BR122020005420B1 - PURIFIED FORM 1 OF THE CRYSTALLINE POLYMORPH OF COMPOUND I - Google Patents

Abstract

the invention relates to solid dispersions, solid molecular complexes, salts and crystalline polymorphs involving {3- [5- (4-chloro-phenyl) -1h-pyrrole [2,3-b] pyridine-3-carbonyl] -2 , 4-difluoro-phenyl} -amide of propane-1-sulfonic acid.

Description

[1] Compositions that include compounds, such as biologically active compounds, and methods for making such compositions are described.

BACKGROUND OF THE INVENTION

[2] PCT Patent Application WO 2007/002325 describes {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro- propyl-1-sulfonic acid phenyl} -amide (see, for example, page 80 and corresponding formula on page 82).

SUMMARY OF THE INVENTION

[3] The present inventions provide compositions that include or refer to Compound I. "Compound I", as used herein, means {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3 -b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -propane-1-sulfonic acid amide (the compound has also been named using the nomenclature "{3- [5- (4-chlorophenyl ) - 1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide of propane-1-sulfonic acid "), salts of such a compound (including pharmaceutically acceptable salts), conjugates of such a compound, derivatives of such a compound, forms of such a compound, and prodrugs of such a compound. The structure of propane-1- acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide sulfonic acid is shown below.

[4] Propane-1- acid acid 3- 3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide sulfonic

[5] As used here, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as described herein includes an active ingredient (for example, Compound I), preferably dispersed among at least one other component, for example, a polymer. In certain embodiments, a solid dispersion as described herein is a pharmaceutical dispersion that includes at least one pharmaceutical or biologically active ingredient (for example, Compound I). In some embodiments, a solid dispersion includes Compound I dispersed molecularly with a polymer. Preferably, the solid dispersion exists as a single-phase system. An especially preferred solid dispersion according to the present invention is a bulky microprecipitate powder (MBP) comprising Compound I.

[6] The term "molecularly dispersed", as used herein, refers to the random distribution of a compound (for example, Compound I) with a polymer. In certain embodiments, the compound is present in the polymer in a final state of subdivision. See, for example, M G, Vachon et al., J Microencapsulation, 14 281-301 (1997) and Vandelli et al ,. J Microencapsulation, 10-55-65 (1993). In some embodiments, a compound (for example, Compound I) can be dispersed within a matrix formed by the polymer in its solid state so that the compound is immobilized in its amorphous form. Whether a compound is molecularly dispersed in a polymer can be evidenced in a variety of ways, for example, by the resulting solid molecular complex that has a unique glass transition temperature.

[7] The term "solid molecular complex", as used herein, means a solid dispersion that includes Compound I molecularly dispersed within a polymeric matrix.

[8] The term "immobilize", as used here with reference to immobilization of the active compound in the polymeric matrix, means that molecules of the compound interact with polymer molecules in such a way that the molecules of the compound are kept in the matrix mentioned above and prevented from crystal nucleation due to lack of mobility. In some embodiments, the polymer can prevent the attachment of intermolecular hydrogen or weak dispersion forces between two or more drug molecules of Compound I. See, for example, Matsumoro and Zografi, Pharmaceutical Research, Vol. 16. No. 11, pp. 1722-1728, 1999.

[9] Therefore, in a first aspect, a solid dispersion is provided that includes Compound I and a polymer. Also provided is a solid molecular complex that includes Compound I and a polymer. The polymer can be a nonionic polymer or an ionic polymer. In certain embodiments, the polymer is selected from the group consisting of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, methacrylic acid copolymers, and the like, as well as mixtures of any two or more of these. In some embodiments, the ratio of the amount by weight of Compound I within the solid dispersion or solid molecular complex to the amount by weight of the ionic polymer there is from about 1: 9 to about 5: 5. In a preferred embodiment of the invention, the ratio of the amount by weight of Compound I within the solid dispersion or the solid molecular complex to the amount by weight of the ionic polymer there is from about 2: 8 to about 4: 6. In various embodiments, the ratio of Compound I to the polymer in the solid dispersion is not 1: 1; for example, the ratio can be about 2: 8; or about 3: 7; or about 4: 6. In a preferred embodiment, the ratio of the amount by weight of Compound I within the solid dispersion or the solid molecular complex to the amount by weight of the ionic polymer therein is about 3: 7. In certain preferred embodiments, Compound I can be present in the solid dispersion in an amount of about 0.1% to about 80%, by weight, of the solid dispersion; or in an amount of about 10% to about 70% by weight, of the solid dispersion; or in an amount of about 20% to about 60%, by weight, of the solid dispersion; or in an amount of about 20% to about 40% by weight, of the solid dispersion; or in an amount of about 30% by weight of the solid dispersion. In certain embodiments of the solid dispersions, the polymer may be present in the solid dispersion in an amount of not less than about 20% by weight of the solid dispersion; or in an amount of about 20% to about 95% by weight of the solid dispersion; or in an amount of about 20% to about 70% by weight of the solid dispersion.

[10] In certain preferred embodiments, Compound I is stable in the solid dispersion (or solid molecular complex) for at least 2 months, at 25 ° C; or for at least 6 months at 25 ° C; or for at least 12 months at 25 ° C; or for at least 15 months at 25 ° C; or for at least 18 months at 25 ° C; or for at least 24 months at 25 ° C; or for at least 2 months at 40 ° C and 75% relative humidity; or for at least 4 months at 40 ° C and 75% relative humidity; or for at least 5 months at 40 ° C and 75% relative humidity; or for at least 6 months at 40 ° C and 75% relative humidity. In certain preferred embodiments, Compound I is immobilized so that it is primarily in amorphous form within the solid dispersion or solid molecular complex for at least three weeks of storage at 40 ° C and 75% relative humidity; or for at least one month of storage at 40 ° C and 75% relative humidity; or for at least two months of storage at 40 ° C and 75% relative humidity; or for at least three months of storage at 40 ° C and 75% relative humidity; or for at least four months of storage at 40 ° C and 75% relative humidity; or for at least five months of storage at 40 ° C and 75% relative humidity; or for at least six months of storage at 40 ° C and 75% and relative humidity.

[11] In some embodiments, Compound I is present in the complex as a tosylate salt; or as a mesylate salt. The complex can further include a pharmaceutically acceptable carrier.

[12] As used here, the term "primarily in amorphous form" means that more than 50%; or more than 55%; or more than 60%; or more than 65%; or more than 70%; or more than 75%; or more than 80%; or more than 85%; or more than 90%; or more than 95% of the compound present in a composition is in amorphous form.

[13] As used here, the term "about", used in the context of quantitative measurements, means the indicated amount ± 10%. For example, "about 2: 8" would mean 1.8-2.2: 7.2-8.8.

[14] As used here in the context of a pharmaceutical or biologically active compound (for example, Compound I), the term "stable" refers to the compound's ability to retain its activity or to retain certain physical or chemical properties under certain specified conditions. In some embodiments, an active compound is "stable" if the activity at the end of the specified period is at least 50%; or at least 60%; or at least 70%; or at least 75%; or at least 80%; or at least 85%; or at least 90%; or at least 95%; or at least 98% of the compound's activity at the beginning of the specified period. In some embodiments, an amorphous compound is stable if at least 50%; or at least 60%; or at least 70%; or at least 75%; or at least 80%; or at least 85%; or at least 90%; or at least 95%; or at least 98% of the compound remains in amorphous form at the end of the specified period. In other embodiments, an amorphous compound is stable if it does not form any crystalline peaks detectable in XRD powder profiles for the indicated period.

[15] The term "methacrylic acid copolymers", as used herein, includes methacrylic acid copolymers, methacrylic acid - methacrylate copolymer, methacrylic acid - ethyl acrylate copolymer, ammonium methacrylate copolymers, amino methacrylate copolymer and methacrylate amino methacrylate copolymer. similar. In certain embodiments, the "methacrylic acid copolymer" can be EUDRAGIT® L 100 and EUDRAGIT® L 12.5 (also referred to as, or in accordance with: "Methacrylic Acid Copolymer, Type A"; "Methacrylic Acid Copolymer - Methyl Methacrylate (1: 1) ";" Methacrylic Acid L Copolymer ";" DMF 1242 "or" PR-MF 6918 "); EUDRAGIT® S 100 and EUDRAGIT® S 12.5 (also referred to as, or in accordance with: "Methacrylic Acid Copolymer, Type B"; "Methacrylic Acid Copolymer - Ethyl Methacrylate (1: 2)"; "Copolymer D Methacrylic Acid ";" DMF 1242 "or" PR-MF 6918 "); EUDRAGIT® L 100-55 (also referred to as, or in accordance with: "Methacrylic Acid Copolymer, Type C"; "Methacrylic Acid Copolymer - Ethyl Acrylate (1: 1) Type A"; "LD Methacrylic Acid Copolymer"; Dry "; or" DMF 2584 "); EUDRAGlT® L 30 D-55 (also referred to as, or in accordance with: "Methacrylic Acid Copolymer Dispersion"; "Methacrylic Acid Copolymer - Ethyl Acetate (1: 1) 30 Percent Dispersion"; "LD Acid Copolymer Methacrylic "; JPE DMF 2584; PR-MF 8216); EUDRAGIT® FS 30 D (also referred to as DMF 13941 or DMF 2006-176); EUDRAGIT® RL 100 (also referred to as, or in accordance with: "Ammonium Methacrylate Copolymer Type A;" Ammonium Methacrylate Copolymer (Type A); "" Ammonium Methacrylate RS Copolymer ";" DMF 1242 "or" PR-MF 6918 "); EUDRAGIT® RL PO (also referred to as, or in accordance with:" Ammonium Methacrylate Copolymer, Type A ";" Ammonium Methacrylate Copolymer (Type A) ";" RS Methacrylate Copolymer " Aminoalkyl ";" "DMF 1242"); EUDRAGIT® RL 12.5 (also referred to as, or in accordance with: "Type A Alkyl Methacrylate Copolymer"; "Ammonium Methacrylate Copolymer (Type A);" "DMF 1242" or "PR-MF 6918") ; EUDRAGIT® L 100-55 (also referred to as, or in accordance with: "Methacrylic Acid Copolymer, Type C"; "Methacrylic Acid Copolymer - Ethyl Acrylate 1: 1) Type A"; "LD Copolymer of Dry Methacrylic Acid"; "DMF 2584"); EUDRAGIT® L 30 D-55 (also referred to as, or in accordance with: "Methacrylic Acid NF Copolymer Dispersion" "30 Percent Methacrylic Acid Copolymer - Methyl Acrylate - (1: 1);" "Copolymer LD of Methacrylic Acid ";" DMF 2584 "or" PR-MF 8216 "); EUDRAGIT® FS 30 D (also referred to as, or in accordance with: "DMF 13941" or "DMF 2006-176"); EUDRAGIT® RL 100 (also referred to as, or in accordance with: "Ammonium Methacrylate Copolymer, Type A;" "Ammonium Methacrylate Copolymer (Type A)"; "Aminoalkyl Methacrylate RS Copolymer;" "DMF 1242; "or" PR-MF 6918 "); EUDRAGIT® RL PO (also referred to as, or in accordance with: "Ammonium Methacrylate Copolymer. Type A;" "Ammonium Methacrylate Copolymer (Type A);" "Aminoaquila Methacrylate RS Copolymer"; or "DMF 1242" "); EUDRAGIT® RL 12.5 (also referred to as, or in accordance with: "Ammonium Methacrylate Copolymer, Type A;" "Ammonium Methacrylate Copolymer (Type A:" "DMF 1242" or "PR-MF 6918") ; EUDRAGIT® RL 30 D (also referred to as, or in accordance with: "Ammonium Methacrylate Copolymer Dispersion, Type A"; "Ammonium Methacrylate Copolymer (Tipe A);" or "DMF 1242"); EUDRAGIT® RS 100 (also referred to as, or in accordance with: "Ammonium Methacrylate Copolymer, Type B;" NF "Ammonium Methacrylate Copolymer (Type B);" "Aminoalkyl Methacrylate RS Copolymer;" "DMF 1242" or "PR-MF 6918"); EUDRAGlT * RS PO (also referred to as, or in accordance with: "Ammonium Methacrylate Copolymer, Type D;" "Ammonium Methacrylate Copolymer (Type B);" "RS Methacrylate Copolymers Aminoalkyl "or" DMF 1242 "); EUDRAGIT® RS 12.5 (also referred to as, or in accordance with:" Ammonium Methacrylate Copolymer, Type B; "NF polymer in accordance with:" Met Copolymer Ammonium acrylate (Type); "" DMF 1242 "or" PR-MF 6918 "); EUDRAGIT * RS 30 D (also referred to as, or in accordance with: "Ammonium Methacrylate Copolymer Dispersion, Type B;" NF polymer in accordance with "Ammonium Methacrylate Copolymer (Type B);" or "DMF 1242" ); EUDRAGIT * E 100 (also referred to as, or in accordance with: "Basic Amino Methacrylate Copolymer"; NF "Basic Butylated Methacrylate Copolymer"; "Aminoalkyl Methacrylate Copolymer E"; "DMF 1242" or "PR-MF 6918" ); EUDRAGIT® E PO (also referred to as, or in accordance with: "Basic Butylated Methacrylate Copolymer E;" "Aminoalkyl Methacrylate E Copolymer"; "Amino Methacrylate Copolymer;" "DMF 1242"); EUDRAGIT® E 12.5 (also referred to as, or in accordance with: "Amino Methacrylate Copolymer"; "Basic Butylated Methacrylate Copolymer"; "DMF 1242" or "PR-MF 6918"); EUDRAGIT * NE 30 D (also referred to as, or in accordance with: "Ethyl Acrylate and Methyl Methacrylate Copolymer Dispersion"; "30 Percent Polyacrylate Dispersion;" ("Poly (ethyl acrylate-methyl methacrylate) - - Dispersion at 30% ");" Ethyl Acrylate-Ethyl Methacrylate Dispersion ";" DMF 2822 "or" PR-MF 6918 "); EUDRAGIT® NE 40 D (also referred to as, or in accordance with: DMF 2822); EUDRAGIT® NM 30 D (also referred to as "Polyacrylate 30% dispersion;" "(Poly (ethyl acrylate-methyl methacrylate) - 30% dispersion);" or "DMF 2822"; PLASTOID® B (also referred to as, or in accordance with: "DMF 12102") ,, or the like.

[16] In a second aspect, methods are provided for making solid dispersions or solid molecular complexes as described here. The method may involve the use of Compound I in the form of a tosylate or mesylate salt.

[17] In a third aspect, Compound I crystalline polymorph Form 1 is provided. In certain embodiments, Compound I crystalline polymorph Form 1 exhibits a powder X-ray diffraction pattern having characteristic peak locations of approximately 4.7, 9.4, 11.0, 12.5 and 15.4 ° 2θ; or having characteristic peak locations of approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 18.6, and 22.2 ° 2θ; or having characteristic peak locations of approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 16.1, 18.6, 19.0, 22, 2 and 26.8 ° 2θ. In certain embodiments, Compound I crystalline polymorph Form 1 exhibits a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern of Figure 1. Methods are also provided for preparing solid and complex dispersions solid molecular molecules as described herein, wherein the solid dispersion or solid molecular complex is prepared from Compound I in the form of crystalline polymorph Form 1.

[18] In a fourth aspect, Compound I crystalline polymorph Form 2 is provided. In certain embodiments, Compound I crystalline polymorph Form 2 exhibits a powder X-ray diffraction pattern having characteristic peak locations of approximately 8.8, 9.2, 13.5, 19.1 and 24.4o 2θ; or having characteristic peak locations of approximately 6.7, 8.8, 9.2, 13.5, 15.0, 17.7, 19,1,19,7, 21,4 and 24,4o 2θ; or having characteristic peak locations of approximately 6.7, 8.8, 9.2, 13.5, 14.1, 14.5, 15.0, 16.2, 17.0, 17.7, 19, 1, 19.7, 21.4, 22.2, 24.1, 24.4, and 28.1o 2θ. In certain embodiments, Compound I crystalline polymorph Form 2 exhibits a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern of figure 2. Methods are also provided for preparing solid and complex dispersions solid molecular molecules as described herein, wherein the solid dispersion or solid complex is prepared from Compound I in the form of crystalline polymorph Form 2.

[19] All atoms within the compound described here are intended to include any such isotope, unless clearly indicated otherwise. It is to be understood that, for any given atom, isotopes can be present essentially in ratios, according to their natural occurrence, or one or more particular atoms can be intensified with respect to one or more isotopes using synthetic methods known to the one versed in technical. Thus, hydrogen includes 1H, 2H, 3H; carbon includes, for example, 11C, 12C, 13C, 14C; oxygen includes, for example, 16O, 17O, 18O; nitrogen includes, for example, 13N, 14N, 15N; sulfur includes, for example, 32S, 33S, 34S, 35S, 36S, 37S, 38S; fluorine includes, for example, 17F, 18F, 19F; chlorine includes, for example, 35Cl, 36Cl, 37Cl, 39Cl; and the like.

[20] As used herein, the term "solid form" refers to a solid preparation (for example, a preparation that is neither a gas nor a liquid) of a pharmaceutically active compound that is suitable for administration to an animal patient intended for therapeutic purposes. The solid form includes any complex, such as a salt, cocrystalline or amorphous complex, as well as any polymorph of the compound. The solid form can be substantially crystalline, semi-crystalline or substantially amorphous. The solid form can be administered directly or used in the preparation of a suitable composition having pharmaceutical properties. For example, the solid form can be used in a formulation that comprises at least one pharmaceutically acceptable carrier or excipient.

[21] As used here, the term "substantially chrysalis" material encompasses material that has more than about 90% crystallinity; and "crystalline" material encompasses material that has more than about 98% crystallinity.

[22] As used here, the term "substantially amorphous" includes material that has no more than about 10% crystallinity; and "amorphous" material includes material that has no more than 2% crystallinity.

[23] As used here, the term "semicrystalline" material encompasses material that has more than 10% crystallinity, but no more than 90% crystallinity; preferably "semi-crystalline" material comprises material that has more than 20% crystallinity, but not more than 80% crystallinity. In one aspect of the present invention, a mixture of solid forms of a compound can be prepared, for example, a mixture of solid amorphous and crystalline forms, for example, to provide a "semi-crystalline" solid form. Such a "semi-crystalline" solid form can be prepared by methods known in the art, for example, by mixing an amorphous solid form with a solid crystalline form in the desired ratio; In some cases, a compound mixed with acid or base forms an amorphous complex; a semicrystalline solid can be prepared by using an amount of the stoichiometric compound in excess of the compound and acid or base in the amorphous complex, thus resulting in an amount of the amorphous complex that is based on its stoichiometry, with excess compound in the crystalline shape. The amount of the excess compound used in the preparation of the complex can be adjusted to provide the desired ratio of amorphous compound to crystalline compound in the mixture resulting from the solid forms. For example, if the amorphous acid or base complex and the compound have 1: 1 stoichiometry, the preparation of said complex with a 2: 2 molar ratio of the compound to acid or base will result in a solid form of 50% amorphous complex and 50% crystalline compound. Such a mixture of solid forms can be beneficial as a drug product, for example, providing an amorphous component with improved biopharmaceutical properties together with the crystalline component. The amorphous component would be more readily available whereas the crystalline component would have a delayed bioavailability. Such a mixture can provide both rapid and prolonged exposure to the active compound.

[24] As used here, the term "complex" refers to a combination of a pharmaceutically active compound and an additional molecular species that forms or produces a new chemical species, in solid form. In some cases, the complex may be a salt, that is, when the additional molecular species provides an acid / base counterion for an acid / base group of the compound resulting in an acid: base interaction that forms a typical salt. Although such salt forms are typically substantially crystalline, they can also be partially crystalline, substantially amorphous, or amorphous forms. In some cases, the additional molecular species, in combination with the pharmaceutically active compound, forms a non-salt cocrystalline, that is, the compound and the molecular species do not interact through acid: typical base interaction, but still form a substantially structure crystalline. Cocrystals can also be formed from a salt of the compound and an additional molecular species. In some cases, the complex is a substantially amorphous complex, which may contain salt-like acid: base interactions, which do not form typical salt crystals, but instead form a substantially amorphous solid, that is, a solid whose diffraction pattern X-ray powder does not exhibit sharp peaks (for example, it exhibits an amorphous halo).

[25] As used here, the term "stoichiometry" refers to the molar ratio of two or more reagents that combine to form a complex, for example, the molar ratio of acid or base to the compound that forms an amorphous complex. For example, a 1: 1 mixture of acid or base with the compound (i.e., 1 mole of acid or base per mole of compound) resulting in a solid amorphous form has 1: 1 stoichiometry.

[26] As used herein, the term "composition" refers to a pharmaceutical preparation suitable for administration to an intended animal patient for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof. The composition can include at least one pharmaceutically additional component to provide an improved formulation of the compound, such as a suitable vehicle or excipient.

[27] The term "pharmaceutically acceptable" indicates that the material indicated does not have properties that would cause a reasonably prudent medical practitioner to avoid administering the material to a patient, taking into account the disease or conditions to be treated and the respective route of treatment. management. For example, it is commonly required that such material is essentially sterile, for example, for injectables.

[28] In the present context, the term "therapeutically effective" or "effective amount" indicates that the materials or the amount of material is effective in preventing, alleviating, or alleviating one or more symptoms of a disease or medical condition, and / or prolong the survival of the patient being treated. In certain embodiments, a "therapeutically effective amount" of Compound I refers to such dosages and / or administration for such periods of time as are necessary to inhibit human b-Raf containing the V600E mutation. In addition, a therapeutically effective amount may be one in which the total therapeutically beneficial effects stand out from the toxic or undesirable side effects. A therapeutically effective amount of Compound I can vary according to the condition of the disease, age and weight of the patient being treated. Thus, dosage regimes are typically adjusted to the individual requirements in each particular case and are within the skill of the art. In certain embodiments, an appropriate daily dose for administration of Compound I to a human adult can be from about 100 mg to about 3,200 mg; or from about 250 mg to about 2,000 mg, although the upper limit can be exceeded when indicated. A daily dosage of Compound I can be administered as a single dose, in divided doses, or, for parenteral administration, it can be given as a subcutaneous injection.

[29] In the present context, the terms "synergistically effective" or "synergistic effect" indicate that two or more compounds that are therapeutically effective, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected on the basis of in the effect of each compound used alone.

[30] As used here, the term "modulation" or "modular" refers to the effect of altering a biological activity, especially a biological activity associated with a particular biomolecule, such as a protein kinase. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, for example, an enzyme, either by increasing (eg, agonist, activator), or by decreasing (eg, antagonist, inhibitor) the activity of the biomolecule , such as an enzyme. Such activity is typically indicated in terms of the inhibitory concentration (IC50) or excitation concentration (EC50) of the compound for an inhibitor or activator, respectively, with respect to, for example, an enzyme.

[31] Additional aspects and modalities will become apparent from the detailed description given below and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[32] Figure 1 is a powder X-ray diffraction pattern for Compound I crystalline polymorph Form 1.

[33] Figure 2 is a powder X-ray diffraction pattern for Compound I crystalline polymorph Form 2.

[34] Figure 3 is a comparison of the powder X-ray diffraction pattern for crystalline polymorph Form 2 and the compound I mesylate salt.

[35] Figure 4 is a comparison of the X-ray diffraction pattern for the crystalline polymorph form and the tosylate salt of Compound I.

[36] Figure 5 is a schematic drawing of an exemplary configuration for manufacturing a solid dispersion (MBP) according to steps a) to d), more specifically according to Example 22 of the present invention.

[37] Figure 6 is a detailed schematic drawing of the high shear mixing unit ((6) in figure 5).

[38] Figures 7A and 7B provide a comparison of X-ray patterns obtained from two batches of solid dispersions (of MBP) containing HPMCAS and Compound I, manufactured via precipitation in the high-shear mixer according to the method described in the Example 22 (see figure 7A) and via conventional spray precipitation (see figure 7B).

DETAILED DESCRIPTION

[39] Propane-1- acid acid 3- 3- [5- (4-Chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide sulfonic is a compound with the following structure:

[40] Propane-1- acid acid 3- 3- [5- (4-Chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide sulfonic (Compound I)

[41] In some embodiments, Compound I is a barren kinase inhibitor. Normally functioning b-Raf is a kinase that is involved in relaying signals from the cell membrane to the nucleus and is active only when it is needed to relay such signals. However, mutant b-Raf is constantly active and thus plays a role in tumor development. b-Raf mutant containing a V600E mutation has been implicated in several tumors, for example, colorectal cancer, melanoma, and thyroid cancer. Propane-1-sulfonic acid {3- [5- (4-Chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide b-Raf mutant containing the V600E mutation. Accordingly, such an inhibitor is used in inhibiting tumors, particularly solid tumors such as melanoma. As previously established, the term "Compound I", as used herein, refers to a {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2 , 4-difluoro-phenyl} -amide of propane-1-sulfonic acid as well as any salt, conjugate, derivative or prodrug thereof.

[42] Compounds that have low water solubility (for example, certain compounds in crystalline form), have a low dissolution rate and, consequently, may exhibit poor bioavailability. Poorly bioavailable compounds can present problems in therapeutic administration to a patient, often due to the unpredictability of dose / therapy effects caused by the patient's erratic absorption of the compound. For example, food intake can affect the patient's ability to absorb such poorly bioavailable compounds, thus potentially requiring dosage regimens that take into account the effect of the food. In addition, when dosing, a wide safety margin may be required for the dose as a result of the effects of unpredictable dosages. In addition, due to poor bioavailability, a large dose of the compound may be required to achieve the desired therapeutic effect, thus potentially resulting in unwanted side effects.

[43] Amorphous forms of Compound I have improved solubility compared to the crystalline form, but are unstable since they tend to crystallize. Thus, it is desirable to formulate Compound I so that it can, stable and primarily, exist in amorphous form.

[44] Thus, in some aspects and modalities disclosed and described here, techniques, methods and compositions for improving the solubility and / or bioavailability of Compound I are provided. In certain embodiments, compositions and methods are provided that involve Compound I in a composition, form, or formulation, in which it has improved water solubility and / or bioavailability compared to Compound I in crystalline form, or Compound I in a primarily crystalline shape.

[45] In some embodiments, compositions are provided that include Compound I in an amorphous form of the compound. The amorphous form of Compound I may have improved water solubility compared to Compound I in crystalline form. In certain embodiments, formulations of Compound I in which Compound I stably exists in amorphous form can be obtained, for example, by immobilizing the compound within a matrix formed by a polymer. See, for example, US Patent 6,350,786.

Solid Dispersions and Solid Molecular Complexes of Compound I and a Polymer

[46] In some aspects and embodiments provided here, solid dispersions and solid molecular complexes are provided which include Compound I. For example, Compound I may be dispersed within a matrix formed by a polymer in its solid state so that it is immobilized in its amorphous form. In some embodiments, the polymer can prevent intramolecular hydrogen binding or weak dispersion forces between two or more drug molecules of Compound I. See, for example, Matsumoro and Zografi, Pharmaceutical Research, Vol. 16, No 11, pp. 1A22-172S, 1999. In certain embodiments, the solid dispersion provides a large surface area, thus still allowing for improved dissolution and bioavailability of Compound I. In certain embodiments, a solid dispersion or solid molecular complex includes a therapeutically effective amount of the Compound. I.

[47] In some embodiments of the present inventions, Compound I is present in the solid dispersion in an amount of about 1% to about 50%, by weight; or from about 10% to about 40% by weight; or from about 20% to about 35% by weight. Or from about 25% to about 30% by weight. In related embodiments, a polymer is present in the solid dispersion in an amount of about 0% to about 50% by weight; or from about 5% to about 60% by weight; or from 10% to about 70% by weight. In certain embodiments, the polymer is present in the solid dispersion in an amount greater than about 10% by weight; or greater than about 20% by weight; or greater than about 30% by weight; or greater than about 40% by weight; or greater than about 50% by weight. In a preferred embodiment, the solid dispersion is about 30% by weight of Compound I and about 70% by weight of polymer.

[48] The solid dispersion can comprise Compound I dispersed in a nonionic polymer. This can be achieved by several means, including: (A) melting the polymer and dissolving the compound in the polymer and then cooling the mixture; and (B) dissolving both the compound of interest and the polymer in an organic solvent and evaporating the solvent in a rotoevaporator, for example. The resulting solid dispersion may comprise the compound dispersed in the polymer in amorphous form.

[49] A solid dispersion can be formed by dispersing Compound I in ionic polymer. Such a solid dispersion can result in increased stability of compound I. This can be achieved by several means, including the methods described above for use in forming a dispersion in nonionic polymer. Due to the fact that ionic polymers have pH-dependent solubility in aqueous systems, the resulting solid dispersion of Compound I and polymer can be stable at a low pH in the stomach and the release of Compound I in the intestine at a higher pH, which is the site absorption. In preferred embodiments, Compound I in such solid dispersions with an anionic polymer may thus be less able to separate from the polymer and may be immobilized by the polymer in its amorphous form. Any ionic polymer can be used in the practice of the present invention. Examples of such ionic polymers include hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), hydroxypropyl methyl cellulose phthalate (HPMCP), and acrylic acid copolymers. Because a purpose of formulating Compound I in a complex with an ionic polymer is to make Compound I immobilized so that it exists primarily in amorphous form, a polymer that is capable of immobilizing Compound I is preferred so that it exist primarily in amorphous form for an extended period of time. Polymers such as HPMC-AS and Eudrganit® L 100-55 (a methacrylic acid copolymer) have been found to be able to immobilize Compound I so that it exists primarily in amorphous form for at least four weeks while in storage at 40 ° C. ° C and 75% relative humidity. Thus, HPMC-AS and Eudragit® L 100-55 are preferred polymers for use in certain embodiments of the present invention.

[50] HPMC-AS (HPMCAS or AQOAT®, which is a form available from, for example, Shin-Etsu) is a particularly preferred polymer for use in the practice of certain embodiments of the present invention. It is available in the following grades: AS-LF, AS MF, AS-HF, AS-LG, AS-MG and AS-HG. HPMC-AS is a polymer of high molecular weight, relatively insoluble in water, anionic, with pH-dependent water solubility, leading to dissolution at pH 5.2 and above. Said dissolution can be adjusted between pH 5.2 and 6.5 according to the grades of HPMC-AS used. HPMC-AS can be relatively resistant to rupture in the acidic environment of the stomach and under normal storage temperatures. At the same time, due to the fact that HPMC-AS dissolves at pH 5.2 and above, it dissolves in the basic medium of the intestine, which thus allows for improved absorption of Compound I and also allows for improved bioavailability of the Compound I. Accordingly, in certain embodiments of the invention, the Compound is in a solid dispersion with at least one polymer selected from grades of HPMC-AS as mentioned above. However, it is contemplated that a mixture of two or more of the various grades of HPMC-AS can also be used in accordance with the present invention.

[51] In an embodiment of the invention, the ratio of the amount by weight of Compound I within the solid complex to the amount by weight of the ionic polymer in it is from about 1: 9 to about 1: 1. In a preferred embodiment of the invention, the ratio of the amount by weight of Compound I within the solid complex to the amount by weight of the ionic polymer in it is from about 2: 8 to about 4: 6. In a preferred embodiment of the invention, the ratio of the amount by weight of Compound I within the solid complex to the amount by weight of the ionic polymer in it is about 3-7.

[52] In an embodiment of the present invention, Compound I is immobilized so that it is primarily in amorphous form within the complex for up to three weeks of storage at 40 ° C and 75% relative humidity. In a preferred embodiment, Compound I is immobilized so that it is primarily in amorphous form within the complex for up to one month of storage and 75% relative humidity. In another preferred embodiment, Compound I is immobilized so that it is primarily in amorphous form within the complex for up to two months of storage at 40 ° C and 75% relative humidity. In another preferred embodiment, Compound I is immobilized so that it is primarily in amorphous form within the complex for up to three months of storage at 40 ° C and 75% relative humidity.

[53] In certain embodiments, HPMC-AS is present in the solid dispersion in an amount of about 1% to about 50% by weight; or from about 5% to about 60% by weight; or from 10% to about 70% by weight. In certain embodiments, HPMC-AS is present in the solid dispersion in an amount greater than about 10% by weight; or greater than about 20% by weight; or greater than 30% by weight; or greater than about 40% by weight; or greater than about 50% by weight.

[54] The present inventions also relate to compositions comprising a solid dispersion or solid molecular complex, as described herein. In addition to the solid dispersion or solid molecular complex, the composition may also comprise therapeutically inert, inorganic or organic vehicles (for example, pharmaceutically acceptable vehicles or excipients). The pharmaceutical composition can also contain additional agents such as preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants. The composition may also contain additional therapeutically active compounds or more than one therapeutically active compound / polymer complex (for example, solid dispersion or solid molecular complex).

[55] In certain embodiments, the composition includes the solid dispersion or solid molecular complex suspended in an aqueous vehicle containing hydroxypropyl cellulose (HPC). In an especially preferred embodiment, the vehicle contains about 2% by weight of HPC. In a preferred embodiment, the composition includes colloidal silicon dioxide (silica).

[56] In certain embodiments, the addition of colloidal silicon dioxide may further improve the stability of the solid dispersion or solid molecular complex. In an especially preferred embodiment, the composition includes at least about 0.5% by weight of colloidal silicon dioxide.

[57] In certain embodiments, compositions are provided that include Compound I (for example, in a solid dispersion or solid molecular complex) and Crospovidone (or Poliplasdone XL; a disintegrating agent for the dosage form), magnesium stearate (a lubricant that can be used in tablet and capsule forming operations), and / or croscarmellose sodium (AcDiSol; a disintegrating agent).

[58] In an especially preferred embodiment, the composition comprises the solid dispersion or solid molecular complex suspended in an aqueous vehicle that contains up to 2% by weight of HPC and at least about 0.5% by weight of colloidal silicon dioxide.

Method for Making a Solid Molecular Complex of Compound I and a Tonic Polymer

[59] Methods are also provided for making solid molecular complexes as described herein and compositions comprising the solid molecular complexes. In the method, Compound I can be microprecipitated with a polymer as described here (for example, HPMC-AS). Microprecipitation can be achieved by means known in the art, for example: spray drying or lyophilization; solvent controlled precipitation; pH controlled precipitation; hot melt extrusion; and supercritical fluid technology. Each of these methods is described in more detail below.

[60] Since the solid dispersion is precipitated from the solution using the various methods, it can be recovered from the solution by procedures known in the art, for example, by filtration, centrifugation, washing, etc. The recovered solid molecular complex can then be dried (for example, in air, oven or vacuum) and the resulting solid can be crushed, pulverized or micronized to a fine powder by means known in the art. The powder form of the solid dispersion can then be dispersed in a vehicle to form a pharmaceutical composition. In a preferred embodiment, at least about 0.5% w / w of colloidal silicon dioxide is added to the composition. a) Spray drying process Atomization or freeze drying

[61] Compound I and a polymer (for example, HPMC-AS) can be dissolved in a common solvent with a low boiling point, for example, ethanol, methanol, acetone, etc. Through spray drying or lyophilization, the solvent is evaporated by instant evaporation at a temperature close to its boiling point, or under high vacuum (low vapor pressure), leaving Compound I precipitated in a matrix formed by the polymer. In certain embodiments, Compound I is in a form of mesylate or tosylate salt, and thus preferably has improved solubility. b) Solvent Controlled Precipitation

[62] Compound I and a polymer (for example, HPMC-AS) can be dissolved in a common organic solvent, for example, dimethylacetamide, dimethylformamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), etc. The Compound I / polymer solution is added to the ice water (0 to 7 ° C, preferably 2 to 5 ° C) adjusted to an appropriate pH (for example, in many embodiments the appropriate pH is a pH of 3 or less). This causes Compound I to microprecipitate in a matrix formed by the polymer (for example, HPMC-AA). The microprecipitate can be washed several times in aqueous medium until the residual solvent falls below an acceptable limit for said solvent. An "acceptable limit" for each solvent is determined according to the guidelines of the International Conference on Harmonization (ICH).

[63] In a preferred embodiment, a solution comprising Compound I, an organic solvent (such as dimethylformamide, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), and the like) and the like ionic polymer is formed. The organic solvent is preferably DMA at 20 to 25 ° C. The solution can be formed by first dissolving Compound I in the organic solvent. Then, with stirring, the polymer is added. The mixture is then heated to between about 50 and about 110 ° C, preferably to about 70 ° C.

[64] A second solution is also formed which is 0.01N HCl. This will be referred to here as the "aqueous phase". The aqueous phase has a temperature between about 0 and about 60 ° C, preferably between 5 and 15 ° C.

[65] The aqueous phase is then circulated through the mixing chamber of a high shear mixer while the organic phase is dosed in the chamber during the operation of the chamber; Dosing can be carried out with, for example, a gear pump, a hose pump, or a syringe pump. In a preferred embodiment, dosing is carried out using a gear pump with an injection nozzle aimed at the mixing chamber. Preferably, the mixing chamber comprises a rotor and a stator. The rotor and stator may, for example, each have one or two rows of teeth. In a preferred embodiment, the rotor and stator each have a row of teeth. The speed of the rotor nozzle is preferably adjusted to between about 15 and about 25 m / s.

[66] During the mixing process, Compound I and the polymer precipitate producing a suspension of particles of the compound of Compound I and the polymer in aqueous organic medium. The suspension can then be subjected to several steps through a dispersing unit to adjust the particle size of the particles of the compound. The suspension can then be centrifuged and washed several times with the aqueous phase to remove the organic solvent, and then washed once with pure water. The product obtained can thus be degrouped and dried to obtain the solid complex of the present invention. During the drying process, the temperature of the complex is preferably below 40 ° C to prevent the recrystallization of Compound I.

[67] In other more specific modalities, the method above includes the following steps,

[68] dissolving Compound I and HPMCAS in the same organic solvent to give a single organic phase;

[69] continuously add the organic phase obtained under (a) in an aqueous phase, which is present in a mixing chamber, in which the mixing chamber is equipped with a high-shear mixing unit and two additional openings that connect said mixing chamber for a closed circuit, in which said aqueous phase is circulated and passes through the mixing chamber;

[70] precipitate a mixture consisting of the amorphous form of Compound I and HPMCAS from the aqueous phase mentioned in (b), while the high-shear mixer is in operation and said aqueous phase is passed through the mixing chamber in a closed circuit , resulting in the formation of an aqueous suspension of the precipitate;

[71] circulate the aqueous suspension continuously through the mixing chamber while the high shear mixing unit is in operation and after the organic solution prepared under (a) has been completely added to the aqueous phase to a defined particle size and / or particle size distribution is obtained;

[72] isolate the solid phase from the suspension;

[73] wash the isolated solid phase with water; and

[74] degum and dry the solid phase;

[75] In even more specific modalities, the present methods include the stages, in which

[76] - the organic phase in step (a) above is a 35% solution of Compound I and HPMCAS in DMA, with the ratio of Compound I to HPMCAS from 30% to 70% (w / w); and

[77] - the continuous addition in step (b) above is obtained via an ejector nozzle that is oriented at an angle between 40 and 50o to the longitudinal axis of the high shear mixer and has a distance of about 1 to about 10 mm of the rotor of said high shear mixer, which is operating with a nozzle speed of about 15 to about 25 m / s.

[78] In yet other specific modalities, the present methods include the stage, in which

[79] - the continuous addition in step (b) above is obtained via an injector nozzle, which is oriented at an angle of about 45o to the longitudinal axis of the high-shear mixer and has a distance of about 2 to about 4 mm of the rotor of said high shear mixer, which is operating with a nozzle speed of about 25 m / s

[80] In other specific modalities, the present methods include, the stage, in which

[81] - drying in step (g) above is obtained via fluidized bed drying.

[82] In another embodiment, the solid dispersions obtained by the method mentioned above are provided.

[83] The dry precipitate obtained by the above method can be further processed for any type of solid pharmaceutical preparations, which are known to those skilled in the art. Particularly preferred are oral dosage forms, such as tablets, capsules, pills, powders, suspensions, and the like.

[84] Consequently, the pharmaceutical preparations thus obtained form other embodiments provided here.

[85] The term "organic solvent" mentioned in step (a) above means any organic solvent, in which both Compound I and HPMCAS are miscible. Preferred organic solvents are N-Methypyrrolidone (NMP), Dimethylformamide (DMF), Dimethyl Sulfoxide (DMSO), Dimethylacetamide (DMA), and the like, where DMA is most preferred. The combined amount of Compound I and HPMCAS together in the organic phase can be within the range of about 15 to 40% by weight, preferably about 25 to 40, more preferably about 35% by weight. The weight ratio of Compound I / HPMCAS in the organic solvent is about 30/70% by weight, respectively. Preferably, the temperature of the organic solvent is adjusted to between 50 and 110 ° C, preferably 60 and 90 ° C, more preferably to about 70 ° C before it is added to the mixing chamber, as mentioned in step (b). The mixture of Compound I and HPMCAS in the organic solvent is also referred to herein as the "organic phase" or "DMA phase".

[86] The term "aqueous phase" mentioned in step (b) preferably consists of acidic water (pH <7, preferably less than 3), more preferably 0.01N hydrochloric acid (HCl). The aqueous phase is maintained at a temperature between about 0 and about 60 ° C, preferably between about 0 and 20 ° C, more preferably between about 5 and about 15 ° C, more preferably about 5 ° C . The aqueous phase circulates outside the bottom valve of its reservoir ((1) in figure 5) due to the current created by the high shear mixer or with an auxiliary pump, preferably a rotary lobe pump, then passes through the high shear mixer , and back to the reservoir. Preferably, the circuit outlet is placed under the level of the fluid maintained in the reservoir, to prevent foaming.

[87] The addition of the organic phase to the mixing chamber as mentioned in step (b) above is done via an injector nozzle that points directly to the aqueous phase. Any conventional nozzle known to one skilled in the art can be used. The preferred injection nozzles show central and accentric geometry and have a diameter of about 1 to 10 mm. Accentric (non-centered) geometry and a diameter of 5 mm are especially preferred. The injector nozzle can point at the rotor of the high shear mixing unit at an angle between 0 and 90o, preferably between 40 and 50o, more preferably at 45o (a, figure 6). During the process according to the present invention, the distance between the nozzle nozzle point and the rotor nozzle of the high shear mixing unit is about 1 to 10 mm, preferably about 2 to 4 mm and more preferably about 2.6 mm. The addition of the organic phase is preferably carried out at dosage rates of about 60/1 to about 300/1 (ratio of aqueous phase to organic phase during precipitation), preferably about 70/1 to about 120 / 1 and more preferably at about 100/1. The final ratio of the aqueous phase / organic phase after precipitation is in the range of about 5/1 to 12/1, preferably 7/1 to 10/1 and, more preferably, 8.5 / 1.

[88] While the organic phase is added (injected) into the aqueous phase of the mixing chamber, the high shear mixing unit is in operation. Any conventional high shear mixing unit (rotor / stator unit) known to the one skilled in the art can be applied. The preferred geometry for the rotor, according to the present invention, uses a rotor / stator unit with a row of teeth, single, radial or row of teeth, double, or a combination thereof. The speed of the rotor nozzle is about 15 to about 25 m / s, preferably 25 m / s.

[89] Subsequent to the complete addition of the organic phase to the aqueous phase, the suspension obtained, thus the precipitate consisting of amorphous Compound I and HPMCAS in the aqueous phase is still circulated in the closed circuit containing the high-shear mixing unit. Outside the high shear mixing unit, circulation must be carried out with the aid of an auxiliary pump, preferably a rotary lobe pump. The suspension is passed through the high shear mixing unit, several times, until the desired particle size and / or desired particle size distribution is obtained. Usually, the suspension is passed through the high shear mixing unit about 1 to 60 times, more preferably, 6 times. The particle size and / or the particle size distribution can be determined by standard techniques, well known to those skilled in the art, such as, for example, dynamic light scattering. The preferred particle size, according to the present invention, is in the range of D50 = 80-230 μm, preferably D50 = 80-160 μm.

[90] The isolation of the solid dispersion (MPB) according to step (e) above can be carried out using conventional filtration techniques or centrifuges. Prior to isolation, the suspension is preferably adjusted to about 5 to 10 ° C. Subsequently, the isolated solid dispersion is washed with acidic water. Preferably 0.01N HCl, followed by another wash with pure water in order to substantially remove the organic solvent between 60 and 70% (w / w), which is preferably dried before any further processing. Drying can be carried out using any standard techniques known to the person skilled in the art, for example, cabinet dryer, at temperatures between 30 and 50 ° C, preferably at about 40 ° C and under reduced pressure, preferably below 2 kPa (20 mbar). Various drying procedures can be combined or used sequentially, in which the use of fluid bed drying is especially preferred as the final drying step according to the present invention.

[91] A specific method for making MBP (HPMCAS-Compound I) according to steps a) to g) above is described in Example 22, which forms another preferred embodiment of the invention. The stability of the solid dispersion (MBP) as obtained by the method of Example 22 was compared with the stability of an MBP obtained via conventional spray precipitation. "Conventional spray precipitation" means that the organic phase was sprayed onto the aqueous phase via a nozzle that is placed outside the aqueous phase, above its surface, as is the case with many conventional spray precipitation techniques. All other procedural parameters are the same for both methods. The stability, thus inhibiting the recrystallization of Compound I, is determined by measuring X-ray diffraction using a conventional wide-angle X-ray diffusion unit as is well known to the person skilled in the art. The sample preparation was identical for both MBPs. The samples were treated in a climatic chamber (50 ° C and 90% humidity (UR)) for several hours and days respectively (0 h, 14 h, 41 h, 4 d, 6 d, 13 d) before measurements of X-rays. The results are shown in figure 7A for the MBP obtained according to Example 22, and figure 7B for the MPB obtained by the conventional method. The older X-ray curves of both MBPs show a wide halo in the wide-angle region with no acute signals, thus showing that both materials are in an amorphous state. Within several days, the acute signals occur on the X-ray curves obtained from the MBP manufactured by the conventional method (see figure 7B), but not on the X-ray curves obtained from the MBP prepared using the method described here (see figure 7A) .

[92] In summary, the results presented in figures 7A and 7B demonstrate that the spray precipitated MPB is less stable against recrystallization than the high shear precipitated MBP as evidenced by the early occurrence of acute signals in the diffractograms (see figure 7B), which may be distributed in the crystalline form of Compound I. The lower line of each figure represents the initial sample, the following lower lines until after storage for 14 h, 41 h, 96 h, 6 d, 13 d, respectively in a climatic chamber controlled (at 50 ° C, 90% RH).

[93] The new processes, as provided here, can preferably be carried out using a configuration as shown in the attached figure 5.

[94] A configuration as substantially illustrated in figure 5 can be used for the following preparation. Thus, figure 5 contemplates two reservoirs (vases) with devices for temperature control, one to provide the aqueous phase at a controlled temperature (1), or the other to provide the organic phase at a controlled temperature (2). Both vessels are also equipped with automatic stirrers (3). The aqueous phase is circulated in a closed circuit (4) using a pump (5), while passing through a high shear mixing unit (6). The organic phase is added to the aqueous phase inside the high shear mixing unit with the help of a metering pump (7) and an injector nozzle which is shown in more detail in figure 6.

[95] As shown in figure 6, the nozzle (8) is placed inside the aqueous phase inside the high shear mixing unit. The nozzle can be oriented within different angles (α) with respect to the rotor (9) of the high shear mixing unit, and within defined distances (d) from the rotor nozzle.

[96] The solid dispersion, in particular the MBP obtainable, according to the methods provided, can be used in a wide variety of drug delivery forms, such as Compound I, including drugs that are poorly soluble in water, and , in particular, oral dosage forms. Examples of oral dosage forms include powders or granules that can be taken orally both dry and reconstituted by adding water to form a paste, slurry, suspension or solution; tablets, capsules, or pills. Various additives can be mixed, crushed or granulated with the solid dispersion as described here to form a material suitable for the above dosage forms. Potentially beneficial additives can, in general, fall into the following classes: other matrix materials or diluents, surfactants, drug complexing agents or solubilizers, fillers, disintegrators, binders, lubricants, and pH modifiers (for example, acids, bases or tampons). Examples of other matrix materials, fillers or diluents, include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch. Examples of surfactants include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing agents or solubilizers include polyethylene glycols, caffeine, xanthene, gentisic acid and cyclodextrins. Examples of disintegrants include sodium amide glycolate, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and croscarmellose sodium. Examples of binders include methyl cellulose, microcrystalline cellulose, starch, and gums, such as guar and tragacanth gum. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH modifiers include acids, such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, and buffers generally comprising mixtures of acids and salts of said acids. At least one function of including such pH modifiers to control the rate of dissolution of the drug, matrix polymer, or both, thereby controlling the local concentration of the drug during dissolution.

[97] Additives can be incorporated into the solid amorphous dispersion during or after formation. In addition to the above additives or excipients, the use of any conventional materials and procedures for the formulation and preparation of oral dosage forms, using the compositions described here, known to those skilled in the art, are potentially useful.

[98] Consequently, another embodiment includes a pharmaceutical preparation containing the solid dispersion as obtained by a method as described here, in particular obtained according to steps a) to g) as mentioned above, and, more particularly as obtained according to the process described in Example 22.

[99] In yet another embodiment, a solid dispersion as obtained according to the present process for use as a medicament is provided, in particular a solid dispersion comprising HPMCAS and Compound I, more particularly the solid dispersion as obtained according to steps a) to g) above or according to Example 22.

[100] Yet another embodiment provides the use of the solid dispersion obtainable by the present steps a) to g) or by the method of Example 22 in the manufacture of medicaments for the treatment of cancer, in particular solid tumors, and, more particularly, metastatic malignant melanomas.

[101] Yet another embodiment, the solid dispersion as obtained according to steps a) to g) above or the method of Example 22 is provided for use as a medicament for the treatment of cancer, in particular solid tumors, and, more particularly melanoma malignant (metastatic). The. PH Controlled Precipitation

[102] The process involves the microprecipitation of Compound I in an ionic polymer (for example, HPMC-AS). In this process, Compound I and the polymer are dissolved at a high pH and precipitated by reducing the pH of the solution or vice versa.

[103] In a preferred embodiment, the polymer is HPMC-AS, which is insoluble at low pH. Compound I and HPMC-AS are dissolved in an organic solvent, such as dimethylformamide, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like. The pH of the solution is then reduced, for example, by adding an acid. The addition of the acid includes mixing the solution of Compound I and polymer and the acid, for example, by adding the acid to the solution of Compound I and polymer, adding the solution of Compound I and polymer to the acid, or mixing the two simultaneously . At reduced pH, both Compound I and HPMC-AS precipitate simultaneously, resulting in a solid molecular complex containing Compound I embedded in a matrix formed by HPMC-AS. The resulting solid molecular complex can then be washed with water to remove the organic solvent. B. Hot Fusion Extrusion Process

[104] Microprecipitation of Compound I in a polymer (such as HPMC-AS) can be obtained in certain embodiments by a hot melt extrusion process. Compound I and the polymer are mixed and then fed continuously to a temperature controlled extruder causing Compound I to be molecularly dispersed in the melting polymer. The resulting extrudate is cooled to room temperature and ground to a fine powder. ç. Supercritical Fluid Process

[105] In this process, Compound I and a polymer (such as HPMC-AS) are dissolved in supercritical fluid, such as liquid nitrogen or liquid carbon dioxide. The supercritical fluid is then removed by evaporation leaving Compound I microprecipated in the matrix formed by the polymer. In a different method, Compound I and a polymer (such as HPMC-AS) are dissolved in a suitable solvent. A microprecipitated powder can then be formed by spraying the solution in a supercritical fluid, which acts as an anti-solvent.

[106] The resulting solid molecular complex prepared by any method can be further processed to provide bioavailability. The solid molecular complex can be processed by compacting in a laminator, for example, the complex and other powders can be mixed and compacted in laminates to form a strip or sheet which is then crushed, mixed with other excipients and encapsulated in 2 parts of shells of hard gelatin capsules, in the desired strength.

Determination of whether Compound I is in amorphous form

[107] The determination of whether Compound I has been successfully immobilized in amorphous form can be carried out by several procedures, including X-ray powder diffraction. In addition, the glass transition temperature of the complex can be measured using modulated DSC and this can also provide information on whether the dispersion is in a multiphase or single-phase. The unifase is indicative of such immobilization. Crystalline Polymorphs 1. Form I of the Crystalline Polymorph

[108] Crystalline polymorphs of propane acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide -1-sulfonic (Compound I) are provided. In one embodiment, crystalline polymorph Form 1 is provided, in which the polymorph exhibits a powder X-ray diffraction pattern having characteristic peak locations of approximately 4.7, 9.4, 11.0, 12.5, and 15.4o 2θ. In one embodiment, Form 1 of the polymorph exhibits an X-ray diffraction pattern with characteristic peak locations of approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15, 4, 18.6, and 22.2o 2θ. In one embodiment, polymorph Form 1 exhibits a powder X-ray diffraction pattern with characteristic peak locations of approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 16.1, 18.6, 19.0, 22.2 and 26.8o 2θ. In one embodiment, Form 1 of the crystalline polymorph exhibits a powder X-ray diffraction pattern substantially equal to the powder X-ray diffraction pattern of Figure 1. In one embodiment, Form I of the purified crystalline polymorph is provided. In one embodiment, a purified crystalline polymorph Form 1 is used in the preparation of a {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] mesylate or tosylate salt form pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide of propane-1-sulfonic acid. In one embodiment, a pharmaceutical composition is provided which comprises Form 1 of the crystalline polymorph and at least one excipient or vehicle.

[109] Methods are provided for making the crystalline polymorph of {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4- propane-1-sulfonic acid diflúor-phenyl} -amide. The method may include recrystallization from any form of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} - propane-1-sulfonic acid amide from a mixture of a lower ketone and a lower alcohol, for example, acetone: absolute ethanol. The propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide can be recrystallized from acetone: absolute ethanol in a ratio of 1: 1 to 5: 1, preferably 2: 1 by volume. (B) Form 2 of the Crystalline Polymorph

[110] {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} - Crystalline Polymorph propane-1-sulfonic acid amide is provided, in which the polymorph exhibits a powder X-ray diffraction pattern having characteristic peak locations of approximately 8.8, 9.2, 13.5, 19.1 and 24, 4th 2θ. In one embodiment, Form 2 of the polymorph exhibits a powder X-ray diffraction pattern having characteristic peak locations of approximately 6.7, 8.8, 9.2, 13.5, 15.0, 17.7, 19.1, 19.7, 21.4 and 24.4o 2θ. In one embodiment, polymorph form 2 exhibits a powder X-ray diffraction pattern having characteristic peak locations of approximately 6.7, 8.8, 9.2, 13.5, 14.1, 14.5, 15.0, 16.2, 17.0, 19.1, 19.7, 21.4, 22.2, 24.1, 24.4, and 28.1o 2θ. In one embodiment, Form 2 of the crystalline polymorph exhibits a powder X-ray diffraction pattern substantially equal to the powder X-ray diffraction pattern of Figure 2. In one embodiment, a Form 2 of the purified crystalline polymorph is provided. In one embodiment, Form 2 of the purified crystalline polymorph is used in the preparation of the {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-mesylate or tosylate salt form Propane-1-sulfonic acid 3-carbonyl] -2,4-difluoro-phenyl} -amide. In one embodiment, a pharmaceutical composition is provided that comprises Form 2 of the crystalline polymorph and at least one excipient or vehicle.

[111] Methods are provided for making {3 [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4- crystalline polymorph propane-1-sulfonic acid diflúor-phenyl} -amide, in which the method comprises the direct crystallization of dimethylacetamide / methanol and recrystallization from any form of {3- [5- (4-chloro-phenyl) -1H-pyrrole [ 2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide of propane-1-sulfonic acid from a suitable solvent (including cyclic ethers) ester or ketone such as methyl ether t-ethyl: tetrahydrofuran, ethyl acetate, or acetone. In one embodiment, {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Form 2 of Propane-1-sulfonic acid is prepared by heating / melting any form of the compound and resolidating.

Compound I Mesylate Salt

[112] A form of the {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} - mesylate salt - propane-1-sulfonic acid amide is provided. In one embodiment, a {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} mesylate salt form -propane-1-sulfonic acid amide is provided. In one embodiment, the mesylate salt form is substantially crystalline. In one embodiment, the mesylate salt form is partially amorphous. In one embodiment, the mesylate salt form is substantially amorphous. In one embodiment, the mesylate salt is used in a mass microprecipitate process to formulate the salt in an amorphous form. In one embodiment, the mesylate salt is generated in situ in a mass microprecipitate process to formulate the salt in amorphous form. In one embodiment, a composition is provided that comprises the mesylate salt.

Compound I Tosylate Salt

[113] A {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide tosylate salt propane-1-sulfonic acid is provided. In one embodiment, the tosylate salt form is substantially crystalline. In one embodiment, the tosylate salt form is partially amorphous. In one embodiment, the tosylate salt form is substantially amorphous. In one embodiment, the tosylate salt is used in a mass microprecipitate process to formulate the salt in an amorphous form. In one embodiment, the tosylate salt is generated in situ in a mass microprecipitate process to formulate the salt in an amorphous form. In one embodiment, a composition is provided that comprises the tosylate salt. Target kinase and indications

[114] Protein kinases play roles in the propagation of biochemical signals in several biological pathways. More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseases or conditions (ie indications), including, for example, but not limited to, cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases . As such, kinases represent important control points for small molecule therapeutic intervention. The description of specific target protein kinases contemplated by the present invention is given below:

[115] A-Raf: The target kinase A-Raf (i.e., v-raf of murine sarcoma viral homologue 1 oncogenic 3611) is a 67.6 kDa serine / threonine kinase encoded by chromosome Xp11.4- p11.2 (symbol: ARAF). The mature protein comprises RBD (i.e. Ras binding domain) and phorbol-ester / DAG finger-like zinc domain and is involved in the transduction of mitogenic signals from the cell membrane to the nucleus. A-Raf inhibitors may be useful in the treatment of neurological diseases such as multi-infarction dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (eg, colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (eg, histiocytic lymphoma), neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis; pain of neuropathic or inflammatory origin, including acute pain, chronic pain, cancer-related pain and migraine; and diseases associated with muscle regeneration or degeneration. Including, but not limited to, vascular restenosis, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne Muscular Dystrophies, Becker, Emery-Dreifuss, Limb Girdle, Facioescapulameral, Myotonic, oculopharyngeal, Distal and Congenital), motor neuronal diseases (including, but not limited to, amyotrophic lateral sclerosis, childhood progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, bulbar spinal muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), neuromuscular joint diseases (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies resulting from endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy), peripheral nerve diseases (including, but not limited to) mitation, Charcot-Marie tooth disease, Dejerine-Sottas disease, and Friedreich ataxia), other myopathies (including, but not limited to, congenital myotonia, congenital paramythonia, central nucleus disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic muscle diseases (including, but not limited to, phosphorylase deficiency, maltase acid deficiency, phosphofrutokinase deficiency, Debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myadenylate deaminase deficiency).

[116] B-Raf: The target kinase B-Raf (ie, B1 homologue of the viral oncogene of murine sarcoma v-raf) is an 84.4 kDa serine / threonine kinase encoded by chromosome 7q34 (symbol: BRAF ). The mature protein comprises the RBD (i.e., ie, Ras binding domain), C1 (i.e., conserved region of protein kinase C) and STK domains (i.e., serine / threonine kinase).

[117] The target kinase B-Raf is involved in the transduction of mitogenic signals from the cell membrane to the nucleus and may play a role in the postsynaptic responses of neurons in the hippocampus. Thus, the genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals. Certainly, the B-Raf kinase is a key component of the RAS-> Raf-> MEK-> ERK / MAP signaling pathway, which plays a key role in regulating cell growth, division and proliferation, and, when constitutively activated , causes tumorigenesis. Among the various isoforms of Raf kinase, type B, or B-Raf, is the strongest activator of MAP kinase signaling downstream.

[118] The BRAF gene is frequently mutated in a variety of human tumors, especially in malignant melanoma and colon carcinoma. The most common reported mutation was the missense transversion of thymine (T) to adenine (A) in nucleotide 1796 (T1796A); amino acid change in B-Raf protein is Val <600> to Glu <600>) seen in 80% of malignant melanoma tumors. Functional analysis reveals that this transversion is the only mutation detected that causes constitutive activation of B-Raf kinase activity, independent of RAS activation, by converting B-Raf into a dominant transforming protein. Based on precedents, human tumors develop resistance to kinase inhibitors by mutating a specific amino acid in the catalytic domain such as servers (Balak, et. Al., Clin Cancer Res. 2006, 12: 6494-501). The mutation of Thr-529 in BRAF to Ile is thus anticipated as a mechanism of resistance to BRAF inhibitors, and this can be imagined as a transition in codon 529 from ACC to ATC.

[119] Niihori et al. report that in 43 individuals with cardio-facio-cutaneous syndrome (CFC), they identified two heterozygous KRAS mutations in three individuals and eight heterozygous mutations in 16 individuals, suggesting that deregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders (Niihori ct al., Nat Genet. 2006, 38 (3): 294-6).

[120] c-Raf-1: The target kinase c-Raf-1 (i.e., murine sarcoma viral oncogene homolog 1 v-raf) is a 73.0 kDa STK encoded by chromosome 3p25 (symbol : RAF1). C-Raf-1 can be targeted to mitochondria by BLC2 (ie, B cell leukemia oncogene 2), which is a regulator of apoptosis cell death. active c-Raf-1 improves resistance to BCL2-mediated apoptosis, and c-Raf-1 phosphoryl BAD (i.e., BCL2 binding protein). C-Raf-1 is implicated in carcinomas, including colorectal, ovarian, pulmonary and renal carcinoma. C-Raf-1 is also implicated as an important mediator of tumor angiogenesis (Hood, ID. Et al., 2002, Science 296, 2404). C-Raf-1 inhibitors may also be useful in the treatment of acute myeloid leukemia and myelodysplastic syndrome (Cramp, Curr Pharm Des 2002, 8 (25): 2243-8). Raf-1 activators may be useful as a treatment for neuroendocrine tumors, such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al., Anticancer Drugs 2006, 17 (2): 139-42) .

[121] A-Raf, B-Raf and / or C-Raf inhibitors may be useful in the treatment of A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or condition, selected from the group which consists of neurological diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, attacks and epilepsy; neoplastic diseases, including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g., gastrointestinal, hepatic, bile duct (cholangiocarcinoma), colorectal, pulmonary, breast, pancreatic, thyroid, renal, ovarian, prostatic), lymphoma (e.g., histiocytic lymphoma), neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, and pheochromocyte; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular diseases, including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (for example, thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion lust; inflammation and / or proliferation including, but not limited to, psoriasis, eczema, arthritis and autoimmune diseases and conditions, osteoarthritis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, rejection of organ transplants, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel disease Lindau, medullary cystic kidney disease, nephronophysis, and cystic fibrosis; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to, Heliobacter pylori, hepatitis and influenza viruses, fever, HIV and sepsis; lung diseases, including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, Noonan syndrome, Costello syndrome, (facial-skeletal syndrome), LEOPARD syndrome, cardiofaciocutaneous syndrome (CFC), and abnormalities of the neural crest syndrome that cause cardiovascular, skeletal diseases, intestinal, skin, capillary and endocrine; and diseases associated with muscle regeneration or degeneration, including, but not limited to, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb Waist, Facio-Scapulameral, Myotonic, Oculopharyngeal, Distal and Congenital) , motor neuronal diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, bulbar spinal muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but without limitation, dermatomyositis, polymyositis, and inclusion body myositis), neuromuscular joint diseases (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies resulting from endocrine abnormalities (including, but not limited to , hyperthyroid myopathy and hypothyroid myopathy), peripheral nerve diseases (including going, but not limited to, Charcot-Marie tooth disease, Dejerine-Sottas disease, and Friedreich ataxia), other myopathies (including, but not limited to, congenital myotonia, congenital paramyotonia, central nucleus disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and muscle metabolic disorders (including, but not limited to, phosphorylase deficiency, maltase acid deficiency, phosphofrutokinase deficiency, Debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, phosphoglycerate mutase deficiency, deficiency lactate dehydrogenase, and myoadenylate deaminase deficiency).

Forms of Alternative or Derivative Compounds

[122] Propane-1- acid [3- [5- (4-Chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide sulfonic content contemplated here is described with reference to the specific compound. In addition, Compound I can exist in several different forms or derivatives, all within the scope of the present invention. Alternative forms or derivatives include, for example, (a) prodrugs, and active metabolites (b), tautomers (c), pharmaceutically acceptable salts and (d) solid forms, including different crystal forms, polymorphic or amorphous solids, including hydrates and solvates of these, and other forms.

Prodrugs and metabolites

[123] Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when stabilized under physiological conditions or when converted by solvolysis, yield the desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, the prodrug is inactive, or less active than the active compound, but can provide one or more advantageous handling, administration, and / or metabolic properties. Prodrugs can include variants, where an -NH group of the compound has undergone acylation, such as position 1 of the pyrrole [2,3-b] pyridine ring or the nitrogen of the sulfonamide group of Compound I or a pharmaceutically acceptable salt thereof, where cleavage of the acyl group provides the -NH group free of the active drug. Some drugs are activated enzymatically to yield the active compound, or a compound may undergo a subsequent chemical reaction to give the active compound. Prodrugs can originate from the form of the prodrug to the active form in a single step or can have one or more intermediate forms, which may themselves be active or may be inactive.

[124] As described in Practice of Medicinal Chemistry, Chapters 31-32 (Ed Wermuth, Academic Press, San Diego, CA, 2001), prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and vehicle prodrugs. Generally, bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, which contains one or more protective groups and is converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products must have acceptably low toxicity. Typically, the formation of the active drug compound involves a metabolic process or reaction that is one of the following types:

[125] Oxidative reactions: Oxidative reactions are exemplified without limitation by reactions, such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O-dealkylation and oxidative S-dealkylation, oxidative deamination, as well as other oxidative reactions.

[126] Reducing reactions: Reducing reactions are exemplified, without limitation, by reactions such as reduced carbonyl functionality, reduced alcohol functionality and double carbon-carbon bonds, reduced nitrogen-containing functional groups, or other reducing reactions.

[127] Reactions without changing the oxidation state: Reactions without changing the oxidation state are exemplified, without limitation, to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of single carbon-carbon bonds, hydrolytic cleavage of non-aromatic heterocycles , hydration and dehydration in multiple bonds, new atomic bonds resulting from dehydration reactions, hydrolytic dehalogenation, removal of the hydrogen halide molecule, and other such reactions.

[128] Vehicle prodrugs are composed of drugs that contain a transport fraction, for example, which improves localized absorption and / or distribution to the site (s) of action. Desirably for such a vehicle prodrug, the link between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, the prodrug and any release transport moiety are acceptably non-toxic. For prodrugs in which the transport fraction is intended to enhance absorption, typically the release of the transport fraction would be rapid. In other cases, it is desirable to use the fraction that provides slow release, for example, certain polymers or other fractions, such as cyclodextrins. (See, for example, Cheng et al., US Patent Publication 20040077595, Application No. 10 / 656,838, incorporated herein by reference). Such transport prodrugs are often advantageous for drugs administered orally. In some cases, the transport fraction provides targeted drug delivery, for example, the drug can be conjugated to an antibody or antibody fragment. Vehicle prodrugs can be used, for example, to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and / or improvement in the formulation of the drug (for example , stability, solubility in water, suppression of an unwanted organoleptic or physicochemical property). For example, lipophilicity can be increased by esterifying hydroxyl groups with lipophilic carboxylic acids, or carboxylic acid groups with alcohols, for example, aliphatic alcohols, Wemuth, supra.

[129] Metabolites, for example, active metabolites, overlap with the prodrugs described above, for example, bioprecursor prodrugs. Thus, such metabolites are pharmacologically active compounds or compounds that still metabolize to pharmacologically active compounds that are derived from metabolic processes in a patient's body. Of these, the active metabolites are such compounds of pharmacologically active derivatives. For prodrugs, the compound of the prodrug is generally inactive or of lower activity than the metabolic product. For active metabolites, the parent compound can be either an active compound or an inactive prodrug. For example, in some compounds, one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacological activity and carboxyl groups can be esterified, for example, glucuronidation. In some cases, there may be more than one metabolite, in which intermediate metabolite (s) is (are) further metabolized to provide an active metabolite. For example, in some cases, a derivative compound resulting from metabolic glucuronidation may be inactive or of low activity, and may be further metabolized to provide an active metabolite.

[130] The metabolites of a compound can be identified using routine procedures known in the art, and their activities determined using tests such as those described here. See, for example, Bertolini et al, 1997, J Med Chan, 40 201 12016, Shan et al, 1997, J Pharm Sci 86 (7) 756-757, Bagshawc, 1995, Drug De \ Res, 34 220-230, Wermuth, supra. Tautomers

[131] It is understood that some compounds can exhibit tautomerism. In such cases, the formulas provided here expressly illustrate and only one of the possible tautomeric forms. Therefore, it is to be understood that Compound I provided here is intended to represent any tautomeric form of the illustrated compound and is not to be limited to the specific tautomeric form illustrated by the design of the compound. Pharmaceutically acceptable salts

[132] Unless otherwise specified, the Compound I specification here includes pharmaceutically acceptable salts of such a compound. Thus, Compound I can be in the form of pharmaceutically acceptable salts, or they can be formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salt forms contemplated include, without limitation, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful changes in physical properties include reducing the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug. Compound I has a sufficiently acidic and sufficiently basic functional group, and therefore can react with any one of several inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[133] Pharmaceutically acceptable salts include acid addition salts such as those containing chloride, bromide, iodide, hydrochloride, acetate, dichloroacetate, phenylacetate, acrylate, ascorbate, aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate, methoxy , methylbenzoate, bicarbonate, butino-1,4-dioate, hexino-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate, glucuronate, glucose-6-phosphate , glutamate, heptanoate, hexanoate, isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, maleate, hydroximaleate, methylmaleate, malonate, mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate, oxalate, oxalate, oxalate, oxalate, oxalate -phosphate, dihydrogen-phosphate, orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate, 3-phosphoglycerate, phthalate, propionate, phenylpropionate, propiolate, pyruvate, quinate, salicylate, 4-aminosalicate bacate, stearate, suberate, succinate, sulfate, pyrosulfate, bisulfate, sulfide, bisulfide, sulfite, bisulfite, sulfamate, sulfonate, benzenesulfonate (i.e., besylate), ethanesulfonate (ie, stylate), ethane-1,2-disulfonate , 2-hydroxyethanesulfonate (i.e., isethionate), methanesulfonate (i.e., mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e., napsylate), propanesulfonate, p-toluenesulfonate (i.e., tosylate), xylenesulfonate , cyclohexylsulfamate, tartrate, and trifluoracetate. Such pharmaceutically acceptable acid addition salts can be prepared using the appropriate corresponding acid.

[134] When acidic functional groups, such as carboxylic acid or phenol, are present, pharmaceutically acceptable salts may also include base addition salts such as those containing benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine , dicyclohexylamine, ethylenediamine, N, N'-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, procaine, aluminum, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium, and mono , di, or trialkylamines (e.g., diethylamine), or salts derived from amino acids such as L-histidine, L-glycine, L-lysine, and L-arginine. For example, see, Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA, Vol. 2, pp. 1457, 1995. Such pharmaceutically acceptable base addition salts can be prepared using the appropriate corresponding base.

[135] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent, such as an aqueous solution or an aqueous alcohol solution containing the appropriate acid, and then isolated by evaporation of the solution. In another example, the salt can be prepared by reacting the free base and free acid, in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base.

Other forms of compounds

[136] In the case of agents that are solid, it is understood by those skilled in the art that compounds and salts may exist in different crystal or polymorphic forms, or may be formulated as co-crystals, or may be in an amorphous form, or they can be any combination of these (for example, crystalline, partially amorphous, or mixtures of polymorphs), all of which are within the scope of the present invention and the specified formulas. Although acid / base addition salts are formed, that is, free base or free acid of the compound of interest forms an acid / base reaction with an addition base or corresponding addition acid, respectively, resulting in ionic charge interaction, the co-crystals they are a chemical species that is formed between neutral compounds, resulting in the compound and an additional molecular species in the same crystal structure.

[137] In some cases, Compound I is complexed with an acid or a base, including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine, acid addition salts , such as acetate, acetylsalicylate, besylate, cansylate, citrate, format, fumarate, glutarate, hydrochloride, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate and tosylate. And amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine. When combining Compound I as the acid or base, an amorphous complex is preferably formed instead of a crystallite material such as a typical or cocrystalline salt. In some cases, the amorphous form of the complex is facilitated by further processing, such as spray drying, mechanical-chemical methods such as laminator compaction, or microwave irradiation of the parent compound mixed with the acid or base. Such amorphous complexes provide several advantages. For example, reducing the melting temperature relative to the free base facilitates further processing, such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound. Also, the amorphous complex is readily friable, which provides improved compression for loading the solid into the capsule or into a tablet form.

[138] In addition, Compound I or salts thereof described herein are intended to cover hydrated or solvated forms as well as unhydrated and unsolvated forms of the identified material. For example, Compound I or salts thereof include both hydrated and unhydrated forms. Other examples of solvates include structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

Formulations and Administration

[139] Compound I or any form thereof as described herein (including solid molecular complexes) will typically be used in therapy for human patients. However, Compound I and its compositions can also be used to treat similar or identical indications in other animal patients, and can be administered by different routes, including injection (i.e., parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular) , oral, transdermal, transmucosal, rectal, or inhalant. Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that make the compound or composition take time to exert its effects. Techniques and formulations are generally found in Remington The Science and Practice of Pharmacy, 21st Edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference).

[140] In some embodiments, the compositions (including the solid complexes described here) include pharmaceutically acceptable vehicles or excipients, such as fillers, binders, disintegrators, glidants, lubricants, complexing agents, solubilizers, and surfactants, which can be chosen to facilitate the administration of the compound by a particular route. Examples of vehicles include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Vehicles also include physiologically compatible liquids as a solvent or for suspensions, including, for example, sterile water for injection (WFI) solutions, saline, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils , polyethylene glycols, liquid paraffin, and the like. Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, microcrystalline cellulose, cross-linked carboxymethyl cellulose, sodium carboxymethyl cellulose, benzoate sodium, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, silo, Stearowet C, magnesium oxide, starch, sodium starch glycolate , glyceryl monostearate, glyceryl dibeenate, glyceryl palmitoestearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor seed oil, mineral oil, polyethylene glycol (eg PEG 4000-8000), polyethylene glycol, poloxamers, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, divinylbenzene methacrylic acid copolymer, sodium docusate, cyclodextrins (eg multiple, 2-hydroxypropyl-delta-cyclodextrin), polysorbates (for example, polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers , polyethylene glycols di-fatty acid ester, or polyoxyalkylene sorbitan fatty acid ester (for example, polyoxyethylene sorbitan ester Tween®), sorbitan fatty acid esters, for example, a sorbitan fatty ester from a fatty acid such as oleic, stearic or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, spray dried lactose, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate , calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropylmethyl cellulose), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, hipro melose, and the like.

[141] In an embodiment of the present invention, a formulation is provided which comprises the solid complex mentioned above in an aqueous vehicle. The formulation may further comprise colloidal silicon dioxide in which it has been found to stabilize the suspension. The silicon dioxide is preferably present in an amount of at least 0.5% by weight of the formulation. The aqueous vehicle is preferably about 2% by weight of hydroxypropyl cellulose.

[142] In some modalities, oral administration can be used. Pharmaceutical preparations for oral use can be formulated in conventional oral dosage forms, such as capsules, tablets, and liquid preparations, such as syrups, elixirs, and concentrated drops. Compound I can be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, then adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (for example, aqueous, alcoholic, or oily) and the like. Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone) ; oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or cod liver oil. Oral dosage formulations may also contain disintegrating agents, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium stearate; a plasticizer such as glycerol or sorbitol; a sweetener such as fructose, lactose or aspartame; a flavoring agent, such as peppermint, gualteria oil, cherry flavoring; or dyes or pigments, which can be used to identify and characterize different doses or combinations. Dragee cores with suitable coatings are also provided. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or mixtures of these.

[143] Pharmaceutical preparations that can be used orally include pressure plug capsules made of gelatin ("gelcaps"), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. Snap-fit can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compound can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.

[144] In some embodiments, the injection (parenteral administration) can be used, for example, intramuscular, intravenous, intraperitoneal, and / or subcutaneous. Compound I and its compositions for injection can be formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline, Hank's solution, or Ringer's solution. The dispersions can also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, and vegetable oils. The solutions may also contain preservatives, such as methyl paraben, propyl paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, Compound I or its compositions can be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended before use.

[145] In some embodiments, transmucosal, topical or transdermal administration may be used. In such formulations of Compound I, penetrators suitable for the barrier to be permeated are used. Such penetrators are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents can be used to facilitate permeation. Transmucosal administration, for example, can be through nasal sprays or suppositories (rectal or vaginal). Compositions I compositions, for topical administration, can be formulated as oils, creams, lotions, ointments, and the like by choosing appropriate carriers of the technique. Such vehicles include vegetable or mineral oils, white petroleum jelly (soft white paraffin), fats and branched-chain oils, animal fats and high molecular weight alcohol (greater than C12). In some embodiments, vehicles are selected so that the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants can also be included as well as coloring and perfuming agents, if desired. Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water, in whose mixture the active ingredient dissolved in a small amount of solvent (for example, oil) is mixed. In addition, administration by transdermal means may comprise a dermal or curative adhesive such as a bandage impregnated with an active ingredient and, optionally, one or more vehicles or diluents known in the art. For administration in the form of a transdermal delivery system, dosing will be continuous rather than intermittent through the dosing regimen.

[146] In some embodiments, Compound I or its compositions are administered as inhalants. Compound I or its compositions can be formulated as a dry powder or a suitable solution, suspension or aerosol. Powders and solutions can be formulated with suitable additives known in the art. For example, powders may include a suitable powder base with suitable additives known in the art. For example, powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts. Such solutions or suspensions can be administered by inhalation via spray, pump, atomizer, or nebulizer, and the like. Compound I or compositions thereof can also be used in combination with other inhaled therapies, for example, corticosteroids such as fluticasone propionate, beclomethasone dipropionate, acetonide triamcinolone, budesonia, and mometasone furoate; beta-agonists such as albuterol, salmeterol, and formoterol; anticholinergic agents such as ipratrium bromide or titrium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; an oligonucleotide, such as single-stranded or double-stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; sodium chromoline; nedocril sodium; and sodium cromoglycate.

[147] The amounts of Compound I or its compositions to be administered can be determined by standard procedures taking into account factors such as the activity of the compound (in vitro, for example, the compound IC50 versus target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (for example, biological half-life or bioavailability), the age, weight size of the patient, and the disorder associated with the patient. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, the dose will be in the range of about 0.01 to 50 mg / kg, also about 0.1 to 20 mg / kg of the patient being treated. Multiple doses can be used.

[148] Compound I or its compositions may be useful in combination with other therapies for the treatment of the same disease. Such combination use includes administration of Compound I and one or more therapeutic products at different times, or co-administration of Compound I and one or more of other therapies. In some embodiments, the dosage can be modified for Compound I or other therapeutic products used in combination, for example, reducing the dosed amount with respect to a compound or therapy used alone, by methods well known to those of ordinary skill in the art.

[149] It is understood that use in combination includes use with other therapies, drugs, medical procedures, etc., in which the other therapy or procedure can be administered at different times (for example, within a short time, such as within hours (for example, 1, 2, 3, 4-24 hours), or within a longer time (for example, 1-2 days, 2-4 days, 4-7 days, 1-4 weeks) than Compound I or compositions thereof, and at the same time as Compound or compositions thereof. Use in combination includes use with a therapy or medical procedure that is administered once or not frequently, such as surgery, together with Compound I or compositions thereof whose administration is carried out within a short time before or after another therapy or procedure In some embodiments, the present invention provides for the distribution of Compound I or compositions thereof and one or more therapeutic drug products distributed via different administration or by the same route of management. The use in combination for any route of administration of Compound I or compositions thereof and one or more other therapeutic drug products distributed by the same route of administration together with any formulation, including formulations in which the two compounds are chemically linked in such a way that they maintain their therapeutic activity when administered. In one aspect, the other drug therapy can be co-administered with Compound I or compositions thereof. Combined use may co-administration includes administration of co-formulations or chemically linked formulations, or administration of two or more compounds in separate formulations within a short time of each other (for example, within an hour, 2 hours, 3 hours, up to 24 hours), administered by the same or different routes. Co-administration of separate formulations includes co-administration by delivery via a device, for example, the same inhaler device, the same syringe, etc., or administration from separate devices within a short time from each other. Co-formulations of Compound I and one or more additional drug therapies delivered via the same route include preparing the materials together so that they can be administered by a device, including separate compounds combined in a formulation, or compounds that are modified in a way that they are chemically linked, and yet retain their biological activity. Such chemically linked compounds can have a bond that is substantially maintained in vivo, or the bond can break in vivo, separating the two active components.

EXAMPLES

[150] Examples related to the present invention are described below. In most cases, alternative techniques can be used. The examples are intended to illustrate the invention and not to limit or restrict the scope of the invention.

Example 1

[151] This example describes the formation of a solid molecular complex comprising Compound I and HPMC-AS.

[152] Propane-1- acid acid 3- 3- [5- (4-Chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide sulfonic and HPMC-As in a 3: 7 ratio (30% compound and 70% polymer) were dissolved in dimethylacetamide (DMA). The resulting solution was then added with stirring to the diluted, very cold hydrochloric acid, resulting in the coprecipitation of {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl Propane-1-sulfonic acid -2,4-diflúor-phenyl} -amide and HPMC-AS as a solid molecular complex in which {3- [5- (4-chloro-phenyl) - 1H-pyrrole [2 , 3-b] propane-1-sulfonic acid pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide was present in a nanoparticle size range. The ratio of DMA to acid was in the range of 1: 5 to 1:10. The coprecipitate was then washed with water to remove DMA, filtered, dried to <2% moisture content and passed through a 30 mesh sieve prior to evaluation. The resulting solid molecular complex was 30% by weight of {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl } -propane-1-sulfonic acid amide and 70% by weight of HPMC-AS.

[153] The properties of the resulting solid molecular complex were as follows.

[154] The solid molecular complexes comprising Compound I and HPMC-AS were prepared using methods analogous to that used in the Example to produce the solid molecular complexes, wherein the weight ratio of {3- [5- ( 4-chloro-phenyl) - 1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide of propane-1-sulfonic acid within the solid molecular complex for the amount in weight of the ionic polymer in it is 3: 7, 5: 5, 5: 5, 4: 6, 4: 6, and 2: 8, respectively.

[155] The solid molecular complexes produced in Examples 1 to 7 were evaluated for amorphous nature by powder XRD. The samples were exposed under OPEN conditions by placing the sample in a bottle in the stability chamber without a lid or closure or cover, at 50 ° C and 75% relative humidity (RH) and the properties of the solid molecular complexes following such exposure were observed. The exposure periods are shown in the table below. At the end of the exposure period, a powder sample was taken from the bottle and placed in a powder X-ray diffraction (XRD) chamber and the diffraction pattern obtained. The samples were considered to be stable if the powder X-ray diffraction profile did not show crystalline peaks. The prepared and stored samples were also evaluated by polarized light microscopy. The incidence of polarized light results in a birefringence phenomenon, if the crystals are present in the sample. For an amorphous sample, such a test could indicate the presence of the crystal material which indicates that the amorphous material is unstable. Table 1 Evaluation of solid drug-HPMC-AS molecular complexes in varying ratios

Example 8

[156] This example describes the formation of a solid molecular complex comprising {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4- propane-1-sulfonic acid diflúor-phenyl} -amide and EUDRAGIT® L 100. EUDRAGIT® L 100 is another anionic polymer, a poly (methyl methacrylate ester) with methacrylic acid as a functional group and dissolves at pH 6 , 0 and above.

[157] Propane-1 acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide -sulfonic and EUDRAGIT® L 100 in a ratio of 3: 7 (30% of the compound and 70% of the polymer) were dissolved in dimethylacetamide (DMA). The resulting solution was then added with stirring to the very cold diluted hydrochloric acid, resulting in the coprecipitation of {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] - Propane-1-sulfonic acid 2,4-difluoro-phenyl} -amide and EUDRAGIT® L 100 as a solid molecular complex, in which the drug was present in a nanoparticulate size range. The coprecipitate was then washed with water to remove DMA, filtered, dried, and ground to a fine powder. The ratio of DMA to acid was in the range of 1: 5 to 1:10. The coprecipitate was then washed with water to remove DNA, filtered, dried to <2% moisture content and passed through a 30 mesh sieve, prior to evaluation. The resulting solid molecular complex was 30% by weight of {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} - propane-1-sulfonic acid amide and EUDRAGIT® L 100

[158] Samples of the solid molecular complex were evaluated for amorphous nature shortly after preparation by XRD powder. The samples were then subjected to storage under OPEN conditions, at 40 ° C / 75% RH for varying periods of time similar to those shown in Examples 1-7. At the end of the exposure period, a powder sample was taken from the bottle and placed in a powder X-ray diffraction (XRD) chamber and the diffraction pattern obtained. The samples were considered stable if the powder XRD profile did not show crystalline peaks. The prepared and stored samples were also evaluated by polarized light microscopy. The incidence of polarized light results in a birefringence phenomenon if crystals are present in the sample. For an amorphous sample, such a test could indicate the presence of crystal material which indicates that the amorphous material is unstable. The results for this Example are shown in Table 2 below.

Example 9

[159] This example was performed with all the same steps as Example 8, except that {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3- carbonyl] -2,4-difluoro-phenyl} -amide of propane-1-sulfonic acid and EUDRAGIT® L 100 were dissolved in dimethylacetamine (DMA) in a ratio of 4: 6 (40% compound and 60% polymer) instead of 3: 7 as in Example 8. The results for this Example are shown in Table 2 below.

Example 10

[160] Solid molecular complexes containing {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide propane-1-sulfonic acid and EUDRAGIT® L 100-55 in 4: 6 and 5: 5 ratios, respectively, were formed using the same microprecipitation process as in Example 1. Eudragit®L 100-55 is similar to L 100 except that it dissolves at pH 5.5 and above, and therefore more closely resembles HPMC-AS in its pH solubility profile. The prepared and stored samples were evaluated by XRD powder. The results for this Example are shown in Table 2 below.

Example 11

[161] This example describes the formation of a solid molecular complex comprising {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2, Propane-1-sulfonic acid 4-difluoro-phenyl} -amide and hydroxypropylmethylcellulose phthalate (HPMCO), another anionic polymer used for enteric purposes. HPMCP is a cellulose polymer in which some of the hydroxyl groups are replaced with phthalic esters of 27-35%. It starts to dissolve at pH 5.5 and higher. Solid molecular complexes containing propane acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide 1-sulfonic and HPMCP in 1: 1 ratio were prepared using the same procedure as that used in Example 1. The prepared and stored samples were evaluated by XRD. The results for this Example are shown in Table 2 below. Table 2 Evaluation of solid drug-polymer molecular complexes for various reasons

[162] Based on Examples 1 - 11, the ratio of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluor -Phenyl} -propane-1-sulfonic acid / polymer 4: 6 was the highest sustainable drug load (40%) upon storage with HPMC-AS as the polymer. Therefore, this ratio was chosen for comparison with other polymers in a separate study.

[163] Examples 12-16 were prepared by a microprecipitation process similar to that for Example 1. The dry powder samples were evaluated for amorphous nature shortly after preparation by XRD powder. The samples were further subjected to storage under OPEN conditions at 40 ° C / 75% RH for various periods of time similar to those shown in Examples 1-7. The results are shown in Table 3 below.

Example 12

[164] Solid molecular complexes containing {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl have been found } - propane-1-sulfonic acid amide and HPMC-AS, in a 4: 6 ratio, were amorphous shortly after preparation (Table 3) and subjected to storage for 4 weeks at 40 ° C / 75% RH.

[165] The XRD of the solid molecular complexes was evaluated.

Example 13

[166] Solid molecular complexes containing {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro- propane-1-sulfonic acid phenyl} -amide and HPMCP in 4: 6 ratio were amorphous immediately after preparation (Table 3) and stored for 4 weeks at 40 ° C / 75% RH. Example 14

[167] Solid molecular complexes containing {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} have been found -propane-1-sulfonic acid amide and Eudragit® L 100-55 in a 4: 6 ratio were amorphous shortly after preparation (Table 3) and stored for 4 weeks at 40 ° C / 75% RH. Example 15

[168] Solid molecular complexes containing {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide propane-1-sulfonic acid and poly (vinyl acetate phthalate (PVAP) in a 4: 6 ratio were crystalline shortly after preparation and therefore not subjected to subsequent testing. PVAP is an anionic enteric polymer formed as the ester of poly (vinyl acetate) phthalate and contains 55-63% of phthalyl groups.It has a low Tg of 42.5 ° C, which makes it unsuitable as a stabilizing polymer matrix. It dissolves at pH> 5. Example 16

[169] Solid molecular complexes containing {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide propane-1-sulfonic acid and cellulose acetate phthalate (CAP) in a 4: 6 ratio were crystalline shortly after preparation, and therefore not subjected to subsequent testing.

[170] The powder XRD profiles of Examples 12-16, in the initial stage, shortly after preparation are shown in Table 3. Table 3 Evaluation of solid molecular drug-polymer complexes in a fixed ratio of 4: 6 (40% drug and 60% polymer):

[171] After 1 week, the sample prepared under Example 3 showed a small peak in XRD of powder indicating conversion to crystalline form. This peak became more pronounced after 2 weeks of storage. Example 17

[172] The samples prepared in Examples 12 and 14 did not indicate any crystalline peak in the XRD powder profiles until the end of 4 weeks of storage.

[173] To subsequently differentiate the samples from Examples 12 and 14, the samples were subjected to the dissolution test by placing an amount of solid molecular complex equivalent to 80 mg of {3- [5- (4-chloro-phenyl) - 1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide of propane-1-sulfonic acid in 900 mL of pH 6.8 phosphate buffer medium containing 0 , 09% HTAB surfactant in a USP Paddle dissolution apparatus, at a speed of 75 rpm.

[174] In a set of experiments, the sieve cut of granules of Examples 12 and 14 was obtained by separating a sieve size fraction of 325/40 mesh and undergoing the dissolution test. The solid molecular complexes with HPMC-AS had increased amounts with respect to the% dissolved in comparison with the solid molecular complexes with Eudragit® L 100-55, in which the solid molecular complexes with HPMC-AS were about 85% dissolved in 200 minutes and with the solid molecular complexes with Eudragit® L 100-55 were about 40% dissolved in 200 minutes.

[175] In another experiment, samples of solid molecular complexes from Examples 12 and 18 were pre-wetted with a vehicle containing hydroxypropyl cellulose (Klucel) for improved dispersion, and subjected to the dissolution test. The solid molecular complexes of HPMC-AS had increased amounts with respect to% dissolved compared to the solid molecular complexes with Eudragit® L 100-55, with the solid molecular complexes with HPMC-AS being about 60-65% dissolved in 200 minutes and with the solid complexes with Eudragit® L 100-55 being about 20-25% dissolved in 200 minutes.

[176] Based on the results of these experiments, HPMC-AS was a superior polymer in drug stabilization, during storage, under stress conditions, but also allowing drug release and maintaining amorphous drug supersaturation during dissolution without reversing to the crystalline form within the test period. Eudragit® L 100-55 did not enhance the release of the drug compared to HPMC-AS, and therefore is not expected to provide exposure and availability as well as HPMC-AS. At the end of 3 hours, almost 90% of the drug was released from Example 12 (HPMC-AS) while Example 14 (Eudragit® L-100-55) had only about 50% of the drug released. Thus, a solid molecular complex of acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide propane-1-sulfonic and HPMC-AS made by the microprecipitation process not only stabilizes the amorphous compound for handling and storage, but also ensures rapid drug release, resulting in superior dissolution and, therefore, bioavailability.

Example 18

[177] This Example demonstrates the stabilization of solid molecular complexes in aqueous systems. The solid drug-HPMC-AS molecular complex is suspended in an aqueous vehicle containing 2% hydroxypropylcellulose (Klucel LF). By adding> 0.5% w / w colloidal silicon dioxide, the resulting suspension was shown to be stable for up to 8 hours under normal conditions and for up to 24 hours under refrigerated conditions.

Example 19

[178] Propane-1- acid acid 3- 3- [5- (4-Chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide sulfonic can exist in polymorphic forms, for example, as polymorphic forms 1 or 2, in which such polymorphic forms can be isolated as the substantially pure polymorph. The desired polymorphic form can be prepared, for example, using appropriate crystallization conditions. For example, Form 1 was isolated by recrystallization from acetone / absolute ethanol (for example, 1: 1 to 5: 1, preferably 2: 1 by volume), as explained in detail here. Form 2 can be formed, for example, directly via crystallization from dimethylacetamide / methanol or under a variety of recrystallization conditions, for example, it is formed by recrystallization from methyl-t-butyl / tetrahydrofuran, acetate ethyl, acetone, or is formed by heating / melting and resolidifying any solid form, such as polymorphic Form 1, or a mixture of solid forms. The isolated polymorphic forms, substantially pure, were characterized by X-Ray Powder Diffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy (see Example 20 below).

[179] To demonstrate the formation of the polymorphic Form 1, {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro- propane-1-sulfonic acid phenyl} -amide (7.8 kg) was treated with acetone: absolute ethanol (1: 4 by volume, 19 kg) in a reactor and stirred at 20 ° C ± 5 ° C for at least least 6 hours. The contents were filtered and the solids were washed with a mixture of acetone: absolute ethanol (1: 4 by volume). The solids were treated with tetrahydrofuran (26.6 kg), and the suspension was heated to 60 ° C ± 5 ° C for at least 30 minutes and stirred. The mixture was cooled to 55 ° C ± 5 ° C and methyl-t-butyl ether (92.3 kg) was added. The contents were filtered and the solids were washed with methyl-t-butyl ether and dried. The solid was treated with acetone: absolute ethanol (2: 1 by volume) in a reactor. The contents were stirred and the suspension was heated to 60 ° C until a solution was obtained. The solution was filtered through a large polishing filter to remove any solid residue from the treatment step with methyl-t-butyl ether. The filtrate was concentrated in vacuo, stirred at 20 ° C ± 5 ° C, for at least 30 minutes and filtered. The solids were washed with pre-cooled ethanol (0 ° C to -5 ° C) and dried at 45 ° C, and then dried at 75 ° C, under vacuum, until reaching constant weight, to provide pure, polymorphic Form 1 of pure propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide . Form 1 was also prepared by treating a sample with 120 ml of acetone: ethanol (1: 1 by volume) under reflux, then hot filtration and removal of the solvent from the filtrate, under vacuum, until precipitation of the solid.

Example 20

[180] Polymorphic Form 1 and Form 2 of [3- [5- (4-chloro-phenyl) - 1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro- propane-1-sulfonic acid phenyl} -amide were characterized by X-ray powder diffraction, infrared spectrometry, and differential scanning calorimetry. The samples were analyzed by X-ray powder diffraction using a Shimadzu XRD-6000 X-ray powder diffractometer (XRPD), using copper Kα radiation. The tube voltage and amperage were set at 40 kV and 40 mA, respectively . The divergence and diffusion slits were set at 1 ° and the receiving slit was set at 0.15 mm. The radiation was detected by a NaI scintillation detector. A continuous θ-2θ scan at 3 ° / min (0.4 s / 0.02 ° per step) of 2.5% to 40% 2θ was used. A silicone pattern was analyzed to check the alignment of the instrument. Data were collected and analyzed using XRD-6100/7000 v.5.0. The sample was prepared for analysis by placing it in an aluminum carrier with silicon insertion. The results are shown in figure 1 (Form 1) and figure 2 (Form 2) and in the following Table 4. Table 4. 2θ values of XRPD for Form 1 and Form 2, polymorphic, P-0001.

[181] Polymorphic Form 1 and Form 2 of {3- [5- (4-chloro-phenyl) - 1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro propane-1-sulfonic acid -phenyl} -amide were further analyzed by infrared spectrometry. Table 5 provides the characteristic wave numbers observed for each sample. Table 5. The values of the wave number of the absorption spectrum in the IV for Form 1 and Form 2 polymorphic P-0001

[182] The polymorphic Form and Form 2 of {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -propane-1-sulfonic acid amide were analyzed by differential scanning calorimetry (DSC), scanning at 10.00 ° C per minute. The DSC thermogram for Form I shows an exothermic displacement at approximately 152-14 ° C and an endothermic peak at 268.0 ° C. The DSC thermogram for Form 2 shows an endothermic peak at 271.2 ° Ç. Example 21

[183] Propane-acid {3- [5- (4-chloro-phenyl) -1H-pyrrol [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide -sulfonic is characterized by having certain functionalities that provide both weakly basic centers and weakly acidic centers, which can form complexes of organic salts, resulting in improved solubility. For example, N-7 of the azaindole portion is weakly basic (approximately 4-5 pKa) and can form an acid addition salt complex with an organic acid, such as benzenesulfonic acid, methylsulfonic acid or toluenesulfonic acid, preferably acid methanesulfonic or toluene sulfonic acid. Such mesylate or tosylate salts have advantages over the free base, such as improved solubility, improved intrinsic dissolution rate, and a lower melting point than the free base. The improved intrinsic dissolution rate provides an advantage in the formulation of the salt, for example, the formulation in amorphous form by methods described in the examples above. The improved solubility provides more effective formulation and a better cost-benefit ratio, for example, spray drying or microprecipitate mass processing can be accomplished using much less solvent volumes due to the intrinsic solubility. Such advantages can also be provided by the formation, in situ, during processing, for example, the spray drying process, solvent controlled precipitation, or pH controlled precipitation. Also reduced melting of the salt forms provides a more efficient hot melt extrusion process, allowing the melt to proceed at lower temperatures.

[184] Acid addition salts, including the sulfonic acid series of organic anions such as tosylate, besylate or mesylate, of {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b ] propane-1-sulfonic acid pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide are preferably formed using acetone, which provides the solubility of the free base and is a non-solvent since the salt is formed. Typically, propane-1- acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Sulfonic is added to 20-50 volumes of acetone solvent with stirring and heating (30-35 ° C), followed by the addition of 1 equivalent of the desired acid counterion. The solution is slowly cooled to 2-8 ° C and the solid is isolated by both filtration and centrifugation, followed by vacuum drying. The resulting solid can be amorphous, partially amorphous or crystalline, and can be recrystallized as needed from alcohol: acetone: ethyl acetate or just alcohol to obtain the desired solid in crystalline form.

[185] The {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide mesylate salt propane-1-sulfonic acid was prepared by suspending 5 g (9.7 mmols) of polymorphic Form 2 in 100 mL of acetone, mixing with heating at 30-35 ° C. Metasulfonic acid (0.63 mL, 9.7 mmols) was added and the solution cooled to 5 ° C for 30 minutes. The resulting solid was isolated by filtration, washed and dried in vacuo to provide the desired salt. The tosylate salt was prepared similarly. Exemplary XRPD standards for the mesylate and tosylate salts are provided in figures 3 and 4, respectively, in comparison with the free base polymorphic Formula 2. The DSC thermogram for the mesylate salt shows an endothermic peak at approximately 231 ° C. The DSC thermogram for tosylate salt shows an endothermic peak at approximately 223 ° C and another at approximately 253 ° C.

[186] The resulting salts are processed using the techniques discussed in the examples above, such as spray drying, solvent controlled precipitation, pH controlled precipitation, or hot melt extrusion to provide the preferred amorphous form, or further processed with suitable excipients to provide a directly compressible or encapsulated dosage form. The salt forms have advantages in such processes, such as to minimize the use of solvent, to increase the yield, purity and productivity, as well as to obtain constructions not obtainable using conventional solvent techniques.

Example 22

[187] This example describes the preparation of a solid dispersion (MBP) of amorphous Compound I in HPMCAS. Preparation of the DMA phase:

[188] The concentration of Compound I and HPMCAS in the organic solvent was 35% (w / w), although the ratio of Compound I and HPMCAS is 30 to 70. The temperature of the solution was adjusted to 70 ° C.

[189] In a 250 ml, double jacketed glass vial reactor, 21 g of Compound I was dissolved in 130 g of Dimethylacetamide (DMA) at 20 - 25 ° C, With stirring, 48.8 g of HPMC- AS were added to the solution. The mixture was heated to 70 ° C. A transparent solution was obtained. Preparation of the aqueous phase

[190] In a 2.0 L double-jacketed reactor, as shown in Figure 5, 1.210 g of 0.01N HCl was quenched to 5 ° C. Outside the reactor bottom valve, the aqueous phase was circulated by the high shear mixer or with an auxiliary pump, a rotary lobe pump was preferred, and then by the high shear mixer, back to the top of the reactor. The recirculation entry into the reactor was under the fluid level to prevent foaming (see figure 5). Precipitation High Shear Mixer (HSM)

[191] The speed of the rotor nozzle in the high shear mixer was set at 25 m / s. A rotor / stator combination with a row of teeth, each for the rotor and the stator was used. Dosage of DMA solution

[192] The DMA solution quenched at 70 ° C was dosed with a gear pump via an injector nozzle, which was pointing at the shear mixer mixing chamber, in the circulating aqueous solution. Dosage rate of the DMA solution

[193] The DMA solution was dosed in the resulting aqueous phase in an HCl / DMA ratio, in the mixing chamber of the 100/1 high shear mixer. Additional dispersion in the HSM (after precipitation), insulation and washing

[194] After adding the DMA solution, the MBP suspension obtained was dispersed for an additional time, corresponding to the batch equivalents passing the high shear mixer. The time corresponded to a renewal in the recirculation times calculated from the batch of times.

[195] The obtained suspension, maintained at 5-10 ° C, was separated from the solid MBP. This was done using a suction filter. The isolated MPB was washed with 0.01N HCl (15 kg of 0.01N HCl / kg of MBP) followed by washing with water (5 kg of water / kg of MBP) to remove the DMA. The isolated (wet) MBP had a water content between 60 and 70%. Degrease and Dry

[196] Before drying, the MBP (wet) was degreased using a sieve mill. The MBP (wet) was dried in a cabinet dryer. During the drying process of the MBP, the temperature of the product was below 40 ° C to avoid recrystallization of the API. The pressure inside the cabinet dryer was below 2 kPa (20 mbar). The water content of MBP after drying was below 2.0% and was indicated as amorphous in the XRPD standard. Example 23

[197] This example describes the spray drying formation of a solid molecular complex comprising Compound 1 and HPMC-AS.

[198] Compound I is prepared with a polymer, such as HPMCAS, optionally including a surfactant (for example, an ionic surfactant such as 1,4-bis (2-ethylhexoxy) -1,4-dioxobutane-2- sodium sulfonate (Docusato Sódico) or a non-ionic surfactant, such as Polysorbate 80). In general, a suitable solvent system, such as 20:80 (w / w) tetrahydrofuran: acetone, is equilibrated to 30 ° C, and Compound I is added to a level of 2-10% solids in 4-6 servings with stirring. HPMCAS in a suitable ratio, for example, 70:30 w / w HPMCAS: Compound I, is added (alternatively HPMCAS and surfactant in, for example, 65: 5: 30 HPMCAS: surfactant: Compound I) is added. The temperature is raised to 35-40 ° C, and the system is optionally filtered to ensure the removal of any unsolubilized solids. The solution is then spray dried to provide spherical particles with a size distribution of 1-20 microns. Further processing may include drying, for example, by compaction with a laminator. As an example, Compound I and HPMCAS in a ratio of 30:70 (w / w) were dissolved to a level of 5.4% solids in a mixture of 20:80 (w / w) of tetrahydrofuran and acetone . The resulting solution was then spray dried to produce a dispersion of solids, such as amorphous powder. The solution was spray dried using a spray dryer, for example, GEA-Niro DSMICRO® Spray Dryer, for smaller batches (eg 10 g solids) and a Niro Mobile Manor Spray Dryer for larger batches (eg , 1 kg of solids). For example, for a 10 mg batch, 35.0 g of tetrahydrofuran were mixed with 140.0 g of acetone from a glass beaker, and 3.0 g of Compound I was added with stirring, for 10 minutes, to dissolve: 70 g of HPMCAS-L (Shin-Etsu gru NF) were then added and stirred. While the solids appeared to be dissolved, the solution was filtered through filter paper before spray drying. The solution was spray dried with GEA-Niro SDMICRO® Spray Dryer with inlet / outlet conditions of 85 ° C and 55 ° C, respectively, with atomizing gas pressure at 50 kPa (0.5 bar). The spray-dried material was collected in the cyclone collector, 5.78 or 58% yield.

[199] A batch of 1.6 kg was also prepared, in which the solution was prepared similarly, only that instead of filtering the solution was stirred overnight at room temperature, to ensure that all solids were dissolved. The 200 mesh sieve was attached to the end of the feed hose to remove any undissolved particles and the solution was spray dried using the Mobile Manor Spray Dryer. The inlet / outlet conditions were 100 ° C and 55 ° C, with gas atomization pressure at 100 kPa (1 bar), with a gas flow rate of 90 kg / h. The material was spray dried in two days, and the material collected after the first day was subjected to vacuum drying at 45 ° C to remove residual solvents. The collected material was evaluated for mass density (0.23 g / mL), particle size (8 microns with normal distribution and standard deviation of 3 microns), residual solvent (after 89 hours of drying under vacuum, batch large had residual solvents of 0.001% acetone and 0.017% tetrahydrofuran), polarized light microscopy, DSC (the DSC thermogram for the small batch shows an endothermic peak at approximately 243 ° C, while the thermogram for the large batch showed no peak) and XRPD (which showed an amorphous material).

[200] All patents and other references are indicative of the level of knowledge of those skilled in the art, and are hereby incorporated by reference in their entirety, including any tables and figures, to the same extent as if each reference had been incorporated as a reference. individual reference in full;

[201] One skilled in the art would readily appreciate that the present invention is well adapted to obtain the mentioned purposes and advantages, as well as those inherent in it. The methods, variations, and compositions described herein as presently representative of the preferred embodiments are exemplary and are not intended to limit the scope of the invention. Changes to the same and other uses will occur to those skilled in the art, which are encompassed by the invention, and defined by the scope of the claims.

[202] It will become readily apparent to one skilled in the art that variable substitutions and modifications can be made to the invention described here without departing from the scope and scope of the invention. For example, variations can be carried out in the conditions of crystallization or cocrystallization for Ret proteins and replacement of Ret and / or various kinase domain sequences can be used. Thus, such additional embodiments are within the scope of the present invention and the appended claims.

[203] The invention illustratively described here can be suitably practiced in the absence of any element or elements, limitations or limitations, which are not specifically described here. Thus, for example, in each case here, any of the terms "comprising", "consisting essentially of" and "consisting of" can be replaced by each of the other two terms. Thus, for one embodiment of the invention using one of the terms, the invention also includes another embodiment, in which one of those terms is replaced by others of those terms. In each modality, the terms must have their meaning established. So for example, one modality could encompass a method "comprising a series of steps, another modality would encompass a method" consisting essentially of "the same steps, and a third modality would encompass a method" consisting of "the same steps. The terms and expressions, which have been used, are used as descriptive and non-limiting terms, and there is no intention in using such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that several modifications are possible, within Therefore, it should be understood that although the present invention has been specifically described by the preferred modalities and optional features, the modification and variation of the concepts described here can be consulted by those skilled in the art, and that such modifications and variations are considered to be within the scope of the invention and defined by the king joined vindications.

[204] In addition, when the characteristics or aspects of the invention are described in terms of the Markush groups or other group of alternatives, those skilled in the art will recognize that the invention is also described here in terms of any individual member or subgroup of group members Markush or another group.

[205] Also, unless otherwise indicated, when the various numerical values are provided for the modalities, additional modalities are described taking either of two different values as extreme points of a range. Such bands are also within the scope of the described invention.

[206] Thus, additional modalities are within the scope of the invention and within the following claims.

Claims (3)

1. Form 1 of the crystalline polymorph of Compound I

characterized by the fact that it exhibits a powder X-ray diffraction pattern having characteristic peak locations of approximately 4.7, 9.4, 11.0, 12.5, and 15.4o 2θ. 2. Crystalline polymorph according to claim 1, characterized by the fact that said polymorph exhibits a powder X-ray diffraction pattern having characteristic peak locations of approximately 4.7, 9.4, 10.0, 11 , 0, 12.5, 14.2, 15.4, 18.6, and 22.2o 2θ. 3. Crystalline polymorph according to claim 1, characterized by the fact that said polymorph exhibits a powder X-ray diffraction pattern having characteristic peak locations of approximately 4.7, 9.4, 10.0, 11 , 0, 12.5, 14.2, 15.4, 16.1, 18.6, 19.0, 22.2 and 26.8o 2θ.