.
Example 22
Micronization of Lercanidipine Hydrochloride
[0222] 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 .mu.m and D
(90%)<15 .mu.m.
[0223] 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 description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
[0224] Patents, patent applications, publications, procedures, and
the like are cited throughout this application, the disclosures of
which are incorporated herein by reference in their entireties.
* * * * *