SOLID FORMS OF A PHARMACEUTICALLY ACTIVE SUBSTANCE, ITS USE AND PHARMACEUTICAL COMPOSITIONS THAT UND

专利摘要:
solid forms of a pharmaceutically active substance, their use and pharmaceutical compositions comprising them. the present invention relates to solid forms of the compound of formula 1 (1) and pharmaceutical uses thereof.
公开号:BR112013021103A2
申请号:R112013021103-2
申请日:2012-02-21
公开日:2020-12-29
发明作者:Ralph Diodone；Karsten Faehnrich；Prabha N. Ibrahim；Shan-Ming Kuang；Gary Conard Visor；Baoshu Zhao；Urs Schwitter
申请人:Plexxikon, Inc.；F.Hoffmann-La Roche Ag；
IPC主号:

专利说明:

Invention Patent Descriptive Report for "SOLID FORMS OF A PHARMACEUTICALLY ACTIVE SUBSTANCE, ITS USE AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM". The present invention relates to the form and formulations of compounds, for example, compounds which are used in pharmaceutical applications. The propane-1-sulfonic acid compound {3- [5- (4-chloro-phenyl) - 1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide (compound 1) is represented by the formula 1: Cl The F N N S
N O O F (1). The compound of formula 1 has been described in WO 2007002433 and WO
2007002325. Crystalline forms 1 and 2 (also I and II), the amorphous form, as well as the tosylate and mesylate salt of compound 1 are described in International Patent Application No. PCT / US10 / 29489. Active pharmaceutical ingredients (API's) can be prepared in a variety of different ways, such as, for example, salts, solves, hydrates, crystals. API's can also be in their amorphous state or one or more crystalline forms (polymorphs). Depending on the shape, the physical and chemical properties of an API can change, leading to, for example, different solubility, thermodynamic stability, density or melting point in different ways. Such physicochemical properties in this way can have a significant influence on the effectiveness or bioavailability of a known API. Summary of the Invention The present invention provides solid forms of the compound of formula 1 selected from the group consisting of: a substantially amorphous form of compound 1, selected from the form XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV , XXV, XXVI or combinations thereof, in which compound 1 is molecularly dispersed;
b) a solvate of the form III, IV, V, VI, VII, IX, X, XI, XII, XIII, XIV, or XV; c) a polymorph of form VIII or XVI; and d) sulfuric acid-, hydrobromic acid- or hydrochloric acid salt of compound 1. In a particular embodiment, the solid ditforma is selected from a solvate of form III, IV, V, VI, VII, IX, X , XI, XII, XIII, XIV or XV.
In another particularly preferred embodiment, the solid shape is selected from a polymorph of shape VIII or XVI.
In yet another preferred embodiment, the solid ditform is selected from sulfuric acid-, hydrobromic acid- or hydrochloric acid salt of compound 1. In yet another preferred embodiment, the solid ditform is a substantially amorphous form of compound 1, selected from form XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV or XXVI or combinations thereof, in which compound I is molecularly dispersed.
In another embodiment, the invention provides a method for treating a disease or condition in a mammal in need of it.
The method includes administering to the mammal an effective amount of a composition comprising a compound in solid form as described herein.
In certain embodiments, diseases or conditions are mediated by b-Raf mutants having V600E, V600M, V600R, V600K or V600G mutations.
In other modalities, diseases or conditions include, but are not limited to, melanoma, thyroid cancer and colorectal cancer.
The solid forms described here can be further processed into any type of solid pharmaceutical preparations or dosage forms, which are known to the person skilled in the art.
Particularly preferred are oral dosage forms such as tablets, capsules, pills, powders, suspensions, pastes and the like.
Detailed descriptions of suitable excipients as well as methods for making such pharmaceutical preparations can, for example, be found at: Raymond C.
Rowe et al, Handbook of Pharmaceuticals Excipients, 6th edition, 2009, Pharmaceutical Press (Publ.); ISBN-10:
0853697922. Consequently, pharmaceutical preparations thus obtained form additional modalities provided here.
Brief Description of Figures 5 Figure 1 shows XRPD patterns of the amorphous form of compound 1 as can be obtained by the method described in Example 1. Figure 2 shows the XRPD patterns of form III of compound 1 as obtained by the method described in the example 3. Figure 3 shows the XRPD patterns of form IV of compound 1 as obtained by the method described in example 4. Figure 4 shows the XRPD patterns of form V of compound 1 as obtained by the method described in example 5. Figure 5 shows the XRPD patterns of form VI of compound 1 as obtained by the method described in example 6. Figure 6 shows the XRPD patterns of form VII of compound 1 as obtained by the method described in example 7. Figure 7 shows the XRPD patterns of form VIII of compound 1 as obtained by the method described in example 8. Figure 8 shows the XRPD patterns of form IX of compound 1 as obtained by the method described in example 9. Figure 9 shows the XRPD patterns of form X of compound 1 as obtained by descrit method o in example 10. Figure 10 shows the XRPD patterns of form XI of compound 1 as obtained by the method described in example 11. Figure 11 shows the XRPD patterns of form XII of compound 1 as obtained by the method described in example 12 Figure 12 shows the XRPD patterns of form XIII of compound 1 as obtained by the method described in example 13. Figure 13 shows the XRPD patterns of form XIV of compound 1 as obtained by the method described in example 14. Figure 14 shows the XRPD patterns of form XV of compound 1 as obtained by the method described in example 15.
Figure 15 shows the Raman spectrum of form XVI of compound 1 as obtained by the method described in example 16. Figure 16 shows the XRPD patterns of pattern 6 of compound 1 as obtained by the method described in example 17. 5 Figure 17 shows the XRPD patterns of the sulfuric acid salt of compound 1 as obtained by the method described in example 18. Figure 18 shows the XRPD patterns of the bromidric acid salt of compound 1 as obtained by the method described in example 19. Figure 19 shows the XRPD patterns of the hydrochloric acid salt of compound 1 as obtained by the method described in example 20. Figure 20 shows the XRPD patterns of form XVII of compound 1 as obtained by the method described in examples 21 and 22. Figure 21 shows the XRPD patterns of form XVIII of compound 1 as obtained by the method described in examples 21 and 22. Figure 22 shows the XRPD patterns of form XIX of compound 1 as obtained by the method described in examples 21 and 22. Figure 23 shows XRPD standards of form XX of compound 1 as obtained by the method described in examples 21 and 22. Figure 24 shows the XRPD patterns of form XXI of compound 1 as obtained by the method described in examples 21 and 22. Figure 25 shows the patterns of XRPD of form XXII of compound 1 as obtained by the method described in examples 21 and 22. Figure 26 shows the XRPD patterns of form XXIII of compound 1 as obtained by the method described in examples 21 and 22. Figure 27 shows the XRPD patterns of form XXIV of compound 1 as obtained by the method described in examples 21 and 22. Figure 28 shows the XRPD patterns of form XXV of compound 1 as obtained by the method described in examples 21 and 22. Figure 29 shows the XRPD patterns of form XXVI of compound 1 as obtained by the method described in examples 21 and 22. Detailed Description of the Invention Definitions
The term "compound 1" as used here means propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4 - difluoro-phenyl} -amide, which is sometimes also referred to as PLX-
4032. 5 As used here, the general term "amorphous forms" denotes a material that lacks long variation order and does not show well-defined X-ray peaks. The X-Ray Powder Diffraction (XRPD) pattern of an amorphous material is characterized by one or more amorphous halos. More specifically, the term "amorphous form" as used here refers to the amorphous form of propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide (compound 1) as such, since the amorphous form does not form a phase system, such as for example a solid dispersion or bulk powder microprecipitate (MBP) together with any type of support material such as polymers or the like. The term "amorphous halo" means a maximum of wide diffraction in the X-ray powder pattern of an amorphous substance, that is, the amorphous form of compound 1. The FWHM (full width at half height) of an amorphous halo is usually greater than two degrees in 2-theta. "Form II" of compound 1 as referred to herein means the thermodynamically stable form of propane-1-sulfonic acid {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3 -carbonyl] -2,4-difluoro-phenyl} -amide. The term "molecularly dispersed", as used herein, refers to the random distribution of compound 1 within a polymer. More particularly, a compound (for example, compound 1) can be dispersed within a matrix formed by the polymer in its solid state in such a way that compound 1 and the matrix form a phase system (solid dispersion) and compound 1 is immobilized in its amorphous form. An example of such a solid dispersion is a micro-precipitated coarse powder (MBP). 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 having a unique glass transition temperature. The term "instantaneous cooling" as used here means cooling with liquid nitrogen.
The term "approximately" in connection with the XRPD standards as described here means that there is an uncertainty in the measurements of the 2-Theta degrees of ± 0.2 degrees (expressed in 2-Theta degrees). 5 The term "polymorph" as used here means one of the different crystal structures in which a compound can crystallize.
Polymorphs are best characterized by their unit cell space group parameters.
This term is reserved for materials with the same elementary analysis.
The term "solvate" as used here means a crystal form that contains stoichiometric or non-stoichiometric amounts of solvent.
The term "substantially amorphous" comprises material that has no more than about 10% crystallinity; and "amorphous" material comprises material that has no more than about 2% crystallinity.
In some embodiments, "amorphous" material means material having no more than 1%, 0.5% or 0.1% crystallinity. "Ambient temperature" means any temperature in the range of 18 to 28 ° C, preferably 20 to 24 ° C.
The term "composition" refers to a pharmaceutical preparation suitable for administration to an animal intended for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof.
The composition can include at least one additional pharmaceutically acceptable component to provide an improved formulation of the compound, such as an appropriate vehicle, additive or excipient.
The term "pharmaceutically acceptable" indicates that the indicated material has no properties that would make a reasonably prudent medical professional to avoid administering the material to a patient, taking into account the disease or conditions to be treated and the respective route administration.
For example, it is commonly required that such material is essentially sterile, for example, for injectables.
The term "therapeutically effective" or "effective amount" indicates that the materials or amount of material are effective in preventing, alleviating, or ameliorating one or more symptoms of a disease or medical condition, and / or in prolonging the survival of a subject being treated. 5 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-Ragf containing a V600E mutation.
In some embodiments, human b-Raf includes mutations V600A, V600M, V600R, V600K or V600G.
Furthermore, a therapeutically effective amount may be one in which the therapeutically beneficial effects all outweigh the toxic or undesirable side effects.
The therapeutically effective amount of Compound I may vary according to the condition of the disease, age and weight of the subject being treated.
Thus, dosing 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 1 to an adult human can be from about 100 mg to about 3200 mg; or from about 250 mg to about 2000 mg, although the upper limit can be exceeded when indicated.
A daily dose of Compound 1 can be administered as a single dose, in divided doses, or, for parenteral administration, it can be given as a subcutaneous injection.
In the dry spray dispersion process, Compound 1 and a polymer can be dissolved in a common solvent having a low boiling point, for example, ethanol, methanol, acetone, etc.
By means of dry spray or lyophilization, the solvent is evaporated by instant evaporation at the temperature near the boiling point or under a high vacuum (low steam pressure), leaving Compound 1 precipitated in a matrix formed by polymer.
In certain embodiments Compound 1 is in the form of a mesylate or tosylate salt, and therefore preferably has improved solubility.
The term "methacrylic acid copolymers" as used herein in the dry spray dispersion process includes, but is not limited to, methacrylic acid copolymers, methacrylic acid - methacrylate copolymers, methacrylic acid - ethyl acrylate copolymers, copolymers of ethyl acrylate ammonium methacrylate, aminoalkyl methacrylate copolymers and the like.
In certain embodiments, a "methacrylic acid copolymer" can be EUDRAGIT® L 100 and EUDRAGIT® L 12.5 (also referred to as, or combined with: "Methacrylic acid copolymer, Type A;" "Acid Methacrylic - Methyl Methacrylate Copolymer (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 adapted to: "Methacrylic Acid Copolymer, Type B;" "Methacrylic Acid - Methyl Methacrylate Copolymer (1: 2);" "Copolymer of Methacrylic Acid S; "" DMF 1242 "or" PR-MF 6918 "); EUDRAGIT® L 100-55 (also referred to as, or adapted to: "Methacrylic Acid Copolymer, Type C;" "Methacrylic Acid - Ethyl Acrylate Copolymer (1: 1) Type A;" "Dry Methacrylic Acid Copolymer LD; "or" DMF 2584 "); EUDRAGIT® L 30 D-55 (also referred to as, or adapted to: "Methacrylic Acid Dispersion Copolymer;" "Methacrylic Acid - Ethyl Acrylate Copolymer (1: 1) 30 Percent Dispersion;" "LD Methacrylic Acid Copolymer;" ; "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 adapted to: "Ammonium Methacrylate Copolymer, Type A;" "Ammonium Methacrylate Copolymer (Type A);" "Aminoalkyl Methacrylate Copolymer RS;" "DMF 1242 "or" PR-MF 6918 "); EUDRAGIT® RL PO (also referred to as, or adapted to: "Ammonium methacrylate copolymer, Type A;" "Ammonium Methacrylate Copolymer (Type A);" "Aminoalkyl Methacrylate Copolymer RS;" "DMF 1242 "); EUDRAGIT® RL 12.5 (also referred to as, or adapted to "Ammonium Methacrylate Copolymer, Type A;" "Ammonium Methacrylate Cup-Type (Type A);" "DMF 1242" or "PR-MF 6918" ); EUDRAGIT® L 100-55 (also referred to as, or adapted to: "Methacrylic Acid Copolymer, Type C;" "Methacrylic Acid - Ethyl Acrylate Copolymer (1: 1) Type A;" "Dry Methacrylic Acid LD Copolymer; "" DMF 2584 "); EUDRAGIT® L 30 D-55 (also referred to as, or adapted to: "Methacrylic Acid Dispersion Copolymer" NF "Methacrylic Acid - Ethyl Acrylate Copolymer (1: 1) 30 Percent Dispersion;" "LD Methacrylic Acid Copolymer;" ; "" DMF 2584 "or" PR-MF 8216 "); EUDRAGIT® FS 30 D (also referred to as, or adapted to: "DMF 13941" or "DMF 2006-176"); EUDRAGIT® RL 5 100 (also referred to as, or adapted to: "Ammonium Methacrylate Copolymer, Type A;" "Ammonium Methacrylate Copolymer (Type A);" "Aminoalkyl Methacrylate Copolymer RS;" "DMF 1242; "or" PR-MF 6918 "); EUDRAGIT® RL PO (also referred to as, or adapted to: "Ammonium Methacrylate Copolymer, Type A;" "Ammonium Methacrylate Copolymer (Type A);" "Aminoalkyl Methacrylate Copolymer RS;" or "DMF 1242" ); EU- DRAGIT® RL 12.5 (also referred to as, or adapted to: polymer adapted to "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 adapted to: "Ammonium Methacrylate Dispersion Copolymer, Type A;" "Ammonium Methacrylate Copolymer (Type A);" or "DMF 1242"); EUDRAGIT® RS 100 (also referred to as, or adapted to: "Ammonium Methacrylate Copolymer, Type B;" NF "Ammonium Methacrylate Copolymer (Type B);" "Aminoalkyl Methacrylate Copolymer RS;" "DMF 1242 "or" PR-MF 6918 "); EUDRAGIT® RS PO (also referred to as, or adapted to: "Ammonium Methacrylate Copolymer, Type B;" "Ammonium Methacrylate Co-polymer (Type B);" "Aminoalkyl Methacrylate Copolymer RS;" or "DMF 1242 "); EUDRAGIT® RS 12.5 (also referred to as, or adapted to: "Ammonium Methacrylate Copolymer, Type B;" NF polymer adapted to "Ammonium Methacrylate Copolymer (Type B);" "DMF 1242" or "PR- MF 6918 "); EUDRAGIT® RS 30 D (also referred to as, or adapted to: "Ammonium Methacrylate Dispersion Copolymer, Type B;" NF polymer adapted to "Ammonium Methacrylate Copolymer (Type B);" or "DMF 1242"); EUDRAGIT® E 100 (also referred to as, or adapted to: "Amino methacrylate copolymer;" NF "Basic butyl methacrylate copolymer;" "E Aminoalkyl methacrylate copolymer;" "DMF 1242" or "PR-MF 6918 "); EUDRAGIT® E PO (also referred to as, or adapted to: "Basic Butylated Methacrylate Copolymer;" "Methacrylate Copolymer of
Aminoalkyl E; "" Amino Methacrylate Copolymer; "" DMF 1242 "); EU-DRAGIT® E 12.5 (also referred to as, or adapted to:" Amino Methacrylate Copolymer; "" Basic Butylated Methacrylate Copolymer; "" "" DMF 1242 "or" PR-MF 6918 "); EUDRAGIT® NE 30 D (also referred to as, or 5 adapted to:" Ethyl Acrylate and Methacrylate Dispersion Copolymer; "" 30 Percent Polyacrylate Dispersion; "(" Poly (ethylacrylate-methylmethacrylate) -Dispersion 30% ");" Ethyl Acrylate Methyl Acrylate Dispersion Copolymer; "" DMF 2822 "or" PR-MF 6918 "); EUDRAGIT® NE 40 D (also referred to as, or adapted to: DMF 2822); EUDRAGIT® NM 30 D (also referred to as "30 Percent Polyacrylate Dispersion;" "(Po-li (ethylacrylate-methylmethacrylate) -30% dispersion);" or "DMF 2822 "; PLASTOID® B (also referred to as, or adapted to:" DMF 12102 "), or the like.
The term "API" as used here means an active pharmaceutical ingredient.
The term "DSC" as used here means Differential Scanning Calorimetry.
The term "DVS" as used here means Dynamic Vapor Absorption.
The term "IV" as used here means Infra Red Spectroscopy.
The term "Raman" as used here means Raman spectroscopy.
The term "XRPD" as used here means X-Ray Powder Diffraction.
The term "TGA" as used here means ThermoGravimetric Analysis.
Characterization Methods DSC curves were recorded using a Mettler-Toledo ™ DSC820, DSC821 or DSC 1 differential scanning calorimeter with an FRS05 sensor. System tests were appropriately performed with Indium as a reference substance and calibrations were performed using Indium,
Benzoic acid, Biphenyl and Zinc as reference substances.
For measurements, approximately 2 - 6 mg of sample were placed in aluminum pans, accurately weighed and hermetically sealed with perforation caps.
Prior to measurement, caps 5 were automatically punctured resulting in approximately 1.5 mm pin holes.
The samples were then heated under a flow of nitrogen of about 100 mL / min using heating rates of usually 10 K / min.
TGA analysis was performed on a Mettler-Toledo ™ thermogravimetric analyzer (TGA850 or TGA851). System suitability tests were performed with Hidranal as a reference substance and calibrations using Aluminum and Indium as reference substances.
For the thermogravimetric analysis, approximately 5 - 10 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed with perforation covers.
Prior to measurement, the caps were automatically punctured, resulting in approximately 1.5 mm pin holes.
The samples were then heated under a nitrogen flow of about 50 mL / min using a heating rate of 5 K / min.
Isothermal DVS were collected in a DVS-1 (SMS Surface Measurement System) moisture balance system.
The absorption / desorption isotherms were measured step by step in a range of 0% RH to 90% RH at 25 ° C.
A weight change of <0.002 mg / min was chosen as the criterion for switching to the next level of relative humidity (with a maximum equilibrium time of six hours, if the criterion was not met). The data were corrected for the initial moisture content of the samples; that is, the weight after drying the sample at 0% relative humidity was adopted as the zero point.
IR spectra were recorded as a film of a Nujol suspension of approximately 5 mg of sample and little Nujol between two sodium chloride plates, with an FTIR spectrometer in transmittance.
The Spectrometer is a Nicolet ™ 20SXB or equivalent (2 cm-1 resolution,
32 or more coadded scans, MCT detector). Raman spectra were recorded in the range of 150-1800 cm-1 in excitation of 785 nm with a Raman ARAMIS microscope (Horiba-JobinYvon) equipped with a cooled Peltier CCD detector, and a 1200 l / mm gradient. X-ray powder diffraction patterns were recorded under ambient conditions in transmission geometry with a STOE STADIP diffractometer (Cu Kα radiation, primary monochromator, position sensitive detector, angular range from 3 ° to 42 ° 2- Theta, approximately 60 minutes of total measurement time). Approximately 25 mg of sample was prepared and analyzed without further processing (for example, crushing or sifting) of the substance. Alternatively, X-ray diffraction patterns were measured on a Scintag X1 X-ray powder diffractometer equipped with a sealed radiation source Kα1 copper. The samples were scanned from 2 ° to 36 ° 2θ at a rate of 1 ° per minute with incident beam widths of 2 and 4 mm and beam beam widths of 0, 3 and 0.2 mm. The amorphous form of compound I according to the present invention is preferably substantially pure, meaning that the a-morph form includes less than about 15%, preferably less than about 10%, preferably less than about 5%, preferably less than about 1%, even more preferably less than 0.1% by weight of impurities, including other polymorphic forms of compound 1. In some embodiments, at least about 30-99% by weight of the compound. total of compound 1 in the composition is present as the amorphous form. In additional modalities, at least about 70%, at least about 80%, at least about 90%, at least about 99% or at least about
99.9% by weight of the total of compound 1 in the composition is present as the amorphous form. Also provided by the invention are compositions consisting essentially of compound 1 in which at least about 97-99% by weight of compound 1 is present in the composition as an amorphous form, a polymorph form, a solvate form as described herein or as
combinations thereof.
The polymorph, solvate or amorphous form of compound I according to the present invention can also be present in mixtures.
In some embodiments, the amorphous form XVII may be present in mixtures 5 with one or more other amorphous forms selected from XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV or XXVI.
Form III of solvate can be present in mixtures with one or more forms of solvate selected from IV, V, VI, VII, IX, X, XI, XII, XIII, XIV or XV.
Polymorph form VIII may be present in a mixture with polymorph form XVI.
Suitable solvents for the preparation of amorphous dry spray dispersion forms of compound 1 include, but are not limited to, acetone, water, alcohols, mixtures thereof, and the like.
Alcohols include, but are not limited to, ethanol, methanol, isopropanol and mixtures thereof.
The solid forms of compound 1 as described here can be used in a wide variety of drug delivery preparations, and in particular for oral dosage forms.
Exemplary dosage forms include powders or granules that can be taken orally dried or reconstituted by adding water to form a paste, fluid paste, suspension or solution; tablets, capsules, or pills.
Various additives can be mixed, crushed or granulated with the dispersion of solids as described here to form a material suitable for the above dosage forms.
Potentially beneficial additives can generally fall into the following classes: other matrix materials or thinners, surface active agents, drug complexing agents or solubilizers, fillers, disintegrants, binders and lubricants.
With respect to solvates and polymorphs as described here, pH modifiers (for example, acids, bases, or buffers) can also be added.
Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch.
Examples of surface active agents include sodium lauryl sulphate and polysorbate 80. Examples of drug complexing agents or solubilizers include polyethylene glycols, caffeine, xanthene, gentisic acid and cilodextrins.
Examples of disintegrants include sodium starch gicolate, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and sodium croscarmellose.
Examples of binders include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth.
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 comprise mixtures of acids and salts of said acids.
At least one function of including such pH modifiers is to control the dissolution rate of the drug, matrix polymer, or both, thereby controlling the local drug concentration during dissolution.
In addition to the additives or excipients above, the use of any conventional materials and procedures for formulating and preparing oral dosage forms using the compositions described here, known to those skilled in the art, are potentially useful.
For example, those skilled in the art can formulate the compositions in an appropriate manner, and in accordance with accepted practices, such as those described in Remington's Pharmaceutical Sciences (Gennaro, Ed., Mack Publishing Co., Pa. 1990). Accordingly, an additional embodiment includes a pharmaceutical preparation containing the solid dispersion as obtained by a method as described herein.
In certain embodiments, the present invention provides a method for preparing a substantially amorphous form of the compound (1), the amorphous form is selected from the form XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV or XXVI or combinations thereof.
The method includes preparing a dry spray dispersion solution of the compound (1) and drying the dispersion solution of the compound (1) under sufficient conditions to obtain the amorphous form XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV , XXV or XXVI or combinations thereof.
In one embodiment, the dry spray dispersion solution is dried under vacuum.
In one embodiment, a dry spray dispersion solution is prepared by dispersing a solution of compound (1) in a polymer solution under conditions sufficient to obtain the dry spray dispersion solution.
Any solvents or a mixture of solvents that is suitable for dissolving the compound (1) can be used.
Exemplary solvents for dissolving compound (1) include, but are not limited to, tetrahydrofuran (THF), acetone, acetonitrile, benzene, ethanol, toluene, ether, ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or a mixture of any two or more of them.
In certain instances, an acid, such as hydrochloric acid, sulfuric acid or nitric acid is added in an organic solvent system in a proportion sufficient to help dissolve the compound (1). The polymer solution can be prepared by dissolving a polymer in an organic solvent or a mixture of solvents in an appropriate proportion.
In certain instances, the polymer is dissolved in a solvent or a mixture of solvents at a temperature ranging from 20 -100 ° C, 30-50 ° C or 40- 100 ° C.
Any polymers as described here can be used for the preparation of the polymer solution.
Exemplary solvents for preparing the polymer solution include, but are not limited to THF, acetone, acetonitrile, benzene, ethanol, toluene, ether, ethyl acetate, DMF, DMSO, H2O or a mixture thereof.
In certain embodiments, the invention provides a method for treating a disease or condition in a mammal in need thereof, said method comprising administering to said mammal an effective amount of a composition comprising at least one solid form of compound I selected from the group consisting of: a) a substantially amorphous form of compound 1, selected from XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI or combinations thereof, in which compound 1 it is molecularly dispersed;
b) a solvate of the form III, IV, V, VI, VII, IX, X, XI, XII, XIII, XIV, or XV; c) a polymorph of form VIII or XVI; and d) the salt of sulfuric acid-, hydrobromic acid- or hydrochloric acid 5 of compound 1. In certain embodiments, the disease or condition for which the method described above is employed is melanoma, thyroid cancer or colon cancer.
In certain embodiments, the invention provides a method for treating a disease or condition in a mammal in need thereof, said method comprising administering to said mammal an effective amount of a composition comprising at least one solid form of compound I as described here.
In certain modalities, the disease or condition for which the method described above is used is melanoma, thyroid cancer or colon cancer.
Examples Example 1 (Reference Example) Preparation of the amorphous form of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl] - amide} of propane-1-sulfonic acid (compound 1) Amorphous material can generally be obtained by instant melting or spray drying.
Other processes such as, for example, lyophilization can also be used. a) Preparation of amorphous material by spray drying 5.0 g of compound 1 were dissolved in 150 g of tetrahydrofuran (THF) at room temperature.
The solution was filtered through a 5 µm filter.
The clear solution was spray-dried using a Buechi spray dryer (model B290) using the following parameters: Air flow inlet [m3 / h] 40 Air inlet temperature [° C] 100 Solvent flow [ %] 20
Spray drying flow [%] 100 Condenser [° C] -10 Yield: 2.8 g (56%) of amorphous compound 1. b) Preparation of amorphous material by the instant cooling of a 5 2 g fusion of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl-2,4-difluoro- phenyl] -amide} of propane-1-sulfonic acid were heated to 300 ° C in a stainless steel pan on a heating plate.
In addition, the material was heated using a heat gun.
After obtaining a complete melting, the pan was submerged in liquid nitrogen.
After 10 min the pot was removed and placed in a desiccator for 48 hours.
For better handling, the glassy material was ground using a mortar. c) Characterization of the amorphous form The amorphous form can be characterized by the lack of well-defined X-ray diffraction peaks in its XRPD block, as well as a glass transition temperature as can be obtained by measuring DSC in the about 100 ° C to 110 ° C.
The exact temperature of the glass transition is largely dependent on the water / solvent content.
Figure 1 shows XRPD patterns of the amorphous form of compound 1 as obtained by the method described in this example.
Example 2 (Reference Example) Preparation of Form I of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl] -amide } of propane-1-sulfonic acid The polymorphic form can generally be obtained by drying the hemi-acetone solvate (Form IX) at> 70 ° C.
Example 3 Preparation of propane-acid form {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl] -amide} 1-sulfonic a) Preparation of form III by balancing in acetonitrile 221.3 mg of amorphous material were digested in 500 µL of acetonitrile at room temperature for 2 days.
The material was then isolated by filtration and dried at 22 ° C / (5 mbar) for 48 hours. b) Characterization of Form III Form III can be characterized by the XRPD standards obtained with Cu Kα radiation having characteristic peaks expressed in grades 2-5 Theta at approximately 9.5, 10.0, 13.0, 16.7, 18.7, 20.1, 21.0, 25.6. The XRPD (X-Ray Powder Diffraction) standard of a typical batch of form III of propane-1-sulfonic acid {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3 - carbonyl-2,4-difluoro-phenyl] -amide} is shown in Figure 2. Example 4 Preparation of form IV of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine Propane-1-sulfonic acid carbonyl-2,4-difluoro-phenyl] -amide} Form IV is a 0.75-solvate THF and can generally be obtained by processes comprising compound 1 and THF as a solvent. a) Preparation of form IV by evaporative crystallization from THF 254.3 mg of compound 1 (form II) were dissolved in 6 ml of THF at 65 ° C.
After 12 hours the clear solution was cooled to 5 ° C.
The crystals were isolated by filtration and dried under ambient conditions. b) Characterization of Form IV Form IV can be characterized by its XRPD patterns obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2-Theta in approximately: 5.5, 7.4, 11.0, 13, 4, 14.8, 16.0, 16.7, 17.1, 17.9, 19.1, 19.5, 20.1, 20.5, 20.9, 21.2, 22.2, 23.0, 23.6, 24.2, 24.5, 25.1. Figure 3 shows the XRPD pattern of a typical batch of form IV of compound 1. Example 5 Preparation of form V of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3 - propyl-1-sulfonic acid carbonyl-2,4-difluoro-phenyl] -amide} Form V is a dioxane monosolvate and can be obtained by the processes comprising compound 1 and dioxane as solvents. a) Preparation of form V by equilibration in dioxane 110.3 mg of amorphous material of compound 1 were suspended in 500 µL of dioxane.
The wet material was digested at room temperature for 2 days.
The material was then isolated by filtration and dried at 22 ° C / (5 mbar) for 48 hours. b) Characterization of the VA Form V can be characterized by its XRPD pattern obtained 5 with Cu Kα radiation having characteristic peaks expressed in 2-theta steps in approximately: 12.7, 13.1, 14.3, 16.3, 19 , 0, 20.1, 22.4, 25.1, 27.1, 28.9. Figure 4 shows the XRPD pattern of a typical batch of Form V of Compound 1. Example 6 Preparation of Form VI of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3 - carbonyl-2,4-difluoro-phenyl] -amide} of propane-1-sulfonic acid Form VI is a DMF monosolvate and can be obtained by procedures comprising compound 1 and DMF as solvents. a) Preparation of form VI by DMF equilibrium 120.3 mg of amorphous material were fluidized in 500 µL of DMF at room temperature for 2 days.
The brownish material was isolated by filtration and dried at 30 ° C / (5 mbar) 48 hours. b) Characterization of Form VI Form VI can be characterized by its XRPD pattern obtained with Cu Kα radiation, having characteristic peaks expressed in degrees 2- Theta at approximately: 7.8, 10.3, 11.4, 11.8, 15.1, 15.6, 16.1, 16.6, 18.6, 18.9, 19.2, 20.4, 21.0, 21.6, 22.8, 24.6, 25, 1, 25.8, 26.1, 27.4, 28.8. Figure 5 shows the XRPD pattern of a typical batch of form VI of compound 1. Example 7 Preparation of form VII of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3 - carbonyl-2,4-difluoro-phenyl] -amide} of propane-1-sulfonic acid Form VII is a THF hemisolvate and can be obtained by processes comprising compound 1 and THF as a solvent. a) Preparation of form VII by THF equilibrium 196.3 mg of amorphous material was broken up into 500 µL of THF for 3 days at room temperature.
The brownish material was then isolated by filtration and dried at 22 ° C / (5 mbar) for 24 hours.
b) Characterization of Form VII Form VII can be characterized by its XRPD pattern obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2-Theta in approximately: 7.6, 9.4, 9.9, 13.1, 15.9, 16.2, 17.0, 18.1, 18.8, 5 19.9, 20.5, 20.7, 21.4, 21.8, 24.3, 24.9, 25 , 3. Figure 6 shows the XRPD pattern of a typical batch of form VII of compound 1. Example 8 Preparation of form VIII of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3 - propane-1-sulfonic acid carbonyl-2,4-difluoro-phenyl] -amide a) Preparation of form VIII by incubation of amorphous material 210 mg of amorphous material of compound 1 were quenched at 130 ° C for 24 h using a tubular oven.
Then the brownish material was cooled to room temperature. b) Characterization of Form VIII Form VIII can be characterized by its XRPD pattern obtained with Cu Kα radiation, having characteristic peaks expressed in degrees 2- Theta in approximately: 5.0, 11.3, 11.6, 12.0 , 13.8, 16.2, 16.7, 19.0, 20.1, 20.8, 22.5, 27.1. Figure 7 shows the XRPD pattern of a typical batch of form VIII of compound 1. Example 9 Preparation of form IX of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine -3- carbonyl-2,4-difluoro-phenyl] -amide} of propane-1-sulfonic acid Form IX is an acetone hemisolvate and can be obtained by processes comprising compound 1 and acetone as a solvent. a) Preparation of form IX by acetone equilibrium 180.5 mg of amorphous material of compound 1 were fragmented in 500 αL of acetone for 3 days at room temperature.
Then the brownish material was isolated by filtration and dried at room temperature for 24 hours. b) Characterization of Form IX Form IX can be characterized by its XRPD pattern obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2-Theta in approximately: 9.5, 9.9, 13.0, 15.9, 16 , 4, 17.0, 17.9, 18.7, 19.9, 20.7, 21.7, 24.8, 25.1. Figure 8 shows the XRPD pattern of a typical batch of form IX of compound 1. Example 10 5 Preparation of form X of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl] -amide} of propane-1-sulfonic acid Form X is a pyridine monosolvate and can generally be obtained by processes comprising compound 1 and pyridine as solvents. a) Preparation of form X by equilibration in pyridine 150.0 mg of compound 1 (Form II) were fragmented in 200 µL of pyridine at room temperature for 10 days.
Then the brownish material was isolated by filtration and dried at 22 ° C in (5 mbar) for 48 hours. b) Characterization of Form X Form X can be characterized by its XRPD pattern obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2- Theta at approximately: 7.4, 9.2, 10.8, 13.6, 14 , 9, 19,0, 20,2, 21,4, 22,4, 23,7, 25,5, 27,0, 29. Figure 9 shows the XRPD pattern of a typical batch of form X of compound 1 Example 11 Preparation of propane acid {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl] -amide} -1-sulfonic Form XI is a 2-methylpyridine monosolvate and can generally be obtained by processes comprising compound 1 and 2-methylpyridine as solvents. a) Preparation of form XI by evaporative crystallization of 2-methylpyridine 150.0 mg of compound 1 (for example in its amorphous form or form II) were dissolved in 4 ml of 2-methylpyridine.
The solution was left to passively evaporate at room temperature.
After 10 days the material was further dried at 22 ° C / (5 mbar) for 48 hours. b) Characterization of form XI
Form XI can be characterized by its XRPD pattern obtained with Cu Kα radiation having characteristic peaks expressed in grades 2- Theta at approximately 8.0, 12.1, 12.6, 13.4, 13.9, 14.8 , 16.2, 17.6, 18.5, 19.2, 20.1, 21.0, 21.4, 21.7, 23.5, 25.3, 25.5, 26.6, 27 , 0, 30.8. Figure 10 5 shows the XRPD pattern of a typical batch of form XI of compound 1. Example 12 Preparation of form XII of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine- 3-carbonyl-2,4-difluoro-phenyl] -amide} of propane-1-sulfonic acid Form XII is a diisopropylamine monosolvate and can generally be obtained by processes comprising compound 1 and diisopropylamine as solvents . a) Preparation of form XII by evaporative crystallization of 2-methylpyridine 243.0 mg of compound 1 (form II) were fluidized in 500 µL of diisopropylamine at 60 ° C for 9 days. Then, the brownish material was isolated by filtration and dried at 22 ° C / (5 mbar) for 48 hours. b) Characterization of Form XII Form XII can be characterized by a powder X-ray powder diffraction pattern obtained with Cu Kα radiation having characteristic peaks expressed in 2-Theta grades at approximately: 7.5, 9.9, 12, 1, 13.6, 16.2, 16.7, 17.1, 17.5, 18.3, 18.5, 20.1, 21.7, 22.4, 23.4, 24.3, 25.6, 26.9, 31.6. Figure 11 shows the XRPD pattern of a typical batch of form XII of the compound
1. Example 13 Preparation of form XIII of acid {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl] -amide} propane-1-sulfonic Form XIII is a morpholine mono-solvate and can generally be obtained by processes comprising compound 1 and morpholine as solvents. a) Preparation from XIII by incubation with morpholine steam 250.3 mg of amorphous material were incubated with morpholine steam for 44 days at room temperature.
b) Characterization of Form XIII Form XIII can be characterized by a X-ray powder diffraction pattern obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2-Theta at approximately 5.1, 5.8, 6.9 , 15.3, 16.2, 5 17.4, 18.4, 18.9, 19.5, 20.4, 21.1, 21.5, 22.2, 22.6, 25.2, 25.7. Figure 12 shows the XRPD pattern of a typical batch of form XIII of compound 1. Example 14 Preparation of form XIV of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3 - propyl-1-sulfonic acid carbonyl-2,4-difluoro-phenyl] -amide} Form XIV is a mono-solvate DMSO and can generally be obtained by processes comprising compound 1 and DMSO as solvents. a) Preparation of form XIV by evaporative crystallization from DMSO 1.2 g of compound 1 (form II) were dissolved in 5 ml of DMSO at room temperature.
The clear solution was concentrated in a vacuum tray dryer at 40 ° C / (20 mbar) for 2 days.
The crystals were isolated by filtration and dried under ambient conditions for 4 days. b) Characterization of Form XIV Form XIV can be characterized by a powder X-ray powder diffraction pattern obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2-Theta at approximately 5.2, 10.2, 12.9 , 13.9, 17.1, 17.6, 18.7, 19.8, 20.1, 20.5, 21.0, 21.7, 22.8, 24.1, 25.1, 25 , 5, 27.1, 27.4. Figure 13 shows the XRPD pattern of a typical batch of form XIV of compound 1. Example 15 Preparation of form XV of {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine -3- carbonyl-2,4-difluoro-phenyl] -amide} of propane-1-sulfonic acid Form XV is a DMSO monosolvate and can generally be obtained by processes comprising compound 1 in DMSO as a solvent. a) Preparation of form XV by incubation with DMSO steam Drops of a solution of 100 mg compound 1 in 500 µL of
DMSO were placed on a glass slide.
After evaporation of the solvent, small crystals were observed.
In 3 of 9 drops form XV was observed.
The other crystallization tests yielded the XIV form. b) Characterization of Form XV 5 Form XV can be characterized by a powder X-ray powder diffraction pattern obtained with Cu Kα radiation having characteristic peaks expressed in 2-Theta grades at approximately 12.6, 13.8, 14, 6, 16.2, 16.6, 17.8, 18.3, 20.4, 20.7, 21.4, 22.4, 23.2, 24.2, 24.5, 25.5, 26.9, 27.8, 28.7. Figure 14 shows the XRPD pattern of form XV of compound 1. Example 16 Preparation of form XVI of propane-1-sulfonic acid {3- [5- (4-chlorophenyl) - 1H-pyrrole [2,3-b] pyridine -3-carbonyl-2,4-difluoro-phenyl] -amide} The polymorphic form XVI can be obtained by heating amorphous fusion films on glass slides.
Form XVI cannot be crystallized pure, but with Form VIII. a) Preparation of form XVI Small amounts of compound 1 (form II) were heated between a microscopic glass slide and glass cover at about 280 ° C.
The melt was then cooled to low temperatures by transferring the blade directly over a cold metal block (for example, chilled to –18 or –196 ° C). The transfer should be as fast as possible.
The obtained amorphous fusion film is then placed in a heating stage under a microscope and observed under cross-polarized light.
Through heating with heating rates between 1 and 10 ° C / min crystallization can be observed in the range of 140 -150 ° C.
During this process, Form VIII and Form XVI crystallized side by side. b) Characterization of Form XVI Form XVI can be characterized by a Raman spectrum as shown in Figure 15. Example 17 Preparation of "Pattern 6" A small amount of amorphous material was prepared in a glass capillary 1 mm in diameter and heated to 150 ° C in a hot stage coupled to a STOE Stadi P diffractometer.
Subsequently the sample was analyzed at 150 ° C. b) Characterization of Pattern 6 5 Pattern 6 can be characterized by an X-ray powder diffraction pattern obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2-Theta at approximately 7.0, 8.4, 8.9, 13.0, 13.8, 17.7, 18.8, 20.7, 25.8, 29.7. Figure 16 shows the XRPD pattern of pattern 6 of compound 1. Example 18 Preparation of propane-1-sulfonic acid {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b sulfuric acid salt] ] pyridine-3-carbonyl-2,4-difluoro-phenyl] -amide} The sulfuric acid salt can be obtained by the processes, comprising compound 1 and sulfuric acid. a) Preparation of sulfuric acid in tetrahydrofuran 6.15 g of compound 1 are fluidized in 168.7 g of tetrahydrofuran.
The suspension is heated to 55 ° C.
A clear solution is obtained.
At 30 ° C a solution of 1.4 g of sulfuric acid in 5 g d and 2-propanol is added.
At 40 ° C and (20 mbar) 80 ml of the solvent are distilled off.
Subsequently 22.3 g of tert-butylmethylether are added.
The solution is stirred for 12 hours at 20 ° C and crystallizes.
The solid is isolated by filtration and rinsed with 17.8 g of tetrahydrofuran.
The product is dried at 40 ° C / (2 mbar) for 12 hours.
Yield: 4.2 g (57.5%). b) Characterization of the sulfuric acid salt The sulfuric acid salt can be characterized by an X-ray powder diffraction pattern obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2-Theta in approximately 4.7, 6 , 7, 10.6, 13.3, 14.5, 15.7, 16, .4, 18.3, 18.6, 18.9, 19.5, 20.1, 20.9, 21, 2, 23.2, 23.7, 24.0, 26.9, 30.0. Figure 17 shows the XRPD pattern of a typical lot of sulfuric acid salt of compound 1. The sulfuric acid salt of compound 1 can be further characterized by a melting point with a starting temperature (DSC) of about 221 ° C to 228 ° C.
Example 19 Preparation of propane-1-sulfonic acid from hydrobromic acid salt {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl ] -amide} (bromide salt 5) The hydrobromic acid salt can be obtained by the processes comprising compound 1 and hydrogen bromide. a) Preparation of the hydrobromic acid salt in tetrahydrofuran 6.15 g of compound 1 are fluidized in 168.7 g of tetrahydrofuran.
The suspension is heated to 55 ° C.
A clear solution is obtained.
At 30 ° C a solution of 3.4 g of hydrobromic acid solution (33% HBr in acetic acid) is added and a white solid is precipitated.
The suspension is mixed for 2 hours at 20 ° C.
The solid is isolated by filtration and rinsed with 17.8 g of tetrahydrofuran.
The product is dried at 40 ° C / (2 mbar) for 12 hours.
Yield: 4.6 g (61.7%). b) Characterization of the bromide salt The bromide salt can be characterized by an X-ray powder diffraction pattern obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2-Theta at approximately 5.7, 6 , 8, 11.4, 13.6, 18.1, 19.8, 20.2, 21.4, 21.8, 24.6, 26.1, 27.3, 29.2. Figure 18 shows an XRPD pattern of a typical batch of compound 1 bromide salt. This salt can be further characterized by a melting point with a start temperature (DSC) in the range of about 240 ° C to 246 ° C.
The melting occurs under de-composition and can vary substantially.
Example 20 Preparation of hydrochloric acid salt of acid {3- [5- (4-chlorophenyl) -1H-pyrrole [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl] -amide} propane-1-sulfonic The hydrochloric acid salt can be obtained by the processes comprising compound 1 and hydrogen chloride. a) Preparation of the hydrochloric acid salt in tetrahydrofuran 10.0 g of compound 1 are fluidized in 176 g of tetrahydrofuran-
at the.
The suspension is stirred at 20 ° C. 4.8 g of a hydrochloric acid solution (4 M in dioxane) is added within 30 minutes.
A white solid is precipitated.
The suspension is stirred for an additional 3 hours at 40 ° C and subsequently cooled to 20 ° C.
The solid is isolated by filtration and rinsed with 17.8 g of tetrahydrofuran.
The product is dried at 40 ° C / (2 mbar) for 12 hours.
R e ntance: 8.9 g (83.7%) b) Characterization of salt chloride Salt chloride can be characterized by a diffraction pattern of X-ray powder obtained with Cu Kα radiation having characteristic peaks expressed in degrees 2-Theta in approximately 6.6, 7.8, 11.2, 12.6, 14.1, 14.7, 16.3, 17.8, 19.3, 19.6, 20, 7, 21.5, 22.7, 24.1, 25.4, 25.8. Figure 19 shows the XRPD pattern of a typical hydrochloric acid salt lot of compound 1. Example 21 Spray-dry dispersion solution Compound (1) was distributed in acetone or a THF / acetone mixture, an excess 1 mol equivalent of 2M hydrochloric acid was dispensed into a flask and stirred until dissolved.
Isopropanol was distributed in the flask and left to shake.
Excess of hydrochloric acid was sufficient to maintain the stability of the solution by spray drying.
Solution of hydroxypropyl methyl cellulose acetate succinate polymers (HPMCAS), methacrylic acid and ethylacrylate copolymers (L100-55) or vinylpyrrolidone-vinyl acetate copolymer (PVPVA) were prepared respectively by dissolving polymers in ethanol, adding an appropriate amount of acetone to the dissolved polymer solution, distributing the compound (1) in the polymer solution, and heating the solution to approximately 45 ° C until all components are fully dissolved.
The solutions were cooled back to the previous room temperature to spray dry.
Example 22 Preparation and manufacture of spray drying dispersion solution
Each formula was spray dried using a target inlet temperature of 100-105 ° C, an outlet temperature of 55 ° C, and an atomizing gas pressure of (0.5 bar). The feed material was atomized using a 0.5 mm two-fluid Schlick nozzle for all applications.
The collection of the product is in the cyclone.
A peristaltic variable speed pump, Master Flex, equipped with # 14 Tygon Chemical tubing, was used to distribute the feed material.
Spray drying dispersions were oven dried under vacuum overnight for 65 hours at 37 ° C under reduced pressure between - 25 to -30 in Hg (Stage 1). These samples were additionally dried in a vacuum oven for an additional 65 hours at 45 ° C under a reduced pressure between -25 to -30 in Hg (Stage 2). Spray drying dispersions were dried in a vacuum oven dried for 65 hours at 45 ° C under reduced pressure between -25 to -30 in Hg.
Residual solvents are below 5000 PPM.
Spray drying dispersion solution for amorphous forms XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV or XXVI were prepared according to the procedure mentioned in example 21. The drying dispersion formulas by spraying amorphous forms XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV or XXVI were prepared according to the procedure mentioned in example 22. Table 1 illustrates the spray drying dispersion of the formulation amorphous XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV and XXVI.
Table 1 Polymer Compound Formulation Solvent No.
XVII HPMCAS Compound (1) -30% THF: Acetone - HPMCAS - 70% 20%: 80% XVIII Compound (1) -30% THF: Acetone - HPMCAS - 70% 20%: 80% XIX Compound (1) -30 % THF: Acetone - HPMCAS - 70% 20%: 80% XX Compound (1) -30% Acetone 100% HPMCAS - 70% HCl salt XXI Compound (1) -50% Acetone 100% HPMCAS - 50% HCl salt XXII Compound (1) -33% Acetone: IPA: water - HPMCAS - 67% 95%: 3.8%: 1.2% HCl of salt XXIII Compound (1) -40% Acetone: IPA: water - HPMCAS - 60% 95%: 3.8 %: 1.2% HCl salt XXIV L100-55 Compound (1) -50% THF: Acetone - L100-55 - 50% 20%: 80% HCl salt XXV PVPVA Compound (1) -33.3% Acetone: Ethanol - PVPVA - 33.3% 20%: 80% PVPK30 - 33.3% XXVI PVPVA Compound (1) -33% Acetone: Ethanol - PVPVA - 67% 20%: 80%
Example 23 Characterization of compounds a) Characterization of solid form XVII Solid form XVII was characterized by the analysis of X-ray powder diffraction obtained with Cu Kα radiation.
The X-ray powder diffraction pattern consists of a large halo peak with well-defined peaks smaller than degrees 2-Theta.
The locations of the smaller well-defined peaks are shown in the table below.
Figure 20 shows an XRPD pattern of a typical batch of a substantially amorphous solid state XVII form.
Angle Value d Intensity Intensity% 2-Theta ° Angstrom Count% 3,276 26,94524 8.42 1.2 4.747 18.59877 32.6 4.8 5.683 15.53955 5.75 0.8 7.591 11.6373 57.9 8.5 8.44 10.46849 48.7 7.2 9.224 9.57963 169 24.9 9, S05 9.29756 403 59.3 9.882 8.9438 421 62 11.651 7.58897 72.9 10.7 11 , 93 7.41246 21.5 3.2 12.645 6.99485 89.4 13.1 13.015 6.79687 277 40.8 13.528 6.54031 47.5 7 14.037 6.30422 53.9 7.9 14.451 6, 12,451 57.5 8.5 14.986 5.90686 88.8 13.1 15.226 5.81445 105 15.5 15.6 5.67585 59.8 8.8 15.929 5.55933 159 23.3 16.281 5.43993 167 24.6 16.922 5.23544 205 30.1 17.36 5.10417 13.9 2 17.842 4.9673 204 29.9 18.377 4.8238 108 15.8 18.635 4.75784 307 45.2 19.074 4.64921 216 31.8 19.83 4.47353 211 31.1 20.596 4.30896 269 39.6 21.4 4.1883 272 40 21.627 4.10574 379 55.7 22.521 3.94481 93.2 13.7
Angle Value d Intensity Intensity% 2-Theta ° Angstrom Bill% 23.038 3.85742 56.8 8.4 23.44 3.79217 35.1 5.2 24.06 3.6983 200 29.4 24.347 3.65298 417 61.3 24.959 3.56467 680 100 25.713 3.4618 277 40.7 26.099 3.4115 162 23.8 26.515 3.35901 90.4 13.3 27.052 3.2348 55.7 8.2 27 753 3.21192 111 16.3 28.041 3.17956 110 16.1 28.742 3.10358 88.4 13 29.18 3.05796 74.8 11 30.077 2.96872 113 16.6 30.5 2.92855 61 9 31.089 2.87436 48.2 7.1 31.572 2.8315 106 15.6 32.076 2.78817 97.1 14.3 32.387 2.76212 85 12.5 32.84 2.72502 44.8 6.6 32.963 2.71514 65, 4 9.6 33.065 2.70701 61 9 33,201 2.669622 63.5 9.3 33.64 2.66201 17.7 2.6 33.924 2.6404 28 4.1 34.462 2.6004 64.3 9.5 35.359 2.53645 44 6.5 35.378 2.53515 44 6.5 35.712 2.51218 72.6 10.7 35.952 2.49597 83.8 12.3 36 736 2.44447 42.5 6.3 37.149 2, 41824 63 9.3 37.764 2.38023 55.7 8.2
Angle Value d Intensity Intensity% 2-Theta ° Angstrom Counts% 37.873 2.37368 50.7 7.5 38.322 2.3469 17.3 2.5 38.6 2.33061 32.6 4.8 38.79 2, 31,961 70.8 10.4 39.147 2.29927 45.2 6.6 39.397 2.2853 70.5 10.4 40-035 2.25029 47.3 7 40.277 2.24737 36.6 5.4 41.1 2.19443 42.6 6.3 41.218 2.1844 37.8 5.6 41.62 2.1621 40.3 5.9 42.496 2.1251 51.5 11.4 42.972 2.10308 52.1 7, 7 43.1 2.09714 72.3 10.6 43.72 2.06881 65.1 9.6 44.24 2.04569 32.9 4.8 44.535 2.03284 36.3 5.3 b) Characterization solid form XVIII Solid form XVIII was characterized by X-ray powder diffraction analysis obtained with Cu Kα radiation.
The X-ray powder diffraction pattern exhibits two broad halo peaks expressed in degrees 2-Theta as 5 shown in Figure 21. c) Characterization of solid form XIX Solid form XIX was characterized by the analysis of X-ray powder diffraction obtained with Cu Kα radiation.
The X-ray powder diffraction pattern consists of a broad halo peak with smaller, well-defined peaks expressed in degrees 2-Theta.
Figure 22 shows an XRPD pattern of a typical batch of a substantially amorphous solid state XIX form. d) Characterization of solid form XX Solid form XX was characterized by the analysis of X-ray powder diffraction obtained with Cu Kα radiation.
The X-ray powder diffraction pattern consists of a broad halo peak with well-defined lower peaks.
expressed in degrees 2-Theta.
Figure 23 shows an XRPD pattern of a typical batch of a substantially amorphous solid form XX. e) Characterization of solid form XXI Solid form XXI was characterized by the analysis of X-ray powder 5 diffraction obtained with Cu Kα radiation.
The X-ray powder diffraction pattern consists of a broad halo peak with smaller, well-defined peaks expressed in degrees 2-Theta.
Figure 24 shows an XRPD pattern of a typical batch of a substantially amorphous solid state XXI form. f) Characterization of solid form XXII Solid form XXII was characterized by the analysis of X-ray powder diffraction obtained with Cu Kα radiation.
The X-ray powder diffraction pattern consists of a broad halo peak expressed in degrees 2-Theta.
Figure 25 shows an XRPD pattern of a typical batch of a substantially amorphous solid state form XXII. g) Characterization of solid form XXIII Solid form XXIII was characterized by the analysis of X-ray powder diffraction obtained with Cu Kα radiation.
The X-ray powder diffraction pattern consists of a broad halo peak expressed in degrees 2-Theta.
Figure 26 shows an XRPD pattern of a typical batch of a substantially amorphous solid state form XXIII. h) Characterization of solid form XXIV Solid form XXIV was characterized by the analysis of X-ray powder diffraction obtained with Cu Kα radiation.
The X-ray powder diffraction pattern consists of a broad halo peak with smaller, well-defined peaks expressed in degrees 2-Theta.
Figure 27 shows an XRPD pattern of a typical batch of substantially amorphous solid state form XXIV. i) Characterization of solid form XXV Solid form XXV was characterized by the analysis of X-ray powder diffraction obtained with Cu Kα radiation.
The X-ray powder diffraction pattern consists of a broad halo peak expressed in degrees 2Teta.
Figure 28 shows an XRPD pattern of a typical batch of a substantially amorphous solid state XXV form.
j) Characterization of solid form XXVI Solid Form XXVI was characterized by the analysis of X-ray powder diffraction obtained with Cu Kα radiation.
The X-ray powder diffraction pattern consists of a broad halo peak expressed in degrees 2Teta.
Figure 29 shows an XRPD pattern of a typical batch of a substantially amorphous solid state XXVI form.

权利要求:
Claims (23)
[1]
1. Solid form, characterized by the fact that it is the compound of formula 1, Cl
The F
N
N S
NOOF (1), in which the said solid form is selected from the group consisting of 5 a) a substantially amorphous form of compound 1 selected in the form XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI or combinations thereof, wherein compound 1 is molecularly dispersed; b) a solvate of the form III, IV, V, VI, VII, IX, X, XI, XII, XIII, XIV or XV; c) a polymorph of form VIII or XVI; and d) the sulfuric acid-, hydrobromic acid- or hydrochloric acid salt of compound 1.
[2]
2. Solid form according to claim 1, characterized by the fact that it is selected in a substantially amorphous form from compound 1 selected from the form XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI or combinations of these, in which compound 1 is molecularly dispersed within a polymer matrix.
[3]
Solid form (XVII) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 20.
[4]
Solid form (XVIII) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 21.
[5]
Solid form (XIX) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 22.
[6]
Solid form (XX) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 23.
[7]
Solid form (XXI) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 24.
[8]
Solid form (XXII) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 25.
[9]
Solid form (XXIII) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 26.
[10]
10. Solid form (XXIV) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 27.
[11]
Solid form (XXV) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 28.
[12]
Solid form (XXVI) according to claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Fig. 29.
[13]
13. Solid form of any of claims 2 to 12, characterized by the fact that the solid form is prepared by a spray dispersion process.
[14]
14. Solid form of any one of claims 2 to 13, characterized by the fact that the polymer is selected from hydroxypropyl methyl cellulose succinate acetate (HPMCAS), hydroxypropylmethyl cellulose, co-polymer of methacrylic acids, polyvinylpyrrolidone ( povidone), 4-vinylpyrrolidone-vinyl copolymer acetate (copovidone) or methacrylic acid and ethylacrylate copolymers (EUDRAGIT® L100-55).
[15]
15. Pharmaceutical composition, characterized in that it comprises at least one solid form, as defined in any one of claims 2 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, additives or excipients.
[16]
Pharmaceutical composition according to claim 15, characterized in that it is for use in the treatment of a disease or condition in a mammal in need of it.
[17]
17. Pharmaceutical composition according to claim 16, characterized by the fact that the disease or condition is melanoma, thyroid cancer or colon cancer.
[18]
18. Solid form according to claim 1, characterized by the fact that it is selected from a solvate of form III, IV, V, VI, VII, IX, X, XI, XII, XIII, XIV or XV, preferably where a) a solid form (form III) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 9.5, 10.0, 13.0, 16.7, 18.7, 20, 1, 21.0 and 25.6 degrees 2-Theta (± 0.2 degree 2-Theta); b) a solid form (form IV) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 5.5, 7.4, 11.0, 13.4, 14.8, 16, 0, 16.7, 17.1, 17.9, 19.1, 19.5, 20.1, 20.5, 20.9, 21.2, 22.2, 23.0, 23.6, 24.2, 24.5 and 25.1 degrees 2-Theta (± 0.2 degree 2-Theta); c) a solid form (form V) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks at approximately 12.7, 13.1, 14.3, 16.3, 19.0, 20, 1, 22.4, 25.1, 27.1 and 28.9 degrees 2-Theta (± 0.2 degree 2-Theta); d) a solid form (form VI) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 7.8, 10.3, 11.4, 11.8, 15.1, 15, 6, 16.1, 16.6, 18.6, 18.9, 19.2, 20.4, 21.0, 21.6, 22.8, 24.6, 25.1, 25.8, 26.1, 27.4 and 28.8 degrees 2-Theta (± 0.2 degree 2-Theta); e) a solid form (form VII) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 7.6, 9.4, 9.9, 13.1, 15.9, 16, 2, 17.0, 18.1, 18.8, 19.9, 20.5,
20.7, 21.4, 21.8, 24.3, 24.9 and 25.3 degrees 2-Theta (± 0.2 degree 2-Theta); f) a solid form (form IX) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 9.5, 9.9, 13.0, 15.9, 16.4, 17, 0, 17.9, 18.7, 19.9, 20.7, 21.7, 24.8 5 and 25.1 degrees 2-Theta (± 0.2 degree 2-Theta); g) a solid form (form X) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 7.4, 9.2, 10.8, 13.6, 14.9, 19, 0, 20.2, 21.4, 22.4, 23.7, 25.5, 27.0 and 29.8 degrees 2-Theta (± 0.2 degrees 2-Theta); h) a solid form (form XI) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 8.0, 12.1, 12.6, 13.4, 13.9, 14, 8, 16.2, 17.6, 18.5, 19.2, 20.1, 21.0, 21.4, 21.7, 23.5, 25.3, 25.5, 26.6, 27.0 and 30.8 degrees 2-Theta (± 0.2 degree 2-Theta); i) a solid form (form XII) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 7.5, 9.9, 12.1, 13.6, 16.2, 16, 7, 17.1, 17.5, 18.3, 18.5, 20.1, 21.7, 22.4, 23.4, 24.3, 25.6, 26.9 and 31.6 degrees 2-Theta (± 0.2 degrees 2-Theta); j) a solid form (form XIII) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 5.1, 5.8, 6.9, 15.3, 16.2, 17, 4, 18.4, 18.9, 19.5, 20.4, 21.1, 21.5, 22.2, 22.6, 25.2 and 25.7 degrees 2-Theta (± 0.2 grade 2-Theta); k) a solid form (form XIV) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 5.2, 10.2, 12.9, 13.9, 17.1, 17, 6, 18.7, 19.8, 20.1, 20.5, 21.0, 21.7, 22.8, 24.1, 25.1, 25.5, 27.1 and 27.4 degrees 2-Theta (± 0.2 degree 2-Theta); l) a solid form (form XV) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 12.6, 13.8, 14.6, 16.2, 16.6, 17, 8, 18.3, 20.4, 20.7, 21.4, 22.4, 23.2, 24.2, 24.5, 25.5, 26.9, 27.8 and 28.7 degrees 2-Theta (± 0.2 degree 2-Theta); or m) a solid form called "pattern 6" is characterized by the fact that it comprises signals on its ray powder diffraction curve
X in positions 7.0, 8.4, 8.9, 13.0, 13.8, 17.7, 18.8, 20.7, 25.8 and 29.7 degrees 2-Theta (± 0, 2 grade 2-Theta).
[19]
19. Solid form according to claim 1, characterized by the fact that it is selected from a polymorph of form VIII or form XVI, 5 preferably in which a) a solid form (form VIII) is characterized by comprising signs in its X-ray powder diffraction curve at positions 5.0, 11.3, 11.6, 12.0, 13.8, 16.2, 16.7, 19.0, 20.1, 20.8, 22.5 and 27.1 degrees 2-Theta (± 0.2 degree 2-Theta); or b) a solid form (form XVI) is characterized by its Raman spectrum as shown in Figure 15.
[20]
20. Solid form according to claim 1, characterized by the fact that it is selected from sulfuric acid salt, hydrobromic acid salt or hydrochloric acid salt, preferably in which: a) the sulfuric acid salt is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 4.7, 6.7, 10.6, 13.3, 14.5, 15.7, 16.4, 18.3, 18.6, 18.9, 19.5, 20.1, 20.9, 21.2, 23.2, 23.7, 24.0, 26.9 and 30.0 degrees 2-Theta (± 0 , 2 degrees 2-Theta); b) the hydrobromic acid salt is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 5.7, 6.8, 11.4, 13.6, 18.1, 19.8, 20.2, 21.4, 21.8, 24.6, 26.1, 27.3 and 29.2 degrees 2-Theta (± 0.2 degree 2-Theta); or c) the hydrochloric acid salt is characterized by an X-ray powder diffraction pattern comprising characteristic peaks of approximately 6.6, 7.8, 11.2, 12.6, 14.1, 14 , 7, 16.3, 17.8, 19.3, 19.6, 20.7, 21.5, 22.7, 24.1, 25.4 and 25.8 degrees 2-Theta (± 0, 2 grade 2-Theta).
[21]
21. Pharmaceutical composition, characterized by the fact that it comprises at least one of the solid forms, as defined in any one of claims 18 to 20, together with pharmaceutically acceptable additives, vehicles or excipients.
[22]
22. Use of at least one solid form, as defined in any of claims 2 to 14 and 18 to 20, characterized in that it is for preparing a composition for the treatment of a disease or condition in a mammal in need of it .
[23]
23. Invention, characterized by any of its embodiments or categories of claim encompassed by the material initially disclosed in the patent application or in its examples presented here.
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法律状态:
2021-01-12| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2021-01-19| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-09-08| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021 |

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2021-09-21| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-12-14| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2022-01-18| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201161444866P| true| 2011-02-21|2011-02-21|

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US61,444,866|2011-02-21|

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PCT/US2012/025965|WO2012161776A1|2011-02-21|2012-02-21|Solid forms of a pharmaceutically active substance|

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