WO2022177927A1 - Unhydrous crystalline form of omecamtiv mecarbil dihydrobromide salt - Google Patents

Unhydrous crystalline form of omecamtiv mecarbil dihydrobromide salt Download PDF

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Publication number
WO2022177927A1
WO2022177927A1 PCT/US2022/016509 US2022016509W WO2022177927A1 WO 2022177927 A1 WO2022177927 A1 WO 2022177927A1 US 2022016509 W US2022016509 W US 2022016509W WO 2022177927 A1 WO2022177927 A1 WO 2022177927A1
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WO
WIPO (PCT)
Prior art keywords
omecamtiv mecarbil
dihbr
crystalline
salt
salt according
Prior art date
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PCT/US2022/016509
Other languages
French (fr)
Inventor
Polina Lapido
Jenny GOLDSHTEIN
Original Assignee
Assia Chemical Industries Ltd
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2022177927A1 publication Critical patent/WO2022177927A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure relates to solid state forms of Omecamtiv mecarbil diHBr salt, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
  • Omecamtiv mecarbil methyl 4-[[2-fluoro-3-[(6-methylpyridin-3- yl)carbamoylamino]phenyl]meihyl]piperazine-l-carboxyiate, has the following formula;
  • Omecamtiv mecarbil is a cardiac-specific myosin activator. It is being studied for a potential role in the treatment of heart failure. Omecamtiv mecarbil is described in U.S. Patent No. 7,507,735. U.S. Patent Application Publication No. 2016/016906 describes a diHCl monohydrate salt of Omecamtiv mecarbil. International Publication No. WO 2020/037164 describes crystalline forms of Omecamtiv mecarbil, different salts of Omecamtiv mecarbil and polymorphs thereof. International Publication No. WO 2020/014406 discloses solid state forms of Omecamtiv mecarbil & Omecamtiv mecarbil diHCl.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single compound like Omecamtiv mecarbil diHBr, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point (mp), 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 (13C-) NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • Different salts and solid state forms (including solvated forms and co-crystals) 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, improving the dissolution profile, 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 provide 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 use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.
  • Discovering new solid state forms, solvates and co-crystals 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 salts or 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. For at least these reasons, there is a need for additional salts of Omecamtiv mecarbil and solid state forms thereof.
  • the present disclosure relates to a solid state form of Omecamtiv mecarbil diHBr salt, to processes for preparation thereof, and to pharmaceutical compositions thereof.
  • the present disclosure relates to the use of the solid state form of Omecamtiv mecarbil diHBr salt for preparing other solid state forms of Omecamtiv mecarbil and/or other salts of Omecamtiv mecarbil and solid state forms thereof.
  • the present disclosure further provides solid state form of Omecamtiv mecarbil diHBr salt for use in the preparation of other solid state forms of Omecamtiv mecarbil and/or other salts of Omecamtiv mecarbil and solid state forms thereof.
  • the present disclosure also encompasses the use of the described solid state form of Omecamtiv mecarbil diHBr salt for the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure further encompasses the described solid state form of Omecamtiv mecarbil diHBr salt for use in the preparation of pharmaceutical compositions and/or formulations for use in medicine, preferably for the treatment of heart failure.
  • the present disclosure provides pharmaceutical compositions comprising the solid state form according to the present disclosure.
  • the present disclosure encompasses pharmaceutical formulations comprising the described solid state form of Omecamtiv mecarbil diHBr salt, or of pharmaceutical compositions comprising the solid state form of Omecamtiv mecarbil diHBr salt, and at least one pharmaceutically acceptable excipient.
  • the present disclosure further encompasses processes to prepare said pharmaceutical formulations comprising combining the solid state form of Omecamtiv mecarbil diHBr salt as described herein; or pharmaceutical compositions comprising it and at least one pharmaceutically acceptable excipient.
  • solid state form as defined herein as well as the pharmaceutical compositions or formulations thereof may be used as medicaments, particularly for the treatment of heart failure.
  • the present disclosure also provides methods of treating heart failure comprising administering a therapeutically effective amount of Omecamtiv mecarbil diHBr salt of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from heart failure, or otherwise in need of the treatment.
  • the present disclosure also provides the uses of the solid state form of Omecamtiv mecarbil diHBr salt of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating heart failure.
  • Figure 1 shows an X-ray powder diffraction (XRPD) pattern of Form I of Omecamtiv mecarbil diHBr salt.
  • Figure 2 shows solid state 13 C NMR of Form I of Omecamtiv mecarbil diHBr salt.
  • the present disclosure relates to solid state form of Omecamtiv mecarbil diHBr salt, to processes for preparation thereof and to pharmaceutical compositions comprising this solid state form.
  • the disclosure also relates to the conversion of Omecamtiv mecarbil diHBr salt of the present disclosure to other solid state forms of Omecamtiv mecarbil or other salts of Omecamtiv mecarbil and solid state forms thereof.
  • the solid state form of Omecamtiv mecarbil diHBr salt 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, adhesive tendencies and advantageous processing and handling characteristics such as compressibility, and 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. 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 diHBr salt 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 Omecamtiv mecarbil diHBr salt, 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% (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.
  • solid state of Omecamtiv mecarbil diHBr salt 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 solid state form.
  • Omecamtiv mecarbil dihydrobromide or Omecamtiv mecarbil diHBr salt refers to a salt of Omecamtiv mecarbil with hidrobromic acid (HBr); wherein the ratio is 1:2; accordingly.
  • anhydrous in relation to crystalline form of Omecamtiv mecarbil diHBr, relates to a crystalline form of Omecamtiv mecarbil diHBr, 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.
  • the term "isolated" in reference to solid state form of Omecamtiv mecarbil diHBr salt of the present disclosure corresponds to solid state form of Omecamtiv mecarbil diHBr salt that is physically separated from the reaction mixture in which it is formed.
  • 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, or 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, or about 10 to about 18 hours, typically about 16 hours.
  • 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.
  • reduced pressure refers to a pressure of about 10 mbar to about 500 mbar.
  • ambient conditions refer to atmospheric pressure, 22-24°C.
  • the present disclosure comprises a crystalline form of Omecamtiv mecarbil diHBr salt designated Form F
  • the crystalline Form I of Omecamtiv mecarbil diHBr salt can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.1, 18.8, 20.3, 21.5 and 26.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 1; and combinations of these data.
  • Crystalline Form I Omecamtiv mecarbil diHBr salt may be further characterized by an XRPD pattern having peaks at 7.1, 18.8, 20.3, 21.5 and 26.4 degrees two theta ⁇ 0.2 degrees two theta, and also having one, two, three, four or five additional peaks selected from 15.0, 18.3, 19.3, 21.0 and 24.6 degrees two theta ⁇ 0.2 degrees two theta.
  • Crystalline Form I of Omecamtiv mecarbil diHBr salt may be further characterized by an XRPD pattern having peaks at 7.1, 15.0, 18.3, 18.8, 19.3, 20.3, 21.0, 21.5, 24.6 and 26.4 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form I of Omecamtiv mecarbil diHBr may alternatively or additionally be characterized by data selected from one or more of the following: a solid state 13 C NMR spectrum with characteristic peaks at: 137.35, 128.31, 124.11, 41.15 and 21.37 ⁇ 2 ppm; a solid state 13 C NMR spectrum having the following chemical shift absolute differences from reference peak at 145.96 ⁇ 2ppm: 8.61, 17.65, 21.85, 104.81 and 124.59 ⁇ 2ppm; or by solid state 13 C NMR spectrum as depicted in Figure 2; or combinations of these data.
  • Omecamtiv mecarbil diHBr salt of the present invention is anhydrous, non- hygroscopic and has shown high thermal stability.
  • Crystalline Form I of Omecamtiv mecarbil diHBr according to the present invention is mechanically and thermodynamically stable.
  • Pharmaceutical molecules may display solid to solid phase transformations and transformations between polymorphs; which may be detected by exposure of the solid state form to stress conditions of e.g., high temperature, high relative humidity, stress and grinding.
  • crystalline Form I of Omecamtiv mecarbil diHBr according to the present invention has shown to be thermodynamically and mechanically stable.
  • the present disclosure also relates to the use of the solid state form of Omecamtiv mecarbil diHBr salt of the present disclosure, for preparing other solid state forms of Omecamtiv mecarbil and/or other Omecamtiv mecarbil salts and solid state forms thereof.
  • the present disclosure further provides solid state form of Omecamtiv mecarbil diHBr salt for use in the preparation of other solid state forms of Omecamtiv mecarbil and/or other Omecamtiv mecarbil salts and solid state forms thereof.
  • the present disclosure also encompasses the use of the described solid state form of Omecamtiv mecarbil diHBr salt for the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure further encompasses the described solid state form of Omecamtiv mecarbil diHBr salt for use in the preparation of pharmaceutical compositions and/or formulations for use in medicine, preferably for the treatment of heart failure.
  • the present disclosure provides pharmaceutical compositions comprising the solid state form according to the present disclosure.
  • the present disclosure encompasses pharmaceutical formulations comprising the described solid state form of Omecamtiv mecarbil diHBr salt, or of pharmaceutical compositions comprising the solid state form of Omecamtiv mecarbil diHBr salt, and at least one pharmaceutically acceptable excipient.
  • the present disclosure further encompasses processes to prepare said pharmaceutical formulations of Omecamtiv mecarbil diHBr salt comprising combining the above described solid state form of Omecamtiv mecarbil diHBr salt and at least one pharmaceutically acceptable excipient.
  • compositions of the present invention contain the solid state form Omecamtiv mecarbil diHBr salt of the present invention.
  • the pharmaceutical formulations of the present invention 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®), 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 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, 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®, Poly
  • 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 invention 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.
  • liquid pharmaceutical compositions of the present invention the active ingredient 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.
  • 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, 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 invention 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 invention 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 invention can be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, 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 invention 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 Omecamtiv mecarbil diHBr salt is preferably formulated for administration to a mammal, preferably a human.
  • Omecamtiv mecarbil diHBr salt can be formulated, for example, as a viscous liquid solution or suspension, preferably 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 ah Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
  • the solid state form as defined herein as well as the pharmaceutical compositions or formulations of the solid state form of Omecamtiv mecarbil dilTBr salt may be used as medicaments, particularly for the treatment of heart failure.
  • the present disclosure also provides methods of treating heart failure comprising administering a therapeutically effective amount of the above described solid state form of Omecamtiv mecarbil dilTBr salt, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from heart failure, or otherwise in need of the treatment.
  • the present disclosure also provides the use of the solid state form of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating heart failure.
  • Powder X-ray diffraction pattern (“PXRD”) method :
  • the starting material Omecamtiv mecarbil (form O-l) can be prepared according to International Publication No. WO 2020/014406.
  • Example 1 Preparation of Omecamtiv mecarbil diHBr salt- Form I [0076] Isopropyl alcohol (10 ml) was added to Omecamtiv mecarbil free base (form O-l, 0.1 grams) and was magnetically stirred at room temperature to give a slurry. Then an aqueous solution of HBr salt (48% w/w, 0.088 ml) was dropwise added and the obtained slurry was magnetically stirred at room temperature during 18 hours. The obtained solid was separated by centrifuge, washed with isopropyl alcohol (1 V*2) and dried in vacuum oven at 45 °C during 18 hours. The obtained solid was characterized by X-ray powder diffraction and designated as Omecamtiv mecarbil diHBr salt- Form I ( Figure 1).
  • Example 2 Preparation of Omecamtiv mecarbil diHBr salt- Form
  • Ethyl acetate (10 ml) was added to Omecamtiv mecarbil free base (form O-l, 0.1 grams) and was magnetically stirred at room temperature to give slurry.
  • an aqueous solution of HBr salt (48% w/w, 0.088 ml) was dropwise added and the obtained slurry was magnetically stirred at room temperature during 18 hours.
  • the obtained solid was separated by centrifuge, washed with ethyl acetate (1 V*2) and dried in vacuum oven at 45 °C during 18 hours.
  • the obtained solid was characterized by X-ray powder diffraction- Omecamtiv mecarbil diHBr salt- Form I.
  • Example 3 Preparation of Omecamtiv mecarbil diHBr salt- Form I
  • Isopropyl alcohol (20 ml, 20V) was added to Omecamtiv mecarbil free base (1 gram, 2.5 mmol) and was magnetically stirred at room temperature to give a slurry.
  • an aqueous solution of HBr (48%w/w, 0.88 ml) was dropwise added and obtained slurry was magnetically stirred at room temperature during 18 hours.
  • the obtained solid was separated by centrifuge, washed with Isopropyl alcohol (2V*2) and dried in vacuum oven at 45 °C during 18 hours.
  • the obtained solid was characterized by X-ray powder diffraction: Omecamtiv mecarbil diHBr salt -Form I was obtained.

Abstract

The present disclosure relates to an anhydrous crystalline form (I) of omecamtiv mecarbil (CK-1827452, methyl 4-[[2-fluoro-3-[(6-methylpyridin-3-y])carbamoylamino]phenyl]methyl]piperazinyl- carboxylate) dihydrobromide salt 2 HBr, characterized by the XRPD pattern of figure 1 having peaks at 7.1, 15.0, 18.3, 18.8, 19.3, 20.3, 21.0, 21.5, 24.6 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta. Omecamtiv mecarbil is a cardiac-specific myosin activator used for the treatment of heart failure.

Description

UNHYDROUS CRYSTALLINE FORM OF OMECAMTIV MECARBIL DIHYDROBROMIDE SALT
TECHNICAL FIELD
[0001] The present disclosure relates to solid state forms of Omecamtiv mecarbil diHBr salt, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
BACKGROUND
[0002] Omecamtiv mecarbil, methyl 4-[[2-fluoro-3-[(6-methylpyridin-3- yl)carbamoylamino]phenyl]meihyl]piperazine-l-carboxyiate, has the following formula;
Figure imgf000003_0001
[0003] Omecamtiv mecarbil is a cardiac-specific myosin activator. It is being studied for a potential role in the treatment of heart failure. Omecamtiv mecarbil is described in U.S. Patent No. 7,507,735. U.S. Patent Application Publication No. 2016/016906 describes a diHCl monohydrate salt of Omecamtiv mecarbil. International Publication No. WO 2020/037164 describes crystalline forms of Omecamtiv mecarbil, different salts of Omecamtiv mecarbil and polymorphs thereof. International Publication No. WO 2020/014406 discloses solid state forms of Omecamtiv mecarbil & Omecamtiv mecarbil diHCl.
[0004] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Omecamtiv mecarbil diHBr, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point (mp), 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 (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
[0005] Different salts and solid state forms (including solvated forms and co-crystals) 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, improving the dissolution profile, 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 provide 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 use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.
[0006] Discovering new solid state forms, solvates and co-crystals 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 salts or 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. For at least these reasons, there is a need for additional salts of Omecamtiv mecarbil and solid state forms thereof.
SUMMARY OF THE DISCLOSURE
[0007] The present disclosure relates to a solid state form of Omecamtiv mecarbil diHBr salt, to processes for preparation thereof, and to pharmaceutical compositions thereof.
[0008] The present disclosure relates to the use of the solid state form of Omecamtiv mecarbil diHBr salt for preparing other solid state forms of Omecamtiv mecarbil and/or other salts of Omecamtiv mecarbil and solid state forms thereof.
[0009] The present disclosure further provides solid state form of Omecamtiv mecarbil diHBr salt for use in the preparation of other solid state forms of Omecamtiv mecarbil and/or other salts of Omecamtiv mecarbil and solid state forms thereof.
[0010] The present disclosure also encompasses the use of the described solid state form of Omecamtiv mecarbil diHBr salt for the preparation of pharmaceutical compositions and/or formulations. The present disclosure further encompasses the described solid state form of Omecamtiv mecarbil diHBr salt for use in the preparation of pharmaceutical compositions and/or formulations for use in medicine, preferably for the treatment of heart failure.
[0011] In another aspect, the present disclosure provides pharmaceutical compositions comprising the solid state form according to the present disclosure.
[0012] In yet another embodiment, the present disclosure encompasses pharmaceutical formulations comprising the described solid state form of Omecamtiv mecarbil diHBr salt, or of pharmaceutical compositions comprising the solid state form of Omecamtiv mecarbil diHBr salt, and at least one pharmaceutically acceptable excipient.
[0013] The present disclosure further encompasses processes to prepare said pharmaceutical formulations comprising combining the solid state form of Omecamtiv mecarbil diHBr salt as described herein; or pharmaceutical compositions comprising it and at least one pharmaceutically acceptable excipient.
[0014] The solid state form as defined herein as well as the pharmaceutical compositions or formulations thereof may be used as medicaments, particularly for the treatment of heart failure.
[0015] The present disclosure also provides methods of treating heart failure comprising administering a therapeutically effective amount of Omecamtiv mecarbil diHBr salt of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from heart failure, or otherwise in need of the treatment.
[0016] The present disclosure also provides the uses of the solid state form of Omecamtiv mecarbil diHBr salt of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating heart failure.
BRIEF DESCRIPTION OF THE DRAWING
[0017] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of Form I of Omecamtiv mecarbil diHBr salt.
[0018] Figure 2 shows solid state 13C NMR of Form I of Omecamtiv mecarbil diHBr salt.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0019] The present disclosure relates to solid state form of Omecamtiv mecarbil diHBr salt, to processes for preparation thereof and to pharmaceutical compositions comprising this solid state form. The disclosure also relates to the conversion of Omecamtiv mecarbil diHBr salt of the present disclosure to other solid state forms of Omecamtiv mecarbil or other salts of Omecamtiv mecarbil and solid state forms thereof. [0020] The solid state form of Omecamtiv mecarbil diHBr salt, 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, adhesive tendencies and advantageous processing and handling characteristics such as compressibility, and bulk density.
[0021] 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. 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 can not 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 factors such as 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.
[0022] A crystal form of diHBr salt 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 Omecamtiv mecarbil diHBr salt, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
[0023] 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. Thus, solid state of Omecamtiv mecarbil diHBr salt 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 solid state form.
[0024] As used herein, unless stated otherwise, XRPD peaks reported herein are preferably measured using CuKa radiation, l = 1.5418 A. XRPD peaks reported herein are measured using CuK a radiation, l = 1.5418 A, at a temperature of 25 ± 3°C.
[0025] As used herein, Omecamtiv mecarbil dihydrobromide or Omecamtiv mecarbil diHBr salt refers to a salt of Omecamtiv mecarbil with hidrobromic acid (HBr); wherein the ratio is 1:2; accordingly.
[0026] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline form of Omecamtiv mecarbil diHBr, relates to a crystalline form of Omecamtiv mecarbil diHBr, 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.
[0027] As used herein, the term "isolated" in reference to solid state form of Omecamtiv mecarbil diHBr salt of the present disclosure corresponds to solid state form of Omecamtiv mecarbil diHBr salt that is physically separated from the reaction mixture in which it is formed.
[0028] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to "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. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25 °C.
[0029] 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 to about 18 hours, typically about 16 hours.
[0030] The amount of solvent employed in a chemical process, e.g., a reaction or a 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.
[0031] As used herein, the term "reduced pressure" refers to a pressure of about 10 mbar to about 500 mbar.
[0032] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure, 22-24°C.
[0033] The present disclosure comprises a crystalline form of Omecamtiv mecarbil diHBr salt designated Form F The crystalline Form I of Omecamtiv mecarbil diHBr salt can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.1, 18.8, 20.3, 21.5 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 1; and combinations of these data.
[0034] Crystalline Form I Omecamtiv mecarbil diHBr salt may be further characterized by an XRPD pattern having peaks at 7.1, 18.8, 20.3, 21.5 and 26.4 degrees two theta ± 0.2 degrees two theta, and also having one, two, three, four or five additional peaks selected from 15.0, 18.3, 19.3, 21.0 and 24.6 degrees two theta ± 0.2 degrees two theta.
[0035] In a further embodiment Crystalline Form I of Omecamtiv mecarbil diHBr salt may be further characterized by an XRPD pattern having peaks at 7.1, 15.0, 18.3, 18.8, 19.3, 20.3, 21.0, 21.5, 24.6 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta.
[0036] Crystalline Form I of Omecamtiv mecarbil diHBr may alternatively or additionally be characterized by data selected from one or more of the following: a solid state 13C NMR spectrum with characteristic peaks at: 137.35, 128.31, 124.11, 41.15 and 21.37 ± 2 ppm; a solid state 13C NMR spectrum having the following chemical shift absolute differences from reference peak at 145.96±2ppm: 8.61, 17.65, 21.85, 104.81 and 124.59±2ppm; or by solid state 13C NMR spectrum as depicted in Figure 2; or combinations of these data.
[0037] Omecamtiv mecarbil diHBr salt of the present invention is anhydrous, non- hygroscopic and has shown high thermal stability.
[0038] In a further embodiment, Crystalline Form I of Omecamtiv mecarbil diHBr according to the present invention is mechanically and thermodynamically stable. Pharmaceutical molecules may display solid to solid phase transformations and transformations between polymorphs; which may be detected by exposure of the solid state form to stress conditions of e.g., high temperature, high relative humidity, stress and grinding. In particular, crystalline Form I of Omecamtiv mecarbil diHBr according to the present invention has shown to be thermodynamically and mechanically stable.
[0039] The present disclosure also relates to the use of the solid state form of Omecamtiv mecarbil diHBr salt of the present disclosure, for preparing other solid state forms of Omecamtiv mecarbil and/or other Omecamtiv mecarbil salts and solid state forms thereof.
[0040] The present disclosure further provides solid state form of Omecamtiv mecarbil diHBr salt for use in the preparation of other solid state forms of Omecamtiv mecarbil and/or other Omecamtiv mecarbil salts and solid state forms thereof.
[0041] The present disclosure also encompasses the use of the described solid state form of Omecamtiv mecarbil diHBr salt for the preparation of pharmaceutical compositions and/or formulations.
[0042] The present disclosure further encompasses the described solid state form of Omecamtiv mecarbil diHBr salt for use in the preparation of pharmaceutical compositions and/or formulations for use in medicine, preferably for the treatment of heart failure.
[0043] In another aspect, the present disclosure provides pharmaceutical compositions comprising the solid state form according to the present disclosure.
[0044] In yet another embodiment, the present disclosure encompasses pharmaceutical formulations comprising the described solid state form of Omecamtiv mecarbil diHBr salt, or of pharmaceutical compositions comprising the solid state form of Omecamtiv mecarbil diHBr salt, and at least one pharmaceutically acceptable excipient.
[0045] The present disclosure further encompasses processes to prepare said pharmaceutical formulations of Omecamtiv mecarbil diHBr salt comprising combining the above described solid state form of Omecamtiv mecarbil diHBr salt and at least one pharmaceutically acceptable excipient.
[0046] Pharmaceutical formulations of the present invention contain the solid state form Omecamtiv mecarbil diHBr salt of the present invention. In addition to the active ingredient, the pharmaceutical formulations of the present invention can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
[0047] 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.
[0048] 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.
[0049] 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. [0050] 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.
[0051] 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.
[0052] 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 invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
[0053] 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.
[0054] In liquid pharmaceutical compositions of the present invention, the active ingredient 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.
[0055] 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.
[0056] 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, and xanthan gum.
[0057] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
[0058] 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.
[0059] According to the present invention, 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.
[0060] The solid compositions of the present invention 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 invention 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.
[0061] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
[0062] The dosage form of the present invention can be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, 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.
[0063] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] A capsule filling of the present invention 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.
[0068] A pharmaceutical formulation of Omecamtiv mecarbil diHBr salt is preferably formulated for administration to a mammal, preferably a human. Omecamtiv mecarbil diHBr salt can be formulated, for example, as a viscous liquid solution or suspension, preferably 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 ah, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
[0069] The solid state form as defined herein as well as the pharmaceutical compositions or formulations of the solid state form of Omecamtiv mecarbil dilTBr salt may be used as medicaments, particularly for the treatment of heart failure.
[0070] The present disclosure also provides methods of treating heart failure comprising administering a therapeutically effective amount of the above described solid state form of Omecamtiv mecarbil dilTBr salt, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from heart failure, or otherwise in need of the treatment. [0071] The present disclosure also provides the use of the solid state form of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating heart failure.
[0072] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further illustrated by reference to the following example describing in detail the preparation of the composition and methods of use of the disclosure.
It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure. Analytical Methods
Powder X-ray diffraction pattern (“PXRD”) method:
[0073] Sample after being powdered in a mortar and pestle is applied directly on a silicon plate holder. XRPD analysis was performed on ARL (SCINTAG) powder X-Ray diffractometer model X’TRA equipped with a solid state detector. Copper radiation of 1.5418 A was used. Scanning parameters: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05°, and a rate of 3 deg/min.
13C Solid state NMR method
[0074] 13C CP/MAS NMR spectra were measured at 125 MHz using Bruker Avance III
HD 500 US / WB NMR spectrometer (Karlsruhe, Germany, 2013). The 13C CP/MAS NMR spectra employing cross-polarization were acquired using the standard pulse scheme at spinning frequency of 11 kHz and controlled temperature at 293 K ± 3°C. A probe using 4 mm o.d. zirconia rotors was employed. The recycle delay was 6-60 s and the cross polarization contact time was 1.75 ms. The strength of spin-locking fields /ii(l3C) expressed in frequency units wi/2p=g6i was 64 kHz. Chemical shifts were referenced via a replacement sample of glycine (carboxyl carbon chemical shift assigned as 176.03 ppm relative to the signal of tetramethyl silane).
Examples
[0075] The starting material Omecamtiv mecarbil (form O-l) can be prepared according to International Publication No. WO 2020/014406.
Example 1: Preparation of Omecamtiv mecarbil diHBr salt- Form I [0076] Isopropyl alcohol (10 ml) was added to Omecamtiv mecarbil free base (form O-l, 0.1 grams) and was magnetically stirred at room temperature to give a slurry. Then an aqueous solution of HBr salt (48% w/w, 0.088 ml) was dropwise added and the obtained slurry was magnetically stirred at room temperature during 18 hours. The obtained solid was separated by centrifuge, washed with isopropyl alcohol (1 V*2) and dried in vacuum oven at 45 °C during 18 hours. The obtained solid was characterized by X-ray powder diffraction and designated as Omecamtiv mecarbil diHBr salt- Form I (Figure 1).
Example 2: Preparation of Omecamtiv mecarbil diHBr salt- Form
Figure imgf000014_0001
[0077] Ethyl acetate (10 ml) was added to Omecamtiv mecarbil free base (form O-l, 0.1 grams) and was magnetically stirred at room temperature to give slurry. Then an aqueous solution of HBr salt (48% w/w, 0.088 ml) was dropwise added and the obtained slurry was magnetically stirred at room temperature during 18 hours. After that, the obtained solid was separated by centrifuge, washed with ethyl acetate (1 V*2) and dried in vacuum oven at 45 °C during 18 hours. The obtained solid was characterized by X-ray powder diffraction- Omecamtiv mecarbil diHBr salt- Form I.
Example 3: Preparation of Omecamtiv mecarbil diHBr salt- Form I [0078] Isopropyl alcohol (20 ml, 20V) was added to Omecamtiv mecarbil free base (1 gram, 2.5 mmol) and was magnetically stirred at room temperature to give a slurry. Then an aqueous solution of HBr (48%w/w, 0.88 ml) was dropwise added and obtained slurry was magnetically stirred at room temperature during 18 hours. The obtained solid was separated by centrifuge, washed with Isopropyl alcohol (2V*2) and dried in vacuum oven at 45 °C during 18 hours. The obtained solid was characterized by X-ray powder diffraction: Omecamtiv mecarbil diHBr salt -Form I was obtained.

Claims

Claims
1. Omecamtiv mecarbil diHBr salt, optionally in crystalline form.
2. A crystalline form of Omecamtiv mecarbil diHBr salt according to Claim 1, designated as Form I, which is characterized by: an X-ray powder diffraction pattern substantially as depicted in Figure 1; or an X-ray powder diffraction pattern having peaks at 7.1, 18.8,
20.3, 21.5 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta.
3. Crystalline Form I of Omecamtiv mecarbil diHBr salt according to Claim 2, which is further characterized by an X-ray powder diffraction pattern having peaks at 7.1, 18.8,
20.3, 21.5 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 15.0, 18.3, 19.3, 21.0 and 24.6 degrees 2- theta ± 0.2 degrees 2-theta.
4. Crystalline Form I of Omecamtiv mecarbil diHBr salt according to Claim 2 or Claim 3, which is characterized by an X-ray powder diffraction pattern having peaks at 7.1, 15.0,
18.3, 18.8, 19.3, 20.3, 21.0, 21.5, 24.6 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta.
5. Omecamtiv mecarbil diHBr salt according to any of Claims 2, 3 or 4, which is polymorphically pure.
6. Crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 2, 3, 4, or 5, which is substantially free of any other solid state forms of Omecamtiv mecarbil or salts thereof.
7. Crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 2, 3, 4, 5, or 6, 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% (w/w) of any other forms of Omecamtiv mecarbil or salts thereof.
8. Use of a crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 1-7 for preparing other crystalline forms of Omecamtiv mecarbil, salts of Omecamtiv mecarbil or crystalline forms thereof, or solvates of Omecamtiv mecarbil or crystalline forms thereof.
9. Use of crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 1-7 for preparing pharmaceutical compositions of Omecamtiv mecarbil or Omecamtiv mecarbil salts.
10. A pharmaceutical composition comprising crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 1-7, and at least one pharmaceutically acceptable excipient.
11. Use of crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 1-7 for the preparation of a pharmaceutical composition and/or formulation.
12. A process for preparing the pharmaceutical composition according to Claim 10, comprising combining crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 1-7 with at least one pharmaceutically acceptable excipient.
13. Crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 1-7, or a pharmaceutical composition according to Claim 10, for use as a medicament; preferably wherein the medicament is for the treatment of heart failure.
14. Crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 1-7, or a pharmaceutical composition according to Claim 10, for the preparation of a pharmaceutical formulation; preferably for the treatment of heart failure.
15. A method of treating heart failure comprising administering a therapeutically effective amount of crystalline Omecamtiv mecarbil diHBr salt according to any of Claims 1-7, or a pharmaceutical composition according to Claim 10, to a subject suffering from heart failure, or otherwise in need of the treatment.
PCT/US2022/016509 2021-02-16 2022-02-16 Unhydrous crystalline form of omecamtiv mecarbil dihydrobromide salt WO2022177927A1 (en)

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