WO2024074986A1 - Solid state form of ecopipam hydrobromide salt - Google Patents
Solid state form of ecopipam hydrobromide salt Download PDFInfo
- Publication number
- WO2024074986A1 WO2024074986A1 PCT/IB2023/059866 IB2023059866W WO2024074986A1 WO 2024074986 A1 WO2024074986 A1 WO 2024074986A1 IB 2023059866 W IB2023059866 W IB 2023059866W WO 2024074986 A1 WO2024074986 A1 WO 2024074986A1
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- WO
- WIPO (PCT)
- Prior art keywords
- ecopipam
- hbr
- theta
- crystalline
- degrees
- Prior art date
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- 239000007787 solid Substances 0.000 title claims abstract description 46
- GAUWIDFICGEZKR-JUOYHRLASA-N (6as,13br)-11-chloro-7-methyl-5,6,6a,8,9,13b-hexahydronaphtho[1,2-a][3]benzazepin-12-ol;hydrobromide Chemical class Br.CN1CCC2=CC(Cl)=C(O)C=C2[C@H]2C3=CC=CC=C3CC[C@H]12 GAUWIDFICGEZKR-JUOYHRLASA-N 0.000 title description 2
- DMJWENQHWZZWDF-PKOBYXMFSA-N (6aS,13bR)-11-chloro-7-methyl-5,6,6a,8,9,13b-hexahydronaphtho[1,2-a][3]benzazepin-12-ol Chemical compound CN1CCC2=CC(Cl)=C(O)C=C2[C@H]2C3=CC=CC=C3CC[C@H]12 DMJWENQHWZZWDF-PKOBYXMFSA-N 0.000 claims abstract description 222
- 229950009714 ecopipam Drugs 0.000 claims abstract description 220
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 326
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
Definitions
- the present disclosure encompasses Ecopipam HBr, particularly crystalline Ecopipam HBr, or a solid state form of Ecopipam HBr.
- Ecopipam is developed for the treatment of Tourette Syndrome (TS) in pediatric patients and for childhood onset fluency disorder (also known as stuttering) in adults and potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
- TS Tourette Syndrome
- RLSa Restless Legs Syndrome with augmentation
- Polymorphism the occurrence of different crystalline forms, is a property of some molecules and molecular complexes.
- a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state ( 13 C) NMR spectrum.
- TGA thermogravimetric analysis
- DSC differential scanning calorimetry
- XRD X-ray diffraction
- 13 C solid state
- Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
- New solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
- New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Ecopipam.
- the present disclosure provides a crystalline polymorph of Ecopipam HBr.
- the crystalline form can be used to prepare other solid state forms of Ecopipam or Ecopipam salts.
- the present disclosure also provides uses of said solid state form of Ecopipam HBr in the preparation of other solid state forms of Ecopipam or Ecopipam salts.
- the present disclosure provides said crystalline form of Ecopipam HBr for use in medicine, including for the treatment of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
- TS Tourette Syndrome
- RLSa Restless Legs Syndrome with augmentation
- the present disclosure also encompasses the use of said crystalline polymorph of Ecopipam HBr for the preparation of pharmaceutical compositions and/or formulations.
- the present disclosure provides pharmaceutical compositions comprising said crystalline polymorph of Ecopipam HBr according to the present disclosure.
- the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining said crystalline polymorph of Ecopipam HBr with at least one pharmaceutically acceptable excipient.
- the crystalline polymorph of Ecopipam HBr as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Ecopipam HBr may be used as medicaments, such as for the treatment of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
- TS Tourette Syndrome
- RLSa Restless Legs Syndrome with augmentation
- the present disclosure also provides methods for the treatment of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa) by administering a therapeutically effective amount of said crystalline polymorph of Ecopipam HBr of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa) or otherwise in need of the treatment.
- TS Tourette Syndrome
- childhood onset fluency disorder also known as stuttering
- RLSa Restless Legs Syndrome with augmentation
- the present disclosure also provides uses of crystalline polymorph of Ecopipam HBr of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
- TS Tourette Syndrome
- RLSa Restless Legs Syndrome with augmentation
- Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Ecopipam HBr Form A.
- Figure 2 shows a characteristic FTIR spectrum of Ecopipam HBr Form A.
- Figure 3 A shows a photograph of a compressed pellet of Ecopipam HC1.
- Figure 3B shows a photograph of a compressed pellet of Ecopipam HBr. DETAILED DESCRIPTION OF THE DISCLOSURE
- the present disclosure encompasses Ecopipam HBr, which is optionally crystalline, or a crystalline form of Ecopipam HBr, processes for preparation thereof, and pharmaceutical compositions thereof.
- Solid state properties of Ecopipam HBr and crystalline polymorphs thereof can be influenced by controlling the conditions under which Ecopipam HBr and crystalline polymorphs thereof are obtained in solid form.
- the crystalline Ecopipam HBr or solid state forms of Ecopipam HBr as described in any aspect or embodiment of the present disclosure may be polymorphically pure, or substantially free of any other solid state (or polymorphic) forms.
- a solid state form may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms.
- the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD.
- polymorphically pure Ecopipam HBr Form A means that the solid state form is substantially free of other solid state forms of Ecopipam HBr.
- a crystalline polymorph of Ecopipam HBr described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Ecopipam HBr.
- the described crystalline polymorph of Ecopipam HBr, salt or cocrystal may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of the same Ecopipam HBr.
- Ecopipam HBr of the present disclosure may have advantageous properties over Ecopipam free base or Ecopipam salts, selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, stability, such as chemical stability as well as thermal and mechanical, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.
- the crystalline polymorphs of Ecopipam HBr of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.
- Ecopipam HBr particularly crystalline Ecopipam HBr, or crystalline Form A of Ecopipam HBr as described in any aspect or embodiment of the present disclosure, may exhibit improved solubility, improved compatibility properties or improved compressibility properties.
- a solid state form such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure.
- Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
- the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone.
- a crystal form of Ecopipam HBr referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Ecopipam HBr characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
- anhydrous in relation to crystalline Ecopipam HBr, or crystalline forms of Ecopipam HBr relates to crystalline Ecopipam HBr or a crystalline form of Ecopipam HBr which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal.
- an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.
- solvate refers to a crystalline product or a crystal form that incorporates a solvent in the crystal structure.
- the solvent is water, the solvate is often referred to as a "hydrate.”
- the solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
- the term "isolated" in reference to Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr of the present disclosure corresponds to Ecopipam HBr, particularly crystalline Ecopipam HBr, or a crystalline polymorph of Ecopipam HBr, respectively, that is physically separated from the reaction mixture in which it is formed.
- the XRPD measurements are taken using copper K a radiation wavelength 1.54184 A.
- a thing e.g., a reaction mixture
- room temperature or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located.
- room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
- the amount of solvent employed in a chemical process may be referred to herein as a number of “volumes” or “vol” or “V.”
- a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
- this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
- v/v may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.
- a process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.
- reduced pressure refers to a pressure that is less than atmospheric pressure.
- reduced pressure is about 10 mbar to about 50 mbar.
- ambient conditions refer to atmospheric pressure and a temperature of 22-24°C.
- the Ecopipam HBr particularly crystalline Ecopipam HBr, or solid state form of Ecopipam HBr as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.
- a compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds.
- chemically pure or purified or “substantially free of any other compounds” refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers.
- a chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w/w) or less, about 5% (w/w) or less, about 4% (w/w) or less, about 3% (w/w) or less, about 2% (w/w) or less, about 1.5% (w/w) or less, about 1% (w/w) or less, about 0.8% (w/w) or less, about 0.6% (w/w) or less, about 0.4% (w/w) or less, about 0.2% (w/w) or less, about 0.1% (w/w) or less, or about 0% of any other compound as measured, for example, by HPLC.
- a chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent or less, about 0.2% area percent or less, about 0.1% area percent or less, or about 0% of any other compound as measured by HPLC.
- pure or purified Ecopipam HBr described herein as substantially free of any compounds would be understood to contain greater than about 90% (w/w), greater than about 95% (w/w), greater than about 96% (w/w), greater than about 97% (w/w), greater than about 98% (w/w), greater than about 98.5% (w/w), greater than about 99% (w/w), greater than about 99.2% (w/w), greater than about 99.4% (w/w), greater than about 99.6% (w/w), greater than about 99.8% (w/w), greater than about 99.9% (w/w), or about 100% of the subject Ecopipam HBr.
- pure or purified Ecopipam HBr described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2% area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% area percent, greater than about 99.9% area percent, or about 100% of the subject Ecopipam HBr.
- the present disclosure encompasses Ecopipam HBr.
- the Ecopipam HBr is preferably in a solid form, and more preferably the Ecopipam HBr is crystalline.
- Ecopipam HBr may be isolated.
- Ecopipam HBr according to any aspect or embodiment may be chemically pure.
- Crystalline Ecopipam HBr according to any aspect or embodiment may be polymorphically pure (i.e.
- Ecopipam HBr containing a single crystalline form of Ecopipam HBr), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Ecopipam HBr, as measured, for example, by XRPD.
- Ecopipam HBr may be anhydrous.
- the present disclosure includes a crystalline polymorph Ecopipam HBr designated Form A.
- the crystalline Form A of Ecopipam HBr may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 14.7, 18.9 and 21.3 degrees 2-theta ⁇ 0.2 degrees 2-theta; a FTIR spectrum having peaks at 3122, 2653, 887 and 672 ⁇ 4 cm’ 1 ; a FUR spectrum substantially as depicted in Figure 2; and combinations of these data.
- Crystalline Form A of Ecopipam HBr may be further characterized by an X-ray powder diffraction pattern having peaks at 14.7, 18.9 and 21.3 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having any one or both additional peaks selected 11.1 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form A of Ecopipam HBr may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form A of Ecopipam HBr may be further characterized by an X-ray powder diffraction pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 11.9, 16.5, 19.4, 20.6 and 25.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form A of Ecopipam HBr may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 11.1, 11.9, 14.7, 16.5, 18.9, 19.4, 20.6, 21.3, 22.8 and 25.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form A of Ecopipam HBr may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 0 to 10.5 degrees 2-theta ⁇ 0.2 degrees 2-theta, 0.5 to 10 degrees ⁇ 0.2 degrees 2-theta, 2.0 to 8.0 degrees 2-theta.
- crystalline Form A of Ecopipam HBr may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 15.2 to 16.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form A of Ecopipam HBr may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and also having an absence of peaks at: 17.0 to 18.4 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form A of Ecopipam HBr may be characterized by an X-ray powder diffraction pattern having peaks at 14.7, 18.9 and 21.3 degrees 2-theta ⁇ 0.2 degrees 2-theta optionally with one or both additional peaks selected from: 11.1 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; or an X-ray powder diffraction pattern having peaks at: 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta, optionally having one, two, three, four or five of the peaks at: 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; or an X-ray powder diffraction pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta, wherein in each case, the X-ray powder diffraction pattern
- crystalline Form A of Ecopipam HBr may be isolated.
- crystalline Form A of Ecopipam HBr according to any aspect or embodiment of the disclosure may be isolated.
- crystalline Form A of Ecopipam HBr may be polymorphically pure.
- crystalline Form A of Ecopipam HBr may be anhydrous.
- Crystalline Form A of Ecopipam HBr may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.
- Ecopipam HBr may be prepared by reacting Ecopipam with hydrobromic acid or hydrogen bromide gas in any suitable solvent or mixture of solvents.
- the solvent or mixture of solvents is preferably selected at least enable dissolution of Ecopipam and/or hydrobromic acid or hydrogen bromide gas, and preferably enables precipitation of the resulting Ecopipam HBr (e.g. through one cooling and/or antisolvent addition and/or evaporation, particularly through cooling, evaporation, or through antisolvent addition optionally with cooling).
- the present disclosure encompasses a process for preparing Form A of Ecopipam HBr as defined in any aspect or embodiment described herein.
- Form A of Ecopipam HBr may be prepared by a process comprising crystallising Ecopipam HBr from one or more organic solvents and/or water.
- Form A of Ecopipam HBr according to any aspect or embodiment of the disclosure may be prepared by a process comprising crystallising Ecopipam HBr from one or more organic solvents, optionally in a mixture with water.
- the process for preparing Form A of Ecopipam HBr may comprise: (a) providing a solution comprising Ecopipam HBr in a solvent, wherein the solvent comprises one or more organic solvents and/or water, and (b) crystallising Form A of Ecopipam HBr from the solution.
- the crystallising step (b) may comprise one or more of evaporation or partial evaporation, cooling and/or addition of antisolvent.
- the crystallising comprises cooling and/or addition of antisolvent.
- step (b) may comprise cooling the mixture or allowing the mixture to cool, and maintaining the mixture, optionally with stirring, until crystallisation occurs.
- the mixture may be maintained at a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C; or at about 48°C).
- step (b) may comprise cooling the mixture, or allowing the mixture to cool, preferably to a temperature of: about 10°C to about 30°C, about 15°C to about 28°C, about 18°C to about 25°C, or about 20°C to about 22°C, or about room temperature.
- the mixture may be maintained at the cooled temperature, preferably for period of: about 1 hour to about 72 hours, about 4 hours to about 48 hours, about 10 hours to about 36 hours, or about 24 hours.
- the solution of Ecopipam HBr in step (a) may be prepared by combining Ecopipam base with hydrobromic acid or hydrogen bromide gas, (preferably wherein the hydrogen bromide gas is in a solution in an organic solvent) in one or more organic solvents and/or water, to form a solution.
- step (a) according to any embodiment of the process may comprise preparing a solution or suspension of Ecopipam base in one or more organic solvents and/or water, and combining the solution or suspension with the hydrobromic acid or hydrogen bromide gas.
- the hydrobromic acid or hydrogen bromide gas is added to the solution or suspension of Ecopipam base.
- the Ecopipam base is provided as a suspension in one or more organic solvents and/or water; more particularly, the Ecopipam base is in a suspension of one or more organic solvents.
- the solution or suspension of Ecopipam base in the one or more organic solvents and/or water may be heated, optionally to a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C.
- the hydrobromic acid or hydrogen bromide gas is added to the, preferably heated solution or suspension, of Ecopipam base, in an amount of about 2.5 to about 1 molar equivalents, about 2 to about 1 molar equivalents, or about 1 molar equivalent.
- the hydrobromic acid or hydrogen bromide gas (wherein preferably the hydrogen bromide gas is dissolved in an organic solvent) may be added to the heated solution or suspension of Ecopipam base.
- hydrobromic acid is used, preferably concentrated (about 47%) aqueous hydrobromic acid is used.
- the solution comprising Ecopipam HBr in step (a) is prepared by combining a solution or suspension of Ecopipam base in one or more organic solvents and/or water, with hydrobromic acid, preferably concentrated (about 47%) hydrobromic acid.
- step (a) comprises combining Ecopipam base in one or more organic solvents and/or water, to form a suspension, heating to a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C, and adding concentrated hydrobromic acid to form a solution.
- the one or more organic solvents may be selected from the group consisting of: alcohols, ethers, and ketones.
- the organic solvent may be selected from the group consisting of: Ci to Ce alcohols, C4 to Cs ethers, and C3 to Cs ketones; preferably wherein the organic solvent is selected from the group consisting of: Ci to C3 alcohols, C4 to Ce ethers, and C3 to Ce ketones; and more preferably wherein the organic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, diethylether, tetrahydrofuran, tert-butylmethylether, acetone, and methylethylketone.
- the organic solvent is selected from the group consisting of: methanol, tert-butylmethylether, and acetone.
- Form A of Ecopipam HBr may be prepared by crystallising Ecopipam HBr in a solvent selected from the group consisting of methanol, tert-butylmethylether, acetone and water, or a mixture thereof, more particularly wherein the solvent is selected from either: a mixture of methanol and tert- butylmethylether and water; or a mixture of acetone and water.
- Form A of Ecopipam HBr may be prepared by a process comprising crystallizing Ecopipam HBr methanol and t-butyl methyl ether and water.
- the Ecopipam HBr may be prepared by a process comprising: combining Ecopipam base in a mixture of methanol and tert- butylmethylether (optionally at a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C; and preferably at about 48°C), and combining with hydrobromic acid (preferably concentrated hydrobromic acid.
- the methanol and tert-butylmethylether may be in a volume ratio of: about 2: 1 to about 1:4, about 1.5: 1 to about 1 :3, about 1.2:1 to about 1:2.5, or about 1 :2.
- the methanol and tert-butylmethyl ether may be used in a concentration of: about 2 ml to about 15 ml, about 3 ml to about 12 ml, or about 4.5 ml to about 11 ml, or about 4.5 ml to about 5 ml, per gram of Ecopipam free base.
- step (b) may comprise cooling the mixture or allowing the mixture to cool, and maintaining the mixture, optionally with stirring, until crystallisation occurs.
- a mixture of methanol and tert-butylmethylether preferably in the same volume ratio as used for suspending or dissolving the Ecopipam free base, and as discussed above
- step (b) may comprise maintaining the mixture for a period of: about 10 minutes to about 24 hours, about 30 minutes to about 12 hours, about 30 minutes to about 4 hours, about 60 minutes.
- the mixture may be maintained at a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C; and preferably at about 48°C).
- the mixture may be cooled, preferably to a temperature of: about 10°C to about 30°C, about 15°C to about 28°C, about 18°C to about 25°C, or about 20°C to about 22°C, or about room temperature.
- the mixture may be maintained at this temperature, preferably for period of: about 1 hour to about 72 hours, about 4 hours to about 48 hours, about 10 hours to about 36 hours, or about 24 hours.
- Form A of Ecopipam HBr may be isolated by any suitable method such as by filtration, centrifuge or decantation, preferably by filtration.
- the Form A of Ecopipam HBr may be dried for a suitable time period, optionally under reduced pressure, and optionally at a temperature about 30°C to about 75°C, about 35°C to about 70°C, about 40°C to about 65°C, about 45°C to about 60°C, or about 45°C to about 55°C; and preferably at about 50°C).
- Form A of Ecopipam HBr may be prepared by a process comprising crystallizing Ecopipam HBr from a solvent mixture of acetone and water.
- the Ecopipam HBr may be prepared by a process comprising: combining Ecopipam base in a mixture of acetone and water (optionally at a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C), and combining with hydrobromic acid (preferably concentrated hydrobromic acid.
- the acetone and water may be in a volume ratio of: about 20: 1 to about 1:5, about 15: 1 to about 1:2, about 12: 1 to about 1:2, or about 10:1.
- the acetone and water may be used in a concentration of: about 2 ml to about 16 ml, about 5 ml to about 14 ml, or about 8 ml to about 12 ml, or about 10 ml, per gram of Ecopipam free base.
- the mixture may be cooled or allowed to cool and maintained, optionally with stirring, until crystallisation occurs.
- the mixture is cooled, preferably to a temperature of: about 10°C to about 30°C, about 15°C to about 28°C, about 18°C to about 25°C, or about 20°C to about 22°C, or about room temperature.
- the mixture may be maintained for a period of: about 1 hour to about 72 hours, about 4 hours to about 48 hours, about 10 hours to about 36 hours, or about 24 hours at the cooled temperature.
- Form A of Ecopipam HBr may be isolated by any suitable method such as by filtration, centrifuge or decantation, preferably by filtration.
- the Form A of Ecopipam HBr may be dried for a suitable time period, optionally under reduced pressure, and optionally at a temperature about 30°C to about 75°C, about 35°C to about 70°C, about 40°C to about 65°C, about 45°C to about 60°C, or about 45°C to about 55°C; and preferably at about 50°C).
- the present disclosure further encompasses a process for preparation of Form A of Ecopipam HBr wherein the process comprises:
- hydrobromic acid or hydrogen bromide gas preferably hydrobromic acid and more preferably concentrated hydrobromic acid
- organic solvents optionally adding one or more organic solvents and/or water, preferably wherein the organic solvents are selected from: alcohols, ethers, or ketones, optionally at the elevated temperature;
- the solvents used in step (i) and step (iii) may optionally be selected from to the following: alcohols (preferably selected from: Ci to C4 alcohols, and particularly methanol, ethanol, propano- l-ol, propan-2-ol, butan-l-ol, and butan-2-ol); ethers (preferably C-ito Ce ethers, and particularly 2-Methoxy-2-methylpropane, tetrahydrofuran, 2-methyloxolane, ethoxyethane, 1 -butoxybutane, 2-[(propan-2-yl)oxy]propane; and ketones [preferably C3 to Ce ketones, and particularly propan-2-one (i.e. acetone), butan-2-one, 4-methylpentan-2-one]; and water.
- alcohols preferably selected from: Ci to C4 alcohols, and particularly methanol, ethanol, propano- l-ol, propan-2-ol, butan-l-ol
- Ecopipam in step (i) is provided in a mixture of methanol and tertbutyl methyl ether. Preferably it is provided in a 1:2 mixture (v/v) of methanol and tert-butyl methyl ether.
- the mixture of solvents may be present in an amount of about 2 to about 10 ml of Ecopipam base, preferably about 3 to about 6 ml of Ecopipam base.
- Ecopipam in step (i), is provided in a mixture of acetone and water. Preferably it is provided in a 10: 1 (v/v) mixture of acetone and water.
- the mixture of solvents may be present in an amount of about 5 to about 20 ml of Ecopipam base, preferably about 7 to about 15 ml of Ecopipam base, most preferably about 10 to about 12 ml of Ecopipam base.
- Steps (i), (ii) and (iii) may be carried out at a temperature of about 40°C to about 80°C, about 45°C to about 75°C, about 50°C to about 70°C or about 55°C to about 65°C.
- the process for preparing Form A of Ecopipam HBr may be dried under reduced pressure, preferably at a temperature of: about 20°C to about 60°C, about 30°C to about 55°C, or about 40°C to about 55°C, or about 50°C for a suitable period of time.
- the drying may be carried out over a period of about 4 hours to about 24 hours, about 6 hours to about 18 hours, or about 10 hours.
- the processes according to any aspects or embodiments of the disclosure may further comprise combining the Ecopipam HBr, crystalline Ecopipam HBr or crystalline Form A of Ecopipam HBr with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition or formulation.
- the present disclosure encompasses processes for preparing Ecopipam HBr, particularly crystalline Ecopipam HBr, or solid state forms of Ecopipam, Ecopipam HBr or other Ecopipam salts.
- the process includes preparing the Ecopipam HBr, particularly crystalline Ecopipam HBr, or solid state form of Ecopipam HBr described herein and converting that product or that form to a different form of Ecopipam, Ecopipam HBr or other Ecopipam salts.
- the conversion may be done, for example, by a process comprising basifying the Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline form of Ecopipam HBr described herein to obtain Ecopipam base.
- the obtained base may be further reacted with an appropriate acid to obtain the corresponding salt.
- the conversion can be done by salt switching, i.e., reacting any of the Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline form of Ecopipam HBr of the present disclosure with an acid having a pKa which is lower than that of the acid of the original salt.
- the present disclosure provides the above described Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr for use in the preparation of pharmaceutical compositions comprising Ecopipam HBr and/or solid state forms thereof.
- the present disclosure also encompasses the use of Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph of Ecopipam HBr and/or solid state forms thereof.
- the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions.
- the processes include combining any one or a combination of the Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr of the present disclosure with at least one pharmaceutically acceptable excipient.
- compositions of the present disclosure contain any one or a combination of the Ecopipam HBr, particularly crystalline Ecopipam HBr, or solid state form of Ecopipam HBr of the present disclosure.
- the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
- Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle.
- Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
- microcrystalline cellulose e.g., Avicel®
- microfine cellulose lactose
- starch pregelatinized starch
- calcium carbonate calcium sulfate
- sugar dextrates
- Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
- Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g.
- Methocel® liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.
- povidone e.g. Kollidon®, Plasdone®
- pregelatinized starch sodium alginate, and starch.
- the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition.
- Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.
- alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplas
- Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
- Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
- a dosage form such as a tablet is made by the compaction of a powdered composition
- the composition is subjected to pressure from a punch and dye.
- Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
- a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
- Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
- Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
- Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
- Ecopipam HBr and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
- Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
- Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
- Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
- a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.
- Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
- Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.
- a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
- the solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions.
- the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral.
- the dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
- Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
- the dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell.
- the shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.
- compositions and dosage forms can be formulated into compositions and dosage forms according to methods known in the art.
- a composition for tableting or capsule filling can be prepared by wet granulation.
- wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules.
- the granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size.
- the granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
- a tableting composition can be prepared conventionally by dry blending.
- the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.
- a blended composition can be compressed directly into a compacted dosage form using direct compression techniques.
- Direct compression produces a more uniform tablet without granules.
- Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
- a capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.
- a pharmaceutical formulation of Ecopipam HBr, particularly crystalline Ecopipam HBr, or Ecopipam HBr can be administered.
- Ecopipam HBr may be formulated for administration to a mammal, in embodiments to a human, by injection.
- Ecopipam HBr can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection.
- the formulation can contain one or more solvents.
- a suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity.
- Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
- the Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr and the pharmaceutical compositions and/or formulations of Ecopipam HBr of the present disclosure can be used as medicaments, in embodiments for the treatment of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
- TS Tourette Syndrome
- RLSa Restless Legs Syndrome with augmentation
- the present disclosure also provides methods of treating of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa) by administering a therapeutically effective amount of any one or a combination of the Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorphs of Ecopipam HBr of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.
- TS Tourette Syndrome
- RLSa Restless Legs Syndrome with augmentation
- Sample is powdered in a mortar and pestle and applied directly on a silicon plate holder.
- FTIR Fourier-transform infrared spectroscopy
- FTIR spectra were recorded on a Nicolet 6700 interferometer between 4000 cm-1 and 650 cm-1 with resolution of 4 cm-1, in ATR technique.
- Ecopipam can be prepared according to methods known from the literature, for example according to the disclosure in WO 95/09156 or the disclosure in J. Med. Chem. 1989, 32, 1913-1921.
- Ecopipam base form 1 (1.0 gram) was suspended in acetone: water (10: 1, 10 mL) at 50 °C and stirred for 20 minutes. 47% hydrobromic acid solution (0.75 mL) was added to the suspension and clear solution was obtained. Heating was discontinued and crystallization occurred during cooling at 40°C. The suspension was cooled to room temperature and stirred for 1 day. The solid was isolated by vacuum filtration over the black ribbon filter paper and dried at 50°C and 10 mbar for 10 hours. The solid was analyzed by XRPD and identified as Ecopipam HBr Form A.
- Ecopipam base (0.5 grams) was suspended in methanol: tert-methyl butyl ether (1:2, 3 mL) at 50 °C and stirred for 30 minutes. 47% hydrobromic acid aqueous solution (0.24 mL) was added to the reaction mixture and clear solution was obtained. After a few seconds precipitate was formed. Heating was discontinued, solution was cooled to room temperature and stirred for 1 day. Solid was isolated by vacuum filtration over the black ribbon filter paper and Ecopipam HBr Form A was obtained.
- Ecopipam HBr has better compressibility with CDI > 7.0 than Ecopipam HC1 with CDI ⁇ 5.0. Accordingly, Ecopipam HBr has a significantly greater compressibility than Ecopipam HBr and hence is advantageous powder formulation for the production of compressed formulations such as tablets.
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Abstract
The present disclosure encompasses Ecopipam HBr, particularly crystalline Ecopipam HBr, or a solid state form of Ecopipam HBr.
Description
SOLID STATE FORM OF ECOPIPAM HYDROBROMIDE SALT
FIELD OF THE DISCLOSURE
[0001] The present disclosure encompasses Ecopipam HBr, particularly crystalline Ecopipam HBr, or a solid state form of Ecopipam HBr.
BACKGROUND OF THE DISCLOSURE
[0002] Ecopipam, (6oc ,13pR)-l l-chloro-7-methyl-5,6,6a,8,9,13b-hexahydronaphtho[l,2- a][3]benzazepin-12-ol, has the following chemical structure:
[0003] Ecopipam is developed for the treatment of Tourette Syndrome (TS) in pediatric patients and for childhood onset fluency disorder (also known as stuttering) in adults and potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
[0004] The compound is described in International Publication No. WO 95/09156 and in J. Med. Chem. 32. 1989, 1913-1921. Ecopipam HC1 is described in U.S. Patent No. 6,875,866 and in Organic Process Research & Development 2004, 8, 754-768. Crystalline forms of Ecopipam and Ecopipam HC1 are disclosed in IPCOM000270653 and IPCOM000270652.
[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the
dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Ecopipam.
SUMMARY OF THE DISCLOSURE
[0008] The present disclosure provides a crystalline polymorph of Ecopipam HBr. The crystalline form can be used to prepare other solid state forms of Ecopipam or Ecopipam salts. [0009] The present disclosure also provides uses of said solid state form of Ecopipam HBr in the preparation of other solid state forms of Ecopipam or Ecopipam salts.
[0010] The present disclosure provides said crystalline form of Ecopipam HBr for use in medicine, including for the treatment of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
[0011] The present disclosure also encompasses the use of said crystalline polymorph of Ecopipam HBr for the preparation of pharmaceutical compositions and/or formulations.
[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising said crystalline polymorph of Ecopipam HBr according to the present disclosure.
[0013] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining said crystalline polymorph of Ecopipam HBr with at least one pharmaceutically acceptable excipient.
[0014] The crystalline polymorph of Ecopipam HBr as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Ecopipam HBr may be used as medicaments, such as for the treatment of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
[0015] The present disclosure also provides methods for the treatment of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa) by administering a therapeutically effective amount of said crystalline polymorph of Ecopipam HBr of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa) or otherwise in need of the treatment.
[0016] The present disclosure also provides uses of crystalline polymorph of Ecopipam HBr of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
BRIEF DESCRIPTION OE THE DRAWINGS
[0017] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Ecopipam HBr Form A.
[0018] Figure 2 shows a characteristic FTIR spectrum of Ecopipam HBr Form A.
[0019] Figure 3 A shows a photograph of a compressed pellet of Ecopipam HC1.
[0020] Figure 3B shows a photograph of a compressed pellet of Ecopipam HBr.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0021] The present disclosure encompasses Ecopipam HBr, which is optionally crystalline, or a crystalline form of Ecopipam HBr, processes for preparation thereof, and pharmaceutical compositions thereof.
[0022] Solid state properties of Ecopipam HBr and crystalline polymorphs thereof can be influenced by controlling the conditions under which Ecopipam HBr and crystalline polymorphs thereof are obtained in solid form.
[0023] The crystalline Ecopipam HBr or solid state forms of Ecopipam HBr as described in any aspect or embodiment of the present disclosure may be polymorphically pure, or substantially free of any other solid state (or polymorphic) forms.
[0024] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. For example, polymorphically pure Ecopipam HBr Form A means that the solid state form is substantially free of other solid state forms of Ecopipam HBr. Thus, a crystalline polymorph of Ecopipam HBr described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Ecopipam HBr. In some embodiments of the disclosure, the described crystalline polymorph of Ecopipam HBr, salt or cocrystal may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of the same Ecopipam HBr.
[0025] Ecopipam HBr of the present disclosure, and particularly crystalline Ecopipam HBr, may have advantageous properties over Ecopipam free base or Ecopipam salts, selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, stability, such as chemical stability as well as thermal and mechanical, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk
density. Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Ecopipam HBr of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density. Particularly, Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline Form A of Ecopipam HBr as described in any aspect or embodiment of the present disclosure, may exhibit improved solubility, improved compatibility properties or improved compressibility properties.
[0026] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Ecopipam HBr referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Ecopipam HBr characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
[0027] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline Ecopipam HBr, or crystalline forms of Ecopipam HBr relates to crystalline Ecopipam HBr or a crystalline form of Ecopipam HBr which does not include any crystalline water (or
other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.
[0028] The term "solvate," as used herein and unless indicated otherwise, refers to a crystalline product or a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
[0029] As used herein, the term "isolated" in reference to Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr of the present disclosure corresponds to Ecopipam HBr, particularly crystalline Ecopipam HBr, or a crystalline polymorph of Ecopipam HBr, respectively, that is physically separated from the reaction mixture in which it is formed.
[0030] As used herein, unless stated otherwise, the XRPD measurements are taken using copper K a radiation wavelength 1.54184 A. XRPD peaks reported herein are optionally measured using CuK a radiation, X = 1.54184 A, typically at a temperature of 25 ± 3°C.
[0031] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
[0032] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.
[0033] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.
[0034] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar. [0035] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.
[0036] The Ecopipam HBr, particularly crystalline Ecopipam HBr, or solid state form of Ecopipam HBr as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.
[0037] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein, the terms "chemically pure" or "purified" or "substantially free of any other compounds" refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers. A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w/w) or less, about 5% (w/w) or less, about 4% (w/w) or less, about 3% (w/w) or less, about 2% (w/w) or less, about 1.5% (w/w) or less, about 1% (w/w) or less, about 0.8% (w/w) or less, about 0.6% (w/w) or less, about 0.4% (w/w) or less, about 0.2% (w/w) or less, about 0.1% (w/w) or less, or about 0% of any other compound as measured, for example, by HPLC. Alternatively, a chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent or less, about 0.2% area percent or less, about 0.1% area percent or less, or about 0% of any other compound as measured by HPLC.
[0038] Thus, pure or purified Ecopipam HBr described herein as substantially free of any compounds would be understood to contain greater than about 90% (w/w), greater than about 95% (w/w), greater than about 96% (w/w), greater than about 97% (w/w), greater than about
98% (w/w), greater than about 98.5% (w/w), greater than about 99% (w/w), greater than about 99.2% (w/w), greater than about 99.4% (w/w), greater than about 99.6% (w/w), greater than about 99.8% (w/w), greater than about 99.9% (w/w), or about 100% of the subject Ecopipam HBr. Alternatively, pure or purified Ecopipam HBr described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2% area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% area percent, greater than about 99.9% area percent, or about 100% of the subject Ecopipam HBr.
[0039] The present disclosure encompasses Ecopipam HBr. In any aspect or embodiment, the Ecopipam HBr is preferably in a solid form, and more preferably the Ecopipam HBr is crystalline. In any aspect or embodiment of the present disclosure, Ecopipam HBr may be isolated. Particularly, Ecopipam HBr according to any aspect or embodiment may be chemically pure. Crystalline Ecopipam HBr according to any aspect or embodiment may be polymorphically pure (i.e. containing a single crystalline form of Ecopipam HBr), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Ecopipam HBr, as measured, for example, by XRPD. In any aspect or embodiment of the present disclosure, Ecopipam HBr may be anhydrous.
[0040] The present disclosure includes a crystalline polymorph Ecopipam HBr designated Form A. The crystalline Form A of Ecopipam HBr may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 14.7, 18.9 and 21.3 degrees 2-theta ± 0.2 degrees 2-theta; a FTIR spectrum having peaks at 3122, 2653, 887 and 672 ± 4 cm’1; a FUR spectrum substantially as depicted in Figure 2; and combinations of these data.
[0041] Crystalline Form A of Ecopipam HBr may be further characterized by an X-ray powder diffraction pattern having peaks at 14.7, 18.9 and 21.3 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one or both additional peaks selected 11.1 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta.
[0042] Crystalline Form A of Ecopipam HBr may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta.
[0043] Crystalline Form A of Ecopipam HBr may be further characterized by an X-ray powder diffraction pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 11.9, 16.5, 19.4, 20.6 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.
[0044] Crystalline Form A of Ecopipam HBr may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 11.1, 11.9, 14.7, 16.5, 18.9, 19.4, 20.6, 21.3, 22.8 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.
[0045] In any aspect or embodiment of the present disclosure, crystalline Form A of Ecopipam HBr may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 0 to 10.5 degrees 2-theta ± 0.2 degrees 2-theta, 0.5 to 10 degrees ± 0.2 degrees 2-theta, 2.0 to 8.0 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form A of Ecopipam HBr may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and wherein the X-ray powder diffraction pattern also has an absence of peaks at: 15.2 to 16.0 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, according to aspect or embodiment of the present disclosure, crystalline Form A of Ecopipam HBr may be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, and also having an absence of peaks at: 17.0 to 18.4 degrees 2-theta ± 0.2 degrees 2-theta.
[0046] In any aspect of aspect or embodiment of the present disclosure, crystalline Form A of Ecopipam HBr may be characterized by an X-ray powder diffraction pattern having peaks at 14.7, 18.9 and 21.3 degrees 2-theta ± 0.2 degrees 2-theta optionally with one or both additional peaks selected from: 11.1 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta; or an X-ray powder diffraction pattern having peaks at: 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta, optionally having one, two, three, four or five of the peaks at: 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta; or an X-ray powder diffraction pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta, wherein in each case, the
X-ray powder diffraction pattern also has an absence of peaks at any one, two or three of: 0 to 10.5 degrees 2-theta ± 0.2 degrees 2-theta, or 15.2 to 16.0 degrees 2-theta ± 0.2 degrees 2-theta, or 17.0 to 18.4 degrees 2-theta ± 0.2 degrees 2-theta.
[0047] In any aspect or embodiment of the present disclosure, crystalline Form A of Ecopipam HBr may be isolated. Particularly, crystalline Form A of Ecopipam HBr according to any aspect or embodiment of the disclosure may be isolated.
[0048] In any aspect or embodiment crystalline Form A of Ecopipam HBr may be polymorphically pure.
[0049] In any aspect or embodiment of the present disclosure, crystalline Form A of Ecopipam HBr may be anhydrous.
[0050] Crystalline Form A of Ecopipam HBr may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.
[0051] Ecopipam HBr according to any aspect or embodiment may be prepared by reacting Ecopipam with hydrobromic acid or hydrogen bromide gas in any suitable solvent or mixture of solvents. The solvent or mixture of solvents is preferably selected at least enable dissolution of Ecopipam and/or hydrobromic acid or hydrogen bromide gas, and preferably enables precipitation of the resulting Ecopipam HBr (e.g. through one cooling and/or antisolvent addition and/or evaporation, particularly through cooling, evaporation, or through antisolvent addition optionally with cooling).
[0052] The present disclosure encompasses a process for preparing Form A of Ecopipam HBr as defined in any aspect or embodiment described herein.
[0053] Form A of Ecopipam HBr according to any aspect or embodiment of the disclosure may be prepared by a process comprising crystallising Ecopipam HBr from one or more organic solvents and/or water. Preferably, Form A of Ecopipam HBr according to any aspect or embodiment of the disclosure may be prepared by a process comprising crystallising Ecopipam HBr from one or more organic solvents, optionally in a mixture with water. The process for preparing Form A of Ecopipam HBr according to any aspect or embodiment of the disclosure, may comprise: (a) providing a solution comprising Ecopipam HBr in a solvent, wherein the solvent comprises one or more organic solvents and/or water, and (b) crystallising Form A of
Ecopipam HBr from the solution. The crystallising step (b) may comprise one or more of evaporation or partial evaporation, cooling and/or addition of antisolvent. Preferably the crystallising comprises cooling and/or addition of antisolvent. In any embodiment of the process, step (b) may comprise cooling the mixture or allowing the mixture to cool, and maintaining the mixture, optionally with stirring, until crystallisation occurs. According to any embodiment, the mixture may be maintained at a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C; or at about 48°C). Alternatively, or additionally, step (b) may comprise cooling the mixture, or allowing the mixture to cool, preferably to a temperature of: about 10°C to about 30°C, about 15°C to about 28°C, about 18°C to about 25°C, or about 20°C to about 22°C, or about room temperature. The mixture may be maintained at the cooled temperature, preferably for period of: about 1 hour to about 72 hours, about 4 hours to about 48 hours, about 10 hours to about 36 hours, or about 24 hours.
[0054] According to any aspect or embodiment of the process, the solution of Ecopipam HBr in step (a) may be prepared by combining Ecopipam base with hydrobromic acid or hydrogen bromide gas, (preferably wherein the hydrogen bromide gas is in a solution in an organic solvent) in one or more organic solvents and/or water, to form a solution. Particularly, step (a) according to any embodiment of the process may comprise preparing a solution or suspension of Ecopipam base in one or more organic solvents and/or water, and combining the solution or suspension with the hydrobromic acid or hydrogen bromide gas. Preferably, the hydrobromic acid or hydrogen bromide gas is added to the solution or suspension of Ecopipam base. According to any embodiment of the process, the Ecopipam base is provided as a suspension in one or more organic solvents and/or water; more particularly, the Ecopipam base is in a suspension of one or more organic solvents. The solution or suspension of Ecopipam base in the one or more organic solvents and/or water may be heated, optionally to a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C. According to any embodiment of the process, the hydrobromic acid or hydrogen bromide gas is added to the, preferably heated solution or suspension, of Ecopipam base, in an amount of about 2.5 to about 1 molar equivalents, about 2 to about 1 molar equivalents, or about 1 molar equivalent. The hydrobromic acid or hydrogen bromide gas (wherein preferably the hydrogen bromide gas is dissolved in an organic solvent)
may be added to the heated solution or suspension of Ecopipam base. According to any embodiment of the process, hydrobromic acid is used, preferably concentrated (about 47%) aqueous hydrobromic acid is used. Preferably, according to any aspect or embodiment of the process, the solution comprising Ecopipam HBr in step (a) is prepared by combining a solution or suspension of Ecopipam base in one or more organic solvents and/or water, with hydrobromic acid, preferably concentrated (about 47%) hydrobromic acid. More preferably, according to any aspect or embodiment of the process, step (a) comprises combining Ecopipam base in one or more organic solvents and/or water, to form a suspension, heating to a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C, and adding concentrated hydrobromic acid to form a solution.
[0055] According to any aspect or embodiment of the process, the one or more organic solvents may be selected from the group consisting of: alcohols, ethers, and ketones. Particularly, the organic solvent may be selected from the group consisting of: Ci to Ce alcohols, C4 to Cs ethers, and C3 to Cs ketones; preferably wherein the organic solvent is selected from the group consisting of: Ci to C3 alcohols, C4 to Ce ethers, and C3 to Ce ketones; and more preferably wherein the organic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, diethylether, tetrahydrofuran, tert-butylmethylether, acetone, and methylethylketone. Particularly, according to any aspect or embodiment of the process, the organic solvent is selected from the group consisting of: methanol, tert-butylmethylether, and acetone. According to any aspect or embodiment of the disclosed process, Form A of Ecopipam HBr may be prepared by crystallising Ecopipam HBr in a solvent selected from the group consisting of methanol, tert-butylmethylether, acetone and water, or a mixture thereof, more particularly wherein the solvent is selected from either: a mixture of methanol and tert- butylmethylether and water; or a mixture of acetone and water.
[0056] According to any aspect or embodiment, Form A of Ecopipam HBr may be prepared by a process comprising crystallizing Ecopipam HBr methanol and t-butyl methyl ether and water. According to any embodiment of this process, the Ecopipam HBr may be prepared by a process comprising: combining Ecopipam base in a mixture of methanol and tert- butylmethylether (optionally at a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C; and
preferably at about 48°C), and combining with hydrobromic acid (preferably concentrated hydrobromic acid. The methanol and tert-butylmethylether may be in a volume ratio of: about 2: 1 to about 1:4, about 1.5: 1 to about 1 :3, about 1.2:1 to about 1:2.5, or about 1 :2. The methanol and tert-butylmethyl ether may be used in a concentration of: about 2 ml to about 15 ml, about 3 ml to about 12 ml, or about 4.5 ml to about 11 ml, or about 4.5 ml to about 5 ml, per gram of Ecopipam free base.
[0057] In any embodiment of the process, step (b) may comprise cooling the mixture or allowing the mixture to cool, and maintaining the mixture, optionally with stirring, until crystallisation occurs. Optionally, a mixture of methanol and tert-butylmethylether (preferably in the same volume ratio as used for suspending or dissolving the Ecopipam free base, and as discussed above) may be added. In any embodiment of the process, step (b) may comprise maintaining the mixture for a period of: about 10 minutes to about 24 hours, about 30 minutes to about 12 hours, about 30 minutes to about 4 hours, about 60 minutes. According to any embodiment, the mixture may be maintained at a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C; and preferably at about 48°C). Alternatively, or additionally, after the addition of hydrobromic acid, the mixture may be cooled, preferably to a temperature of: about 10°C to about 30°C, about 15°C to about 28°C, about 18°C to about 25°C, or about 20°C to about 22°C, or about room temperature. The mixture may be maintained at this temperature, preferably for period of: about 1 hour to about 72 hours, about 4 hours to about 48 hours, about 10 hours to about 36 hours, or about 24 hours. Form A of Ecopipam HBr may be isolated by any suitable method such as by filtration, centrifuge or decantation, preferably by filtration. The Form A of Ecopipam HBr may be dried for a suitable time period, optionally under reduced pressure, and optionally at a temperature about 30°C to about 75°C, about 35°C to about 70°C, about 40°C to about 65°C, about 45°C to about 60°C, or about 45°C to about 55°C; and preferably at about 50°C).
[0058] According to any aspect or embodiment, Form A of Ecopipam HBr may be prepared by a process comprising crystallizing Ecopipam HBr from a solvent mixture of acetone and water. According to any embodiment of this process, the Ecopipam HBr may be prepared by a process comprising: combining Ecopipam base in a mixture of acetone and water (optionally at a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C,
about 45°C to about 55°C, or about 50°C), and combining with hydrobromic acid (preferably concentrated hydrobromic acid. The acetone and water may be in a volume ratio of: about 20: 1 to about 1:5, about 15: 1 to about 1:2, about 12: 1 to about 1:2, or about 10:1. The acetone and water may be used in a concentration of: about 2 ml to about 16 ml, about 5 ml to about 14 ml, or about 8 ml to about 12 ml, or about 10 ml, per gram of Ecopipam free base. After the addition of the hydrobromic acid/hydrogen bromide, the mixture may be cooled or allowed to cool and maintained, optionally with stirring, until crystallisation occurs. Preferably, the mixture is cooled, preferably to a temperature of: about 10°C to about 30°C, about 15°C to about 28°C, about 18°C to about 25°C, or about 20°C to about 22°C, or about room temperature. According to any embodiment, the mixture may be maintained for a period of: about 1 hour to about 72 hours, about 4 hours to about 48 hours, about 10 hours to about 36 hours, or about 24 hours at the cooled temperature. Form A of Ecopipam HBr may be isolated by any suitable method such as by filtration, centrifuge or decantation, preferably by filtration. The Form A of Ecopipam HBr may be dried for a suitable time period, optionally under reduced pressure, and optionally at a temperature about 30°C to about 75°C, about 35°C to about 70°C, about 40°C to about 65°C, about 45°C to about 60°C, or about 45°C to about 55°C; and preferably at about 50°C).
[0059] In another aspect, the present disclosure further encompasses a process for preparation of Form A of Ecopipam HBr wherein the process comprises:
(i) providing Ecopipam in one or more organic solvents, preferably wherein the organic solvents are selected from: alcohols, ethers, ketone solvents; and/or water, or a mixture thereof, optionally at elevated temperature (preferably at a temperature of: about 30°C to about 70°C, about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 48°C to 50°C);
(ii) adding hydrobromic acid or hydrogen bromide gas, preferably hydrobromic acid and more preferably concentrated hydrobromic acid;
(iii) optionally adding one or more organic solvents and/or water, preferably wherein the organic solvents are selected from: alcohols, ethers, or ketones, optionally at the elevated temperature;
(iv) optionally cooling the reaction mixture; and
(v) optionally isolating Form A of Ecopipam HBr.
[0060] The solvents used in step (i) and step (iii) may optionally be selected from to the following: alcohols (preferably selected from: Ci to C4 alcohols, and particularly methanol, ethanol, propano- l-ol, propan-2-ol, butan-l-ol, and butan-2-ol); ethers (preferably C-ito Ce ethers, and particularly 2-Methoxy-2-methylpropane, tetrahydrofuran, 2-methyloxolane, ethoxyethane, 1 -butoxybutane, 2-[(propan-2-yl)oxy]propane; and ketones [preferably C3 to Ce ketones, and particularly propan-2-one (i.e. acetone), butan-2-one, 4-methylpentan-2-one]; and water.
[0061] In embodiments, in step (i) Ecopipam is provided in a mixture of methanol and tertbutyl methyl ether. Preferably it is provided in a 1:2 mixture (v/v) of methanol and tert-butyl methyl ether. The mixture of solvents may be present in an amount of about 2 to about 10 ml of Ecopipam base, preferably about 3 to about 6 ml of Ecopipam base.
[0062] In other embodiments, in step (i), Ecopipam is provided in a mixture of acetone and water. Preferably it is provided in a 10: 1 (v/v) mixture of acetone and water. The mixture of solvents may be present in an amount of about 5 to about 20 ml of Ecopipam base, preferably about 7 to about 15 ml of Ecopipam base, most preferably about 10 to about 12 ml of Ecopipam base.
[0063] Steps (i), (ii) and (iii) may be carried out at a temperature of about 40°C to about 80°C, about 45°C to about 75°C, about 50°C to about 70°C or about 55°C to about 65°C.
[0064] According to any embodiment, the process for preparing Form A of Ecopipam HBr, may be dried under reduced pressure, preferably at a temperature of: about 20°C to about 60°C, about 30°C to about 55°C, or about 40°C to about 55°C, or about 50°C for a suitable period of time. For example, the drying may be carried out over a period of about 4 hours to about 24 hours, about 6 hours to about 18 hours, or about 10 hours.
[0065] The processes according to any aspects or embodiments of the disclosure may further comprise combining the Ecopipam HBr, crystalline Ecopipam HBr or crystalline Form A of Ecopipam HBr with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition or formulation.
[0066] The present disclosure encompasses processes for preparing Ecopipam HBr, particularly crystalline Ecopipam HBr, or solid state forms of Ecopipam, Ecopipam HBr or other Ecopipam salts. The process includes preparing the Ecopipam HBr, particularly crystalline Ecopipam HBr, or solid state form of Ecopipam HBr described herein and converting that
product or that form to a different form of Ecopipam, Ecopipam HBr or other Ecopipam salts. The conversion may be done, for example, by a process comprising basifying the Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline form of Ecopipam HBr described herein to obtain Ecopipam base. The obtained base may be further reacted with an appropriate acid to obtain the corresponding salt. Alternatively, the conversion can be done by salt switching, i.e., reacting any of the Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline form of Ecopipam HBr of the present disclosure with an acid having a pKa which is lower than that of the acid of the original salt.
[0067] The present disclosure provides the above described Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr for use in the preparation of pharmaceutical compositions comprising Ecopipam HBr and/or solid state forms thereof. [0068] The present disclosure also encompasses the use of Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph of Ecopipam HBr and/or solid state forms thereof.
[0069] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr of the present disclosure with at least one pharmaceutically acceptable excipient.
[0070] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the Ecopipam HBr, particularly crystalline Ecopipam HBr, or solid state form of Ecopipam HBr of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
[0071] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol,
polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
[0072] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.
[0073] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.
[0074] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
[0075] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
[0076] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be
included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
[0077] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
[0078] In liquid pharmaceutical compositions of the present invention, Ecopipam HBr and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
[0079] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
[0080] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.
[0081] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
[0082] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.
[0083] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
[0084] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
[0085] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [0086] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.
[0087] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.
[0088] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
[0089] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.
[0090] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct
compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
[0091] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.
[0092] A pharmaceutical formulation of Ecopipam HBr, particularly crystalline Ecopipam HBr, or Ecopipam HBr can be administered. Ecopipam HBr may be formulated for administration to a mammal, in embodiments to a human, by injection. Ecopipam HBr can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
[0093] The Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorph of Ecopipam HBr and the pharmaceutical compositions and/or formulations of Ecopipam HBr of the present disclosure can be used as medicaments, in embodiments for the treatment of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa).
[0094] The present disclosure also provides methods of treating of patients with Tourette Syndrome (TS) in pediatric patients, and for childhood onset fluency disorder (also known as stuttering) in adults, and/or potentially for the treatment of Restless Legs Syndrome with augmentation (RLSa) by administering a therapeutically effective amount of any one or a combination of the Ecopipam HBr, particularly crystalline Ecopipam HBr, or crystalline polymorphs of Ecopipam HBr of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.
[0095] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the
disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.
Powder X-ray Diffraction ("XRPD") method
[0096] Sample is powdered in a mortar and pestle and applied directly on a silicon plate holder. The X-ray powder diffraction pattern was measured with Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.54184 A (Angstrom), X’Celerator (2.022° 20) detector. Scanning parameters: angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuous scan.
[0097] The described peak positions were determined without using silicon powder as an internal standard in an admixture with the sample measured.
Fourier-transform infrared spectroscopy ("FTIR")
[0098] FTIR spectra were recorded on a Nicolet 6700 interferometer between 4000 cm-1 and 650 cm-1 with resolution of 4 cm-1, in ATR technique.
EXAMPLES
Preparation of starting materials
[0099] Ecopipam can be prepared according to methods known from the literature, for example according to the disclosure in WO 95/09156 or the disclosure in J. Med. Chem. 1989, 32, 1913-1921.
Example 1: Preparation of Ecopipam HBr crystalline Form A
Procedure A
[00100] Ecopipam base (1.02 grams; 3.25 mmol) was suspended in methanol: tert-methyl butyl ether (1:2, 5 mL) at 48 °C and stirred for 30 minutes. 47% hydrobromic acid solution (0.75 mL; 6.48 mmol) was added to the reaction mixture and clear solution was obtained. After a few seconds precipitate was formed. Additional methanol : tert-methyl butyl ether (1:2, 5 mL) was added and the mixture was stirred for 60 minutes. Heating was discontinued, solution was cooled to room temperature and stirred for 1 day. Solid was isolated by vacuum filtration over the black ribbon filter paper and dried at 50°C and 10 mbar for 10 hours. Solid was analyzed by XRPD and Ecopipam HBr Form A was obtained. The XRPD pattern is presented in Figure 1.
Procedure B
[00101] Ecopipam base form 1 (1.0 gram) was suspended in acetone: water (10: 1, 10 mL) at 50 °C and stirred for 20 minutes. 47% hydrobromic acid solution (0.75 mL) was added to the suspension and clear solution was obtained. Heating was discontinued and crystallization occurred during cooling at 40°C. The suspension was cooled to room temperature and stirred for 1 day. The solid was isolated by vacuum filtration over the black ribbon filter paper and dried at 50°C and 10 mbar for 10 hours. The solid was analyzed by XRPD and identified as Ecopipam HBr Form A.
Procedure C
[00102] Ecopipam base (0.5 grams) was suspended in methanol: tert-methyl butyl ether (1:2, 3 mL) at 50 °C and stirred for 30 minutes. 47% hydrobromic acid aqueous solution (0.24 mL) was added to the reaction mixture and clear solution was obtained. After a few seconds precipitate was formed. Heating was discontinued, solution was cooled to room temperature and stirred for 1 day. Solid was isolated by vacuum filtration over the black ribbon filter paper and Ecopipam HBr Form A was obtained.
Example 2: Stability of Ecopipam HBr
(A) Tablet Formation
[00103] A sample of Ecopipam HBr was pressed into a pellet on a tablet press (Specac® manual hydraulic press) under a pressure of 1 ton for 1 minute. The resulting pellet was uniform in shape, and had a high structural order, showing no delamination or breaking. In contrast, a sample of Ecopipam HC1 was pressed on the tablet press under the same conditions. The surface of the resulting pellet delaminated, and the pellet broke. The results are depicted in the photographs in Figure 3A (Ecopipam HC1) and Figure 3B (Ecopipam HBr).
(B) Compressibility
[00104] The packing density of powders of Ecopipam HBr and Ecopipam HC1 were determined as compression profiles under low pressures using a die and a flat-faced punch fitted on a TA-XTplus Texture analyser (Stable Micro Systems Ltd., Godaiming, UK). 200 mg ± 2 mg of a sample of the drug was compressed in a steel mould (rate of displacement 0.03 mm/s). A cyclic procedure (similar to tapping) was performed in 10 compressive force steps of in 1
increments of 1 kg, force relaxation for 10 s, then retracting to zero, and then repeated compressive steps (altogether up to 10 steps). The resulting compression profile data acquired in the low pressure range (< 5 MPa) enabled analysis of the texture and determination of the compressed density index (CDI) (Table 1).
able 1
[00105] According to texture analysis and the CDI data in Table 1, Ecopipam HBr has better compressibility with CDI > 7.0 than Ecopipam HC1 with CDI < 5.0. Accordingly, Ecopipam HBr has a significantly greater compressibility than Ecopipam HBr and hence is advantageous powder formulation for the production of compressed formulations such as tablets.
Claims
1. Ecopipam HBr, preferably in solid form, and more preferably crystalline Ecopipam HBr.
2. A crystalline form of Ecopipam HBr designated Form A according to Claim 1, which is characterized by data selected from:
(a) an X-ray powder diffraction pattern having peaks at 14.7, 18.9 and 21.3 degrees 2- theta ± 0.2 degrees 2-theta;
(b) an X-ray powder diffraction pattern substantially as depicted in Figure 1;
(c) a FTIR spectrum having peaks at 3122, 2653, 887 and 672 ± 4 cm'1;
(d) an FTIR spectrum substantially as depicted in Figure 2; and
(e) a combination of (a), (b), (c) and (d).
3. A crystalline form of Ecopipam HBr according to Claim 1 or Claim 2, which is characterized by an X-ray powder diffraction pattern having peaks at 14.7, 18.9 and 21.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one or both additional peaks selected 11.1 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta.
4. A crystalline form of Ecopipam HBr according to any of Claims 1, 2 or 3, which is characterized by an X-ray powder diffraction pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta.
5. A crystalline form of Ecopipam HBr according to any of claims 1, 2. 3, or 4, which is characterized by an X-ray powder diffraction pattern having peaks at 11.1, 14.7, 18.9, 21.3 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta and also having one, two, three, four or five additional peaks selected from 11.9, 16.5, 19.4, 20.6 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.
6. A crystalline form of Ecopipam HBr according to any one of claims 1, 2, 3, 4, or5, which is characterized by an X-ray powder diffraction pattern having peaks at 11.1, 11.9, 14.7, 16.5, 18.9, 19.4, 20.6, 21.3, 22.8 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.
7. A crystalline product according to any one of claims 1-6, wherein the crystalline product is anhydrous.
8. A crystalline product according to any preceding claims, which is isolated.
9. A crystalline product according to any preceding claims, which is polymorphically pure; preferably wherein the crystalline product contains: about 20% (w/w) or less, about 10%
(w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline forms of the same compound, and/or wherein the crystalline product contains: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any amorphous forms of the same compound. Use of crystalline product according to any preceding claim for the preparation of other crystalline polymorphs of Ecopipam, Ecopipam salts, or Ecopipam co-crystals; or as an intermediate for the purification of Ecopipam, Ecopipam salts, or Ecopipam co-crystals. Use of crystalline product according to any of claims 1 to 9, for the preparation of pharmaceutical compositions comprising Ecopipam or Ecopipam salts, or Ecopipam cocrystals and/or crystalline polymorphs thereof. A pharmaceutical composition or formulation comprising a crystalline product according to any of Claims 1 to 9, and at least one pharmaceutically acceptable excipient, optionally in the form of a solid dosage form, particularly a capsule or tablet, and more preferably a tablet. A process preparing a pharmaceutical composition or formulation according to Claim 12, comprising combining a crystalline product according to any of Claims 1 to 9 with at least one pharmaceutically acceptable excipient. A crystalline product to any of Claims 1 to 9, or a pharmaceutical composition or formulation according to Claim 12, for use as a medicament. A crystalline product according to any of Claims 1 to 9, or a pharmaceutical composition or formulation according to Claim 12, for use in the treatment of Tourette Syndrome (TS) in pediatric patients, childhood onset fluency disorder in adults, and/or for the treatment of Restless Legs Syndrome with augmentation (RLSa). A method of treating Tourette Syndrome (TS) in pediatric patients, childhood onset fluency disorder in adults, and/or for the treatment of Restless Legs Syndrome with augmentation (RLSa) comprising administering a therapeutically effective amount of the crystalline product according to any of Claims 1 to 9, or a pharmaceutical composition or formulation according to Claim 12, to a subject in need of the treatment.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995009156A1 (en) | 1993-09-27 | 1995-04-06 | Schering Corporation | Processes and intermediates for the enantiospecific synthesis of benzo(d)naphth(2.1-b)azepines |
WO1995009154A1 (en) * | 1993-09-27 | 1995-04-06 | Schering Corporation | Processes and intermediates for the enantiospecific synthesis of benzo(d)naphth(2,1-b)azepines |
US6875866B2 (en) | 2002-02-21 | 2005-04-05 | Schering Corporation | Process for synthesis of D1 receptor antagonists |
-
2023
- 2023-10-02 WO PCT/IB2023/059866 patent/WO2024074986A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995009156A1 (en) | 1993-09-27 | 1995-04-06 | Schering Corporation | Processes and intermediates for the enantiospecific synthesis of benzo(d)naphth(2.1-b)azepines |
WO1995009154A1 (en) * | 1993-09-27 | 1995-04-06 | Schering Corporation | Processes and intermediates for the enantiospecific synthesis of benzo(d)naphth(2,1-b)azepines |
US6875866B2 (en) | 2002-02-21 | 2005-04-05 | Schering Corporation | Process for synthesis of D1 receptor antagonists |
Non-Patent Citations (4)
Title |
---|
ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems" |
J. MED. CHEM., vol. 32, 1989, pages 1913 - 1921 |
ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 8, 2004, pages 754 - 768 |
SAUMEN HAJRA ET AL: "Catalytic enantioselective synthesis of the dopamine D1 antagonist ecopipam", TETRAHEDRON ASYMMETRY, PERGAMON PRESS LTD, OXFORD, GB, vol. 23, no. 2, 31 January 2012 (2012-01-31), pages 151 - 156, XP008166308, ISSN: 0957-4166, [retrieved on 20120216], DOI: 10.1016/J.TETASY.2012.01.017 * |
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