KR20110115607A - Solid pharmaceutical composition containing 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta(c)chromen-3-yl sulfamate and polymorphs thereof - Google Patents

Abstract

The present invention relates to a solid pharmaceutical composition comprising 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate as active ingredient. The present invention also relates to polymorphs of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate compound.

Description

Solid pharmaceutical compositions containing 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta (C) chromen-3-yl sulfamate and its polymorphs {SOLID PHARMACEUTICAL COMPOSITION CONTAINING 6-OXO- 6,7,8,9,10,11-HEXAHYDROCYCLOHEPTA (C) CHROMEN-3-YL SULFAMATE AND POLYMORPHS THEREOF}

The present invention relates to a solid pharmaceutical composition comprising compound 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate as active ingredient. The present invention also relates to the preparation of such pharmaceutical compositions, their use as medicaments, more particularly their use as medicaments for the treatment of certain cancers, Compound 1 targeting the enzyme steroid sulfatase.

Composition according to the invention containing compound 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate (hereinafter referred to as compound 1) as active ingredient Is a stable oral pharmaceutical composition and has the advantage of providing adequate bioavailability.

Compound 1:

Is described in patent EP 880514. At present, L.W. Woo et al. As described in Chemistry & Biology, 2000, 7, 773-91, there is increasing interest in this compound because of its sulfatase inhibitory activity and the therapeutic application with which it is associated. Inhibition of steroid-sulfatase (STS), an enzyme involved in the hydrolysis of steroid sulfates, represents a promising new treatment for postmenopausal patients with, for example, hormone-dependent breast cancer [Clin. Cancer Res. 2006; 12 (5)].

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

Compound 1 belongs to class 2 of the biopharmaceutical classification system or BCS proposed by G. Amido (GL Amidon et al., "A theoretical basis for a biopharmaceutical drug classification: the correlation of in vitro drug dissolution and in vivo bioavailability ", Pharm. Res. 12 (1995) 413-420). Its absorption, and therefore its bioavailability, depend largely on the rate of dissolution of the pharmaceutical form being administered.

Methods and preparations known from the prior art using self-emulsifying agents ("self-emulsifying drug delivery systems") used in an aqueous phase, such as in a standard manner, to increase the solubility of the compounds of class 2, include the excipients used and The aqueous phase is not suitable because it is incompatible with compound 1 and induces chemical degradation during the preparation step.

Due to the problems of stability and low solubility of compound 1, it has been difficult to obtain a formulation which is capable of producing a tablet which is sufficiently stable over time and comprises a sufficient concentration of active ingredient. In addition, compositions with poor compressibility were crushed during dry tableting and had a too slow dissolution profile. Due to the instability of compound 1, which can be easily hydrolyzed in the presence of water, it was difficult to envision a wet granulation process.

Unexpectedly, a wet granulation process yielded a formulation from which a dry oral form of compound 1 could be obtained.

In the case of wet granulation, the components are mixed and granulated in the wet phase with a binder. The binder may be dissolved in the wet phase or incorporated into the mixture of powders to be granulated. In order to form tablets prior to compression, the wet granules are sifted, dried and optionally ground.

Unexpectedly, it has been found that new solid pharmaceutical compositions intended for administration by the oral route of Compound 1 solve the problems specific to these active ingredients and can be obtained by wet granulation processes.

Such oral compositions, in the form of tablets or gelatin capsules, are stable while dissolving solids rapidly and thus provide immediate release with effective bioavailability.

Accordingly, subjects of the present invention are 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate and at least one pharmaceutically acceptable as active ingredient. Solid pharmaceutical compositions containing excipients.

Subjects of the present invention also provide 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] as the active ingredient for oral administration, preferably for immediate release. Solid pharmaceutical composition containing chromen-3-yl sulfamate and at least one pharmaceutically acceptable excipient.

Also subject to the invention are solid pharmaceutical compositions for administration by the oral route, comprising Compound 1 and at least one disintegrant as well as one or more moisture protectants as active ingredients.

Thus, such agents protect the active ingredient against hydrolysis and thus prevent its degradation. Preferably, compound 1 is micronized.

It has been observed that during the preparation of the pharmaceutical composition its degradation occurs mainly, especially during the wet granulation step. Unexpectedly, it has been found in the art that the addition of excipients used for their properties as binders and diluents provides the effect of protecting the active ingredient.

Subject of the present invention is also a method of preparing a pharmaceutical composition as described below. The method according to the invention can be carried out using standard forms of adjuvant and excipients to produce tablets using wet granulation.

"Immediate release oral administration" or "immediate release oral form" or "immediate release composition" is, according to the invention, at least 45 minutes, preferably 30 minutes, of the active ingredient in accordance with a suitable in vitro dissolution test. Administration of an oral composition developed for Compound 1, capable of dissolving 80% by weight in vitro. This test is carried out using a paddle dissolution apparatus at 37 ° C. under agitation at 100 rpm in a buffered hydrochloric acid solution of pH 1.2 according to US Pharmacopoeia Standard comprising 0.1% surfactant, cetyl trimethyl ammonium bromide, which is active ingredient in the test medium. Allow sufficient solubility of to be obtained. Analysis is carried out by ultraviolet (UV) / visible absorption spectrophotometry at a wavelength of 311 nm.

The term "lubricant" or "fluid" as used in accordance with the present invention means an agent which improves the flow and flow of adjuvant and excipients and granules called lubricants.

The term "percent preparation" as used according to the present invention means a given proportion by weight of the active ingredient or excipient relative to the total weight of the composition.

The term "binder" or binder according to the present invention refers to an adjuvant or excipient used to maintain the structure and aggregation of the herbal form. They can be granulated in the form of granules of ingredients during the granulation step and have the property of ensuring coagulation of the herbal form after compression.

The term "disintegrant" according to the present invention denotes an excipient or adjuvant that can be added to the formulation to promote disintegration of the tablet when the tablet is placed in a liquid environment, such as water or gastric juice.

<Brief Description of Drawings>

1: Comparative dissolution curves of the composition of compound 1 as a function of time and the micronization effect of the active ingredient in the composition. Each curve corresponds to a solid composition comprising Compound I with different micronizations.

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.

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

The present invention has a number of advantages, in particular

Increased stability and

Increased bioavailability associated with immediate dissolution of the pharmaceutical form (at least 80% within 30 minutes)

Represents a combination.

Preferably, the method used for the preparation of the tablets according to the invention is subjected to a wet granulation step before the forming step of the tablets.

In fact, it has been surprisingly found that, despite the low stability of Compound 1 in the aqueous phase, tablets can be prepared by methods including wet granulation steps. The preparation of the tablets according to the invention has the advantage from the stabilization of compound 1 in the aqueous phase in the presence of well selected excipients.

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

Pharmaceutically acceptable excipients suitable for the preparation of the pharmaceutical compositions of the present invention are, 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 copovidone) such as copolymer collidone VA64, carboxymethylcellulose, Pregelatinized starch, methylcellulose, polyethylene glycol, macrogol, polyglycol, polyoxyethylene, pyrrolidone-2, colloidal silica, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil Sodium lauryl sulfate, calcium phosphate, sugars, dextrins, starches, gelatin, cellulose, waxes, or water, organic solvents such as glycerol Or glycols, as well as mixtures thereof in various proportions with or without water. Such excipients added to the active ingredient have the following functions:

Diluents, for example mannitol, lactose or lactose monohydrate, starch, calcium carbonate, microcrystalline cellulose or maltodextrin;

Disintegrants, for example starch, croscarmellose sodium, sodium starch glycolate or crospovidone;

Binders such as polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (or copovidone), carboxymethylcellulose, pregelatinized starch or methylcellulose;

Glidants or glidants, for example colloidal silica, or starch;

Lubricants, for example magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid or hydrogenated vegetable oils;

Solubilizers such as macrogol (polyethylene glycol), polyglycol, polyoxyethylene glycol, polydiol, pyrrolidone-2, or polyvinylpyrrolidone;

Surfactants (or surface active agents) such as sodium lauryl sulfate.

Subject of the present invention is a solid pharmaceutical composition for oral administration containing Compound 1 as an active ingredient, which comprises Compound 1 and at least one disintegrant, 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 gelatin capsule. Preferably, the pharmaceutical composition according to the invention in solid form for oral administration is a tablet.

In the following compositions, each type of excipient may be used alone or in a mixture. Thus, "x% of binder" means x% of the binder alone or of the binder mixture.

The composition according to the invention comprises 1 to 30% active ingredient, preferably 5 to 20%; 40 to 92% diluent, preferably 65 to 92%, very 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% solubilizer, preferably 0%; 0.1 to 3% flow agent, preferably 0.9 to 1.4%; It may be formulated into gelatin capsules according to a percentage formulation containing 0.5 to 3% lubricant, preferably 0.6 to 2.8%.

Preferably, the pharmaceutical composition as defined above is a gelatin capsule; More preferably 5 to 30% active ingredient; 40 to 92% diluent; 0 to 8% binder; Preferably 0 to 5%; 0-30% disintegrant; 0 to 5% surfactant; 0-5% solubilizer; 0.1 to 3% flow agent; And a gelatin capsule of a percentage formulation containing 0.5 to 3% lubricant.

Pharmaceutically acceptable excipients for formulating such gelatin capsules are mannitol, lactose, corn starch, colloidal silica, magnesium stearate, and sodium lauryl sulfate, more particularly mannitol, lactose, colloidal silica and stearic Magnesium acid.

The composition according to the invention comprises 1 to 30% by weight active ingredient, preferably 5 to 20%, very preferably 8 to 20%, based on the total weight of the composition; 40 to 92% diluent, preferably 65 to 92%, very preferably 70 to 85%; 0.1 to 20% disintegrant, preferably 0.1 to 10%, very preferably 1 to 5%; 0.1 to 8% binder, preferably 2 to 5%; 0.1 to 3% lubricant, preferably 0.5 to 1.4%; It may be formulated into a tablet, preferably a film-coated tablet, of a percentage formulation containing 0.2 to 3% lubricant, preferably 0.5 to 2.8%.

Preferred excipients for formulating such 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, the pharmaceutical composition as defined above comprises 8 to 20% by weight active ingredient relative to the total weight of the tablet; 70 to 85% diluent; 1 to 5% disintegrant; 2 to 5% binder; 0.5 to 1.4% flow agent; And a tablet, preferably a film-coated tablet, of 0.5 to 2.8% lubricant as well as a percentage formulation comprising approximately 4.5 to 5%, preferably 4.8% coating solution relative to the total weight of the coated tablet.

Preferably, the pharmaceutical composition according to the invention comprises a diluent selected from the following excipients: mannitol, lactose or lactose monohydrate, starch, calcium carbonate, microcrystalline cellulose or maltodextrin.

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

Preferably, the pharmaceutical composition according to the invention comprises the following excipients: polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (copovidone), carboxymethylcellulose (CMC), pregelatinization Binders selected from starch or methylcellulose.

Preferably, the pharmaceutical composition according to the invention comprises a lubricant selected from the following excipients: magnesium stearate, sodium stearyl fumarate, calcium stearate or hydrogenated vegetable oils.

Preferably, the pharmaceutical composition according to the invention comprises microcrystalline cellulose (MCC) and / or copovidone or microcrystalline cellulose (MCC) and / or carboxymethylcellulose (CMC). Preferably, the CMC is at a level of 4 to 6%. Very preferably, the pharmaceutical composition according to the invention comprises microcrystalline cellulose (MCC). Very preferably, the pharmaceutical composition according to the invention comprises copovidone. Very preferably, the pharmaceutical composition according to the invention comprises microcrystalline cellulose (MCC) and copovidone. Very preferably, the pharmaceutical composition according to the invention comprises microcrystalline cellulose (MCC). Very preferably, the pharmaceutical composition according to the invention comprises carboxymethylcellulose (CMC). Very preferably, the pharmaceutical composition according to the invention comprises microcrystalline cellulose (MCC) and carboxymethylcellulose (CMC).

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

Preferably, the lubricant selected is magnesium stearate. Disintegrants added to tablet formulations as excipients increase dissolution rate and can achieve immediate dissolution even in tablets with high tack. According to the literature (see, eg, J. Balasubramaniam, T. Bee, Pharmaceutical Technology Europe, Vol. 21, Number 9, 2009, pp 44-49), the most effective disintegrants are crospovidone types A and B Followed by croscarmellose sodium.

Preferably, in the preparation of the tablets according to the invention, the disintegrants used are preferably sodium starch glycolate at the level of 1 to 5%, very preferably 3 to 4%.

Preferably, the pharmaceutical composition according to the invention comprises 8 to 20% compound 1, based on the total weight of the tablet; 20 to 40% lactose and 25 to 50% microcrystalline cellulose used as diluent; 2-8% copovidone used as binder; 1 to 5% sodium starch glycolate used as disintegrant; 0.2-1.4% flow agent; And 0.5 to 2% lubricant, very preferably 8 to 15% Compound 1 relative to the total weight of the tablet; 30-40% lactose and 40-50% microcrystalline cellulose used as diluent; 2 to 5% copovidone used as binder; 3 to 4.5% sodium starch glycolate used as disintegrant; 0.2-1.4% flow agent; And 0.5 to 2% lubricant.

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

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

Preferably, such coatings do not have a significant effect on the immediate release of the active ingredient, ie the rate of in vivo release of the active ingredient does not change.

Also preferably, the coating has the advantage of masking the taste of the active ingredient and can be handled safely to treat the solid composition in the form of a tablet.

Coating processes that can be used for the tablets described herein are 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, but not limited to, polyethylene glycol, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (hypromellose) . Particularly, coatings of aqueous film in solid oral pharmaceutical form such as those sold under the tradename Opadry ^® II White (Lactose Monohydrate, Hypromellose, Titanium Dioxide (E171), Triacetin) (Colorcon Company) To this end, film-coating mixtures containing already formulated polyethylene glycol (macrogol) and hydroxypropylmethylcellulose can be used. Opadry ^® II white is soluble in water and immediately disintegrates the oral pharmaceutical composition in the form of a tablet.

Preferably, the solid pharmaceutical composition according to the present invention is in tablet form. The present invention also relates to tablets that are applied with coatings or films as well as tablets that dissolve immediately.

Pharmaceutical compositions are described as examples and in no way limit the scope of the invention.

Accordingly, the subject matter of the present invention comprises 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-, characterized by reducing the size of the particles. From one sulfamate is a process for the preparation of the compounds according to the invention described above.

Preferentially, the size of the particles is reduced by micronization in an aprotic solvent medium or by the dry route.

Also preferentially, the size of the particles is reduced by wet milling with an aprotic organic solvent.

The invention also relates to a process for the preparation of a solid pharmaceutical composition of the invention, characterized by the following steps:

Sieving the components;

Preparing tablets without coatings (wet granulation, mixing and compression);

To prepare a coating solution.

Preferably, according to the method according to the invention, the mass of water relative to the total mass of active ingredient and premixed binder, diluent and disintegrant during the wet granulation step is approximately 10-30%.

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

During all stages of the manufacturing process, the composition is prepared by conventional devices known to those skilled in the art.

The preparations according to the invention can be prepared according to the following methods: A first mixture consisting of the active ingredient is prepared and sieved simultaneously with the particular excipient included in the composition comprising the binder and one or more diluents as well as the disintegrant.

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

The sieved material is then introduced into a mixer-granulator and mixed for approximately 5 minutes. The mixing speed depends on the device selected.

Subsequently, a mass of water is prepared for granulation so that the ratio to the solid phase to be granulated is preferably approximately 10 to 30%. By solid phase to be granulated means the total mass of the premixed active ingredient and excipient added to the mass of the binder.

The binder for granulation is added to the mixer in a pulverized form or preferentially dissolved in the mass of water to make up the granulation solution.

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

The granules obtained from this last step can be dried, for example, in a conventional apparatus such as a fluid bed dryer. Preferably, the granules are dried until less than 3% residual moisture is obtained. The granules thus dried make up a part called the inner phase of the tablet. Then, these are adjusted by grinding.

A second mixture is prepared, consisting of some of the previously obtained adjusted granules and disintegrants, a flow agent capable of improving the flowability of the powder, and finally a so-called external phase.

The excipients on the outside are first sieved in a suitable device such as a passive sieve.

Granules, disintegrants and flow agents are mixed and then a lubricant is introduced.

In order to prepare the formulation in tablet form, the resulting mixture can be made into tablets, for example using a rotary press.

The hardness of a 400 mg tablet may consist of 6 to 12 kPascal (kPa). The hardness of a 100 mg tablet may consist of 4 to 8 kPa.

The tablets can then be coated in a film coating turbine, preferably by spraying a pre-made coating suspension by adding 16% of Opadry II ^® to the purified water.

The temperature of the product during the film coating is 35 to 55 ° C.

Preferably, the mass gain of the tablet after drying is 4-6% of the mass of the tablet before film coating.

The tablets may then be packaged and stored in a blister pack or bottle.

According to the invention, the non-coated tablets preferably do not exceed the total weight of 800 mg, preferably 400 mg.

Finally, the present invention relates to the use of the pharmaceutical composition according to the invention described above for the treatment of cancer, preferably hormone-dependent cancer, preferentially breast cancer, prostate cancer, endometrial cancer or ovarian cancer.

The present application also relates to compounds 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 polymorph of Compound 1). The invention also relates to the preparation of such polymorphic forms, to active ingredients, and more particularly their use as active ingredients for the treatment of certain cancers. The present invention also relates to pharmaceutical compositions containing such polymorphic forms as active ingredients.

The form, briefly described by Woo and called variant I hereafter, produces a characteristic band of absorption in the infrared. Applicants obtained single crystals of appropriate size and quality to fully characterize their structure.

Crystals obtained in the prior art do not have good bioavailability and cannot change their preparation on an industrial scale.

Applicants also obtained crystals of Compound 1 by industrial processes. Microscopic observation can observe the gradual opacity of the crystals from about 140-145 ° C. This phenomenon is not reversible: crystals do not recover their initial appearance even after slow or rapid cooling. In DSC, an endothermic phenomenon corresponding to solid-solid transition from 140 ° C. is observed. A second endothermic peak is observed at 170 ° C., corresponding to melting of the non-converted variant I. A third endothermic peak is observed at 180 ° C. This third endothermic peak corresponds to the melting of the other polymorphic forms that occurred during the solid-solid transition. By X-ray powder diffraction performed on a compound heated to 160 ° C. and subsequently cooled to a temperature of 18 to 25 ° C., additional peaks are observed in the properties of variant I of compound 1, which peaks occur during heating Corresponding to other polymorphic forms.

That is, the crystals obtained under industrial conditions exhibit heterogeneity detected by DSC and / or X-ray powder diffraction after heating to 160 ° C., wherein the heterogeneity enables the germination and growth of other crystal forms and heating the product during heating of the compound. Makes it unstable during heating

Heterogeneity refers to twins or multiples that can be detected by conventional optical microscopes or microscopes equipped with polarizing devices and / or by differential calorimetry analysis and / or by X-ray powder diffraction and / or by confocal Raman microscopy Defects on or within a crystal containing form. The presence of such heterogeneity in the crystal can cause a number of problems during the storage of the active ingredient or during the manufacturing process of tablets, gelatin capsules, creams or other herbal forms. For example, relative humidity stress may cause unacceptable behavior for pharmaceutical active ingredients. In addition, as shown in Y. Mnyukh in Fundamentals of solid-state phase transitions, ferromagnetism and ferroelectricity (2001), the drawback can pre-encrypt solid-solid transition through mechanism-growth germination.

Now, for the clinical development of such molecules, it is necessary to select the crystalline form and achieve its manufacture under industrial conditions, the main factors being thermal stability and its bioavailability.

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

One skilled in the art knows that treatments aimed at reducing particle size by mechanical treatment can cause defects, residual stresses in the crystallization phase, optionally polymorph transitions associated with chemical decomposition, partial or total amorphousness [Jet- milling; from a particle perspective predicting particle fracture based on mechanical material properties Onno M. de Vegt; PhD thesis University of Groningen; 19 October 2007; Garnier, S.,; Petit, S .; Mallet, F .; Petit, M.-N .; Lemarchand, D .; Coste, S .; Lefebvre, J .: Coquerel, G., Influence of ageing, grinding and preheating on the thermal behavior of α-lactose monohydrate. Int. J. Pharm. 2008, 361, 131-140.

The ability of a compound to exist in more than one crystal form is defined by the term polymorphism, and its different crystal forms are known as "polymorph modifications" or "polymorphs". Polymorphism can affect many properties of the solid state of the active ingredient. Different polymorphs of a material can vary considerably from material to material, for example by physical properties that can directly affect their solubility. Polymorphisms have been demonstrated for many organic compounds.

Very unexpectedly, the Applicant believes that a suitable treatment of Compound 1 obtained under industrial conditions aimed at reducing the size of the particles has a particle size that matches the formulation of the active compound while simultaneously reducing the concentration of heterogeneity in the crystal. It was found that variant I of 1 can be produced, thus providing a stable and bioavailable form of compound 1 under conditions that can be used on an industrial scale. DSC and X-ray powder diffraction analysis described in the experimental section may demonstrate that variant I thus obtained has increased stability.

Thus, low particle sized variant I of the present invention can be characterized by different analytical methods such as X-ray powder diffraction, differential scanning calorimetry (DSC) analysis, Raman spectroscopy, infrared spectroscopy or NMR of solids.

Also subject to this invention are solvates of crystalline DMSO of Form 2 of Compound 1, characterized by characteristic peaks expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 7.6; 18.7; 24.2; 29.9 is represented.

Very unexpectedly, the Applicant has found that the crystals of Form I obtained under industrial conditions have heterogeneity which allows the germination and growth of other crystalline forms during heating of a stable compound: Form III at high temperatures. Subject of the invention is this novel form III of compound 1. This Form III has the advantage of being thermodynamically stable at temperatures above 145 ° C.

There are several synthetic routes to Compound 1 of Form III, one of which according to the invention is via an intermediate of another novel crystalline form of Compound 1 called Form II.

<Brief Description of Drawings>

3: Calculated X-ray diffraction diagram of DMSO solvate of Form 2 of Compound 1. FIG.

4: Experimental X-ray diffraction diagram of DMSO solvate of Form 2 of Compound 1. FIG.

5: Calculated X-ray powder diffraction diagram of variant I of compound 1.

6: Experimental X-ray powder diffraction diagram of variant I of compound 1.

7: DSC thermogram of variant I of compound 1. FIG.

8: IR spectrum of Variant I of Compound 1. FIG.

9: NMR spectrum of solid of Variant I of Compound 1. FIG.

FIG. 10: Calculated X-ray diffraction diagram of DMSO solvate of Form 1 of Compound 1.

FIG. 11: Experimental X-ray powder diffraction diagram of DMSO solvate of Form 1 of Compound 1. FIG.

12: Calculated X-ray diffraction diagram of DMSO solvate of Form 3 of Compound 1. FIG.

FIG. 13: Experimental X-ray powder diffraction diagram of DMSO solvate of form 3 of compound 1. FIG.

FIG. 14: Calculated X-ray diffraction diagram of Polymorph Form III of Compound 1.

15: Experimental X-ray powder diffraction diagram of Polymorph Form III of Compound 1. FIG.

16: DSC thermogram of Polymorph Form III of Compound 1. FIG.

FIG. 17: IR spectrum of Polymorph Form III of Compound 1.

FIG. 18: NMR spectrum of solid of Polymorph Form III of Compound 1.

Figure 19: Calculated X-ray diffraction diagram of the 1,4-dioxane antisolvate of compound 1.

FIG. 20: Experimental X-ray powder diffraction diagram of the 1,4-dioxane antisolvate of compound 1.

FIG. 21: TG-DSC thermogram of 1,4-dioxane antisolvate of compound 1.

22: Experimental X-ray powder diffraction diagram of Polymorph Form III of Compound 1. FIG.

FIG. 23: DSC thermogram of Polymorph Form II of Compound 1.

24: IR spectrum of Polymorph Form II of Compound 1. FIG.

FIG. 25: NMR spectrum of solid of Polymorph Form II of Compound 1.

Variant I of Compound 1 has a characteristic peak expressed in degrees (° 2 theta) to approximately ± 0.1 ° 2 theta: 7.5; 10.9; 13.1; 17.7; X-ray powder diffraction with a diffraction diagram with 19.0 can be characterized.

Angles with an error of ± 0.1 ° 2 theta (° 2 theta) represent the angle of reflection according to Bragg's law, that is, the angle of incidence of the X-ray beam in the sample.

Variants I of Compound 1 may be characterized by single crystal X-ray analysis before reducing the particle size.

Variation I of compound 1 of reduced particle size can be characterized by an X-ray powder diffraction diagram (FIG. 6).

Variant I of Compound 1 described above can be characterized by DSC thermograms (FIG. 7).

Variant I of Compound 1 described above can be characterized by the infrared spectrum (FIG. 8).

Variant I of Compound 1 described above can be characterized by the NMR spectrum of a solid (FIG. 9).

Applicant therefore proposes variant I of compound 1 obtained by suitable treatment to obtain a particle size of 0.1 to 20 μm.

The present invention has a number of advantages, in particular increased stability and bioavailability.

Accordingly, the subject of the present invention has a characteristic peak having a particle size of 0.1 to 20 μm and represented by angle (° 2 theta) to ± 0.1 ° 2 theta by X-ray powder diffraction: 7.5; 10.9; 13.1; 17.7; Polymorphic compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate showing 19.0.

Preferably, the compounds according to the invention have a particle size of 1 to 15 μm.

More preferably, the compounds according to the invention have a particle size of 3 to 7 μm.

Even more preferably, the compounds according to the invention have a size of 5 μm ± 1 μm.

Preferably, the compound as defined above has a characteristic peak expressed by angle (° 2 theta) to ± 0.1 ° 2 theta by X-ray powder diffraction: 7.5; 10.9; 13.1; 15.0; 15.8; 17.0; 17.7; 19.0; 22.5.

Preferably, the compound as defined above is further added to correspond to the form generated during heating to 160 ° C. by X-ray powder diffraction performed after heating to 160 ° C. and then back to a temperature of 18 to 25 ° C. Characteristic peaks expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta with no peak: 7.5; 10.9; 13.1; 17.7; 19.0.

Very preferably, the compound defined above exhibits an endothermic melt peak of 170 ° C. ± 5 ° C. and an endothermic peak of 180 ° C. ± 2 ° C. using DSC with a temperature gradient of 5 ° C. min ⁻¹ , and at 180 ° C. It is understood that the peak represents up to 10% of the enthalpy changed while melting at 170 ° C.

Very preferably, the compound as defined above does not exhibit an endothermic phenomenon of 140 to 155 ° C. using DSC.

More preferably, the compound as defined above has a characteristic peak expressed in cm ⁻¹ to ± 5 cm ^{− 1} using infrared spectroscopy: 3310; 3167; 3059; 891; 798; 733; 679; 455; Even more preferably the characteristic peaks expressed in cm ⁻¹ to ± 5 cm ^{− 1} : 3310; 3167; 3059; 2928; 2858; 1690; 1605; 1454; 1385; 1261; 1188; 1126; 941; 891; 853; 798; 733; 679; 598; 544; 455 is represented.

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

The compounds according to the invention can be formulated in a variety of pharmaceutical compositions. In the case of a solid form, it may be for example a powder, granules, tablets, gelatin capsules, liposomes or suppositories. In the case of liquid form, for example, it can be a solution, emulsion, suspension or syrup. Administration of the compounds according to the invention can be carried out, for example, in the form of topical, oral, parenteral routes, intramuscular, subcutaneous injections, in particular in the form of gelatin capsules, tablets, patches or creams.

Suitable supports or excipients are for example maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, croscarmellose sodium, polyvinyl-polypyrrolidone (or crospovidone), polyvinylpyrrolidone, carboxy Methylcellulose, pregelatinized starch, methylcellulose, polyethylene glycol, macrogel, polyglycol, polyoxyethylene, polydiol, pyrrolidone-2, colloidal silica, talc, magnesium stearate, sodium stearyl fumarate, calcium Stearate, hydrogenated vegetable oil, sodium lauryl sulfate, calcium phosphate, sugar, dextrin, starch, gelatin, cellulose, wax or water, organic solvents such as glycerol or glycol, similarly with varying proportions of these with or without water It may be a mixture of. Such supports added to the active ingredient serve as:

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

Disintegrants such as starch, sodium croscarmellose, 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 oils;

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

Surfactants (or surface active agents) such as sodium lauryl sulfate.

The composition according to the invention comprises 5 to 30% active ingredient (preferably 6 to 13%); 40 to 92% diluent (preferably 65 to 92%, very preferably 85 to 90%); 0 to 30% disintegrant (preferably 0 to 22%, very preferably 0%); 0-5% surfactant (preferably 0%); 0-5% solubilizer (preferably 0%); 0.1 to 3% flow agent (preferably 0.9 to 1.4%); It may be formulated into gelatin capsules containing 0.5 to 3% lubricant (preferably 0.6 to 2.8%).

Preferred excipients for formulating such gelatin capsules are mannitol, lactose, corn starch, colloidal silica, magnesium stearate, and sodium lauryl sulfate and more particularly mannitol, lactose, colloidal silica and magnesium stearate.

The composition according to the invention comprises 5 to 30% active ingredient (preferably 7 to 15%, very preferably 10 to 15%); 40 to 92% diluent (preferably 34 to 89%, very preferably 70 to 85%); 0-40% disintegrant (preferably 0-20%, very preferably 3-5%); 0-8% binder (preferably 2-5%); 0.1 to 3% flow agent (preferably 0.5 to 1.4%); It may be formulated into a tablet containing 0.5 to 3% lubricant (preferably 0.5 to 2.8%).

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

According to a variant, the present invention provides 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate having a particle size of 0.1 to 20 μm as an active ingredient. To a pharmaceutical composition comprising with at least one pharmaceutically acceptable support; Preferably 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulphate has a particle size of 1 to 15 μm, more preferably 3 to 7 μm. Having a particle size of μm, more preferably 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate has a size of 5 μm ± 1 μm Has

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

Very preferably, the pharmaceutical composition as defined above is a gelatin capsule; More preferably 5 to 30% active ingredient; 40 to 92% diluent; 0-30% disintegrant; 0 to 5% surfactant; 0-5% solubilizer; 0.1 to 3% flow agent; And 0.5 to 3% lubricant.

Also very preferably, the pharmaceutical composition as defined above is a tablet, more preferably 5 to 30% active ingredient; 40 to 92% diluent; 0 to 40% disintegrant; 0 to 8% binder; 0.1 to 3% flow agent; And 0.5 to 3% lubricant.

Synthetic routes for compound 1 are described in patent EP 880514 or in L.W. Woo et al., Chemistry & Biology, 2000, 7, 773-91.

Applicants have now found that such compounds can be synthesized in two chemical steps. The first step is to condensate 2-carbethoxycycloheptanone with resorcinol in a strong acid (such as sulfuric acid, trifluoroacetic acid or methanesulfonic acid) and use an alcohol / water mixture (e.g. ethanol then water Isolating intermediate 3-hydroxy-8,9,10,11-tetrahydrocyclohepta [c] chromen-6 (7H) -one by precipitation). In the second step, sulfonylisocyanate chloride is converted to sulfamoyl chloride by the action of formic acid in toluene solution, followed by condensation with the 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 crude compound 1 is then precipitated from the organic phase by addition of an antisolvent (preferably methylcyclohexane). Finally, the crude product is recrystallized by dissolving in acetone or ethyl acetate at high temperature and pure compound 1 is obtained by precipitation by adding antisolvent (preferably methylcyclohexane).

As a result, the subject of the present invention is the following steps:

Condensation of 2-carbethoxycycloheptanone with resorcinol in a strong acid,

Isolating 3-hydroxy-8,9,10,11-tetrahydrocyclohepta [c] chromen-6 (7H) -one obtained by precipitation using an alcohol / water mixture,

Condensation of 3-hydroxy-8,9,10,11-tetrahydrocyclohepta [c] chromen-6 (7H) -one with chloride sulfamoyl in an aprotic solvent,

Recrystallising the crude product obtained by dissolving in acetone or ethyl acetate at high temperature and adding an antisolvent such as methylcyclohexane

Characterized in that it comprises a 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate.

The compounds according to the invention as described above are obtained from compound 1 in the form of variant I by treatment aimed at reducing particle size.

Accordingly, the subject matter of the present invention comprises 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3, characterized by reducing the size of the particles. A process for the preparation of the compounds according to the invention as described above from one sulfamate.

Preferably, the size of the particles is reduced by micronization.

Preferably, the size of the particles is reduced by wet milling with an organic non-protic solvent.

Subjects of the invention are characterized by the characteristic peaks expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 8.6; 11.3; Polymorphic compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, representing 28.6 (compound of Form III). Preferably, such compound Form III has a characteristic peak expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta: 8.6; 11.3; 12.0; 16.6; 20.9; 23.0; 28.6.

More particular subjects of the present invention are the following cell parameters using single crystal X-ray diffraction:

Equivalent isotropic motion parameters of the reduced coordinates (× 10 ⁴ ) and (Å ² × 10 ³ ):

The coordinates (× 10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) of the following hydrogen atoms (U (eq) is equal to 1/3 of the value of the orthogonal tensor Uij):

The following in-plane spacing is shown:

Preferably, the subject of the invention is a compound as defined above (Form III) which exhibits an endothermic melt peak of 180 ° C. ± 2 ° C. using DSC at 5 ° C. min ⁻¹ .

Preferably, the compounds according to the invention (type III), the use of infrared spectroscopy cm ^-1 to ± 5 cm as defined above ^- to be described as a ^first characteristic peaks: 3406; 3217; 1678; 1011; 563,

Very preferably, cm ^-1 to ± 5 cm ^- to the ^one represented by characteristic peaks: 3406; 3217; 3082; 2924; 1678; 1385; 1269; 1134; 1011; 934; 845; 601; 563; 536 is shown.

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

Subject of the invention is a pharmaceutical composition comprising as an active ingredient a compound of Form III as defined above in combination with at least one pharmaceutically acceptable support.

Subjects of the invention also feature characteristic peaks expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 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; Form 1 of compound 1 showing 28.3.

Subjects of the present invention also feature characteristic peaks expressed as angles (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 9.8; 13.9; 16.0; 17.7; 19.1; Crystalline DMSO solvate of form 3 of compound 1 that represents 22.1.

Subjects of the present invention also feature characteristic peaks expressed as angles (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 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, which is a crystalline 1,4-dioxane antisolvate.

Subjects of the invention also feature characteristic peaks expressed as angles (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 9.4; 10.7; 12.8; 18.2; 18.9; 19.7; 20.4; 23.2, and preferably peaks expressed as angles (° 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; The polymorphic compound of compound 1 which is a compound of form II which shows 23.2.

Preferably, the compound of Form II exhibits an endothermic melt peak of 165 ° C. ± 5 ° C. using DSC at 5 ° C. min ⁻¹ ; More preferably using infrared spectroscopy cm ^-1 to ± 5 cm ^- characteristic peaks expressed in ^1: 3356; 3321; 3186; 1504; 872; 787, even more preferably a characteristic peak represented by 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 is represented.

Compounds according to the invention are obtained from compound 1 by the following additional steps as described above:

Desolvation of form 1 DMSO solvate in water,

Desolvation of form 3 DMSO solvate in water,

Atomization in ethanol,

-Atomization in acetone,

Reimpasting in cumene under reflux,

Heat treatment followed by micronization followed by a second heat treatment, or

-Heat treatment of Form II.

Accordingly, according to a variant, the subject of the invention is a process for the preparation of a compound of Form III as defined above according to one of the following methods starting from compound 1:

a) stirring and precipitation from DMSO to induce crystalline DMSO solvate of Form 1 as defined above, followed by desolvation of the compound in water;

b) stirring and precipitation from DMSO to induce crystalline DMSO solvate of form 3 as defined above, and then desolvating the compound in water;

c) atomization in ethanol;

d) atomization in acetone;

e) recoating in cumene under reflux;

f) heat treatment for 10-20 minutes at a temperature of 155-165 ° C. followed by micronization, followed by a second heat treatment for 10-20 minutes at a temperature of 155-165 ° C.,

g) atomization of the compound in 1,4-dioxane, or

Stirring and precipitating the compound from 1,4-dioxane to derive the crystalline 1,4-dioxane antisolvate as defined above, and then compounding at 20-80 ° C. at 5 ° C. min ⁻¹ under inert gas flow By desolvation by heating,

Treatment of a compound of Form II obtained and defined above,

The treatment here consists of heat treatment for 6 to 10 minutes at a temperature of 155 to 165 ° C.

Preferably, the process according to the invention is subjected to desolvation of crystalline DMSO solvate of Form 1 as defined above in water.

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

Preferably, the process according to the invention is subjected to atomization in ethanol.

Also preferably, the process according to the invention is subjected to atomization in acetone.

Very preferably, the process according to the invention is subjected to reapplication in cumene under reflux.

Even more preferably, the process according to the invention comprises heat treatment at a temperature of 155-165 ° C. for 10-20 minutes and then micronization followed by a second heat treatment at a temperature of 155-165 ° C. for 10-20 minutes. Going through; Preferably the heat treatment is carried out at 160 ° C. ± 1 ° C. for 15 minutes.

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

Preferably, the compound of Form II as defined above is obtained by nebulization of compound 1 in 1,4-dioxane; Or a compound of Form II as defined above is obtained by desolvation of the crystalline 1,4-dioxane antisolvate as defined above.

According to a variant, the subject of the invention is a process for the preparation of crystalline DMSO solvate of Form 1 as defined above by stirring and precipitation from DMSO starting from compound 1.

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

According to a variant, the subject of the invention is a process for the preparation of crystalline 1,4-dioxane antisolvate as defined above by stirring and precipitation from 1.4-dioxane starting from compound 1.

With regard to the above-mentioned Form II, it can be obtained according to two synthetic routes:

Directly by atomization in 1,4-dioxane,

By desolvation of the 1,4-dioxane antisolvate of compound 1 previously obtained by precipitation from 1,4-dioxane.

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

Atomization in 1,4-dioxane;

Stirring and precipitation from 1,4-dioxane to derive the crystalline 1,4-dioxane antisolvate as defined above, and then the compound from 5 ° C.min ⁻¹ to 20 to 80 ° C. under a flow of inert gas. It desolvates by heating.

Preferably, the process for preparing the compound of Form II as defined above is subject to the desolvation of the crystalline 1,4-dioxane antisolvate as defined above.

Also preferably, the process for the preparation of the compound of Form II as defined above is subjected to atomization in 1,4-dioxane.

Alternatively, the subject of the invention is a variant I as defined above for the preparation of a medicament for the treatment of cancer, preferably hormone-dependent cancer, preferably breast cancer, prostate cancer, endometrial cancer or ovarian cancer Use of the compound of Form III.

The following experiments are presented to illustrate the procedure, and in no case should this be regarded as limiting the scope of the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, all patents (or patent applications) as well as other bibliographic references are cited.

Experiment

1. Composition according to the present invention

Example  1a:

The composition in the form of a tablet comprising Compound 1 as the active ingredient is shown in Table 1 below. Such compositions can be prepared by wet granulation according to Scheme 1 below for 5 kg ash and 40 mg doses.

The coating applied to the 40 mg tablet consists of Opadry® II White (Colorcon); This is a commonly available mixture of coatings used for immediate release tablets. The main purpose of such coatings is to mask the bad taste of pharmaceutical substances. It is also to reduce the risks associated with handling during the packaging operation of tablets containing strong active ingredients.

Example  1b:

The compositions in the form of gelatin capsules and comprising Compound 1 as active ingredient are shown in Table 2 below.

2. for dissolution profile Disintegrant  effect

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

The effect of the disintegrant is shown by comparing the solubility values of Compositions 2 and 17 described in item 3 below without sodium starch glycolate at 30 minutes.

Different tests were conducted regarding the effect of addition of disintegrants on the dissolution profile and the disintegration time of the tablets was studied. Four compositions of tablets were prepared to study the effects of two disintegrants, sodium starch glycolate, type A (Exflotab®) and pregelatinized corn starch (starch 1500®).

The results obtained indicate that the addition of disintegrants promotes the dissolution profile of the tablets and brings them closer to the control capsule (see FIG. 2).

3. Wet Granulation  Protective effect of the binder on the active ingredient during the process

A study was conducted demonstrating the protective effect of binders and / or diluents (microcrystalline cellulose, copovidone, carboxymethyl cellulose) by comparing the behavior of these formulations during preparation as well as the final levels of impurities. Different solid compositions obtained by wet granulation by HPLC (high performance liquid chromatography) were analyzed in an Alliance 2695 system with 2487 UV detectors (waters) according to the conditions described in Table (Table 4) below.

4. Blister  At 6 and 12 months in the pack, 5 as a function of storage conditions mg  And stability of the tablets administered at 40 mg

The tablet form (percent formulation of Example 1a) was stabilized after initial packaging in a blister pack.

The purpose of this is to check this type of stability over a period of 6 months and 12 months.

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

In addition, other storage conditions (eg 40 ° C./75% RH) were investigated until the end of the 6-month stability time and the resulting data is shown in Tables 8 and 9 for tablets administered at 5 mg and 40 mg, respectively. .

Table 6 provides a compilation of analysis, impurity and dissolution test results from stability studies of tablets packed in blister packs containing 5 mg of active ingredient and stored at 25 ° C./60% RH.

Table 7 provides a compilation of assay, impurity and dissolution test results from stability studies of tablets packed in blister packs containing 40 mg of active ingredient and stored at 25 ° C./60% RH.

Table 8 provides a compilation of assay, impurity and dissolution test results from stability studies of tablets packed in blister packs containing 5 mg of active ingredient and stored at different storage conditions.

In Table 9, the analysis, impurity and solubility tests of the stability studies of tablets packed in blister packs containing 40 mg of active ingredient and stored at different storage conditions are shown together.

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

Statistical analysis of the results obtained by the regression line with a 95% confidence interval guarantees at least three years of conformity by product quality regulations.

Promoted stability at temperatures of 40 ° C. and 75% relative humidity (40 ° C./75% RH) indicates compliance results by product quality regulations.

The stability of the product under the most severe conditions enhances the reliability in the scheme carried out for the tablets stored at 25 ° C./60% RH.

5. Compound 1 Variant  Manufacture of I

5.1 Synthesis of Compound 1

Example 5 The first step consists of condensing 2-carbethoxycycloheptanone with resorcinol in methanesulfonic acid and the reaction takes 4 hours to 25 ° C. The intermediate 3-hydroxy-8,9,10,11-tetrahydrocyclohepta [c] chromen-6 (7H) -one thus formed is precipitated by addition of ethanol followed by water and then isolated by filtration and under vacuum Dry at 60 ° C. and yield of 78% is obtained. In the second step, sulfonylisocyanate chloride is converted to sulfamoyl chloride by the action of formic acid in toluene solution, followed by condensation with the previous intermediate dissolved in N, N-dimethylacetamide (DMA). The reaction medium is treated with water and extracted with 2-methyltetrahydrofuran (2-MeTHF). Crude compound 1 is obtained by filtration of the precipitate obtained by adding methylcyclohexane to the organic phase. Finally, the crude product 1 is obtained by precipitation by dissolving in acetone at high temperature to recrystallize the crude product and adding methylcyclohexane (addition of antisolvent methylcyclohexane whose main purpose is to increase yield).

Compound 1 is obtained with a yield of 65%, which is shown below.

Example 1 thus obtained may be subjected to appropriate treatment for the purpose of reducing particle size, such as micronization (below point 5.3) or wet grinding (below point 5).

5.2. Of Form 2 of Compound 1 in water DMSO  Desolvation of Solvates

Example 5a : DMSO Solvate of Form 2 of Compound 1

Pour 1 mL of DMSO (Bp = 189 ° C.) into the medicine box and add 1 g of compound 1 (Example 1). The solution is stirred using a magnetic stir bar and magnetic stirrer. Pass the solid through the solution quickly. 1 g of compound 1 is added again under magnetic stirring. The solid is partially dissolved and then solidification is observed. The solidified sample is analyzed while still wet by X-ray powder diffraction. The analysis shown below shows that this is a DMSO solvate of Form 2 of Compound 1 (Example 5a).

Example  5b:

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

Compound 1 is obtained with a yield of 50% and this is shown below.

Example 5b thus obtained may be subjected to appropriate treatment for the purpose of reducing particle size such as micronization or wet grinding.

5.3. Micronization

Micronization is performed using an air-jet micronizer compressed at a temperature of 18-25 ° C. The characteristics of the compressed air used are as follows:

CO: <5 ppm,

CO ₂ : <500 ppm,

Hydrocarbon: <0.5 mg · m ⁻³ ,

-number of particles greater than 0.5μ per ft ³ : <10000,

Maximum performance: 2300 cfm at 13 bar,

Maximum working pressure: 13 bar

Example 5c Variants I of Compound 1 with Particle Size 3 μm

249 g of Compound 1 (Example 1) is micronized using a compressed air-jet micronizer. The micronization parameters are a venturi pressure of 80 psi, a pressure in a micronizer of 110 psi, and a feed rate of 12 kg · h ⁻¹ .

Example 3-1 is obtained in 97% yield.

Example 5d Variant I of Compound 1 with Particle Size 5 μm

16.5 kg of Compound 1 (Example 5) are micronized using a compressed air-jet micronizer. The micronization parameters are a venturi pressure of 80 psi, a pressure of micronizer of 32 psi, and a feed rate of 14.4 kg · h ⁻¹ .

Example 5d is obtained in a yield of 98% and shown below.

Example 5e Variant I of Compound 1 having a particle size of 9 μm

150 g of Compound 1 (Example 51) is micronized using a compressed air-jet micronizer. The micronization parameters are a venturi pressure of 50 psi, a microprocessor pressure of 60 psi, and a feed rate of 15 kg · h ⁻¹ .

Example 5e is obtained in a yield of 98%.

Example 5f Variant I of Compound 1 having a Particle Size of 15 μm

39 g of Compound 1 (Example 5) is micronized using a compressed air-jet micronizer. Micronization parameters are 30 psi venturi pressure, 10 psi micron pressure, and a feed rate of 40 g within 15 minutes.

Example 5f is obtained in a yield of 74%.

5.4 wet grinding

Example 5g : 0.69 g of Compound 1 (Example 5) was ground with 0.068 g of methylcyclohexane in a frish-type planetary gear model P4 ball mill.

The wet grinding parameters were as follows: 7 agate spheres with a diameter of 10 mm; Grinding torque of 100-100 rpm Ω (rotational speed of the disc)-ω (rotational speed of the flask), a period of 12 hours valid for a total of 18 hours according to the following 72 sequences; 10 minutes of milling-5 minutes of stopping, mass ratio of spheres to solute mass = 14.1; The ratio of the temperature of 22 ° C. and the mass of compound 1 / mass of methylcyclohexane of 9%.

Example 3 is obtained in a yield of 99% and shown below.

6. The obtained  Explanation of the Decision

6.1 Devices Used

6.1.1 X-ray Powder and Single Crystal Diffraction

Siemens D5005 Diffractometer, Scintillation Detector

Wavelength: 1.54056 Cu, Voltage 40kV, Strength 40 mA

Measuring range: 3 °-30 ° 2 theta

Interval: 0.04 ° 2 theta

Interval period: 4s

Fixed slot: 1.6 mm

Kβ filter (Ni)

No internal standard

EVA software for data processing (v 12.0)

Smart Apex Bruker Diffractometers, 2-D Detector

SMART software for determining parameters and orientation of crystalline substrates

SAINT software for data integration and processing

WinGX software for the determination of spatial group and structural analysis

6.1.2. DSC

Netzsch DSC 204F1

Aluminum crucible and perforated lid

Atmosphere: Helium

Initial temperature: 20 ℃

Final temperature: 200 ° C

Temperature gradient: 5 ° Cmin ^-1

6.1.3. IR

KBr pellets

Brooker IFS28 type spectrometer

Spectrum range: 400 to 4000 cm ^-1

6.1.4. Solid NMR

Brooker Avens 500 MHz spectrometer

MAS (Magic Angle Spinning) 4mm probe

Brooker XWIN NMR Software

VACP (variable width cross-polarized light) with MAS (11 kHz) and proton decoupling (speed 64, 65 kHz)

External contrast: Adamantane

6.1.5. Particle size distribution

Malvern Master Sizer S Laser Particle Size Analyzer

Sample size: 30-50 mg

Dispersion medium: 0.50% (m / v) Noni Soap in water

Mie theory as refractive index: particle RI = 1.55; Virtual RI = 1.00; Variance RI = 1.38

Ultrasonic processing time: 60 seconds

Ultrasonic Treatment Energy: 50 to 60 Hz

Recirculation time: 30 seconds at 2000 rpm ^-1

Obscurity: 15-25%

6.2. Example  Characterization

6.2.1. Examples 5 and 5b

Single crystals can be isolated by slow evaporation of saturated solution in ethanol for 2 days at 4 ° C. This single crystal makes it possible to analyze the complete structure of variant I of compound 1 by X-ray diffraction.

X-ray single crystal diffraction: The crystal structure of compound 1 variant I is analyzed and the following cell parameters are shown:

The reduced coordinates (× 10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) of Compound 1 Form I are as follows:

The reduced coordinates (× 10 ⁴ ) of the hydrogen atoms of compound 1 variant I are as follows:

The in-plane spacing of compound 1 variant I is as follows:

6.2.2. Example  5a

Single crystals can be isolated by slowly evaporating a saturated solution of DMSO at ambient temperature. This single crystal made it possible to analyze the complete structure of the DMSO solvate of Form 2 of Compound 1 by X-ray diffraction.

Single Crystal X-Ray Diffraction: The crystal structure of DMSO solvate of Form 2 of Compound 1 was analyzed and the following cell parameters are shown:

The atomic coordinates (× 10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) (U (eq)) of atoms in the cells of DMSO solvate of form 2 of compound 1 are equal to 1/3 of the value of orthogonal tensor Uij Is the same):

Coordinates (× 10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) of hydrogen atoms of DMSO solvate of form 2 of compound 1 (U (eq) is equal to 1/3 of the value of orthogonal tensor Uij) Is as follows:

The in-plane spacing of DMSO solvate of Form 2 of Compound 1 is as follows:

The X-ray powder diffraction diagram of the DMSO solvate of Form 2 of Compound 1 has a characteristic peak expressed as angle (° 2 theta) to approximately ± 0.1 ° 2 theta: 7.6; 18.7; 24.2; 29.9 (FIGS. 1 and 2).

6.2.3. Example 5c-5g

6.2.3.1 X-Ray Powder Diffraction (FIGS. 5 and 6)

The X-ray powder diffraction diagram of variant I of compound 1 after micronization or wet grinding is characterized by characteristic peaks expressed as angles (° 2 theta) to 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 is indicated.

The X-ray powder diffraction diagram of Variant I of Compound 1 after micronized or wet milled and then heated to 160 ° C. was obtained at angle (° 2 theta) without additional peaks corresponding to the new form formed during heating to 160 ° C. ) To a characteristic peak expressed as 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 is indicated.

6.2.3.2. DSC (FIG. 7)

Using DSC, the thermogram obtained at 5 ° C. · min ⁻¹ of Variant I of Compound 1 after micronization or wet milling includes the melting peak of Variant I (starting 170 ± 5 ° C.) and optionally during The resulting small polymorphic small melt peak (starting 180 ± 2 ° C.) represents less than 10% of the total heat exchanged during the melt peak of variant I, and any endothermic phenomenon (or less than 0.5 J / g) between 140 and 155 ° C. ) Is also not shown.

6.2.3.3. IR (Figure 8)

The IR spectrum of Variant I of Compound 1 after micronization or wet grinding is characterized by a characteristic peak expressed in cm ⁻¹ to 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 is represented.

6.2.3.4. NMR of solids (FIG. 9)

The spectrum of variant I of compound 1 after micronization or wet milling obtained by NMR of solids has a characteristic peak expressed in ppm to approximately ± 0.2 ppm: 163.1; 156.1; 153.8; 153.1; 130.4; 127.6; 107.6; 35; 25 is represented.

6.2.3.5. Particle size

The particle size distribution of variant I of compound 1 after micronization according to example 2-2 is as follows: D (10%) = 1.2 μm; D50 (%) = 5.2 μm and D90 (%) = 11.0 μm.

The particle size distribution of variant I of compound 1 after wet milling according to example 3 is as follows: D (10%) = 0.6 μm; D50 (%) = 3.1 μm and D90 (%) = 13.7 μm.

7. Formulation

7.1 Preparations in the form of gelatin capsules

Variant I of compound 1 according to the invention comprises 5 to 30% active ingredient (preferably 6 to 13%), 40 to 92% diluent (preferably 65 to 92%, very preferably 85 to 90%), 0 to 30% disintegrant (preferably 0 to 22%, very preferably 0%), 0 to 5% surfactant (preferably 0%), 0 to 5% solubilizer (preferably 0%) , Gelatin capsules containing 0.1 to 3% flow agent (preferably 0.9 to 1.4%), 0.5 to 3% lubricant (preferably 0.6 to 2.8%).

Preferred excipients for formulating such gelatin capsules are mannitol, lactose, corn starch, colloidal silica, magnesium stearate, and sodium lauryl sulfate, more particularly mannitol, lactose, colloidal silica and magnesium stearate.

The gelatin capsules shown below were prepared by mixing powders according to standard techniques known to those skilled in the art.

M = mannitol; L = lactose; CS = corn starch; SLS = sodium lauryl sulfate; PEG = polyethylene glycol; CS = colloidal silica; MS = magnesium stearate

Example 7j An example of gelatin capsule 7j is prepared from compound 1 of example 5: 40 mg of compound 1 was mixed with 260 mg of lactose and placed in gelatin capsule.

Example 7k An example of gelatin capsule 7k is prepared according to Formulation 7g using Example 5c as the active ingredient instead of Example 5d.

Example 7l An example of 7l of gelatin capsules is prepared with 7.2% Example 5d, 31.9% mannitol, 59.4% lactose and 1.5% colloidal silica.

Example 7m An example of 7m of gelatin capsules is prepared according to Formulation Example 7g using Example 5d as the active ingredient.

Example 7n An example of gelatin capsule 4n is prepared according to Formulation Example 4 g using Example 5e as the active ingredient instead of Example 5d.

Example 7o An example of a gelatin capsule 4o is prepared with Example 5f as the active ingredient: 40 mg of Example 5f is mixed with 260 mg of lactose and placed in a gelatin capsule.

7.2. Formulations in Tablet Form

Variant I of compound 1 according to the invention comprises 5 to 30% active ingredient (preferably 7 to 20%, very preferably 10 to 15%), 40 to 92% diluent (preferably 34 to 89%, very Preferably 70 to 85%), 0 to 40% disintegrant (preferably 0 to 20%, very preferably 3 to 5%), 0 to 8% binder (preferably 2 to 5%), It may be formulated into tablets containing 0.1 to 3% flow agent (preferably 0.5 to 1.4%), 0.5 to 3% lubricant (preferably 0.5 to 2.8%).

Preferred excipients for formulating such gelatin capsules are maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, crospovidone, polyvinylpyrrolidone, carboxymethyl cellulose, colloidal silica, magnesium stearyl fumar Rate, and magnesium stearate, more particularly microcrystalline cellulose, lactose, sodium starch glycolate, polyvinylpyrrolidone, colloidal silica and magnesium stearate.

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

8. Physical-chemical and biological properties

8.1 Dissolution rate

Dissolution rates (expressed as percent of Compound 1 dissolved as a function of time) according to standard techniques known to those skilled in the art are measured according to standard techniques known to those skilled in the art and shown in the table below.

The dissolution result is expressed as a percentage of theoretical strength. The theoretical strength in gelatin capsules 4j to 4n is 40 mg of active ingredient. This example is experimental and a slight excess of active ingredient is possible during weighing, which accounts for more than 100% percent at the final dissolution point.

8.2 Bioavailability

Comparative bioavailability of Compound 1 was studied in dogs after a single administration of two gelatin capsules by the oral route. 1 after administration; 1.5; 2; 4; 6; 9. 12; 24; Blood samples were collected at 30 and 48 hours. The area under the curve (AUC) is one of the pharmacokinetic parameters measured in plasma samples from dogs. The results obtained are shown in the table below.

8.3 Chemical stability

A stability study was performed at 100 ° C. between variant I of compound 1 and compound 1 described in patent EP 880514. The chemical stability of Compound 1 is studied using HPLC with different scores.

The operating conditions of the HPLC method are as follows:

Column: Interchim UP3HDO-15XS, 150 × 4.6 mm

Eluent A:-water 2500

           Trifluoroacetic acid0.5

Eluent B:-Acetonitrile

·gradient

Detection: 205 nm,

Injection: 20 microliters

Temperature: 40 ℃

Injection solution: 0.5 mgmL- ¹ (acetonitrile)

9. shape III Preparation of Compound 1

Form III of Compound 1 described in this application is obtained by following the following additional steps: Synthesis of Compound 1 (Example 5):

Desolvation of DMSO Solvate of Form 1 in Water: Example 9a

Desolvation of DMSO solvate of form 3 in water: Example 9b

Atomization in ethanol: Example 9c

Atomization in acetone: Example 9d

Recoating in cumene under reflux: Example 9e

Heat treatment followed by micronization followed by a second heat treatment: Example 9f

Heat treatment of Form II: Example 9g

9.1 Of mode 1 in water DMSO  Desolvation of Solvates

Example 9 aa : DMSO Solvate of Form 1 of Compound 1

Pour 1 mL of DMSO (Bp = 189 ° C) into the medicine box and add 1 g of compound 1 (Example 5). The solution is stirred using a magnetic stir bar and magnetic stirrer. Pass the solid through the solution quickly. 1 g of compound 1 is added again under magnetic stirring. The solid is partially dissolved and then solidification is observed. The solidified sample is analyzed while still wet by X-ray powder diffraction. The analysis shown below indicates that this is a DMSO solvate of Form 1 of Compound 1 (Example 9aa).

Example  9a:

DMSO solvate of form 2 of compound 1 (Example 9aa) is immersed in cold water and left under stirring for 5 minutes at ambient temperature. The suspension is then filtered and dried.

Compound 1 of Form III is obtained with a yield of 50%, which is shown below.

9.2 Of Mode 3 In Water DMSO  Desolvation of Solvates

Example 9 ba : DMSO Solvate of Form 3 of Compound 1

Pour 1 mL of DMSO (Bp = 189 ° C.) into the medicine box and add 1 g of compound 1 (Example 1). The solution is stirred using a magnetic stir bar and magnetic stirrer. Pass the solid through the solution quickly. The solution is placed under magnetic stirring for 24 hours. The solidified sample is then analyzed while still solidified by X-ray powder diffraction when solidification is observed. The assay shown below indicates that this is a DMSO solvate of form 3 of compound 1 (Example 9ba).

Example  9b:

DMSO solvate of form 3 of compound 1 (Example 3ba) is immersed in cold water and left under stirring for 5 minutes at ambient temperature. The suspension is then filtered and dried.

Compound 1 of Form III is obtained with a yield of 50%, which is shown below.

9.3 in ethanol Atomization

Example 9c:

The product obtained is prepared in a Büi 190 spray-dryer. 2 g of compound 1 (Example 5) are dissolved in 200 mL of ethanol (Bp = 78 ° C.). The dry air injection temperature is adjusted to 90 ° C. at a pressure of 3 bar. The outlet temperature is measured at 38 ° C. during atomization. Adjust the outlet flow rate to 700 NI / hour. 570 mg of dry powder is recovered and analyzed by X-ray powder diffraction. This analysis shows that this is Form III of Compound 1 and is structurally pure compared to the diagram calculated from the single crystal structure analyzed.

Compound 1 of Form III is obtained in 29% yield and is shown below.

9.4 in acetone Atomization

Example 9d :

The product obtained is prepared in a Büi 290 spray-dryer with an inert loop. 2 g of compound 1 (Example 1) are dissolved in 100 mL of acetone (Bp = 56 ° C.). The dry air injection temperature is adjusted to 70 ° C. The outlet temperature is measured at 50 ° C. during atomization. Adjust the outlet flow rate to 7600 NI / hour. 1 g of dry powder is recovered and analyzed by X-ray powder diffraction. This analysis shows that this is Form III of Compound 1 and is structurally pure compared to the diagram calculated from the single crystal structure analyzed.

Compound 1 of Form III is obtained in 50% yield and is shown below.

9.5 under reflux Cumen  Reapplication

Example 9e :

10 g of compound 1 (Example 5) is suspended in 100 mL of cumene (Bp = 152 ° C.). The mixture is refluxed under stirring and cooled to ambient temperature. Analysis of the recovered and dried powder indicates that this is Form III of Compound 1.

Compound 1 of Form III is obtained in 99% yield and shown below.

9.6. Heat treatment followed by micronization followed by second heat treatment

Example 9f :

150 g of compound 1 is heated in a ventilated oven at 160 ° C. for 15 minutes. This heated product is micronized using a compressed air-jet micronator. Micronization parameters for first pass: Venturi pressure of 80 psi, pressure of micronizer at 120 psi and flow rate of 1.2 kg · h ^-1 , Micronization parameters for second pass: Venturi pressure of 50 psi , A pressure of 50 psi micronizer and a flow rate of 1.2 kg · h ⁻¹ . Micronization yield is 69%. 15 g of the obtained product are heated in aeration oven at 160 ° C. for 15 minutes.

Compound 1 of Form III is obtained in a yield of 69% and shown below.

9.7 form II Heat treatment

9.7.1. To give a form II

Form II of Compound 1 can be obtained by two synthetic routes:

Desolvation of 1,4-dioxane antisolvate of compound 1 previously obtained by precipitation from 1,4-dioxane;

Directly atomization in 1,4-dioxane;

Example 9h 1,4-dioxane antisolvate of compound 1

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

The 1,4-dioxane antisolvate of compound 1 was obtained in a yield of 80% and shown below.

Example 9i Compound 1 of Form II

According to the first synthetic route, the 1,4-dioxane antisolvate of compound 1 (Example 9h) was heated from 20 ° C to 80 ° C at 5 ° Cmin ^{- 1} under a flow of inert gas, by desolvation Form II of Compound 1 is characterized by an X-ray diffraction pattern.

Compound 1 of Form II is obtained in 99% yield and shown below.

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

Compound 1 of Form II is obtained in a yield of 50% and shown below.

9.7.2. To give a form III

Example 9g:

The recovered dry powder of compound 1 of Form II (Example 9i) was left in an oven at 160 ° C. for 6-10 minutes, preferably 7.5 minutes. The powder recovered after this treatment was analyzed by X-ray diffraction and found to be Form III of Structurally pure Compound 1 compared to the calculated diagram obtained from the analyzed single crystal structure.

Compound 1 of Form III is obtained in 99% yield and shown below.

10. The obtained Solid phase Characterization

10.1 Devices Used

10.1.1. X-ray powder and single crystal diffraction

Siemens D5005 Diffractometer, Scintillation Detector

Wavelength: 1.54056 Cu, voltage 40 kV, intensity 40 mA

Measuring range: 3 °-30 ° 2 theta

Interval: 0.04 ° 2 theta

Interval period: 4s

Fixed slot: 1.6 mm

Kβ filter (Ni)

No internal standard

EVA software for data processing (v 12.0)

Smart Apex Bruker Diffractometers, 2-D Detector

SMART software for determining parameters and orientation of crystalline substrates

SAINT software for data integration and processing

WinGX software for the determination of spatial group and structural analysis

10.1.2. DSC

Netsushi DSC 204F1

Aluminum crucible and perforated lid

Atmosphere: Helium

Initial temperature: 20 ℃

Final temperature; 200 ℃

Temperature gradient: 5 ° Cmin ^-1

10.1.3. TG-DSC

Netsushi STA 449C

Aluminum crucible and perforated lid

Atmosphere: Helium

Initial temperature: 25 ℃

Final temperature; 200 ℃

Temperature gradient: 5 ° Cmin ^-1

10.1.4 IR

KBr pellets

Brooker IFS28 type spectrometer

Spectrum range: 400 to 4000 cm ^-1

10.1.5. Solid NMR

Brooker Avens 500 MHz spectrometer

MAS (magic angular spin) 4 mm probe

Brooker XWIN NMR Software

VACP (variable width cross-polarized light) with MAS (11 kHz) and proton decoupling (speed 64, 65 kHz)

External contrast: Adamantane

10.2. Example Characterization

10.2.1. Form I of Compound 1

The X-ray powder diffraction diagram of Form I of Compound 1 shows the following characteristic peaks, expressed as angles (° 2 theta) to 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. DMSO solvate form of compound 11

Single crystals can be isolated by slowly evaporating a saturated solution of DMSO at ambient temperature. This single crystal made it possible to analyze the complete structure of the DMSO solvate of Form 1 of Compound 1 by X-ray diffraction.

Single-crystal X-ray diffraction: The crystal structure of DMSO solvate of Form 1 of Compound 1 shows the following cell parameters.

The atomic coordinates (× 10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) of the atoms in the cell (U (eq) is equal to 1/3 of the value of the orthogonal tensor Uij) are:

The coordinates of the hydrogen atom (× 10 ⁴ ) and the equivalent isotropic displacement parameter () ² × 10 ³ ) (U (eq) is equal to 1/3 of the value of the orthogonal tensor Uij) are:

The in-plane spacing of DMSO solvate Form 1 is as follows:

The X-ray powder diffraction diagram of the DMSO solvate of Form 1 of Compound 1 has the following characteristic peaks, expressed as angles (° 2 theta) to 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 (FIGS. 1 and 2) are shown.

10.2.3. DMSO solvate form of compound 13

Single crystals can be isolated by slowly evaporating a saturated solution of DMSO at ambient temperature. This single crystal made it possible to analyze the complete structure of the DMSO solvate of Form 3 of Compound 1 by X-ray diffraction.

Single-crystal X-ray diffraction: The crystal structure of DMSO solvate of Form 3 of Compound 1 was analyzed and the following cell parameters are shown.

The coordinates of the hydrogen atom (× 10 ⁴ ) and the equivalent isotropic displacement parameter () ² × 10 ³ ) (U (eq) is equal to 1/3 of the value of the orthogonal tensor Uij) are:

The coordinates of the hydrogen atom (× 10 ⁴ ) and the equivalent isotropic displacement parameter () ² × 10 ³ ) (U (eq) is equal to 1/3 of the value of the orthogonal tensor Uij) are:

The in-plane spacing of DMSO solvate Form 3 is as follows:

The X-ray powder diffraction diagram of DMSO solvate of Form 3 of Compound 1 shows the following characteristic peaks, expressed as angles (° 2 theta) to approximately ± 0.1 ° 2 theta: (FIGS. 3 and 4) 9.7; 13.9; 16.0; 17.8; 19.1; 22.1.

10.2.4. Form III , Single Crystal X-Ray Diffraction

By a slow evaporation of the acetone / n-heptane mixture, a saturated solution of compound 1 at 50% v / v at ambient temperature, X-ray diffraction could isolate a single crystal capable of analyzing the complete structure of form III of compound 1 Could.

Single-crystal X-ray diffraction: The crystal structure of Compound 1 Form III was analyzed and the following cell parameters are shown.

The reduced coordinates (× 10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) of Compound 1 Form III are as follows:

The coordinates of the hydrogen atom (× 10 ⁴ ) and the equivalent isotropic displacement parameter () ² × 10 ³ ) (U (eq) is equal to 1/3 of the value of the orthogonal tensor Uij) are:

The in-plane spacing is as follows:

10.2.5. Example  9a-9g: mode III Compound of 1

Analysis of solids by X-ray powder diffraction, single crystal X-ray diffraction, DSC, IR, and NMR of solids showed that Example 9a is Example 9b, Example 9c, Example 9d, Example 9e, and Example 9f. And Example 9g.

10.2.5.1. X-ray powder diffraction

The X-ray powder diffraction diagram of Form III of Compound 1 has the following characteristic peaks, expressed in degrees (° 2 theta) to 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 (FIGS. 5 and 6).

10.2.5.2. DSC

The thermogram of Form III of Compound 1 in DSC includes the melting peak of Form III (starting 180 ± 2 ° C.) (FIG. 7).

10.2.5.3. IR

The IR spectrum of Form III of Compound 1 is characterized by the characteristic peaks represented by cm ⁻¹ to about ± 5 cm ^{− 1} : 3406; 3217; 3082; 2924; 1678; 1385; 1269; 1134; 1011; 934; 845; 601; 563; 536 (FIG. 8) is shown.

10.2.5.4. Solid NMR

The spectrum of Form III obtained by NMR of solids has a characteristic peak expressed in ppm to approximately ± 0.2 ppm: 162.9; 156.4; 151.3; 126.1; 124.7; 118.8; 117.1; 112.9; 35; 20 is shown (FIG. 9).

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

10.2.6.1. Single crystal X-ray diffraction

By slowly evaporating a saturated solution of compound 1 in 1,4-dioxane at ambient temperature, isolating a single crystal capable of analyzing the complete structure of the 1,4-dioxane antisolvate of compound 1 by X-ray diffraction Could.

The crystalline structure of the 1,4-dioxane antisolvate of compound 1 shows the following cell parameters:

The reduced coordinates (× 10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) from the 1,4-dioxane antisolvate of compound 1 are as follows:

The hydrogen coordinates (× 10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) of the 1,4-dioxane antisolvate of compound 1 are as follows:

The in-plane spacing of 1,4-dioxane antisolvate is as follows:

10.2.6.2. X-ray powder diffraction

The X-ray powder diffraction diagram of the 1,4-dioxane antisolvate of Compound 1 is characterized by the following characteristic peaks expressed in degrees (° 2 theta) to 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 (FIGS. 10 and 11).

10.2.6.2. TG - DSC

Using TG-DSC, the thermogram of the 1,4-dioxane antisolvate of Compound 1 shows that the solvate releases 1,4-dioxane starting at 75 ° C. to produce Form II of Compound 1. (FIG. 12).

10.2.7. Example  9i: form II Compound of 1

10.2.7.1. X-ray powder diffraction

The X-ray powder diffraction diagram of Form II of Compound 1 is characterized by the following characteristic peaks expressed in degrees (° 2 theta) to 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 (FIG. 13) is shown.

10.2.7.2. DSC

Using DSC, the thermogram of Form II of Compound 1 includes an endothermic phenomenon corresponding to the metastable melt of Form II at 165 ° C. ± 5 ° C., followed by recrystallization to another form, followed by another melting phenomenon (FIG. 14).

10.2.7.3. IR

The IR spectrum of Form II of Compound 1 is characterized by a characteristic peak expressed in cm ⁻¹ to approximately ± 5 cm ^{− 1} : 3356; 3321; 3186; 3078; 2932; 2851; 1693; 1609; 1504; 1462; 1377; 1265; 1192; 1123; 937; 872; 837; 787; 594 is shown (FIG. 15).

10.2.7.4. Solid NMR

The spectrum of Form II obtained by NMR of a solid has a characteristic peak expressed in ppm to approximately ± 0.2 ppm: 163.0; 154.5; 153.5; 151.6; 128.6; 118.5; 111.4; 108.2; 35; 25 is shown (FIG. 16).

11. Physical-chemical and biological properties

11.1 Conversion experiment

Applicants conducted a conversion experiment between different polymorphic forms of Compound 1 to show that Form III was a stable form at high temperatures (T> 145 ° C). This important property makes it possible to remove traces of solvent by heating under vacuum [Polymorphism in the Pharmaceutical Industry, Wiley 2006, Ed Hilfiker; Wiley, ISBN: 978-3-527-31146-0. By returning to ambient temperature, Form III of Compound 1 remains unchanged, which constitutes a major advantage in the pharmaceutical industry.

11.2. Chemical stability

Stability studies were performed at 150 ° C. between compound 1 of form III and compound 1 described in patent EP 880514. This chemical stability of compound 1 was studied using HPLC.

The operating conditions of the HPLC method are as follows:

Column: Interkim UP3HDO-15XS, 150 × 4.6 mm,

Eluent A:-water 2500

           Trifluoroacetic acid0.5

Eluent B:-Acetonitrile

·gradient

Detection: 205 nm,

Injection: 20 microliters

Temperature: 40 ℃

Injection solution: 0.5 mgmL- ¹ (acetonitrile)

Claims (35)

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 gelatin capsules. The pharmaceutical composition of claim 1, wherein the solid form is a tablet. The composition of claim 3, wherein the tablet comprises 1 to 30% active ingredient based on the total weight of the composition; 40 to 92% diluent; 0.1 to 20% disintegrant; 0.1 to 8% binder; 0.1 to 3% lubricant; And about 4.8% coating solution based on 0.5-3% lubricant as well as 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, croscarmellose sodium, sodium starch glycolate or crospovidone. The method of claim 4, wherein the binder is a copolymer of the following excipients: polyvinylpyrrolidone, N-vinyl-2-pyrrolidone and vinyl acetate (or copovidone), carboxymethylcellulose, pregelatinized starch, or methylcellulose Pharmaceutical composition. 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 oils. A pharmaceutical composition according to any one of claims 1 and 2 to 8 comprising microcrystalline cellulose (MCC) and / or copovidone or microcrystalline cellulose (MCC) and / or carboxymethylcellulose (CMC). . 10. The composition of claim 1, wherein the composition comprises 8 to 20% active ingredient, based on the total weight of the tablet; 20 to 40% lactose and 25 to 50% microcrystalline cellulose used as diluent; 2-8% copovidone used as binder; 1 to 5% sodium starch glycolate used as disintegrant; 0.2-1.4% flow agent; And 0.5 to 2% lubricant in the form of a tablet. The method of claim 1, wherein the 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate is 1-20 μm. Pharmaceutical composition having a particle size of. The method of claim 1, wherein the 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate is from 1 to 15 μm. Pharmaceutical composition having a particle size of. The pharmaceutical composition according to any one of claims 1 to 12, for immediate release. The pharmaceutical composition according to any one of claims 1 to 13, wherein the uncoated tablet does not exceed the total weight of 800 mg, preferably 400 mg. Starting from 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, characterized by reducing the particle size of the active ingredient A method for preparing a solid pharmaceutical composition according to claim 1. The method of claim 15, wherein the size of the particles is reduced by micronization. Characterized in that the mixture may comprise a substance added to the powder, which may improve its fluidity, such as a lubricant,
Below steps:
-Constitution of ingredients
Wet granulation followed by mixing and compacting of the components
Preparation of coating solutions
A method of making a solid pharmaceutical composition according to any one of claims 1 to 14 comprising. 18. The method of claim 17, wherein the lubricant is a colloidal solution of silicon dioxide. 18. The method of claim 17, wherein, during the wet granulation step, the mass of water is about 10-30% relative to the total mass of active ingredient and premixed binder, diluent and disintegrant. 18. The method of claim 17, wherein after the wet granulation step, the granules are dried until less than 3% residual moisture is obtained. Characteristic peaks having a particle size of 0.1 to 20 μm and expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 7.5; 10.9; 13.1; 17.7; Polymorphic compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, which shows 19.0. The compound of claim 21, wherein the particles have a size of 1 to 15 μm. The compound of claim 21, wherein the particles have a size of 3 to 7 μm. The compound of claim 21, having a size of 5 μm ± 1 μm. The system of claim 21, wherein the characteristic peaks are expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 7.5; 10.9; 13.1; 15.0; 15.8; 17.0; 17.7; 19.0; A compound characterized by 22.5. 26. The form according to claim 21, wherein the form is produced during heating to 160 ° C. using X-ray powder diffraction performed after heating to 160 ° C. and then back to a temperature of 18 to 25 ° C. 27. Characteristic peaks expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta without further peaks corresponding to: 7.5; 10.9; 13.1; 17.7; A compound characterized by 19.0. 26. An endothermic melt peak at 170 ° C ± 5 ° C and an endothermic peak at 180 ° C ± 2 ° C, using DSC for a heating rate of 5 ° C.min ^-1 . And a peak at 180 ° C. represents a maximum of 10% of the enthalpy exchanged during melting at 170 ° C. The compound according to any one of claims 1 to 7, characterized in that no endothermic phenomenon is exhibited at 140 to 155 ° C. using DSC. Using infrared spectrometry expressed in cm ^-1 to about ± 5cm ^-1 characteristic peaks: 3310; 3167; 3059; 891; 798; 733; 679; A compound according to any one of claims 1 to 8, characterized in that it represents 455. Characteristic peaks expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 8.6; 11.3; Polymorphic compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, representing 28.6. 31. The method of claim 30 wherein the characteristic peaks are expressed in degrees (° 2 theta) to ± 0.1 ° 2 theta using X-ray powder diffraction: 8.6; 11.3; 12.0; 16.6; 20.9; 23.0; A compound characterized by showing 28.6. 32. The method of claim 30 or 31, wherein the single cell X-ray diffraction is used to determine the following cell parameters:

The following reduced coordinates (× 10 ⁴ ) and equivalent isotropic motion parameters (Å ² × 10 ³ ):

A compound characterized by the above-mentioned. 33. A compound according to any one of claims 30 to 32, characterized by an endothermic melt peak of 180 ° C ± 2 ° C using DSC at 5 ° C.min ^{- 1} . Of claim 30 to claim 33 according to any one of items, using infrared spectroscopy with characteristic peaks expressed in cm ^-1 to about ± 5cm ^-1: 3406; 3217; 1678; 1011; 563 is represented. Of claim 34 wherein, using infrared spectrometry expressed in cm ^-1 to about ± 5cm ^-1 in the characteristic peaks: 3406; 3217; 3082; 2924; 1678; 1385; 1269; 1134; 1011; 934; 845; 601; 563; 536 represented by the compound.

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