The present invention relates to novel solid forms of the compound of formula (I)
As well as solvates thereof, inclusion complexes with other suitable compounds, solvates of inclusion complexes thereof with other suitable compounds, processes for their manufacture, pharmaceutical compositions containing these solid forms, and their use as medicaments.
Background
Polymorphism is the ability of a compound to crystallize into more than one different crystal species. Different polymorphs (or polymorphs) have different arrangements or conformations of molecules in a crystal lattice. A solid is considered amorphous if it does not have a distinguishable crystal lattice and the molecular arrangement of the molecules is disordered. The amorphous State is structurally similar to the liquid State [ w.mccrone, phys.chem.org.solid State (1965) 2: 725767].
Polymorphs of a drug can have different chemical, physical and physico-technical properties. The distinction may result, for example, from the packing of the molecules in the crystal structure (density, refractive index, conductivity, hygroscopicity), thermodynamic properties (melting point, heat capacity, vapor pressure, solubility), kinetic properties (dissolution rate, stability), surface properties (surface free energy, interfacial tension, shape, morphology), and mechanical properties (baroplasticity, tensile strength). These properties may have a direct impact on the ability to process and manufacture Active Pharmaceutical Ingredients (APIs) and drug products. Polymorphism is also of pharmacological interest due to altered solid state properties and suitability for particular formulations. Thus, polymorphism of APIs may affect the quality, safety, efficacy and developability of drug products and is therefore principally important [ d.giron et al, j.therm.anal.cal. (2004) 77: 709].
In addition to polymorphic variants, the API may be crystallized with suitable counter ions in different salt forms. Similar to polymorphism, salt forms differ from each other in solubility and many other physical and chemical factors, as noted above. Suitable salt forms may provide improved water solubility, dissolution rate, hygroscopicity, chemical stability, melting point, or mechanical properties, as compared to the free acid or free base of the API.
Solvates, also known as pseudopolymorphs, are crystalline forms having a stoichiometric or non-stoichiometric amount of solvent incorporated in the crystal lattice. If the solvent incorporated is water, the solvate is often referred to as a hydrate.
Both the salt and the inclusion complex are multicomponent systems. Salts are formed by ionic bond interactions with complete proton transfer between the acid and base, while in inclusion complexes the molecules are neutral in the crystalline state and are linked mainly by hydrogen bonds or van der waals interactions [ s.l. morissette et al, adv. drug del.rev. (2004) 56: 275-300].
Cyclodextrins are composed of six, seven, or eight glucose units, respectively, and have a hydrophilic cavity exterior and a hydrophobic cavity interior [ v.j.stella et al, adv.drug del.rev. (2007) 59: 677-694]. These properties are responsible for their water solubility and the ability to bind hydrophobic molecular moieties within their cavities. Cyclodextrins may be employed as inclusion complex formers for inclusion complexes with APIs, wherein the APIs are captured by the cavities of the cyclodextrin molecules. It is reported in the literature that the crystal structure of cyclodextrin inclusion complexes is typically dominated by the spatial arrangement of the host molecule. Thus cyclodextrins can form a defined packing arrangement similar to the crystalline state without the API occupying a well-defined lattice position [ t.uyar et al, crystal.growth Des. (2006) 6: 1113-1119, T. Toropain et al, pharm. Res. (2007) 24: 1058-1066].
Among commercially available cyclodextrins, gamma-cyclodextrin (gamma-CD) is reported to be stable and found to be safe for oral administration [ i.c. munro et al, regulation biology and Pharmacology (2004) 39: S3-S13 ]. However, gamma-cyclodextrin has not heretofore been used in the preparation of commercially available drugs. This monograph has only recently (12/2008) been included in the european pharmacopoeia. The formation of inclusion complexes with cyclodextrins is unpredictable and requires extensive experimental investigation. In those cases where inclusion complexes with gamma-cyclodextrin are formed, a majority of the active pharmaceutical ingredient forms a 2: 1 complex (the ratio between the inclusion complex formation and the API). The formation of cyclodextrin inclusion complexes and their guest-to-host stoichiometric ratio are highly dependent on the molecular structure and geometry of the guest molecule [ t.uyar et al, crystal.growth Des. (2006) 6: 11l3-ll19 ].
Compounds of formula (I), their preparation, their pharmacological activity as inverse agonists of the GABA a α 5 receptor, and their use for the treatment, prevention and/or delay of various Central Nervous System (CNS) disorders have been described in WO 2009/071476. Based on their physicochemical properties, the compounds of formula (I) as described in WO 2009/071476 are BCS2 compounds exhibiting low water solubility and high permeability, according to the biopharmaceutical classification system [ g.l.amidon, h.lennernas, v.p.shah, j.r.crison, pharm.res. (1995) 12: 413-420]. Therefore, limited oral bioavailability is a major problem in the development of oral formulations.
If anhydrous solid forms of the compounds of formula (I) as described in WO 2009/071476 are selected for clinical development, physical instability in terms of hydrate formation during pharmaceutical processing and/or storage of the drug product is possible. The anhydrous solid form a of the compound of formula (I) as described in WO 2009/071476 and herein was also found to be only metastable and thus may be converted to a different solid form. Thus, there is a need to find new solid forms characterized by improved physicochemical properties and increased bioavailability.
Furthermore, the discovery of new solid forms of APIs (polymorphs, solvates, salts, inclusion complexes) expands the choice of materials available to the formulation scientist for designing pharmaceutical dosage forms for drugs with targeted release profiles or other desired characteristics. Therefore, there is a need to find more solid forms of the compounds of formula (I).
It has now been unexpectedly found that under specific conditions, new solid forms, in particular crystalline or amorphous forms, most in particular crystalline forms, of the compound of formula (I) can be obtained, which are described hereinafter, and which have beneficial utility and properties. They exhibit significantly different and superior physical and physicochemical properties, which can be beneficial in a number of aspects related to API and drug product development, such as for dissolution of APIs, stability and shelf life of API and drug products, and/or convenient routes of manufacture or purification. The present invention provides novel solid forms of the compound of formula (I) having improved solubility, dissolution rate, oral bioavailability and increased API stability.
Furthermore, the present invention provides novel inclusion complexes of compounds of formula (I) with cyclodextrins. Such inclusion complexes are also characterized by improved dissolution rates and bioavailability.
The novel solid forms as described herein can be resolved by X-ray powder diffraction, crystal structure analysis, vibrational spectroscopy, magnetic resonance and mass spectroscopy, calorimetry, thermogravimetry, dynamic vapor adsorption, and by microscopy.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.
Unless otherwise indicated, the terms used in this application are based on IUPAC systematic nomenclature.
Unless otherwise mentioned, the open valencies appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein refer to the presence of hydrogen.
The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom of a parent molecule.
The term "substituted" means that the specified group bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When indicating the number of substituents, the term "one or more" means the substitution of one substituent up to the highest possible number of substituents, i.e. the substitution of one hydrogen to the substitution of all hydrogens by substituents.
The term "halogen" refers to fluorine, chlorine, bromine or iodine. A particular halogen is fluorine.
The term "alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, the alkyl group has from 1 to 7 carbon atoms, and in more particular embodiments, from 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. A particular alkyl group is methyl.
The term "alkoxy" refers to a group of the formula-O-R ', wherein R' is alkyl. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.
The term "haloalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom, particularly a fluorine atom. Examples of haloalkyl include monofluoro-, difluoro-or trifluoromethyl, -ethyl or-propyl, such as 3, 3, 3-trifluoropropyl, 2-fluoroethyl, 2, 2, 2-trifluoroethyl, fluoromethyl or trifluoromethyl. The term "perhaloalkyl" refers to an alkyl group wherein all of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms.
The term "hydroxyalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group is replaced by a hydroxyl group. Examples of hydroxyalkyl groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl or 2- (hydroxymethyl) -3-hydroxypropyl.
The term "heterocycloalkyl" refers to 3 to 9 ring atoms, including 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being a monovalent saturated or partially unsaturated mono-or bicyclic ring system of carbon. In particular embodiments, heterocycloalkyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, including 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, and the like,Oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepinyl, diazepanyl, homopiperazinyl, or oxepinyl. An example of a bicyclic saturated heterocycloalkyl is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl, 3-oxa-9-aza-bicyclo [3.3.1]Nonyl or 3-thia-9-aza-bicyclo [3.3.1]Nonyl radical. Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolidinyl, dihydro-Oxazolyl, tetrahydro-pyridyl or dihydropyranyl. A particular heterocycloalkyl radical is (1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl).
The term "aromatic" refers to the conventional concept of aromaticity as defined in the literature, especially in IUPAC-Complex of Chemical technology, 2nd, A.D.McNaught & A.Wilkinson (Eds.) Blackwell Scientific Publications, Oxford (1997).
The term "aryl" refers to a monovalent aromatic carbocyclic mono-or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. A particular aryl group is phenyl.
The term "heteroaryl" refers to a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, including 1, 2, 3, or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furyl, thienyl, imidazolyl, and the like,Oxazolyl, thiazolyl, triazolyl,Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azaRadical diazaBasic group, heteroAzolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolylAzolyl, benzisoylAzolyl, benzothiazolyl, benzisothiazolyl, benzoOxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl or quinolylA quinoline group.
The term "active pharmaceutical ingredient" (or "API") refers to a compound in a pharmaceutical composition that has particular biological activity.
The term "pharmaceutically acceptable" refers to the property of a material that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and that is acceptable for veterinary as well as human pharmaceutical use.
The terms "pharmaceutically acceptable excipient" and "therapeutically inert excipient" are used interchangeably and refer to any pharmaceutical ingredient in a pharmaceutical composition that is not therapeutically active and that is not toxic to the subject, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.
The term "pharmaceutical composition" refers to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient and pharmaceutically acceptable excipients for administration to a mammal, e.g., a human, as needed.
The term "solid form" or "form" is a general term that refers to crystalline and/or amorphous forms of a solid material.
The terms "crystalline form" and "crystalline form" may be used interchangeably to refer to both polymorphic and pseudopolymorphic forms of a crystalline solid.
The terms "polymorph" and "variant" may be used synonymously to denote a specific crystal structure in which a compound may be crystallized. Different polymorphs have different molecular arrangements or conformations in the crystal lattice, but all share the same elemental composition.
The term "polymorphism" refers to the ability of a compound to form more than one polymorph.
The term "reciprocity" refers to the relationship between two or more polymorphs of the same substance in which the order of the thermodynamic stability of the polymorphs changes reversibly at a specified temperature.
The term "monotropic" refers to a relationship between two or more crystalline forms of the same substance in which the order of the thermodynamic stability of the polymorphs remains unchanged at all temperatures below the melting point. The "metastable" form is the crystalline form that does not have the highest order of thermodynamic stability.
The terms "solvate" and "pseudopolymorph" may be used synonymously to denote a crystal having a stoichiometric or non-stoichiometric amount of solvent incorporated in the crystal lattice. If the solvent incorporated is water, the solvate formed is a "hydrate". When the solvent incorporated is an alcohol, the solvate formed is an "alcoholate".
The term "salt" refers to a material consisting of two components, an acid and a base, in a well-defined stoichiometric ratio of the two salt formers. Salt crystals are formed by ionic bonding interactions in which the hydrogen ions between the acid and base are completely transferred.
The term "crystal shape" refers to one or more base elements (one or more polyhedrons) from which a single crystal is constructed. The crystal shape is described by the Miller index of the lattice planes of one or more polyhedra.
The term "crystalline habit" refers to the physical appearance of a crystalline form and thus a solid form. The difference in crystal habit is caused by the different growth rates of the lattice planes. The following habit can be distinguished [ USP, General Chapter <776> (Optical Microcopy) ]:
a)a)isometric crystalAre of equal size (e.g., cube or sphere);
b)b)boardAre planar, flat crystals and have similar breadth and width; thicker than the thin skin;
c)c)sheetIs a thin, flat crystal with similar breadth and width;
d)d)blade(lath) is an elongated, thin and blade-like crystal;
e)e)needleAre needle-like, thin and highly elongated crystals with similar width and breadth;
f)f)columnAre elongated, prismatic crystals having a greater width and thickness than the needles.
The term "equivalent spherical diameter" (or ESD) of a non-spherical object, such as an irregularly shaped particle, is the diameter of a sphere of equal volume.
The terms "d 50 value" and "mass median diameter" (or MMD) may be used interchangeably and refer to the average particle size by mass, i.e. the average equivalent diameter of the particles, which is defined as the diameter at which 50% (w) of the particles in the population have a larger equivalent spherical diameter and the other 50% (w) have a smaller equivalent spherical diameter.
The term "amorphous form" refers to a solid material that does not possess a distinguishable crystal lattice and the molecular arrangement of the molecules lacks long-range order. In particular, amorphous refers to a material that does not exhibit sharp bragg diffraction peaks. Bragg law describes diffraction of a crystalline material with the formula "2 d · sin (θ) = n · λ", where "d" refers to the perpendicular distance (in angstroms) between adjacent pairs of planes in the crystal ("d spacing"), "θ" refers to the bragg angle, "λ" refers to the wavelength, and "n" is an integer. When the bragg law is satisfied, the reflected beams are within the phase plane and constructively interfere so that a bragg diffraction peak is observed in the X-ray diffraction pattern. At incident angles other than the bragg angle, the reflected beams are out of the plane of the phase and destructively interfere or cancel. The amorphous material does not satisfy bragg's law, and no sharp bragg diffraction peak is observed in the X-ray diffraction pattern. The XRPD pattern of the amorphous material is further characterized by one or more amorphous halos.
The term "inclusion complex" refers to a stoichiometric amount of a multicomponent complex. In contrast to salts, no or only a portion of the protons are expected to be transferred in the inclusion complex. The inclusion complex may be in an amorphous form or a crystalline form. In particular, the inclusion complex is in a crystalline form. The inclusion complex formation is a solid at room temperature. Particular inclusion complex formations are cyclodextrins, most particularly gamma-cyclodextrin (gamma-CD). In particular, the inclusion complex former is in a crystalline state in the inclusion complex. In particular, the inclusion complex is a stoichiometric 1: 1 or 2: 1 inclusion complex (ratio between inclusion complex formation and API). Most particularly, the inclusion complex is a stoichiometric 1: 1 inclusion complex (ratio between inclusion complex formation and API). Inclusion complexes may form solvates, hydrates and may exist as different polymorphs.
Terms as used herein"form A" means (1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-a crystalline anhydrous polymorph a of pyridin-3-yl } -methanone.
The term "form B" as used herein refers to (1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-a crystalline polymorph B of pyridin-3-yl } -methanone monohydrate.
The term "form C" as used herein refers to (1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-crystalline anhydrous polymorph C of pyridin-3-yl } -methanone.
The term "form D" as used herein refers to (1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanone trifluoroethanol mono-solvate crystalline polymorph D.
The term "form E" as used herein refers to (1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-an anhydrous crystalline polymorph E of pyridin-3-yl } -methanone.
The term "amorphous form" as used herein refers to (1, 1-dioxo-1. lamda.)6-thiomorpholine-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-isoAzol-4-ylmethoxy]-an amorphous form of pyridin-3-yl } -methanone.
The term "γ -CD inclusion complex" as used herein refers to (1, 1-dioxo-1. lambda6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]A crystalline 1: 1 inclusion complex of-pyridin-3-yl } -methanone with gamma-cyclodextrin.
The term "XRPD" refers to the analytical method of X-ray powder diffraction. XRPD patterns were recorded under ambient conditions in transmission geometry using a STOE STADI P diffractometer (Cu ka radiation source, primary monochromator, position sensitive detector, angular range 3 ° to 42 ° 2 θ, approximately 60 minutes total measurement time). The repeatability of the angle values is in the range of 2 theta + -0.2 deg.. The term "about" given in connection with the angle values refers to repeatability in the range of 2 θ ± 0.2 °. Samples are prepared and analyzed without further processing (e.g., grinding or screening) of the material. The relative XRPD peak intensities depend on many factors such as structural factors, temperature factors, crystallinity, polarization factors, diversity, and Lorentz factor. The relative intensities may vary significantly from one measurement to another due to preferred orientation effects.
Humidity controlled XRPD analysis was performed in reflection geometry with a Siemens D5000 differential meter (Cu radiation source, Ni K β filter, science detector, angle range 3 ° to 42 ° 2 θ, approximately 180 minutes total measurement time per humidity level). The diffractometer was equipped with an mri (materials Research instruments) humidity chamber. The humidity in the room was adjusted using an ANSYCO humidity controller (SYCOSH-HOT).
For single crystal structure analysis, single crystal samples were mounted in nylon rings on a goniometer and measured at ambient conditions. Alternatively, the crystals are cooled in the nitrogen stream during the measurement. Data were collected on a GEMINI R Ultra diffractometer from Oxford Diffraction. Use ofCu-radiation of wavelength was used for data collection. The data was processed using Oxford Diffraction CRYSALIS software. The crystal structure was solved and optimized with standard crystallography software. In this case, the program ShelXTL from Bruker AXS (Karlsruhe) was used.
The abbreviation "FWHM" refers to the full width at half maximum, which is the width of a peak (e.g., as it appears in a spectrum, particularly in an XRPD pattern) at its half height.
The term "sharp bragg diffraction peak" as used in connection with an X-ray diffraction pattern refers to the peak observed if the bragg diffraction law is satisfied. Typically, the FWHM of the sharp Bragg diffraction peak is less than 0.5 deg. 2-theta.
The term "amorphous halo" in relation to an X-ray diffraction pattern refers to an approximately bell-shaped diffraction maximum in the X-ray powder diffraction pattern of an amorphous material. The FWHM of the amorphous halo is in principle larger than the FWHM of the peak of the crystalline material.
The terms "FTIR" and "IR" refer to infrared spectroscopic analysis methods. The IR spectrum of the sample was recorded in the form of a film of Nujol suspension consisting of approximately 5mg of the sample and approximately 5mg of Nujol (mineral oil) between two sodium chloride plates (cross section 13mm) in terms of transmission by means of an FTIR spectrometer. At 4000cm-1To 600cm-１Spectrum was recorded in the spectral range between, resolution 2cm-１And scans were superimposed 300 on Magna860 (thermo/Nicolet) equipped with a DTGS detector.
The term "raman" refers to an analytical method of raman spectroscopy. To record the raman spectra, the samples were smeared onto glass slides. At 150--１In the range of (1) with an ARAMIS (horiba JobinYvon) Raman microscope equipped with a Peltier-cooled CCD detector, excitation at 633nm, a 1200 l/mm grating, an x50 objective and exposure with 3 exposures for 3s, or for twoThe raman spectrum was recorded for 7s on the weak raman scatterer.
The term "DSC" refers to differential scanning calorimetry analysis. Using Mettler-ToledoTMDifferential scanning calorimeter DSC820, DSC821 or DSC1 DSC thermograms were recorded with FRS05 sensor. System suitability tests were performed with indium as reference substance and calibration was performed using indium, benzoic acid, biphenyl and zinc as reference substances.
For the measurement, approximately 2-6mg of the sample was placed in an aluminum pan, accurately weighed and closed with a perforated lid. Prior to measurement, the cap was automatically pierced creating an approximately 1.5mm pinhole. The sample was then heated under a nitrogen flow of about 100 mL/min using a heating rate of typically 10K/min.
For the amorphous form of the measurement, approximately 2-6mg of the sample was placed in an aluminum pan, accurately weighed and closed. The sample was then heated under a nitrogen flow of about 100 mL/min using a heating rate of 10K/min.
The term "onset" refers to the intersection between the baseline and the complex reflection tangent before the transition.
The term "glass transition temperature" (Tg) refers to the temperature above which a glassy amorphous solid becomes rubbery.
The term "TGA" refers to an analytical method of thermogravimetric analysis. In Mettler-ToledoTMTGA analysis was performed on a thermogravimetric analyzer (TGA850 or TGA 851). System adequacy tests were performed with Hydranal as a reference substance and calibration was performed using aluminum and indium as reference substances.
For thermogravimetric analysis, approximately 5-10mg of the sample was placed in an aluminum pan, accurately weighed and closed with a perforated lid. Prior to measurement, the cap was automatically pierced creating an approximately 1.5mm pinhole. The sample was then heated under a nitrogen flow of about 50 mL/min using a heating rate of 5K/min.
The term "micronisation" refers to a process in which the particle size of the solid material is reduced to a d50 value of less than 10 μm by means of a suitable method, such as grinding, beating or roller compaction.
The term "polish filtration" means a process in which the solution is filtered using a 0.2 μm filter, in particular Pall N66Filtration method with 0.2 μm cartridge filter to remove fines.
The term "distillative solvent exchange" refers to thermal distillation at reduced or standard pressure, wherein one liquid (solvent or antisolvent) is replaced by another liquid (solvent or antisolvent), typically at a constant reactor level.
The term "solvent" refers to any type of liquid in which the product is at least partially soluble (solubility of the product >1 g/l).
The term "anti-solvent" refers to any type of liquid in which the product is insoluble or at most sparingly soluble (solubility of the product <0.01 mol/l).
The term "antisolvent crystallization" refers to a process in which supersaturation is achieved by adding an antisolvent to a product solution, and crystallization occurs as a result thereof.
The term "ambient conditions" refers to conditions experienced in a standard laboratory, such as atmospheric pressure, air, ambient temperature of 18 ℃ to 28 ℃, humidity of 30% rH to 80% rH.
The term "hygroscopic" describes the ability of a solid material to adsorb moisture. The hygroscopicity of a given API is characterized by [ European Pharmacopoeia-6 th edition (2008), chapter 5.11) an increase in mass when the relative humidity is raised from 0% rH to 90% rH:
no moisture absorption: weight gain Δ m < 0.2%;
slightly hygroscopic: the weight is increased by more than or equal to 0.2 percent and more than or equal to 2.0 percent;
moisture absorption: the weight is increased by 2.0 percent to less than or equal to Delta m and less than 15.0 percent;
o very hygroscopic: the weight increase delta m is more than or equal to 15.0 percent;
deliquescence: sufficient water is adsorbed to form a liquid.
The IUPAC lambda force method (W.H.Powell, Pure & appl.chem. (1984)56 (6): 769-778) provides a general method for indicating the non-standard valency of heteroatoms in molecules. The number of bonds "n" of a heteroatom is the sum of the total number of valencies to adjacent atoms, if any, and the number of hydrogen atoms attached. The number of bonds of the heteroatoms is standard when it has the values given in the table below:
n=4：C、Si、Ge、Sn、Pb；
n=3：B、N、P、As、Sb、Bi
n=2：O、S、Se、Te、Po；
n=1；F、Cl、Br、I、At。
the number of non-canonical bonds of the (neutral) heteroatom is given by the symbol "lambdan"display, where" n "is the number of bonds. If a position, i.e. a number indicating a position within the molecule, is used for a heteroatom having a non-standard number of bonds, λ is quoted just after this positionnAnd (4) a symbol.
The term (1, 1-dioxo-1. lamda.) is used interchangeably herein6-thiomorpholin-4-yl) -, (1, 1-dioxo-1 λ 6-thiomorpholin-4-yl) -and (1, 1-dioxo-thiomorpholin-4-yl) -, to represent a thiomorpholinyl-group of the following structure, wherein the sulphur ring atom is substituted with two oxo groups:
Detailed Description
In detail, the present invention relates to new solid forms, in particular crystalline or amorphous forms, most particularly crystalline forms, of the compound of formula (I),
or a solvate thereof; or an inclusion complex thereof with one or more inclusion complex forming agents; or a solvate of an inclusion complex thereof with one or more inclusion complex forming agents.
(1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanone [ CAS number 1159600-41-5]Are intended to mean compounds of formula (I) and vice versa.
In a particular embodiment, the invention relates to a solid form of the compound of formula (I) as described above, characterized in that the XRPD pattern comprises at least one XRPD peak in the range of diffraction angles 2 θ from 10.3 ° to 13.3 °.
In a particular embodiment, the present invention relates to a solid form of the compound of formula (I) as described above; or a solvate thereof; or an inclusion complex thereof with one or more inclusion complex forming agents; or a solvate of an inclusion complex thereof with one or more inclusion complex forming agents; characterized in that the XRPD pattern comprises at least one XRPD peak in the range of diffraction angles 2 theta of 10.3 DEG to 13.3 deg.
In a particular embodiment of the invention, the solid form of the compound of formula (I) as described above is a crystalline form.
In a particular embodiment of the invention, the solid form of the compound of formula (I) as described above is present in a specific solid form of at least 90% (w/w), in particular at least 95% (w/w), most in particular at least 99% (w/w) purity.
Anhydrous polymorph A (Form(s) ofA) Of (1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-methylAzol-4-ylmethoxy]-pyridin-3-yl } -methanone is described in WO 2009/071476.
Form a was found to be a metastable polymorph with a melting temperature (extrapolated peak DSC) of about 145 ℃. Form a is not optimally suited for pharmaceutical product development due to its metastable character.
Form a is characterized by XRPD peaks at diffraction angles 2 Θ of 3.3 °, 10.1 °, 14.2 °, 14.4 °, 15.7 °, 16.1 °, 17.2 °, 17.3 °, 19.5 °, 19.8 °, 20.2 °, 20.8 °, 22.5 °, 24.8 °, 25.0 °, 25.9 °, 27.7 °; XRPD peaks observed in particular at diffraction angles 2 θ of 14.4 °, 20.2 °, 22.5 °, 25.9 °.
Form a is characterized by the XRPD diffraction pattern of fig. 1.
Form a is characterized by an XRPD diffraction pattern comprising XRPD peaks at the peak positions given in table 2.
Form a is characterized by the FTIR spectrum of fig. 8.
Form a is characterized by the raman spectrum of fig. 14.
Form a is characterized by a melting point having an onset temperature (DSC) in the range of about 141 ℃ to 145 ℃.
It was found that (1, 1-dioxo-1. lamda. can be substituted6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanones, depending on the preparation process, separate into other different crystalline and amorphous modifications, which are distinguishable by their X-ray powder diffraction patterns, vibrational spectra and their melting behavior, and which exhibit an unexpected but relatively more beneficial behaviour for API and pharmaceutical product development and administration compared to form a previously describedThe benefits of (1).
In addition to the previously described (1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]Form a of pyridin-3-yl } -methanone, two other polymorphic anhydrous forms (form C and form E), one monohydrate form (form B), the trifluoroethanol form (form D) and the amorphous form were found and characterized.
(1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]Form B of-pyridin-3-yl } -methanone is a hygroscopic monohydrate which is heated to>After 100 ℃ it is converted into form A. Form B has significantly increased stability in the presence of moisture, e.g., at ambient conditions, as compared to form a.
Temperature-controlled XRPD analysis of form B showed a phase change to form a at elevated temperatures. In the temperature range of 105 ℃ and 135 ℃, only form A is present. Within the temperature range of 65-95 ℃, an intermediate state is observed, characterized by a significant change in peak position.
A particular embodiment of the present invention relates to polymorph B (B), (B) as described hereinForm(s) ofB) (1, 1-dioxo-1. lamda.) of6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanone monohydrate.
In a particular embodiment of the invention, form B is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 13.3 °, 20.6 °, 22.5 °.
In a particular embodiment of the invention, form B is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 Θ of about 10.9 °, 13.0 °, 13.3 °, 14.1 °, 14.8 °, 16.5 °, 17.0 °, 18.9 °, 20.6 °, 21.0 °, 22.5 °, 23.4 °, 24.8 °, 26.9 °.
In a particular embodiment of the invention, form B is characterized by the XRPD diffraction pattern of figure 2.
In a particular embodiment of the invention, form B is characterized by an XRPD diffraction pattern comprising XRPD peaks at peak positions as given in table 3.
In a particular embodiment of the invention, form B is characterized by the FTIR spectrum of fig. 9.
In a particular embodiment of the invention, form B is characterized by the raman spectrum of figure 15.
In a particular embodiment of the invention, form B is characterized by a broad endothermic signal with weight loss (measured by TGA) from 90 ℃ to 110 ℃.
(1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]Form C of-pyridin-3-yl } -methanone was found to be a more stable form than form a. In fact, form C was found to be the most stable polymorph in all. Further, form C is less hygroscopic than form a and has a melting temperature (extrapolated peak DSC) of about 151 ℃. Form C has significantly improved solubility in Simulated Gastric Fluid (SGF) compared to form B. Form C is converted to form B in suspension in the presence of water, while storage at 100% rH does not induce this phase change for an extended period of time at ambient temperature, e.g., for 30 days.
Temperature controlled XRPD analysis of polymorph a and form C did not show solid form changes at elevated temperatures.
A particular embodiment of the present invention relates to the absence of water as described hereinPolymorph C (Form(s) ofC) (1, 1-dioxo-1. lamda.) of6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanone.
In a particular embodiment of the invention, form C is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 17.4 °, 23.4 °.
In a particular embodiment of the invention, form C is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 11.7 °, 17.4 °, 23.4 °.
In a particular embodiment of the invention, form C is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 10.5 °, 11.7 °, 14.2 °, 16.3 °, 16.7 °, 17.4 °, 17.9 °, 19.3 °, 23.4 °, 24.7 °, 25.1 °, 25.9 °.
In a particular embodiment of the invention, form C is characterized by the XRPD diffraction pattern of figure 3.
In a particular embodiment of the invention, form C is characterized by an XRPD diffraction pattern comprising XRPD peaks at peak positions as given in table 4.
In a particular embodiment of the invention, form C is characterized by the FTIR spectrum of fig. 10.
In a particular embodiment of the invention, form C is characterized by the raman spectrum of figure 16.
In a particular embodiment of the invention, form C is characterized by a melting point having an onset temperature (DSC) in the range of about 146 ℃ to 150 ℃.
(1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzole-4-methoxymethoxy group]Form D of-pyridin-3-yl } -methanone is a trifluoroethanol mono-solvate, which can be produced by crystallization from a trifluoroethanol/methanol mixture. Form D provides benefits over form a, which is readily available with trifluoroethanol employed in the manufacturing process.
A particular embodiment of the present invention relates to polymorph D (a), (b), (c), (D), (Form(s) ofD) (1, 1-dioxo-1. lamda.) of6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanone trifluoroethanol mono-solvate. Form D has a melting temperature (extrapolated Peak DSC) of about 97.9 deg.C
In a particular embodiment of the invention, form D is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 6.1 °, 16.8 °, 22.6 °.
In a particular embodiment of the invention, form D is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 6.1 °, 11.0 °, 16.8 °, 22.6 °.
In a particular embodiment of the invention, form D is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 6.1 °, 8.1 °, 11.0 °, 13.5 °, 15.4 °, 16.8 °, 18.4 °, 19.2 °, 19.5 °, 21.1 °, 21.4 °, 22.6 °, 24.7 °, 28.1 °.
In a particular embodiment of the invention, form D is characterized by the XRPD diffraction pattern of fig. 4.
In a particular embodiment of the invention, form D is characterized by an XRPD diffraction pattern comprising XRPD peaks at peak positions as indicated in table 5.
In a particular embodiment of the invention, form D is characterized by the FTIR spectrum of fig. 11.
In a particular embodiment of the invention, form D is characterized by a melting point having an onset temperature (DSC) in the range of about 96 ℃ to 100 ℃.
(1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]Form E of-pyridin-3-yl } -methanone is dehydrated, which exhibits only limited stability under ambient conditions. Form E is achieved by form B via<Dehydration from 5% rH storage. When exposed to>A rapid reversion of form E to form B was observed after 5% rH.
Similarly, form E was also observed at 0% rH after drying monohydrate form B by means of humidity controlled XRPD analysis.
A particular embodiment of the present invention relates to the anhydrous polymorph form E (b), (c), (dForm(s) ofE) (1, 1-dioxo-1. lamda.) of6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanone.
In a particular embodiment of the invention, form E is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 Θ of about 16.5 °, 20.8 °.
In a particular embodiment of the invention, form E is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 13.1 °, 16.5 °, 20.8 °.
In a particular embodiment of the invention, form E is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 Θ of about 5.5 °, 13.1 °, 13.3 °, 14.2 °, 16.5 °, 19.1 °, 20.8 °, 22.3 °, 23.9 °, 25.1 °, 25.5 °, 26.4 °, 29.0 °.
In a particular embodiment of the invention, form E is characterized by an XRPD diffraction pattern comprising XRPD peaks at peak positions as given in table 6.
In a particular embodiment of the invention, form E is characterized by the XRPD diffraction pattern of figure 5.
In a particular embodiment of the invention, form E is characterized by the raman spectrum of fig. 17.
(1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]The glass transition temperature of the amorphous form of pyridin-3-yl } -methanone was about 66 ℃ (midpoint of second heating). Amorphous materials are slightly hygroscopic, but no phase change is observed after 100% rH storage at ambient temperature.
A particular embodiment of the present invention relates to amorphous (1, 1-dioxo-1. lamda.) as described herein6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanone (In amorphous form)。
In a particular embodiment of the invention, the amorphous form is characterized by at least one amorphous halo in the XRPD diffraction pattern and by the absence of sharp bragg diffraction peaks.
In a particular embodiment of the invention, the amorphous form is characterized by the XRPD diffraction pattern of fig. 6.
In a particular embodiment of the invention, the amorphous form is characterized by the FTIR spectrum of fig. 12.
In a particular embodiment of the invention, the amorphous form is characterized by the raman spectrum of fig. 18.
In a particular embodiment of the invention, the amorphous form is characterized by a glass transition temperature Tg of 60 ℃ to 70 ℃, particularly 65 ℃ to 67 ℃, most particularly 66 ℃.
Furthermore, (1, 1-dioxo-1. lamda.) with advantageous properties was found in the present invention6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]A 1: 1 inclusion complex of-pyridin-3-yl } -methanone with gamma-cyclodextrin (gamma-CD inclusion complex). The gamma-CD inclusion complex is highly crystalline (as confirmed by XRPD). The dried γ -CD inclusion complex was found to contain a residual water content of about 7.3% (as confirmed by TGA). It was found that the dried gamma-CD inclusion complex and the wet powder sample showed different XRPD patterns. The crystal structure of the gamma-CD complex appears to correlate with the water content of the sample. Water appears to stabilize the crystal structure of the inclusion complex, and a substantial loss of water may result in a change in crystal structure. Inclusion complexes of γ -CD including residual water were found to have improved solubility in water compared to dry inclusion complexes of γ -CD [ t.toropainen et al, pharm.res. (2007) 24: 1058-1066]. The molar ratio between API and gamma-CD in the gamma-CD inclusion complex was found to be 1: 1 (as confirmed by UPLC). 510.4M was calculated for the inclusion complex of a compound of formula (I) and gamma-CD as described herein-1Complex binding constant of (2). The binding constant and in vitro dissolution profile show increased dissolution rates and thus improved bioavailability compared to other solid forms (fig. 21)&22)。
A particular embodiment of the invention relates to (1, 1-dioxo-1. lamda. as described herein6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]1: 1 inclusion complex of (E) -pyridin-3-yl } -methanone with gamma-cyclodextrin (I)γ-CDInclusion complex)。
A particular embodiment of the invention relates to (1, 1-dioxo-1. lamda. as described herein6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-a 1: 1 inclusion complex of pyridin-3-yl } -methanone with gamma-cyclodextrin (gamma-CD inclusion complex) comprising a residual water content of 1% to 20% (w/w), in particular 5% to 15% (w/w), most in particular 8% to 12% (w/w).
In a particular embodiment of the invention, form E is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 7.4 °, 14.9 °, 16.7 °, 21.8 °.
In a particular embodiment of the invention, form E is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 θ of about 7.4 °, 12.1 °, 14.9 °, 16.7 °, 21.8 °.
In a particular embodiment of the invention, form E is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles 2 Θ of about 3.8 °, 5.2 °, 7.4 °, 9.2 °, 10.6 °, 11.5 °, 11.8 °, 12.1 °, 14.2 °, 14.9 °, 15.8 °, 16.7 °, 19.2 °, 20.3 °, 21.2 °, 21.8 °, 22.5 °, 23.7 °, 26.8 °.
In a particular embodiment of the invention, the γ -CD inclusion complex is characterized by the XRPD diffraction pattern of FIG. 7.
In a particular embodiment of the invention, the γ -CD inclusion complex is characterized by an XRPD diffraction pattern comprising XRPD peaks at peak positions as given in table 7.
In a particular embodiment of the invention, the γ -CD inclusion complex is characterized by the FTIR spectrum of FIG. 13.
In a particular embodiment of the invention, the γ -CD inclusion complex is characterized by the raman spectrum of fig. 19.
Table 1 shows (1, 1-dioxo-1. lamda.)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-relevant crystal structure data for form a, form B, form C and form D of pyridin-3-yl } -methanone. Refining the crystal structures of form a, form B, form C and form D. Form E crystallizes only under dry conditions and at relative humidity>With 5% rehydration, single crystal samples were not available.
The lattice constant, unit cell volume and calculated density are based on ambient temperature data. For this purpose, the lattice constants obtained from the single crystal structure analysis were refined with the experimental environmental conditions XRPD reference pattern using the software TOPAS4.0, BrukerAXS.
Watch (A)1: form(s) ofA、B、CAndDsingle crystal structure data of
*Ambient temperature data
Watch (A)2、3And4: form(s) ofA、BAndCis/are as followsXRPDPeak position and mainXRPDRelative intensity of the peaks.
*The relative intensity may vary significantly from one measurement to another.
Watch (A)5、6And7: form(s) ofD、EAnd gamma-CDInclusion complexIs/are as followsXRPDPeak position and mainXRPDRelative intensity of the peaks.
*The relative intensity may vary significantly from one measurement to another.
The present invention also relates to a distillative solvent exchange process for the preparation of a solid form of a compound of formula (I) as defined above, said process comprising:
a) dissolving the educt solid form in a solvent;
b) distilling the solvent while keeping the reactor level constant by replacing the distillate with the anti-solvent;
c) the desired solid form is physically separated from the suspension.
In a particular embodiment, crystalline (1, 1-dioxo-1. lamda. -is obtained in the desired form as defined above for anhydrous polymorph C (form C) by this distillative solvent exchange in step C)6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanone.
In a particular embodiment, the educt solid form in step a) is selected from form a or form B, most particularly from form B.
In a particular embodiment, the solvent employed in step a) is selected from THF, DMF or acetone or a mixture thereof, in particular from THF.
In a particular embodiment, the anti-solvent employed in step b) is selected from ethanol, isopropanol or n-heptane or mixtures thereof, in particular from ethanol.
In a particular embodiment, step b) is carried out at elevated temperature, in particular at from 50 to 80 ℃.
In a particular embodiment, step b) is carried out at reduced pressure, in particular at 100-300 mbar.
In a particular embodiment, step b) is optionally performed or completed by seeding as powder or suspension with the desired solid form, most particularly with 1-10% (w/w) (relative to the final yield) of the desired solid form.
In a particular embodiment, the physical separation in step c) is performed via filtration.
The present invention also relates to a high shear process for the preparation of a solid form of a compound of formula (I) as defined above, said process comprising:
d) injecting a solution of the educt solid form in a solvent into a high shear mixer comprising an anti-solvent;
e) stirring the rotor-stator system of the high shear mixer;
f) the desired solid form is physically separated from the suspension.
In a particular embodiment, the desired solid form obtained by the high shear process in step f) is crystalline (1, 1-dioxo-1. lamda. -1. mu. dioxo-C) of anhydrous polymorph C (form C) as described above6-thiomorpholin-4-yl) - {6- [3- (4-fluoro-phenyl) -5-methyl-iso-cycloAzol-4-ylmethoxy]-pyridin-3-yl } -methanone.
In a particular embodiment, the educt solid form in step d) is selected from form a or form B, in particular from form B.
In a particular embodiment, the solution of the educt in solid form in step d) is injected at a constant flow rate of 1.6 g/min.
In a particular embodiment, the solvent employed in step d) is selected from THF, DMF or acetone or a mixture thereof, in particular from THF.
In a particular embodiment, the anti-solvent employed in step d) is selected from ethanol, isopropanol or n-heptane or mixtures thereof, in particular from n-heptane.
In a particular embodiment, the antisolvent is circulated through the high shear mixer in steps d) and e) at a constant rate, in particular at a constant rate of 20 l/h.
In a particular embodiment, the anti-solvent of step d) optionally comprises seed particles in the desired solid form, in particular seed particles in the desired solid form in the range of 1-10% (w/w) (relative to the final yield), most in particular seed particles in the desired solid form in the range of 5-10% (w/w) (relative to the final yield).
In a particular embodiment, the rotor-stator system in step e) is rotated at a rotation rate of 15000RPM to 24000 RPM.
In a particular embodiment, steps d) and e) are carried out at reduced temperatures, in particular at-20 ℃ to 0 ℃, most particularly at-5 ℃.
In a particular embodiment, the physical separation in step f) is performed via filtration.
Another embodiment provides a pharmaceutical composition or medicament comprising a solid form of a compound of formula (I) as described herein and pharmaceutically acceptable excipients, and methods of using the compounds of the invention for the preparation of such compositions and medicaments.
The compositions are formulated, dosed and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the procedure of administration and other factors known to the practitioner.
The solid forms of the compounds of formula (I) as described herein may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, dermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathoracic and epidural and intranasal, and, if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.
The solid form of the compound of formula (I) as described herein may be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, ointments and the like. Such compositions may contain ingredients in conventional pharmaceutical preparations, for example, diluents, carriers, pH modifying agents, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents, antioxidants and other active agents. They may also contain still other therapeutically valuable substances.
Typical formulations are prepared by mixing a solid form of a compound of formula (I) as described herein and a pharmaceutically acceptable excipient. Suitable excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C., et al, Ansel's pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; gennaro a.r. et al Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and RoweR.C, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, aromas, diluents, and other known additives to provide an elegant appearance to the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., a drug).
The dosage of the solid forms of the compounds of formula (I) as described herein that can be administered may vary within wide limits and is of course adjusted in each particular case to suit the individual requirements. Generally, in the case of oral administration, a daily dosage of about 0.1 to 1000mg per person of a solid form of a compound of formula (I) as described herein should be suitable, although the above upper limit may also be exceeded when desired. Particular embodiments of the present invention relate to daily doses of 0.1 to 1000mg (p.o.), particularly 10 to 500mg (p.o.), most particularly 75 to 350mg (p.o.).
An example of a suitable oral pharmaceutical dosage form is a solid form tablet containing from about 100mg to 500mg of a compound of formula (I) as described herein, admixed with from about 90 to 30mg of anhydrous lactose, from about 5 to 40mg of croscarmellose sodium, from about 5 to 30mg of polyvinylpyrrolidone (PVP) K30, and from about 1 to 10mg of magnesium stearate. The ingredients of the powder are first mixed together and then mixed with a solution of PVP. The resulting composition may be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment.
An example of an aerosol formulation may be prepared by dissolving a solid form of a compound of formula (I) as described herein, for example 10 to 100mg, in a suitable buffer solution, for example a phosphate buffer solution, and if necessary adding an isotonicity agent, for example a salt such as sodium chloride. The solution may be filtered, for example, using a 0.2 μm filter, to remove impurities and contaminants.
Solid forms of the compounds of formula (I) as described herein possess valuable pharmacological properties and are found to be ligands for the GABAA α 5 receptor. The solid forms of the compounds of formula (I) of the invention can therefore be used, either alone or in combination with other medicaments, for the treatment or prevention of diseases which are modulated by ligands for the GABAA receptor containing the α 5 subunit. These diseases include, but are not limited to: acute and/or chronic neurological disorders (acute and/or chronic neurological disorders), cognitive disorders (cognitive disorders), Alzheimer's disease, memory deficits (memory deficits), schizophrenia (schizophrenia), positive, negative and/or cognitive symptoms associated with schizophrenia (positive, negative and/or cognitive aspects), bipolar disorders (bipolar disorders), autism (autism), Down syndrome, neurofibromatosis type I (neurofibromatosis type I), sleep disorders (sleep disorders), disorders (rhythm of cognitive disorders), amyotrophic lateral sclerosis (amyotrophic lateral sclerosis) (AIDS), dementia induced by psychotropic disorders (AIDS), generalized anxiety disorder (systemic disorder), panic disorder (systemic disorder), delusional disorder (delusional disorder), obsessive/complex disorder), acute stress disorder (acute stress disorder), drug addiction (drug addictions), movement disorder (kinetic disorders), Parkinson's disease (Parkinson's disease), restless leg Syndrome (stress Syndrome), cognitive impairment (cognitive impairment disorders), multi-infarct dementia (multi-infarct impairment), mood disorder (mood disorder), depression (depression), neuropsychiatric disorder (neuropsychiatric conditions), psychosis (psychosis), attention deficit/hyperactivity disorder (Fetal depression/Multiple Sclerosis), neuroleptic disorder (acute neuroleptic disorder), neuroleptic disorder (neuroleptic disorder), the development of CNS disorders (CNS conditions after stroke), and the need for cognitive enhancement.
The present invention therefore also relates to a pharmaceutical composition comprising a solid form of a compound of formula (I) as described herein and a pharmaceutically acceptable excipient.
The invention also includes solid forms of the compounds of formula (I) as described herein for use as therapeutically active substances.
The invention also encompasses solid forms of the compounds of formula (I) as described herein for use as therapeutically active substances for the treatment or prevention of diseases related to the GABA a α 5 receptor.
The invention likewise comprises solid forms of compounds of formula (I) as described herein for use as therapeutically active substances for acute and/or chronic neurological disorders, cognitive disorders, alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, Amyotrophic Lateral Sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addiction, movement disorders, parkinson's disease, restless leg syndrome, cognitive deficits, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, the treatment or prevention of psychosis, attention deficit/hyperactivity disorder, neuropathic pain, stroke, Multiple Sclerosis (MS), acute meningitis, fetal alcohol syndrome, and attention deficit disorder, for use in stroke recovery therapy, or for use as a cognitive enhancer.
In another embodiment, the invention relates to a method for the treatment or prevention of diseases related to the gaba a α 5 receptor comprising administering a solid form of the compound of formula (I) as described herein to a human being or animal.
In another embodiment, the invention relates to a method for treating acute and/or chronic neurological disorders, cognitive disorders, alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorder, autism, down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, Amyotrophic Lateral Sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addictions, movement disorders, parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke, a method for the treatment or prevention of Multiple Sclerosis (MS), acute meningitis, fetal alcohol syndrome, and attention disorders, for stroke recovery therapy, or for cognitive enhancement, comprising administering a compound of formula (I), particularly a solid form of a compound of formula (I) as described herein, to a human or animal.
The invention also includes the use of a solid form of a compound of formula (I) as described herein for the treatment or prevention of diseases associated with the gaba a α 5 receptor.
The invention also encompasses the use of a solid form of a compound of formula (I) as described herein for the treatment of acute and/or chronic neurological disorders, cognitive disorders, alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, Amyotrophic Lateral Sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addictions, movement disorders, parkinson's disease, restless leg syndrome, cognitive deficits, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention deficit/hyperactivity disorder, use of neuropathic pain, stroke, Multiple Sclerosis (MS), acute meningitis, fetal alcohol syndrome, and attention disorders for the treatment or prevention, or for cognitive enhancement.
The present invention also relates to the use of a solid form of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of diseases related to the GABA a α 5 receptor, in particular for acute and/or chronic neurological disorders, cognitive disorders, alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, Amyotrophic Lateral Sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive compulsive disorder, acute stress disorder, drug addiction, movement disorders, parkinson's disease, restless leg syndrome, cognitive deficits, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke, Multiple Sclerosis (MS), acute meningitis, fetal alcohol syndrome, and attention-deficit disorder, for the treatment or prevention of stroke recovery, or for the preparation of cognitive enhancing drugs. Such medicaments comprise a compound as described above.
More specifically, the present invention relates to the use of a solid form of a compound of formula (I) as described herein for the treatment, prevention and/or delay of progression of a CNS disorder caused by a neurodevelopmental defect resulting in excessive GABAergic inhibition in the cortex and hippocampus, wherein said CNS disorder is selected from the group consisting of down syndrome, autism, cognitive deficits in neurofibromatosis type I, or cognitive deficits after stroke.
The treatment or prevention of cognitive disorders, alzheimer's disease, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, down's syndrome and neurofibromatosis type I are particular embodiments of the present invention.
Particular embodiments of the invention include the treatment or prevention of alzheimer's disease.
Particular embodiments of the invention include the treatment or prevention of Down syndrome.
Particular embodiments of the present invention include the treatment or prevention of type I neurofibromatosis.
Particular embodiments of the invention include recovery after stroke.