Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
  • A61K31/37—Coumarins, e.g. psoralen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings

Definitions

• the present invention relates to a solid pharmaceutical composition
• a solid pharmaceutical composition comprising as active ingredient the compound 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate.
• the invention also relates to the preparation of this pharmaceutical composition, its use as a medicament, and more particularly as a medicament for the treatment of certain cancers, the compound 1 targeting the steroid sulphatase enzyme.
• a composition according to the invention containing as active principle the compound 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate (also called subsequently compound 1). advantage of being a stable oral pharmaceutical composition and offering appropriate bioavailability.
• compositions such as tablets can be made by three methods: wet granulation, dry granulation and direct compression.
• Compound 1 belongs to class 2 of the Biopharmaceutical Classification System (BCS) proposed by G. Amidon (see GL Amidon et al., "A guideline for a biopharmaceutical drug classification: the in vitro correlation drug dissolution and in vivo bioavailability ", Pharm Res, 12 (1995) 413-420). Its absorption, and therefore its bioavailability, thus strongly depend on the dissolution rate of the administered dosage form.
• BCS Biopharmaceutical Classification System
• aqueous phases such as self-emulsifying drug delivery systems, conventionally used to increase the apparent solubility of class 2 compounds, are not suitable because the excipients and the aqueous phases used are not compatible with compound 1, and lead to chemical degradation during the production step.
• the low compressibility composition caused fragmentation during dry compression as well as a slow dissolution profile.
• the components are mixed and granulated in the wet phase by means of a binder.
• the binder can be either dissolved in the wet phase or incorporated into the powder mixture to be granulated.
• the wet granules are then sieved, dried and optionally crushed before compression to form the tablets.
• a novel solid pharmaceutical composition for oral administration of compound 1 has been found to solve the specific problems of this active ingredient and to obtain it by a wet granulation method.
• This oral composition in tablet or capsule form, is stable with rapid dissolution of the solid form thus producing immediate release with effective bioavailability.
• the present invention therefore relates to a solid pharmaceutical composition containing as active ingredient 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate and at least one pharmaceutically acceptable excipient.
• the subject of the present invention is also a solid pharmaceutical composition containing as active principle 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate and at least one pharmaceutically acceptable excipient, for oral administration and preferably for oral immediate release administration.
• the present invention also relates to a solid pharmaceutical composition for oral administration comprising compound 1 as active ingredient and at least one disintegrating agent and one or more protective agents against moisture.
• Such agents thus protect the active principle from hydrolysis and thus prevent its degradation.
• compound 1 is micronized.
• the present invention also relates to the process for the manufacture of pharmaceutical compositions as described below. It is thus possible to carry out the process according to the invention using adjuvants and excipients of the conventional type for the production of tablets using a wet granulation.
• immediate oral administration or “immediate release oral form” or “immediate release composition” is meant according to the invention an administration or oral composition allowing an in vitro dissolution of at least 80% by weight of the active ingredient in 45 minutes, preferably 30 minutes in accordance with the appropriate in vitro dissolution test, developed for compound 1.
• This test is carried out with a dissolution apparatus to pale at 37 ° C with stirring at 100 rpm, in buffered solution of hydrochloric acid at pH 1, 2 according to the standards of the US Pharmacopoeia, and comprising 0.1% of a surfactant, cetyl trimethyl ammonium bromide, which makes it possible to obtain sufficient solubility of the active principle in the test medium.
• the assay is performed by ultraviolet (UV) / visible absorption spectrophotometry at the wavelength of 311 nm.
• slip agent or “flow agents” used according to the invention is also meant adjuvants and excipients sometimes called lubricants and agents improving the fluidity and flow of granules.
• centesimal formulation is meant according to the invention a proportion of active ingredient or excipient given in% by weight, relative to the total weight of the composition.
• binding agent or binder is meant according to the invention adjuvants or excipients used to maintain the structure and cohesion of the dosage form. They have the property of allowing the granular assembly of the ingredients during the granulation step and to ensure the cohesion of the dosage form after compression.
• disintegrant is meant according to the invention excipients or adjuvants which can be added to the formulations to facilitate the disintegration of the tablets when they are in a liquid environment, such as water or gastric juices.
• Fig. 1 shows the comparative dissolution curves of the composition of compound I as a function of time and the influence of the micronization of the active ingredient in the composition. Each curve corresponds to a solid composition comprising compound I with a different micronization.
• Fig. 2 shows the comparative dissolution curves of different compositions of compound 1 as a function of time. Each curve corresponds to a solid composition containing different disintegrants.
• Figures 1 and 2 show the effect of the excipients as well as the in vitro behavior of the solid composition.
• the present invention shows many advantages, in particular the combination:
• the method used for the preparation of the tablet according to the invention passes through a wet granulation step preceding the tablet forming step.
• the tablet can be prepared by a process comprising a wet granulation step. Obtaining the tablet according to this method stabilization of the compound 1 in the aqueous phase in the presence of well-chosen excipients.
• compound 1 is obtained by a suitable treatment in order to obtain a particle size of between 0.1 and 20 ⁇ m.
• the compound 1 has a particle size of between 1 and 15 ⁇ m, and more preferably between 2 and 10 ⁇ m. Even more preferably, compound 1 has a size of 5 ⁇ m ⁇ 2 ⁇ m.
• compositions of the invention may be, for example, maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, croscarmellose sodium, partially crosslinked poly (N-vinyl-2-pyrrolidone) or crospovidone, polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (or copovidones) such as Kollidon copolymer VA64, carboxymethylcellulose , pregelatinized starch, methylcellulose, polyethylene glycol, macrogols, polyglycols, polyoxyethylene, pyrrolidone-2, colloidal silica, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, sodium lauryl sulphate, calcium phosphate, sugars, dextrin, starch, gelatin, cellulose, wax
• diluents such as, for example, mannitol, lactose or lactose monohydrate, starch, calcium carbonate, microcrystalline cellulose, or maltodextrin;
• disintegrants such as, for example, starch, croscarmellose sodium, sodium starch glycolate, or crospovidone;
• binders such as, for example, polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (or copovidones), carboxymethylcellulose, pregelatinized starch, or methylcellulose;
• flow agents or slip agents such as, for example, colloidal silica, or talc
• lubricants such as, for example, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid or hydrogenated vegetable oil;
• solubilizing agents such as macrogol (polyethylene glycol), polyglycol, polyoxyethylene glycol, polydiol, pyrrolidone-2, or polyvinylpyrrolidone; surfactants (or surfactants) such as sodium lauryl sulphate.
• the present invention also relates to a solid pharmaceutical composition for oral administration of compound 1 as active ingredient, characterized in that it comprises compound 1 and at least one disintegrating agent, one or more diluents and one or more binders.
• the compound is micronized.
• the pharmaceutical composition according to the invention, in solid form for oral administration is a capsule.
• the pharmaceutical composition according to the invention, in solid form for oral administration is a tablet.
• each type of excipient may be alone or in admixture.
• x% of a binder means x% of a single binder or a mixture of binders.
• composition according to the invention may be formulated in a capsule according to a centesimal formulation containing: 1 to 30% of active ingredient, preferably 5 to 20%; 40 to 92% diluent, preferably 65 to 92%, most preferably 75 to 90%; 0 to 10% binder, preferably 0 to 8%; 0 to 30% disintegrant preferably 0 to 20%; 0 to 5% surfactant, preferably 0%; 0 to 5% solubilizing agent, preferably 0%; 0.1 to 3% flow agent, preferably 0.9 to 1.4%; 0.5 to 3% lubricant, preferably 0.6 to 2.8%.
• a centesimal formulation containing: 1 to 30% of active ingredient, preferably 5 to 20%; 40 to 92% diluent, preferably 65 to 92%, most preferably 75 to 90%; 0 to 10% binder, preferably 0 to 8%; 0 to 30% disintegrant preferably 0 to 20%; 0 to 5% surfactant, preferably 0%; 0 to 5%
• the pharmaceutical composition as defined above is a capsule; and more preferably a capsule of centesimal formulation comprising 5 to 30% of active principle; 40 to 92% diluent; 0 to 8% binder, preferably 0 to 5%; 0 to 30% disintegrant; 0 to 5% surfactant; 0 to 5% solubilizing agent; 0.1 to 3% flow agent; and 0.5 to 3% of lubricant.
• the preferred pharmaceutically acceptable excipients for formulating these capsules are mannitol, lactose, corn starch, colloidal silica, magnesium stearate, and sodium lauryl sulphate, and more particularly mannitol, lactose, colloidal silica, and magnesium stearate.
• composition according to the invention may also be formulated in a preferably film-coated tablet or a centesimal formulation film containing: 1 to 30% by weight relative to the total weight of the active ingredient composition, preferably 5 to 20% by weight and very preferably preferably 8 to 20%; 40 to 92% of diluent, preferably 65 to 92% and most preferably 70 to 85%; 0.1 to 20% disintegrant, preferably 0.1 to 10% and most preferably 1 to 5%; 0.1 to 8% of binder, preferably 2 to 5%; 0.1 to 3% slip agent preferably 0.5 to 1.4%; 0.2 to 3% of lubricant, preferably 0.5 to 2.8%.
• Preferred excipients for formulating these tablets are maltodextrin, mannitol, microcrystalline cellulose, lactose or lactose monohydrate, corn starch, sodium starch glycolate, crospovidone, polyvinylpyrrolidone, copovidone, carboxymethylcellulose, colloidal silica, sodium stearyl fumarate, and magnesium stearate and more particularly microcrystalline cellulose, lactose, sodium starch glycolate, copovidone, colloidal silica, and magnesium stearate.
• the pharmaceutical composition as defined above is a tablet preferably filmed, centesimal formulation comprising 8 to 20% of active ingredient; 70 to 85% diluent; 1 to 5% disintegrant; 2-5% binder; 0.5 to 1.4% flow agent; and 0.5 to 2.8% of lubricant relative to the total weight of the tablet as well as about 4.5 to 5%, preferably 4.8% of coating solution based on the total weight of the coated tablet.
• a pharmaceutical composition according to the present invention comprises a diluent selected from the following excipients: mannitol, lactose or lactose monohydrate, starch, calcium carbonate, microcrystalline cellulose, or maltodextrin.
• a pharmaceutical composition according to the present invention comprises a disintegrant selected from the following excipients: starch, croscarmellose sodium, sodium starch glycolate, or crospovidone.
• a pharmaceutical composition according to the present invention comprises a binder selected from the following excipients: polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (copovidones), carboxymethylcellulose (CMC), pregelatinized starch, or methylcellulose.
• a binder selected from the following excipients: polyvinylpyrrolidone, copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (copovidones), carboxymethylcellulose (CMC), pregelatinized starch, or methylcellulose.
• a pharmaceutical composition according to the present invention comprises a lubricant selected from the following excipients: magnesium stearate, sodium stearyl fumarate, calcium stearate or hydrogenated vegetable oil.
• a pharmaceutical composition according to the present invention comprises either microcrystalline cellulose (MCC) and / or copovidone or microcrystalline cellulose (MCC) and / or carboxymethylcellulose (CMC).
• the CMC is at a rate of 4 to 6%.
• a The pharmaceutical composition according to the present invention comprises microcrystalline cellulose (MCC).
• a pharmaceutical composition according to the present invention comprises copovidone.
• a pharmaceutical composition according to the present invention comprises microcrystalline cellulose (MCC) and copovidone.
• a pharmaceutical composition according to the present invention comprises microcrystalline cellulose (MCC).
• a pharmaceutical composition according to the present invention comprises carboxymethylcellulose (CMC).
• a pharmaceutical composition according to the present invention comprises microcrystalline cellulose (MCC) and carboxymethylcellulose (CMC).
• the flow agent selected is colloidal silica (or colloidal solution of silicon dioxide).
• the lubricant selected is magnesium stearate.
• the disintegrant which is added to the formulation of the tablets as an excipient, increases the rate of dissolution, and allows immediate dissolutions, even with high cohesive tablets. According to the literature (eg J. Balasubramaniam, T. Bee, Pharmaceutical Technology Europe, Vol 21, No 9, 2009, pp 44-49), the most effective disintegrators are crospovidone type A and B, followed by croscarmellose sodium.
• the disintegrant used is sodium starch glycolate, and preferably at a level of 1 to 5% and very preferably of 3 to 4%.
• the pharmaceutical composition according to the present invention is a tablet containing from 8 to 20% of compound 1; from 20 to 40% lactose and from 25 to 50% microcrystalline cellulose used as diluents; from 2 to 8% of copovidone used as a binding agent; from 1 to 5% of sodium starch glycolate used as a disintegrating agent; 0.2 to 1.4% flow agent; and 0.5 to 2% of lubricant relative to the total weight of the tablet,
• the compound 1 from 30 to 40% lactose and from 40 to 50%, microcrystalline cellulose used as diluents; from 2 to 5% of copovidone used as a binding agent; from 3 to 4.5% of sodium starch glycolate used as a disintegrant; 0.2 to 1.4% flow agent; and 0.5 to 2% of lubricant relative to the total weight of the tablet.
• the pharmaceutical composition as described above is a tablet containing about 10% of compound 1; 36.5% lactose; 45% microcrystalline cellulose; 3% copovidone; 4% sodium starch glycolate; 0.5% colloidal silica; 1% magnesium stearate based on the total weight of the tablet.
• the term "about” means ⁇ 0.5%.
• the composition may comprise a coating or film coating.
• such a coating has no significant effect on the immediate release of the active principle, that is to say that the kinetics of in vivo release of the active principle is not modified.
• the coating has the advantage of masking the taste of the active ingredient and allows secure handling for packaging the solid composition in tablet form.
• the tablet comprises a coating
• the latter preferably comprises a polymer selected from the group consisting of polyethylene glycols, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellullose (hypromellose) but not limited thereto.
• Opadry ® II White is water soluble, and allows immediate disintegration of the oral pharmaceutical composition in tablet form.
• the solid pharmaceutical composition according to the present invention is in tablet form.
• the invention also relates to instant dissolving tablets as well as coated tablets or films.
• compositions are described by way of example and in no way limit the scope of the invention.
• the subject of the invention is also a process for the preparation of the compound according to the invention as described above, starting from 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3 -yl sulfamate characterized in that it comprises a step of reducing the size of the particles.
• the size of the particles is reduced by micronization, either in an aprotic solvent medium or by the dry route.
• the particle size is reduced by wet grinding with an aprotic organic solvent.
• the invention also relates to the process for producing the solid pharmaceutical compositions of the invention, characterized by the following steps:
• the mass of water relative to the total mass of the active ingredient and the binder, diluent and disintegrator mixed beforehand is between about 10 and 30%.
• the granules are dried until a residual moisture content of less than 3% is obtained.
• composition during all stages of the manufacturing process is produced using conventional equipment and known to those skilled in the art.
• a formulation according to the present invention may be prepared according to the following method: a first mixture is made consisting of the active principle which is first sieved together with certain excipients entering the composition comprising a binder, and one or more diluents as well as a disintegrator.
• the sieving step is carried out using a sieve in a suitable device such as a manual screen.
• the sieved materials are then introduced into a mixer-granulator and mixed for about 5 minutes.
• the mixing speed depends on the equipment chosen.
• a mass of water for granulation is then prepared so that its proportion relative to the solid phase to be granulated is preferably between about 10 and 30%. It will be understood by solid phase to granulate the total mass of the active ingredient and excipients previously mixed, added the binder mass.
• the binder for granulation is added in powder form to the mixer or preferably dissolved in the body of water to form the granulation solution.
• the mixture obtained at the beginning of the process is then wet granulated with the granulation solution, in a mixer-granulator preferably of the "high shear” or “high shear” type.
• the granulation time after addition of the solution to be granulated will be less than 10 minutes and preferably less than 5 minutes.
• the granules resulting from this last step can then be dried in a conventional apparatus such as for example a fluidized air bed dryer.
• a conventional apparatus such as for example a fluidized air bed dryer.
• the granules are dried until a residual moisture of less than 3% is obtained.
• the granules thus dried constitute the part conventionally called the internal phase of the tablet. They are then calibrated by grinding.
• a second mixture is made, which consists of the previously obtained calibrated granules and a so-called external phase consisting of: a disintegrating portion, a flow agent that improves the fluidity of the powder, and finally a lubricant.
• the excipients of the external phase are first screened in a suitable device such as a manual screen.
• the granules, the disintegrant and the flow agent are then mixed and the lubricant is introduced.
• the resulting final mixture can then be compressed by means of a press, rotary type for example.
• the hardness for a 400 mg tablet can be between 6 and 12 kPascal (kPa).
• the hardness of a 100 mg tablet can be between 4 and 8 kPa.
• the tablets can then be coated in a coating turbine by spraying a coating suspension which has been prepared beforehand, preferably by addition of 16% Opadry II ® in purified water.
• the temperature of the product during the filming will be between 35 and 55 ° C
• the mass gain of the tablet after drying will be between 4 and 6% of the mass of the tablet before coating.
• the tablets can then be packaged and kept in blister or vial.
• the uncoated tablet preferably does not exceed a total weight of 800 mg, preferably 400 mg.
• the invention finally relates to the use of a pharmaceutical composition according to the invention as described above for treating cancers, preferentially hormone-dependent cancers, and preferentially also, breast, prostate, endometrial cancers. or ovary.
• the present application also relates to polymorphs of the compound 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate (or sulfamic acid)
• the invention also relates to the preparation of these polymorphic forms, their use as an active ingredient, and more particularly as an active ingredient for the treatment of certain cancers.
• the invention further relates to pharmaceutical compositions containing these polymorphic forms as an active ingredient
• the applicant obtained crystals of compound 1 by an industrial process. Their observation under the microscope makes it possible to observe a gradual opacification of the crystal from about 140-145 ° C. The phenomenon is not reversible: the crystal does not return to its original appearance after slow or rapid cooling.
• DSC an endothermic phenomenon corresponding to a solid-solid transition is observed at 140 ° C.
• a second endothermic peak is observed at 170 ° C. corresponding to the fusion of the untransformed variety I.
• a third endothermic peak is observed at 180 ° C. This third peak corresponds to the fusion of another polymorphic form generated during the solid-solid transition.
• the crystals obtained under industrial conditions exhibit heterogeneities detected by DSC and / or by powder X-ray diffraction after heating at 160 ° C., heterogeneities which allow the germination and growth of another crystalline form during the heating of the compound, making the product unstable to heating.
• Heterogeneities are understood to mean defects in or on crystals, including twins or polytypism, which can be detected by a conventional optical microscope or equipped with a polarized light device and / or by differential scanning and / or X-ray diffraction analysis. on powder and / or confocal Raman microscopy.
• the presence of such heterogeneities in the crystals can thus generate numerous problems during the storage of the active ingredient, or during the manufacturing processes of tablets, capsules, creams or other galenic forms. For example, relative humidity stress can lead to unacceptable behaviors for a pharmaceutically active ingredient.
• Y. Mnyukh has shown in Fundamentals of solid-state phase transitions, ferromagnetism and ferroelectricity (2001), defects can pre-code a solid-solid transition via a germination-growth mechanism.
• the technical problem that the applicant proposes to solve is therefore to provide a stable and bioavailable form of compound 1 under conditions that can be used on an industrial scale.
• the treatment aimed at reducing the particle size by mechanical treatment can introduce: defects, residual stresses in the crystallized phases, a polymorphic transition, a partial or total amorphization, possibly associated with a chemical degradation (Jet-Milling) from a particle perspective Predicting Particle Fracture based on Onno mechanical material properties
• polymorphism The ability of a compound to exist in more than one crystalline form is defined by the term polymorphism and its different crystalline forms are known as "polymorphic varieties" or "polymorphs". Polymorphism can influence many properties of the solid state of an active ingredient. Different polymorphs of a substance can differ considerably from one to another, by their physical properties which can directly influence their solubility for example. Polymorphism has been demonstrated for many organic compounds.
• this variety I of small particle size, object of the invention can be characterized by different analytical methods such as powder X-ray diffraction, differential scanning calorimetry (DSC), Raman spectroscopy, infrared spectroscopy or solid NMR. .
• the subject of the invention is the form 2 crystalline DMSO solvate of compound 1, exhibiting, by powder X-ray diffraction, the characteristic peaks expressed at angle (° 2 theta) at ⁇ 0.1 ° 2 theta: 7.6; 18.7; 24.2; 29.9.
• the applicant has found that the form I crystals obtained under industrial conditions have heterogeneities that allow the germination and growth of another crystalline form during heating of the compound: form III, stable at high temperature .
• the present invention relates to this new form III of compound 1.
• This form III has the advantage of being thermodynamically stable at temperatures above 145 ° C.
• FIG. 3 Calculated X-ray diffractogram of the DMSO solvate of form 2 of compound 1
• FIG. 4 Experimental X-ray diffractogram on DMSO solvate powder of form 2 of compound 1
• FIG. 5 Calculated X-ray diffractogram of compound I of compound 1
• FIG. 6 Experimental powder X-ray diffractogram of variety I of compound 1
• FIG. 10 Calculated X-ray diffractogram of the DMSO solvate of Form 1 of compound 1
• FIG. 11 Experimental X-Ray Diffractogram on Powder of DMSO Solvate of Form 1 of Compound 1
• FIG. 12 Calculated RX diffractogram of DMSO solvate of form 3 of compound 1
• FIG. 13 Experimental X-Ray Diffractogram on Powder of DMSO Solubate of Form 3 of Compound 1
• FIG. 15 Experimental X-Ray Diffractogram on Powder of Polymorphic Form III of Compound 1
• FIG. 20 Experimental RX diffractogram on powder of 1,4-dioxane semisolvate of compound 1
• FIG. 22 Experimental X-Ray Diffractogram on Powder of Polymorphic Form II of Compound 1
• NMR spectrum of the solid of the polymorphic form II of the compound 1 Variety I of compound 1 can be characterized by powder X-ray diffraction with a diffractogram having in particular characteristic peaks expressed at an angle ( ⁇ 2 theta) at approximately ⁇ 0.1 ° 2 theta: 7.5; 10.9; 13, 1; 17.7; 19.0.
• angles (° 2 theta) with an uncertainty of ⁇ 0.1 ° 2 theta represent the angle of reflection according to the Bragg Law, that is to say the angle of incidence of the beam of X-ray on the sample.
• Variety I of compound 1 before particle size reduction can be characterized by single crystal X-ray analysis.
• Variety I of compound 1, of reduced particle size can be characterized by a powder X-ray diffractogram (FIG. 6).
• the Applicant therefore proposes the variety I of the compound 1 obtained by a suitable treatment in order to obtain a particle size of between 0.1 and 20 ⁇ m.
• the present invention has many advantages, in particular increased stability and bioavailability.
• the subject of the present invention is therefore a polymorphic compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulphamate with a particle size of between 0.1 and 20 ⁇ m, and having by X-ray powder diffraction the characteristic peaks expressed in angle (° 2 theta) to ⁇ 0.1 ° 2 theta: 7.5; 10.9; 13.1; 17.7; 19.0.
• the compound according to the invention has a particle size of between 1 and 15 ⁇ m.
• the compound according to the invention has a particle size of between 3 and 7 ⁇ m.
• the compound according to the invention has a size of 5 ⁇ m ⁇ 1 ⁇ m.
• the compound as defined above exhibits, by X-ray powder diffraction, the characteristic peaks expressed at an angle ( ⁇ 2 theta) at ⁇ 0.1 ° 2 theta: 7.5; 10.9; 13.1; 15.0; 15.8; 17.0; 17.7; 19.0; 22.5.
• the compound as defined above is obtained by X-ray powder diffraction carried out after heating at 160 ° C. and then returning to temperature between 18 and 25 ° C. the following characteristic peaks expressed in angle (° 2 theta) at ⁇ 0.1 ° 2 theta: 7.5; 10.9; 13.1; 17.7; 19.0 without additional peaks corresponding to the shape generated during heating at 160 ° C.
• the compound as defined above exhibits in DSC with a temperature ramp of 5 ° C. min -1 an endothermic melting point at 170 ° C. ⁇ 5 ° C. and an endothermic peak at 180 ° C. ⁇ 2 ° C it being understood that the peak at 180 ° C. represents at most 10% of the enthalpy exchanged during the melting at 170 ° C.
• the compound as defined above does not have a DSC endothermic event between 140 and 155 ° C.
• the compound as defined above exhibits, by infrared spectroscopy, the characteristic peaks expressed in cm -1 at ⁇ 5 cm -1: 3310; 3167; 3059; 891; 798; 733; 679; 455; and more preferably still characteristic peaks expressed in cm -1 to ⁇ 5 cm -1: 3310; 3167; 3059; 2928; 2858; 1690; 1605; 1454; 1385; 1261; 1188; 1126; 941; 891; 853; 798; 733; 679; 598; 544; 455.
• the invention relates to a compound as defined above as a medicament.
• the compound according to the invention can be formulated in various pharmaceutical compositions.
• a solid form it may be for example powder, granules, tablets, capsules, liposomes or suppositories.
• liquid form it may be, for example, solutions, emulsions, suspensions or syrups.
• administration of the compound according to the invention may be carried out, for example, topically, orally, parenterally, by intramuscular injection, subcutaneously and especially in the form of a capsule, tablet, patch or cream.
• Suitable carriers or excipients may be, for example, maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, sodium croscarmellose, polyvinylpolypyrrolidone (or crospovidone), polyvinylpyrrolidone, carboxymethylcellulose, pregelatinized starch, methylcellulose, polyethylene glycol, macrogol, polyglycol, polyoxyethylene, polydiol, pyrrolidone-2, colloidal silica, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, sodium lauryl sulphate, calcium phosphate, sugars, dextrin, starch, gelatin, cellulose, wax, or water organic solvents such as glycerol or glycols, as well as their mixtures, in various proportions, with or without water.
• These supports, added to the active ingredient have the function of being:
• diluents such as mannitol, lactose, starch, calcium carbonate, microcrystalline cellulose, or maltodextrin;
• disintegrants such as starch, croscarmellose sodium, sodium starch glycolate, or crospovidone
• binders such as polyvinylpyrrolidone, carboxymethylcellulose, pregelatinized starch, or methylcellulose;
• flow agents such as colloidal silica, or talc
• lubricants such as magnesium stearate, sodium stearyl fumarate, calcium stearate or hydrogenated vegetable oil;
• solubilizing agents such as polyethylene glycol, macrogol, polyglycol, polyoxyethylene, polydiol, pyrrolidone-2, or polyvinylpyrrolidone;
• surfactants such as sodium lauryl sulphate.
• composition according to the invention can be formulated in a capsule containing: 5 to 30% of active ingredient (preferably 6 to 13%); 40 to 92% of diluent (preferentially 65 to 92%, very preferably 85 to 90%); 0 to 30% of disintegrant (preferentially 0 to 22%, very preferably 0%); 0 to 5% of surfactant (preferentially 0%); 0 to 5% of solubilizing agent (preferentially 0%); 0.1 to 3% of flow agent (preferentially 0.9 to 1.4%); 0.5 to 3% of lubricant (preferentially 0.6 to 2.8%).
• the preferred excipients for formulating these capsules are mannitol, lactose, corn starch, colloidal silica, magnesium stearate, and sodium lauryl sulphate, and more particularly mannitol, lactose, colloidal silica, and the like. magnesium stearate.
• composition according to the invention can also be formulated in a tablet containing: 5 to 30% of active principle (preferably 7 to 15% and very preferably 10 to 15%); 40 to 92% of diluent (preferentially 34 to 89% and very preferably 70 to 85%); 0 to 40% of disintegrant (preferentially 0 to 20% and very preferably 3 to 5%); 0 to 8% of binder (preferentially 2 to 5%); 0.1 to 3% of flow agent (preferentially 0.5 to 1.4%); 0.5 to 3% of lubricant (preferentially 0.5 to 2.8%).
• Preferred excipients for formulating these tablets are maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, crospovidone, polyvinylpyrrolidone, carboxymethylcellulose, colloidal silica, sodium stearyl fumarate, and the like.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising, as active ingredient, 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate of particle size between 0.1 and 20 ⁇ m, in combination with at least one pharmaceutically acceptable carrier; preferentially, the 6-oxo
• chromen-3-yl sulfamate has a particle size of between 1 and 15 ⁇ m; more preferably between 3 and 7 ⁇ m and more preferably still 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate has a size of 5 ⁇ m ⁇ 1 ⁇ m.
• the pharmaceutical composition as defined above comprises, as active ingredient, compound 1 of variety I as defined above.
• the pharmaceutical composition as defined above is a capsule; and more preferably still a capsule comprising 5 to 30% of active ingredient; 40 to 92% diluent; 0 to 30% disintegrant; 0 to 5% surfactant; 0 to 5% solubilizing agent; 0.1 to 3% flow agent; and 0.5 to 3% of lubricant.
• the pharmaceutical composition as defined above is a tablet, and more preferably still a tablet comprising 5 to 30% of active principle; 40 to 92% diluent; 0 to 40% disintegrant; 0 to 8% binder; 0.1 to 3% flow agent; and 0.5 to 3% of lubricant.
• Compound 1 synthetic routes are contemplated in the prior art, as described in EP 880514 or by LW Woo, et al. in Chemistry & Biology, 2000, 7, 773-91.
• the Applicant has found that this compound can be synthesized in two chemical steps.
• the first step consists in condensing in a strong acid (such as sulfuric acid, trifluoroacetic acid or methanesulfonic acid) 2-carbetoxycycloheptanone with resorcinol, the intermediate 3-hydroxy-8, 9,10, 11-Tetrahydrocyclohepta [c] chromen-6 (7H) -one is isolated by precipitation with an alcohol / water mixture (for example by adding ethanol then water).
• a strong acid such as sulfuric acid, trifluoroacetic acid or methanesulfonic acid
• 2-carbetoxycycloheptanone with resorcinol 2-carbetoxycycloheptanone with resorcinol
• chromen-6 (7H) -one is isolated by precipitation with an alcohol / water mixture (for example by adding ethanol then water).
• sulfonylisocyanate chloride is converted, in toluene solution, sulfamoyl chloride by the action of formic acid, and then condensed on the previous intermediate dissolved in a solvent such as DMA.
• the reaction medium is treated with water and extracted with an organic solvent (preferably 2-methyltetrahydrofuran: MeTHF), and the crude compound 1 is then precipitated from the organic phase by addition of an antisolvent (preferably methylcyclohexane).
• an antisolvent preferably methylcyclohexane
• the subject of the invention is also the process for preparing 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, characterized in that it comprises the steps following:
• the subject of the invention is also a process for the preparation of the compound according to the invention as described above, starting from 6-oxo-6,7,8,9,10,11- hexahydrocyclohepta [c] chromen-3-yl sulfamate characterized in that it comprises a step of reducing the size of the particles.
• the particle size is reduced by micronization.
• the particle size is reduced by wet grinding with a non-protic organic solvent.
• the subject of the present invention is also a polymorphic compound of 6-oxo-6,7,8,9,10,11-hexahydrocyclohepta [c] chromen-3-yl sulfamate, exhibiting, by X-ray powder diffraction, the characteristic peaks expressed at angle ( ⁇ 2 theta) to ⁇ 0.1 ° 2 theta: 8.6; 11, 3; 28.6 (compound of Form III).
• this compound of form III has the characteristic peaks expressed in angle (° 2 theta) at ⁇ 0.1 ° 2 theta: 8.6; 11, 3; 12.0; 16.6; 20.9; 23.0; 28.6.
• the subject of the invention is more particularly a compound of form III as defined previously which exhibits, by X-ray diffraction on monocrystal, the following mesh parameters:
• the subject of the invention is preferably a compound (IHI form) as defined previously which exhibits in DSC at 5 ° C. min -1 an endothermic melting peak of 180 ° C. ⁇ 2 ° C.
• the compound (Form III) according to the invention exhibits, by infrared spectroscopy, the characteristic peaks expressed in cm -1 to the following ⁇ 5 cm -1 : 3406; 3217; 1678; 1011; 563;
• the subject of the invention is a compound of form III as defined above, as a medicament.
• the subject of the invention is also a pharmaceutical composition
• a pharmaceutical composition comprising, as active principle, a compound of HII form as defined above, in association with at least one pharmaceutically acceptable carrier.
• the subject of the invention is the form 1 crystalline DMSO solvate of compound 1, exhibiting, by powder X-ray diffraction, the characteristic peaks expressed at angle (° 2 theta) at ⁇ 0.1 ° 2 theta: 6.6; 10.9; 13.1; 14.3; 15.7; 16.7; 17.4; 18.3; 19.6; 20.8; 21, 9; 22.6; 23.0; 24.7; 24.9; 25.2; 25.5; 25.8; 26.6; 26.9; 27.2; 28.3.
• the object of the invention is the form 3 crystalline DMSO solvate of compound 1, exhibiting, by powder X-ray diffraction, the characteristic peaks expressed at angle ( ⁇ 2 theta) at ⁇ 0.1 ° 2 theta: 9.8; 13.9; 16.0; 17.7; 19.1; 22.1.
• the subject of the invention is also the crystalline 1,4-dioxane hemisolvate of compound 1, exhibiting, by powder X-ray diffraction, the characteristic peaks expressed at angle (° 2 theta) at ⁇ 0.1 ° 2 theta: 9.8; 10.0; 10.8; 13.6; 13.9; 14.1; 15.9; 16.1; 18.0; 18.3; 19.0; 19.6; 20.0; 20.1; 20.2; 20.6; 21, 4; 21, 7; 21, 8; 22.0; 22.2; 22.3;
• the subject of the invention is also the polymorphic compound of compound 1, composed of form II, having, by powder X-ray diffraction, the characteristic peaks expressed at angle ( ⁇ 2 theta) at ⁇ 0.1 ° 2 theta: 9, 4; 10.7; 12.8; 18.2; 18.9; 19.7; 20.4; 23.2; and preferentially the characteristic peaks expressed at angle ( ⁇ 2 theta) to ⁇ 0.1 ° 2 theta: 9.4; 10.7; 12.2; 12.8; 15.1; 18.2; 18.9; 19.7; 20.4; 21, 1; 22.0; 23.2.
• this compound of form II exhibits at DSC at 5 ° C. min -1 an endothermic melting peak at 165 ° C.
• the subject of the invention is the process for preparing a compound of form III as defined above from compound 1, according to one of the following methods:
• the process according to the invention involves the desolvation in water of crystalline DMSO solvate of form 1 as defined above.
• the process according to the invention involves the desolvation in water of crystalline DMSO solvate of form 3 as defined above.
• the method according to the invention passes through the atomization in ethanol.
• the process according to the invention is carried out by atomization in acetone.
• the process according to the invention is carried out by recoating in cumene under reflux.
• the process according to the invention passes through the heat treatment at a temperature of between 155 ° C. and 165 ° C. for 10 to 20 minutes, followed by micronization and then a second heat treatment at a temperature comprised between between 155 ° C and 165 ° C for 10 to 20 minutes;
• the heat treatments are made at 160 ° C. ⁇ 1 ° C. for 15 minutes.
• the process according to the invention involves the heat treatment of a compound of Form II as defined above, at a temperature of between 155 ° C. and 165 ° C. for 6 to 10 minutes; and preferentially the heat treatment is at 160 ° C ⁇ 1 ° C for 7.5 minutes.
• the compound of form II as defined above is obtained by the atomization of compound 1 in 1,4-dioxane; or the compound of form II as defined above, is obtained by the desolvation of a crystalline 1,4-dioxane hemisolvate as defined above.
• the subject of the invention is the process for preparing crystalline DMSO solvate of form 1 as defined above, starting from compound 1, by stirring and precipitation in DMSO.
• the subject of the invention is the process for preparing crystalline DMSO solvate of form 3 as defined above, starting from compound 1, by stirring and precipitation in DMSO.
• the subject of the invention is the process for preparing a crystalline 1,4-dioxane hemisolvate as defined above, starting from compound 1, by stirring and precipitation in 1,4-dioxane.
• the subject of the invention is the process for preparing a compound of form II as defined above, starting from compound 1, according to one of the following methods:
• the process for the preparation of a compound of form II as defined above passes through the desolvation of a crystalline 1,4-dioxane hemisolvate as defined above. Also preferably, the process for the preparation of a compound of form II as defined above, passes through the atomization in 1,4-dioxane.
• the subject of the invention is the use of a compound of variety I or of form III as defined above for the manufacture of a medicament intended to treat cancers; preferentially hormone-dependent cancers and preferably also a cancer selected from breast, prostate, endometrial or ovarian cancers.
• a tablet composition comprising Compound 1 as the active ingredient is shown in Table 1 below.
• Such a composition can be prepared by wet granulation according to scheme 1 below for a batch of 5 kg and a dose of 40 mg.
• the coating which has been applied to 40 mg tablets, consists of Opadry ® II white (Colorcon); it is a commercially available blend of coatings used for immediate release tablets.
• the main purpose of this coating is to mask the bad taste of the drug substance. It also reduces the risks associated with handling during packaging operations for tablets containing strong active ingredients.
• a capsule composition comprising Compound 1 as the active ingredient is shown in Table 2 below.
• Table 5 Solid compositions containing compound 1 and using different excipients.
• a compressed form (centesimal formula of Example 1a) was set to stability after blistering.
• the goal is to check the stability of this form over periods of 6 months and 12 months.
• the recommended normal storage conditions are 25 ° C and 60% relative humidity (25 ° C / 60% RH) and the data generated under these conditions are presented in Tables 6 and 7 for 5 mg tablets. and 40 mg respectively.
• Table 6 Stability study on tablets packaged in blister packs containing 5 mg of active ingredient and stored at 25 ° C / 60% RH.
• Table 6 are grouped tests of dosage, impurities and dissolution of the stability study on tablets packaged in blister containing 5 mg of active ingredient and stored at 25 ° C / 60% RH.
• Table 7 Stability study on tablets packaged in blister packs containing 40 mg of active ingredient and stored at 25 ° C./60% RH.
• Table 7 are grouped assays, impurities and dissolution of the stability study on tablets packaged in blister containing 40 mg of active ingredient and stored at 25 ° C / 60% RH.
• Table 8 Stability studies on tablets packaged in blister packs containing 5 mg of active ingredient and stored under different storage conditions
• Table 8 are grouped tests of dosage, impurities and dissolution of stability studies on tablets packaged in blister containing 5 mg of active ingredient and stored under different storage conditions.
• Table 9 Stability studies on blister packs containing 40 mg of active ingredient and stored under different storage conditions
• Table 8 are grouped tests of dosage, impurities and dissolution of stability studies on tablets packaged in blister containing 40 mg of active ingredient and stored under different conditions of conservation
• Example 5 The first step consists in condensing in methanesulfonic acid 2-carbetoxycycloheptanone with resorcinol, the reaction is conducted at 25 ° C for 4 hours.
• the 3-hydroxy-8,9,10,11-tetrahydrocyclohepta [c] chromen-6 (7H) -one intermediate thus formed precipitates by addition of ethanol and then water, and is then isolated by filtration, dried under vacuum at 60 ° C, a yield of 78% is obtained.
• sulfonylisocyanate chloride is converted, in toluene solution, sulfamoyl chloride by the action of formic acid, and then condensed on the previous intermediate dissolved in N 1 N-dimethylacetamide (DMA).
• DMA N 1 N-dimethylacetamide
• the reaction medium is treated with water and extracted with 2-methyltetrahydrofuran (2-MeTHF).
• 2-MeTHF 2-methyltetrahydrofuran
• the pure compound 1 is obtained by recrystallization of the crude product by hot dissolution in acetone and precipitation by addition of methylcyclohexane (the addition of the methylcyclohexane antisolvent whose main purpose is a yield gain).
• Example 1 thus obtained can undergo an appropriate treatment aimed at reducing the particle size such as micronisation (point 5.3 below) or wet grinding (point 5. below).
• the DMSO solvate of form 2 of compound 1 (Example 5b) is immersed in cold water and left stirring for five minutes at room temperature. The suspension was then filtered and dried.
• Example 5b thus obtained can undergo appropriate treatment to reduce particle size such as micronization or wet milling.
• Micronization is carried out using a compressed air jet micronizer at a temperature between 18 and 25 ° C.
• the characteristics of the compressed air used are as follows:
• Example 5c Variety I of compound 1 with particle size of 3 ⁇ m
• compound 1 (example 1) are micronized using a compressed air jet micronizer.
• the micronization parameters are: 80 psi Venturi pressure, 110 psi micronizer pressure and 12 kg feed rate. h "1 .
• Example 3-1 is thus obtained with a yield of 97%.
• Example 5d Variety I of Compound 1 with a Granulometry of 5 ⁇ m
• Example 5 16.5 kg of compound 1 (Example 5) are micronized using a compressed air jet micronizer.
• the micronization parameters are: 80 psi Venturi pressure, 32 psi micronizer pressure and 14.4 kg feed rate. h "1 .
• Example 5d is thus obtained with a yield of 98% and presented below.
• Example 5e Variety I of compound 1 with a particle size of 9 ⁇ m
• 150 g of compound 1 (Example 51) are micronized using a compressed air jet micronizer.
• the micronization parameters are: 50 psi Venturi pressure, 60 psi micronizer pressure, and 15 kg feed rate. h "1 .
• Example 5e is thus obtained with a yield of 98%.
• Example 5f Variety I of compound 1 with a particle size of 15 ⁇ m
• 39 g of compound 1 (Example 5) are micronized using a compressed air jet micronizer.
• the micronization parameters are: Venturi pressure of 30 psi, micronizer pressure of 10 psi and feed rate of 40 g in 15 minutes.
• Example 5f is thus obtained with a yield of 74%.
• Example 5q 0.69 g of compound 1 (Example 5) are ground with 0.068 g of methylcyclohexane in a model P4 planetary type Fritsch ball mill.
• the parameters of the wet grinding are: 7 agate balls 10 mm in diameter, a grinding torque ⁇ (speed of rotation of the disc) - co (rotational speed of the bottles) of 100 - 100 rpm, a duration of 12 hours effective over a total of 18 hours according to the following 72 sequences: 10 minutes of grinding - 5 minutes break, a ball mass / solute mass ratio of 14.1; a temperature of 22 ° C. and a mass ratio of compound 1 / mass of methylcyclohexane of 9%.
• Example 5g is thus obtained with a yield of 99% and presented below. 6. DESCRIPTION OF THE CRYSTALS OBTAINED
• Dispersion medium 0.50% (m / v) Nonidet in water
• the reduced coordinates of the hydrogen atoms (x10 4 ) of the compound 1 variety I are as follows:
• the atomic coordinates of the atoms in the mesh (x10 4 ) and equivalent isotropic displacement parameters (A 2 x 10 3 ) (U (eq) is one third of the value of the orthogonal tensor Uij) of the form 2 DMSO solvate of the compound 1 are the following:
• the 2-DMSO solvate powder X-ray diffractogram of compound 1 has the following characteristic peaks expressed at angle ( ⁇ 2 theta) at approximately ⁇ 0.1 ° 2 theta: ( Figures 1 and 2). 7.6; 18.7; 24.2; 29.9.
• the powder X-ray diffractogram of variety I of compound 1 after micronization or wet grinding exhibits the following characteristic peaks expressed as angle ( ⁇ 2 theta) at approximately ⁇ 0.1 ° 2 theta: 7.5; 10.9; 1, 7; 13.1; 14.6; 15.0; 15.8; 17.0; 17.3; 17.5; 17.7; 17.9; 19.0; 19.9; 20.0; 21, 4; 21, 8; 22.5; 23.5; 23.9; 24.7; 24.9; 25.5; 25.9; 26.2; 26.4; 26.6; 27.2; 27.4; 27.6; 27.8; 28.2; 28.8; 29.0; 29.4; 29.8.
• the X-ray powder diffractogram of variety I of compound 1 after micronisation or wet grinding and then heating at 160 ° C. has the following characteristic peaks expressed in angle (° 2 theta) at approximately ⁇ 0.1 ⁇ 2 theta: 7 , 5; 10.9; 11, 7; 13.1; 14.6; 15.0; 15.8; 17.0; 17.3; 17.5; 17.7; 17.9; 19.0; 19.9; 20.0; 21, 4; 21, 8; 22.5; 23.5; 23.9; 24.7; 24.9; 25.5; 25.9; 26.2; 26.4; 26.6; 27.2; 27.4; 27.6; 27.8; 28.2; 28.8; 29.0; 29.4; 29.8 without additional peaks corresponding to the new shape generated during heating at 160 ° C.
• thermogram obtained at 5 ° C. min -1 of variety I of compound 1 after micronisation or wet grinding comprises the melting peak of variety I (onset 170 ° ⁇ 5 ° C.), possibly a small peak of melting of a new polymorphic form generated during the analysis (onset 180 ⁇ 2 ° C) representing less than 10% of the enthalpy exchanged during the melting peak of the variety I and exhibits no endothermic event (or less than 0.5 J / g) between 140-155 ° C.
• the variety I of the compound 1 according to the invention can be formulated in a capsule containing: 5 to 30% of active principle (preferably 6 to 13%), 40 to 92% of diluent (preferably 65 to 92%, very preferably at 90%), 0 to 30% of disintegrant (preferentially 0 to 22%, very preferably 0%), 0 to 5% of surfactant (preferentially 0%), 0 to 5% of solubilizing agent (preferentially 0%) 0.1 to 3% of flow agent (preferably 0.9 to 1.4%), 0.5 to 3% of lubricant (preferentially 0.6 to 2.8%).
• active principle preferably 6 to 13%)
• 40 to 92% of diluent preferably 65 to 92%, very preferably at 90%
• 0 to 30% of disintegrant preferentially 0 to 22%, very preferably 0%
• surfactant preferentially 0%
• solubilizing agent preferentially 0%
• flow agent preferably 0.9 to 1.4%
• the preferred excipients for formulating these capsules are mannitol, lactose, corn starch, colloidal silica, magnesium stearate, and sodium lauryl sulphate, and more particularly mannitol, lactose, colloidal silica, and the like. magnesium stearate.
• the capsules presented below were made by mixing powder according to conventional techniques known to those skilled in the art.
• M mannitol
• L lactose
• AM corn starch
• LS sodium lauryl sulphate
• PEG polyethylene glycol
• SC colloidal silica
• SM magnesium stearate
• Example 7i The example of capsules 7j is prepared from compound 1 of example 5: 40 mg of compound 1 are mixed with 260 mg of lactose and put in capsules.
• Example 7k The example of capsules 7k is prepared according to formula 7g with active ingredient Example 5c instead of Example 5d.
• Example of capsules 71 is prepared with 7.2% of Example 5d, 31.9% of mannitol, 59.4% of lactose and 1.5% of colloidal silica.
• Example 7m The example of capsules 7m is prepared according to formula 7g with active ingredient as example 5d.
• Example 7n The example of capsules 4n is prepared according to formula 4g with active ingredient Example 5e instead of Example 5d.
• EXAMPLE 7O The example of capsules 40 is prepared with the active principle of Example 5f: 40 mg of Example 5f are mixed with 260 mg of lactose and put into capsules.
• the variety I of the compound 1 according to the invention can be formulated in a tablet containing: 5 to 30% of active principle (preferably 7 to 20% and very preferably 10 to 15%), 40 to 92% of diluent (preferentially at 89% and very preferably 70 to 85%), 0 to 40% of disintegrant (preferentially 0 to 20% and very preferably 3 to 5%), 0 to 8% of binder (preferentially 2 to 5%), 0.1 at 3% of flow agent (preferably 0.5 to 1.4%), 0.5 to 3% of lubricant (preferentially 0.5 to 2.8%).
• the preferred excipients for formulating these capsules are maltodextrin, mannitol, microcrystalline cellulose, lactose, corn starch, sodium starch glycolate, crospovidone, polyvinylpyrrolidone, carboxymethylcellulose, colloidal silica, stearyl fumarate and the like.
• the tablets shown below were made by wet granulation according to conventional techniques known to those skilled in the art.
• the dissolution kinetics (expressed as a percentage of dissolved compound 1 as a function of time) are measured according to standard techniques known to those skilled in the art, and presented in the table below.
• AUC Area under the curve
• the operating conditions of the HPLC method are as follows:
• Form III of compound 1 as described in the present application is obtained by a synthesis step of compound 1 (Example 5) followed by an additional step which can be:
• Example 9aa Form 1 DMSO solvate of compound 1
• Example 9aa The DMSO solvate of Form 1 of compound 1 (Example 9aa) is immersed in cold water and stirred for five minutes at room temperature. The suspension was then filtered and dried.
• the DMSO solvate of form 3 of compound 1 (Example 3ba) is immersed in cold water and left stirring for five minutes at room temperature. The suspension was then filtered and dried.
• the product obtained is produced with a B -chi 190 spray-dryer.
• the dry air inlet temperature was adjusted to 90 ° C with a pressure of 3 bar.
• the outlet temperature was measured at 38 ° C during atomization.
• the output rate was set at 700 NI / hour. 570 mg of dry powder are recovered and analyzed by powder X-ray diffraction. This analysis shows that it is form III of structurally pure compound 1 in comparison with the diagram calculated from the resolved structure on single crystal.
• the product obtained is produced with a B ⁇ chi B290 spray dryer with an inerting loop.
• the dry air inlet temperature was adjusted to 70 ° C.
• the outlet temperature was measured at 50 ° C during atomization.
• the output rate has been set to 600 NI / hour.
• 1 g of dry powder is recovered and analyzed by X-ray powder diffraction. This analysis shows that it is form III of structurally pure compound 1 in comparison with the diagram calculated from the resolved structure on single crystal.
• 150 g of compound 1 are heated in a ventilated oven at 160 ° C. for 15 minutes.
• the product thus heated is then micronized using a compressed air jet micronizer.
• the micronization parameters are for the first pass: a Venturi pressure of 80 psi, a micronizer pressure of 120 psi and a feeding speed of 1.2 kg. h "and 1 for the second pass.. a venturi pressure of 50 psi, a pressure of 50 psi and micronizer a feed rate of 1, 2 kg h -1
• the yield of micronization is 69% 15.
• the product thus obtained is heated at 160 ° C. for 15 minutes in a ventilated oven.
• Form II of compound 1 can be obtained according to two synthetic routes:
• the hringsolvate of 1, 4-dioxane compound 1 (Example 9) was heated to 20 to 80 ° C at 5 ° C min "1 under a stream of inert gas and provides, for the desolvation Form II of compound 1 characterized by its X-ray diffraction pattern.
• Example 9i The dry powder recovered from compound 1 of Form II (Example 9i) was placed in an oven at 160 ° C. for a period of between 6 and 10 minutes, preferably for 7.5 minutes.
• the powder recovered after this treatment analyzed by X-ray diffraction, shows that it is form III of structurally pure compound 1 as compared with the calculated diagram obtained from the resolved single-crystal structure.
• Wavelength 1, 54056 Cu, voltage 40 KV, current 40 mA
• the X-ray powder diffractogram of Form I of Compound 1 exhibits the following characteristic peaks expressed at angle ( ⁇ 2 theta) at approximately ⁇ 0.1 ° 2 theta: 7.5; 10.9; 11, 7; 13.1; 14.6; 15.0; 15.8; 17.0; 17.3; 17.5; 17.7; 17.9; 19.0; 19.9; 20.0; 21, 4; 21, 8; 22.5; 23.5; 23.9; 24.7; 24.9; 25.5; 25.9; 26.2; 26.4; 26.6; 27.2; 27.4; 27.6; 27.8; 28.2; 28.8; 29.0; 29.4; 29.8.
• I has the following characteristic peaks expressed as angle ( ⁇ 2 theta) at approximately ⁇ 0.1 ° 2 theta: 6.6; 10.9; 13.1; 14.3; 15.7; 16.7; 17.4; 18.3; 19.6; 20.8; 21, 9; 22.6; 23.0; 24.7; 24.9; 25.2; 25.5; 25.8; 26.6; 26.9; 27.2; 28.3 ( Figures 1 and 2).
• the DMSO 3-form DMSO solvate powder X-ray diffractogram of compound 1 exhibits the following characteristic peaks expressed at angle ( ⁇ 2 theta) at approximately ⁇ 0.1 ° 2 theta: ( Figures 3 and 4). 9.7; 13.9; 16.0; 17.8; 19.1; 22.1. 2.2.4 Single-crystal RX of Form III
• the crystalline structure of the compound 1 form has the following mesh parameters:
• Example 9a is identical to Example 9b, Example 9c, Example 9d, in Example 9e, Example 9f and Example 9g.
• the X-ray powder diffractogram of Form III of Compound 1 exhibits the following characteristic peaks expressed as angle ( ⁇ 2 theta) at approximately ⁇ 0.1 ° 2 theta: 8.6; 11, 3; 12.0; 16.7; 17.4; 17.9; 20.9; 22.6; 23.0; 23.4; 23.8; 25.7; 28.6 ( Figures 5 and 6).
• thermogram of Form III of Compound 1 comprises the melting peak of Form III (onset 180 ° ⁇ 2 ° C) ( Figure 7).
• the IR spectrum of Form III of Compound 1 shows the characteristic peaks expressed in cm -1 at approximately ⁇ 5 cm -1 : 3406, 3217, 3082, 2924, 1678, 138, 1269, 1134, 1011, 934, 845; 601, 563, 536 ( Figure 8).
• the solid NMR form III spectrum exhibited the following characteristic peaks expressed in ppm at approximately ⁇ 0.2 ppm: 162.9; 156.4; 151, 3; 126.1; 124.7; 118.8; 117.1; 112.9; 35; 20 ( Figure 9).
• the crystalline structure of the 1,4-dioxane hemisolvate of compound 1 has the following mesh parameters:
• the X-ray powder diffractogram of 1,4-dioxane hemisolvate of compound 1 exhibits the following characteristic peaks expressed as angle ( ⁇ 2 theta) at approximately ⁇ 0.1 ° 2 theta: 9.8; 10.0; 10.8; 13.6; 13.9; 14.1; 15.9; 16.1; 18.0; 18.3; 19.0; 19.6; 20.0; 20.1; 20.2; 20.6; 21, 4; 21, 7; 21, 8; 22.0; 22.2; 22.3; 23.4; 23.9; 24.3; 24.4; 24.9; 25.3; 25.4; 26.2; 27.0; 27.1; 27.3; 27.5; 28.2; 28.4;
• thermogram of 1,4-dioxane hemisolvate of Compound 1 shows that the solvate releases 1,4-dioxane from 75 ° C to give Form II of Compound 1 ( Figure 12).
• the X-ray powder diffractogram of Form II of Compound 1 exhibits the following characteristic peaks expressed in angle (° 2 theta) at approximately
• thermogram of form II of compound 1 comprises an endothermic phenomenon which corresponds to the metastable melting of form II at 165 ° C ⁇ 5 ° C, followed by recrystallization to other forms, followed by other melting ( Figure 14).
• the IR spectrum of Form II of Compound 1 shows characteristic peaks expressed in cm -1 at approximately ⁇ 5 cm -1 : 3356; 3321; 3186; 3078; 2932; 2851; 1693; 1609; 1504; 1462; 1377; 1265; 1192; 1123; 937; 872; 837; 787; 594 (Figure 15).
• the Applicant has carried out conversion experiments between the different polymorphic forms of compound 1 which have shown that form III is the form stable at high temperature (T> 145 ° C). This important property allows vacuum heating to remove traces of solvent (Polymorphism in the Pharmaceutical Industry, Wiley 2006, Ed Hilfiker, Wiley, ISBN: 978-3-527-31146-0). By returning to ambient temperature, the form III of compound 1 remains unchanged which is, again, a primary advantage in the pharmaceutical industry.
• the operating conditions of the HPLC method are as follows:

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