EP2396311A2

EP2396311A2 - Solid pharmaceutical composition comprising the 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta(c)chromen-3-yl sulfamate and polymorphs thereof

Info

Publication number: EP2396311A2
Application number: EP10707096A
Authority: EP
Inventors: Nathalie Mondoly; Bertrand Poirot; Anne Brochard; Joël Richard; Delphine Delahaye; Christian Diolez; Alain Rolland; Francis Diancourt; Gérard Coquerel; Damien Martins; Julie Linol; Ophélie HOUSSIN; Marie-Noêlle PETIT; Barry Victor Lloyd Potter; Lok Wai Lawrence Woo
Original assignee: Ipsen Pharma SAS
Current assignee: Ipsen Pharma SAS
Priority date: 2009-02-13
Filing date: 2010-02-12
Publication date: 2011-12-21
Also published as: CA2751393A1; CN102317276A; WO2010092260A2; JP2012517988A; MX2011008239A; WO2010092260A8; BRPI1008422A2; WO2010092260A3; RU2011137516A; KR20110115607A; AU2010212753A1

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.

Description

Pharmaceutical compositions 11-hexahvdrocyclohepta

Mchromen-3-vl sulfamate

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 sulfamate. 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, the compound 1 targeting the steroid sulphatase enzyme.

A composition according to the invention, containing as active principle the compound 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate (also called subsequently compound 1). advantage of being a stable oral pharmaceutical composition and offering appropriate bioavailability.

Compound 1, of structure:

is described in EP 880514. Nowadays, increasing attention is paid to this compound for its sulfatase inhibitory activity and the therapeutic applications that it involves, as described by L.W. Woo, et al. in Chemistry & Biology, 2000, 7, 773-91. Inhibition of steroid sulphatase (STS), the enzyme responsible for the hydrolysis of steroid sulphates, is, for example, a promising new treatment in post-menopausal patients with hormone-dependent breast cancer (Clin. Cancer Res 2006; 12 (5).

In general, pharmaceutical compositions such as tablets can be made by three methods: wet granulation, dry granulation and direct compression.

Compound 1 belongs to class 2 of the Biopharmaceutical Classification System (BCS) proposed by G. Amidon (see GL Amidon et al., "A guideline for a biopharmaceutical drug classification: the in vitro correlation 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 administered dosage form.

Processes and formulations known from the prior art using aqueous phases, such as self-emulsifying drug delivery systems, conventionally used to increase the apparent solubility of class 2 compounds, are not suitable because the excipients and the aqueous phases used are not compatible with compound 1, and lead to chemical degradation during the production step.

Due to intrinsic stability problems and low solubility of the compound 1, it was difficult to obtain a formulation which allows the production of tablets which are sufficiently stable over time and which comprise a sufficient concentration of active principle. In addition, the low compressibility composition caused fragmentation during dry compression as well as a slow dissolution profile.

Because of the instability of compound 1 in the presence of water that is readily hydrolyzable, it was difficult to envision a wet granulation process.

Unexpectedly, formulations for obtaining dry oral forms of compound 1 by a wet granulation method were obtained.

In the case of wet granulation, the components are mixed and granulated in the wet phase by means of a binder. The binder can be either dissolved in the wet phase or incorporated into the powder mixture to be granulated. The wet granules are then sieved, dried and optionally crushed before compression to form the tablets.

Unexpectedly, a novel solid pharmaceutical composition for oral administration of compound 1 has been found to solve the specific problems of this active ingredient and to obtain it by a wet granulation method.

This oral composition, in tablet or capsule form, is stable with rapid dissolution of the solid form thus producing immediate release with effective bioavailability.

The present invention therefore relates to a solid pharmaceutical composition containing as active ingredient 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate and at least one pharmaceutically acceptable excipient. The subject of the present invention is also a solid pharmaceutical composition containing as active principle 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate and at least one pharmaceutically acceptable excipient, for oral administration and preferably for oral immediate release administration.

The present invention also relates to a solid pharmaceutical composition for oral administration comprising compound 1 as active ingredient and at least one disintegrating agent and one or more protective agents against moisture. Such agents thus protect the active principle from hydrolysis and thus prevent its degradation. Preferably, compound 1 is micronized.

It has been observed that this degradation occurs mainly during the manufacture of the pharmaceutical composition and in particular during the wet granulation step. Unexpectedly, it has been demonstrated a protective effect of the active ingredient provided by the addition of excipients, used for their binder and diluent properties in the technical field considered.

The present invention also relates to the process for the manufacture of pharmaceutical compositions as described below. It is thus possible to carry out the process according to the invention using adjuvants and excipients of the conventional type for the production of tablets using a wet granulation.

By "immediate oral administration" or "immediate release oral form" or "immediate release composition" is meant according to the invention an administration or oral composition allowing an in vitro dissolution of at least 80% by weight of the active ingredient in 45 minutes, preferably 30 minutes in accordance with the appropriate in vitro dissolution test, developed for compound 1. This test is carried out with a dissolution apparatus to pale at 37 ° C with stirring at 100 rpm, in buffered solution of hydrochloric acid at pH 1, 2 according to the standards of the US Pharmacopoeia, and comprising 0.1% of a surfactant, cetyl trimethyl ammonium bromide, which makes it possible to obtain sufficient solubility of the active principle in the test medium. The assay is performed by ultraviolet (UV) / visible absorption spectrophotometry at the wavelength of 311 nm.

By the term "slip agent" or "flow agents" used according to the invention is also meant adjuvants and excipients sometimes called lubricants and agents improving the fluidity and flow of granules. By the term "centesimal formulation" is meant according to the invention a proportion of active ingredient or excipient given in% by weight, relative to the total weight of the composition.

By the term "binding agent" or binder is meant according to the invention adjuvants or excipients used to maintain the structure and cohesion of the dosage form. They have the property of allowing the granular assembly of the ingredients during the granulation step and to ensure the cohesion of the dosage form after compression.

By the term "disintegrant" is meant according to the invention excipients or adjuvants which can be added to the formulations to facilitate the disintegration of the tablets when they are in a liquid environment, such as water or gastric juices.

Description of the figures:

Fig. 1: shows the comparative dissolution curves of the composition of compound I 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 I with a different micronization.

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 disintegrants.

Figures 1 and 2 show the effect of the excipients as well as the in vitro behavior of the solid composition.

The present invention shows many advantages, in particular the combination:

• increased stability and

• increased bioavailability linked to immediate dissolution (at least 80% in

30 minutes) of the pharmaceutical form.

Preferably, the method used for the preparation of the tablet according to the invention passes through a wet granulation step preceding the tablet forming step.

Indeed, it has been shown that unexpectedly, despite the low stability of the compound 1 in aqueous phase, the tablet can be prepared by a process comprising a wet granulation step. Obtaining the tablet according to this method stabilization of the compound 1 in the aqueous phase in the presence of well-chosen excipients.

According to a first characteristic of the invention, compound 1 is obtained by a suitable treatment in order to obtain a particle size of between 0.1 and 20 μm. Preferably, the compound 1 has a particle size of between 1 and 15 μm, and more preferably between 2 and 10 μm. Even more preferably, compound 1 has a size of 5 μm ± 2 μm.

Pharmaceutically acceptable excipients suitable for the manufacture of the pharmaceutical compositions of the invention may be, for example, maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, croscarmellose sodium, partially crosslinked poly (N-vinyl-2-pyrrolidone) or crospovidone, polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (or copovidones) such as Kollidon copolymer 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 water, nes organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, with or without water. These excipients, added to the active ingredient, have the function of being:

diluents, such as, for example, mannitol, lactose or lactose monohydrate, starch, calcium carbonate, microcrystalline cellulose, or maltodextrin;

disintegrants, such as, for example, starch, croscarmellose sodium, sodium starch glycolate, or crospovidone;

binders, such as, for example, polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (or copovidones), carboxymethylcellulose, pregelatinized starch, or methylcellulose;

flow agents or slip agents, such as, for example, colloidal silica, or talc;

lubricants, such as, for example, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid or hydrogenated vegetable oil;

solubilizing agents, such as macrogol (polyethylene glycol), polyglycol, polyoxyethylene glycol, polydiol, pyrrolidone-2, or polyvinylpyrrolidone; surfactants (or surfactants) such as sodium lauryl sulphate.

The present invention also relates to a solid pharmaceutical composition for oral administration of compound 1 as active ingredient, characterized in that it comprises compound 1 and at least one disintegrating agent, one or more diluents and one or more binders. Preferably, the compound is micronized.

Preferably, the pharmaceutical composition according to the invention, in solid form for oral administration, is a capsule. Preferably, the pharmaceutical composition according to the invention, in solid form for oral administration, is a tablet.

In the compositions below, each type of excipient may be alone or in admixture. Thus "x% of a binder" means x% of a single binder or a mixture of binders.

The composition according to the invention may be formulated in a capsule according to a centesimal formulation containing: 1 to 30% of active ingredient, preferably 5 to 20%; 40 to 92% diluent, preferably 65 to 92%, most preferably 75 to 90%; 0 to 10% binder, preferably 0 to 8%; 0 to 30% disintegrant 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%.

Preferably, the pharmaceutical composition as defined above is a capsule; and more preferably a capsule of centesimal formulation comprising 5 to 30% of active principle; 40 to 92% diluent; 0 to 8% binder, preferably 0 to 5%; 0 to 30% disintegrant; 0 to 5% surfactant; 0 to 5% solubilizing agent; 0.1 to 3% flow agent; and 0.5 to 3% of lubricant.

The preferred pharmaceutically acceptable excipients for formulating these capsules are mannitol, lactose, corn starch, colloidal silica, magnesium stearate, and sodium lauryl sulphate, and more particularly mannitol, lactose, colloidal silica, and magnesium stearate.

The composition according to the invention may also be formulated in a preferably film-coated tablet or a centesimal formulation film containing: 1 to 30% by weight relative to the total weight of the active ingredient composition, preferably 5 to 20% by weight and very preferably preferably 8 to 20%; 40 to 92% of diluent, preferably 65 to 92% and most preferably 70 to 85%; 0.1 to 20% disintegrant, preferably 0.1 to 10% and most preferably 1 to 5%; 0.1 to 8% of binder, preferably 2 to 5%; 0.1 to 3% slip agent preferably 0.5 to 1.4%; 0.2 to 3% of lubricant, preferably 0.5 to 2.8%.

Preferred excipients 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.

Preferably also, the pharmaceutical composition as defined above is a tablet preferably filmed, centesimal formulation comprising 8 to 20% of active ingredient; 70 to 85% diluent; 1 to 5% disintegrant; 2-5% binder; 0.5 to 1.4% flow agent; and 0.5 to 2.8% of lubricant relative to the total weight of the tablet as well as about 4.5 to 5%, preferably 4.8% of coating solution based on the total weight of the coated tablet.

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.

Preferably, a pharmaceutical composition according to the present invention comprises a disintegrant selected from the following excipients: starch, croscarmellose sodium, sodium starch glycolate, or crospovidone.

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.

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.

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 rate of 4 to 6%. Very preferentially, a The pharmaceutical composition according to the present invention comprises microcrystalline cellulose (MCC). Very preferably, a pharmaceutical composition according to the present invention comprises copovidone. Very preferably also, a pharmaceutical composition according to the present invention comprises microcrystalline cellulose (MCC) and copovidone. Very preferably, a pharmaceutical composition according to the present invention comprises microcrystalline cellulose (MCC). Very preferably, a pharmaceutical composition according to the present invention comprises carboxymethylcellulose (CMC). Very preferably, a pharmaceutical composition according to the present invention comprises microcrystalline cellulose (MCC) and carboxymethylcellulose (CMC).

Also preferably, the flow agent selected is colloidal silica (or colloidal solution of silicon dioxide).

Also preferably, the lubricant selected is magnesium stearate. The disintegrant, which is added to the formulation of the tablets as an excipient, increases the rate of dissolution, and allows immediate dissolutions, even with high cohesive tablets. According to the literature (eg J. Balasubramaniam, T. Bee, Pharmaceutical Technology Europe, Vol 21, No 9, 2009, pp 44-49), the most effective disintegrators are crospovidone type A and B, followed by croscarmellose sodium.

Preferably, in the tablet formulations according to the present invention, the disintegrant used is sodium starch glycolate, and preferably at a level of 1 to 5% and very preferably of 3 to 4%.

Preferably, the pharmaceutical composition according to the present invention is a tablet containing from 8 to 20% of compound 1; from 20 to 40% lactose and from 25 to 50% microcrystalline cellulose used as diluents; from 2 to 8% of copovidone used as a binding agent; from 1 to 5% of sodium starch glycolate used as a disintegrating agent; 0.2 to 1.4% flow agent; and 0.5 to 2% of lubricant relative to the total weight of the tablet,

and, very preferably, 8 to 15% of the compound 1; from 30 to 40% lactose and from 40 to 50%, microcrystalline cellulose used as diluents; from 2 to 5% of copovidone used as a binding agent; from 3 to 4.5% of sodium starch glycolate used as a disintegrant; 0.2 to 1.4% flow agent; and 0.5 to 2% of lubricant relative to the total weight of the tablet.

Most preferably also, the pharmaceutical composition as described above is a tablet containing about 10% of compound 1; 36.5% lactose; 45% microcrystalline cellulose; 3% copovidone; 4% sodium starch glycolate; 0.5% colloidal silica; 1% magnesium stearate based on the total weight of the tablet. The term "about" means ± 0.5%.

According to a variant of the invention, the composition may comprise a coating or film coating.

Preferably, such a coating has no significant effect on the immediate release of the active principle, that is to say that the kinetics of in vivo release of the active principle is not modified.

Also preferably, the coating has the advantage of masking the taste of the active ingredient and allows secure handling for packaging the solid composition in tablet form.

The coating methods that can be used for the tablet described in the invention are well known to those skilled in the art.

When the tablet comprises a coating, the latter preferably comprises a polymer selected from the group consisting of polyethylene glycols, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellullose (hypromellose) but not limited thereto. Can be used in particular a film-coating mixture containing polyethylene glycol (macrogol) and rhydroxypropylméthylcellullose already formulated, for aqueous film coating of solid oral dosage forms such as that marketed under the name Opadry ^® II White (lactose monohydrate, hypromellose titanium dioxide (E171), triacetin) by Colorcon. Opadry ^® II White is water soluble, and allows immediate disintegration of the oral pharmaceutical composition in tablet form.

Preferably, the solid pharmaceutical composition according to the present invention is in tablet form. The invention also relates to instant dissolving tablets as well as coated tablets or films.

Pharmaceutical compositions are described by way of example and in no way limit the scope of the invention.

Thus, the subject of the invention is also a process for the preparation of the compound according to the invention as described above, starting from 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3 -yl sulfamate characterized in that it comprises a step of reducing the size of the particles. Preferably, the size of the particles is reduced by micronization, either in an aprotic solvent medium or by the dry route.

Preferably also, the particle size is reduced by wet grinding with an aprotic organic solvent.

The invention also relates to the process for producing the solid pharmaceutical compositions of the invention, characterized by the following steps:

• sieving of components;

• preparation of tablets without coating (wet granulation, mixing and compression);

• preparation of the coating solution.

Preferably, according to the process according to the invention, during the wet granulation step, the mass of water relative to the total mass of the active ingredient and the binder, diluent and disintegrator mixed beforehand, is between about 10 and 30%.

Preferably, according to the process according to the invention, after the wet granulation step, the granules are dried until a residual moisture content of less than 3% is obtained.

The composition during all stages of the manufacturing process is produced using conventional equipment and known to those skilled in the art.

A formulation according to the present invention may be prepared according to the following method: a first mixture is made consisting of the active principle which is first sieved together with certain excipients entering the composition comprising a binder, and one or more diluents as well as a disintegrator.

The sieving step is carried out using a sieve in a suitable device such as a manual screen.

The sieved materials are then introduced into a mixer-granulator and mixed for about 5 minutes. The mixing speed depends on the equipment chosen.

A mass of water for granulation is then prepared so that its proportion relative to the solid phase to be granulated is preferably between about 10 and 30%. It will be understood by solid phase to granulate the total mass of the active ingredient and excipients previously mixed, added the binder mass. The binder for granulation is added in powder form to the mixer or preferably dissolved in the body of water to form the granulation solution.

The mixture obtained at the beginning of the process is then wet granulated with the granulation solution, in a mixer-granulator preferably of the "high shear" or "high shear" type. The granulation time after addition of the solution to be granulated will be less than 10 minutes and preferably less than 5 minutes.

The granules resulting from this last step can then be dried in a conventional apparatus such as for example a fluidized air 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.

A second mixture is made, which consists of the previously obtained calibrated granules and a so-called external phase consisting of: a disintegrating portion, a flow agent that improves the fluidity of the powder, and finally a lubricant.

The excipients of the external phase are first screened in a suitable device such as a manual screen.

The granules, the disintegrant and the flow agent are then mixed and the lubricant is introduced.

For the formulation formulation in tablet form, the resulting final mixture can then be compressed by means of a press, rotary type for example.

The hardness for a 400 mg tablet can be between 6 and 12 kPascal (kPa). The hardness of a 100 mg tablet can be between 4 and 8 kPa.

The tablets can then be coated in a coating turbine by spraying a coating suspension which has been prepared beforehand, preferably by addition of 16% Opadry II ^® in purified water.

The temperature of the product during the filming will be between 35 and 55 ° C,

Preferably, the mass gain of the tablet after drying will be between 4 and 6% of the mass of the tablet before coating. The tablets can then be packaged and kept in blister or vial.

According to the invention the uncoated tablet preferably does not exceed a total weight of 800 mg, preferably 400 mg.

The invention finally relates to the use of a pharmaceutical composition according to the invention as described above for treating cancers, preferentially hormone-dependent cancers, and preferentially also, breast, prostate, endometrial cancers. or ovary.

The present application also relates to polymorphs of the compound 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate (or sulfamic 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 an active ingredient, and more particularly as an active ingredient for the treatment of certain cancers. The invention further relates to pharmaceutical compositions containing these polymorphic forms as an active ingredient

The form succinctly described by Woo and subsequently called variety I gives characteristic absorption bands in infrared. The Applicant has obtained single crystals of suitable size and quality for a complete characterization of its structure.

The crystals obtained in the prior art do not allow good bioavailability and their preparation is not transferable on an industrial scale.

Moreover, the applicant obtained crystals of compound 1 by an industrial process. Their observation under the microscope makes it possible to observe a gradual opacification of the crystal from about 140-145 ° C. The phenomenon is not reversible: the crystal does not return to its original appearance after slow or rapid cooling. In DSC, an endothermic phenomenon corresponding to a solid-solid transition is observed at 140 ° C. A second endothermic peak is observed at 170 ° C. corresponding to the fusion of the untransformed variety I. A third endothermic peak is observed at 180 ° C. This third peak corresponds to the fusion of another polymorphic form generated during the solid-solid transition. By X-ray powder diffraction carried out on the compound successively heated to 160 ° C. and then cooled to a temperature between 18 and 25 ° C., additional peaks to those characteristic of variety I of compound 1 are observed, these peaks corresponding to another polymorphic form generated during heating. Thus, the crystals obtained under industrial conditions exhibit heterogeneities detected by DSC and / or by powder X-ray diffraction after heating at 160 ° C., heterogeneities which allow the germination and growth of another crystalline form during the heating of the compound, making the product unstable to heating.

Heterogeneities are understood to mean defects in or on crystals, including twins or polytypism, which can be detected by a conventional optical microscope or equipped with a polarized light device and / or by differential scanning and / or X-ray diffraction analysis. on powder and / or confocal Raman microscopy. The presence of such heterogeneities in the crystals can thus generate numerous problems during the storage of the active ingredient, or during the manufacturing processes of tablets, capsules, creams or other galenic forms. For example, relative humidity stress can lead to unacceptable behaviors for a pharmaceutically active ingredient. Moreover, as Y. Mnyukh has shown in Fundamentals of solid-state phase transitions, ferromagnetism and ferroelectricity (2001), defects can pre-code a solid-solid transition via a germination-growth mechanism.

However, 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 bioavailability.

The technical problem that the applicant proposes to solve is therefore to provide a stable and bioavailable form of compound 1 under conditions that can be used on an industrial scale.

Those skilled in the art know that the treatment aimed at reducing the particle size by mechanical treatment can introduce: defects, residual stresses in the crystallized phases, a polymorphic transition, a partial or total amorphization, possibly associated with a chemical degradation (Jet-Milling) from a particle perspective Predicting Particle Fracture based on Onno mechanical material properties

Mr. de Vegt; PhD thesis University of Groningen; 19 October 2007; Garnier, S .; Small, S .; Mallet, F .; Petit, M.-N .; Lemarchand, D .; Coste, S .; Lefebvre, J .; Coquerel, G.,

Influence of aging, grinding and preheating on the thermal behavior of α-lactose monohydrate. Int. J. Pharm. 2008, 361, 131-140).

The ability of a compound to exist in 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 many 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 many organic compounds.

Very unexpectedly, the applicant has now found that an appropriate treatment of the compound 1 obtained under industrial conditions, aimed at reducing the particle size can produce the 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 commercially usable conditions. The DSC and powder X-ray diffraction analyzes as described in the experimental section make it possible to demonstrate that the variety I thus obtained has an increased stability.

Thus, this variety I of small particle size, object of the invention, can be characterized by different analytical methods such as powder X-ray diffraction, differential scanning calorimetry (DSC), Raman spectroscopy, infrared spectroscopy or solid NMR. .

Also, the subject of the invention is the form 2 crystalline DMSO solvate of compound 1, exhibiting, by powder X-ray diffraction, the characteristic peaks expressed at angle (° 2 theta) at ± 0.1 ° 2 theta: 7.6; 18.7; 24.2; 29.9.

Very unexpectedly, the applicant has found that the form I crystals obtained under industrial conditions have heterogeneities that allow the germination and growth of another crystalline form during heating of the compound: form III, stable at high temperature . The present invention relates to this new form III of compound 1. This form III has the advantage of being thermodynamically stable at temperatures above 145 ° C.

There are several routes of synthesis of compound 1 of form III, according to the invention, one of which passes through another new crystalline form of compound 1, called form II.

Description of the figures:

FIG. 3: Calculated X-ray diffractogram of the DMSO solvate of form 2 of compound 1

FIG. 4: Experimental X-ray diffractogram on DMSO solvate powder of form 2 of compound 1

FIG. 5: Calculated X-ray diffractogram of compound I of compound 1 FIG. 6: Experimental powder X-ray diffractogram of variety I of compound 1

Figure 7: DSC Thermogram of Variety I of Compound 1

Figure 8: IR spectrum of variety I of compound 1

Figure 9: NMR spectrum of the solid of the variety I of the compound 1

FIG. 10: Calculated X-ray diffractogram of the DMSO solvate of Form 1 of compound 1

FIG. 11: Experimental X-Ray Diffractogram on Powder of DMSO Solvate of Form 1 of Compound 1

FIG. 12: Calculated RX diffractogram of DMSO solvate of form 3 of compound 1

FIG. 13: Experimental X-Ray Diffractogram on Powder of DMSO Solubate of Form 3 of Compound 1

Figure 14: Calculated X-ray diffractogram of polymorphic form III of compound 1

FIG. 15: Experimental X-Ray Diffractogram on Powder of Polymorphic Form III of Compound 1

Figure 16: DSC thermogram of polymorphic form III of compound 1 Figure 17: IR spectrum of polymorphic form III of compound 1

Figure 18: NMR spectrum of the solid of the polymorphic form III of the compound 1

Figure 19: Calculated X-ray diffractogram of 1,4-dioxane hemisolvate of compound 1

FIG. 20: Experimental RX diffractogram on powder of 1,4-dioxane semisolvate of compound 1

Figure 21: TG-DSC thermogram of the 1, 4-dioxane hemisolvate of compound 1

FIG. 22: Experimental X-Ray Diffractogram on Powder of Polymorphic Form II of Compound 1

Figure 23: DSC thermogram of polymorphic form II of compound 1

Figure 24: IR spectrum of polymorphic form II of compound 1

Figure 25: NMR spectrum of the solid of the polymorphic form II of the compound 1 Variety I of compound 1 can be characterized by powder X-ray diffraction with a diffractogram having in particular characteristic peaks expressed at an angle (θ 2 theta) at approximately ± 0.1 ° 2 theta: 7.5; 10.9; 13, 1; 17.7; 19.0.

The angles (° 2 theta) with an uncertainty of ± 0.1 ° 2 theta represent the angle of reflection according to the Bragg Law, that is to say the angle of incidence of the beam of X-ray on the sample.

Variety I of compound 1 before particle size reduction can be characterized by single crystal X-ray analysis.

Variety I of compound 1, of reduced particle size, can be characterized by a powder X-ray diffractogram (FIG. 6).

Variety I of compound 1, as described above, can also be characterized by a DSC thermogram (Figure 7).

Variety I of compound 1, as described above, can also be characterized by an infrared spectrum (Figure 8).

Variety I of compound 1, as described above, can also be characterized by an NMR spectrum of the solid (Figure 9).

The Applicant therefore proposes the variety I of the compound 1 obtained by a suitable treatment in order to obtain a particle size of between 0.1 and 20 μm.

The present invention has many advantages, in particular increased stability and bioavailability.

The 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 with a particle size of between 0.1 and 20 μm, and having by X-ray powder diffraction the characteristic peaks expressed in angle (° 2 theta) to ± 0.1 ° 2 theta: 7.5; 10.9; 13.1; 17.7; 19.0.

Preferably, the compound according to the invention has a particle size of between 1 and 15 μm.

More preferentially, the compound according to the invention has a particle size of between 3 and 7 μm.

Even more preferentially, the compound according to the invention has a size of 5 μm ± 1 μm. Preferably, the compound as defined above exhibits, by X-ray powder diffraction, the characteristic peaks expressed at an angle (θ 2 theta) at ± 0.1 ° 2 theta: 7.5; 10.9; 13.1; 15.0; 15.8; 17.0; 17.7; 19.0; 22.5.

Also preferably, the compound as defined above is obtained by X-ray powder diffraction carried out after heating at 160 ° C. and then returning to temperature between 18 and 25 ° C. the following characteristic peaks expressed in angle (° 2 theta) at ± 0.1 ° 2 theta: 7.5; 10.9; 13.1; 17.7; 19.0 without additional peaks corresponding to the shape generated during heating at 160 ° C.

Very preferably, the compound as defined above exhibits in DSC with a temperature ramp of 5 ° C. min ^-1 an endothermic melting point at 170 ° C. ± 5 ° C. and an endothermic peak at 180 ° C. ± 2 ° C it being understood that the peak at 180 ^° C. represents at most 10% of the enthalpy exchanged during the melting at 170 ^° C.

Very preferably also, the compound as defined above does not have a DSC endothermic event between 140 and 155 ° C.

Even more preferably, the compound as defined above exhibits, by infrared spectroscopy, the characteristic peaks expressed in cm -1 at ± 5 cm -1: 3310; 3167; 3059; 891; 798; 733; 679; 455; and more preferably still 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.

According to one variant, the invention relates to a compound as defined above as a medicament.

The compound according to the invention can be formulated in various pharmaceutical compositions. In the case of a solid form, it may be for example powder, granules, tablets, capsules, liposomes or suppositories.

In the case of a liquid form, it may be, for example, solutions, emulsions, suspensions or syrups. The administration of the compound according to the invention may be carried out, for example, topically, orally, parenterally, by intramuscular injection, subcutaneously and especially in the form of a capsule, tablet, patch or cream.

Suitable carriers or excipients may be, for example, maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, sodium croscarmellose, polyvinylpolypyrrolidone (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 water organic solvents such as glycerol or glycols, as well as their mixtures, in various proportions, with or without water. These supports, added to the active ingredient, have the function of being:

diluents, such as mannitol, lactose, starch, calcium carbonate, microcrystalline cellulose, or maltodextrin;

disintegrants, such as starch, croscarmellose sodium, sodium starch glycolate, or crospovidone;

binders, such as polyvinylpyrrolidone, carboxymethylcellulose, pregelatinized starch, or methylcellulose;

flow agents, such as colloidal silica, or talc;

lubricants, such as magnesium stearate, sodium stearyl fumarate, calcium stearate or hydrogenated vegetable oil;

solubilizing agents, such as polyethylene glycol, macrogol, polyglycol, polyoxyethylene, polydiol, pyrrolidone-2, or polyvinylpyrrolidone;

surfactants (or surfactants) such as sodium lauryl sulphate.

The composition according to the invention can be formulated in a capsule containing: 5 to 30% of active ingredient (preferably 6 to 13%); 40 to 92% of diluent (preferentially 65 to 92%, very preferably 85 to 90%); 0 to 30% of disintegrant (preferentially 0 to 22%, very preferably 0%); 0 to 5% of surfactant (preferentially 0%); 0 to 5% of solubilizing agent (preferentially 0%); 0.1 to 3% of flow agent (preferentially 0.9 to 1.4%); 0.5 to 3% of lubricant (preferentially 0.6 to 2.8%).

The preferred excipients for formulating these capsules are mannitol, lactose, corn starch, colloidal silica, magnesium stearate, and sodium lauryl sulphate, and more particularly mannitol, lactose, colloidal silica, and the like. magnesium stearate. The composition according to the invention can also be formulated in a tablet containing: 5 to 30% of active principle (preferably 7 to 15% and very preferably 10 to 15%); 40 to 92% of diluent (preferentially 34 to 89% and very preferably 70 to 85%); 0 to 40% of disintegrant (preferentially 0 to 20% and very preferably 3 to 5%); 0 to 8% of binder (preferentially 2 to 5%); 0.1 to 3% of flow agent (preferentially 0.5 to 1.4%); 0.5 to 3% of lubricant (preferentially 0.5 to 2.8%).

Preferred excipients for formulating these tablets are maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, crospovidone, polyvinylpyrrolidone, carboxymethylcellulose, colloidal silica, sodium stearyl fumarate, and the like. magnesium, and magnesium stearate and more particularly microcrystalline cellulose, lactose, sodium starch glycolate, polyvinylpyrrolidone, colloidal silica, and magnesium stearate.

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 sulfamate of particle size between 0.1 and 20 μm, in combination with at least one pharmaceutically acceptable carrier; preferentially, the 6-oxo

6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate has a particle size of between 1 and 15 μm; more preferably between 3 and 7 μm and more preferably still 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate has a size of 5 μm ± 1 μm.

Preferably, the pharmaceutical composition as defined above comprises, as active ingredient, compound 1 of variety I as defined above.

Very preferably, the pharmaceutical composition as defined above is a capsule; and more preferably still a capsule comprising 5 to 30% of active ingredient; 40 to 92% diluent; 0 to 30% disintegrant; 0 to 5% surfactant; 0 to 5% solubilizing agent; 0.1 to 3% flow agent; and 0.5 to 3% of lubricant.

Very preferably also, the pharmaceutical composition as defined above is a tablet, and more preferably still a tablet comprising 5 to 30% of active principle; 40 to 92% diluent; 0 to 40% disintegrant; 0 to 8% binder; 0.1 to 3% flow agent; and 0.5 to 3% of lubricant. Compound 1 synthetic routes are contemplated in the prior art, as described in EP 880514 or by LW Woo, et al. in Chemistry & Biology, 2000, 7, 773-91.

At present, the Applicant has found that this compound can be synthesized in two chemical steps. The first step consists in condensing in a strong acid (such as sulfuric acid, trifluoroacetic acid or methanesulfonic acid) 2-carbetoxycycloheptanone with resorcinol, the intermediate 3-hydroxy-8, 9,10, 11-Tetrahydrocyclohepta [c] chromen-6 (7H) -one is isolated by precipitation with an alcohol / water mixture (for example by adding ethanol then water). In a second step, sulfonylisocyanate chloride is converted, in toluene solution, sulfamoyl chloride by the action of formic acid, and then condensed on the previous intermediate dissolved in a solvent such as DMA. The reaction medium is treated with water and extracted with an organic solvent (preferably 2-methyltetrahydrofuran: MeTHF), and the crude compound 1 is then precipitated from the organic phase by addition of an antisolvent (preferably methylcyclohexane). . Finally pure compound 1 is obtained by recrystallization of the crude product by hot dissolution in acetone or ethyl acetate and precipitation by addition of an antisolvent (preferably methylcyclohexane).

Therefore, the subject of the invention is also the process for preparing 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, characterized in that it comprises the steps following:

condensation of 2-carbetoxycycloheptanone with resorcinol in a strong acid,

isolation of the 3-hydroxy-8,9,10,11-tetrahydrocyclohepta [c] chromen-6 (7H) -one thus obtained by precipitation with an alcohol / water mixture, condensation of the 3-hydroxy- 8, 9, 10,11-tetrahydrocyclohepta [c] chromen-6 (7H) -one with sulfamoyl chloride in an aprotic solvent, recrystallization of the crude product obtained by hot dissolution in acetone or ethyl acetate and adding an antisolvent such as methylcyclohexane. The compound according to the invention, as described above, is obtained from compound 1 in the form of variety I by a treatment aimed at reducing the size of the particles.

Thus, the subject of the invention is also a process for the preparation of the compound according to the invention as described above, starting from 6-oxo-6,7,8,9,10,11- hexahydrocyclohepta [c] chromen-3-yl sulfamate characterized in that it comprises a step of reducing the size of the particles.

Preferably, the particle size is reduced by micronization.

Preferably also, the particle size is reduced by wet grinding with a non-protic organic solvent.

The subject of the present invention is also a polymorphic compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, exhibiting, by X-ray powder diffraction, the characteristic peaks expressed at angle (θ 2 theta) to ± 0.1 ° 2 theta: 8.6; 11, 3; 28.6 (compound of Form III). Preferably, this compound of form III has the characteristic peaks expressed in angle (° 2 theta) at ± 0.1 ° 2 theta: 8.6; 11, 3; 12.0; 16.6; 20.9; 23.0; 28.6.

The subject of the invention is more particularly a compound of form III as defined previously which exhibits, by X-ray diffraction on monocrystal, the following mesh parameters:

the reduced coordinates (x10 ⁴ ) and the equivalent equivalents of isotropic stirring (A2 x 10 ³ ):

the coordinates of the hydrogen atoms (x10 ⁴ ) and equivalent isotropic displacement parameters (A ² x 10 ³ ) (U (eq) is one third of the value of the orthogonal tensor Uij) as follows:

the following inter-reticular distances: The subject of the invention is preferably a compound (IHI form) as defined previously which exhibits in DSC at 5 ° C. min ^-1 an endothermic melting peak of 180 ° C. ± 2 ° C.

Preferably, the compound (Form III) according to the invention, as defined above, exhibits, by infrared spectroscopy, the characteristic peaks expressed in cm ^-1 to the following ± 5 cm ^-1 : 3406; 3217; 1678; 1011; 563;

and most preferably the characteristic peaks expressed in cm ^-1 to ± 5 cm ^-1 following: 3406; 3217; 3082; 2924; 1678; 1385; 1269; 1134; 1011; 934; 845; 601; 563; 536.

According to one variant, the subject of the invention is a compound of form III as defined above, as a medicament.

The subject of the invention is also a pharmaceutical composition comprising, as active principle, a compound of HII form as defined above, in association with at least one pharmaceutically acceptable carrier.

Also, the subject of the invention is the form 1 crystalline DMSO solvate of compound 1, exhibiting, by powder X-ray diffraction, the characteristic peaks expressed at angle (° 2 theta) at ± 0.1 ° 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.

Also, the object of the invention is the form 3 crystalline DMSO solvate of compound 1, exhibiting, by powder X-ray diffraction, the characteristic peaks expressed at angle (θ 2 theta) at ± 0.1 ° 2 theta: 9.8; 13.9; 16.0; 17.7; 19.1; 22.1.

In addition, the subject of the invention is also the crystalline 1,4-dioxane hemisolvate of compound 1, exhibiting, by powder X-ray diffraction, the characteristic peaks expressed at angle (° 2 theta) at ± 0.1 ° 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.

In addition, the subject of the invention is also the polymorphic compound of compound 1, composed of form II, having, by powder X-ray diffraction, the characteristic peaks expressed at angle (θ 2 theta) at ± 0.1 ° 2 theta: 9, 4; 10.7; 12.8; 18.2; 18.9; 19.7; 20.4; 23.2; and preferentially the characteristic peaks expressed at angle (θ 2 theta) to ± 0.1 ° 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. Preferably, this compound of form II exhibits at DSC at 5 ° C. min ^-1 an endothermic melting peak at 165 ° C. ± 5 ° C. More preferentially, it presents, by infrared spectroscopy, the characteristic peaks expressed in cm ^-1 to ± 5 cm ^-1 : 3356, 3321, 3186, 1504, 872, 787, and even more preferably the characteristic peaks expressed in cm ^-1 to 5 cm ^-1 : 3356, 3321, 3186, 3078, 2932, 2851, 1693; 1609, 1504, 1462, 1377, 1265, 1192, 1123, 937, 872, 837, 787, 594.

The compound according to the invention, as described above, is obtained from compound 1 by an additional step which can be:

a desolvation of the DMSO solvate of form 1 in water,

a desolvation of the DMSO solvate of form 3 in water,

an atomization in ethanol,

an atomization in acetone,

- re-slaking in cumene at reflux,

a heat treatment then a micronisation, then a second heat treatment, or else

a heat treatment of the form II.

Thus, according to one variant, the subject of the invention is the process for preparing a compound of form III as defined above from compound 1, according to one of the following methods:

a) stirring and precipitating in DMSO in order to yield crystalline DMSO solvate of form 1 as defined previously, which compound is then desolvated in water;

b) by agitation and precipitation in DMSO in order to yield crystalline DMSO solvate of form 3 as defined previously, which compound is then desolvated in water;

- c) by atomization in ethanol;

- d) by atomization in acetone;

e) by reattempting in refluxing cumene; f) by heat treatment at a temperature between 155 ° C and 165 ° C for 10 to 20 minutes, followed by micronization, and then a second heat treatment at a temperature between 155 ° C and 165 ° C for 10 to 20 minutes,

- g) by treatment of a compound of Form II as defined above, and obtained:

by atomization of compound 1 in 1,4-dioxane,

or by stirring and precipitating compound 1 in 1,4-dioxane in order to give crystalline 1,4-dioxane hemisolvate as defined previously, which compound is then desolvated by heating from 20 to 80 ° C. ° C. min ^'1 under a stream of inert gas,

treatment which consists of a heat treatment at a temperature between 155 ° C and 165 ° C for 6 to 10 minutes.

Preferably, the process according to the invention involves the desolvation in water of crystalline DMSO solvate of form 1 as defined above.

Preferably, the process according to the invention involves the desolvation in water of crystalline DMSO solvate of form 3 as defined above.

Preferably also, the method according to the invention passes through the atomization in ethanol.

Also preferably, the process according to the invention is carried out by atomization in acetone.

Very preferably, the process according to the invention is carried out by recoating in cumene under reflux.

Even more preferentially, the process according to the invention passes through the heat treatment at a temperature of between 155 ° C. and 165 ° C. for 10 to 20 minutes, followed by micronization and then a second heat treatment at a temperature comprised between between 155 ° C and 165 ° C for 10 to 20 minutes;

and, preferably, the heat treatments are made at 160 ° C. ± 1 ° C. for 15 minutes.

Even more preferably, the process according to the invention involves the heat treatment of a compound of Form II as defined above, at a temperature of between 155 ° C. and 165 ° C. for 6 to 10 minutes; and preferentially the heat treatment is at 160 ° C ± 1 ° C for 7.5 minutes.

Also preferably, the compound of form II as defined above, is obtained by the atomization of compound 1 in 1,4-dioxane; or the compound of form II as defined above, is obtained by the desolvation of a crystalline 1,4-dioxane hemisolvate as defined above.

According to one variant, the subject of the invention is the process for preparing crystalline DMSO solvate of form 1 as defined above, starting from compound 1, by stirring and precipitation in DMSO.

According to one variant, the subject of the invention is the process for preparing crystalline DMSO solvate of form 3 as defined above, starting from compound 1, by stirring and precipitation in DMSO.

According to one variant, the subject of the invention is the process for preparing a crystalline 1,4-dioxane hemisolvate as defined above, starting from compound 1, by stirring and precipitation in 1,4-dioxane.

The form II mentioned above can be obtained as for it according to two ways of synthesis:

- directly, by atomization in 1, 4-dioxane

by desolvation of the 1-4-dioxane hemisolvate of compound 1 obtained beforehand by precipitation in 1,4-dioxane.

Also, according to another variant, the subject of the invention is the process for preparing a compound of form II as defined above, starting from compound 1, according to one of the following methods:

- atomization in 1,4-dioxane;

- agitation and precipitation in 1, 4-dioxane to yield a hémisolvate of 1, 4-dioxane crystalline as defined above, which compound is then subjected to desolvation by heating from 20 to 80 ° C at 5 ° C.min ^{" 1} under a stream of inert gas.

Preferably, the process for the preparation of a compound of form II as defined above, passes through the desolvation of a crystalline 1,4-dioxane hemisolvate as defined above. Also preferably, the process for the preparation of a compound of form II as defined above, passes through the atomization in 1,4-dioxane.

Alternatively, the subject of the invention is the use of a compound of variety I or of form III as defined above for the manufacture of a medicament intended to treat cancers; preferentially hormone-dependent cancers and preferably also a cancer selected from breast, prostate, endometrial or ovarian cancers.

The following experimental part is presented to illustrate the above procedures and should in no way be considered a limit to the scope of the invention.

Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by an ordinary specialist in the field to which the invention belongs. In addition, all patents (or patent applications) as well as other bibliographic references are incorporated by reference.

Experimental part :

1. Compositions according to the invention

Example 1 a:

A tablet composition comprising Compound 1 as the active ingredient is shown in Table 1 below. Such a composition can be prepared by wet granulation according to scheme 1 below for a batch of 5 kg and a dose of 40 mg.

Table 1 Centesimal Composition of a Tablet and Coating

The coating, which has been applied to 40 mg tablets, consists of Opadry ® II white (Colorcon); it is a commercially available blend of coatings used for immediate release tablets. The main purpose of this coating is to mask the bad taste of the drug substance. It also reduces the risks associated with handling during packaging operations for tablets containing strong active ingredients.

Example 1b:

A capsule composition comprising Compound 1 as the active ingredient is shown in Table 2 below.

Table 2: Centesimal composition of a capsule

2. Effect of the disintegrant on the dissolution profiles

All excipients are analyzed according to the monographs of the current European Pharmacopoeia.

The effect of the disintegrator appears by comparison of the dissolution values at 30 minutes of the compositions 2 and 17 described in Chapter 3 below, without sodium starch glycolate.

Various tests were carried out on the effect of the addition of a disintegrant on the dissolution profile and disintegration time of the tablet was studied. Four tablet compositions were made to study the effect of two disintegrants, sodium starch glycolate, type A (Explotab ^® ) and pregelatinized corn starch (Starch 1500 ^® ).

The results obtained show that the addition of a disintegrant accelerates the dissolution profile of the tablet to make it closer to the reference capsule (see Figure 2).

3. Protective effect of binders on the active ingredient during the wet granulation process

A study demonstrating the protective effect of binder and / or diluent (microcrystalline cellulose, copovidone, carboxymethyl cellulose) was performed by comparing the final impurity rate and the behavior of these formulations during their manufacture. Different solid compositions obtained by wet granulation were analyzed by HPLC on an Alliance 2695 chain with UV 2487 detector from Waters (high performance liquid chromatography) according to the conditions described in the table (Table 4) below. Table 4: Analytical HPLC analysis method of tablets at 40 mg of compound

Table 5: Solid compositions containing compound 1 and using different excipients.

4. Stability of tablets at 5 mq and 40 mg depending on storage conditions, at 6 months and at 12 months in blister

A compressed form (centesimal formula of Example 1a) was set to stability after blistering.

The goal is to check the stability of this form over periods of 6 months and 12 months.

The recommended normal storage conditions are 25 ° C and 60% relative humidity (25 ° C / 60% RH) and the data generated under these conditions are presented in Tables 6 and 7 for 5 mg tablets. and 40 mg respectively.

In addition, other storage conditions (eg 40 ° C / 75% RH) were also investigated until 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 6: Stability study on tablets packaged in blister packs containing 5 mg of active ingredient and stored at 25 ° C / 60% RH.

In Table 6 are grouped tests of dosage, impurities and dissolution of the stability study on tablets packaged in blister containing 5 mg of active ingredient and stored at 25 ° C / 60% RH. Table 7: Stability study on tablets packaged in blister packs containing 40 mg of active ingredient and stored at 25 ° C./60% RH.

In Table 7 are grouped assays, impurities and dissolution of the stability study on tablets packaged in blister containing 40 mg of active ingredient and stored at 25 ° C / 60% RH.

Table 8: Stability studies on tablets packaged in blister packs containing 5 mg of active ingredient and stored under different storage conditions

In Table 8 are grouped tests of dosage, impurities and dissolution of stability studies on tablets packaged in blister containing 5 mg of active ingredient and stored under different storage conditions. Table 9: Stability studies on blister packs containing 40 mg of active ingredient and stored under different storage conditions

In Table 8 are grouped tests of dosage, impurities and dissolution of stability studies on tablets packaged in blister containing 40 mg of active ingredient and stored under different conditions of conservation

After 12 months storage at 25 ° C / 60% RH, no significant changes were observed for the assay and dissolution.

Statistical analysis of the results obtained by right of regression with a 95% confidence interval gives an expectation of compliance with product quality specifications of at least three years.

The accelerated stabilities at a temperature of 40 ° C and 75% relative humidity (40 ° C / 75% RH) show results in accordance with the product quality specifications.

The stability of the product under the most severe conditions reinforces the confidence in the projections made for the tablets kept at 25 ° C / 60% RH. 5. PREPARATION OF COMPOUND 1 VARIETY I

5.1 Synthesis of compound 1

Example 5: The first step consists in condensing in methanesulfonic acid 2-carbetoxycycloheptanone with resorcinol, the reaction is conducted at 25 ° C for 4 hours. The 3-hydroxy-8,9,10,11-tetrahydrocyclohepta [c] chromen-6 (7H) -one intermediate thus formed precipitates by addition of ethanol and then water, and is then isolated by filtration, dried under vacuum at 60 ° C, a yield of 78% is obtained. In a second step, sulfonylisocyanate chloride is converted, in toluene solution, sulfamoyl chloride by the action of formic acid, and then condensed on the previous intermediate dissolved in N ₁ N-dimethylacetamide (DMA). The reaction medium is treated with water and extracted with 2-methyltetrahydrofuran (2-MeTHF). The crude compound 1 is then obtained by filtration of the precipitate obtained by adding methylcyclohexane to the organic phase. Finally, the pure compound 1 is obtained by recrystallization of the crude product by hot dissolution in acetone and precipitation by addition of methylcyclohexane (the addition of the methylcyclohexane antisolvent whose main purpose is a yield gain).

Compound 1 is thus obtained with a yield of 65%, and presented hereinafter.

Example 1 thus obtained can undergo an appropriate treatment aimed at reducing the particle size such as micronisation (point 5.3 below) or wet grinding (point 5. below).

5.2 Desolvation of Form 2 DMSO Solvate of Compound 1 in Water

Example 5a: Form 2 DMSO Solvate of Compound 1

In a pillbox, 1 ml of DMSO (Bp = 189 ° C.) is poured in, then 1 g of compound 1 (Example 1) is added. The solution is stirred using a magnetic stir bar and a magnetic stirrer. The solid goes into solution quickly. 1 g of compound 1 is again added, still with magnetic stirring. The solid dissolves in part, then a build-up is observed. A sample of the caking is analyzed still wet in powder X-ray diffraction. This analysis, presented below, shows that it is the DMSO solvate of form 2 of compound 1 (Example 5a). Example 5b:

The DMSO solvate of form 2 of compound 1 (Example 5b) is immersed in cold water and left stirring for five minutes at room temperature. The suspension was then filtered and dried.

Compound 1 is thus obtained in a yield of 50% and presented below.

Example 5b thus obtained can undergo appropriate treatment to reduce particle size such as micronization or wet milling.

5.3 Micronization

Micronization is carried out using a compressed air jet micronizer at a temperature between 18 and 25 ° C. The characteristics of the compressed air used are as follows:

- CO: <5 ppm,

- CO ₂ : <500 ppm,

- Hydrocarbons: <0.5 mg.m ^'3 ,

- Number of particles per ft ³ > 0.5 μ: <10000,

- Maximum performance: 2300 cfm at 13 bar,

- Maximum operating pressure: 13 bar.

Example 5c: Variety I of compound 1 with particle size of 3 μm

249 g of compound 1 (example 1) are micronized using a compressed air jet micronizer. The micronization parameters are: 80 psi Venturi pressure, 110 psi micronizer pressure and 12 kg feed rate. h ^"1 .

Example 3-1 is thus obtained with a yield of 97%. Example 5d: Variety I of Compound 1 with a Granulometry of 5 μm

16.5 kg of compound 1 (Example 5) are micronized using a compressed air jet micronizer. The micronization parameters are: 80 psi Venturi pressure, 32 psi micronizer pressure and 14.4 kg feed rate. h ^"1 .

Example 5d is thus obtained with a yield of 98% and presented below.

Example 5e: Variety I of compound 1 with a particle size of 9 μm

150 g of compound 1 (Example 51) are micronized using a compressed air jet micronizer. The micronization parameters are: 50 psi Venturi pressure, 60 psi micronizer pressure, and 15 kg feed rate. h ^"1 .

Example 5e is thus obtained with a yield of 98%.

Example 5f: Variety I of compound 1 with a particle size of 15 μm

39 g of compound 1 (Example 5) are micronized using a compressed air jet micronizer. The micronization parameters are: Venturi pressure of 30 psi, micronizer pressure of 10 psi and feed rate of 40 g in 15 minutes.

Example 5f is thus obtained with a yield of 74%.

5.4 Wet grinding

Example 5q: 0.69 g of compound 1 (Example 5) are ground with 0.068 g of methylcyclohexane in a model P4 planetary type Fritsch ball mill.

The parameters of the wet grinding are: 7 agate balls 10 mm in diameter, a grinding torque Ω (speed of rotation of the disc) - co (rotational speed of the bottles) of 100 - 100 rpm, a duration of 12 hours effective over a total of 18 hours according to the following 72 sequences: 10 minutes of grinding - 5 minutes break, a ball mass / solute mass ratio of 14.1; a temperature of 22 ° C. and a mass ratio of compound 1 / mass of methylcyclohexane of 9%.

Example 5g is thus obtained with a yield of 99% and presented below. 6. DESCRIPTION OF THE CRYSTALS OBTAINED

6.1 Equipment used

6.1.1 RX on powder and single crystal

Siemens D5005 Diffractometer, Scintillation Detector

• Wavelength: 1, 54056 Cu, voltage 40 KV, current 40 mA

• Measurement range: 3 ° - 30 ° 2 theta

• Range: 0.04 ° 2 theta

• Duration of the interval: 4s

• Fixed slots: 1, 6 mm

- Kβ filter (Ni)

• Without internal reference

• EVA software (v 12.0) for data processing

Smart Apex Bruker Diffractometer, two-dimensional detector

• SMART software for determining the parameters and orientation of the crystal matrix

• SAINT software for integration and data processing

• WinGX software for space group determination and structure resolution

6.1.2 DSC

- Netzsch DSC 204F1

• Aluminum capsule and pierced lid

• Atmosphere: Helium

• Initial temperature: 20 ° C

• Final temperature: 200 ° C • Temperature ramp: 5 ° C. min ^"1

6.1.3 IR

• KBr capsule

• Bruker type IFS28 spectrometer

• Spectrum range: 400-4000cm ^{~ 1}

6.1.4 Solid state NMR

• Bruker Avance 500 MHz Spectrometer

• Magic Angle Spinning (MAS) probe 4 mm

• Bruker Xwinnmr Software

- VACP (Variable Amplitude Cross-Polarization) with MAS (11 kHz) and proton decoupling (spinal64, 65 kHz)

• External reference: Adamantane

6.1.5 Qranulometric distribution

• Malvern Mastersizer S laser granulometer

• Sample size: 30 to 50 mg

• Dispersion medium: 0.50% (m / v) Nonidet in water

• Mie theory with refractive indices: Rl particles = 1, 55; Imaginary R1 = 1.00; Rl dispersant = 1, 38

• Sonication time: 60 seconds

• Sonication energy: 50 to 60 Hz

• Recirculation time: 30 seconds at 2000 rpm ^"1

• Obscuration: 15-25%

6.2 Characterization of examples

6.2.1 Examples 5 and 5b It was possible to isolate single crystals by slow evaporation of a saturated solution in ethanol at 4 ° C for 2 days. These single crystals made it possible to solve the complete structure of variety I of compound 1 by X-ray diffraction.

RX on single crystal: the crystal structure of compound 1 variety I has been solved and has the following mesh parameters:

The reduced coordinates (x10 ⁴ ) and equivalent isotropic displacement parameters (A ² × 10 ³ ) of the compound 1 variety I are as follows:

The reduced coordinates of the hydrogen atoms (x10 ⁴ ) of the compound 1 variety I are as follows:

The inter-reticular distances of the compound 1 variety I are as follows

6.2.2 Example 5a

It was possible to isolate single crystals by slow evaporation of a saturated solution of DMSO at room temperature. These single crystals made it possible to solve the complete structure of the form 2 DMSO solvate of compound 1 by X-ray diffraction.

Single-crystal XR: The crystalline structure of the Form 2 DMSO solvate of compound 1 has been resolved and has the following mesh parameters:

The atomic coordinates of the atoms in the mesh (x10 ⁴ ) and equivalent isotropic displacement parameters (A ² x 10 ³ ) (U (eq) is one third of the value of the orthogonal tensor Uij) of the form 2 DMSO solvate of the compound 1 are the following:

The coordinates of the hydrogen atoms (x10 ⁴ ) and equivalent isotropic displacement parameters (A ² × 10 ³ ) (U (eq) is one third of the value of the orthogonal tensor Uij) of the form 2 DMSO solvate of the compound 1 are the following :

The inter-reticular distances of the form 2 DMSO solvate of compound 1 are as follows:

The 2-DMSO solvate powder X-ray diffractogram of compound 1 has the following characteristic peaks expressed at angle (θ 2 theta) at approximately ± 0.1 ° 2 theta: (Figures 1 and 2). 7.6; 18.7; 24.2; 29.9.

6.2.3 Examples 5c-5q

6.2.3.1 Powder RX (Figures 5 and 6)

The powder X-ray diffractogram of variety I of compound 1 after micronization or wet grinding exhibits the following characteristic peaks expressed as angle (θ 2 theta) at approximately ± 0.1 ° 2 theta: 7.5; 10.9; 1, 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.

The X-ray powder diffractogram of variety I of compound 1 after micronisation or wet grinding and then heating at 160 ^° C. has the following characteristic peaks expressed in angle (° 2 theta) at approximately ± 0.1 ^β 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 new shape generated during heating at 160 ° C.

6.2.3.2 DSC (Figure 7)

In DSC, the thermogram obtained at 5 ° C. min ^-1 of variety I of compound 1 after micronisation or wet grinding comprises the melting peak of variety I (onset 170 ° ± 5 ° C.), possibly a small peak of melting of a new polymorphic form generated during the analysis (onset 180 ± 2 ° C) representing less than 10% of the enthalpy exchanged during the melting peak of the variety I and exhibits no endothermic event (or less than 0.5 J / g) between 140-155 ° C.

6.2.3.3 IR (Figure 8)

The IR spectrum of variety I of compound 1 after micronization or wet milling exhibited the characteristic peaks expressed in cm ^-1 at approximately 5 cm ^-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 Solid-state NMR (Figure 9)

The spectrum of variety I of compound 1 after micronisation or wet milling obtained by NMR of the solid has the following characteristic peaks expressed in ppm at 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

The particle size distribution of variety I of compound 1 after micronization according to example 2-2 is as follows: D10 (%) = 1, 2 μm; D50 (%) = 5.2 μm and D90 (%) = 11.0 μm.

The particle size distribution of variety I of compound 1 after wet milling according to example 3 is as follows: D10 (%) = 0.6 μm; D50 (%) = 3.1 μm and D90 (%) = 13.7 μm.

7. FORMULATION

7.1 Formulation in capsule form

The variety I of the compound 1 according to the invention can be formulated in a capsule containing: 5 to 30% of active principle (preferably 6 to 13%), 40 to 92% of diluent (preferably 65 to 92%, very preferably at 90%), 0 to 30% of disintegrant (preferentially 0 to 22%, very preferably 0%), 0 to 5% of surfactant (preferentially 0%), 0 to 5% of solubilizing agent (preferentially 0%) 0.1 to 3% of flow agent (preferably 0.9 to 1.4%), 0.5 to 3% of lubricant (preferentially 0.6 to 2.8%).

The preferred excipients for formulating these capsules are mannitol, lactose, corn starch, colloidal silica, magnesium stearate, and sodium lauryl sulphate, and more particularly mannitol, lactose, colloidal silica, and the like. magnesium stearate.

The capsules presented below were made by mixing powder according to conventional techniques known to those skilled in the art.

M = mannitol; L = lactose; AM = corn starch; LS = sodium lauryl sulphate; PEG = polyethylene glycol; SC = colloidal silica; SM = magnesium stearate

Example 7i: The example of capsules 7j is prepared from compound 1 of example 5: 40 mg of compound 1 are mixed with 260 mg of lactose and put in capsules.

Example 7k: The example of capsules 7k is prepared according to formula 7g with active ingredient Example 5c instead of Example 5d.

Example 71: Example of capsules 71 is prepared with 7.2% of Example 5d, 31.9% of mannitol, 59.4% of lactose and 1.5% of colloidal silica.

Example 7m: The example of capsules 7m is prepared according to formula 7g with active ingredient as example 5d.

Example 7n: The example of capsules 4n is prepared according to formula 4g with active ingredient Example 5e instead of Example 5d.

EXAMPLE 7O: The example of capsules 40 is prepared with the active principle of Example 5f: 40 mg of Example 5f are mixed with 260 mg of lactose and put into capsules.

7.2 Formulation in tablet form

The variety I of the compound 1 according to the invention can be formulated in a tablet containing: 5 to 30% of active principle (preferably 7 to 20% and very preferably 10 to 15%), 40 to 92% of diluent (preferentially at 89% and very preferably 70 to 85%), 0 to 40% of disintegrant (preferentially 0 to 20% and very preferably 3 to 5%), 0 to 8% of binder (preferentially 2 to 5%), 0.1 at 3% of flow agent (preferably 0.5 to 1.4%), 0.5 to 3% of lubricant (preferentially 0.5 to 2.8%). The preferred excipients for formulating these capsules are maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, crospovidone, polyvinylpyrrolidone, carboxymethylcellulose, colloidal silica, stearyl fumarate and the like. magnesium, and magnesium stearate and more particularly microcrystalline cellulose, lactose, sodium starch glycolate, polyvinylpyrrolidone, colloidal silica, and magnesium stearate.

The tablets shown below were made by wet granulation according to conventional techniques known to those skilled in the art.

8. PHYSICAL AND CHEMICAL PROPERTIES AND BIOLOGICAL

8.1 Kinetics of dissolution

The dissolution kinetics (expressed as a percentage of dissolved compound 1 as a function of time) are measured according to standard techniques known to those skilled in the art, and presented in the table below.

The above dissolution results are expressed as percentage of theoretical strength. The theoretical strength in capsules 7j to 7n is 40 mg of active ingredient. These examples are experimental, a slight excess of active substance during weighing is possible and explains percentages greater than 100% at the end point of the dissolution.

8.2 Bioavailability

The comparative bioavailability of compound 1 has been studied in dogs following a single oral administration of two capsules. Blood samples are taken at 1; 1, 5; 2; 4; 6; 9; 12; 24; 30 and 48 hours after administration. Area under the curve (AUC) is one of the pharmacokinetic parameters measured in dog plasma samples. The results obtained are shown in the table below.

8.3 Chemical stability

A stability study was carried out at 100 ° C. between the variety I of compound 1 and the compound 1 described in patent EP 880514. The chemical stability of compound 1 is studied by HPLC at different scores.

The operating conditions of the HPLC method are as follows:

column: Interchim UP3HDO-15XS, 150 x 4.6 mm,

Eluent A: - 2500 water

- trifluoroacetic acid 0.5

Eluent B: - Acetonitrile Radiate:

detection: 205 nm,

injection: 20 microliters,

temperature: 40 ° C,

solution injected: 0.5 mg.mL ^"1 (acetonitrile)

9. PREPARATION OF COMPOUND 1 OF FORM III

Form III of compound 1 as described in the present application is obtained by a synthesis step of compound 1 (Example 5) followed by an additional step which can be:

a desolvation of the DMSO solvate of Form 1 in water: Example 9a,

a desolvation of the DMSO solvate of form 3 in water: Example 9b,

an atomization in ethanol: Example 9c,

an atomization in acetone: example 9d

- Refolding in cumene at reflux: Example 9e,

a heat treatment then a micronisation, then a second heat treatment: example 9f,

a heat treatment of Form II: Example 9g.

9.1 Desolvation of the DMSO solvate of Form 1 in water

Example 9aa: Form 1 DMSO solvate of compound 1

In a pill dispenser, 1 ml of DMSO (Bp = 189 ° C) is poured, then 1 g of compound 1 is added (Example 5). The solution is stirred using a magnetic stir bar and a magnetic stirrer. The solid goes into solution quickly. 1 g of compound 1 is again added, still with magnetic stirring. The solid dissolves in part, then a build-up is observed. A sample of the caking is analyzed still wet in powder X-ray diffraction. This analysis, presented below, shows that it is the DMSO solvate of Form 1 of compound 1 (Example 9aa).

Example 9a:

The DMSO solvate of Form 1 of compound 1 (Example 9aa) is immersed in cold water and stirred for five minutes at room temperature. The suspension was then filtered and dried.

Compound 1 of form III is thus obtained with a yield of 50% and presented below. 9.2 Desolvation of form 3 DMSO solvate in water

Example 9ba: Form 3 DMSO Solvate of Compound 1

In a pillbox, 1 ml of DMSO (Bp = 189 ^° C.) is poured in, then 1 g of compound 1 (Example 1) is added. The solution is stirred using a magnetic stir bar and a magnetic stirrer. The solid goes into solution quickly. The solution is left stirring for 24 hours. A setting in mass is then observed. A sample of the caking is analyzed still wet in powder X-ray diffraction. This analysis, presented below, shows that it is the DMSO solvate of form 3 of compound 1 (Example 9ba).

Example 9b:

The DMSO solvate of form 3 of compound 1 (Example 3ba) is immersed in cold water and left stirring for five minutes at room temperature. The suspension was then filtered and dried.

Compound 1 of form III is thus obtained with a yield of 50% and presented below.

9.3 Atomization in ethanol

Example 9c:

The product obtained is produced with a B -chi 190 spray-dryer. 2 g of compound 1 (Example 5) were dissolved in 200 ml of ethanol (Bp = 78 ° C.). The dry air inlet temperature was adjusted to 90 ° C with a pressure of 3 bar. The outlet temperature was measured at 38 ° C during atomization. The output rate was set at 700 NI / hour. 570 mg of dry powder are recovered and analyzed by powder X-ray diffraction. This analysis shows that it is form III of structurally pure compound 1 in comparison with the diagram calculated from the resolved structure on single crystal.

Compound 1 of form III is thus obtained with a yield of 29% and presented below.

9.4 Atomization in acetone

Example 9d:

The product obtained is produced with a Bϋchi B290 spray dryer with an inerting loop. 2 g of compound 1 (example 1) were dissolved in 10O mL of acetone (Bp = 56 ° C). The dry air inlet temperature was adjusted to 70 ° C. The outlet temperature was measured at 50 ° C during atomization. The output rate has been set to 600 NI / hour. 1 g of dry powder is recovered and analyzed by X-ray powder diffraction. This analysis shows that it is form III of structurally pure compound 1 in comparison with the diagram calculated from the resolved structure on single crystal.

9.5 Refolding in cumene at reflux

Example 9e:

10 g of compound 1 (Example 5) are suspended in 100 ml of cumene (Bp = 152 ° C.). The mixture is refluxed with stirring and then cooled to room temperature. The analysis of the recovered and dried powder shows that it is Form III of compound 1.

Compound 1 of form III is thus obtained with a yield of 99% and presented below.

9.6 Heat treatment then micronization. then second heat treatment

Example 9f:

150 g of compound 1 are heated in a ventilated oven at 160 ° 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 micronizer pressure of 120 psi and a feeding speed of 1.2 kg. h ^{"and 1} for the second pass.. a venturi pressure of 50 psi, a pressure of 50 psi and micronizer a feed rate of 1, 2 kg ^{h -1} The yield of micronization is 69% 15. The product thus obtained is heated at 160 ° C. for 15 minutes in a ventilated oven.

Compound 1 of form III is thus obtained with a yield of 69% and presented below. 9.7 Heat treatment of Form II

9.7.1 Obtaining Form II

Form II of compound 1 can be obtained according to two synthetic routes:

by desolvation of the 1,4-dioxane hemisolvate of compound 1 previously obtained by precipitation in 1,4-dioxane;

directly, by atomization in 1,4-dioxane.

Example 9h: 1,4-dioxane hemisolvate of compound 1

A solution of compound 1 (Example 5) in 1,4-dioxane was prepared at room temperature and stirred for 24 hours. During the stirring, a strong precipitation was observed. The solid was then filtered and analyzed by X-ray powder diffraction. The product obtained at the end of this step is the 1,4-dioxane semisolvate of compound 1.

The 1,4-dioxane hemisolvate of compound 1 is thus obtained in 80% yield and presented hereinafter.

Example 9i: Compound 1 of Form II

According to a first synthetic route, the hémisolvate of 1, 4-dioxane compound 1 (Example 9) was heated to 20 to 80 ° C at 5 ° C min ^"1 under a stream of inert gas and provides, for the desolvation Form II of compound 1 characterized by its X-ray diffraction pattern.

Compound 1 of Form II is thus obtained with a yield of 99% and presented below.

According to a second synthetic route, compound 1 of Form II can be obtained in the following manner: 1 g of compound 1 (Example 5) was dissolved in 100 ml of 1,4-dioxane (Bp = 101 ° C.). Inlet temperature: Dust-free dry air was adjusted to 130 ° C with a pressure of 3 bar. The outlet temperature was measured at 88 ° C during atomization. The output rate was set at 700 NI / hour. The product obtained at the end of this step is Form II.

Compound 1 of Form II is thus obtained with a yield of 50% and presented hereinafter. 9.7.2 Obtaining Form III

Example 9g:

The dry powder recovered from compound 1 of Form II (Example 9i) was placed in an oven at 160 ^° 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, shows that it is form III of structurally pure compound 1 as compared with the calculated diagram obtained from the resolved single-crystal structure.

10. CHARACTERIZATION OF THE SOLID PHASES OBTAINED

10.1 Equipment used

10.1.1 RX on powder and single crystal

Siemens D5005 Diffractometer, Scintillation Detector

Wavelength: 1, 54056 Cu, voltage 40 KV, current 40 mA

- Measurement range: 3 ° - 30 ° 2 theta

- Range: 0.04 ° 2 theta

Duration of the interval: 4s

Fixed slots: 1, 6 mm

- Kβ filter (Ni)

- Without internal reference

- EVA software (v 12.0) for data processing

Smart Apex Bruker Diffractometer, two-dimensional detector

SMART software for determining the parameters and orientation of the crystal matrix

- SAINT software for integration and data processing WinGX software for space group determination and structure resolution

10.1.2 DSC

- Netzsch DSC 204F 1 - Aluminum capsule and pierced lid

- Atmosphere: Helium

- Initial temperature: 20 ° C

- Final temperature: 200 ° C Temperature ramp: 5 ° C min ^{. 1} 10.1.3 TG-DSC

- Netzsch STA449C

- Aluminum caspule and pierced lid

- Atmosphere: Helium

- Initial temperature: 25 ° C - Final temperature: 200 ° C

Temperature ramp: 5 ° C. min ^"1 10.1.41R

- KBr capsule

- Bruker type IFS28 spectrometer - Spectrum range: 400-4000cm ^"1

10.1.5 Solid state NMR

- Bruker Avance 500 MHz Spectrometer

- Magic Angle Spinning (MAS) probe 4 mm Software Bruker Xwinnmr VACP (Variable Amplitude Cross-Polarization) with MAS (11 kHz) and proton decoupling (spinal 64, 65 kHz)

External Reference: Adamantane

10.2 Characterization of examples

10.2.1 Form I of compound 1

The X-ray powder diffractogram of Form I of Compound 1 exhibits the following characteristic peaks expressed at angle (θ 2 theta) at approximately ± 0.1 ° 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 Form 1 DMSO Solvate of Compound 1

It was possible to isolate single crystals by slow evaporation of a saturated solution of DMSO at room temperature. These single crystals made it possible to solve the complete structure of the form 1 DMSO solvate of compound 1 by X-ray diffraction.

Single-crystal X-ray: The crystalline structure of the DMSO solvate of Form 1 of compound 1 has been resolved and has the following mesh parameters:

The atomic coordinates of the atoms in the mesh (x10 ⁴ ) and equivalent isotropic displacement parameters (A ² x 10 ³ ) (U (eq) is one third of the value of the orthogonal tensor Uij) are as follows:

The coordinates of hydrogen atoms (x10 ⁴ ) and equivalent isotropic displacement parameters (A ² x 10 ³ ) (U (eq) is one third of the value of the orthogonal tensor Uij) are as follows:

The inter-reticular distances of the solvate of DMSO form 1 are as follows

The X-ray diffractogram on DMSO solvate powder of form 1 of the compound

I has the following characteristic peaks expressed as angle (θ 2 theta) at approximately ± 0.1 ° 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 (Figures 1 and 2).

2.2.3 Form 3 DMSO Solvate of Compound 1

It was possible to isolate single crystals by slow evaporation of a saturated solution of DMSO at room temperature. These single crystals made it possible to solve the complete structure of the DMSO solvate of form 3 of compound 1 by X-ray diffraction.

Single crystal X-ray: The crystalline structure of the DMSO 3 solvate of compound 1 has been resolved and has the following mesh parameters:

The coordinates of the hydrogen atoms (x10 ⁴ ) and equivalent isotropic displacement parameters (A ² x 10 ³ ) (U (eq) is one third of the value of the orthogonal tensor Uij) are the following:

The inter-reticular distances of the solvate of DMSO form 3 are as follows:

The DMSO 3-form DMSO solvate powder X-ray diffractogram of compound 1 exhibits the following characteristic peaks expressed at angle (θ 2 theta) at approximately ± 0.1 ° 2 theta: (Figures 3 and 4). 9.7; 13.9; 16.0; 17.8; 19.1; 22.1. 2.2.4 Single-crystal RX of Form III

By slow evaporation at room temperature of a saturated solution of compound 1 in a mixture of acetone / n-heptane at 50% v / v, it was possible to isolate single crystals which made it possible to solve the complete structure of form III of compound 1 by X-ray diffraction.

The crystalline structure of the compound 1 form has the following mesh parameters:

The reduced coordinates (x10 ⁴ ) and the equivalent isotropic stirring parameters (A ² × 10 ³ ) of the compound 1 form III are as follows:

The inter-reticular distances are as follows: 10.2.5 Examples 9a-9g: compound 1 of form III

The X-ray diffraction analyzes on powder, single crystal X-ray diffraction, DSC ₁ by IR and solid NMR show that Example 9a is identical to Example 9b, Example 9c, Example 9d, in Example 9e, Example 9f and Example 9g.

10.2.5.1 RX on powder

The X-ray powder diffractogram of Form III of Compound 1 exhibits the following characteristic peaks expressed as angle (θ 2 theta) at approximately ± 0.1 ° 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 (Figures 5 and 6).

10.2.5.2 DSC

In DSC, the thermogram of Form III of Compound 1 comprises the melting peak of Form III (onset 180 ° ± 2 ° C) (Figure 7).

10.2.5.3 IR

The IR spectrum of Form III of Compound 1 shows the characteristic peaks expressed in cm ^-1 at approximately ± 5 cm ^-1 : 3406, 3217, 3082, 2924, 1678, 138, 1269, 1134, 1011, 934, 845; 601, 563, 536 (Figure 8).

10.2.5.4 Solid state NMR

The solid NMR form III spectrum exhibited the following characteristic peaks expressed in ppm at approximately ± 0.2 ppm: 162.9; 156.4; 151, 3; 126.1; 124.7; 118.8; 117.1; 112.9; 35; 20 (Figure 9).

10.2.6 Example 9h: 1,4-dioxane hemisolvate of compound 1

10.2.6.1 RX on single crystal

By slow evaporation at room 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 the 1,4-dioxane hemisolvate of the compound 1 by X-ray diffraction.

The crystalline structure of the 1,4-dioxane hemisolvate of compound 1 has the following mesh parameters:

The reduced coordinates (x10 ⁴ ) and the equivalent isotropic stirring parameters (A ² × 10 ³ ) of the 1,4-dioxane hemisolvate of Comose 1 are as follows:

The coordinates of the hydrogens (x10 ⁴ ) and the isotropic equivalent displacement parameters (A ² × 10 ³ ) of the 1,4-dioxane semisolvate of compound 1 are as follows:

The inter-reticular distances of the 1,4-dioxane hemisolvate are as follows:

10.2.6.2 RX on powder

The X-ray powder diffractogram of 1,4-dioxane hemisolvate of compound 1 exhibits the following characteristic peaks expressed as angle (θ 2 theta) at approximately ± 0.1 ° 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 (Figures 10 and 11).

10.2.6.2 TG-DSC

In TG-DSC, the thermogram of 1,4-dioxane hemisolvate of Compound 1 shows that the solvate releases 1,4-dioxane from 75 ° C to give Form II of Compound 1 (Figure 12).

10.2.7 Example 9i: Compound 1 of Form II

10.2.7.1 RX on powder

The X-ray powder diffractogram of Form II of Compound 1 exhibits the following characteristic peaks expressed in angle (° 2 theta) at approximately

± 0.1 ° 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 (Figure 13).

10.2.7.2 DSC

In DSC, the thermogram of form II of compound 1 comprises an endothermic phenomenon which corresponds to the metastable melting of form II at 165 ° C ± 5 ° C, followed by recrystallization to other forms, followed by other melting (Figure 14).

10.2.7.3 IR

The IR spectrum of Form II of Compound 1 shows characteristic peaks expressed in cm ^-1 at approximately ± 5 cm ^-1 : 3356; 3321; 3186; 3078; 2932; 2851; 1693; 1609; 1504; 1462; 1377; 1265; 1192; 1123; 937; 872; 837; 787; 594 (Figure 15).

10.2.7.4 Solid state NMR

The spectrum of Form II obtained by solid NMR shows the following characteristic peaks expressed in ppm at approximately ± 0.2 ppm: 163.0; 154.5; 153.5; 151, 6; 128.6; 118.5; 111, 4; 108.2; 35; 25 (Figure 16).

11. PHYSICO-CHEMICAL AND BIOLOGICAL PROPERTIES

11.1 Conversion Experiences

The Applicant has carried out conversion experiments between the different polymorphic forms of compound 1 which have shown that form III is the form stable at high temperature (T> 145 ° C). This important property allows vacuum heating to remove traces of solvent (Polymorphism in the Pharmaceutical Industry, Wiley 2006, Ed Hilfiker, Wiley, ISBN: 978-3-527-31146-0). By returning to ambient temperature, the form III of compound 1 remains unchanged which is, again, a primary advantage in the pharmaceutical industry.

11.2 Chemical stability

A stability study was carried out at 150 ° C. between compound 1 of form III and compound 1 described in patent EP 880514. This chemical stability is studied by HPLC.

The operating conditions of the HPLC method are as follows:

delete:

detection: 205 nm,

injection: 20 microliters,

temperature: 40 ° C,

solution injected: 0.5 mg.mL ^"1 (acetonitrile)

Claims

A solid pharmaceutical composition containing 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate as active ingredient and at least one pharmaceutically acceptable excipient.

The pharmaceutical composition of claim 1 wherein the solid form for oral administration is a capsule.

The pharmaceutical composition of claim 1 wherein the solid form is a tablet.

4. Pharmaceutical composition according to claim 3 wherein the tablet comprises, based on the total weight of the composition 1 to 30% of active principle; 40 to 92% diluent; 0.1 to 20% disintegrant; 0.1 to 8% binder; 0.1 to 3% slip agent; and 0.5 to 3% lubricant and about 4.8% coating solution based on the total weight of the coated tablet.

The pharmaceutical composition of claim 4 wherein the diluent is selected from the following excipients: mannitol, lactose or lactose monohydrate, starch, calcium carbonate, microcrystalline cellulose, or maltodextrin.

The pharmaceutical composition of claim 4 wherein the disintegrant is selected from the following excipients: starch, sodium croscarmellose, sodium starch glycolate, or crospovidone.

7. Pharmaceutical composition according to claim 4 wherein the binder is selected from the following excipients: polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (or copovidones), carboxymethylcellulose, pregelatinized starch , or methylcellulose.

The pharmaceutical composition of claim 4 wherein the lubricant is selected from the following excipients: magnesium stearate, sodium stearyl fumarate, calcium stearate or hydrogenated vegetable oil.

9. The pharmaceutical composition according to claims 1 and 2 to 8, comprising either microcrystalline cellulose (MCC) and / or copovidone or microcrystalline cellulose (MCC) and / or carboxymethylcellulose (CMC).

10. The pharmaceutical composition according to one of claims 1 and 3 to 9, in tablet form and containing from 8 to 20% of active principle; from 20 to 40% lactose and from 25 to 50% microcrystalline cellulose used as diluents; from 2 to 8% of copovidone used as a binding agent; from 1 to 5% of sodium starch glycolate used as a disintegrating agent; 0.2 to 1.4% flow agent; and 0.5 to 2% of lubricant relative to the total weight of the tablet.

11. Pharmaceutical composition according to one of the preceding claims, wherein the 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate has a particle size of between 1 and 20 microns. .

12. Pharmaceutical composition according to one of the preceding claims, wherein the 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate has a particle size of between 1 and 15 microns. .

13. Pharmaceutical composition according to one of the preceding claims, characterized in that it is immediate release.

14. Pharmaceutical composition according to one of the preceding claims and wherein the uncoated tablet does not exceed the total weight of 800 mg, preferably 400 mg.

15. Process for the preparation of a solid pharmaceutical composition according to one of the preceding claims from 6-oxo-6,7,8,9,10,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, characterized in that it comprises a step of reducing the particle size of the active ingredient.

The method of claim 15 wherein the size of the particles is reduced by micronization.

17. Process for the preparation of the solid pharmaceutical composition according to one of claims 1 to 14 comprising the following steps:

• sieving of components

• wet granulation then mixing of components and compression

• preparation of the coating solution characterized in that the mixture may comprise a substance which, added to the powder improves its fluidity such as a slip agent.

The method of claim 17, wherein the slip agent is a colloidal solution of silicon dioxide.

19. The method of claim 17, wherein during the wet granulation step, the mass of water relative to the total mass of the active ingredient and the binder, diluent and disintegrator premixed, is between about 10 and 30 %.

20. The method of claim 17, wherein after the wet granulation step, the granules are dried to a residual moisture less than 3%.

21. A polymorphic compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate having a particle size of 0.1 to 20 μm, and having X-ray diffraction on powder the characteristic peaks expressed in angle (° 2 theta) to ± 0.1 ° 2 theta: 7.5; 10.9; 13.1; 17.7; 19.0.

22. Compound according to claim 21 characterized in that the size of the particles is between 1 and 15 microns.

23. A compound according to claim 21 characterized in that the size of the particles is between 3 and 7 microns.

24. Compound according to claim 21, characterized in that it has a size of 5 μm ± 1 μm.

25. Compound according to one of claims 21 to 24, characterized in that it presents, by X-ray powder diffraction, the characteristic peaks expressed at angle (° 2 theta) at ± 0.1 ° 2 theta: 7.5; 10.9; 13.1; 15.0; 15.8; 17.0; 17.7; 19.0; 22.5.

26. Compound according to one of claims 21 to 25, characterized in that it has X-ray powder diffraction carried out after heating to 160 ° C and then returning to temperature between 18 and 25 ° C characteristic peaks expressed in angle (° 2 theta) to ± 0.1 ° 2 theta: 7.5; 10.9; 13.1; 17.7; 19.0 without additional peaks corresponding to the shape generated during heating at 160 ° C.

27. Compound according to one of claims 21 to 25 characterized in that it has a DSC for a heating rate of 5 ° C.min ^'1 endothermic melting peak at 170 ° C ± 5 ° C and a peak endothermic at 180 ° C ± 2 ° C it being understood that the peak at 180 ° C represents at most 10% of the enthalpy exchanged during the melting at 170 ^° C.

28. Compound according to one of claims 1 to 7 characterized in that it does not have a DSC endothermic event between 140 and 155 ° C.

29. Compound according to one of claims 1 to 8 characterized in that it has by infrared spectroscopy characteristic peaks expressed in cm ^'1 to ± 5 cm ^"1 : 3310; 3167; 3059; 891; 798; 733; 679; 455.

30. A polymorphic compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, exhibiting, by powder X-ray diffraction, the characteristic peaks expressed as angle (θ 2 theta) ) at ± 0.1 ° 2 theta: 8.6; 11, 3; 28.6.

31. Compound according to claim 30, characterized in that it presents, by X-ray powder diffraction, the characteristic peaks expressed at angle (θ 2 theta) at ± 0.1 ° 2 theta: 8.6; 11, 3; 12.0; 16.6; 20.9; 23.0; 28.6.

32. Compound according to one of claims 30 or 31, characterized in that it exhibits by X-ray diffraction on single crystal the following mesh parameters:

33. Compound according to one of claims 30 to 32 characterized in that it has in DSC at 5 ° C. min ^-1 an endothermic melting peak of 180 ° C. ± 2 ° C.

34. Compound according to one of claims 30 to 33 characterized in that it has by infrared spectroscopy characteristic peaks expressed in cm ^"1 to ± 5 cm ^{" 1} : 3406; 3217; 1678; 1011; 563.

35. Compound according to claim 34, characterized in that it exhibits, by infrared spectroscopy, the characteristic peaks expressed in cm ^-1 to ± 5 cm ^-1 : 3406; 3217; 3082; 2924; 1678; 1385; 1269; 1134; 1011; 934; 845; 601; 563; 536.