U.S. patent application number 13/957067 was filed with the patent office on 2014-02-27 for solid pharmaceutical composition containing 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta (c)chromen-3-yl sulfamate and polymorphs thereof.
This patent application is currently assigned to Ipsen Pharma S.A.S.. The applicant listed for this patent is Anne Brochard, Gerard Coquerel, Delphine Delahaye, Francis Diancourt, Christian Diolez, Ophelie Houssin, Julie Linol, Damien Martins, Nathalie MONDOLY, Marie-No lle Petit, Bertrand Poirot, Barry, Victor, Lloyd Potter, Joel Richard, Alain Rolland, Lok, Wai Lawrence Woo. Invention is credited to Anne Brochard, Gerard Coquerel, Delphine Delahaye, Francis Diancourt, Christian Diolez, Ophelie Houssin, Julie Linol, Damien Martins, Nathalie MONDOLY, Marie-No lle Petit, Bertrand Poirot, Barry, Victor, Lloyd Potter, Joel Richard, Alain Rolland, Lok, Wai Lawrence Woo.
Application Number | 20140056977 13/957067 |
Document ID | / |
Family ID | 47353865 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140056977 |
Kind Code |
A1 |
MONDOLY; Nathalie ; et
al. |
February 27, 2014 |
SOLID PHARMACEUTICAL COMPOSITION CONTAINING
6-OXO-6,7,8,9,10,11-HEXAHYDROCYCLOHEPTA (C)CHROMEN-3-YL SULFAMATE
AND POLYMORPHS THEREOF
Abstract
The present invention relates to a solid pharmaceutical
composition including the active principle
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulfamate.
The present invention also relates to polymorphs of the
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulfamate
compound.
Inventors: |
MONDOLY; Nathalie; (Le
Chesnay, FR) ; Poirot; Bertrand; (Gasville Oiseme,
FR) ; Brochard; Anne; (Dreux, FR) ; Richard;
Joel; (Montfort l'Amaury, FR) ; Delahaye;
Delphine; (Massy, FR) ; Diolez; Christian;
(Palaiseau, FR) ; Rolland; Alain; (Palaiseau,
FR) ; Diancourt; Francis; (Epernon, FR) ;
Coquerel; Gerard; (Boos, FR) ; Martins; Damien;
(Rouen, FR) ; Linol; Julie; (Rouen, FR) ;
Houssin; Ophelie; (Le Mans, FR) ; Petit; Marie-No
lle; (Mont Saint Aignan, FR) ; Potter; Barry, Victor,
Lloyd; (Bathford, GB) ; Woo; Lok, Wai Lawrence;
(Limpley Stoke, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MONDOLY; Nathalie
Poirot; Bertrand
Brochard; Anne
Richard; Joel
Delahaye; Delphine
Diolez; Christian
Rolland; Alain
Diancourt; Francis
Coquerel; Gerard
Martins; Damien
Linol; Julie
Houssin; Ophelie
Petit; Marie-No lle
Potter; Barry, Victor, Lloyd
Woo; Lok, Wai Lawrence |
Le Chesnay
Gasville Oiseme
Dreux
Montfort l'Amaury
Massy
Palaiseau
Palaiseau
Epernon
Boos
Rouen
Rouen
Le Mans
Mont Saint Aignan
Bathford
Limpley Stoke |
|
FR
FR
FR
FR
FR
FR
FR
FR
FR
FR
FR
FR
FR
GB
GB |
|
|
Assignee: |
Ipsen Pharma S.A.S.
Boulogne-Billancourt
FR
|
Family ID: |
47353865 |
Appl. No.: |
13/957067 |
Filed: |
August 1, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13430523 |
Mar 26, 2012 |
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13957067 |
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13201614 |
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PCT/FR2010/000117 |
Feb 12, 2010 |
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13430523 |
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Current U.S.
Class: |
424/465 ;
424/489; 427/2.14; 514/455 |
Current CPC
Class: |
Y10T 428/2982 20150115;
A61K 9/1623 20130101; A61P 35/04 20180101; A61K 9/2004 20130101;
A61K 47/38 20130101; A61K 9/284 20130101; A61K 47/32 20130101; A61K
9/2095 20130101; A61K 31/366 20130101; A61K 9/2018 20130101; A61K
9/2054 20130101; A61K 9/2027 20130101; A61K 31/37 20130101; A61K
9/4858 20130101; C07D 311/94 20130101; A61K 9/145 20130101; A61K
9/2059 20130101 |
Class at
Publication: |
424/465 ;
514/455; 424/489; 427/2.14 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 47/32 20060101 A61K047/32; A61K 47/38 20060101
A61K047/38; A61K 31/366 20060101 A61K031/366 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 13, 2009 |
FR |
FR 0900655 |
Feb 13, 2009 |
FR |
FR 0900656 |
Claims
1. A solid pharmaceutical composition comprising a
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulfamate as
an active ingredient and at least one pharmaceutically acceptable
carrier.
2. The pharmaceutical composition according to claim 1, wherein the
solid composition is a capsule.
3. The pharmaceutical composition according to claim 1, wherein the
solid composition is a tablet.
4. The pharmaceutical composition according to claim 3, wherein the
tablet comprises by total weight of the composition 1 to 30% active
ingredient, from 40 to 92% thinner, 0.1 to 20% disintegrant, 0.1 to
8% binder, 0.1 to 3% slip agent, and 0.5 to 3% of lubricant, and
about 4.8% coating solution in relation to the total weight of the
tablet.
5. The pharmaceutical composition according to claim 4, further
comprising a diluent of mannitol, lactose or lactose monohydrate,
starch, calcium carbonate, microcrystalline cellulose or
maltodextrin.
6. The pharmaceutical composition according to claim 4, wherein the
disintegrant is starch, croscarmellose sodium, sodium starch
glycolate or crospovidone.
7. The pharmaceutical composition according to claim 4, wherein the
binder is polyvinyl pyrrolidone, copolymers of
N-vinyl-2-pyrrolidone and vinyl acetate, carboxymethylcellulose,
pregelatinized starch or methylcellulose.
8. The pharmaceutical composition according to claim 4, wherein the
lubricant is magnesium stearate, sodium stearyl fumarate, calcium
stearate or hydrogenated vegetable oil.
9. The pharmaceutical composition according to claim 1, comprising
either: (a) microcrystalline cellulose and/or copolymers of
N-vinyl-2-pyrrolidone and vinyl acetate; or (b) microcrystalline
cellulose and/or carboxymethylcellulose.
10. The pharmaceutical composition according to claim 3, wherein
the tablet comprises by total weight of the composition 8 to 20%
active ingredient, 20 to 40% lactose, 25 to 50% of microcrystalline
cellulose 2 to 8% copolymers of N-vinyl-2-pyrrolidone and vinyl
acetate 1 to 5% of sodium starch glycolate, 0.2 to 1.4% flow agent,
and 0.5 to 2% of lubricant on the total weight of the tablet.
11. (canceled)
12. The pharmaceutical composition according to claim 1, wherein
the 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl
sulfamate is a particle size between 1 and 15 .mu.m.
13. The pharmaceutical composition according to claim, wherein the
active ingredient is immediately released.
14. The pharmaceutical composition according to claim 3, wherein
the tablet does not exceed 800 mg.
15. A method for preparing a solid pharmaceutical composition
comprising the
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulfamate
according to claim 1, comprising a step of reducing the particle
size of the active ingredient.
16. The method of claim 15, comprising reducing the particle size
by micronization.
17. A method for preparing the solid pharmaceutical composition
according to claim 1 comprising the steps of: (a) screening the
components; (b) wet granulating, mixing, and compressing the
components; and (c) preparing and applying a coating solution,
wherein said coating solution may include a substance that improves
fluidity.
18. The method according to claim 17, wherein the substance that
improves fluidity is a slip agent.
19. The method according to claim 17, wherein during the wet
granulating step, the mass of water relative to the total mass of
the active ingredient to the premixed binder, diluent and
disintegrant, is between about 10 and 30%.
20. The method according to claim 17, wherein after the wet
granulating step, the granules are dried to a residual moisture of
less than 3%.
21-35. (canceled)
36. The pharmaceutical composition according to claim 14, wherein
the tablet does not exceed 400 mg.
37. The method according to claim 18, wherein the substance the
slip agent is a colloidal solution of silicon dioxide.
Description
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/430,523, filed Mar. 26, 2012, which is a Continuation
of U.S. patent application Ser. No. 13/201,614, filed Aug. 15,
2011, which is a national stage of filing of PCT/FR2010/000117,
filed Feb. 12, 2010, the subject matter of which is incorporated
herein in its entirety. This application further claims priority to
FR 0900655, filed Feb. 13, 2009, and FR 0900656, filed Feb. 13,
2009, the subject matter of which is incorporated herein in its
entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0002] The present invention relates to a solid pharmaceutical
composition comprising as active ingredient the compound
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate.
The invention also relates to the preparation of this
pharmaceutical composition, its use as a medicament, and more
particularly as a medicament for the treatment of certain cancers,
compound 1 targeting the enzyme steroid sulphatase.
[0003] A composition according to the invention, containing as
active ingredient the compound
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate
(hereafter also called compound 1) has the advantage of being a
stable oral pharmaceutical composition and offering appropriate
bioavailability.
[0004] Compound 1, of structure:
##STR00001##
is described in patent EP 880514. Nowadays, increasing attention is
being paid to this compound for its sulphatase inhibiting activity
and the therapeutic applications that this involves, as described
by L. W. Woo, et al. in Chemistry & Biology, 2000, 7, 773-91.
The inhibition of the steroid-sulphatase (STS), the enzyme
responsible for the hydrolysis of steroid sulphates, represents for
example a promising novel treatment for postmenopausal patients
with hormone-dependent breast cancer (Clin. Cancer Res. 2006; 12
(5).
[0005] As a general rule, the pharmaceutical compositions such as
tablets can be produced according to three processes: wet
granulation, dry granulation and direct compression.
[0006] Compound 1 belongs to Class 2 of the Biopharmaceutical
Classification System or BCS proposed by G. Amidon (cf. G. L.
Amidon et al., "A theoretical basis for a biopharmaceutical drug
classification: the correlation of in vitro drug dissolution and in
vivo bioavailability", Pharm. Res. 12 (1995) 413-420). Its
absorption, and therefore its bioavailability, thus strongly depend
on the dissolution rate of the pharmaceutical form
administered.
[0007] The processes and formulations known from the prior art
using aqueous phases, such as the self-emulsifying formulations
("Self-Emulsifying Drug Delivery Systems") used in a standard
fashion in order to increase the solubility of the compounds of
Class 2 are not suitable, as the excipients and the aqueous phases
used are not compatible with compound 1, and lead to chemical
degradations during the production stage.
[0008] Due to problems of stability and a low solubility of
compound 1, it was difficult to obtain a formulation allowing the
production of tablets which are sufficiently stable over time and
comprising a sufficient concentration of active ingredient.
Furthermore, the composition which was poorly compressible resulted
in fragmentations during the dry pressing as well as too slow a
dissolution profile. Due to the instability of compound 1 in the
presence of water, being easily hydrolyzable, it was difficult to
envisage a wet granulation process.
[0009] Unexpectedly, formulations making it possible to obtain dry
oral forms of compound 1 by a wet granulation process have been
obtained.
[0010] In the case of wet granulation, the components are mixed and
granulated in wet phase by means of a binder. The binder can be
either dissolved in the wet phase or incorporated in the mixture of
powder to be granulated. The wet granules are then sieved, dried
and optionally ground, before compression in order to form the
tablets.
[0011] Unexpectedly, a novel solid pharmaceutical composition has
been found, intended for the administration by oral route of
compound 1, making it possible to solve the problems specific to
this active ingredient and to obtain it by a wet granulation
process.
[0012] This oral composition, in the form of a tablet or gelatin
capsule, is stable with rapid dissolution of the solid form thus
providing immediate release with effective bioavailability.
[0013] A subject of the present invention is therefore a solid
pharmaceutical composition containing as active ingredient
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate
and at least one pharmaceutically acceptable excipient.
[0014] A subject of the present invention is also a solid
pharmaceutical composition containing as active ingredient
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl 30
sulphamate and at least one pharmaceutically acceptable excipient,
for oral administration and preferably for oral administration with
immediate release.
[0015] A subject of the present invention is also a solid
pharmaceutical composition for administration by oral route
comprising compound 1 as active ingredient and at least one
disintegration agent as well as one or more agents protecting
against moisture.
[0016] Such agents therefore protect the active ingredient against
hydrolysis, thus preventing its degradation. Preferably, compound 1
is micronized.
[0017] It was observed that this degradation occurs mainly during
the manufacture of the pharmaceutical composition and in particular
during the wet granulation stage. Unexpectedly, it was shown that
the addition of excipients, used for their properties as binders
and diluents in the technical field considered, provided an effect
of protecting the active ingredient.
[0018] A subject of the present invention is also the manufacturing
process of the pharmaceutical compositions as described below. It
is thus possible to carry out the process according to the
invention using adjuvants and excipients of the standard type for
the manufacture of the tablets using wet granulation.
[0019] By "oral administration with immediate release" or "oral
form with immediate release" or also "composition with immediate
release", is meant according to the invention an administration or
oral composition allowing in vitro dissolution of at least 80% by
weight of the active ingredient in 45 minutes, preferably in 30
minutes according to the appropriate in vitro dissolution test,
developed for compound 1. This test is carried out with a paddle
dissolution apparatus at 37.degree. C. under stirring at 100 rpm,
in a buffered hydrochloric acid solution at pH 1.2 according to the
US Pharmacopeia standards, and comprising 0.1% a surfactant, cetyl
trimethyl ammonium bromide, which makes it possible to obtain
sufficient solubility of the active ingredient in the test medium.
The assay is carried out by ultra-violet (UV)/visible absorption
spectrophotometry at a wavelength of 311 nm.
[0020] By the term "gliding agents" or "flow agents" used according
to the invention, is also meant the adjuvants and excipients
sometimes called lubricants and agents improving the fluidity and
flow of the granules.
[0021] By the term "centesimal formulation" is meant according to
the invention a given proportion of active ingredient or excipient
in % by weight, with respect to the total weight of the
composition.
[0022] The term "binding agent" or binder denotes, according to the
invention, adjuvants or excipients used to maintain the structure
and cohesion of the galenic form. They have the property of
allowing assembly in the form of granules of the ingredients during
the granulation stage and ensuring the cohesion of the galenic form
after compression.
[0023] The term "disintegration agent" denotes, according to the
invention, excipients or adjuvants which can be added to the
formulations in order to facilitate the disintegration of the
tablets when they are found in a liquid environment, such as water
or the gastric juices.
DESCRIPTION OF THE FIGURES
[0024] FIG. 1: shows the comparative dissolution curves of the
composition of compound 1 as a function of time and the influence
of the micronization of the active ingredient in the composition.
Each curve corresponds to a solid composition comprising compound 1
with a different micronization.
[0025] FIG. 2: shows the comparative dissolution curves of
different compositions of compound 1 as a function of time. Each
curve corresponds to a solid composition containing different
disintegration agents.
[0026] FIGS. 1 and 2 show the effect of the excipients as well as
the in vitro behaviour of the solid composition.
[0027] FIG. 3: calculated X-ray diffraction diagram of the DMSO
solvate of form 2 of compound 1
[0028] FIG. 4: experimental X-ray powder diffraction diagram of the
DMSO solvate of form 2 of compound 1
[0029] FIG. 5: calculated X-ray powder diffraction diagram of
variety I of compound 1
[0030] FIG. 6: experimental X-ray powder diffraction diagram of
variety I of compound 1
[0031] FIG. 7: DSC thermogram of variety I of compound 1
[0032] FIG. 8: IR spectrum of variety I of compound 1
[0033] FIG. 9: NMR spectrum of the solid of variety I of compound
1
[0034] FIG. 10: calculated X-ray diffraction diagram of the DMSO
solvate of form 1 of compound 1
[0035] FIG. 11: experimental X-ray powder diffraction diagram of
the DMSO solvate of form 1 of compound 1
[0036] FIG. 12: calculated X-ray diffraction diagram of the DMSO
solvate of form 3 of compound 1
[0037] FIG. 13: experimental X-ray powder diffraction diagram of
the DMSO solvate of form 3 of compound 1
[0038] FIG. 14: calculated X-ray diffraction diagram of polymorphic
form III of compound 1
[0039] FIG. 15: experimental X-ray powder diffraction diagram of
polymorphic form III of compound 1
[0040] FIG. 16: DSC thermogram of polymorphic form III of compound
1
[0041] FIG. 17: IR spectrum of polymorphic form III of compound 1
FIG. 18: NMR spectrum of the solid of polymorphic form III of
compound 1
[0042] FIG. 19: calculated X-ray diffraction diagram of 1,4-dioxane
hemisolvate of compound 1
[0043] FIG. 20: experimental X-ray powder diffraction diagram of
1,4-dioxane hemisolvate of 5 compound 1
[0044] FIG. 21: TG-DSC thermogram of 1,4-dioxane hemisolvate of
compound 1
[0045] FIG. 22: experimental X-ray powder diffraction diagram of
polymorphic form II of compound 1
[0046] FIG. 23: DSC thermogram of polymorphic form II of compound
1
[0047] FIG. 24: IR spectrum of polymorphic form II of compound
1
[0048] FIG. 25: NMR spectrum of the solid of polymorphic form II of
compound 1
[0049] FIG. 26: shows a schematic for the preparation of a tablet
form of the composition by wet granulation
[0050] The present invention exhibits numerous advantages, in
particular the combination: [0051] of increased stability and
[0052] of increased bioavailability linked to the immediate
dissolution (at least 80% in 30 minutes) of the pharmaceutical
form.
[0053] Preferably, the process used for the preparation of the
tablet according to the invention passes through a wet granulation
stage preceding the stage of formation of the tablet.
[0054] In fact, it was unexpectedly shown that, in spite of the low
stability of compound 1 in aqueous phase, the tablet can be
prepared by a process comprising a wet granulation stage. The
production of the tablet according to this process benefits from a
stabilization of compound 1 in aqueous phase in the presence of
well-chosen excipients.
[0055] According to a first characteristic of the invention,
compound 1 is obtained by an appropriate treatment in order to
obtain a particle size comprised between 0.1 and 20 .mu.m.
Preferentially, compound 1 has a particle size comprised between 1
and 15 .mu.m, and more preferentially between 2 and 10 .mu.m. Even
more preferentially compound 1 has a size of 5 .mu.m.+-.2
.mu.m.
[0056] Pharmaceutically acceptable excipients appropriate for the
manufacture of the pharmaceutical compositions of the invention can
be, for example, maltodextrin, mannitol, microcrystalline
cellulose, lactose, corn starch, sodium starch glycolate,
croscarmellose sodium, partially cross-linked
poly(N-vinyl-2-pyrrolidone) or crospovidone, polyvinylpyrrolidone,
copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (or
copovidones) such as the copolymer Kollidon VA64,
carboxymethylcellulose, pregelatinized starch, methylcellulose,
polyethylene glycol, macrogols, polyglycols, polyoxyethylene,
pyrrolidone-2, colloidal silica, talc, magnesium stearate, sodium
stearyl fumarate, calcium stearate, hydrogenated vegetable oil,
sodium lauryl sulphate, calcium phosphate, sugars, dextrin, starch,
gelatin, cellulose, wax, or also water, organic solvents such as
glycerol or the glycols, as well as mixtures thereof, in varying
proportions, with or without water. These excipients, added to the
active ingredient, have the function of being: [0057] diluents,
such as for example mannitol, lactose or lactose monohydrate,
starch, calcium carbonate, microcrystalline cellulose, or
maltodextrin; [0058] disintegration agents, such as for example
starch, croscarmellose sodium, sodium starch glycolate, or
crospovidone; [0059] binders, such as for example
polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl
acetate (or copovidones), carboxymethylcellulose, pregelatinized
starch, or methylcellulose; [0060] flow agents or gliding agent,
such as for example colloidal silica, or talc; [0061] lubricants,
such as for example magnesium stearate, sodium stearyl fumarate,
calcium stearate, stearic acid or hydrogenated vegetable oil;
[0062] solubilizing agents, such as macrogol (polyethylene glycol),
polyglycol, polyoxyethylene glycol, polydiol, pyrrolidone-2, or
polyvinylpyrrolidone; [0063] surfactants (or surface active agents)
such as sodium lauryl sulphate.
[0064] A subject of the present invention is also a solid
pharmaceutical composition for administration by oral route of
compound 1 as active ingredient, characterized in that it comprises
compound 1 and at least one disintegration agent, one or more
diluents and one or more binders. Preferably, the compound is
micronized.
[0065] Preferably, the pharmaceutical composition according to the
invention, in the solid form for oral administration, is a gelatin
capsule. Preferably, the pharmaceutical composition according to
the invention, in the solid form for oral administration, is a
tablet.
[0066] In the compositions below, each type of excipient can be
alone or in a mixture. Thus "x % of a binder" means x % of a binder
alone or of a mixture of binders.
[0067] The composition according to the invention, can be
formulated in a gelatin capsule according to a centesimal
formulation containing: 1 to 30% active ingredient, preferably 5 to
20%; 40 to 92% diluent, preferably 65 to 92%, very preferentially
75 to 90%; 0 to 10% binder, preferably, 0 to 8%; 0 to 30%
disintegration agent, preferably 0 to 20%; 0 to 5% surfactant,
preferably 0%; 0 to 5% solubilizing agent, preferably 0%; 0.1 to 3%
flow agent, preferably 0.9 to 1.4%; 0.5 to 3% lubricant, preferably
0.6 to 2.8%.
[0068] Preferentially, the pharmaceutical composition as defined
above is a gelatin capsule; and more preferentially a gelatin
capsule of centesimal formulation comprising 5 to 30% active
ingredient; 40 to 92% diluent; 0 to 8% binder, preferably 0 to 5%;
0 to 30% disintegration agent; 0 to 5% surfactant; 0 to 5%
solubilizing agent; 0.1 to 3% flow agent; and 0.5 to 3%
lubricant.
[0069] The preferred pharmaceutically acceptable excipients for
formulating these gelatin capsules are mannitol, lactose, corn
starch, colloidal silica, magnesium stearate, and sodium lauryl
sulphate, and more particularly mannitol, lactose, colloidal
silica, and magnesium stearate.
[0070] The composition according to the invention can also be
formulated in a tablet, preferably film-coated, of centesimal
formulation containing: 1 to 30% by weight active ingredient with
respect to the total weight of the composition, preferably 5 to 20%
and very preferentially 8 to 20%; 40 to 92% diluent, preferably 65
to 92% and very preferentially 70 to 85%; 0.1 to 20% disintegration
agent, preferably 0.1 to 10% and very preferentially 1 to 5%; 0.1
to 8% binder, preferably 2 to 5%; 0.1 to 3% gliding agent,
preferably 0.5 to 1.4%; 0.2 to 3% lubricant, preferably 0.5 to
2.8%.
[0071] The excipients preferred for formulating these tablets are
maltodextrin, mannitol, microcrystalline cellulose, lactose or
lactose monohydrate, corn starch, sodium starch glycolate,
crospovidone, polyvinylpyrrolidone, copovidone,
carboxymethylcellulose, colloidal silica, sodium stearyl fumarate,
and magnesium stearate and more particularly microcrystalline
cellulose, lactose, sodium starch glycolate, copovidone, colloidal
silica, and magnesium stearate.
[0072] Preferentially also, the pharmaceutical composition as
defined above is a tablet, preferably film-coated, of centesimal
formulation comprising 8 to 20% active ingredient; 70 to 85%
diluent; 1 to 5% disintegration agent; 2 to 5% binder; 0.5 to 1.4%
flow agent; and 0.5 to 2.8% lubricant with respect to the total
weight of the tablet as well as approximately 4.5 to 5%, preferably
4.8% coating solution with respect to the total weight of the
coated tablet.
[0073] Preferably, a pharmaceutical composition according to the
present invention comprises a diluent selected from the following
excipients: mannitol, lactose or lactose monohydrate, starch,
calcium carbonate, microcrystalline cellulose, or maltodextrin.
[0074] Preferably, a pharmaceutical composition according to the
present invention comprises a disintegration agent selected from
the following excipients: starch, croscarmellose sodium, sodium
starch glycolate, or crospovidone.
[0075] Preferably, a pharmaceutical composition according to the
present invention comprises a binder selected from the following
excipients: polyvinylpyrrolidone, copolymers of
N-vinyl-2-pyrrolidone and vinyl acetate (copovidones),
carboxymethylcellulose (CMC), pregelatinized starch, or
methylcellulose.
[0076] Preferably, a pharmaceutical composition according to the
present invention comprises a lubricant selected from the following
excipients: magnesium stearate, sodium stearyl fumarate, calcium
stearate or hydrogenated vegetable oil.
[0077] Preferably, a pharmaceutical composition according to the
present invention comprises either microcrystalline cellulose (MCC)
and/or copovidone or microcrystalline cellulose (MCC) and/or
carboxymethylcellulose (CMC). Preferably, the CMC is at a level of
4 to 6%. Very preferentially, a pharmaceutical composition
according to the present invention comprises microcrystalline
cellulose (MCC). Very preferentially, a pharmaceutical composition
according to the present invention comprises copovidone. Very
preferentially also, a pharmaceutical composition according to the
present invention comprises microcrystalline cellulose (MCC) and
copovidone. Very preferentially, a pharmaceutical composition
according to the present invention comprises microcrystalline
cellulose (MCC). Very preferentially, a pharmaceutical composition
according to the present invention comprises carboxymethylcellulose
(CMC). Very preferentially, a pharmaceutical composition according
to the present invention comprises microcrystalline cellulose (MCC)
and carboxymethylcellulose (CMC).
[0078] Preferably also, the flow agent chosen is colloidal silica
(or colloidal solution of silicon dioxide).
[0079] Preferably also, the lubricant chosen is magnesium stearate.
The disintegration agent which is added to the formulation of the
tablets as excipient increases the dissolution rate, and makes it
possible to achieve immediate dissolution, even with tablets with
high cohesion. According to the literature (e.g. J.
Balasubramaniam, T. Bee, Pharmaceutical Technology Europe, Vol. 21,
Number 9, 2009, pp 44-49), the most effective disintegration agents
are crospovidone type A and B, followed by croscarmellose
sodium.
[0080] Preferably, in the formulations of tablets according to the
present invention, the disintegration agent used is sodium starch
glycolate, and preferentially at a level of 1 to 5% and very
preferentially of 3 to 4%.
[0081] Preferably, the pharmaceutical composition according to the
present invention is a tablet containing 8 to 20% compound 1; 20 to
40% lactose and 25 to 50% micro-crystalline cellulose used as
diluents; 2 to 8% copovidone used as binding agent; 1 to 5% sodium
starch glycolate used as disintegration agent; 0.2 to 1.4% flow
agent; and 0.5 to 2% lubricant with respect to the total weight of
the tablet, and, very preferentially, 8 to 15% compound 1; 30 to
40% lactose and 40 to 50% micro-crystalline cellulose used as
diluents; 2 to 5% copovidone used as binding agent; 3 to 4.5%
sodium starch glycolate used as disintegration agent; 0.2 to 1.4%
flow agent; and 0.5 to 2% lubricant with respect to the total
weight of the tablet.
[0082] Very preferentially also, the pharmaceutical composition as
described above is a tablet containing approximately 10% compound
1; 36.5% lactose; 45% micro-crystalline cellulose; 3% copovidone;
4% sodium starch glycolate; 0.5% colloidal silica; 1% magnesium
stearate with respect to the total weight of the tablet. The term
"approximately" means .+-.0.5%.
[0083] According to a variant of the invention, the composition can
comprise a coating or film coating.
[0084] Preferably such a coating has no significant effect on the
immediate release of the active ingredient, i.e. the in vivo
release kinetics of the active ingredient are unchanged.
[0085] Preferably also, the coating has the advantage of masking
the taste of the active ingredient and allows secure handling for
processing the solid composition in the form of a tablet.
[0086] The coating processes which can be used for the tablet
described in the invention are well known to a person skilled in
the art.
[0087] When the tablet comprises a coating the latter preferably
comprises a polymer chosen from the group constituted by the
polyethylene glycols, ethylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellullose (hypromellose) but not limited to
these. It is possible to use in particular a film-coating mixture
containing polyethylene glycol (macrogol) and
hydroxypropylmethylcellullose already formulated, for the aqueous
film coating of solid oral pharmaceutical forms such as that
marketed under the name Opadry.RTM. II white (lactose monohydrate,
hypromellose, titanium dioxide (E171), triacetin) by the company
Colorcon. Opadry.RTM. II white is soluble in water, and allows
immediate disintegration of the oral pharmaceutical composition in
the form of a tablet.
[0088] Preferably, the solid pharmaceutical composition according
to the present invention is presented in tablet form. The invention
also relates to tablets with immediate dissolution as well as
tablets covered with a coating or film.
[0089] Pharmaceutical compositions are described as examples and in
no way limit the scope of the invention.
[0090] Thus, a subject of the invention is also a process for the
preparation of the compound according to the invention as described
previously, from
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate
characterized in that it comprises a stage of reducing the size of
the particles.
[0091] Preferentially, the size of the particles is reduced by
micronization, either in aprotic solvent medium, or by dry
route.
[0092] Preferentially also, the size of the particles is reduced by
wet grinding with an aprotic organic solvent.
[0093] The invention also relates to the manufacturing process of
the solid pharmaceutical compositions of the invention,
characterized by the following stages: [0094] sieving of the
components; [0095] preparation of the tablets without coating (wet
granulation, mixing and compression); [0096] preparation of the
coating solution.
[0097] Preferably, according to the process according to the
invention, during the wet granulation stage, the mass of water with
respect to the total mass of the active ingredient and of the
binder, diluent and disintegration agent mixed beforehand, is
comprised between approximately 10 and 30%.
[0098] Preferably, according to the process according to the
invention, after the wet granulation stage, the granules are dried
until residual moisture of less than 3% is obtained.
[0099] The composition during all the stages of the manufacturing
process is produced by means of conventional equipment known to a
person skilled in the art.
[0100] A formulation according to the present invention can be
prepared according to the following process: a first mixture is
produced constituted by the active ingredient which is first sieved
at the same time as certain excipients included in the composition
comprising a binder, and one or more diluents as well as a
disintegration agent.
[0101] The sieving stage is carried out using a sieve in a suitable
device such as a manual sieve.
[0102] The sieved substances are then introduced into a
mixer-granulator and mixed for approximately 5 min. The mixing
speed depends on the equipment chosen.
[0103] A mass of water for the granulation is then prepared so that
its proportion with respect to the solid phase to be granulated is
preferentially comprised between approximately 10 and 30%. By solid
phase to be granulated is meant the total mass of the active
ingredient and of the excipients mixed beforehand, added to the
mass of binder.
[0104] The binder for the granulation is added to the mixer in its
pulverulent form or preferentially dissolved in the mass of water
in order to constitute the granulation solution.
[0105] The mixture obtained at the start of the process is then
granulated by wet route with the granulation solution, in a
mixer-granulator preferably of "high shear" type. The granulation
time after the addition of the solution to be granulated is less
than 10 min and preferentially less than 5 minutes.
[0106] The granules resulting from this last stage can then be
dried in a conventional device such as for example a fluidized bed
dryer. Preferably, the granules are dried until a residual moisture
of less than 3% is obtained. The granules thus dried constitute the
part conventionally called the internal phase of the tablet. They
are then calibrated by grinding.
[0107] A second mixture is produced, which is constituted by the
calibrated granules obtained previously and a so-called external
phase constituted by: a portion of disintegration agent, a flow
agent which makes it possible to improve the fluidity of the
powder, and finally a lubricant.
[0108] The excipients of the external phase are first sieved in a
suitable device such as a manual sieve.
[0109] The granules, the disintegration agent and the flow agent
are then mixed, then the lubricant is introduced.
[0110] For the preparation of formulation in the form of tablets,
the final resultant mixture can then be made into tablets using a
press, of rotary type for example.
[0111] The hardness of a 400 mg tablet can be comprised between 6
and 12 kPascal (kPa). The hardness of a 100 mg tablet can be
comprised between 4 and 8 kPa.
[0112] The tablets can then be coated in a film coating turbine by
spraying of a coating suspension which has been prepared
beforehand, preferably by addition of 16% of Opadry II.RTM. in
purified water.
[0113] The temperature of the product during the film coating is
comprised between 35 and 55.degree. C.,
[0114] Preferably, the gain in mass of the tablet after drying is
between 4 and 6% of the mass of the tablet before film coating.
[0115] The tablets can then be packaged and stored in blister packs
or bottles.
[0116] According to the invention the non-coated tablet preferably
does not exceed a total weight of 800 mg, preferably 400 mg.
[0117] The invention finally relates to the use of a pharmaceutical
composition according to the invention as described previously for
treating cancers, preferentially the hormone-dependent cancers, and
also preferentially, breast, prostate, endometrial or ovarian
cancers.
[0118] The present application also relates to polymorphs of the
compound 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl
sulphamate (or sulphamic acid
6,7,8,9,10,11-hexahydro-6-oxobenzo[b]cyclohepta[d]pyran-3-yl ester
or compound 1). The invention also relates to the preparation of
these polymorphic forms, their use as active ingredient, and more
particularly as active ingredient for the treatment of certain
cancers. The invention also relates to the pharmaceutical
compositions containing these polymorphic forms as active
ingredient.
[0119] The form succinctly described by Woo and called variety I
hereafter produces characteristic absorption bands in the infrared.
The Applicant obtained single crystals of suitable size and quality
for a complete characterization of its structure.
[0120] The crystals obtained in the prior art do not allow good
bioavailability and their preparation cannot be transferred to the
industrial scale.
[0121] Moreover, the Applicant obtained crystals of compound 1 by
an industrial process. Microscopic observation makes it possible to
observe progressive opacification of the crystal from approximately
140-145.degree. C. The phenomenon is not reversible: the crystal
does not recover its initial appearance after slow or rapid cooling
down. In DSC, an endothermic phenomenon corresponding to a
solid-solid transition is observed as from 140.degree. C. A second
endothermic peak is observed at 170.degree. C. corresponding to the
melting of the non-converted variety I. A third endothermic peak is
observed at 180.degree. C. This third peak corresponds to the
melting of another polymorphic form generated during the
solid-solid transition. By X-ray powder diffraction carried out on
the compound successively heated to 160.degree. C. then cooled down
to a temperature comprised between 18 and 25.degree. C., peaks
additional to those characteristic of variety I of compound 1 are
observed, these peaks corresponding to another polymorphic form
generated during the heating.
[0122] Thus, the crystals obtained under industrial conditions
exhibit heterogeneities detected by DSC and/or by X-ray powder
diffraction after heating to 160.degree. C., heterogeneities which
allow the germination and the growth of another crystalline form
during the heating of the compound, making the product unstable
during heating.
[0123] By heterogeneities is meant here defects in or on the
crystals including macles or polytypism which can be detected by a
conventional optical microscope or a microscope equipped with a
polarized light device and/or by differential enthalpic analysis
and/or by X-ray powder diffraction and/or by confocal Raman
microscopy. The presence of such heterogeneities in the crystals
can thus lead to numerous problems during storage of the active
ingredient, or during the manufacturing process of tablets, gelatin
capsules, creams, or other galenic forms. For example, a relative
humidity stress can lead to unacceptable behaviour for a
pharmaceutically active ingredient. Furthermore, as shown by Y.
Mnyukh in Fundamentals of solid-state phase transitions,
ferromagnetism and ferroelectricity (2001), the defects can
pre-code a solid--solid transition via a mechanism--growth
germination.
[0124] Now, for a clinical development of this molecule it is
necessary to choose a crystalline form, achieve its production
under industrial conditions, key factors being its thermal
stability and its bioavailability.
[0125] The technical problem that the Applicant proposes to resolve
is therefore to provide a stable and bioavailable form of compound
1 under conditions which can be used on an industrial scale.
[0126] A person skilled in the art knows that the treatment aimed
at reducing the size of the particles by mechanical treatment can
introduce defects, residual stresses in the crystallized phases, a
polymorphic transition, a partial or total amorphization,
optionally associated with a chemical degradation (Jet-milling;
from a particle perspective predicting particle fracture based on
mechanical material properties Onno M. de Vegt; PhD thesis
University of Groningen; 19 Oct. 2007; Garnier, S.; Petit, S.;
Mallet, F.; Petit, M.-N.; Lemarchand, D.; Coste, S.; Lefebvre, J.;
Coquerel, G., Influence of ageing, grinding and preheating on the
thermal behaviour of .alpha.-lactose monohydrate. Int. J. Pharm.
2008, 361, 131-140).
[0127] The ability of a compound to exist under more than one
crystalline form is defined by the term polymorphism and its
different crystalline forms are known as "polymorphic varieties" or
"polymorphs". Polymorphism can influence numerous properties of the
solid state of an active ingredient. Different polymorphs of a
substance can differ considerably from one to another, by their
physical properties which can directly influence their solubility
for example. Polymorphism has been demonstrated for numerous
organic compounds.
[0128] Very unexpectedly, the Applicant has now found that an
appropriate treatment of compound 1 obtained under industrial
conditions, aim at reducing the size of the particles can produce
variety I of compound 1 with a particle size compatible with the
formulation of the active compound while concomitantly reducing the
concentration of heterogeneities in the crystals, thus providing a
stable and bioavailable form of compound 1 under conditions which
can be used on an industrial scale. The DSC and X-ray powder
diffraction analyses as described in the experimental part make it
possible to demonstrate that the variety I thus obtained has an
increased stability.
[0129] Thus, this variety I of low particle size, which is a
subject of the invention, can be characterized by different
analytical methods such as X-ray powder diffraction, differential
scanning calorimetry (DSC) analysis, Raman spectroscopy, infrared
spectroscopy or NMR of the solid.
[0130] Also, a subject of the invention is the solvate of
crystalline DMSO of form 2 of compound 1, exhibiting using X-ray
powder diffraction the characteristic peaks expressed as an angle
(.degree.2 theta) to .+-.0.1.degree.2 theta: 7.6; 18.7; 24.2;
29.9.
[0131] Very unexpectedly, the Applicant has now found that the
crystals of form I obtained under industrial conditions having
heterogeneities which allow the germination and growth of another
crystalline form during heating of the compound: form III, stable
at high temperature. A subject of the present invention is this
novel form III of compound 1. This form III has the advantage of
being thermodynamically stable at temperatures greater than
145.degree. C.
[0132] Several synthesis routes exist for compound 1 of form III,
according to the invention, of which one is via the intermediate of
another novel crystalline form of compound 1, called form II.
[0133] Variety I of compound 1 can be characterized by X-ray powder
diffraction with a diffraction diagram having in particular
characteristic peaks expressed as an angle (.degree.2 theta) to
approximately .+-.0.1.degree.2 theta: 7.5; 10.9; 13.1; 17.7;
19.0.
[0134] The angles (.degree.2 theta) with a error of
.+-.0.1.degree.2 theta represent the reflection angle according to
Bragg's Law i.e. the angle of incidence of the X-ray beam on the
sample.
[0135] Variety I of compound 1 before reduction of the size of the
particles can be characterized by a single crystal X-ray
analysis.
[0136] Variety I of compound 1, of reduced particle size, can be
characterized by an X-ray powder diffraction diagram (FIG. 6).
[0137] Variety I of compound 1, as described above, can also be
characterized by a DSC thermogram (FIG. 7).
[0138] Variety I of compound 1, as described above, can also be
characterized by an infrared spectrum (FIG. 8).
[0139] Variety I of compound 1, as described above, can also be
characterized by an NMR spectrum of the solid (FIG. 9).
[0140] The Applicant therefore proposes variety I of compound 1
obtained by an appropriate treatment in order to obtain a particle
size comprised between 0.1 and 20 .mu.m.
[0141] The present invention has numerous advantages, in particular
an increased stability and a bioavailability.
[0142] A subject of the present invention is therefore a
polymorphic compound of
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate
of particle size comprised between 0.1 and 20 pm, and exhibiting by
X-ray powder diffraction the characteristic peaks expressed as an
angle (.degree.2 theta) to .+-.0.1.degree.2 theta: 7.5; 10.9; 13.1;
17.7; 19.0.
[0143] Preferentially, the compound according to the invention has
a particle size comprised between 1 and 15 .mu.m.
[0144] More preferentially, the compound according to the invention
has a particle size comprised between 3 and 7 .mu.m.
[0145] Even more preferentially the compound according to the
invention has a size of 5 pm.+-.1 .mu.m.
[0146] Preferably, the compound as defined above exhibits by X-ray
powder diffraction the characteristic peaks expressed as an angle
(.degree.2 theta) to .+-.0.1.degree.2 theta: 7.5; 10.9; 13.1; 15.0;
15.8; 17.0; 17.7; 19.0; 22.5.
[0147] Preferentially also, the compound as defined above exhibits
by X-ray powder diffraction carried out after heating to
160.degree. C. then returning to a temperature comprised between 18
and 25.degree. C. the following characteristic peaks expressed as
an angle (.degree.2 theta) to .+-.0.1.degree.2 theta: 7.5; 10.9;
13.1; 17.7; 19.0 without additional peaks corresponding to the form
generated during the heating to 160.degree. C.
[0148] Very preferentially, the compound as defined above exhibits
using DSC with a temperature gradient of 5.degree. C.min.sup.-1 an
endothermic melting peak at 170.degree. C..+-.5.degree. C. and an
endothermic peak at 180.degree. C..+-.2.degree. C. it being
understood that the peak at 180.degree. C. represents at maximum
10% of the enthalpy exchanged during melting at 170.degree. C.
[0149] Very preferentially also, the compound as defined above does
not exhibit using DSC an endothermic event between 140 and
155.degree. C.
[0150] Yet more preferentially, the compound as defined above
exhibits using infrared spectroscopy, the characteristic peaks
expressed in cm-1 to .+-.5 cm-1: 3310; 3167; 3059; 891; 798; 733;
679; 455; and even more preferentially the characteristic peaks
expressed in cm-1 to .+-.5 cm-1: 3310; 3167; 3059; 2928; 2858;
1690; 1605; 1454; 1385; 1261; 1188; 1126; 941; 891; 853; 798; 733;
679; 598; 544; 455.
[0151] According to a variant, the invention relates to a compound
as defined above as a medicament.
[0152] The compound according to the invention can be formulated in
various pharmaceutical compositions. In the case of a solid form,
it can be for example powder, granules, tablets, gelatin capsules,
liposomes or suppositories. In the case of a liquid form, it can be
for example, solutions, emulsions, suspensions or syrups. The
administration of compound according to the invention can be done
for example by topical, oral, parenteral route, by intramuscular,
sub-cutaneous injection and in particular in the form of a gelatin
capsule, tablet, patch or cream.
[0153] Appropriate supports or excipients can be, for example,
maltodextrin, mannitol, microcrystalline cellulose, lactose, corn
starch, sodium starch glycolate, croscarmellose sodium,
polyvinyl-polypyrrolidone (or crospovidone), polyvinylpyrrolidone,
carboxymethylcellulose, pregelatinized starch, methylcellulose,
polyethylene glycol, macrogol, polyglycol, polyoxyethylene,
polydiol, pyrrolidone-2, colloidal silica, talc, magnesium
stearate, sodium stearyl fumarate, calcium stearate, hydrogenated
vegetable oil, sodium lauryl sulphate, calcium phosphate, sugars,
dextrin, starch, gelatin, cellulose, wax, or also water, organic
solvents such as glycerol or the glycols, similarly their mixtures,
in varying proportions, with or without water. These supports,
added to the active ingredient, serve as: [0154] diluents, such as
mannitol, lactose, starch, calcium carbonate, microcrystalline
cellulose, or maltodextrin; [0155] disintegration agents, such as
starch, sodium croscarmellose, sodium starch glycolate, or
crospovidone; [0156] binders, such as polyvinylpyrrolidone,
carboxymethylcellulose, pregelatinized starch, or methylcellulose;
[0157] flow agents, such as colloidal silica, or talc; [0158]
lubricants, such as magnesium stearate, sodium stearyl fumarate,
calcium stearate or hydrogenated vegetable oil; [0159] solubilizing
agents, such as polyethylene glycol, macrogol, polyglycol,
polyoxyethylene, polydiol, pyrrolidone-2, or polyvinylpyrrolidone;
[0160] surfactants (or surface active agents) such as sodium lauryl
sulphate.
[0161] The composition according to the invention, can be
formulated in a gelatin capsule containing: 5 to 30% active
ingredient (preferentially 6 to 13%); 40 to 92% diluent
(preferentially 65 to 92%; very preferentially 85 to 90%); 0 to 30%
disintegration agent (preferentially 0 to 22%; very preferentially
0%); 0 to 5% surfactant (preferentially 0%); 0 to 5% solubilizing
agent (preferentially 0%); 0.1 to 3% flow agent (preferentially 0.9
to 1.4%); 0.5 to 3% lubricant (preferentially 0.6 to 2.8%).
[0162] The preferred excipients for formulating these gelatin
capsules are mannitol, lactose, corn starch, colloidal silica,
magnesium stearate, and sodium lauryl sulphate, and more
particularly mannitol, lactose, colloidal silica, and magnesium
stearate.
[0163] The composition according to the invention, can also be
formulated in a tablet containing: 5 to 30% active ingredient
(preferentially 7 to 15% and very preferentially 10 to 15%); 40 to
92% diluent (preferentially 34 to 89% and very preferentially 70 to
85%); 0 to 40% disintegration agent (preferentially 0 to 20% and
very preferentially 3 to 5%); 0 to 8% binder (preferentially 2 to
5%); 0.1 to 3% flow agent (preferentially 0.5 to 1.4%); 0.5 to 3%
lubricant (preferentially 0.5 to 2.8%).
[0164] The excipients preferred for formulating these tablets are
maltodextrin, mannitol, microcrystalline cellulose, lactose, corn
starch, sodium starch glycolate, crospovidone,
polyvinylpyrrolidone, carboxymethylcellulose, colloidal silica,
magnesium stearylfumarate, and magnesium stearate and more
particularly microcrystalline cellulose, lactose, sodium starch
glycolate, polyvinylpyrrolidone, colloidal silica, and magnesium
stearate.
[0165] According to a variant, the invention relates to a
pharmaceutical composition comprising, as active ingredient,
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate
of particle size comprised between 0.1 and 20 .mu.m, in combination
with at least one pharmaceutically acceptable support;
preferentially,
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate
has a particle size comprised between 1 and 15 .mu.m; more
preferentially between 3 and 7 pm and more preferentially also
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate
has a size of 5 .mu.m.+-.1 .mu.m.
[0166] Preferentially, the pharmaceutical composition as defined
above, comprises as active ingredient, compound 1 of variety I as
defined previously.
[0167] Very preferentially, the pharmaceutical composition as
defined above is a gelatin capsule; and more preferentially also a
gelatin capsule comprising 5 to 30% active ingredient; 40 to 92%
diluent; 0 to 30% disintegration agent; 0 to 5% surfactant; 0 to 5%
solubilizing agent; 0.1 to 3% flow agent; and 0.5 to 3%
lubricant.
[0168] Very preferentially also, the pharmaceutical composition as
defined above is a tablet, and more preferentially also a tablet
comprising 5 to 30% active ingredient; 40 to 92% diluent; 0 to 40%
disintegration agent; 0 to 8% binder; 0.1 to 3% flow agent; and 0.5
to 3% lubricant.
[0169] The synthesis routes for compound 1 are envisaged in the
prior art, as described in patent EP 880514 or by L. W. Woo, et al.
in Chemistry & Biology, 2000, 7, 773-91.
[0170] The Applicant has now found that this compound can be
synthesized in two chemical stages. The first stage consists of
condensing in a strong acid (such as sulphuric acid,
trifluoroacetic acid or methanesulphonic acid)
2-carbetoxycycloheptanone with resorcinol, intermediate
3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one is
isolated by precipitation using an alcohol/water mixture (for
example by adding ethanol then water). In a second stage,
sulphonylisocyanate chloride is converted, in toluenic solution, to
sulphamoyl chloride, by the action of formic acid, then condensed
with the previous intermediate dissolved in a solvent such as DMA.
The reaction medium is treated with water and extracted by an
organic solvent (preferably 2-methyltetrahydrofurane: MeTHF), and
crude compound 1 is then precipitated from the organic phase by
adding an antisolvent (preferably methylcyclohexane). Finally pure
compound 1 is obtained by recrystallization of the crude product by
dissolution in acetone or ethyl acetate while hot and precipitation
by adding an antisolvent (preferably methylcyclohexane).
[0171] As a result, a subject of the invention is also the
preparation process for
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate
characterized in that it comprises the following stages: [0172]
condensation of 2-carbetoxycycloheptanone with resorcinol in a
strong acid, [0173] isolation of
3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one thus
obtained by precipitation using an alcohol/water mixture, [0174]
condensation of
3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one with
chloride sulphamoyl in an aprotic solvent, [0175] recrystallization
of the crude product obtained by dissolution in acetone while hot
or ethyl acetate and the addition of an antisolvent such as
methylcyclohexane.
[0176] The compound according to the invention, as described
previously, is obtained from compound 1 in the form of variety I by
a treatment aimed at reducing the size of the particles.
[0177] Thus, a subject of the invention is also a process for the
preparation of the compound according to the invention as described
previously, from
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulphamate
characterized in that it comprises a stage of reducing the size of
the particles.
[0178] Preferentially, the size of the particles is reduced by
micronization.
[0179] Preferentially also, the size of the particles is reduced by
wet grinding with an organic non-protic solvent.
[0180] A subject of the present invention is also a polymorphic
compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl
sulphamate, exhibiting using X-ray powder diffraction the
characteristic peaks expressed as an angle (.degree.2 theta) to
.+-.0.1.degree.2 theta: 8.6; 11.3; 28.6 (compound of form III).
Preferably, this compound form III exhibits the characteristic
peaks expressed as an angle (.degree.2 theta) to .+-.0.1.degree.2
theta: 8.6; 11.3; 12.0; 16.6; 20.9; 23.0; 28.6.
[0181] A more particular subject of the invention is a compound of
form III as defined previously which, using single crystal X-ray
diffraction, exhibits the following cell parameters:
TABLE-US-00001 Cell structure Monoclinic Space group Cc (no. 9)
Cell parameter a 11.327(1) .ANG. Cell parameter b 20.489(2) .ANG.
Cell parameter c 7.870(1) .ANG. Cell parameter .beta. 131.55(1)
.degree. Cell volume 1366.9(2) .ANG..sup.3 Number of molecules 4
per cell: Z Calculated density 1.53 g cm.sup.-3
the following reduced coordinates (.times.10.sup.4) and the
equivalent isotropic motion parameters of
(.ANG.2.times.10.sup.3):
TABLE-US-00002 X y Z U(eq) S(1) 14534(1) -1891(1) 11571(1) 41(1)
O(1) 9079(2) -569(1) 5756(3) 39(1) O(2) 13824(2) -1450(1) 12407(3)
48(1) O(3) 6862(3) -250(1) 2510(3) 57(1) O(4) 13672(3) -1754(1)
9246(3) 62(1) O(5) 14551(3) -2522(1) 12277(5) 73(1) N(1) 16289(3)
-1661(2) 12982(5) 55(1) C(1) 12910(3) -904(1) 11114(4) 36(1) C(2)
11424(3) -995(1) 9041(4) 37(1) C(3) 10541(3) -449(1) 7814(4) 31(1)
C(4) 11093(3) 187(1) 8587(4) 32(1) C(5) 12593(3) 249(1) 10745(4)
40(1) C(6) 13504(3) -284(1) 11996(4) 42(1) C(7) 8111(3) -78(1)
4284(4) 39(1) C(8) 8699(3) 589(1) 4976(4) 37(1) C(9) 10098(3)
718(1) 7049(4) 34(1) C(10) 10637(3) 1421(1) 7790(5) 43(1) C(11)
9541(4) 1809(1) 7904(5) 46(1) C(12) 8072(4) 2076(1) 5641(5) 56(1)
C(13) 6921(4) 1568(2) 3890(5) 55(1) C(14) 7630(4) 1111(1) 3226(5)
48(1)
the following coordinates of the hydrogen atoms (.times.10.sup.4)
and equivalent isotropic displacement parameters
(.ANG..sup.2.times.10.sup.3) (U(eq) equals a third of the value of
the orthogonal tensor Uij):
TABLE-US-00003 X y Z U(eq) HN1 16970(60) -1842(18) 14350(80) 78(13)
HN2 16430(50) -1342(19) 12870(60) 56(12) H(2) 11025 -1412 8483 44
H(5) 12982 664 11349 48 H(6) 14506 -231 13414 50 H(10A) 10682 1631
6729 52 H(10B) 11693 1424 9273 52 H(11A) 9218 1531 8530 55 H(11B)
10129 2172 8944 55 H(12A) 7523 2355 5918 67 H(12B) 8398 2347 5004
67 H(13A) 6016 1789 2538 66 H(13B) 6550 1309 4487 66 H(14A) 6778
901 1798 57 H(14B) 8227 1369 2988 57
the following interplanar spacings:
TABLE-US-00004 H K L 2Theta/deg d/.ANG. l/rel, |F(hkl)| 0 2 0 8.63
10.24 16.76 35.88 1 1 0 11.29 7.83 37.69 49.89 -1 1 1 12.05 7.34
59.53 66.98 1 3 0 16.66 5.32 57.37 91.43 -1 3 1 17.18 5.16 11.98
43.15 0 2 1 17.35 5.11 92.5 121.09 -2 2 1 17.92 4.95 73.94 111.89 2
0 0 20.94 4.24 13.54 79.54 -2 0 2 22.60 3.93 89.64 221.49 2 2 0
22.69 3.92 23.89 81.17 0 4 1 22.99 3.87 27.76 88.74 -2 4 1 23.43
3.79 43.01 112.65 1 1 1 23.81 3.73 20.41 78.91 1 5 0 24.10 3.69
13.86 65.87 -2 2 2 24.23 3.67 3.27 32.19 -3 1 1 24.64 3.61 12.1 63
-1 1 2 24.92 3.57 10.88 60.46 -3 1 2 25.73 3.46 100 189.5 0 6 0
26.07 3.41 11.99 94.11 2 4 0 27.29 3.27 2.04 28.78 -3 3 1 27.59
3.23 12.23 71.34 -3 3 2 28.57 3.12 46.83 144.9
[0182] Preferentially a subject of the invention is a compound
(form IIII) as defined previously which exhibits using DSC at
5.degree. C.min.sup.-1 an endothermic melting peak of 180.degree.
C..+-.2.degree. C.
[0183] Preferably the compound (form III) according to the
invention, as defined previously, exhibits using infrared
spectroscopy the following characteristic peaks expressed in
cm.sup.-1 to .+-.5 cm.sup.-1: 3406; 3217; 1678; 1011; 563; and very
preferentially the following characteristic peaks expressed in
cm.sup.-1 to .+-.5 cm.sup.-1: 3406; 3217; 3082; 2924; 1678; 1385;
1269; 1134; 1011; 934; 845; 601; 563; 536.
[0184] According to a variant, a subject of the invention is a
compound of form III as defined above, as a medicament.
[0185] A subject of the invention is also a pharmaceutical
composition comprising as active ingredient, a compound of form
IIII as defined previously, in combination with at least one
pharmaceutically acceptable support.
[0186] Also, a subject of the invention is the crystalline DMSO
solvate of form 1 of compound 1, exhibiting using X-ray powder
diffraction the characteristic peaks expressed as an angle
(.degree.2 theta) to .+-.0.1.degree.2 theta: 6.6; 10.9; 13.1; 14.3;
15.7; 16.7; 17.4; 18.3; 19.6; 20.8; 21.9; 22.6; 23.0; 24.7; 24.9;
25.2; 25.5; 25.8; 26.6; 26.9; 27.2; 28.3.
[0187] Also, a subject of the invention is the crystalline DMSO
solvate of form 3 of compound 1, exhibiting using X-ray powder
diffraction the characteristic peaks expressed as an angle
(.degree.2 theta) to .+-.0.1.degree.2 theta: 9.8; 13.9; 16.0; 17.7;
19.1; 22.1.
[0188] Furthermore, a subject of the invention is also the
crystalline 1,4-dioxane hemisolvate of compound 1, exhibiting using
X-ray powder diffraction the characteristic peaks expressed as an
angle (.degree.2 theta) to .+-.0.1.degree.2 theta: 9.8; 10.0; 10.8;
13.6; 13.9; 14.1; 15.9; 16.1; 18.0; 18.3; 19.0; 19.6; 20.0; 20.1;
20.2; 20.6; 21.4; 21.7; 21.8; 22.0; 22.2; 22.3; 23.4; 23.9; 24.3;
24.4; 24.9; 25.3; 25.4; 26.2; 27.0; 27.1; 27.3; 27.5; 28.2; 28.4;
28.5; 28.7; 29.1; 29.4.
[0189] Moreover, a subject of the invention is also the polymorphic
compound of compound 1, a compound of form II, exhibiting using
X-ray powder diffraction the characteristic peaks expressed as an
angle (.degree.2 theta) to .+-.0.1.degree.2 theta: 9.4; 10.7; 12.8;
18.2; 18.9; 19.7; 20.4; 23.2; and preferentially the characteristic
peaks expressed as an angle (.degree.2 theta) to .+-.0.1.degree.2
theta: 9.4; 10.7; 12.2; 12.8; 15.1; 18.2; 18.9; 19.7; 20.4; 21.1;
22.0; 23.2.
[0190] Preferentially, this compound of form II exhibits using DSC
at 5.degree. C.min.sup.-1 an endothermic melting peak at
165.degree. C..+-.5.degree. C.; more preferentially, it exhibits
using infrared spectroscopy the characteristic peaks expressed in
cm.sup.-1 to .+-.5 cm.sup.-1: 3356; 3321; 3186; 1504; 872; 787; and
even more preferentially the characteristic peaks expressed in
cm.sup.-1 to .+-.5 cm.sup.-1: 3356; 3321; 3186; 3078; 2932; 2851;
1693; 1609; 1504; 1462; 1377; 1265; 1192; 1123; 937; 872; 837; 787;
594.
[0191] The compound according to the invention, as described
previously, is obtained from compound 1 by an additional stage
which can be: [0192] a desolvation of the DMSO solvate of form 1 in
water, [0193] a desolvation of the DMSO solvate of form 3 in water,
[0194] an atomization in ethanol, [0195] an atomization in acetone,
[0196] a reimpasting in cumene under reflux, [0197] a heat
treatment then a micronization, then a second heat treatment, or
[0198] a heat treatment of form II.
[0199] Thus, according to a variant, a subject of the invention is
the process for the preparation of a compound of form III as
defined previously starting from compound 1, according to one of
the following methods: [0200] a) by stirring and precipitation from
DMSO in order to lead to the crystalline DMSO solvate of form 1 as
defined previously, which compound is then desolvated in water;
[0201] b) by stirring and precipitation from DMSO in order to lead
to the crystalline DMSO solvate of form 3 as defined previously,
which compound is then desolvated in water; [0202] c) by
atomization in ethanol; [0203] d) by atomization in acetone; [0204]
e) by reimpasting in cumene under reflux; [0205] f) by heat
treatment at a temperature comprised between 155.degree. C. and
165.degree. C. for 10 to minutes, followed by a micronization, then
by a second heat treatment at a temperature comprised between
155.degree. C. and 165.degree. C. for 10 to 20 minutes, [0206] g)
by treatment of a compound of form II as defined previously, and
obtained: [0207] either by atomization of compound 1 in
1,4-dioxane, [0208] or by stirring and precipitation of compound 1
from 1,4-dioxane in order to lead to the crystalline 1,4-dioxane
hemisolvate as defined previously, which compound is then
desolvated by heating from 20 to 80.degree. C. at 5.degree.
C.min.sup.-1 under a stream of inert gas, which treatment consists
of a heat treatment at a temperature comprised between 155.degree.
C. and 165.degree. C. for 6 to 10 minutes.
[0209] Preferentially, the process according to the invention goes
through desolvation in water of the crystalline DMSO solvate of
form 1 as defined previously.
[0210] Preferentially, the process according to the invention goes
through desolvation in water of the crystalline DMSO solvate of
form 3 as defined previously.
[0211] Preferentially also, the process according to the invention
goes through atomization in ethanol.
[0212] Preferentially also, the process according to the invention
goes through atomization in acetone.
[0213] Very preferentially, the process according to the invention
goes through reimpasting in cumene under reflux.
[0214] Even more preferentially, the process according to the
invention goes through heat treatment at a temperature comprised
between 155.degree. C. and 165.degree. C. for 10 to 20 minutes,
followed by a micronization, then a second heat treatment at a
temperature comprised between 155.degree. C. and 165.degree. C. for
10 to 20 minutes;
and preferentially, the heat treatments are carried out at
160.degree. C..+-.1.degree. C. for 15 minutes.
[0215] Even more preferentially also, the process according to the
invention goes through heat treatment of a compound of form II as
defined previously, at a temperature comprised between 155.degree.
C. and 165.degree. C. for 6 to 10 minutes;
and preferentially the heat treatment is carried out at 160.degree.
C..+-.1.degree. 0 for 7.5 minutes.
[0216] Preferably also, the compound of form II as defined
previously, is obtained by the atomization of compound 1 in
1,4-dioxane; or, the compound of form II as defined previously, is
obtained by the desolvation of a crystalline 1,4-dioxane
hemisolvate as defined previously.
[0217] According to a variant, a subject of the invention is the
process for the preparation of the crystalline DMSO solvate of form
1 as defined previously, starting from compound 1, by stirring and
precipitation from DMSO.
[0218] According to a variant, a subject of the invention is the
process for the preparation of the crystalline DMSO solvate of form
3 as defined previously, starting from compound 1, by stirring and
precipitation from DMSO.
[0219] According to a variant, a subject of the invention is the
process for the preparation of a crystalline 1,4-dioxane
hemisolvate as defined previously, starting from compound 1, by
stirring and precipitation from 1,4-dioxane.
[0220] As for form II mentioned above it can be obtained it
according to two synthesis routes: [0221] directly, by atomization
in 1,4-dioxane [0222] by desolvation of the 1-4-dioxane hemisolvate
of compound 1 obtained beforehand by precipitation from
1,4-dioxane.
[0223] Also, according to another variant, a subject of the
invention is the process for the preparation of a compound of form
II as defined previously, starting from compound 1, according to
one of the following methods: [0224] atomization in 1,4-dioxane;
[0225] stirring and precipitation from 1,4-dioxane in order to lead
to a crystalline 1,4-dioxane hemisolvate as defined previously,
which compound is then subjected to a desolvation by heating from
20 to 80.degree. C. at 5.degree. C.min.sup.-1 under a stream of
inert gas.
[0226] Preferentially, the process for the preparation of a
compound of form II as defined previously, goes through desolvation
of a crystalline 1,4-dioxane hemisolvate as defined previously.
[0227] Preferentially also, the process for the preparation of a
compound of form II as defined previously, goes through atomization
in 1,4-dioxane.
[0228] Alternatively, the subject of the invention is the use of a
compound of variety I or of form III as defined previously in order
to produce a medicament intended to treat cancers; preferentially
hormone-dependent cancers and preferentially also, a cancer chosen
from breast, prostate, endometrial or ovarian cancers.
[0229] The experimental part which follows is presented in order to
illustrate the above procedures and should in no event be
considered as limiting the scope of the invention.
[0230] Unless defined otherwise, all the technical and scientific
terms used in the present application have the same meaning as that
usually understood by an ordinary specialist in the field to which
the invention belongs. Moreover, all the patents (or patent
applications) as well as the other bibliographical references are
incorporated by way of reference.
EXPERIMENTAL PART
1. Compositions According to the Invention
Example 1 a
[0231] A composition in the form of a tablet and comprising
compound 1 as active ingredient is shown in Table 1 below. Such a
composition can be prepared by wet granulation according to diagram
1 below for a 5 kg batch and a 40 mg dose.
TABLE-US-00005 TABLE 1 centesimal composition of a tablet and
coating Composition mass centesimal composition (mg/tablet) formula
(%) Compound 1 40.0 10.0 Monohydrated lactose 146.0 36.5
Microcrystalline cellulose 180.0 45.0 Sodium starch glycolate, type
A 16.0 4.0 Copovidone 12.0 3.0 Colloidal silica 2.0 0.5 Magnesium
stearate 4.0 1.0 Water -- -- Total mass of the tablet 400.0 100.0
tablet 400.0 95.2 Opadry .RTM. II 20.0 4.8 White/coating
[0232] The coating, which was applied to 40 mg tablets, is composed
of Opadry.RTM. II white (Colorcon); this is a commercially
available mixture of coatings used for immediate release tablets.
The main objective of this coating is to mask the bad taste of the
medicamentous substance. It also reduces the risks linked to
handling during the packaging operations of the tablets containing
powerful active ingredients.
Example 1 b
[0233] A composition in the form of a gelatin capsule and
comprising compound 1 as active ingredient is shown in Table 2
below.
TABLE-US-00006 TABLE 2 centesimal composition of a gelatin capsule
Composition Centesimal formula (%) Compound 1 7.0 Mannitol 31.0
Monohydrated lactose 57.7 anhydrous colloidal silica 1.4 magnesium
stearate 2.8 gelatin capsule --
2. Effect of Disintegration Agent on the Dissolution Profiles
[0234] All the excipients are analyzed according to the monographs
of the current European Pharmacopoeia.
[0235] The effect of the disintegration agent appears by comparison
of the dissolution values at 30 minutes of compositions 2 and 17
described in section 3 below, without sodium starch glycolate.
[0236] Different tests have been carried out on the effect of the
addition of a disintegration agent on the dissolution profile and
the disintegration time of the tablet was studied. Four
compositions of tablets were produced in order to study the effect
of two disintegration agents, sodium starch glycolate, type A
(Explotab.RTM.) and pregelatinized corn starch (Starch
1500.RTM.).
TABLE-US-00007 TABLE 3 Composition of the tablet without coating
Centesimal formulation (%) Composition 1 2 3 4 internal phase
Compound I 15.0 15.0 15.0 15.0 Sodium starch glycolate, type A --
1.0 -- 1.5 Lactose 30.0 26.0 30.0 25.0 Microcrystalline cellulose
49.2 37.4 46.0 36.4 Copovidone 4.2 4.0 4.0 4.0 external phase -- --
-- -- pregelatinized corn starch -- 15.0 -- 15.0 Sodium starch
glycolate, type A -- -- 3.0 1.5 anhydrous colloidal silica 0.8 0.8
1.0 0.8 magnesium stearate 0.8 0.8 1.0 0.8 Total 100.0 100.0 100.0
100.0
[0237] The results obtained show that the addition of a
disintegration agent accelerates the dissolution profile of the
tablet making it closer to the reference capsule (cf. FIG. 2).
3. Protective Effect of Binders on the Active Ingredient During the
Wet Granulation Process
[0238] A study demonstrating the protective effect of binder and/or
diluent (microcrystalline cellulose, copovidone, carboxymethyl
cellulose) was carried out by comparison of the final level of
impurity as well as the behaviour of these formulations during
their manufacture. Different solid compositions obtained by wet
granulation were analyzed by HPLC, on an Alliance 2695 system with
2487 UV detector from Waters (high performance liquid
chromatography) according to the conditions described in the table
(Table 4) below.
TABLE-US-00008 TABLE 4 HPLC analytical method for the analysis of
40 mg tablets of compound I. HPLC method used for the assay of
compound I and impurities Parameters Conditions Column Phenomenex
POLAR RP 250 .times. 4.6 mm - particle sizes 4 .mu.m Elution rate
1.2 ml/min Temperature of the column 20 .+-. 2.degree. C. Detection
UV 215 nm Mobile phase Isocratic acetonitrile/acidified water (0.1%
acid orthophosphoric) 51/49 v/v Analysis time 15 min Diluent
acetonitrile Reference solution 0.2 mg/ml in solution in
acetonitrile Sample solution 0.2 mg/ml in acetonitrile Temperature
of the Ambient temperature samples
TABLE-US-00009 TABLE 5 Solid compositions containing compound 1 and
using different excipients. Micronized Compound 1 Colloidal
Magnesium No. of ref. 5 .mu.m % mannitol MCC % Lactose % silica %
stearate % Impurities % composition (m/m) % (m/m) (mini) (m/m)
(m/m) (m/m) (m/m) Copovidone % (m/m) 1 7 31.0 -- 57.8 -- 1.4 2.8
9.9% 2 7 -- 31.0 52.8 5.0 1.4 2.8 1.4% 17 15 -- 49.2 30.0 4.2 0.8
0.8 1.7% carboxy- methyl cellulose 3 7 -- 31.0 52.8 5 1.4 2.8
1.1
4. Stability of the Tablets Dosed at 5 mg and at 40 mg as a
Function of the Storage Conditions, at 6 Months and at 12 Months in
Blister Packs
[0239] A tablet form (centesimal formula of Example 1a) was
stabilized after primary packaging in blister packs.
[0240] The purpose of this is to check the stability of this form
over periods of 6 months and 12 months.
[0241] The recommended normal storage conditions are 25.degree. C.
and 60% relative humidity (25.degree. C./60% RH) and the data
generated under these conditions are shown in Tables 6 and 7 for
the tablets dosed at 5 mg and 40 mg respectively.
[0242] In addition, other storage conditions (e.g. 40.degree.
C./75% RH) were also investigated up to the end of the 6-month
stability period and the data generated are shown in Tables 8 and 9
for tablets dosed at 5 mg and 40 mg respectively.
TABLE-US-00010 TABLE 6 Stability study on tablets packaged in
blister packs containing 5 mg of active ingredient and stored at
25.degree. C./60% RH. Stability scores (months) Tests initial 3 6 9
12 Dosage: Compound 1 5.0 5.0 4.9 5.0 5.0 (mg/unit) Impurities (%)
(m/m) <0.1 0.2 0.3 0.4 0.5 Dissolution % compound I dissolved
(Min-Max) at time [min] 10 minutes 58-64 61-66 61-65 61-64 62-65 20
minutes 76-80 78-82 77-81 77-80 79-82 30 minutes 83-87 85-90 84-89
84-87 86-89 60 minutes 91-95 92-97 91-97 91-95 94-98 90 minutes
92-97 95-100 94-99 94-98 96-101
[0243] Table 6 provides a compilation of assay, impurity and
dissolution test results from the stability study of tablets
packaged in blister packs, containing 5 mg of active ingredient and
stored at 25.degree. C./60% RH.
TABLE-US-00011 TABLE 7 Stability study of tablets packaged in
blister packs, containing 40 mg of active ingredient and stored at
25.degree. C./60% RH. Stability scores (months) Tests initial 3 6 9
12 Dosage: Compound 1 38.9 39.2 38.7 39.4 39.4 (mg/unit) Impurities
(%) (m/m) <0.1 0.2 0.2 0.3 0.4 Dissolution % compound I
dissolved (Min-Max) at time [min] 10 minutes 62-66 63-65 64-65
63-65 64-66 20 minutes 77-80 77-79 77-79 78-79 78-80 30 minutes
83-86 84-86 83-85 84-86 84-86 60 minutes 90-94 91-93 91-93 91-93
92-93 90 minutes 93-97 94-96 93-96 94-96 95-96
[0244] Table 7 provides a compilation of assay, impurity and
dissolution test results from the stability study of tablets
packaged in blister packs, containing 40 mg of active ingredient
and stored at 25.degree. C./60% RH.
TABLE-US-00012 TABLE 8 Stability study of tablets packaged in
blister packs, containing 5 mg of active ingredient and stored
under different storage conditions Stability scores
(months)/storage conditions 6 months/ 6 months/ 6 months/
25.degree. C./ 40.degree. C./ Tests initial 2-8.degree. C. 60% RH
75% RH Dosage: Compound 1 5.0 5.0 4.9 4.8 (mg/unit) Impurities (%)
(m/m) <0.1 <0.1 0.3 1.9 Dissolution compound I dissolved
(Min-Max) within the time [min] 10 minutes 58-64 59-65 61-65 62-65
20 minutes 76-80 77-82 77-81 78-82 30 minutes 83-87 85-89 84-89
85-89 60 minutes 91-95 92-98 91-97 92-98 90 minutes 92-97 94-100
94-99 95-100
[0245] Table 8 provides a compilation of assay, impurity and
dissolution test results from the stability study of tablets
packaged in blister packs, containing 5 mg of active ingredient and
stored under different storage conditions.
TABLE-US-00013 TABLE 9 Stability study of the tablets packaged in
blister packs containing 40 mg of active ingredient and stored
under different storage conditions Stability scores
(months)/storage conditions 6 months/ 6 months/ 6 months/
25.degree. C./ 40.degree. C./ Tests initial 2-8.degree. C. 60% RH
75% RH Dosage: Compound 1 38.9 39.0 38.7 38.3 (mg/unit) Impurities
(%) (m/m) <0.1 <0.1 0.2 1.4 Dissolution % compound I
dissolved (Min-Max) within the time [min] 10 minutes 62-66 62-65
64-65 62-65 20 minutes 77-80 76-78 77-79 78-79 30 minutes 83-86
83-84 83-85 84-85 60 minutes 90-94 90-92 91-93 91-93 90 minutes
93-97 93-94 93-96 94-95
[0246] In Table 8 tests of assay, impurities and of dissolution of
the stability study of tablets packaged in blister packs containing
40 mg of active ingredient and stored under different storage
conditions are grouped together.
[0247] After 12 months' storage at 25.degree. C./60% RH, no
significant change was observed for the assay and the
dissolution.
[0248] Statistical analysis of the results obtained by regression
line with a confidence interval of 95% promises at least three
years' conformity with the product quality specifications.
[0249] The accelerated stabilities at a temperature of 40.degree.
C. and 75% relative humidity (40.degree. C./75% RH) show results in
conformity with the product quality specifications.
[0250] The stability of the product under the most severe
conditions reinforces confidence in the projections carried out for
the tablets stored at 25.degree. C./60% RH.
5. Preparation of Compound 1 Variety I
5.1 Synthesis of Compound 1
Example 5
[0251] The first stage consists of condensing
2-carbetoxycycloheptanone with resorcinol in methanesulphonic acid,
the reaction is taken to 25.degree. C. for 4 hours. The
intermediate
3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(71-1)-one thus
formed precipitates by adding ethanol then water then it is
isolated by filtration, dried under vacuum at 60.degree. C. and a
yield of 78% is obtained. In a second stage, sulphonylisocyanate
chloride is converted, in toluenic solution, to sulphamoyl chloride
by the action of the formic acid, then condensed with the previous
intermediate dissolved in N,N-dimethylacetamide (DMA). The reaction
medium is treated with water and extracted with
2-methyltetrahydrofurane (2-MeTHF). The crude compound 1 is then
obtained by filtration of the precipitate obtained by adding
methylcyclohexane to the organic phase. Finally, pure compound 1 is
obtained by recrystallization of the crude product by dissolution
in acetone while hot and precipitation by adding methylcyclohexane
(the addition of the antisolvent methylcyclohexane having the main
purpose of increasing the yield).
[0252] Compound 1 is thus obtained with a yield of 65%, and
presented hereafter.
[0253] Example 1 thus obtained can be subjected to an appropriate
treatment aimed at reducing the size of the particles such as
micronization (point 5.3 below) or wet grinding (point 5.
below).
5.2 Desolvation of the DMSO Solvate of Form 2 of Compound 1 in
Water
Example 5a
DMSO Solvate of Form 2 of Compound 1
[0254] 1 mL of DMSO (Bp=189.degree. C.) is poured into a pill box,
then 1 g of compound 1 (Example 1) is added. The solution is
stirred using a magnetic stirring bar and a magnetic stirrer. The
solid passes into solution rapidly. 1 g of compound 1 is again
added, still under magnetic stirring. The solid partly dissolves,
then caking is observed. A sample of the caking is analyzed while
still moist by X-ray powder diffraction. This analysis, presented
hereafter, shows that this is the DMSO solvate of form 2 of
compound 1 (Example 5a).
Example 5b
[0255] The DMSO solvate of form 2 of compound 1 (Example 5b) is
immersed in cold water and left under stirring for five minutes at
ambient temperature. The suspension is then filtered and dried.
[0256] Compound 1 is thus obtained with a yield of 50% and
presented hereafter.
[0257] Example 5b thus obtained can be subjected to an appropriate
treatment aimed at reducing the size of the particles such as
micronization or wet grinding.
5.3 Micronization
[0258] Micronization is carried out using a compressed air-jet
micronizer at a temperature comprised between 18 and 25.degree. C.
The characteristics of the compressed air used are the following:
[0259] CO: <5 ppm, [0260] CO.sub.2: <500 ppm, [0261]
Hydrocarbons: <0.5 mgm.sup.-3, [0262] Number of particles per
ft.sup.3>0.5.mu.<10000, [0263] Maximum performance: 2300 cfm
at 13 bar, [0264] Maximum operating pressure: 13 bar.
Example 5c
Variety I of Compound 1 with a Particle Size 3 .mu.m
[0265] 249 g of compound 1 (Example 1) are micronized using a
compressed air-jet micronizer. The micronization parameters are: a
Venturi pressure of 80 psi, a pressure of the micronizer of 110 psi
and a feed rate of 12 kgh.sup.-1.
[0266] Example 3-1 is thus obtained with a yield of 97%.
Example 5d
Variety I of Compound 1 with a Particle Size 5 .mu.m
[0267] 16.5 kg of compound 1 (Example 5) are micronized using a
compressed air-jet micronizer. The micronization parameters are: a
Venturi pressure of 80 psi, a pressure of the micronizer of 32 psi
and a feed rate of 14.4 kgh.sup.-1.
[0268] Example 5d is thus obtained with a yield of 98% and
presented hereafter.
Example 5e
Variety I of Compound 1 with a Particle Size 9 .mu.m
[0269] 150 g of compound 1 (Example 51) are micronized using a
compressed air-jet micronizer. The micronization parameters are: a
Venturi pressure of 50 psi, a pressure of the micronizer of 60 psi
and a feed rate of 15 kgh.sup.-1.
[0270] Example 5e is thus obtained with a yield of 98%.
Example 5f
Variety I of Compound 1 with a Particle Size 15 .mu.m
[0271] 39 g of compound 1 (Example 5) are micronized using a
compressed air-jet micronizer. The micronization parameters are: a
Venturi pressure of 30 psi, a pressure of the micronizer of 10 psi
and a feed rate of 40 g in 15 minutes.
[0272] Example 5f is thus obtained with a yield of 74%.
5.4 Wet Grinding
Example 5g
[0273] 0.69 g of compound 1 (Example 5) are ground with 0.068 g of
methylcyclohexane in a Fritsch type planetary model P4 ball
mill.
[0274] The wet grinding parameters are: 7 agate balls 10 mm in
diameter, a grinding torque .OMEGA. (speed of rotation of the
disc)-.omega. (speed of rotation of the flasks) of 100-100 rpm, a
period of 12 effective hours out of a total of 18 hours according
to the following 72 sequences: 10 minutes of grinding-5 minutes'
pause, a mass of balls/mass of solute ratio of 14.1; a temperature
of 22.degree. C. and a mass of compound 1/mass of methylcyclohexane
ratio of 9%.
[0275] Example 3 is thus obtained with a yield of 99% and presented
hereafter.
6. Description of the Crystals Obtained
6.1 Equipment Used
6.1.1 X-Ray Powder and Single Crystal Diffraction
[0276] Siemens D5005 diffractometer, scintillation detector [0277]
Wavelength: 1.54056 Cu, voltage 40 KV, intensity 40 mA [0278]
Measurement range: 3.degree.-30.degree.2 theta [0279] Interval:
0.04.degree.2 theta [0280] Duration of the interval: 4 s [0281]
Fixed slots: 1.6 mm [0282] K.beta. filter (Ni) [0283] Without
internal reference [0284] EVA software (v 12.0) for data processing
Smart Apex Bruker diffractometer, two-dimensional detector [0285]
SMART software for determination of the parameters and orientation
of the crystal matrix [0286] SAINT software for data integration
and processing [0287] WinGX software for determination of the space
group and the structural resolution
6.1.2 DSC
[0287] [0288] Netzsch DSC 204F1 [0289] Aluminium crucible and
pierced lid [0290] Atmosphere: Helium [0291] Initial temperature:
20.degree. C. [0292] Final temperature: 200.degree. C. [0293]
Temperature gradient: 5.degree. C.min.sup.-1
6.1.3 IR
[0293] [0294] KBr pellet [0295] Bruker IFS28 type spectrometer
[0296] Spectral range: 400-4000 cm.sup.-1
6.1.4 NMR of the solid
[0296] [0297] Bruker Avance 500 MHz spectrometer [0298] MAS (Magic
Angle Spinning) 4 mm probe [0299] Bruker XwinNMR software [0300]
VACP (Variable Amplitude Cross-Polarization) with MAS (11 kHz) and
proton decoupling (spinal 64, 65 kHz) [0301] External reference:
Adamantane
6.1.5 Particle size distribution
[0301] [0302] Malvern Mastersizer S laser granulometer [0303] Size
of the sample: 30 to 50 mg [0304] Dispersion medium: 0.50% (m/v)
Nonidet in water [0305] Mie theory with as refractive indices:
particle RI=1.55; imaginary RI=1.00; dispersant RI=1.38 [0306]
Sonication time: 60 seconds [0307] Sonication energy: 50 to 60 Hz
[0308] Recirculation time: 30 seconds at 2000 rpm.sup.-1 [0309]
Obscuration: 15-25%
6.2 Characterization of the Examples
6.2.1 Examples 5 and 5b
[0310] It has been possible to isolate single crystals by slow
evaporation of a saturated solution in ethanol at 4.degree. C. for
2 days. These single crystals have made it possible to resolve the
complete structure of variety I of compound 1 by X-ray
diffraction.
[0311] X-ray single crystal diffraction: the crystalline structure
of compound 1 variety I has been resolved and exhibits the
following cell parameters:
TABLE-US-00014 Cell structure Monoclinic Space group P2.sub.1/c
(no. 14) Cell parameter a 11.995(5) .ANG. Cell parameter b
11.236(5) .ANG. Cell parameter c 10.403(5) .ANG. Cell parameter a
90.degree. Cell parameter p 99.09.degree. Cell parameter y
90.degree. Cell volume 1384.5(10) .ANG..sup.3 Number of molecules
per cell: Z 4 Calculated density 1.484 g cm.sup.-3
[0312] The reduced coordinates (.times.10.sup.4) and equivalent
isotropic displacement parameters (.ANG..sup.2.times.10.sup.3) of
compound 1 variety I are the following:
TABLE-US-00015 X Y Z U(eq) C(1) 8517(2) 4055(2) 6064(2) 49(1) C(2)
9769(2) 4143(2) 6671(2) 48(1) C(3) 10572(2) 3420(2) 5997(2) 54(1)
C(4) 10389(2) 2096(2) 5973(3) 55(1) C(5) 9230(2) 1711(2) 5284(2)
52(1) C(6) 8303(2) 1868(2) 6098(2) 40(1) C(7) 7962(1) 2946(2)
6473(2) 39(1) C(8) 7097(1) 3009(2) 7309(2) 38(1) C(9) 6675(1)
1951(2) 7734(2) 37(1) C(10) 7790(1) 791(2) 6485(2) 40(1) C(11)
6681(2) 4058(2) 7781(2) 48(1) C(12) 5914(2) 4037(2) 8627(2) 50(1)
C(13) 5561(2) 2959(2) 9052(2) 41(1) C(14) 5924(2) 1896(2) 8619(2)
41(1) N 2943(1) 2531(2) 8742(2) 47(1) O(1) 7012(1) 872(1) 7312(1)
45(1) O(2) 8002(1) -206(1) 6149(2) 54(1) O(3) 4881(1) 3037(1)
10036(1) 53(1) O(4) 3320(1) 2749(1) 11088(1) 58(1) O(6) 4066(1)
1037(1) 10021(2) 69(1) S(1) 3768(1) 2248(1) 10030(1) 41(1)
[0313] The reduced coordinates of the hydrogen atoms
(.times.10.sup.4) of compound 1 variety I are the following:
TABLE-US-00016 x Y Z U(eq) H(11) 6924(18) 4720(20) 7470(20) 55(6)
H(12) 5679(19) 4770(20) 8940(20) 63(6) H(14) 5738(17) 1098(19)
8870(20) 54(6) H(1A) 8120(18) 4743(19) 6260(20) 55(6) H(2A)
9964(17) 4984(19) 6657(19) 53(6) H(3A) 11368(19) 3541(19) 6340(20)
60(6) H(4A) 10960(20) 1750(20) 5580(20) 68(7) H(5A) 9062(19)
2184(19) 4450(20) 61(7) H(1B) 8421(19) 4050(19) 5070(20) 66(6)
H(2B) 9894(16) 3890(17) 7600(20) 48(5) H(3B) 10467(17) 3666(18)
5110(20) 53(6) H(4B) 10461(19) 1776(19) 6860(20) 61(7) H(5B)
9219(19) 900(20) 5100(20) 63(7) H(1N) 2770(20) 3270(20) 8750(20)
68(8) H(2N) 3240(20) 2300(20) 8060(20) 72(8)
[0314] The interplanar spacings of compound 1 variety I are the
following:
TABLE-US-00017 H K L 2Theta/deg d/.ANG. 1/rel, |F(hk1)1 1 0 0 7.46
11.84 53.58 69.88 1 1 0 10.85 8.15 11.9 33.95 -1 1 1 13.10 6.75
3.97 23.76 1 1 1 14.58 6.07 2.02 18.88 2 0 0 14.95 5.92 2.18 28.47
0 2 0 15.76 5.62 66.66 166.12 2 1 0 16.91 5.24 16.31 62.45 0 0 2
17.25 5.14 6.51 56.96 1 2 0 17.46 5.08 22.31 75.46 -1 0 2 17.69
5.01 17.58 96 -2 1 1 17.88 4.96 6.14 40.56 0 1 2 18.98 4.67 10.23
55.68 1 2 1 20.01 4.43 6.69 47.56 1 1 2 21.41 4.15 100 197.19 -2 1
2 22.47 3.95 26.25 106.22 3 0 0 22.50 3.95 8.86 87.39 -2 2 1 22.56
3.94 7.86 58.39 0 2 2 23.45 3.79 13.11 78.51 3 1 0 23.87 3.72 2.91
37.71 2 0 2 24.65 3.61 40.18 204.83 1 3 0 24.91 3.57 16.69 94.37 1
2 2 25.47 3.49 6.03 58.08 2 1 2 25.91 3.44 23.6 116.99 -3 0 2 26.19
3.40 3.64 65.73 -2 2 2 26.38 3.38 2.42 38.19 3 1 1 26.62 3.35 6.43
62.81 3 2 0 27.59 3.23 6.14 63.74 -3 2 1 27.84 3.20 4.33 54.08 2 3
0 28.17 3.17 4.87 58.06 -2 3 1 28.78 3.10 2.52 42.75 1 1 3 29.35
3.04 3.06 48.04 2 2 2 29.40 3.04 2.08 39.73
6.2.2 Example 5a
[0315] It was possible to isolate single crystals by slow
evaporation of a saturated solution of DMSO at ambient temperature.
These single crystals made it possible to resolve the complete
structure of the DMSO solvate of form 2 of compound 1 by X-ray
diffraction.
[0316] Single crystal X-ray diffraction: The crystalline structure
of the DMSO solvate of form 2 of compound 1 was resolved and
exhibits the following cell parameters:
TABLE-US-00018 Cell structure Monoclinic Space group C2/c (no. 15)
Cell parameter a 28.713(2) .ANG. Cell parameter b 9.399(7) .ANG.
Cell parameter c 16.6487(12) .ANG. Cell parameter .beta. 126.015(9)
.degree. Cell volume 3634(3) .ANG..sup.3 Z, Z' 8, 1 Calculated
density .sup. 1.416 g cm.sup.-3
[0317] The atomic coordinates of the atoms in the cell
(.times.10.sup.4) and equivalent isotropic displacement parameters
(.ANG..sup.2.times.10.sup.3) (U(eq) equals a third of the value of
the orthogonal tensor Uij) of the DMSO solvate of form 2 of
compound 1 are the following:
TABLE-US-00019 x Y Z U(eq) DMSO S(1S) 2081(1) 5757(4) 1369(3) 94(1)
O(1S) 2139(4) 5214(12) 2274(8) 134(4) C(1S) 2694(6) 6782(14)
1798(12) 115(5) C(2S) 2252(6) 4239(14) 912(13) 114(5) compound 1
S(1) 1113(1) 7393(3) 2439(2) 73(1) O(1) -859(2) 4386(7) 1159(5)
65(2) O(2) 705(3) 6637(7) 1385(5) 75(2) O(3) -1629(3) 3534(7)
975(6) 78(2) O(4) 788(4) 7592(8) 2833(7) 89(2) O(5) 1316(4) 8561(8)
2190(6) 97(3) N(1) 1623(4) 6326(9) 3100(6) 74(2) C(1) 433(4)
5393(11) 1383(7) 67(3) C(2) -81(4) 5473(10) 1307(7) 62(2) C(3)
-349(4) 4271(10) 1238(7) 55(2) C(4) -144(4) 2931(9) 1268(7) 52(2)
C(5) 390(4) 2899(10) 1371(7) 62(3) C(6) 665(4) 4097(11) 1428(7)
68(3) C(7) -1196(4) 3258(10) 1019(7) 61(2) C(8) -992(4) 1858(10)
995(8) 60(2) C(9) -477(4) 1725(8) 1161(6) 49(2) C(10) -266(4)
209(9) 1168(7) 66(3) C(11) -585(4) -44(11) 169(7) 69(3) C(12)
-1167(5) -1113(14) -192(10) 89(4) C(13) -1582(5) -65(12) -242(9)
86(4) C(14) -1408(5) 699(12) 721(10) 86(3)
[0318] The coordinates of the hydrogen atoms (.times.10.sup.4) and
equivalent isotropic displacement parameters
(.ANG..sup.2.times.10.sup.3) (U(eq) equals a third of the value of
the orthogonal tensor Uij) of the DMSO solvate of form 2 of
compound 1 are the following:
TABLE-US-00020 x Y Z U(eq) DMSO H(1S1) 2689 7616 2126 172 H(1S2)
2697 7060 1247 172 H(1S3) 3032 6232 2258 172 H(2S1) 2582 3754 1460
172 H(2S2) 2335 4560 461 172 H(2S3) 1930 3599 573 172 compound 1
H(2) -232 6351 1304 75 H(5) 550 2024 1399 75 H(6) 1011 4045 1496 82
H(10A) 140 250 1442 79 H(10B) -305 -390 1599 79 H(11A) -345 -1179
174 83 H(11B) -652 273 -305 83 H(12A) -1342 -1518 -846 107 H(12B)
-1101 -1882 253 107 H(13A) -1940 -563 -505 103 H(13B) -1661 662
-721 103 H(14A) -1750 1087 628 103 H(14B) -1239 14 1259 103
[0319] The interplanar spacings of the DMSO solvate of form 2 of
compound 1 are the following:
TABLE-US-00021 H K L 2Theta/deg d/.ANG. l/rel, |F(hkl)| 2 0 0 7.61
11.61 93.62 158.42 1 1 0 10.15 8.71 44.56 103.26 -2 0 2 10.62 8.32
5.71 54.77 -1 1 1 10.80 8.18 10.04 52.22 -4 0 2 13.01 6.80 9.86
88.39 0 0 2 13.14 6.73 24.61 141 -3 1 1 13.19 6.71 75.41 175.25 1 1
1 13.26 6.67 58.06 154.51 4 0 0 15.25 5.81 8.76 97.89 -5 1 2 18.19
4.87 39.9 176.99 1 1 2 18.33 4.84 72.53 240.47 -6 0 2 18.53 4.78
41.04 258.66 -3 1 3 18.55 4.78 24.52 141.58 -5 1 1 18.68 4.75 21.01
131.96 2 0 2 18.71 4.74 8.13 116.24 3 1 1 18.77 4.72 6.81 75.49 -2
2 1 19.97 4.44 27.29 161.17 0 2 1 20.00 4.44 4.3 64.06 -5 1 3 20.02
4.43 50.8 220.36 -1 1 3 20.14 4.41 33.54 180.21 2 2 0 20.37 4.36
5.62 74.65 5 1 0 21.32 4.16 24.81 164.42 -4 0 4 21.33 4.16 58.24
356.44 -2 2 2 21.70 4.09 10.75 110.24 -4 2 1 22.73 3.91 2.86 59.66
-2 0 4 22.75 3.91 32.04 282.72 6 0 0 22.96 3.87 3.7 96.94 -4 2 2
22.99 3.87 55.47 265.91 0 2 2 23.06 3.85 30.27 197.08 -5 1 4 23.64
3.76 2.09 53.09 -7 1 2 23.79 3.74 2.79 61.84 3 1 2 23.96 3.71 9.87
117.16 -7 1 3 24.00 3.71 11.93 128.99 1 1 3 24.21 3.67 100 376.83 4
2 0 24.35 3.65 22.95 181.63 -8 0 2 25.26 3.52 14.41 211.56 4 0 2
25.46 3.50 2.89 95.47 5 1 1 25.48 3.49 9.78 124.38 -7 1 4 25.97
3.43 3.4 74.81 -1 1 4 26.17 3.40 38.29 253.11 -8 0 4 26.20 3.40
4.21 118.77 0 0 4 26.45 3.37 22.75 279.11 -6 2 3 27.32 3.26 2.61
69.16 4 2 1 27.54 3.24 3.15 76.69 -5 1 5 28.42 3.14 5.77 107.23 7 1
0 28.51 3.13 18.44 192.32 -1 3 1 28.98 3.08 5.27 104.63 -7 1 5
29.39 3.04 2.61 74.74 -3 1 5 29.53 3.02 15.12 180.83 3 1 3 29.81
3.00 2.86 79.49 6 2 0 29.88 2.99 4.93 104.61
[0320] The X-ray powder diffraction diagram of DMSO solvate of form
2 of compound 1 exhibits the following characteristic peaks
expressed as an angle (.degree.2 theta) to approximately
.+-.0.1.degree.2 theta: (FIGS. 1 and 2). 7.6; 18.7; 24.2; 29.9.
6.2.3 Examples 5c-5g
6.2.3.1 X-Ray Powder Diffraction (FIGS. 5 and 6)
[0321] The X-ray powder diffraction diagram of variety I of
compound 1 after micronization or wet grinding exhibits the
following characteristic peaks expressed as an angle (.degree.2
theta) to approximately .+-.0.1.degree.2 theta: 7.5; 10.9; 11.7;
13.1; 14.6; 15.0; 15.8; 17.0; 17.3; 17.5; 17.7; 17.9; 19.0; 19.9;
20.0; 21.4; 21.8; 22.5; 23.5; 23.9; 24.7; 24.9; 25.5; 25.9; 26.2;
26.4; 26.6; 27.2; 27.4; 27.6; 27.8; 28.2; 28.8; 29.0; 29.4;
29.8.
[0322] The X-ray powder diffraction diagram of variety I of
compound 1 after micronization or wet grinding and then heating to
160.degree. C. exhibits the following characteristic peaks
expressed as an angle (.degree.2 theta) to approximately
.+-.0.1.degree.2 theta: 7.5; 10.9; 11.7; 13.1; 14.6; 15.0; 15.8;
17.0; 17.3; 17.5; 17.7; 17.9; 19.0; 19.9; 20.0; 21.4; 21.8; 22.5;
23.5; 23.9; 24.7; 24.9; 25.5; 25.9; 26.2; 26.4; 26.6; 27.2; 27.4;
27.6; 27.8; 28.2; 28.8; 29.0; 29.4; 29.8 without additional peaks
corresponding to the novel form produced during heating to
160.degree. C.
6.2.3.2 DSC (FIG. 7)
[0323] Using DSC, the thermogram obtained at 5.degree. C.min.sup.-1
of variety I of compound 1 after micronization or wet grinding
comprises the melting peak of variety I (onset
170.degree..+-.5.degree. C.), optionally a small melting peak of a
novel polymorphic form produced during analysis (onset
180.+-.2.degree. C.) representing less than 10% of the enthalpy
exchanged during the melting peak of variety I and does not exhibit
any endothermic event (or less than 0.5 J/g) between
140-155.degree. C.
6.2.3.3 IR (FIG. 8)
[0324] The IR spectrum of variety I of compound 1 after
micronization or wet grinding exhibits the characteristic peaks
expressed in cm.sup.-1 to approximately .+-.5 cm.sup.-1: 3310;
3167; 3059; 2928; 2858; 1690; 1605; 1454; 1385; 1261; 1188; 1126;
941; 891; 853; 798; 733; 679; 598; 544; 455.
6.2.3.4 NMR of the Solid (FIG. 9)
[0325] The spectrum of variety I of compound 1 after micronization
or wet grinding obtained by NMR of the solid exhibits the following
characteristic peaks expressed in ppm to approximately .+-.0.2 ppm
163.1; 156.1; 153.8; 153.1; 130.4; 127.6; 107.6; 35; 25.
6.2.3.5 Particle Size
[0326] The particle size distribution of variety I of compound 1
after micronization according to Example 2-2 is the following:
D10(%)=1.2 .mu.m; D50(%)=5.2 .mu.m and D90(%)=11.0 .mu.m.
[0327] The particle size distribution of variety I of compound 1
after wet grinding according to Example 3 is the following:
D10(%)=0.6 .mu.m; D50(%)=3.1 pm and D90(%)=13.7 .mu.m.
7. Formulation
7.1 Formulation in the Form of Gelatin Capsules
[0328] Variety I of compound 1 according to the invention, can be
formulated in a gelatin
[0329] capsule containing: 5 to 30% active ingredient (preferably 6
to 13%), 40 to 92% diluent (preferably 65 to 92%, very preferably
85 to 90%), 0 to 30% disintegration agent (preferably 0 to 22%,
very preferably 0%), 0 to 5% surfactant (preferably 0%), 0 to 5%
solubilizant (preferably 0%), 0.1 to 3% flow agent (preferably 0.9
to 1.4%), 0.5 to 3% lubricant (preferably 0.6 to 2.8%).
[0330] The preferred excipients for formulating these gelatin
capsules are mannitol, lactose, corn starch, colloidal silica,
magnesium stearate, and sodium lauryl sulphate, and more
particularly mannitol, lactose, colloidal silica, and magnesium
stearate.
[0331] The gelatin capsules presented below were manufactured by
mixing powder according to the standard techniques known to a
person skilled in the art.
TABLE-US-00022 Ex Ex 5d M L CS SLS PEG CS MS 7a 6.0% 87.2% / / 4.8%
/ 1.3% 0.7% 7b 6.0% 87.2% / / / 4.8% 1.3% 0.7% 7c 6.0% 43.6% 43.6%
/ 4.8% / 1.3% 0.7% 7d 6.0% 43.6% 43.6% / / 4.8% 1.3% 0.7% 7e 12.3%
65.0% 21.2% / / / 0.9% 0.6% 7f 12.3% / 65.0% 21.2% / / 0.9% 0.6% 7g
7.0% 31.0% 57.8% / / / 1.4% 2.8% 7h 6.0% 92.0% / / / / 1.3% 0.7% 7i
6.0% 46.0% 46.0% / / / 1.3% 0.7% M = mannitol; L = lactose; CS =
Corn starch; SLS = Sodium lauryl sulphate; PEG = polyethylene
glycol; CS = colloidal silica; MS = magnesium stearate
Example 71
[0332] The example of gelatin capsules 7j is prepared from compound
1 of Example 5: 40 mg of compound 1 are mixed with 260 mg of
lactose and placed in gelatin capsules.
Example 7k
[0333] The example of gelatin capsules 7k is prepared according to
formula 7g with Example 5c as active ingredient instead of Example
5d.
Example 7l
[0334] The example of gelatin capsules 7l is prepared with 7.2%
example 5d, 31.9% mannitol, 59.4% lactose and 1.5% colloidal
silica.
Example 7m
[0335] The example of gelatin capsules 7m is prepared according to
formula 7g with Example 5d as active ingredient.
Example 7n
[0336] The example of gelatin capsules 4n is prepared according to
formula 4g with Example 5e as active ingredient instead of Example
5d.
Example 7o
[0337] The example of gelatin capsules 4o is prepared with Example
5f as active ingredient: 40 mg of Example 5f are mixed with 260 mg
of lactose and placed in gelatin capsules.
7.2 Formulation in the Form of Tablets
[0338] Variety I of compound 1 according to the invention, can be
formulated in a tablet containing: 5 to 30% active ingredient
(preferably 7 to 20% and very preferably 10 to 15%), 40 to 92%
diluent (preferably 34 to 89% and very preferably 70 to 85%), 0 to
40% disintegration agent (preferably 0 to 20% and very preferably 3
to 5%), 0 to 8% binding agent (preferably 2 to 5%), 0.1 to 3% flow
agent (preferably 0.5 to 1.4%), 0.5 to 3% lubricant (preferably 0.5
to 2.8%).
[0339] The preferred excipients for formulating these gelatin
capsules are maltodextrin, mannitol, microcrystalline cellulose,
lactose, corn starch, sodium starch glycolate, crospovidone,
polyvinylpyrrolidone, carboxymethyl cellulose, colloidal silica,
magnesium stearyl fumarate, and magnesium stearate and more
particularly microcrystalline cellulose, lactose, sodium starch
glycolate, polyvinylpyrrolidone, colloidal silica, and magnesium
stearate.
[0340] The tablets presented below were manufactured by wet
granulation according to the standard techniques known to a person
skilled in the art.
TABLE-US-00023 Example/ % Microcrystalline Sodium starch Excipient
% Example 5d % Maltodextrin Mannitol cellulose % Lactose % Corn
starch glycolate 7aa 7.0 / 31.0 / 57.8 / / 7ab 7.0 / 31.0 / 52.8 /
/ 7ac 7.0 / 31.0 / 52.8 / / 7ad 20.0 / / 44.2 28.3 / / 7ae 15.0 /
36.0 / 41.5 3.0 / 7af 15.0 27.5 26.0 25.0 / 5.0 / 7ag 15.0 26.5 /
25.0 26.0 6.0 / 7ah 15.0 18.0 / 20.0 40.0 4.5 / 7ai 15.0 8.0 / 10.0
45.0 15.5 4.0 7aj 15.0 14.5 / 20.0 / 40.0 / 7ak 10.0 / / 45.0 36.5
/ 4.0 7al 15.0 30.5 / 10.0 35.0 5.0 / 7am 15.0 / / 12.5 35.0 35.0 /
7an 15.0 / / 39.2 21.7 / 16.7 7ao 15.0 / / 46.7 30.8 / / 7ap 15.0 /
/ 45.8 30.0 / / 7aq 15.0 / / 49.2 30.0 / / Tar 15.0 / / 46.7 30.8 /
/ 7s 10.0 / / 37.0 37.0 10.0 4.0 Example/ % Polyvinyl- % Polyvinyl-
% Carboxymethyl- % Sodium stearyl % Magnesium Excipient
polypyrrolidone pyrrolidone cellulose % Colloidal silica fumarate
stearate 7aa / / / 1.4 / 2.8 7ab / 5.0 / 1.4 / 2.8 7ac / / 5.0 1.4
/ 2.8 7ad / 4.2 / 0.8 / 2.5 7ae / 3.0 / 1.0 / 0.5 7af / / / 1.0 /
0.5 7ag / / / 1.0 / 0.5 7ah / / / 1.0 / 1.5 7ai / / / 1.0 / 1.5 7aj
/ 8.0 / 1.0 / 1.5 7ak / 3.0 / 0.5 / 1.0 7al / 2.0 / 1.0 / 1.5 7am /
/ / 1.0 / 1.5 7an / 4.2 / 0.8 / 2.5 7ao / 4.2 / 0.8 2.5 / 7ap 1.7
4.2 / 0.8 / 2.5 7aq / 4.2 / 0.8 / 0.8 Tar / 4.2 / 0.8 / 2.5 7s / /
/ 1.0 / 1.0
8. Physico-Chemical and Biological Properties
8.1 Dissolution Kinetics
[0341] The dissolution kinetics (expressed as a percentage of
compound 1 dissolved as a function of time) are measured according
to the standard techniques known to a person skilled in the art,
and presented in the table below.
TABLE-US-00024 Time Example Example Example (min.) 7j Example 7k 7l
Example 7n 7o 0 0% 0% 0% 0% 0% 10 4.3% 58.0% 53.1% 58.0% 46.9% 20
7.8% 78.1% 82.0% 84.5% 65.6% 30 10.6% 84.8% 93.8% 92.6% 73.7% 60
15.7% 94.3% 102.6% 100.8% 82.7% 90 18.8% 98.0% 104.6% 105.1%
87.5%
[0342] The above dissolution results are expressed as a percentage
of theoretical strength. The theoretical strength in gelatin
capsules 4j to 4n is 40 mg of active ingredient. These examples are
experimental, a slight excess of active ingredient during weighing
is possible and explains percentages greater than 100% at the final
dissolution point.
8.2 Bioavailability
[0343] The comparative bioavailability of compound 1 was studied in
dogs after a single administration of two gelatin capsules by oral
route. The blood samples are taken 1; 1.5; 2; 4; 6; 9; 12; 24; 30
and 48 hours after administration. The area under the curve (AUC)
is one of the pharmacokinetic parameters measured in the samples of
plasma from the dogs. The results obtained are presented in the
table below
TABLE-US-00025 Example AUC (ng mL.sup.-1 h) Example 4k 826 Example
41 844 Example 4m 806 Example 4n 581
8.3 Chemical Stability
[0344] A stability study was carried out at 100.degree. C. between
variety I of compound 1 and the compound 1 described in patent EP
880514. The chemical stability of compound 1 is studied using HPLC
with different scores.
[0345] The operating conditions of the HPLC method are the
following: [0346] column: Interchim UP3HDO-15XS, 150.times.4.6
mm,
TABLE-US-00026 [0346] eluent A: water 2500 trifluoroacetic acid 0.5
eluent B: acetonitrile
[0347] gradient:
TABLE-US-00027 [0347] Time (min) % A % B 0 80 20 22 5 95 24.2 80
20
[0348] detection: 205 nm, [0349] injection: 20 microlitres, [0350]
temperature: 40.degree. C., [0351] solution injected: 0.5
mgmL.sup.-1 (acetonitrile)
TABLE-US-00028 [0351] HPLC Purity Compound 1 Variety I Scores
Patent EP 880514 of compound 1 T0 99.6% 99.6% T1 day at 100.degree.
C. 99.1% 99.6% T2 days at 100.degree. C. 98.8% 99.7% T3 days at
100.degree. C. 98.7% 99.7% T7 days at 100.degree. C. 98.0%
99.7%
9. Preparation of Compound 1 of Form III
[0352] Form III of compound 1 as described in the present
application is obtained by a stage of synthesis of compound 1
(Example 5) followed by an additional stage which can be: [0353] a
desolvation of the DMSO solvate of form 1 in water: Example 9a,
[0354] a desolvation of the DMSO solvate of form 3 in water:
Example 9b, [0355] an atomization in ethanol: Example 9c, [0356] an
atomization in acetone: Example 9d [0357] a reimpasting in cumene
under reflux: Example 9e, [0358] a heat treatment then a
micronization, then a second heat treatment: Example 9f, [0359] a
heat treatment of form II: Example 9g.
9.1 Desolvation of the DMSO Solvate of Form 1 in Water
Example 9aa
DMSO Solvate of Form 1 of Compound 1
[0360] 1 mL of DMSO (Bp=189.degree. C.) is poured into a pill box,
then 1 g of compound 1 (Example 5) is added. The solution is
stirred using a magnetic stirring bar and a magnetic stirrer. The
solid passes into solution rapidly. 1 g of compound 1 is again
added, still under magnetic stirring. The solid partly dissolves,
then caking is observed. A sample of the caking is analyzed while
still moist by X-ray powder diffraction. This analysis, presented
hereafter, shows that this is the DMSO solvate of form 1 of
compound 1 (Example 9aa).
Example 9a
[0361] The DMSO solvate of form 2 of compound 1 (Example 9aa) is
immersed in cold water and left under stirring for five minutes at
ambient temperature. The suspension is then filtered and dried.
[0362] Compound 1 of form III is thus obtained with a yield of 50%
and presented hereafter.
9.2 Desolvation of the DMSO Solvate of Form 3 in Water
Example 9ba
DMSO Solvate of Form 3 of Compound 1
[0363] 1 mL of DMSO (Bp=189.degree. C.) is poured into a pill box,
then 1 g of compound 1 (Example 1) is added. The solution is
stirred using a magnetic stirring bar and a magnetic stirrer. The
solid passes into solution rapidly. The solution is left under
magnetic stirring for 24 hours. Caking is then observed. A sample
of the caking is analyzed while still moist by X-ray powder
diffraction. This analysis, presented hereafter, shows that this is
the DMSO solvate of form 3 of compound 1 (Example 9ba).
Example 9b
[0364] The DMSO solvate of form 3 of compound 1 (Example 3ba) is
immersed in cold water and left under stirring for five minutes at
ambient temperature. The suspension is then filtered and dried.
[0365] Compound 1 of form III is thus obtained with a yield of 50%
and presented hereafter.
9.3 Atomization in Ethanol
Example 9c
[0366] The product obtained is produced with a Buchi 190
spray-dryer. 2 g of compound 1 (Example 5) are dissolved in 200 mL
of ethanol (Bp=78.degree. C.). The dry air inlet temperature is
adjusted to 90.degree. C. with a pressure of 3 bar. The outlet
temperature is measured at 38.degree. C. during the atomization.
The outlet flow rate is adjusted to 700 NI/hour. 570 mg of dry
powder are recovered and analyzed by X-ray powder diffraction. This
analysis shows that this is form III of compound 1 which is
structurally pure by comparison with the diagram calculated from
the resolved single crystal structure.
[0367] Compound 1 of form III is thus obtained with a yield of 29%
and presented hereafter.
9.4 Atomization in Acetone
Example 9d
[0368] The product obtained is produced with a Buchi 290
spray-dryer comprising an inert loop. 2 g of compound 1 (Example 1)
are dissolved in 100 mL of acetone (Bp=56.degree. C.). The dry air
inlet temperature is adjusted to 70.degree. C. The outlet
temperature is measured at 50.degree. C. during the atomization.
The outlet flow rate is adjusted to 7600 NI/hour. 1 g of dry powder
is recovered and analyzed by X-ray powder diffraction. This
analysis shows that this is form III of compound 1 which is
structurally pure by comparison with the diagram calculated from
the resolved single crystal structure.
[0369] Compound 1 of form III is thus obtained with a yield of 50%
and presented hereafter
9.5 Reimpasting in Cumene Under Reflux
Example 9e
[0370] 10 g of compound 1 (Example 5) are suspended in 100 mL of
cumene (Bp=152.degree. C.). The mixture is taken to reflux under
stirring, then cooled down to ambient temperature. Analysis of the
powder recovered and dried shows that it is form III of compound
1.
[0371] Compound 1 of form III is thus obtained with a yield of 99%
and presented hereafter.
9.6 Heat Treatment then Micronization, then Second Heat
Treatment
Example 9f
[0372] 150 g of compound 1 are heated in a ventilated oven at
160.degree. C. for 15 minutes. The product thus heated is then
micronized using a compressed air-jet micronizer. The micronization
parameters are for the first pass: a Venturi pressure of 80 psi, a
pressure of the micronizer of 120 psi and a feed rate of 1.2
kgh.sup.-1 and for the second pass: a Venturi pressure of 50 psi, a
pressure of the micronizer of 50 psi and a feed rate of 1.2
kgh.sup.-1. The micronization yield is 69%. 15 g of the product
thus obtained is heated at 160.degree. C. for 15 minutes in a
ventilated oven.
[0373] Compound 1 of form III is thus obtained with a yield of 69%
and presented hereafter.
9.7 Heat Treatment of Form II
9.7.1 Obtaining form II
[0374] Form II of compound 1 can be obtained by two synthesis
routes: [0375] by desolvation of 1,4-dioxane hemisolvate of
compound 1 obtained beforehand by precipitation from 1,4-dioxane;
[0376] directly, by atomization in 1,4-dioxane.
Example 9h
1,4-Dioxane Hemisolvate of Compound 1
[0377] A solution of compound 1 (Example 5) in 1,4-dioxane was
prepared at ambient temperature and left under stirring for 24
hours. During the stirring, significant precipitation was observed.
The solid was then filtered and analyzed by X-ray powder
diffraction. The product obtained at the end of this stage is
1,4-dioxane hemisolvate of compound 1.
[0378] The 1,4-dioxane hemisolvate of compound 1 is thus obtained
with a yield of 80% and presented hereafter.
Example 9i
Compound 1 of Form II
[0379] According to a first synthesis route, 1,4-dioxane
hemisolvate of compound 1 (Example 9h) is heated from 20 to
80.degree. C. at 5.degree. C.min.sup.-1 under a flow of inert gas
and produces, by desolvation, form II of compound 1 characterized
by its X-ray diffraction pattern.
[0380] Compound 1 of form II is thus obtained with a yield of 99%
and presented hereafter.
[0381] According to a second synthesis route, compound 1 of form II
can be obtained as follows: 1 g of compound 1 (Example 5) was
dissolved in 100 mL of 1,4-dioxane (Bp=101.degree. C.). The inlet
temperature: dust-free dry air was adjusted to 130.degree. C. with
a pressure of 3 bars. The outlet temperature was measured at
88.degree. C. during the atomization. The outlet flow rate was
adjusted to 700 NI/hour. The product obtained at the end of this
stage is form II.
[0382] Compound 1 of form II is thus obtained with a yield of 50%
and presented hereafter.
9.7.2 Obtaining Form III
Example 9g
[0383] The recovered dry powder of compound 1 of form II (Example
9i), was placed in an oven at 160.degree. C. for a period of
between 6 and 10 minutes, preferably for 7.5 minutes. The powder
recovered after this treatment, analyzed by X-ray diffraction, is
shown to be form III of compound 1 which is structurally pure by
comparison with the calculated diagram obtained from the resolved
single crystal structure.
[0384] Compound 1 of form III is thus obtained with a yield of 99%
and presented hereafter
10. Characterization of the Solid Phases Obtained
10.1 Equipment Used
10.1.1 X-Ray Powder and Single Crystal Diffraction
[0385] Siemens D5005 diffractometer, scintillation detector [0386]
Wavelength: 1.54056 Cu, voltage 40 KV, intensity 40 mA [0387]
Measurement range: 3.degree.-30.degree.2 theta [0388] Interval:
0.04.degree.2 theta [0389] Duration of the interval: 4 s [0390]
Fixed slots: 1.6 mm [0391] K.beta. filter (Ni) [0392] Without
internal reference [0393] EVA software (v 12.0) for data processing
Smart Apex Bruker diffractometer, two-dimensional detector [0394]
SMART software for determination of the parameters and orientation
of the crystal matrix [0395] SAINT software for data integration
and processing [0396] WinGX software for determination of the space
group and the structural resolution
10.1.2 DSC
[0396] [0397] Netzsch DSC 204F1 [0398] Aluminium crucible and
pierced lid [0399] Atmosphere: Helium [0400] Initial temperature:
20.degree. C. [0401] Final temperature: 200.degree. C. [0402]
Temperature gradient: 5.degree. C.min.sup.-1
10.1.3 TG-DSC
[0402] [0403] Netzsch STA449C [0404] Aluminium crucible and pierced
lid [0405] Atmosphere: Helium [0406] Initial temperature:
25.degree. C. [0407] Final temperature: 200.degree. C. [0408]
Temperature gradient: 5.degree. C.min.sup.-1
10.1.4 IR
[0408] [0409] KBr pellet [0410] Bruker IFS28 type spectrometer
[0411] Spectral range: 400-4000 cm.sup.-1
10.1.5 NMR of the Solid
[0411] [0412] Bruker Avance 500 MHz spectrometer [0413] MAS (Magic
Angle Spinning) 4 mm probe [0414] Bruker XwinNMR software [0415]
VACP (Variable Amplitude Cross-Polarization) with MAS (11 kHz) and
proton decoupling (spinal 64, 65 kHz) [0416] External reference:
Adamantane
10.2 Characterization of the Examples
10.2.1 Form I of Compound 1
[0417] The X-ray powder diffraction diagram of form I of compound 1
exhibits the following characteristic peaks expressed as an angle
(.degree.2 theta) to approximately .+-.0.1.degree.2 theta: 7.5;
10.9; 11.7; 13.1; 14.6; 15.0; 15.8; 17.0; 17.3; 17.5; 17.7; 17.9;
19.0; 19.9; 20.0; 21.4; 21.8; 22.5; 23.5; 23.9; 24.7; 24.9; 25.5;
25.9; 26.2; 26.4; 26.6; 27.2; 27.4; 27.6; 27.8; 28.2; 28.8; 29.0;
29.4; 29.8.
10.2.2 DMSO Solvate of Form 1 of Compound 1
[0418] It was possible to isolate single crystals by slow
evaporation of a saturated solution of DMSO at ambient temperature.
These single crystals made it possible to resolve the complete
structure of the DMSO solvate of form 1 of compound 1 by X-ray
diffraction.
[0419] Single-crystal X-ray diffraction: The crystalline structure
of DMSO solvate of form 1 of compound 1 exhibits the following cell
parameters:
TABLE-US-00029 Cell structure Orthorhombic Space group P n a 21
(no. 33) Cell parameter a 7.865(2).ANG. Cell parameter b
26.831(7).ANG. Cell parameter c 8.552(2).ANG. Cell volume
1804.7(8).ANG..sup.3 Z, Z' 4, 1 Calculated density 1.426 g
cm.sup.-3
[0420] The atomic coordinates of the atoms in the cell
(.times.10.sup.4) and equivalent isotropic displacement parameters
(.ANG..sup.2.times.10) (U(eq) equals a third of the value of the
orthogonal tensor Uij) are the following:
TABLE-US-00030 x Y Z U(eq) DMSO S(1S) -sof 82% 3004(1) -4776(1)
3282(1) 53(1) C(1S) -sof 82% 1525(19) -5222(5) 3781(17) 111(5)
C(2S) -sof 82% 3218(15) -4964(4) 1289(10) 90(3) S(1B) -sof 18%
1716(9) -4777(3) 2442(10) 89(3) C(1S) -sof 18% 1470(70) -5220(20)
4050(50) 64(14) C(2S) -sof 18% 3630(80) -4960(20) 1660(80) 150(30)
O(1S) -sof 100% 2086(3) -4288(1) 3208(3) 71(1) compound 1 S(1)
3171(1) -3991(1) -2614(1) 50(1) O(1) 3373(2) -2953(1) 2905(2) 45(1)
O(2) 1598(3) -3716(1) -1780(3) 56(1) O(3) 4389(3) -2669(1) 5103(2)
61(1) O(4) 2553(4) -4480(1) -2855(3) 76(1) O(5) 4621(3) -3906(1)
-1670(3) 74(1) N(1) 3426(4) -3741(1) -4247(3) 55(1) C(1) 1942(3)
-3277(1) -938(3) 45(1) C(2) 2474(4) -3321(1) 585(3) 42(1) C(3)
2806(3) -2890(1) 1397(3) 39(1) C(4) 2600(4) -2416(1) 761(3) 39(1)
C(5) 1978(4) -2393(1) -768(4) 50(1) C(6) 1654(4) -2819(1) -1618(4)
53(1) C(7) 3867(4) -2561(1) 3808(3) 43(1) C(8) 3741(3) -2061(1)
3159(3) 41(1) C(9) 3098(3) -1989(1) 1720(3) 41(1) C(10) 2897(4)
-1464(1) 1080(4) 54(1) C(11) 1668(4) -1148(1) 2029(5) 62(1) C(12)
2392(5) -921(1) 3500(5) 74(1) C(13) 2971(5) -1291(1) 4739(5) 72(1)
C(14) 4365(4) -1646(1) 4198(4) 54(1)
[0421] The coordinates of the hydrogen atoms (.times.10.sup.4) and
equivalent isotropic displacement parameters
(.ANG..sup.2.times.10.sup.3) (U(eq) equals a third of the value of
the orthogonal tensor Uij) are the following:
TABLE-US-00031 x Y Z U(eq) DMSO H(1S1) -sof 82% 1272 -5197 4877 166
H(1S2) -sof 82% 1975 -5547 3560 166 H(1S3) -sof 82% 505 -5171 3186
166 H(2S1) -sof 82% 2119 -4966 799 135 H(2S2) -sof 82% 3699 -5292
1245 135 H(2S3) -sof 82% 3949 -4734 751 135 H(1S4) -sof 18% 2436
-5201 4734 96 H(1S5) -sof 18% 1380 -5553 3640 96 H(1S6) -sof 18%
456 -5143 4632 96 H(2S4) -sof 18% 4360 -5076 2485 224 H(2S5) -sof
18% 4157 -4679 1154 224 H(2S6) -sof 18% 3449 -5220 918 224 compound
1 H(1N) 3930(40) -3453(9) -4340(50) 80(12) H(2N) 2890(40) -3888(11)
-5020(30) 64(11) H(2) 2605 -3631 1051 51 H(5) 1778 -2083 -1222 60
H(6) 1247 -2797 -2636 63 H(10A) 2494 -1482 10 65 H(10B) 4000 -1302
1068 65 H(11A) 1251 -881 1368 75 H(11B) 701 -1353 2313 75 H(12A)
1537 -706 3958 89 H(12B) 3353 -714 3215 89 H(13A) 1998 -1486 5073
87 H(13B) 3380 -1107 5640 87 H(14A) 5219 -1456 3636 64 H(14B) 4908
-1790 5110 64
[0422] The interplanar spacings of the DMSO solvate form 1 are the
following:
TABLE-US-00032 H K L 2Theta/deg d/.ANG. 1/rel, |F(hkl)| 0 2 0 6.58
13.42 26.46 51.61 0 1 1 10.85 8.15 19.64 51.99 1 1 0 11.72 7.55
5.73 30.36 1 2 0 13.04 6.78 50.44 100.35 0 3 1 14.32 6.18 35.57
92.69 1 1 1 15.65 5.66 11.88 41.47 1 2 1 16.67 5.32 6.67 33.15 1 4
0 17.36 5.10 4.75 41.24 1 3 1 18.24 4.86 100 140.76 0 5 1 19.51
4.55 3.97 42.54 1 5 0 20.02 4.43 4.96 48.79 0 0 2 20.76 4.28 19.58
142.36 0 2 2 21.80 4.07 15.41 93.94 1 5 1 22.58 3.94 58.83 134.63 2
0 0 22.59 3.93 59.76 271.6 2 1 0 22.84 3.89 14.54 95.81 1 6 0 22.86
3.89 5.27 57.75 1 1 2 23.90 3.72 4.68 40.32 1 2 2 24.59 3.62 15.88
76.48 2 0 1 24.90 3.57 12 95.3 2 1 1 25.12 3.54 17.07 81.13 1 6 1
25.14 3.54 4.28 40.67 0 7 1 25.45 3.50 10.41 90.79 2 2 1 25.78 3.45
31.33 112.94 0 8 0 26.56 3.35 6.34 104.82 2 3 1 26.85 3.32 21.73
98.17 1 4 2 27.19 3.28 8.87 63.57 2 4 1 28.28 3.15 16.18 89.51 0 6
2 28.87 3.09 2.69 52.79 1 5 2 28.99 3.08 2.13 33.37
[0423] The X-ray powder diffraction diagram of the DMSO solvate of
form 1 of compound 1 exhibits the following characteristic peaks
expressed as an angle (.degree.2 theta) to approximately
.+-.0.1.degree.2 theta: 6.6; 10.9; 13.1; 14.3; 15.7; 16.7; 17.4;
18.3; 19.6; 20.8; 21.9; 22.6; 23.0; 24.7; 24.9; 25.2; 25.5; 25.8;
26.6; 26.9; 27.2; 28.3 (FIGS. 1 and 2).
2.2.3 DMSO Solvate of Form 3 of Compound 1
[0424] It was possible to isolate single crystals by slow
evaporation of a saturated solution of DMSO at ambient temperature.
These single crystals made it possible to resolve the complete
structure of the DMSO solvate of form 3 of compound 1 by X-ray
diffraction.
[0425] Single crystal X-ray diffraction: The crystalline structure
of the DMSO solvate of form 3 of compound 1 was resolved and
exhibits the following cell parameters:
TABLE-US-00033 Cell structure Monoclinic Space group P2.sub.1/c
Cell parameter a 13.842(1).ANG. Cell parameter b 7.243(1) .ANG.
Cell parameter c 18.778(1).ANG. Cell parameter .beta.
104.950(2).degree. Cell volume 1818.8(3).ANG..sup.3 Z, Z' 4, 1
Calculated density 1.415 g cm.sup.-3
[0426] The coordinates of the hydrogen atoms (.times.10.sup.4) and
equivalent isotropic displacement parameters
(.ANG..sup.2.times.10.sup.3) (U(eq) equals a third of the value of
the orthogonal tensor Uij) are the following:
TABLE-US-00034 X Y Z U(eq) DMSO S(1S) 5679(1) -678(1) 1794(1) 60(1)
O(1S) 5140(1) -2300(3) 1995(1) 76(1) C(2S) 4755(3) 819(4) 1282(2)
82(1) C(1S) 6168(2) -1393(5) 1053(2) 88(1) compound 1 S(1) 6816(1)
4107(1) -341(1) 44(1) N(1) 6172(2) 4790(3) -1114(1) 56(1) 0(1)
10785(1) 2986(2) 1043(1) 41(1) 0(2) 7556(1) 2659(2) -587(1) 44(1)
0(3) 12316(1) 3301(2) 1722(1) 62(1) O(4) 7413(1) 5558(2) 47(1)
68(1) 0(5) 6214(1) 3068(3) 19(1) 63(1) C(1) 8322(1) 1848(3) -41(1)
35(1) C(2) 9174(1) 2840(2) 267(1) 37(1) C(3) 9947(1) 1942(2) 760(1)
33(1) C(4) 9902(1) 94(2) 954(1) 32(1) C(5) 9009(1) -851(2) 624(1)
36(1) C(6) 8229(1) 6(3) 132(1) 38(1) C(7) 11620(1) 2256(3) 1521(1)
40(1) C(8) 11595(1) 332(3) 1739(1) 36(1) C(9) 10769(1) -716(2)
1466(1) 33(1) C(10) 10762(2) -2712(3) 1689(1) 44(1) C(11) 10836(2)
-2998(3) 2510(1) 55(1) C(12) 11875(2) -2835(4) 3005(1) 62(1) C(13)
12374(2) -977(4) 3018(1) 58(1) C(14) 12530(2) -382(3) 2271(1)
47(1)
[0427] The coordinates of the hydrogen atoms (.times.10.sup.4) and
equivalent isotropic displacement parameters
(.ANG..sup.2.times.10.sup.3) (U(eq) equals a third of the value of
the orthogonal tensor Uij) are the following:
TABLE-US-00035 X y Z U(eq) DMSO H(2S1) 4344 167 869 123 H(2S2) 5069
1847 1109 123 H(2S3) 4348 1260 1590 123 H(1S1) 6696 -2271 1229 132
H(1S2) 6427 -341 852 132 H(1S3) 5647 -1955 677 132 compound 1 HN1
5730(20) 3950(40) -1360(15) 67(8) HN2 6490(20) 5300(40) -1342(16)
64(9) H(2) 9230 4075 148 45 H(5) 8946 -2085 741 43 H(6) 7646 -641
-81 45 H(10A) 11319 -3338 1568 53 H(10B) 10151 -3281 1403 53 H(11A)
10412 -2096 2663 66 H(11B) 10576 -4213 2575 66 H(12A) 12292 -3756
2855 74 H(12B) 11851 -3134 3503 74 H(13A) 13019 -1014 3376 70
H(13B) 11970 -53 3179 70 H(14A) 13037 574 2353 56 H(14B) 12779
-1429 2049 56
[0428] The interplanar spacings of the DMSO solvate form 3 are the
following:
TABLE-US-00036 h k l 20/.degree. d/.ANG. l/rel. |F(hkl)| 1 0 0 6.60
13.37 17.46 34.28 0 0 2 9.74 9.07 17.01 50.02 -1 0 2 10.27 8.61
60.85 99.75 1 0 2 13.12 6.74 8.70 48.35 0 1 1 13.15 6.73 2.09 16.81
1 1 0 13.89 6.37 32.93 70.48 -1 1 1 14.15 6.25 9.87 39.31 1 1 1
15.29 5.79 18.39 58.07 -1 1 2 15.98 5.54 70.84 119.22 -2 1 1 17.77
4.99 100.00 157.96 1 1 2 17.96 4.93 2.26 23.99 2 1 0 18.04 4.91
3.73 31.00 2 0 2 18.39 4.82 22.48 109.68 -2 1 2 18.83 4.71 25.27
84.24 0 1 3 19.10 4.64 44.16 113.07 2 1 1 19.58 4.53 3.05 30.49 -3
0 2 19.78 4.49 13.70 92.30 -2 0 4 20.62 4.30 95.08 253.85 1 1 3
21.45 4.14 51.77 138.03 2 1 2 22.13 4.01 4.74 43.13 -1 1 4 22.61
3.93 24.41 100.12 -3 1 1 22.84 3.89 64.70 164.68 -3 1 2 23.31 3.81
2.35 32.07 -2 1 4 24.03 3.70 60.09 167.40 3 0 2 24.40 3.65 14.20
116.93 0 2 1 25.06 3.55 4.08 45.58 2 1 3 25.41 3.50 4.75 49.91 1 1
4 25.45 3.50 16.21 92.36 1 2 0 25.46 3.50 9.39 70.33 1 2 1 26.27
3.39 10.61 77.23 -1 1 5 26.72 3.33 4.25 49.77 -3 1 4 27.09 3.29
7.04 65.01 -2 2 1 27.82 3.20 11.13 84.10 -1 0 6 28.51 3.13 2.66
59.69 -2 2 2 28.52 3.13 3.31 47.10 -1 2 3 28.60 3.12 5.99 63.51 2 2
1 29.04 3.07 6.40 66.75 -2 0 6 29.08 3.07 12.26 130.81 2 1 4 29.20
3.06 21.47 122.94 4 1 0 29.40 3.04 5.99 65.40 0 0 6 29.52 3.02 8.88
113.14 -4 1 3 29.65 3.01 2.46 42.34
[0429] The X-ray powder diffraction diagram of the DMSO solvate of
form 3 of compound 1 exhibits the following characteristic peaks
expressed as an angle (.degree.2 theta) to approximately
.+-.0.1.degree.2 theta: (FIGS. 3 and 4). 9.7; 13.9; 16.0; 17.8;
19.1; 22.1.
2.2.4 Single Crystal X-Ray Diffraction of the Form III
[0430] By slow evaporation at ambient temperature of a saturated
solution of compound 1 in an acetone/n-heptane mixture, 50% v/v, it
was possible to isolate single crystals which have made it possible
to resolve the complete structure of form III of compound 1 by
X-ray diffraction.
[0431] Single crystal X-ray diffraction: The crystalline structure
of compound 1 form III was resolved and exhibits the following cell
parameters
TABLE-US-00037 Cell structure Monoclinic Space group Cc (no. 9)
Cell parameter a 11.327(1).ANG. Cell parameter b 20.489(2).ANG.
Cell parameter c 7.870(1).ANG. Cell parameter .beta.
131.55(1).degree. Cell volume 1366.9(2).ANG..sup.3 Number of
molecules per cell: Z 4 Calculated density 1.53 g cm.sup.-3
[0432] The reduced coordinates (.times.10.sup.4) and the equivalent
isotropic motion parameters (.ANG..sup.2.times.10.sup.3) of
compound 1 form III are the following:
TABLE-US-00038 X y z U(eq) S(1) 14534(1) -1891(1) 11571(1) 41(1)
O(1) 9079(2) -569(1) 5756(3) 39(1) O(2) 13824(2) -1450(1) 12407(3)
48(1) O(3) 6862(3) -250(1) 2510(3) 57(1) O(4) 13672(3) -1754(1)
9246(3) 62(1) O(5) 14551(3) -2522(1) 12277(5) 73(1) N(1) 16289(3)
-1661(2) 12982(5) 55(1) C(1) 12910(3) -904(1) 11114(4) 36(1) C(2)
11424(3) -995(1) 9041(4) 37(1) C(3) 10541(3) -449(1) 7814(4) 31(1)
C(4) 11093(3) 187(1) 8587(4) 32(1) C(5) 12593(3) 249(1) 10745(4)
40(1) C(6) 13504(3) -284(1) 11996(4) 42(1) C(7) 8111(3) -78(1)
4284(4) 39(1) C(8) 8699(3) 589(1) 4976(4) 37(1) C(9) 10098(3)
718(1) 7049(4) 34(1) C(10) 10637(3) 1421(1) 7790(5) 43(1) C(11)
9541(4) 1809(1) 7904(5) 46(1) C(12) 8072(4) 2076(1) 5641(5) 56(1)
C(13) 6921(4) 1568(2) 3890(5) 55(1) C(14) 7630(4) 1111(1) 3226(5)
48(1)
[0433] The coordinates of the hydrogen atoms (.times.10.sup.4) and
equivalent isotropic displacement parameters
(.ANG..sup.2.times.10.sup.3) (U(eq) equals a third of the value of
the orthogonal tensor Uij) are the following:
TABLE-US-00039 X y Z U(eq) HN1 16970(60) -1842(18) 14350(80) 78(13)
HN2 16430(50) -1342(19) 12870(60) 56(12) H(2) 11025 -1412 8483 44
H(5) 12982 664 11349 48 H(6) 14506 -231 13414 50 H(10A) 10682 1631
6729 52 H(10B) 11693 1424 9273 52 H(11A) 9218 1531 8530 55 H(11B)
10129 2172 8944 55 H(12A) 7523 2355 5918 67 H(12B) 8398 2347 5004
67 H(13A) 6016 1789 2538 66 H(13B) 6550 1309 4487 66 H(14A) 6778
901 1798 57 H(14B) 8227 1369 2988 57
[0434] The interplanar spacings are the following:
TABLE-US-00040 H K L 2Theta/deg d/.ANG. l/rel, |F(hkl)| 0 2 0 8.63
10.24 16.76 35.88 1 1 0 11.29 7.83 37.69 49.89 -1 1 1 12.05 7.34
59.53 66.98 1 3 0 16.66 5.32 57.37 91.43 -1 3 1 17.18 5.16 11.98
43.15 0 2 1 17.35 5.11 92.5 121.09 -2 2 1 17.92 4.95 73.94 111.89 2
0 0 20.94 4.24 13.54 79.54 -2 0 2 22.60 3.93 89.64 221.49 2 2 0
22.69 3.92 23.89 81.17 0 4 1 22.99 3.87 27.76 88.74 -2 4 1 23.43
3.79 43.01 112.65 1 1 1 23.81 3.73 20.41 78.91 1 5 0 24.10 3.69
13.86 65.87 -2 2 2 24.23 3.67 3.27 32.19 -3 1 1 24.64 3.61 12.1 63
-1 1 2 24.92 3.57 10.88 60.46 -3 1 2 25.73 3.46 100 189.5 0 6 0
26.07 3.41 11.99 94.11 2 4 0 27.29 3.27 2.04 28.78 -3 3 1 27.59
3.23 12.23 71.34 -3 3 2 28.57 3.12 46.83 144.9
10.2.5 Examples 9a-9g
Compound 1 of Form III
[0435] Analyses by X-ray powder diffraction, by single crystal
X-ray diffraction, by DSC, by IR and by NMR of the solid show that
Example 9a is identical to Example 9b, to Example 9c, to Example
9d, to Example 9e, to Example 9f and to Example 9g.
10.2.5.1 X-Ray Powder Diffraction
[0436] The X-ray powder diffraction diagram of form III of compound
1 exhibits the following characteristic peaks expressed as an angle
(.degree.2 theta) to approximately .+-.0.1.degree.2 theta: 8.6;
11.3; 12.0; 16.7; 17.4; 17.9; 20.9; 22.6; 23.0; 23.4; 23.8; 25.7;
28.6 (FIGS. 5 and 6).
10.2.5.2 DSC
[0437] In DSC, the thermogram of form III of compound 1 comprises
the melting peak of form III (onset 180.degree..+-.2.degree. C.)
(FIG. 7).
10.2.5.3 IR
[0438] The IR spectrum of form III of compound 1 exhibits the
characteristic peaks expressed in cm.sup.-1 to approximately .+-.5
cm.sup.-1: 3406; 3217; 3082; 2924; 1678; 1385; 1269; 1134; 1011;
934; 845; 601; 563; 536 (FIG. 8).
10.2.5.4 NMR of the Solid
[0439] The spectrum of form III obtained by NMR of the solid
exhibits the following characteristic peaks expressed in ppm to
approximately .+-.0.2 ppm: 162.9; 156.4; 151.3; 126.1; 124.7;
118.8; 117.1; 112.9; 35; 20 (FIG. 9).
10.2.6 Example 9h
1,4-dioxane Hemisolvate of Compound 1
10.2.6.1 Single Crystal X-Ray Diffraction
[0440] By slow evaporation at ambient temperature of a saturated
solution of compound 1 in 1,4-dioxane, it was possible to isolate
single crystals which made it possible to resolve the complete
structure of 1,4-dioxane hemisolvate of compound 1 by X-ray
diffraction.
[0441] The crystalline structure of 1,4-dioxane hemisolvate of
compound 1 exhibits the following cell parameters:
TABLE-US-00041 Cell structure Triclinic Space group P-1 (no. 2)
Cell parameter a 9.016(4).ANG. Cell parameter b 9.765(5).ANG. Cell
parameter c 10.068(5).ANG. Cell parameter .alpha. 67.731(9).degree.
Cell parameter .beta. 78.939(8).degree. Cell parameter .gamma.
86.504(9).degree. Cell volume 805.0(7).ANG..sup.3 Z, Z' 2.1
Calculated density 1.46 g cm.sup.-3
[0442] The reduced coordinates (.times.10.sup.4) and the equivalent
isotropic motion parameters (.ANG..sup.2.times.10.sup.3) of
1,4-dioxane hemisolvate of compound 1 are the following:
TABLE-US-00042 x Y z U(eq) compound 1 S 475(1) 7183(1) 1077(1)
41(1) N(1) 763(4) 5616(4) 989(3) 47(1) O(1) -1281(2) 11547(2)
2861(2) 43(1) O(2) 133(2) 6737(2) 2827(2) 47(1) O(3) -1860(3)
13790(3) 2773(3) 54(1) O(4) -870(2) 7799(3) 566(2) 57(1) O(5)
1837(3) 8014(3) 527(3) 63(1) C(1) -523(3) 7714(4) 3486(3) 37(1)
C(2) -582(3) 9222(4) 2787(3) 38(1) C(3) -1256(3) 10032(3) 3607(3)
34(1) C(4) -1856(3) 9411(3) 5087(3) 34(1) C(5) -1743(3) 7874(4)
5739(3) 39(1) C(6) -1092(3) 7036(4) 4965(3) 41(1) C(7) -1928(3)
12484(4) 3529(4) 41(1) C(8) -2612(3) 11855(4) 5064(3) 38(1) C(9)
-2564(3) 10376(4) 5824(3) 35(1) C(10) -3269(4) 9731(4) 7424(3)
45(1) C(11) -4991(4) 9893(4) 7686(4) 56(1) C(12) -5519(4) 11392(4)
7687(4) 59(1) C(13) -5070(4) 12689(4) 6262(4) 57(1) C(14) -3361(4)
12922(4) 5733(4) 50(1) 1,4-dioxane O(1B) 3697(2) 4239(3) 922(2)
52(1) C(2B) -4194(4) 15845(4) 477(4) 51(1) C(3B) -5035(4) 14451(4)
1488(4) 59(1)
[0443] The hydrogen coordinates (.times.10.sup.4) and the
equivalent isotropic displacement parameters
(.ANG..sup.2.times.10.sup.3) of 1,4-dioxane hemisolvate of compound
1 are the following:
TABLE-US-00043 x Y z U(eq) compound 1 H(1N) 1690(40) 5240(40)
1000(30) 47(11) H(2N) 60(40) 5060(40) 1390(40) 54(12) H(2) -183
9683 1798 46 H(5) -2123 7407 6730 46 H(6) -1030 6015 5430 49 H(10A)
-2839 10225 7939 55 H(10B) -3023 8691 7822 55 H(11A) -5381 9711
6934 67 H(11B) -5416 9141 8618 67 H(12A) -5123 11569 8439 71 H(12B)
-6612 11361 7953 71 H(13A) -5500 13581 6377 69 H(13B) -5506 12541
5516 69 H(14A) -3170 13922 5018 60 H(14B) -2896 12835 6554 60
1,4-dioxane H(2B1) -4849 16689 390 61 H(2B2) -3331 15974 865 61
H(3B1) -4365 13614 1606 70 H(3B2) -5381 14507 2440 70
[0444] The interplanar spacings of 1,4-dioxane hemisolvate are the
following:
TABLE-US-00044 H K L 2Theta/deg d/.ANG. 1/rel, |F(hkl)| 0 1 0 9.78
9.04 8.88 16.31 1 0 0 9.99 8.85 96.1 54.8 0 1 1 10.87 8.14 11.91 21
1 1 1 13.62 6.50 5.21 17.46 1 -1 0 13.91 6.36 5 17.48 1 1 0 14.09
6.28 20.11 35.51 -1 1 1 15.86 5.58 5.85 21.61 0 -1 1 16.14 5.49
97.94 90.03 1 -1 1 17.98 4.93 2.67 16.6 0 2 1 18.34 4.83 2.6 16.71
1 1 2 18.99 4.67 57.23 81.32 0 2 0 19.63 4.52 12.83 39.85 -1 -1 1
20.00 4.44 3.87 22.31 2 0 0 20.06 4.42 13.37 41.58 1 2 1 20.18 4.40
28.43 61.01 2 0 1 20.62 4.30 57.35 88.64 2 1 1 21.35 4.16 100
121.33 -1 2 1 21.65 4.10 22.75 58.7 0 2 2 21.83 4.07 4.02 24.89 1
-2 0 21.96 4.05 19.56 55.24 1 2 0 22.19 4.00 23.96 61.82 2 -1 0
22.24 3.99 15.45 49.77 -1 1 2 22.34 3.98 28.24 67.59 -1 0 2 23.43
3.79 4.95 29.72 -2 0 1 23.86 3.73 2.29 20.61 2 -1 1 24.30 3.66 29.1
74.91 2 1 2 24.44 3.64 28.94 75.16 0 -1 2 24.85 3.58 13.62 52.47 2
0 2 25.29 3.52 29.21 78.26 -1 2 2 25.42 3.50 8.32 42 1 -2 1 26.21
3.40 3.8 29.32 1 1 3 27.01 3.30 13.64 57.32 0 1 3 27.07 3.29 13.27
56.7 -2 -1 1 27.32 3.26 3.16 27.92 0 3 1 27.46 3.25 14.04 59.19 -1
-1 2 28.22 3.16 7.33 44.04 2 2 0 28.40 3.14 3.67 31.36 0 2 3 28.47
3.13 3.36 30.09 0 3 2 28.70 3.11 6.78 43.12 1 0 3 29.12 3.06 2.24
25.18 1 3 2 29.37 3.04 2.07 24.42
10.2.6.2 X-Ray Powder Diffraction
[0445] The X-ray powder diffraction diagram of 1,4-dioxane
hemisolvate of compound 1 exhibits the following characteristic
peaks expressed as an angle (.degree.2 theta) to approximately
.+-.0.1.degree.2 theta: 9.8; 10.0; 10.8; 13.6; 13.9; 14.1; 15.9;
16.1; 18.0; 18.3; 19.0; 19.6; 20.0; 20.1; 20.2; 20.6; 21.4; 21.7;
21.8; 22.0; 22.2; 22.3; 23.4; 23.9; 24.3; 24.4; 24.9; 25.3; 25.4;
26.2; 27.0; 27.1; 27.3; 27.5; 28.2; 28.4; 28.5; 28.7; 29.1; 29.4
(FIGS. 10 and 11).
10.2.6.2 TG-DSC
[0446] Using TG-DSC, the thermogram of 1,4-dioxane hemisolvate of
compound 1 shows that the solvate releases 1,4-dioxane starting
from 75.degree. C. in order to produce form II of compound 1 (FIG.
12).
10.2.7 Example 9i
Compound 1 of Form II
10.2.7.1 X-Ray Powder Diffraction
[0447] The X-ray powder diffraction diagram of form II of compound
1 exhibits the following characteristic peaks expressed as an angle
(.degree.2 theta) to approximately .+-.0.1.degree.2 theta: 9.4;
10.7; 12.2; 12.8; 14.3; 15.1; 15.9; 16.9; 18.2; 18.9; 19.4; 19.7;
20.4; 21.1; 21.4; 21.8; 22.0; 22.7; 23.0; 23.2; 23.7; 23.9; 24.4;
24.8; 25.5; 26.8; 27.1; 27.4; 28.1; 28.3; 29.5 (FIG. 13).
10.2.7.2 DSC
[0448] Using DSC, the thermogram of form II of compound 1 comprises
an endothermic phenomenon which corresponds to the metastable
melting of form II at 165.degree. C..+-.5.degree. C., then
recrystallization to other forms, followed by other melting
phenomena (FIG. 14).
10.2.7.3 IR
[0449] The IR spectrum of form II of compound 1 exhibits the
characteristic peaks expressed in cm.sup.-1 to approximately .+-.5
cm.sup.-1: 3356; 3321; 3186; 3078; 2932; 2851; 1693; 1609; 1504;
1462; 1377; 1265; 1192; 1123; 937; 872; 837; 787; 594 (FIG.
15).
10.2.7.4 NMR of the Solid
[0450] The spectrum of form II obtained by NMR of the solid
exhibits the following characteristic peaks expressed in ppm to
approximately .+-.0.2 ppm: 163.0; 154.5; 153.5; 151.6; 128.6;
118.5; 111.4; 108.2; 35; 25 (FIG. 16).
11. Physico-Chemical and Biological Properties
11.1 Conversion Experiments
[0451] The applicant has carried out conversion experiments between
the different polymorphic forms of compound 1 which have shown that
form III is the form which is stable at a high temperature
(T>145.degree. C.). This significant property makes it possible,
by heating under vacuum, to eliminate traces of solvent
(Polymorphism in the Pharmaceutical Industry, Wiley 2006, Ed
Hilfiker; Wiley, ISBN: 978-3-527-31146-0). By returning to ambient
temperature, form III of compound 1 remains unchanged, which also
constitutes a prime advantage in the pharmaceutical industry
11.2 Chemical Stability
[0452] A stability study was carried out at 150.degree. C. between
compound 1 of form III and the compound 1 described in patent EP
880514. This chemical stability of compound 1 is studied using
HPLC
[0453] The operating conditions of the HPLC method are the
following: [0454] column: Interchim UP3HDO-15XS, 150.times.4.6
mm,
TABLE-US-00045 [0454] eluent A: water 2500 trifluoroacetic acid 0.5
eluent B: acetonitrile
[0455] gradient:
TABLE-US-00046 [0455] Time (min) % A % B 0 80 20 22 5 95 24.2 80
20
[0456] detection: 205 nm, [0457] injection: 20 microlitres, [0458]
temperature: 40.degree. C., [0459] solution injected: 0.5
mgmL.sup.-1 (acetonitrile)
TABLE-US-00047 [0459] HPLC Purity Compound 1 Compound 1 Scores
patent EP 880514 of form III T0 99.6% 99.4% T2 hours at 150.degree.
C. 7.3% 41.2%
* * * * *