Solid forms of mavacamten and methods for their preparation

Abstract

The present disclosure encompasses solid forms of mavacamten, and in some embodiments, crystalline polymorphs of mavacamten, methods for their preparation, and pharmaceutical compositions thereof.

Description

[Technical Field]

[0001] The present disclosure encompasses solid forms of mavacamten, and in some embodiments, crystalline polymorphs of mavacamten, methods for their preparation, and pharmaceutical compositions thereof. [Background technology]

[0002] Mavacamten, 6-{[(1S)-1-phenylethyl]amino}-3-(propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione, has the following chemical structure:

[0003] [ka]

[0004] Mavacamten is being developed for the treatment of hypertrophic obstructive cardiomyopathy (oHCM).

[0005] The compound is described in US Pat. No. 9,181,200.

[0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. Single molecules can be characterized by unique crystalline structures, as well as melting points, thermal behavior (measured, for example, by thermogravimetric analysis ("TGA") or differential scanning calorimetry ("DSC")), X-ray diffraction (XRD) patterns, infrared absorption fingerprints, and solid state ( 13 C) Different polymorphs may occur, having different physical properties such as NMR spectra. One or more of these techniques may be used to distinguish between various polymorphs of a compound.

[0007] Various salts and solid forms (including solvated forms) of an active pharmaceutical ingredient can have different properties. Such variations in the properties of various salts and solid forms and solvates can provide a basis for improving formulations, for example, by promoting better processing or handling characteristics, favorably altering the dissolution profile, or improving stability (polymorphic and chemical stability) and shelf life. These variations in the properties of various salts and solid forms can also improve the final dosage form, for example, if they serve to improve bioavailability. Various salts and solid forms and solvates of an active pharmaceutical ingredient can also give rise to various polymorphs or crystalline forms, thereby providing further opportunities for evaluating variations in the properties and characteristics of the solid active pharmaceutical ingredient.

[0008] The discovery of new solid forms and solvates of a pharmaceutical can result in materials with desirable processing properties, such as ease of handling, processing, storage stability, and purification, or can result in intermediate crystalline forms that facilitate conversion to other polymorphs as desired. New solid forms of a pharmaceutically useful compound can also provide opportunities to improve the performance characteristics of a pharmaceutical. The forms can provide products with different properties, including, for example, different crystal habits, higher crystallinity, or polymorphic stability, thereby expanding the repertoire of materials available to pharmaceutical scientists for formulation optimization by potentially imparting better processing or handling characteristics, improved dissolution profiles, or improved shelf life (chemical / physical stability). For at least these reasons, there is a need for additional solid forms of mavacamten, including solvated forms. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 9,181,200 [Non-patent literature]

[0010] [Non-Patent Document 1] Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. [Non-patent document 2] Dolomanov, OV, Bourhis, LJ, Gildea, RJ, Howard, JAK & Puschmann, H. (2009), J. Appl. Cryst. 42, pp. 339-341. [Non-patent document 3] Sheldrick, GM (2015). Acta Cryst. A71, pp. 3-8. [Non-patent document 4] Sheldrick, GM (2015). Acta Cryst. C71, pp. 3-8. Summary of the Invention [Means for solving the problem]

[0011] The present disclosure provides crystalline polymorphs of mavacamten, methods for their preparation, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid forms of mavacamten, mavacamten salts, and solid forms thereof.

[0012] The present disclosure also provides the use of said solid forms of mavacamten in the preparation of other solid forms of mavacamten or salts thereof.

[0013] The present disclosure provides crystalline polymorphs of mavacamten for use in medicine, including the treatment of cardiovascular disease, particularly hypertrophic obstructive cardiomyopathy (oHCM).

[0014] The present disclosure also encompasses the use of the disclosed crystalline polymorphs of mavacamten to prepare pharmaceutical compositions and / or formulations.

[0015] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline polymorph of mavacamten according to the present disclosure.

[0016] The present disclosure includes methods for preparing the aforementioned pharmaceutical compositions, which methods comprise combining any one or a combination of crystalline polymorphs of mavacamten with at least one pharmaceutically acceptable excipient.

[0017] The crystalline polymorphs of mavacamten defined herein, and pharmaceutical compositions or formulations of the crystalline polymorphs of mavacamten, can be used, for example, as medicaments for the treatment of obstructive hypertrophic cardiomyopathy (oHCM). The present disclosure also provides methods of treating obstructive hypertrophic cardiomyopathy (oHCM) by administering a therapeutically effective amount of any one or combination of the crystalline polymorphs of mavacamten disclosed herein, or at least one of the pharmaceutical compositions described above, to a subject suffering from or otherwise in need of treatment with oHCM.

[0018] The present disclosure also provides the use of at least one of the crystalline polymorphs of mavacamten of the present disclosure, or the pharmaceutical composition described above, for the manufacture of a medicament for treating, for example, hypertrophic obstructive cardiomyopathy. [Brief explanation of the drawings]

[0019] [Figure 1] 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of mavacamten Form 1. [Figure 2] 1 shows a characteristic XRPD of mavacamten form 2. [Figure 3] 1 shows a characteristic XRPD of amorphous mavacamten. [Figure 4] 1 shows a characteristic XRPD of mavacamten form 4. [Figure 5] 1 shows a characteristic XRPD of mavacamten form 5. [Figure 6] 1 shows a characteristic XRPD of mavacamten form 6. [Figure 7] 1 shows an SEM image of the prismatic morphology of mavacamten Form 1, prepared according to Example 9. [Figure 8] 1 shows an optical microscope image of the rod-like morphology of mavacamten Form 1, prepared according to Example 10. [Figure 9] 1 shows an SEM image of the plate-like morphology of mavacamten Form 5, prepared according to Example 11. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure encompasses solid forms of mavacamten, including crystalline polymorphs of mavacamten, methods for their preparation, and pharmaceutical compositions thereof.

[0021] The solid state properties of mavacamten and its crystalline polymorphs can be influenced by controlling the conditions under which mavacamten and its crystalline polymorphs are obtained in solid form.

[0022] A solid form (or polymorph) may be referred to herein as being polymorphically pure or as being substantially free of any other solid (or polymorphic) forms. As used herein, in this context, the phrase "substantially free of any other forms" is understood to mean that the solid 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 form of the subject compound, as measured, for example, by XRPD. Thus, a crystalline polymorph of mavacamten described herein as being substantially free of any other solid form can be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of mavacamten. In some embodiments of the present disclosure, the described crystalline polymorph of mavacamten can contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other crystalline polymorphs of the same mavacamten.

[0023] Depending on the other crystalline polymorphs to which it is compared, the crystalline polymorphs of mavacamten of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability with respect to polymorphic transformation, e.g., chemical stability, and thermal and mechanical stability, stability against dehydration and / or storage stability, low content of residual solvents, lower moisture absorption, flowability, and advantageous processing and handling characteristics, e.g., compressibility and bulk density.

[0024] Solid forms, e.g., crystalline or amorphous forms, may be referred to herein as being characterized by graphical data "as depicted in" or "substantially 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, graphical data potentially provides additional technical information to further define each solid form (a so-called "fingerprint") that cannot necessarily be described by reference to numerical values ​​or peak positions alone. In any event, those skilled in the art will understand that such graphical representations of data may be subject to slight variations, e.g., in the relative intensities of peaks and peak positions, due to certain factors, such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to those skilled in the art. Nevertheless, those skilled in the art will be able to readily compare the graphical data of a figure herein with graphical data generated for an unknown crystalline form and determine whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms. Thus, a crystalline form of mavacamten referred to herein as being characterized by graphical data "as depicted in" or "substantially as depicted in" a figure will be understood to include any crystalline form of mavacamten characterized using graphical data with such slight variations as would be known to one skilled in the art upon comparison with the figure.

[0025] As used herein, unless otherwise stated, the term "anhydrous" with respect to a crystalline form of mavacamten refers to a crystalline form of mavacamten that does not contain any water of crystallization (or other solvent) in a stoichiometric amount defined within the crystal. Furthermore, an "anhydrous" form will generally not contain more than 1% (w / w) of either water or organic solvent, as measured, for example, by TGA.

[0026] The term "solvate," as used herein, unless otherwise specified, refers to a crystalline form that incorporates a solvent into the crystalline structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate can be present in either stoichiometric or non-stoichiometric amounts.

[0027] As used herein, the term "isolated" with respect to the crystalline forms of mavacamten of the present disclosure corresponds to the physical separation of the mavacamten crystalline polymorph from the reaction mixture in which it is formed.

[0028] As used herein, unless otherwise stated, XRPD measurements are made using copper Kα radiation, wavelength 1.5418 Å. XRPD peaks reported herein are measured using Cu Kα radiation, λ=1.5418 Å, typically at a temperature of 25±3° C.

[0029] An object, such as a reaction mixture, may be characterized herein as being at or at "room temperature" or "ambient temperature," often abbreviated as "RT." This means that the temperature of the object is close to or the same as the temperature of the space in which the object is located, e.g., a room or fume hood. Typically, room temperature is about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0030] The amount of solvent used in a chemical process, such as a reaction or crystallization, may be referred to herein as a numerical value of "volume" or "vol" or "V." For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this context, this expression may be understood to mean milliliters of solvent per gram of suspended material; thus, suspending 5 grams of a material in 10 volumes of solvent means that the solvent is used in an amount of 10 milliliters of solvent per gram of suspended material, i.e., 50 mL of solvent in this example. In other contexts, the term "v / v" may be used to indicate a numerical value of the volume of solvent added to a liquid mixture, based on the volume of the mixture. For example, adding solvent X (1.5 v / v) to 100 ml of reaction mixture may indicate that 150 mL of solvent X has been added.

[0031] A method or step may be referred to herein as being performed "overnight." This refers, for example, to a time period for the method or step that spans overnight, when the method or step may not be actively observed. This time period may be about 8 to about 20 hours, or about 10 to 18 hours, or in some cases about 16 hours.

[0032] As used herein, the term "reduced pressure" refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is from about 10 mbar to about 50 mbar.

[0033] As used herein, unless otherwise specified, the term "ambient conditions" refers to atmospheric pressure and a temperature of 22-24°C.

[0034] The present disclosure includes a crystalline polymorph of mavacamten designated Form 1. Crystalline Form 1 of mavacamten can be characterized by data selected from one or more of an X-ray powder diffraction pattern substantially as depicted in Figure 1 below, an X-ray powder diffraction pattern having peaks at 11.7, 16.3, 18.7, 20.0, and 23.4 degrees 2-theta ±0.2 degrees 2-theta, and combinations of these data.

[0035] Crystalline Form 1 of mavacamten can be further characterized by an X-ray powder diffraction pattern having peaks at 11.7, 16.3, 18.7, 20.0 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta, and any one, two or three additional peaks selected from 17.4, 29.1 and 31.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0036] In one embodiment of the present disclosure, crystalline Form 1 of mavacamten is isolated.

[0037] Crystalline Form 1 of mavacamten can be anhydrous.

[0038] In other embodiments, crystalline Form 1 of mavacamten can be characterized by the following cell parameters:

[0039] [Table 1]

[0040] In some embodiments of the present invention, crystalline Form 1 of mavacamten, as defined according to any aspect or embodiment described herein, may be provided in a particular morphology. In particular, crystalline Form 1 may comprise particles having a prismatic or rod-like morphology. Crystalline Form 1 having the morphology described herein provides advantageous processing characteristics and / or stability due to the particles having a uniform morphology.

[0041] In a further embodiment, crystalline Form 1 of mavacamten according to the present invention is stable when exposed to elevated temperatures and high relative humidity.

[0042] The present invention also provides a method for preparing mavacamten Form 1, the method comprising: - providing mavacamten in an organic solvent, preferably an alcohol, in particular methanol, 2-butanol, isobutanol, 1-propanol or dimethylformamide; - heating to reflux temperature; - crystallizing Form 1 by evaporating the solvent under room temperature conditions or by cooling the solution to about 0°C, preferably by an ice bath; Includes:

[0043] In another aspect of the present invention, there is provided a process for preparing crystalline Form 1 of mavacamten, comprising providing a suspension of mavacamten in an organic solvent, preferably an ether, more preferably a cyclic ether, especially tetrahydrofuran, at reflux temperature, and removing the solvent, preferably by evaporation under room temperature conditions.

[0044] The present disclosure also provides mavacamten Form 2. Crystalline Form (From) 2 of mavacamten can be characterized by data selected from one or more of an X-ray powder diffraction pattern substantially as depicted in Figure 2 below, an X-ray powder diffraction pattern having peaks at 7.8, 8.5, 11.2, 17.0 and 21.5 degrees 2-theta ±0.2 degrees 2-theta, and combinations of these data.

[0045] Crystalline Form 2 of mavacamten can be further characterized by an X-ray powder diffraction pattern having peaks at 7.8, 8.5, 11.2, 17.0, and 21.5 degrees 2-theta ± 0.2 degrees 2-theta, and any one, two, three, four, or five additional peaks selected from 11.9, 15.6, 23.9, 25.6, and 26.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0046] In one embodiment of the present disclosure, crystalline Form 2 of mavacamten is isolated.

[0047] In a further embodiment, crystalline Form 2 of mavacamten may be anhydrous.

[0048] The present disclosure also includes a crystalline polymorph of mavacamten designated Form 4. Crystalline Form 4 of mavacamten can be characterized by data selected from one or more of an X-ray powder diffraction pattern substantially as depicted in Figure 4 below, an X-ray powder diffraction pattern having peaks at 11.4, 13.0, 19.3, 19.7, and 23.2 degrees 2-theta ±0.2 degrees 2-theta, and combinations of these data.

[0049] Crystalline Form 4 of mavacamten can be further characterized by an X-ray powder diffraction pattern having peaks at 11.4, 13.0, 19.3, 19.7, and 23.2 degrees 2-theta ± 0.2 degrees 2-theta, and any one, two, three, or four additional peaks selected from 12.0, 13.5, 17.1, and 18.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0050] In one embodiment of the present disclosure, crystalline Form 4 of mavacamten is isolated.

[0051] In a further embodiment, crystalline Form 4 of mavacamten may be anhydrous.

[0052] In a further embodiment, crystalline Form 4 of mavacamten can be characterized by the following cell parameters:

[0053] [Table 2]

[0054] The present disclosure also provides a crystalline polymorph of mavacamten designated Form 5. Crystalline Form 5 of mavacamten can be characterized by data selected from one or more of an X-ray powder diffraction pattern substantially as depicted in Figure 5 below, an X-ray powder diffraction pattern having peaks at 13.4, 14.8, 21.8, 23.8, and 24.6 degrees 2-theta ± 0.2 degrees 2-theta, and combinations of these data.

[0055] Crystalline Form 5 of mavacamten can be further characterized by an X-ray powder diffraction pattern having peaks at 13.4, 14.8, 21.8, 23.8, and 24.6 degrees 2-theta ± 0.2 degrees 2-theta, and any one, two, three, or four additional peaks selected from 11.9, 15.8, 18.9, and 20.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0056] In one embodiment of the present disclosure, crystalline Form 5 of mavacamten is isolated.

[0057] In a further embodiment, crystalline Form 5 of mavacamten may be anhydrous.

[0058] In another embodiment, crystalline Form 5 of mavacamten can be characterized by the following cell parameters:

[0059] [Table 3]

[0060] In some embodiments of the present invention, crystalline Form 5 of mavacamten, as defined according to any aspect or embodiment described herein, may exhibit a plate-like morphology. Crystalline Form 5 having the morphology described herein provides advantageous processing characteristics and / or stability due to particles having a uniform morphology.

[0061] In a further embodiment, crystalline form 5 of mavacamten according to the present invention is a stable form, i.e. does not exhibit solid-to-solid phase transformation, even when exposed to high temperatures and high relative humidity.

[0062] Another aspect of the present invention is a process for preparing mavacamten Form 5, comprising: - providing a solution of mavacamten in an organic solvent, preferably a monocarboxylic acid or a monocarboxylic acid amide, in particular N,N-dimethylacetamide, or acetic acid; - optionally heating to reflux temperature; - crystallizing Form 5, optionally in the presence of an anti-solvent; The present invention relates to a method, comprising:

[0063] In another aspect of the present invention, there is provided a process for preparing crystalline form 5 of mavacamten, comprising providing a suspension of mavacamten in an organic solvent, preferably an alkane, more preferably a linear alkane, especially n-heptane, at an elevated temperature, and isolating form 5 of mavacamten.

[0064] The present disclosure also includes a crystalline polymorph of mavacamten designated Form 6. Crystalline Form 6 of mavacamten can be characterized by data selected from one or more of the X-ray powder diffraction pattern substantially as depicted in Figure 6 below, X-ray powder diffraction patterns having peaks at 6.4, 9.3, 12.7, 13.3 and 20.8±0.2 degrees two-theta, and combinations of these data.

[0065] Form 6 of mavacamten can be anhydrous.

[0066] The above mentioned polymorphs can be used to prepare other polymorphs of mavacamten, mavacamten salts and solid forms thereof.

[0067] The present disclosure encompasses other solid forms of mavacamten, mavacamten salts, and methods for preparing these solid forms. The method for preparing a salt of mavacamten comprises acidifying any one or a combination of the aforementioned solid forms of mavacamten to obtain the corresponding salt.

[0068] The present disclosure also encompasses the use of the disclosed crystalline polymorphs of mavacamten for the preparation of pharmaceutical compositions of the crystalline polymorphs of mavacamten and / or the crystalline polymorphs thereof.

[0069] The present disclosure includes methods for preparing the aforementioned pharmaceutical compositions, which methods comprise combining any one or combination of the crystalline polymorphs of mavacamten disclosed herein with at least one pharmaceutically acceptable excipient.

[0070] The pharmaceutical combinations or formulations of the present disclosure contain any one or combination of the solid forms of mavacamten disclosed herein. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for various purposes.

[0071] Diluents can add bulk to a solid pharmaceutical composition, making pharmaceutical dosage forms containing the composition easier for patients and caregivers to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, dextrates, dextrin, dextrose, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0072] Solid pharmaceutical compositions that are compressed into dosage forms such as tablets can contain 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), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0073] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition, including 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, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0074] Glidants can be added to improve the flowability of non-compacted solid compositions and improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0075] When a dosage form such as a tablet is produced by compressing a powdered composition, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients tend to adhere to the surfaces of the punch and die, which can cause pitting and other surface irregularities in the product. To reduce adhesion and facilitate release of the product from the die, a lubricant can be added to the composition. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0076] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceuticals that can be included in the compositions of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0077] Solid and liquid compositions may also be dyed using any pharmaceutically acceptable coloring agent to improve their appearance and / or to allow the patient to easily identify the product and unit dosage level.

[0078] In liquid pharmaceutical compositions of the present invention, mavacamten and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0079] Liquid pharmaceutical compositions may contain emulsifying agents to uniformly disperse active ingredients or other excipients that are not soluble in the liquid carrier throughout the composition. Emulsifying agents that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0080] The liquid pharmaceutical compositions of the present invention may also contain viscosity enhancing agents to improve the mouthfeel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, bentonite alginate, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum, and combinations thereof.

[0081] To improve the taste, sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added.

[0082] To improve storage stability, preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid can be added at levels safe for consumption.

[0083] According to the present disclosure, the liquid composition may also contain a buffering agent, such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The choice of excipients and the amounts to be used can be readily determined by a formulation scientist based on experience and consideration of standard procedures and referenced studies in the field.

[0084] The solid compositions of the present disclosure include powders, granules, aggregates, and compressed compositions. Dosages include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. While the most appropriate administration in any given case will vary depending on the nature and severity of the condition being treated, in some embodiments, the route of administration is oral. Dosages are conveniently presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy.

[0085] Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0086] The dosage form of the present disclosure may also be a capsule containing the composition of the present disclosure, such as a powdered or granulated solid composition, in either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer, such as glycerin and / or sorbitol, an opacifying agent, and / or a colorant.

[0087] The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0088] Compositions 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, which causes the powder to clump into granules. The granules are sieved and / or milled, dried, and then sieved and / or milled to the desired particle size. The granules can then be compressed into tablets, or other excipients such as glidants and / or lubricants can be added before tableting.

[0089] Tablet compositions can be conventionally prepared by dry blending. For example, the blended active agent and excipient composition can be compressed into a slug or a sheet and then comminuted into compacted granules. The compacted granules can then be compressed into tablets.

[0090] As an alternative to dry granulation, the blended composition can be directly compressed into a compressed dosage form using direct compression technology. 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 appropriate use of these and other excipients in direct compression tableting is known to those skilled in the art, especially those who have experienced the formulation challenges of direct compression tableting.

[0091] The capsule filling of the present disclosure may include any of the foregoing blends and granules described with respect to tableting, but which do not undergo a final tableting step.

[0092] Mavacamten can be formulated for administration by injection to mammals, in some embodiments, humans. Mavacamten can be formulated, for example, as a viscous liquid solution or suspension for injection, e.g., a clear solution. 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 may allow syringeability), flowability, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and castor oil USP. Additional substances, such as buffers, solubilizers, and antioxidants, among others, can be added to the formulation. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition.

[0093] The disclosed crystalline polymorphs of mavacamten and pharmaceutical compositions and / or formulations of mavacamten can, in some embodiments, be used as medicaments in the treatment of hypertrophic obstructive cardiomyopathy (oHCM).

[0094] The present disclosure also provides a method for treating obstructive hypertrophic cardiomyopathy by administering to a subject in need thereof a therapeutically effective amount of any one or combination of the crystalline polymorphs of mavacamten disclosed herein, or at least one of the pharmaceutical compositions and / or formulations described above.

[0095] While the present disclosure has thus been described with reference to certain preferred embodiments and illustrative examples, those skilled in the art will recognize that modifications may be made to the present disclosure as described and illustrated without departing from the spirit and scope of the disclosure as disclosed herein. The examples are set forth to aid in the understanding of the present disclosure, but are in no way intended to, and should not be understood to, limit the scope of the disclosure.

[0096] X-ray Powder Diffraction ("XRPD") Method The sample was powdered with a mortar and pestle and then directly applied to a silicon plate holder. X-ray powder diffraction patterns were measured using a Philips X'Pert PRO X-ray powder diffractometer equipped with a Cu source at 1.54184 Å (Angstroms) and an X'Celerator (2.022° 2θ) detector. Scanning parameters were: angle range 3-40°, step size 0.0167, time per step 37 s, continuous scan. The peak positions reported were determined using silicon powder as an internal standard.

[0097] SEM method SEM micrographs were taken on a Jeol JSM-5800 scanning microscope at 20 kV, WD 20-22, low current. Samples were sputtered with gold using an Edwards S150 sputter coater.

[0098] optical microscope Samples were analyzed with an Olympus BX53 optical microscope with an Olympus XC50 camera using silicon oil as the carrier medium.

[0099] Single Crystal X-ray Diffraction ("SCXRD") Method A suitable crystal was selected and directly mounted on an Xcalibur goniometer, a Sapphire3, or a Gemini diffractometer. The crystal was maintained at 298 K during data collection. Data collection was performed using CrysAlis Pro (Rigaku Oxford Diffraction). The structure was solved using Olex2 (Dolomanov, OV, Bourhis, LJ, Gildea, RJ, Howard, JAK & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341) using intrinsic phasing with the SHELXT (Sheldrick, GM (2015). Acta Cryst. A71, 3-8) structure analysis program and refined using least squares minimization with the SHELXL (Sheldrick, GM (2015). Acta Cryst. C71, 3-8) refinement package. [Example]

[0100] Preparation of starting materials Mavacamten can be prepared according to methods known from the literature, for example US Pat. No. 9,181,200 (Example 1).

[0101] Example 1 Preparation of mavacamten form 1 Mavacamten (50 mg) was dissolved in methanol (2 ml) at reflux temperature. The prepared solution was left open at room temperature to allow the solvent to evaporate. After crystallization occurred, the crystals were filtered off and analyzed by XRPD. Mavacamten Form 1 was obtained, as shown in Figure 1.

[0102] Example 2 Preparation of mavacamten form 2 Mavacamten (Form 1, 50 mg) was heated from 30° C. to 241° C. at 10° C. / step with a heating rate of 10° C. / min, and then cooled to 30° C. The sample temperature was controlled using an Anton Paar TCU100 temperature control unit. The sample was analyzed by XRPD. Mavacamten Form 2 was obtained, as shown in FIG. 2.

[0103] Example 3 Preparation of amorphous mavacamten Mavacamten (2.0 grams) was dissolved in absolute ethanol (90 ml) by heating to 52° C. The prepared solution was then subjected to the following conditions: T (inlet) = 100° C., suction = 35 ml 3 time -1 The mixture was spray dried at a pump rate of 6.9 ml / min. The resulting material was analyzed by XRPD. As shown in Figure 3, an amorphous material was obtained.

[0104] Example 4 Preparation of mavacamten form 4 Amorphous mavacamten (20 mg) was exposed to atmospheric vapors of cyclohexane for 7 days. The resulting product was analyzed by XRPD. As shown in Figure 4, mavacamten Form 4 was obtained.

[0105] Example 5 Preparation of mavacamten form 5 Amorphous mavacamten (200 mg) was suspended in n-heptane (2 ml) at 40° C. for 4 hours and stirred at 20-25° C. for 16 hours. The material was isolated by vacuum filtration and analyzed by XRPD. Mavacamten Form 5 was obtained, as shown in FIG. 5.

[0106] Example 6 Preparation of mavacamten form 6 Amorphous mavacamten (20 mg) was placed in an Eppendorf tube, and the tube was placed in a crystallization flask with 2 mL of chloroform. The crystallization flask was then closed. After exposing the sample to chloroform vapor for 14 days, the material was analyzed by XRPD. As shown in Figure 6, mavacamten Form 6 was obtained.

[0107] Example 7 Preparation of mavacamten form 1 Mavacamten (50 mg) was suspended in tetrahydrofuran (5 ml) at reflux temperature. The suspension was left open at room conditions to allow the solvent to evaporate. After crystallization occurred, the crystals were filtered off and analyzed by XRPD to obtain mavacamten Form 1.

[0108] Example 8 Preparation of mavacamten form 5 Mavacamten (50 mg) was dissolved in N,N-dimethylacetamide (1 ml) at a temperature of 100° C. The solution was left open at room conditions to allow the solvent to evaporate. After crystallization occurred, the crystals were filtered off and analyzed by XRPD to obtain mavacamten Form 5.

[0109] Example 9 Preparation of mavacamten form 1 Mavacamten (1 gram) was dissolved in isobutanol (30 ml) at 80° C. The resulting solution was cooled to room temperature, stirred overnight, and then cooled (ice bath) for 1 hour. The resulting precipitate was filtered off and analyzed by XRPD to obtain mavacamten Form 1.

[0110] Example 10 Preparation of mavacamten form 1 Mavacamten (50 mg) was dissolved in ethanol (2 ml) at 60° C. The solution was left open at room conditions to allow the solvent to evaporate. After crystallization occurred, the crystals were filtered off and analyzed by XRPD to obtain mavacamten Form 1.

[0111] Example 11 Preparation of mavacamten form 5 Mavacamten (3 grams) was dissolved in acetic acid (25 ml) at 55° C. The resulting solution was cooled to room temperature and added dropwise to water (100 ml). The crystals were filtered off and analyzed by XRPD to obtain mavacamten Form 5.

Claims

1. A crystalline product of mavacamten designated Form 1, characterized by an X-ray powder diffraction pattern with peaks at 11.7, 16.3, 18.7, 20.0 and 23.4 degrees 2-theta ±0.2 degrees 2-theta.

2. 10. The crystalline product of claim 1, characterized by an XRPD having peaks at 11.7, 16.3, 18.7, 20.0, and 23.4 degrees 2-theta ± 0.2 degrees 2-theta, and further characterized by having one, two, or three additional peaks selected from 17.4, 29.1, and 31.6 degrees 2-theta ± 0.2 degrees 2-theta.

3. 3. The crystalline product of claim 2, characterized by an XRPD having peaks at 11.7, 16.3, 17.4, 18.7, 20.0, 23.4, 29.1, and 31.6 degrees two-theta ±0.2 degrees two-theta.

4. A crystalline product described in any one of claims 1 to 3 characterized by the following X-ray powder diffraction pattern: Table 1

5. 5. The crystalline product of any one of claims 1 to 4, in anhydrous form.

6. A crystalline product of mavacamten designated Form 5, characterized by an X-ray powder diffraction pattern with peaks at 13.4, 14.8, 21.8, 23.8, and 24.6 degrees 2-theta ±0.2 degrees 2-theta.

7. 7. The crystalline product of claim 6, characterized by an XRPD having peaks at 13.4, 14.8, 21.8, 23.8, and 24.6 degrees 2-theta ± 0.2 degrees 2-theta, and further characterized by having one, two, three, or four additional peaks selected from 11.9, 15.8, 18.9, and 20.1 degrees 2-theta ± 0.2 degrees 2-theta.

8. 8. The crystalline product of claim 6 or claim 7, characterized by an XRPD having peaks at 11.9, 13.4, 14.8, 15.8, 18.9, 20.1, 21.8, 23.8 and 24.6 degrees 2-theta ±0.2 degrees 2-theta.

9. A crystalline product described in any one of claims 6 to 8, characterized by the following X-ray powder diffraction pattern: Table 2

10. 10. The crystalline product of any one of claims 6 to 9, in anhydrous form.

11. 11. A pharmaceutical composition comprising the crystalline product of any one of claims 1 to 10 and at least one pharmaceutically acceptable excipient.

12. 11. Use of a crystalline product according to any one of claims 1 to 10 for the preparation of a pharmaceutical composition and / or formulation.

13. 12. A method for preparing the pharmaceutical composition of claim 11, comprising combining the crystalline product of any one of claims 1 to 10 with at least one pharmaceutically acceptable excipient.

14. 12. A crystalline product according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use as a medicament.

15. 12. A crystalline product according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use in the treatment of obstructive hypertrophic cardiomyopathy (oHCM).

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