WO2020139670A1 - Formes à l'état solide de balovaptan - Google Patents

Formes à l'état solide de balovaptan Download PDF

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Publication number
WO2020139670A1
WO2020139670A1 PCT/US2019/067314 US2019067314W WO2020139670A1 WO 2020139670 A1 WO2020139670 A1 WO 2020139670A1 US 2019067314 W US2019067314 W US 2019067314W WO 2020139670 A1 WO2020139670 A1 WO 2020139670A1
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Prior art keywords
balovaptan
solvent
theta
crystalline form
process according
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PCT/US2019/067314
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English (en)
Inventor
Anantha Rajmohan MUTHUSAMY
Sundara Lakshmi Kanniah
Amit Singh
Siva Rama Krishna MUPPALLA
Amol Gulab KHATIK
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Teva Pharmaceuticals International Gmbh
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2020139670A1 publication Critical patent/WO2020139670A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present disclosure relates to solid state forms of Balovaptan, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof
  • Balovaptan has the chemical name trans-8-Chloro-5-methyl-l-[4-(pyridin-2-yloxy)- cyclohexyl]-5,6-dihydro-4H— 2,3,5,10B-tetraaza-benzo[E]azulene.
  • Balovaptan has the following chemical structure:
  • Balovaptan acts as a Vasopressin la receptor antagonist and is disclosed in international patent application W02010060836.
  • Activity of Via receptor antagonists are known to be useful for treatment of various conditions such as, dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, anxiety, schizophrenia, depressive disorder, obsessive compulsive disorder.
  • Balovaptan is being developed by Roche for the treatment of autistic spectrum disorders (ASD).
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single compound like Balovaptan, 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 powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state ( 13 C-) NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • XRPD X-ray powder diffraction
  • Different solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different 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 use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.
  • Discovering new solid state forms and solvates of a pharmaceutical product can provide 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 polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.
  • the present disclosure relates to solid state forms of Balovaptan.
  • the present disclosure also relates to processes for preparation thereof, and to pharmaceutical compositions comprising the solid state forms of Balovaptan.
  • the present disclosure provides crystalline forms of Balovaptan designated as Forms BT1, BT2, BT3, BT4, BT5 and BT6 (defined herein).
  • the present disclosure further provides process for preparing Balovaptan and solid state forms thereof.
  • the present disclosure also provides use of the said solid state forms of Balovaptan in the preparation of other solid state forms of Balovaptan.
  • the present disclosure also provides the said solid state forms of Balovaptan for use in the preparation of other solid state forms of Balovaptan. [0014] In another embodiment, the present disclosure encompasses use of the described solid state forms of Balovaptan in the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure encompasses the described solid state forms of Balovaptan for use in the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure further provides pharmaceutical compositions comprising any one or a combination of the solid state forms of Balovaptan according to the present disclosure.
  • the present disclosure encompasses pharmaceutical formulations comprising any one or a combination of the described solid state forms of Balovaptan and at least one pharmaceutically acceptable excipient.
  • the present disclosure encompasses processes to prepare said pharmaceutical formulations of Balovaptan comprising combining any one or a combination of the described solid state forms of Balovaptan and at least one pharmaceutically acceptable excipient.
  • solid state forms defined herein as well as the pharmaceutical compositions or formulations of the solid state forms of Balovaptan can be used as medicaments, preferably for the treatment of Autistic Spectrum disorders (ASD).
  • ASD Autistic Spectrum disorders
  • the present disclosure also provides methods of treating Autistic Spectrum disorders (ASD), by administering a therapeutically effective amount of any one or a combination of the solid state forms of Balovaptan of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject with Autistic Spectrum disorders (ASD) or otherwise in need of the treatment.
  • ASD Autistic Spectrum disorders
  • Figure 1 shows an X-ray powder diffractogram (XRPD) of crystalline form BT1 of Balovaptan.
  • Figure 2 shows an X-ray powder diffractogram (XRPD) of crystalline form BT2 of Balovaptan.
  • Figure 3 shows an X-ray powder diffractogram (XRPD) of crystalline form BT3 of Balovaptan.
  • Figure 4 shows an X-ray powder diffractogram (XRPD) of crystalline form BT4 of Balovaptan.
  • Figure 5 shows an X-ray powder diffractogram (XRPD) of amorphous Balovaptan.
  • Figure 6 shows an X-ray powder diffractogram (XRPD) of crystalline form BT5 of Balovaptan.
  • Figure 7 shows an X-ray powder diffractogram (XRPD) of crystalline form BT6 of Balovaptan.
  • Figure 8 shows Solid state 13 C-NMR spectrum of Form BT4 of Balovaptan at the range of 200-0 ppm.
  • Figure 9 shows Solid state 13 C-NMR spectrum of Form BT4 of Balovaptan at the range of 200-100 ppm.
  • Figure 10 shows Solid state 13 C-NMR spectrum of Form BT4 of Balovaptan at the range of 100-0 ppm.
  • the present disclosure relates to solid state forms of Balovaptan.
  • the present disclosure also relates to processes for preparation thereof, and pharmaceutical compositions comprising the disclosed solid state forms.
  • the solid state forms of Balovaptan according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, 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, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, or bulk density.
  • a crystal form may be referred to herein as being characterized by graphical data "as 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 can not necessarily be described by reference to numerical values or peak positions alone.
  • 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 factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person.
  • a crystal form of Balovaptan referred to herein as being characterized by graphical data "as depicted in" a Figure will thus be understood to include any crystal forms of the Balovaptan, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
  • 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% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or 0% of any other forms of the subject compound as measured, for example, by XRPD.
  • the solid state form of Balovaptan described herein as is 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 100% of the subject solid state form of Balovaptan. Accordingly, in some embodiments of the disclosure, the described solid state form of Balovaptan 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 solid state forms of the Balovaptan.
  • anhydrous in relation to crystalline Balovaptan relates to crystalline Balovaptan which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form does not contain more than about 1% (w/w) of either water or organic solvents as measured for example by TGA.
  • solvate refers to 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.
  • a thing e.g., a reaction mixture
  • room temperature often abbreviated "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, about 22°C to about 27°C, or about 25°C.
  • 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, about 10 to about 18 hours, or about 16 hours.
  • 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.”
  • 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 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.
  • 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 methyl tert-butyl ether (MTBE) (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.
  • MTBE methyl tert-butyl ether
  • reduced pressure refers to a pressure of from about 10 mbar to 50 mbar.
  • ambient conditions refer to atmospheric pressure, 22-24°C.
  • the present disclosure relates to a crystalline form of Balovaptan designated Form BT1.
  • the crystalline form BT1 of Balovaptan may be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.5, 9.2, 11.7, 15.5, 17.0 and 25.9 degrees 2- theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1; and combinations of these data;
  • Crystalline Form BT1 of Balovaptan may be further characterized by an XRPD pattern having peaks at 5.5, 9.2, 11.7, 15.5, 17.0 and 25.9 deg-2-theta ⁇ 0.2 degrees 2-theta, and also having at least one additional peak selected from 15.0, 15.5, 17.7 and 22.6 deg-2 -theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form BT1 of Balovaptan may alternatively be characterized by an XRPD pattern having peaks at 5.5, 9.2, 11.7, 15.5, 17.0 and 25.9 deg-2-theta ⁇ 0.2 degrees 2- theta, and also having one, two or three additional peaks selected from 15.0, 17.7 and 22.6 deg-2- theta ⁇ 0.2 degrees 2-theta; for example crystalline Form BT1 of Balovaptan may be characterized by an XRPD pattern having peaks at 5.5, 9.2, 11.7, 15.0, 15.5, 17.0, 17.7, 22.6 and 25.9 deg-2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form BT1 of Balovaptan is isolated.
  • Form BT1 maybe a cyclohexane solvate.
  • Crystalline form BT1 of Balovaptan may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.5, 9.2, 11.7, 15.5, 17.0 and 25.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.
  • the present disclosure further relates to a crystalline form of Balovaptan designated Form BT2.
  • the crystalline form BT2 of Balovaptan may be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 13.4, 18.3, 21.3, 22.5, 23.1 and 25.5 deg-2-theta ⁇ 0.2 degrees 2-theta.; an XRPD pattern as depicted in Figure 2; and combinations of these data;
  • Crystalline form BT2 of Balovaptan may be further characterized by an XRPD pattern having peaks at 13.4, 18.3, 21.3, 22.5, 23.1 and 25.5 deg-2-theta ⁇ 0.2 degrees 2-theta and also having at least one additional peak selected from 9.7, 16.2, 16.5, 20.1 and 27.1 deg-2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form BT2 of Balovaptan may alternatively be characterized by an XRPD pattern having peaks at 13.4, 18.3, 21.3, 22.5, 23.1 and 25.5 deg-2 -theta ⁇ 0.2 degrees 2- theta.
  • crystalline form BT2 of Balovaptan may be characterized by an XRPD pattern having peaks at 9.7, 13.4, 16.2, 16.5, 18.3, 20.1, 21.3, 22.5, 23.1, 25.5 and 27.1 deg-2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form BT2 of Balovaptan is isolated.
  • Form BT2 may be a methanol solvate.
  • Crystalline form BT2 of Balovaptan may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 13.4, 18.3, 21.3, 22.5, 23.1 and 25.5 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.
  • the present disclosure relates to a crystalline form of Balovaptan designated Form BT3.
  • the crystalline form BT3 of Balovaptan may be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.6, 11.5, 18.8, 19.2, 21.7, 23.0 and 25.0 deg- 2-theta ⁇ 0.2 degrees 2-theta.; an XRPD pattern as depicted in Figure 3; and combinations of these data;
  • Crystalline Form BT3 of Balovaptan may be further characterized by an XRPD pattern having peaks at 7.6, 11.5, 18.8, 19.2, 21.7, 23.0 and 25.0 deg-2-theta ⁇ 0.2 degrees 2-theta., and also having at least one additional peak selected from 15.3, 16.9, 24.2 and 34.8 deg-2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form BT3 of Balovaptan may alternatively be characterized by an XRPD pattern having peaks at 7.6, 11.5, 18.8, 19.2, 21.7, 23.0 and 25.0 deg-2-theta ⁇ 0.2 degrees 2-theta., and also having one, two, three or four additional peaks selected from 15.3, 16.9, 24.2 and 34.8 deg-2 -theta ⁇ 0.2 degrees 2-theta; for example crystalline Form BT3 of Balovaptan may be characterized by an XRPD pattern having peaks at 7.6, 11.5, 15.3, 16.9, 18.8, 19.2, 21.7, 23.0, 24.2, 25.0 and 34.8 deg-2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form BT3 of Balovaptan is isolated.
  • From BT3 may be a formamide solvate.
  • Crystalline form BT3 of Balovaptan may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.6,
  • the present disclosure relates to a crystalline form of Balovaptan designated Form BT4.
  • the crystalline formBT4 of Balovaptan may be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 8.3, 15.0, 16.3, 17.0, 17.5 and 22.3 deg-2- theta ⁇ 0.2 deg 2-theta; an XRPD pattern as depicted in Figure 4; a solid state 13 C-NMR spectrum having characteristic peaks at the range of 100-200 ppm at 163.7, 157.3, 140.3, 124.2, 118.2 and 113.1 ppm ⁇ 0.2 ppm; a solid state 13 C-NMR spectrum having the following chemical shift absolute differences from a reference peak at 26.8 ppm ⁇ 2 ppm of 136.9, 130.5, 113.5, 97.4,
  • Crystalline Form BT4 of Balovaptan may be further characterized by an XRPD pattern having peaks at 8.3, 15.0, 16.3, 17.0, 17.5 and 22.3 deg-2 -theta ⁇ 0.2 deg 2-theta, and also having at least one additional peak selected from 13.2, 18.5, 19.6, 22.9, 23.5 and 26.0 deg-2- theta ⁇ 0.2 deg 2-theta.
  • Crystalline Form BT4 of Balovaptan may alternatively be characterized by an XRPD pattern having peaks at 8.3, 15.0, 16.3, 17.0, 17.5 and 22.3 deg-2 -theta ⁇ 0.2 deg 2- theta, and also having one, two, three, four, five or six additional peaks selected from 13.2, 18.5,
  • crystalline Form BT4 of Balovaptan may be characterized by an XRPD pattern having peaks at 8.3, 13.2, 15.0, 16.3, 17.0, 17.5, 18.5, 19.6, 22.3, 22.9, 23.5 and 26.0 deg-2-theta ⁇ 0.2 deg 2-theta.
  • crystalline Form BT4 of Balovaptan is isolated.
  • Form BT4 may be anhydrous form. Typically the water content is less than 1% w/w, preferably less than 0.5%.
  • Balovaptan form BT4 is polymorphically pure.
  • Form BT4 of Balovaptan according to the present disclosure may have advantageous properties as described above, for example improved solubility.
  • the above Balovaptan Form BT4 can be prepared by a process including a solvent/anti solvent crystallization.
  • Balovaptan Form BT4 is prepared by crystallization from a mixture of a solvent and an antisolvent, wherein the solvent is selected from: cyclic ethers (such as a C4 to C 6 ether), aromatic ethers (such as a C7 to C10 aromatic ether); aliphatic monohydric alcohols (such as a C1-C6 monohydric alcohol), glycol ethers (such as a C3 to C 6 glycol ether), ketones (such as a C3- C 6 ketone), organocarbonates [such an alkylenecarbonates - e.g.
  • Balovaptan Form BT4 may be prepared by crystallisation of Balovaptan from a mixture of a solvent and an antisolvent, wherein the solvent is selected from: a cyclic ether, a glycol ether, or an aliphatic monohydric alcohol, and wherein the antisolvent is diisopropylether or hexane (typically diisopropylether).
  • Balovaptan Form BT4 may be prepared by crystallisation of Balovaptan from a mixture of a solvent and an antisolvent, wherein the solvent is selected from the group consisting of: a C4-C7 or a C4-C5 cyclic ether; a C4-C7 or a C4-C5 glycol ether; and a C1-C7 or a C3-C5 aliphatic monohydric alcohol; and wherein the antisolvent is diisopropylether or hexane (typically diisopropylether).
  • the solvent is selected from the group consisting of: a C4-C7 or a C4-C5 cyclic ether; a C4-C7 or a C4-C5 glycol ether; and a C1-C7 or a C3-C5 aliphatic monohydric alcohol; and wherein the antisolvent is diisopropylether or hexane (typically diisopropyl
  • Balovaptan Form BT4 can be prepared by a process comprising crystallization from a mixture of: 2-methyltetrahydrofuran and diisopropyl ether; 1 -butanol and diisopropyl ether; isopropanol and diisopropyl ether, isoamyl alcohol and diisopropyl ether; l-methoxy-2 -propanol (propylene glycol methyl ether) and diisopropylether; or 1,4-dioxane and diisopropylether.
  • Balovaptan Form BT4 can be prepared by a process comprising crystallization from a mixture of: 2-methyltetrahydrofuran and hexane; 1 -butanol and hexane; isopropanol and hexane, isoamyl alcohol and hexane; l-methoxy-2-propanol (propylene glycol methyl ether) and hexane; or 1,4-dioxane and hexane.
  • the process includes:
  • a solution of Balovaptan in a solvent as described in any embodiment above such as cyclic ethers, aliphatic monohydric alcohols, glycol ethers, ketones, organocarbonates or nitriles
  • a solvent such as cyclic ethers, aliphatic monohydric alcohols, glycol ethers, ketones, organocarbonates or nitriles
  • di-isopropyl ether or hexane typically diisopropylether
  • the solvent in step (a) may be a cyclic ether, a glycol ether, or an aliphatic monohydric alcohol; and the antisolvent is diisopropylether or hexane.
  • the solvent in step (a) may be a cyclic ether, a glycol ether, or an aliphatic monohydric alcohol; and the antisolvent is diisopropylether.
  • the solvent in step (a) is selected from the group consisting of: a C4-C7 or a C4-C5 cyclic ether; a C4-Cv or a C4-C5 glycol ether; and a C1-C7 or a C3-C5 aliphatic monohydric alcohol; and the antisolvent is diisopropylether or hexane.
  • the solvent in step (a) is selected from the group consisting of: a C4-C7 or a C4-C5 cyclic ether; a C4-C7 ora C4-C5 glycol ether; and a Ci- C7 or a C3-C5 aliphatic monohydric alcohol; and the antisolvent is diisopropylether.
  • the aliphatic monohydric alcohol in stage a) can be preferably selected from isobutanol, isopropyl alcohol, and isoamyl alcohol.
  • the cyclic ethers can be preferably selected from: 2-methyl THF and 1,4-dioxane.
  • the aromatic ether can be anisole.
  • the glycol ether is selected from the group consisting of 2-dimethoxyethane and l-methoxy-2- propanol (propylene glycol methylether).
  • the ketone can be preferably selected from acetone, acetophenone, butanone, preferably acetone.
  • the organocarbonates may be an alkylenecarbonate such as a (C3-6 alkylene)carbonate, or may be a dialkylcarbonate, such as a di(Ci- 3 alkyl)carbonate, particularly dimethyl carbonate, ethylene carbonate, propylene carbonate, and is typically dimethyl carbonate.
  • the nitrile can be preferably selected from isobutyronitrile, acetonitrile and propionitrile, preferably isobutyronitrile.
  • the solvent is used an amount of about 1 vol to about 20 vol, about 4 vol to about 15 vol and preferably about 5 to 10 vol relative to Balovaptan.
  • the solvent when the solvent is a cyclic ether, the solvent may be used in an amount of about 3 to about 8 vol (i.e. about 3 ml to about 8 ml per gram of Balovaptan), or about 4 to about 7 vol, or about 5 to about 6 vol.
  • the solvent when the solvent is an aliphatic monohydric alcohol or a glycol ether, the solvent may be used in an amount of about 5 vol to about 15 vol (i.e. about 5 ml to about 15 ml per gram of Balovaptan), or about 8 to about 12 vol, or about 9 to about 11 vol, or about 10 vol.
  • the mixture of Balovaptan in the solvent is preferably heated to a temperature of about 50°C to about 80°C, in embodiments about 55°C to about 80°C, and in other embodiments to about 60°C to about 70°C, preferably with stirring.
  • the resulting solution may be filtered in order to remove undissolved particles. The filtration can be carried out at elevated temperature or at room temperature.
  • Step (a) may comprise addition of the solution of Balovaptan to the antisolvent (e.g. diisopropyl ether or hexane, typically diisopropylether) or, preferably the di isopropyl ether or hexane antisolvent (typically diisopropylether) is added to the solution of Balovaptan.
  • the resulting mixture may be maintained at room temperature.
  • the mixture may be stirred during the addition.
  • the addition may be carried out over a period of about 1 to about 30 minutes, about 1 to about 20 minutes, about 2 to about 10 or about 3 to about 8 minutes, or about 5 minutes.
  • the solution of Balovaptan may be at a temperature of about 30°C to about 60°C, or about 40°C to about 50°C prior to the addition of the diisopropylether antisolvent.
  • the volume ratio of the solvent to antisolvent e.g. diisopropyl ether or hexane, typically
  • diisopropylether is: about 1 : 1 to about 1 : 10, about 1 :2 to about 1 :8, about 1 :3 to about 1 :7, about 1 :4 to about 1 :6, and in some embodiments about 1 :5 (v/v).
  • the antisolvent e.g. di-isopropyl ether or hexane, typically
  • diisopropylether is added drop-wise into Balovaptan solution which is maintained at room temperature.
  • the addition may be carried out over a period of about 2 to about 60 minutes, about 2 to about 45 minutes, and in some embodiments in about 5 minutes or in about 30 to about 40 minutes, preferably with stirring.
  • the reaction mixture comprising Balovaptan, solvent and antisolvent may be maintained at room temperature (such as at about 20 to about 30°C) for about 1 to about 48 hours, about 10 to about 30 hours, preferably about 24 hours, preferably with stirring.
  • step (b) may include isolation of Balovaptan Form BT4.
  • the isolation may be done by filtration.
  • the filtration is carried out at temperature of about 10 to about 40°C, preferably about 20 to about 30°C.
  • the product may be washed, and optionally dried. Drying may be done by nitrogen or air or under vacuum. Drying may be performed at a temperature of about 20 to about 30°C.
  • a reduced pressure of: about 1 or about 200 mbar, about 1 to about 100 mbar, about 1 to about 50 mbar, and particularly about 5 to about 40 mbar or more particularly, about 20 mbar, is used.
  • embodiments may further include a step of combining the Balovaptan Form BT4 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition of
  • the present disclosure relates to a crystalline form of Balovaptan designated Form BT5.
  • the crystalline form BT5 of Balovaptan may be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 13.8, 17.1, 20.2, 24.3 and 30.0 degrees -2- theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6; and combinations of these data;
  • Crystalline Form BT5 of Balovaptan may be further characterized by an XRPD pattern having peaks at 13.8, 17.1, 20.2, 24.3 and 30.0 deg-2-theta ⁇ 0.2 degrees 2-theta, and also having at least one additional peak selected from 9.7, 15.5, 17.9, 19.2, 21.2 and 22.6 deg-2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form BT5 of Balovaptan may alternatively be characterized by an XRPD pattern having peaks at 13.8, 17.1, 20.2, 24.3 and 30.0 deg-2-theta ⁇ 0.2 degrees 2-theta, and also having one, two, three, four, five or six additional peaks selected from 9.7, 15.5.
  • crystalline Form BT5 of Balovaptan may be characterized by an XRPD pattern having peaks at 9.7, 13.8, 15.5, 17.1, 17.9, 19.2, 20.2, 21.2, 22.6 and 24.3 and 30.0 deg-2 -theta ⁇ 0.2 degrees 2-theta.
  • Form BT5 may be an ethylene glycol solvate, more preferably a hemi ethylene glycol solvate.
  • Crystalline form BT5 of Balovaptan may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 13.8, 17.1, 20.2, 24.3 and 30.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6, and combinations thereof.
  • crystalline Form BT5 of Balovaptan is isolated.
  • the present disclosure relates to a crystalline form of Balovaptan designated Form BT6.
  • the crystalline form BT6 of Balovaptan may be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 15.4, 16.8, 18.0, 19.9, 20.8 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 7; and combinations of these data; [0083] Crystalline Form BT6 of Balovaptan may be further characterized by an XRPD pattern having peaks at 15.4, 16.8, 18.0, 19.9, 20.8 and 22.8 deg-2-theta ⁇ 0.2 degrees 2-theta, and also having at least one additional peak selected from 9.5, 15.2, 22.2 and 30.8 deg-2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form BT6 of Balovaptan may be further characterized by an XRPD pattern having peaks at 15.4, 16.8, 18.0, 19.9, 20.8 and 22.8 deg-2-theta ⁇ 0.2 degrees 2-theta, and also having one, two, three or four additional peaks selected from 9.5, 15.2, 22.2 and 30.8 deg-2-theta ⁇ 0.2 degrees2-theta; for example, crystalline Form BT6 of Balovaptan may be characterized by an XRPD pattern having peaks at 9.5, 15.2, 15.4, 16.8, 18.0, 19.9, 20.8, 22.2 , 22.8 and 30.8 deg-2 -theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form BT4 of Balovaptan is isolated.
  • Form BT6 maybe a propylene glycol solvate, more preferably a hemi propylene glycol solvate.
  • Crystalline form BT6 of Balovaptan may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 15.4, 16.8, 18.0, 19.9, 20.8 and 22.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 7, and combinations thereof.
  • the present disclosure also provides the use of the solid state forms of Balovaptan in the preparation of other solid state forms of Balovaptan.
  • the present disclosure also provides the said solid state forms of Balovaptan for use in the preparation of other solid state forms of Balovaptan.
  • the present disclosure encompasses use of the described solid state forms of Balovaptan in the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of ASD.
  • the present disclosure encompasses the described solid state forms of Balovaptan for use in the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of ASD.
  • the present disclosure further provides pharmaceutical compositions comprising any one or a combination of the solid state forms of Balovaptan according to the present disclosure.
  • the present disclosure encompasses pharmaceutical formulations comprising any one or a combination of the described solid state forms of Balovaptan and at least one pharmaceutically acceptable excipient.
  • the present disclosure encompasses processes to prepare said pharmaceutical formulations of Balovaptan comprising combining any one or a combination of the described solid state forms of Balovaptan and at least one pharmaceutically acceptable excipient.
  • 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®), microfme 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®
  • microfme cellulose lactose
  • starch pregelatinized starch
  • calcium carbonate
  • 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, hydroxyethyl 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®, Polyplasdone®),
  • 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.
  • Balovaptan and any other solid excipients are 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 disclosure 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 disclosure 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 glycol ate, starch tragacanth, and xanthan gum.
  • 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.
  • a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • 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, the most preferred route of the present disclosure 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, preferably 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 sorbitol, and an opacifying agent 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 comprise 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 Balovaptan can be administered.
  • Balovaptan is preferably formulated for administration to a mammal, preferably a human, by oral administration.
  • Balovaptan can be formulated, for example, as a tablet or capsule.
  • 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.
  • solid state forms defined herein as well as the pharmaceutical compositions or formulations of the improved solid state form of Balovaptan can be used as medicaments, particularly for the treatment of Autistic Spectrum Disorder (ASD) as specified above.
  • ASD Autistic Spectrum Disorder
  • the present disclosure also provides methods of treating Autistic Spectrum Disorder (ASD), as specified above comprising administering a therapeutically effective amount of any one or a combination of the solid state form of Balovaptan of the present disclosure, or at least one of the herein described pharmaceutical compositions or formulations, to a subject with ASD, or otherwise in need of the treatment.
  • ASD Autistic Spectrum Disorder
  • the present disclosure also provides uses of the solid state forms of Balovaptan of the present disclosure, or at least one of the above pharmaceutical compositions or formulations for the manufacture of medicaments, particularly for the treatment as specified above.
  • Preparation of the starting material Balovaptan can be done according to any process disclosed in the literature.
  • Amorphous Balovaptan 50 mg was combined with cyclohexane ( 1.0 mL) at a temperature of 0°C-5°C.
  • the obtained slurry mass was maintained at this temperature under stirring (300 rpm) for 7-days. After 7 days, the slurry mass was filtered and dried under vacuum at room temperature for 10-15 minutes.
  • the obtained solid material was analyzed by XRPD, form BT1 was obtained. XRPD pattern is presented in Figure 1.
  • Amorphous Balovaptan (0.2 grams) was combined with cyclohexane (4.0mL) at a temperature of 0°C-5°C. The obtained slurry mass was maintained under stirring (300 rpm) for 3 -days. After 3 days, the slurry mass was filtered and dried under vacuum at temperature of 22°C-25°C for 10-15 minutes. A solid material was obtained and was analyzed by XRPD, form BT1 was obtained.
  • Amorphous Balovaptan (0.5 grams) was dissolved in methanol (1.5 mL) at a temperature of 50-55°C The clear solution was cooled down to 22-25°C and filtered through to remove any undissolved particulates. The clear solution was maintained at temperature of 25- 30°C for 24 hours. Then, the obtained solid was dried on air for 5-10 minutes. The solid was analyzed by XRPD Form BT2, was obtained.
  • Amorphous Balovaptan (2.0 grams) was dissolved in methanol (8.0 mL) at a temperature of 50°C-55°C. The clear solution was cooled down to 22°C-25°C and filtered to remove any undissolved particulates. Seeds of Form BT2 was added into the solution and maintained at temperature of 22°C-25°C. After 24 hours, the obtained solid was filtered and dried under vacuum at a temperature of 22°C-25°C for 10-15 minutes. The obtained solid (1.2 g) was analyzed by XRPD, form BT2 was obtained. XRPD pattern is presented in Figure 2.
  • Balovaptan (0.1 grams) was dissolved in Isopropyl alcohol (1.0 mL) at a temperature of 60-70°C to obtain a clear solution. The solution was filter to remove undissolved particulate. Di-isopropyl ether (5.0 mL, solvent temperature 20-30°C) was added over a period of 5 minutes under stirring (500 rpm) to the clear solution of balovaptan until a solid material was observed (about 2-3 hours). The obtained slurry was maintained for 24 hours, and then the obtained solid was filtered under vacuum at temperature of 20-30°C and suck dried for 5-10 minutes. The obtained solid was analyzed by XRPD, Balovaptan Form BT4 was obtained.
  • Balovaptan (0.1 grams) was dissolved in Isoamyl alcohol (1.0 mL) at a temperature of 60-70°C to obtain a clear solution. The solution was filter to remove undissolved particulate. Di isopropyl ether (5.0 mL, solvent temperature 20-30°C) was added over a period of 5 minutes under stirring (500 rpm) to the clear solution of balovaptan until a solid material was observed (about 2-3 hours). The obtained slurry was maintained for 24 hours, and then the obtained solid was filtered under vacuum at temperature of 20-30°C and suck dried for 5-10 minutes. The obtained solid was analyzed by XRPD, Balovaptan Form BT4 was obtained.
  • Balovaptan (0.1 grams) was dissolved in l-methoxy-2-propanol (1.0 mL) at a temperature of 60-70°C to obtain a clear solution. The solution was filter to remove unwanted particulate. Di-isopropyl ether (5.0 mL, solvent temperature 20-30°C) was added over a period of 5 minutes under stirring (500 rpm) to the clear solution of Balovaptan until a solid material was observed (about 2-3 hours). The obtained slurry was maintained for 24 hours, and then the obtained solid was filtered under vacuum at temperature of 20-30°C and suck dried for 5-10 minutes. The obtained solid was analyzed by XRPD, Balovaptan Form BT4 was obtained.
  • Balovaptan (0.1 grams) was dissolved in 1,4-Dioxane (0.5 mL) at a temparture of 60- 70°C to obtain a clear solution. The solution was filter to remove unwanted particulate. Di isopropyl ether (5.0 mL, solvent temperature 20-30°C) was added over a period of 5 minutes under stirring (500 rpm) to the clear solution of balovaptan until a solid material was observed (about 2-3 hours). The obtained slurry was maintained for 24 hours, and then the obtained solid was filtered under vacuum at temperature of 20-30°C and suck dried for 5-10 minutes. The obtained solid was analyzed by XRPD, Balovaptan Form BT4 was obtained.

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Abstract

L'invention concerne une forme cristalline de balovaptan appelée forme BT4, des procédés pour sa préparation, des compositions pharmaceutiques la comprenant et son utilisation médicale dans le traitement de troubles du spectre autistique (TSA).
PCT/US2019/067314 2018-12-27 2019-12-19 Formes à l'état solide de balovaptan WO2020139670A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010060836A1 (fr) 2008-11-28 2010-06-03 F. Hoffmann-La Roche Ag Arylcyclohexyléthers de dihydrotétrazabenzoazulènes pour emploi en tant qu'antagonistes du récepteur v1a de la vasopressine
WO2015082370A1 (fr) 2013-12-05 2015-06-11 F. Hoffmann-La Roche Ag Synthèse de trans-8-chloro-5-méthyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4 h-2,3,5,10b-tétraaza-benzo[e]azulène et leurs formes cristallines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010060836A1 (fr) 2008-11-28 2010-06-03 F. Hoffmann-La Roche Ag Arylcyclohexyléthers de dihydrotétrazabenzoazulènes pour emploi en tant qu'antagonistes du récepteur v1a de la vasopressine
WO2015082370A1 (fr) 2013-12-05 2015-06-11 F. Hoffmann-La Roche Ag Synthèse de trans-8-chloro-5-méthyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4 h-2,3,5,10b-tétraaza-benzo[e]azulène et leurs formes cristallines

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Title
BYRN, S. ET AL.: "Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations", PHARMACEUTICAL RESEARCH, vol. 12, no. 7, 1995, pages 945 - 954, XP055531015, DOI: 10.1023/A:1016241927429 *
GUILLORY, J.K.: "GENERATION OF POLYMORPHS, HYDRATES, SOLVATES, AND AMORPHOUS SOLIDS", 1999, POLYMORPHISM IN PHARMACEUTICAL SOLIDS, M. DEKKER, New York, ISBN: 978-0-8247-0237-3, pages: 183 - 225, XP002350313 *

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