Crystalline forms of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide and related products and methods

Abstract

Crystalline forms of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]-phenyl}-5-methylpyridine-3-carboxamide are provided. Pharmaceutical compositions and dosage forms containing the crystalline forms are also provided, including related methods for modulating kinases generally, and for treating PAH in particular.

Description

[Technical field]

[0001] The present invention relates to crystalline forms of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide, as well as products containing such crystalline forms and related methods of their use and preparation. [Background technology]

[0002] Receptor tyrosine kinases are transmembrane polypeptides that regulate cell renewal, remodeling, development and differentiation. Among the receptor tyrosine kinases is the platelet derived growth factor receptor (PDGFR), which is associated with pulmonary disease, tissue fibrosis, and solid tumors.

[0003] Among pulmonary diseases, pulmonary hypertension (PH) is a rare disorder of the pulmonary vasculature associated with high morbidity and mortality. The pathology of this disease includes plexiform lesions of unregulated angiogenesis and abnormal neointimal cell proliferation that impede blood flow through pulmonary arterioles. Known kinase receptor inhibitors, particularly known PDGFR inhibitors, are not orally available, are associated with off-target effects that may contribute to PH development, and / or are associated with dose-limiting side effects. Thus, there is a need for agents that can inhibit PDGFRα and / or PDGFRβ with improved potency and selectivity over other kinases (e.g., cKit, FLT3, and VEGFR2) that are known to be involved in dose-limiting side effects.

[0004] N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide (hereinafter referred to as "Compound 1"), also known as GB002 or Seralutinib, is a highly potent and selective inhibitor of PDGFRα and PDGFRβ signaling. Compound 1 is in clinical development as an inhaled treatment for pulmonary arterial hypertension (PAH). Amorphous forms of Compound 1 are described in U.S. Pat. Nos. 9,815,815 and 10,231,966, and a spray-dried powder formulation is described in U.S. Pat. No. 9,925,184. Compound 1 has the following structure:

[0005] [ka]

[0006] In view of the clinical promise of Compound 1, particularly in the context of pharmaceutical drug products suitable for delivery by inhalation, there is a need for new, improved, and / or enhanced forms of Compound 1, as well as compositions comprising Compound 1, and methods for their preparation and use. The present invention meets these and related needs, as evidenced by the following detailed description and the accompanying drawings. Summary of the Invention

[0007] A solid drug form can exist in either an amorphous or crystalline state. In crystalline forms, the molecules are located in three-dimensional lattice sites. When a compound recrystallizes from a solution or slurry, it may crystallize in different spatial lattice arrangements, a property called "polymorphism," and different crystalline forms are called "polymorphs" or individually "polymorphs." Different polymorphs of a given substance may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compression behavior, flow properties, and / or solid-state stability. For chemicals that exist in two (or more) polymorphic forms, the unstable form will generally convert to a more thermodynamically stable form at a given temperature after a sufficient amount of time. If this conversion is not rapid, the thermodynamically unstable form is called a "metastable" form. In general, a stable form exhibits the highest melting point, the lowest solubility, and the greatest chemical stability. However, a metastable form may exhibit sufficient chemical and physical stability under normal storage conditions to allow its use in a commercial form. In this case, the metastable form is less stable but may exhibit more desirable properties than the stable form, such as increased solubility or better oral bioavailability.

[0008] Thus, in one embodiment, there is provided a novel solid crystalline form of Compound 1. In a more specific embodiment, the novel solid crystalline forms are two distinct polymorphs of Compound 1, referred to herein as "Form A" and "Form B."

[0009] In one embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form is Form A, and in a further embodiment is substantially pure Form A. Form A may be characterized by various analytical techniques disclosed herein, including (for example) X-ray powder diffraction (XRPD) and the characteristic diffractograms generated thereby.

[0010] In one embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form is Form B, and in a further embodiment is substantially pure Form B. Form B may be characterized by various analytical techniques disclosed herein, including (for example) X-ray powder diffraction (XRPD) and the characteristic diffractograms generated thereby.

[0011] In one embodiment, a crystalline form of Compound 1 is provided, which is a mixture of Form A and Form B. As defined below, a mixture is provided when one crystalline form is present in a ratio ranging from 5 to 95% by weight of the other crystalline form (ratios of Form A and Form B above or below this range are characteristic of substantially pure crystalline forms).

[0012] In another embodiment, a pharmaceutical composition is provided that comprises a solid crystalline form of Compound 1 in combination with one or more pharma- ceutically acceptable carriers. Such compositions may be formulated in various forms. For example, the compositions may be formulated for administration to the respiratory tract, for example in the form of an inhalable powder, or as a dry powder. Such powder forms may be further characterized, for example, by their size (e.g., by the volume distribution where half is above a certain diameter and half is below a certain diameter, abbreviated as "Dv50").

[0013] In one embodiment, the pharmaceutical composition may include an additional therapeutically active agent (ie, in addition to the crystalline form of Compound 1).

[0014] In one embodiment, the pharmaceutical composition can include leucine, and in a more specific embodiment, the leucine coats the solid crystalline form of Compound 1. In a related embodiment, the leucine coated form is obtained by wet grinding.

[0015] In another embodiment, a solid unit dosage form is provided that comprises the solid crystalline form of Compound 1. Such dosage form refers to the form of drug product that is marketed for use.For example, the unit dosage form can be, for example, inhalable powder form or dry powder, including capsule or blister that contains the form suitable for administration to respiratory tract, for example, that is used with dry powder inhaler.

[0016] In another embodiment, a method is provided for treating a disease or condition modulated by kinase inhibition, comprising administering to a subject in need thereof an effective amount of a crystalline form, a pharmaceutical composition comprising same, or a solid unit dosage form comprising same of Compound 1. In a more specific embodiment, the kinase is a tyrosine kinase such as, but not limited to, platelet derived growth factor PDGFR, more specifically PDGFRα and / or PDGFRβ.

[0017] In one embodiment, the disease or condition is PAH, primary PAH, idiopathic PAH, hereditary PAH, refractory PAH, drug-induced PAH, toxin-induced PAH, or PAH with secondary disease, and in a more specific embodiment, PAH.

[0018] In yet another embodiment, a process is provided for preparing a solid crystalline form of Compound 1 by crystallization from a solvent comprising ethyl acetate. In one embodiment, the solvent may further comprise water and either n-heptane or ethanol.

[0019] In one embodiment, Applicants have surprisingly discovered a process for preparing crystalline form B from crystalline form A by slurrying form A of compound 1 in ethyl acetate and holding the temperature at about 10° C. to about 45° C. for 1 minute to 90 hours. [Brief description of the drawings]

[0020] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Figure 1] XRPD of amorphous Compound 1 after heating at 100° C. (lower trace) and 150° C. (upper trace). [Diagram 2] DSC of amorphous compound 1 heated to 320°C. [Diagram 3] DSC of amorphous compound 1 heated to 200°C. [Figure 4] DSC of amorphous Compound 1, first scan to 200° C. for Tg and ΔCp. [Diagram 5] H NMR spectrum of amorphous compound 1. [Figure 6] 1H-13C Heteronuclear Single Quantum Coherence (HSQC) NMR spectrum of amorphous compound 1. [Figure 7] Plot of heating rate (q) versus 1 / Tg for amorphous compound 1. [Figure 8] Comparison of X-Ray Powder Diffractograms (XRPD) for the ethanol slurry described in Example 3B (crystalline form B): starting material (top trace 1), after 24 hours (2), after 24 hours (3), and after addition of water and 72 hours (bottom trace 4). [Figure 9] XRPD of Compound 1, Form A. [Figure 10] XRPD of Compound 1, Form B. [Figure 11] DSC curve of compound 1, form A. [Figure 12] DSC curve of Compound 1, Form B. [Figure 13] TGA thermogram of Compound 1, Form A. [Figure 14] TGA thermogram of Compound 1, Form B. [Figure 15] Infrared spectrum of compound 1, form A [Figure 16] Infrared spectrum of compound 1, form B [Figure 17] XRPD of a slurry of crystalline Form A of Compound 1 in ethanol at 10° C. [Figure 18] XRPD of a slurry of crystalline Form A of Compound 1 in ethanol at room temperature. [Figure 19] XRPD of a slurry of crystalline form A of the compound in ethanol at 45° C. [Figure 20] Solubility curves in ethyl acetate±water for crystalline forms A and B of Compound 1 (mg / mL versus temperature). [Figure 21] Comparison of the solubility curves of crystalline forms A and B of Compound 1. [Figure 22] TGA for a sample containing a mixture of crystalline forms A and B of Compound 1. [Figure 23] Diffractogram comparison: reference (top), sample after TGA (middle), and initial sample (bottom). [Figure 24] ORTEP plot representation of the crystal structure of Compound 1, Form A. [Diagram 25] XRPD 2θ diffractogram of crystalline polymorphic form A of compound 1. [Figure 26] Visible unpolarized (top) and polarized (bottom) microscope images of compound 1. [Figure 27] LC-MS spectrum of compound 1. [Figure 28] HPLC chromatogram of compound 1. [Figure 29] TG / DTA thermogram of compound 1, TG upper trace|DT lower trace. [Diagram 30] DSC thermograms of compound 1: (a) first heating step; (b) cooling step and second heating (20-200° C.). [Diagram 31] GVS isotherm for compound 1 (dual cycle). [Diagram 32] GVS kinetic plot for compound 1. [Diagram 33] XRPD 2θ diffractograms of compound 1 before (top) and after (bottom) lyophilization. [Diagram 34] XRPD diffractograms of compound 1 after 1 week of storage under various conditions of temperature (ambient, 25° C., 40° C., 80° C.) and relative humidity (ambient, 60%, 75%). [Diagram 35] XRPD diffractograms of compound 1 before and after slurrying in various buffers. [Diagram 36] ORTEP-plot representation of the structure of compound 1, form B (50%). [Figure 37] PXRD comparison of the simulated pattern from SCXRD (bottom) with the reference Form B pattern (top). [Figure 38A] Mean concentration-time profiles (±SD) of Compound 1 over 4 and 72 hours, respectively. (Treatment A - test formulation, Treatment B - reference formulation). [Figure 38B] Mean concentration-time profiles (±SD) of Compound 1 over 4 and 72 hours, respectively. (Treatment A - test formulation, Treatment B - reference formulation). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] According to the present disclosure, novel solid crystalline forms of Compound 1 are provided. In a more specific embodiment, the novel solid crystalline forms are two distinct polymorphs of Compound 1, namely, Form A and Form B. Forms A and B differ from the amorphous form of Compound 1 in the structure of the crystal lattice, and each form gives a unique X-ray powder diffraction (XRPD) pattern and differential scanning calorimeter (DSC) thermogram.

[0022] As used herein, "amorphous" refers to the absence of ordered diffraction lines resulting from the absence of a repeating crystal lattice. As used herein, the amorphous form of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide can be prepared according to the procedures described in U.S. Patent No. 9,815,815 (see column 29, line 25 to column 31, line 11), the disclosure of which is incorporated herein by reference in its entirety.

[0023] Thus, in one embodiment, the present disclosure provides Form A characterized by an XRPD pattern having peaks at 5.5, 7.8, 11.0, 12.3 and 15.6±0.2 degrees two-theta.

[0024] In another embodiment, there is provided Form A, further characterized by an XRPD pattern substantially as shown in FIG.

[0025] In the practice of the present invention, a single polymorph (i.e., Form A or Form B) may be utilized in substantially pure form, or as a mixture of polymorphs (i.e., a mixture of Form A and Form B).

[0026] In one embodiment, one crystalline form (i.e., Form A or Form B) is present in an amount greater than 95% by weight relative to the other crystalline form. Thus, substantially pure Form A contains less than 5% by weight of Form B. Conversely, substantially pure Form B contains less than 5% by weight of Form A. In a further embodiment, one crystalline form (i.e., Form A or Form B) is present in an amount greater than 96%, 97%, 98% or 99% by weight relative to the other crystalline form (i.e., the other crystalline form is present in an amount less than 4%, 3%, 2% or 1% by weight of the other form). In another embodiment, one crystalline form (i.e., Form A or Form B) is present in an amount greater than 99.2%, 99.4%, 99.6% or 99.8% by weight relative to the other crystalline form.

[0027] In another embodiment, the crystalline form of Compound 1 contains a mixture of Form A and Form B. As used herein, a mixture of Form A and Form B means that Form A is present in a ratio ranging from 5 to 95% by weight of Form A compared to Form B, or conversely, Form A is present in a ratio ranging from 5 to 95% by weight of Form B compared to Form A. As defined above, Form A or Form B is considered to be substantially pure with respect to the other form when either Form A or Form B is present in an amount greater than 95% by weight compared to the other form.

[0028] In one embodiment, Form A comprises at least 80% Form A.

[0029] In another embodiment, Form A comprises at least 90% Form A.

[0030] In one embodiment, form B is provided, characterized by an XRPD pattern having peaks at 5.2, 6.1, 7.6, 11.5, and 12.3±0.2 degrees two-theta.

[0031] In another embodiment, there is provided Form B, further characterized by an XRPD pattern substantially as shown in FIG.

[0032] In another embodiment, Form B comprises 80% Form B.

[0033] In another embodiment, Form B comprises 90% Form B.

[0034] In one embodiment, the crystalline form of Compound 1 contains substantially pure Form A or substantially pure Form B.

[0035] Surprisingly, it has been found that crystalline forms of Compound 1 are particularly advantageous with regard to their use as pharmaceutical agents, particularly in connection with administration by inhalation.

[0036] In one embodiment, micronization of the crystalline form to a respirable fraction size is provided by the present disclosure.

[0037] In another embodiment, the respirable fraction size is measured by the median particle size.

[0038] In yet other embodiments, the median particle size is less than 5 μM, in some cases between 2-4 μM, and in still other cases between 3-3.5 μM.

[0039] In one embodiment, crystalline form A is micronized.

[0040] In another embodiment, crystalline Form A is micronized without reverting to the amorphous form of Compound 1.

[0041] In yet another embodiment, the micronization is performed using wet grinding.

[0042] In yet another embodiment, micronization of the crystalline forms is carried out using a mixture of Forms A and B of Compound 1.

[0043] In one embodiment, Form A of Compound 1 is characterized as having high solubility in an ethanol / water mixture in the range of about 2 mg / mL to about 350 mg / mL and exhibits no decrease in solubility over a 24 hour period.

[0044] In another embodiment, Form A of Compound 1 is also characterized as having moderate solubility in phosphate buffer at pH 7.4 and does not exhibit a decrease in solubility over a 24 hour period, in contrast to the amorphous form of Compound 1, which exhibits a gradual decrease in solubility.

[0045] Applicants have found that when amorphous Compound 1 was attempted to be scaled up in connection with the manufacture of a pharmaceutical drug product for clinical trials, the attempt was unsuccessful. Applicants have surprisingly discovered that crystalline Compound I can be scaled up with an improved purity profile.

[0046] In a further embodiment, the crystalline form of Compound 1 contains less than 2% by weight total impurities, less than about 1% by weight water, and / or less than about 0.5% by weight residual organic solvents.

[0047] In one embodiment, the purity and chemical structure of the crystalline forms, Form A and Form B, can be verified using liquid phase NMR spectroscopy.

[0048] In another embodiment, thermogravimetric (TGA) analysis can be used to confirm that the polymorph is anhydrous. With reference to Figures 7-8, TGA shows that the crystalline form is anhydrous. In one embodiment, Form B of Compound 1 has a slightly higher melting point compared to Form A as measured by differential scanning calorimetry.

[0049] The applicants have discovered a method to convert one particular crystalline polymorph of Compound 1 into another. Thus, in another embodiment, as described in more detail in the following examples, Form B is an anhydrous / non-solvated solid, and Form A slowly converts to Form B, which is believed to indicate that Forms A and B are enantiotropically related. Thus, Form A can also be referred to as a metastable form, since conversion from Form A to Form B is observed (but conversion from Form B to Form A is not observed), and Form A has a lower melting point compared to that of Form B. The crystalline forms A and B of Compound 1 differ in their crystal structures, as determined, for example, by X-ray powder diffraction (XRPD). The XRPD patterns of Forms A and B are provided in Table 7 below.

[0050] In one embodiment, crystalline Form A of Compound 1 is slurried in ethyl acetate and the temperature is maintained at about 10° C. to about 45° C. for a period of 1 minute to 90 hours sufficient for the conversion of Form A to Form B. Samples were withdrawn at regular time intervals and their XRPD patterns were determined.

[0051] The present disclosure also provides processes for the preparation of crystalline forms of Compound 1, including crystallization.

[0052] In one embodiment, crystallization involves dissolving amorphous Compound 1 in 1,4-dioxane, lyophilizing the solution, and adding the test solvent and allowing it to evaporate after thermal cycling.

[0053] In one embodiment, the test solvent is ethyl acetate.

[0054] In another embodiment, the test solvent is acetonitrile.

[0055] In yet another embodiment, the test solvent is equal parts ethyl acetate / tBME.

[0056] In another embodiment, crystallization is induced by the addition of an anti-solvent.

[0057] In yet another embodiment, the anti-solvent is heptane.

[0058] In one embodiment, a process is provided for preparing Form B directly from amorphous Compound 1 using a first solvent and a second solvent or anti-solvent.

[0059] In yet another embodiment, the first solvent is ethanol and the second solvent or anti-solvent is water.

[0060] Also, as mentioned above, Compound 1 has only been obtained in amorphous form before. Substantially pure Form A and substantially pure Form B, as well as mixtures of Form A and Form B, can be obtained by the techniques disclosed in the following examples. Once obtained, such crystalline forms can be used in the preparation of pharmaceutical compositions comprising them in combination with one or more pharma- ceutically acceptable carriers. The compositions of the present invention may also contain other therapeutic agents, as described below, and can be formulated, for example, by using conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of the type appropriate for the desired mode of administration, such as excipients, binders, preservatives, stabilizers, flavoring agents, etc., according to techniques well known in the art of pharmaceutical formulation.

[0061] A pharmaceutical composition is typically formulated to suit its intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous, intradermal, intraperitoneal or subcutaneous), oral, inhalation, transdermal (topical), ocular, iontophoretic, and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetic acid, citric acid, or phosphoric acid, and agents for adjusting tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic. For the convenience of the patient or treating physician, the dosage formulations may be provided in a kit which contains all the necessary equipment for the treatment process.

[0062] The crystalline form of Compound 1 of the present disclosure may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders, sublingually, bucally, parenterally, such as by subcutaneous, intravenous, intramuscular, intradermal (transdermal) or intracerebral injection or infusion techniques, for example, as a sterile injectable aqueous or non-aqueous solution or suspension, nasally, for example, by inhalation spray or insufflation, topically, for example, in the form of a cream or ointment, intraocularly in the form of a solution or suspension, intravaginally in the form of a pessary, tampon or cream, or rectally, for example, in the form of a suppository, in a unit dosage formulation containing a non-toxic pharmaceutically acceptable vehicle or diluent. The crystalline form of Compound 1 may be administered, for example, in a form suitable for immediate release or sustained release. Immediate release or sustained release may be achieved by the use of a suitable pharmaceutical composition containing the crystalline form of Compound 1, or, in the case of sustained release, by the use of a device such as a subcutaneous implant or an osmotic pump.

[0063] For administration to the respiratory tract, including intranasal administration, for example, inhalation, the active compound can be administered by any of the methods and formulations used in the art for administration to the respiratory tract.Thus, the active compound can be administered, for example, in the form of a solution, a suspension, or as a dry powder, with the dry powder form being a preferred embodiment.The agent according to this aspect of the invention can also be administered directly to the respiratory tract in the form of an aerosol.For use as an aerosol, the compound of the invention in solution or suspension can be packaged in a pressurized aerosol container with a suitable propellant, for example, a hydrocarbon propellant such as propane, butane, or isobutane, in addition to conventional adjuvants.The material of the invention can also be administered in a non-pressurized form, such as a nebulizer or atomizer.

[0064] In one embodiment intended for administration to the respiratory tract, the crystalline form of Compound 1 is micronized. In a more specific embodiment, micronization is achieved by wet grinding or jet milling.

[0065] In one embodiment, the micronized form is loaded into a capsule for administration as a dosage form for use in a dry powder inhaler. In another embodiment, the micronized form is loaded into a blister for administration as a dosage form for use in a dry powder inhaler. In another embodiment, the micronized form is loaded directly into a dry powder inhaler for administration.

[0066] In one embodiment intended for administration to the respiratory tract, the pharmaceutical composition may include leucine as a force control agent. In a more specific embodiment, leucine is micronized (e.g., co-milled) with a crystalline form of Compound 1.

[0067] In another embodiment, leucine coats a solid crystalline form of Compound 1, and in a more specific embodiment, a micronized crystalline form of Compound 1.

[0068] In yet another embodiment, the leucine coated form is obtained by micronization, and in a more specific embodiment, by micronization of the solid crystalline form of Compound 1 followed by spray drying of the aqueous suspension.

[0069] In another embodiment, the micronization step to obtain the crystalline form of Compound 1 coated with leucine is accomplished by jet milling.

[0070] In another embodiment, the micronization step to obtain the crystalline form of Compound 1 coated with leucine is accomplished by wet grinding.

[0071] In one embodiment, the leucine coated micronized crystalline form of Compound 1 is filled into a capsule for administration as a dosage form.

[0072] In another embodiment, the leucine coated micronized crystalline form of Compound 1 is loaded into blisters for administration as a dosage form for use in a dry powder inhaler.

[0073] In another embodiment, the leucine coated micronized crystalline form of Compound 1 is loaded directly into a dry powder inhaler for administration.

[0074] In another embodiment, a leucine coated micronized crystalline dosage form of Compound 1 has a higher drug loading than an amorphous dosage form.

[0075] The propellant-driven inhalation aerosols that can be used according to the invention can also contain other components, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. The propellant-driven inhalation aerosols according to the invention that can be used according to the invention can be administered using inhalers known in the art, such as metered dose inhalers. As another alternative, the agents of the invention can be administered to the airways in the form of pulmonary surfactant preparations. Pulmonary surfactant preparations can include exogenous pulmonary surfactant preparations (e.g., Infasurf® (Forest Laboratories), Survanta® (Ross Products), and Curosurf® (DEY, California, USA), or synthetic pulmonary surfactant preparations (e.g., Exosurf® (GlaxoWellcome Inc.), and ALEC). These surfactant preparations are administered via airway instillation (i.e., after intubation) or intratracheally.

[0076] As a further alternative, the crystalline form of compound 1 of the present invention may be administered to the airways in the form of an inhalable powder. The powder formulation may contain physiologically acceptable excipients such as amino acids (e.g., leucine), monosaccharides (e.g., glucose or arabinose), disaccharides (e.g., lactose, saccharose and maltose), oligosaccharides and polysaccharides (e.g., dextran), polyalcohols (e.g., sorbitol, mannitol, xylitol), salts (e.g., sodium chloride, calcium carbonate), or mixtures of these excipients with each other. Preferably, monosaccharides or disaccharides are used, and the use of lactose or glucose is preferred, particularly, but not exclusively, in hydrate form.

[0077] Within the scope of the inhalable powders according to the invention, the excipients have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, most preferably between 15 and 80 μm. Sometimes it may seem appropriate to add finer excipient fractions with an average particle size between 1 and 9 μm to the excipients mentioned above. These finer excipients are also selected from the group of possible excipients listed above. Finally, to prepare the inhalable powders according to the invention, a micronized preparation, preferably with an average particle size between 0.5 and 10 μm, is added to the excipient mixture. The processes for producing the inhalable powders according to the invention by grinding, micronizing and finally mixing the components together are known from the prior art.

[0078] In formulations intended for respiratory administration, including intranasal formulations, active compound is typically configured to have small particle size, for example, about 5 microns or less, such as through micronization technology.In some embodiments, a sustained release formulation of active compound is used.In some embodiments, active compound is administered by oral inhalation as a free-flowing powder through an inhaler.

[0079] The pharmaceutical compositions and methods of the present disclosure further include additional therapeutically active compounds (second agents) as described herein and / or known in the art that are typically used in conjunction with compositions comprising Compound 1 of the present disclosure to treat one or more pathological conditions. The combination of therapeutic agents acts synergistically to provide treatment or prevention of various diseases, disorders, and / or conditions described herein. Such second agents include prostanoids, endothelin antagonists, cytoplasmic kinase inhibitors, receptor kinase inhibitors, endothelin receptor antagonists, such as ambrisentan, bosentan, and sitaxsentan, PDE5 (PDE-V) inhibitors, such as sildenafil, tadalafil, and vardenafil, calcium antagonists, such as amlodipine, felodipine, valepamil, diltiazem, and menthol, prostacyclin, treprostinil, iloprost, beraprostin, val ... Antibodies such as cyclosporine, e.g., cyclosporine A, CTLA4-Ig, ICAM-3, anti-IL-2 receptor (anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents that block the interaction of CD40 with gp39, e.g., antibodies specific for CD40 and / or gp39, i.e., CD154, fusion proteins constructed from CD40 and gp39 (CD40 1g and CD8gp39), inhibitors such as nuclear translocation inhibitors of NF-κB function, e.g., deoxyspergualin (DSG), cholesterol biosynthesis inhibitors, e.g., HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal anti-inflammatory drugs, e.g., ibuprofen, aspirin, acetaminophen, etc.drugs, NSAIDs), cyclooxygenase inhibitors such as leflunomide, deoxyspergualin, and celecoxib, steroids such as prednisolone or dexamethasone, gold compounds, beta agonists such as salbutamol, LABAs such as salmeterol, leukotriene antagonists such as montelukast, antiproliferatives such as methotrexate, cytotoxic agents such as FK506 (tacrolimus, Prograf), mycophenolate mofetil, and azathioprine, VP-16, etoposide, fludarabine, doxorubine, adriamycin, amsam Examples of the crystalline solid crystalline form of Compound 1 include, but are not limited to, cyclophosphamide, camptothecin, cytarabine, gemcitabine, fluorodeoxyuridine, melphalan, and cyclophosphamide, antimetabolites such as methotrexate, topoisomerase inhibitors such as camptothecin, DNA alkylating agents such as cisplatin, kinase inhibitors such as sorafenib, microtubule poisons such as paclitaxel, TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors, hydroxyurea, rapamycin (sirolimus or Rapamune), or derivatives thereof. Thus, in another embodiment, a method is provided for treating a disease or condition in a subject in need of such treatment by administering to the subject an effective amount of a solid crystalline form of Compound 1 or a pharmaceutical composition comprising the same. As used herein, "administration" to a subject includes any route that introduces or delivers a solid crystalline form of Compound 1 to a subject to perform its intended function. Administration can be by any suitable route, including oral, intranasal, inhalation, parenteral (intravenous, intramuscular, intraperitoneal, or subcutaneous), rectal, or topical. Administration includes self-administration and administration by another. It should also be understood that the various modes of treating or preventing the described medical conditions are intended to mean "substantial", which includes not only complete treatment or prevention, but also less than complete treatment or prevention, where some biologically or medically relevant result is achieved.

[0080] Similarly, the term "effective amount" or "pharmaceutical effective amount" refers to an amount sufficient to achieve the desired therapeutic and / or prophylactic effect, e.g., an amount that results in the prevention or reduction of symptoms associated with the disease being treated. The amount of solid crystalline form of Compound 1 administered to a subject will depend on the type and severity of the disease, as well as individual characteristics such as general health, age, sex, weight, and tolerance to drugs. It will also depend on the extent, severity, and type of disease. Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors. The compositions of the present invention may also be administered in combination with one or more additional therapeutic compounds.

[0081] Such administration of a crystalline form of Compound 1 will elicit a response in the subject, e.g., in cells, tissues, or bodily fluids, as desired by the clinician. In treating or preventing a condition mediated by or associated with kinase inhibition, e.g., RTK inhibition, an appropriate dosage level is administered. In some embodiments, about 0.01 to 500 mg / kg of subject body weight per day is administered in a single dose or multiple doses. Thus, dosage levels are in some embodiments about 0.1 to about 250 mg / kg per day, and in other embodiments about 0.5 to about 100 mg / kg per day administered to the subject. Suitable dosage levels include, for example, about 0.01 to 250 mg / kg / day, about 0.05 to 100 mg / kg / day, or about 0.1 to 50 mg / kg / day. Within this range, in some embodiments, the dosage is about 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the compositions are provided in the form of tablets containing 1.0 to 1000 mg of active ingredient, including but not limited to 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg. Dosages may be selected to any dose within any of these ranges, for example, for therapeutic efficacy and / or symptom control of the dosage to the subject being treated. In some embodiments, the compounds of the disclosure are administered 1-20 times, 1-15 times, 1-10 times, 1-5 times, 1-4 times, or 1-3 times per day, or once or twice per day, by inhalation, e.g., as described in U.S. Patent No. 8,257,741, U.S. Patent No. 8,263,128, WO 2010 / 132827, WO 2010 / 102066, WO 2012 / 040502, WO 2012 / 031129, and / or WO 2010 / 102065. In some embodiments, the compounds of the disclosure are administered 1-5 times per day.

[0082] In some embodiments, the unit dose has the following properties: (a) when administered to a subject, a C of the compound of about 1-5000 ng / mL in the subject's plasma maxor C of about 1 to 5000 ng / mL of the compound in the subject's blood max and (b) sufficient to provide one or more of about 1-5000 ng / mL of the compound in the subject's plasma 24 hours after administration to the subject, or about 1-5000 ng / mL of the compound in the subject's blood 24 hours after administration to the subject.

[0083] In particular, the crystalline form of Compound 1, in the form of a pharmaceutical composition, inhibits the activity of cell division cycle 2 kinase (Cdc2 kinase), c-Kit, c-ABL, p60src, AKT, VEGFR3, PDGFRα, PDGFRβ, PDGFR-αα, PDGFR-ββ, PDGFR-αβ, FGFR3, FLT-3, FYN oncogene kinase associated with SRC, FGR, YES (Fyn, lymphocyte-specific protein tyrosine kinase (Lck), tyrosine kinase with Ig and EGF homology domains (Tie-2), FMS (CSF-I), and CYP2A1 (CYP2A1). Kinase inhibition, including those mediated by or associated with kinases such as R), KDR, EphA2, EphA3, EphA8, FLT1, FLT4, HCK, PTK5, RET, SYK, DDR1, DDR2, glycogen synthase kinase 3 (GSK-3), cyclin-dependent kinase 2 (Cdk2), cyclin-dependent kinase 4 (Cdk4), MEK1, NEK-2, CHK2, CKlε, Raf, checkpoint kinase 1 (CHK1), ribosomal S6 kinase 2 (Rsk2), and PAR-1. In particular, tyrosine kinases such as cell division cycle 2 kinase (Cdc2 kinase), ERK1 / 2, STAT3, AKT, c-Kit, c-ABL, p60src, VEGFR3, PDGFRα, PDGFRβ, PDGFR-αα, PDGFR-ββ, PDGFR-αβ, FGFR3, FLT-3, FYN oncogene kinase associated with SRC, FGR, YES (Fyn), lymphocyte-specific protein tyrosine kinase ( Compounds, compositions, and methods that inhibit Lck), tyrosine kinase with Ig and EGF homology domains (Tie-2), FMS (CSF-1R), KDR, EphA2, EphA3, EphA8, FLT1, FLT4, HCK, PTK5, RET, SYK, DDR1, and DDR2. In some embodiments, the tyrosine kinase is a receptor tyrosine kinase (RTK), such as, for example, PDGFR, PDGFR-αα, PDGFR-ββ, PDGFR-αβ, or c-Kit, or a combination thereof.

[0084] Representative diseases or conditions that may be treated with a crystalline form of Compound 1 or a pharmaceutical composition comprising same include PAH, primary PAH, idiopathic PAH, hereditary PAH, refractory PAH, BMPR2, ALK1, endoglin associated with hereditary hemorrhagic telangiectasia, endoglin not associated with hereditary hemorrhagic telangiectasia, drug-induced PAH, and toxin-induced PAH, PAH associated with or secondary to one or more of systemic sclerosis, mixed connective tissue disease, cancer, refractory cancer, metastatic cancer, neoplasia, hypoplasia, hyperplasia, dysplasia, polyplasia, preplasia, fibrosis, angiogenic diseases, pulmonary dysfunction, cardiovascular dysfunction, HIV infection, hepatitis, portal hypertension, pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, persistent pulmonary hypertension of the newborn, pulmonary veno-occlusive disease (PVOD), pulmonary capillary hemangiomatosis, and / or other conditions that may be treated with a crystalline form of Compound 1 or a pharmaceutical composition comprising the same. hemangiomatosis, PCH), left heart disease, pulmonary hypertension, systolic dysfunction, diastolic dysfunction, valvular disease, pulmonary disease, interstitial lung disease, pulmonary fibrosis, schistosomiasis, chronic obstructive pulmonary disease (COPD), sleep-disordered breathing, alveolar hypoventilation, chronic exposure to high altitude, developmental abnormalities, chronic thromboembolic pulmonary hypertension (CTEPH), multifactorial pulmonary hypertension, hematological disorders, myeloproliferative disorders, splenectomy, systemic diseases, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangiomatosis, neurofibromatosis, vasculitis, metabolic disorders, glycogen storage diseases, Gaucher disease, thyroid disease, neoplastic obstruction, fibrosing mediastinitis, and chronic renal failure during dialysis;and diseases, such as pulmonary hypertension, congenital heart disease, hypoxia, chronic hemolytic anemia, persistent pulmonary hypertension of the newborn, pulmonary veno-occlusive disease (PVOD), pulmonary capillary hemangiomatosis (PCH), left heart disease pulmonary hypertension, systolic dysfunction, diastolic dysfunction, valvular disease, lung disease, interstitial lung disease, pulmonary fibrosis, schistosomiasis, chronic obstructive pulmonary disease (COPD), sleep-disordered breathing, alveolar hypoventilation, chronic exposure to high altitude, growth abnormalities, chronic thromboembolic pulmonary hypertension (CTEPH), multifactorial These include, but are not limited to, chronic pulmonary hypertension, blood disorders, myeloproliferative disorders, splenectomy, systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangiomatosis, neurofibromatosis, vasculitis, metabolic disorders, glycogen storage diseases, Gaucher's disease, thyroid disorders, neoplastic obstructive disorders, fibrosing mediastinitis, immune and inflammatory disorders, hyperproliferative disorders, renal and kidney disorders, bone remodeling disorders, metabolic disorders, vascular disorders, and chronic renal failure on dialysis;

[0085] In one aspect, the disease or condition is pulmonary arterial hypertension (PAH) and a therapeutically effective amount of a crystalline form of Compound 1 is administered to a subject in need thereof. In a specific embodiment, the disease or condition is PAH, primary PAH, idiopathic PAH, hereditary PAH, refractory PAH, drug-induced PAH, toxin-induced PAH, or PAH with secondary disease.

[0086] This invention is further illustrated by the following examples, which should not be construed as limiting in any way. EXAMPLES

[0087] Example 1 Preparation of Amorphous Compound 1 (Prior Art) The synthesis of compound 1 is disclosed in U.S. Patent No. 9,815,815 (see column 29, line 25 to column 31, line 11) with reference to known synthetic procedures, including those disclosed in WO 2008 / 058341 (corresponding to U.S. Patent No. 8,461,161). Therefore, for comparison, compound 1 was prepared by known techniques as follows.

[0088] The synthesis of the intermediate (S)-N-(3-(1-((6-chloropyrazin-2-yl)amino)ethyl)phenyl)-6-methylnicotinamide is described in Example 1 of U.S. Pat. No. 8,461,161 (see column 107, line 64 to column 109, line 9). The synthesis of the intermediate (S)-N-(3-(1-((6-chloropyrazin-2-yl)amino)ethyl)phenyl)-5-methylnicotinamide (i.e., the methyl group of nicotinamide at the 5-position instead of the 6-position) was accomplished by the same procedure, as shown by the following reaction scheme:

[0089] [ka]

[0090] Compound 1 was then prepared via Suzuki cross-coupling reaction of intermediate (S)-N-(3-(1-((6-chloropyrazin-2-yl)amino)ethyl)phenyl)-5-methylnicotinamide with 3,4-dimethoxyphenylboronic acid pinacol, as shown by the following reaction scheme, and purified by column chromatography.

[0091] [ka]

[0092] In particular, the intermediate (S)-N-(3-(1-((6-chloropyrazin-2-yl)amino)ethyl)-phenyl)-5-methylnicotinamide (crude from previous step; 1.10 kg), 3,4-dimethoxyphenylboronic acid pinacol ester (0.82 kg) and sodium carbonate solution (0.48 kg in 1.76 L water) were added to a mixture of toluene (8.8 L) and 1-propanol (4.4 L) under nitrogen and stirred for at least 30 minutes. Pd(PPh3)4 (0.14 kg) was added. The mixture was stirred for at least 10 minutes and then heated to 80±5° C. with stirring under nitrogen for not less than 12 hours. A sample was analyzed by HPLC to confirm the reaction was complete (≦0.50% starting material). Once the reaction was deemed complete, it was cooled to 25±5° C. and filtered. The reaction flask and filter were washed with ethyl acetate and the combined filtrate was allowed to separate. The (top) organic layer was isolated, washed with water (1×2.75 L) and brine (25% aqueous NaCl, 1×2.75 L), dried over anhydrous sodium sulfate (2 kg), and concentrated to dryness using a rotary evaporator (maximum temperature 50° C.). The resulting solid was redissolved in ethyl acetate (2.2 L), silica MetThiol (Pd scavenger, 0.44 kg) was added, and the resulting slurry was stirred at 20±5° C. for not less than 12 hours. Stirring was continued until ≦20 ppm Pd was detected (additional silica MetThiol may be added if necessary). Once Pd removal was deemed complete, the slurry was filtered and the filtrate was concentrated to dryness using a rotary evaporator (maximum temperature 60° C.).

[0093] [Table 1]

[0094] The crude product was purified by column chromatography: glass columns packed with silica gel (7 kg / column; 2 columns; 14 kg total) in a slurry of 5:95 (v / v) ethyl acetate 99%:hexane (30 L total). The crude product was dissolved in DCM (2 L) and loaded onto columns (half on each column). Each column was eluted with 5:95 ethyl acetate, 99%:hexane (10 L / column, 20 L total), followed by 25:75 ethyl acetate, 99%:hexane (30 L / column, 60 L total), followed by 50:50 ethyl acetate, 99%:hexane (30 L / column, 60 L total), followed by 75:25 ethyl acetate, 99%:hexane (30 L / column, 60 L total), and finally ethyl acetate, 99% (370 L / column, 740 L total). The eluate was collected in 10 L fractions until product elution and in 20 L fractions until product elution was complete. The product-containing fractions were combined and concentrated to dryness using a rotary evaporator (maximum temperature 60° C.). The resulting solid (1.10 kg) was dissolved in dilute hydrochloric acid (0.5 N, 7.98 L) while maintaining the temperature below 30° C. The product-HCl solution was slowly added to aqueous sodium bicarbonate (9%, 12.1 L) while maintaining the temperature below 30° C. The resulting slurry was stirred for at least 2 hours, and the resulting solid was collected by filtration through a GMP filter, and the filter cake was dried in a vacuum oven at 50° C. or lower to obtain an amorphous form of compound 1.

[0095] Example 2 Characterization of amorphous compound 1 The solid state characterization of amorphous Compound 1 (Example 1) was performed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and fragility and relaxation time analysis. The results show that amorphous Compound 1 forms only glasses and does not show any tendency to crystallize.

[0096] IX-ray powder diffraction (XRPD) Two samples of amorphous Compound 1 were examined by XRPD performed on a Bruker D8-Advance XRPD S / N: 202298 using the following parameters: Configuration: Theta / Theta Bragg Brentano Incident beam optics: Soller slit = 2°; divergence slit = 0.2 mm; anti-scatter screen = 21 mm Detector beam optics: Soller slit = 2.5° Ni filter; anti-scatter slit = 3 mm Detector: PSD: Lynx Eye with 1° window Tube: CuKαλ=1.5418Å; voltage=40kV, current=40mA Scanning parameters: 2~50°2θ. Step size 0.049°2θ. Time per step 1 sec. Total scan time: 16.5 min.

[0097] The first sample was heated to 100° C. in a DSC pan. It changed color from white to pale yellow but remained a powder. The sample was covered and placed at −20° C. for about 24 hours, then spread on a Si zero background plate. This sample did not liquefy, so a second sample was prepared by sprinkling it on a Si zero background plate and placing it in a 150° C. oven for about 1 hour until liquid was observed. The plate was then covered and transferred to a −20° C. freezer for about 24 hours. XRPD results for the two above samples (100° C. and 150° C.) are provided in FIG. 1 and show that they are both amorphous. The small peaks at about 31.8° 2θ and 45.5° 2θ are believed to be from NaCl, which has the two strongest peaks at these positions.

[0098] II. Differential Scanning Calorimetry (DSC) and Glass Transition Temperature (Tg) A sample of amorphous Compound 1 was prepared in an Al Tzero pan using standard crimp sealing. An initial DSC evaluation to determine Tg and possible crystallization and melting events was performed as follows: (1) Heat at 10°C / min to 100°C; (2) maintaining the temperature at 40° C. for 5 minutes; (3) cooling to −20° C. at 10° C. / min; (4) maintaining the temperature at 40° C. for 5 minutes; (5) heating at 10°C / min to 320°C; (6) cooling to −20° C. at 10° C. / min; and (7) Heating at 10°C / min to 320°C.

[0099] The initial DSC scan is shown in Figure 2. Decomposition occurred at approximately 270°C with no melting peak. Inspection of the DSC pan after the experiment revealed charred / darkened material. Assuming a Tg=89°C (midpoint), the Tm was estimated to be 210°C (applying a 4 / 3 factor to the Kelvin scale). The initial DSC test was repeated on a new sample (reducing the upper temperature limits in steps (5) and (7) to 200°C to avoid decomposition) and is shown in Figure 3. Heating to 320°C and 200°C with cooling and reheating showed no evidence of crystallization. The first scan to 200°C is shown in Figure 4, from which the Tg and ΔCp (heat capacity) were obtained: Tg (midpoint) = 87.05°C. From ΔCp = 0.5066 J / gK, the constitutive heat capacity is estimated to be ΔconstitutiveCp = ΔCp / 0.9 = 0.5629 J / gK.

[0100] III 1 H and 1 H- 13 C Nuclear Magnetic Resonance (NMR) NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz for protons. Experiments were performed in deuterated DMSO and each sample was prepared to a concentration of approximately 10 mM. 1 The H NMR spectrum is shown in Figure 5 and is consistent with the chemical structure. Residual (<0.01 equivalent) ethyl acetate peaks (4.04, 1.99, and 1.17 ppm) were present in the sample. 1 H- 13 The C heteronuclear single quantum coherence (HSQC) NMR spectrum is shown in Figure 6 and is consistent with the chemical structure. Two amine peaks (10.36 and 7.66 ppm, not attached to C) were observed in the aromatic region. All other peaks correspond to CH / CH groups.

[0101] IV solubility Amorphous Compound 1 (180 mg) was dissolved in 1,4-dioxane (18 mL) and aliquoted into 18 vials. The test solvent / solvent system (50 μL) was added to the vial and the mixture was evaluated for dissolution. If dissolution was not evident, the mixture was heated to approximately 40° C. and reevaluated. If dissolution was still incomplete, the cycle was repeated and an additional 50 μL of solvent was added. After 300 μL of solvent was added, an aliquot of 100 μL was added. This procedure was continued until complete dissolution was observed or until 1 mL of solvent had been added. Solvent solubilities are shown in Table 1. Complete dissolution was observed for 13 of the 17 solvent systems.

[0102] [Table 2]

[0103] V Vulnerability and mitigation time Amorphous Compound 1 samples were prepared in Al Tzero pans using standard crimp sealing. Fragility and relaxation time parameters were determined by measuring Tg as a function of heating rate. Four heating rates were used: 1, 5, 10 and 20 °C / min. DSC measurements were performed as follows: (1) Heat at 10°C / min to 100°C; (2) maintaining the temperature at 40° C. for 5 minutes; (3) cooling to −20° C. at 10° C. / min; (4) maintaining the temperature at 40° C. for 5 minutes; and (5) Heating at 10° C. / min to 130° C.

[0104] The results of Tg versus scan rate are shown in Table 2.

[0105] [Table 3]

[0106] A plot of the heating rate (q) versus 1 / Tg for amorphous Compound 1 is shown in Figure 7. The slope was used to calculate the activation enthalpy (ΔH * ) was calculated, from which the vulnerability parameters m, D, and T0 were calculated according to the following formulas: ΔH * =-8.314*slope m = ΔH * / (2.303×8.314×T g ) D=2.303×m 2 min / (mm min ) T0=T g ×(1-m min / m) m min =16

[0107] The calculated vulnerability parameters are: Tg=362K or 89°C (10°C / min), ΔH * = 508118 J / mol, m=73.3, T0=283K or 10°C, and D = 10.3 (within the range of 7 to 15 typically observed for organic glasses).

[0108] The fragility parameters were used to calculate the initial structural relaxation time according to the following equation (γ = 0.9 and τ = 10 -14 s) and was determined to be 3 months at 25°C.

[0109]

number

[0110] Example 3 Identification of the crystalline form of compound 1 Experiments were conducted to identify and isolate crystalline forms of Compound 1, including polymorph screening, as described below.

[0111] Example 3A: Polymorph Screening No. 1 Amorphous Compound 1 (450 mg) was dissolved in 1,4-dioxane (72 mL) and aliquoted into 9 vials, which were frozen at -50°C and then lyophilized overnight. Test solvent / solvents (see Table 3 for amounts) were added to the lyophilized material in the vials to form a slurry. The slurry / solution was then thermally cycled (with stirring) for approximately 72 hours, with no specified heating / cooling rate, between 4 hours at ambient temperature and then 40°C for 4 hours. Any solid material remaining after the temperature cycle was isolated by centrifugal filtration and the isolated material was analyzed by XRPD. The remaining mother liquor, either after filtration or when no solid material was present, was divided equally into three portions and subjected to the following: (a) Evaporation - the cap was removed from the vial and solvent evaporation was allowed to occur under ambient conditions; (b) anti-solvent addition - 1 mL of anti-solvent was added (heptane, water and THF were used for all samples except acetonitrile and water, respectively) and the sample was left overnight; and (c) Crash cooling to 5°C–18°C by placing the vial in a freezer.

[0112] Any solids isolated were analyzed by XRPD and the results are presented in Table 4. Table 4 shows that most solids isolated after thermal cycling or from drying were crystalline in nature and were the distinctive crystalline form A, while any solids recovered from evaporation were amorphous. Little solid material was obtained by cooling or evaporation of the mother liquor, and no solids were isolated by crash cooling at 5° C. or −18° C.

[0113] [Table 4]

[0114] [Table 5] A=Form A Am = amorphous solid NM=Not Measured -= no solids *= Evaporation was followed by drying in a vacuum oven (40°C, 3 hours)

[0115] evaporation: Evaporation of ethyl acetate, methanol, and EtOAc / tBME (50:50) produced crystalline form A. An amorphous solid was isolated from tBME, water, and 75:25 EtOAc / tBME. A weak peak for form A was observed in the diffractogram of the solid isolated from EtOAc / tBME (25:75).

[0116] After thermal cycling: Crystalline Form A was produced from acetonitrile, ethyl acetate, ethyl acetate / tBME (50:50% v / v), tBME, 1-butanol, 2-propanol, isopropyl acetate, and MIBK. Amorphous solids were isolated from water and MeOH / water (40:60% v / v). All other solvent systems (acetone, chloroform, ethanol, and MEK) provided only solutions (no solid material) after thermal cycling. Therefore, new samples were prepared using less solvent volume, which provided solids from acetone, ethanol, and MEK after thermal cycling, which were confirmed to be crystalline Form A.

[0117] After drying: All crystalline solids remained unchanged after drying. The amorphous solids isolated from water appeared to give rise to some weak peaks indicative of crystalline form A upon drying indicating partial recrystallization.

[0118] evaporation: Amorphous solids were isolated by evaporation of ethyl acetate, EtOAc / tBME (50:50% v / v), 1-butanol, IPA, MeOH, MIBK, MeOH / water (80:20% v / v), and MeOH / water (95:5% v / v). Evaporation of all other samples provided only a viscous oil, which was dried in a vacuum oven (40° C., 3 h). Amorphous solid material was isolated from ethanol and MEK.

[0119] Antisolvent addition: Precipitation was observed in all solvent systems except water when anti-solvent was added to the mother liquor. After standing for 24 hours under ambient conditions, solid material was isolated from acetone, chloroform, ethanol, MEK, tBME, 1-BuOH, isopropyl acetate, and MIBK. Crystalline Form A was produced from ethanol, MEK, butanol, and MIBK when heptane was added as the anti-solvent. Amorphous solids were produced from acetone, chloroform, tBME, and isopropyl acetate when heptane was added as the anti-solvent.

[0120] Crash Cooling: Neither sample provided any solid material when the mother liquors were cooled to 5° C. for 72 hours after thermal cycling. Further cooling to −18° C. for 72 hours also did not result in any solid material.

[0121] Example 3B: Polymorph Screening No. 2 Dissolution in ethanol Amorphous Compound 1 was dissolved in ethanol (6 mL / g) and stirred at room temperature. Aliquots were removed after 24 and 48 hours and analyzed by XRPD, which showed them to be identical to the starting material. Water (0.02 mL) was then added to the suspension. After 72 hours, the resulting solid was pure crystalline Form B. The XRPD trace is shown in FIG. 2.

[0122] Example 3C: Polymorph Screening No. 3 Solvent Screening Compound 1 (80 mg) was suspended in various solvent / water solvent mixtures as shown in Table 5. Dissolution was observed in methanol, acetone and THF. Water was added to the sample, which was then stirred at room temperature for 24 hours, filtered under vacuum and the isolated solid was analyzed by XRPD. The results are summarized in Table 5 and show that pure crystalline form B was isolated from ethanol, while all others showed no change in morphology from the starting material.

[0123] [Table 6] A=Form A B=Form B

[0124] Example 3D: Polymorph Screening No. 4 Solid Compound 1 (200 mg) was suspended in each of the following: A mixture of ethyl acetate / n-heptane 1 / 1 (5 mL / g) + 1% water at room temperature, A mixture of ethyl acetate / n-heptane 1 / 1 (5 mL / g) + 1% water at 60°C, Ethyl acetate (2.5L / Kg) + 2% water at 60°C, and Mixture of ethanol-water 3 / 7 (5 mL / g) at 60°C.

[0125] The suspension was stirred for 24 hours and then filtered under vacuum. The resulting solid was analyzed by XRPD. Table 6 summarizes the conditions and results. A mixture of ethyl acetate and n-heptane resulted in a heterogeneous suspension. After 24 hours no change was observed and the resulting solid was identical to the original mixture of polymorphs. Only ethyl acetate (+2% water) resulted in dissolution of the solid. More solid was added until a suspension was obtained. After 24 hours at 60° C. a thick suspension was obtained. The resulting solid was Form B with traces of Form A. Using ethanol a partial solution was observed. Addition of water (0.5 Kg / L) resulted in the formation of a precipitate which was isolated and found to be pure Form B.

[0126] [Table 7]

[0127] Example 4 Comparative properties of crystal forms A and B I XRPD X-ray powder diffractograms (XRPD) were obtained on a PANalytical X'Pert Pro using Datacollector software with a 3152 / 63 focusing X-ray mirror and pixel detector. The instrument conditions are given below.

[0128] [Table 8]

[0129] The XRPD of crystalline form A of compound 1 obtained in is shown in Figure 3. The XRPD of crystalline form B of compound 1 obtained in is shown in Figure 10. Table 7 lists the diffractogram peaks for form A (left column) and form B (right column).

[0130] [Table 9]

[0131] II. Differential Scanning Calorimetry Differential scanning calorimetry (DSC) was performed on a Mettler Toledo 823E instrument using STARe V15.00 software with aluminum (40 μL) pans and covers at a temperature range of 35-250 °C (10 °C / min) and nitrogen (60 ml / min) as purge gas. The DSC curves are shown in Figure 11 (crystal form A) and Figure 12 (crystal form B).

[0132] III TGA TGA thermograms of crystalline forms A and B of compound 1 were obtained using a Mettler Toledo TGA / DSC 3+ (software: STARe V16.00) with aluminum (100 μL) pans at a temperature range of 35-250 °C (10 °C / min) and nitrogen (50 ml / min) as purge gas. The TGA thermogram of crystalline form A of compound 1 is shown in Figure 7, and the TGA thermogram of crystalline form B of compound 1 is shown in Figure 8.

[0133] IV Infrared The infrared spectrum of crystalline form A of compound 1 was recorded on a Perkin Elmer Spectrum 2 using a MIR source, LiTaO3 detector and OptKBr beam splitter with a Universal ATR Diamond accessory. The infrared spectrum of crystalline form B of compound 1 was recorded on a Perkin Elmer Spectrum 100 using a MIR source, LiTaO3 detector and OptKBr beam splitter with a Universal ATR Diamond / ZnSe accessory. In both cases, the infrared spectrum was recorded between 4000 and 650 cm. -1 Four scans were collected over the spectral range at a scan rate of 0.2 and a resolution of 4. The infrared spectrum of crystalline form A of compound 1 is shown in Figure 9. The infrared spectrum of crystalline form B of compound 1 is shown in Figure 10. Table 8 lists the major IR peaks for form A (left column) and form B (right column).

[0134] [Table 10]

[0135] V Slurries in ethyl acetate at various temperatures The starting material was crystalline form A of Compound 1 containing very small amounts of crystalline form B. This material was slurried in ethyl acetate and stirred under the conditions of time, volume, and temperature shown in Table 9 (note - an experiment performed at 60°C resulted in complete dissolution but is not listed in Table 9). Mixtures at lower temperatures (10°C and room temperature) showed very slow conversion of crystalline form A to form B. At higher temperatures (45°C), pure form B was obtained after 89 hours. Figures 11, 12, and 13 show the XRPD for each slurry (at 10°C, room temperature, and 45°C, respectively) compared to the starting material and the pure polymorph. The results are summarized in Table 9.

[0136] [Table 11]

[0137] VI Solubility Studies The solubility of crystalline forms A and B of compound 1 in ethyl acetate was determined using a Crystal16® parallel crystallizer. Two heating rates were used: 1° C. / min and 0.5° C. / min. The suspension was heated to 78° C., cooled to 10° C. at 0.2° C. / min, and maintained at 10° C. for 2 hours. FIG. 14 shows the resulting solubility curves (concentration in mg / mL vs. temperature), which demonstrate that the solubility is similar for both crystalline forms A and B. The solubility was also determined in ethyl acetate+2% water. The suspension was heated to 78° C. at 1° C. / min, cooled to 10° C. at 0.2° C. / min, and maintained at 10° C. for 2 hours. FIG. 15 compares the resulting solubility curves with pure ethyl acetate. The results demonstrate that crystalline forms A and B have similar solubilities in ethyl acetate+2% water, and are significantly more soluble in the presence of water (2%) compared to pure ethyl acetate. In both systems, crystalline form B is slightly less soluble.

[0138] VII DSC and TGA of Form A and Form B Crystalline forms A and B of compound 1 were analyzed by DSC and TGA. The results are shown in Table 10. DSC and TGA analysis show that crystalline form B is an anhydrous polymorph. Crystalline form B has a slightly higher melting point and a slightly lower enthalpy of fusion, suggesting that the two polymorphs are entropically related.

[0139] [Table 12]

[0140] VII. TGA of a mixture of crystalline forms A and B Compound 1 (20 mg), containing a mixture of crystalline forms A and B, was heated to 85° C. at 5° C. / min, held at 85° C. for 10 minutes, and cooled to room temperature. The TGA thermogram is shown in FIG. 22 and shows a total weight loss of 0.25%. The resulting solid was analyzed by XRPD, which showed that crystalline form B was still present after the TGA experiment, as shown in FIG. 23 (reference (top), post-TGA sample (middle), and initial sample (bottom)).

[0141] IX Sample Stress Two samples, one containing pure crystalline form A of Compound 1 and the second containing a mixture of crystalline forms A and B of Compound 1, were placed in open vials at 40° C. and 75% relative humidity for 6 days and then analyzed by XRPD. The results are shown in Table 11. No changes were observed by XRPD.

[0142] [Table 13]

[0143] X Lyophilization Crystalline form A of compound 1 (10 mg) dissolved in 1,4-dioxane (1 mL) was frozen at -50°C and then lyophilized overnight. The starting material and the lyophilized product were analyzed by XRPD, and the resulting diffractograms demonstrate that lyophilization converts crystalline form A to an amorphous form. More specifically, this analysis showed that forms A and B have similar stability, but form B is an anhydrous / nonsolvated solid, form A slowly converts to form B, and may be enantiotropically related.

[0144] Example 5 Single crystal X-ray structure of crystalline form A of compound 1 Single crystals of crystalline form A of compound 1 were obtained from dichloromethane / pentane.

[0145] A colorless crystal of 0.15 × 0.08 × 0.04 mm was mounted on a Cryoloop using paraton oil. Single crystal X-ray diffraction studies showed that Cu K α The data were collected on a Bruker Microstar APEX II CCD diffractometer equipped with a 100 nm ion beam (λ=1.54178 Å). Data were collected at 100 K in a nitrogen gas stream, with φ and

[0146]

number

[0147] Figure 24 shows an ORTEP plot representation of the crystal structure of crystalline form A of compound 1. In addition, the following tables provide the following structural features of crystalline form A of compound 1: Table 12 summarizes the crystallographic data, Table 13 shows the bond lengths [Å], Table 14 shows the bond angles [°], and Table 15 shows the atomic coordinates (×10 4 ) and equivalent isotropic displacement parameter (Å 2 ×10 3 ), and Table 16 shows the hydrogen coordinates (×10 4 ) and isotropic displacement parameters (Å 2 ×10 3 ) and Table 17 shows the anisotropic displacement parameters (Å 2 ×10 3 ) is shown.

[0148] [Table 14]

[0149] [Table 15]

[0150] [Table 16-1]

[0151] [Table 16-2]

[0152] [Table 17]

[0153] [Table 18]

[0154] [Table 19]

[0155] Example 6 Analysis of Crystal Form A of Compound 1 IX-ray powder diffraction (XRPD) XRPD analysis was performed on a PANalytical X'pert pro equipped with a PIXcel detector (128 channels) and samples were scanned from 3 to 35 degrees 2θ. The material was gently ground to release aggregates and loaded onto a multi-well plate with a Kapton or Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and analyzed using Cu K radiation (α1λ=1.54060 Å, α2=1.54443 Å, β=1.39225 Å, α1:α2 ratio=0.5) and a generator setting of 40 kV / 40 mA, run in transmission mode (step size 0.0130 degrees 2θ, step time 18.87 s). Data were visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017). The XRPD 2θ diffractogram of crystalline Form A of Compound 1 is shown in FIG. 25 and reveals that the material is highly crystalline.

[0156] II. Polarized Light Microscopy The presence of crystallinity (birefringence) was determined using an Olympus BX50 polarized light microscope equipped with a Motic camera and image capture software (Motic Images Plus 2.0). All images were recorded at 200x magnification using a 20x objective lens unless otherwise stated. Visible unpolarized (top) and polarized (bottom) light microscopy images of crystalline Form A of Compound 1 are shown in Figure 26 and show aggregated particles with no distinct morphology.

[0157] III. Liquid Chromatography-Mass Spectrometry (LC-MS) The LC-MS of crystalline form A of compound 1 was determined using the following parameters: Column: ACE EXCEL3 Super C18, 3.0 μm, 75 × 4.6 mm Mobile phase A: 0.1% formic acid in HO Mobile phase B: 0.1% formic acid in MeCN Diluent: 50:50 MeCN / H2O (%%v / v) Flow rate: 15mL / min Run time: 20 minutes Column temperature: 30℃ Injection volume: 10μL PDA range: 190~400nm

[0158] [Table 20]

[0159] The LC-MS spectrum of crystalline form A of compound 1 is shown in FIG. 27 and the observed peaks are as follows: m / z 470.1 [M+H] + : Matches the chemical structure, m / z 236.0 [M+2H] 2+ , m / z 256.0 [M+H+Na] 2+ , and m / z 938.9 [2M+H] + .

[0160] IV High Performance Liquid Chromatography (HPLC) Crystalline Form A of Compound 1 was run on PLC as follows. Column: Accucore RP-MS 150mm x 4.6mm, 2.6μm Column temperature: 20℃ Autosampler Temperature: Ambient UV wavelength: 270nm Injection volume: 15μL Flow rate: 15mL / min Mobile phase A: 0.1% TFA in HO:MeCN (75:25% v / v) Mobile phase B: 0.1% TFA in MeCN

[0161] [Table 21]

[0162] The HPLC chromatogram of crystalline Form A of Compound 1 is shown in Figure 28 and confirms that the sample was 99.3% pure. The integration results are shown in Table 18.

[0163] [Table 22]

[0164] V Thermogravimetric / differential thermal analyzer (TG / DTA) Approximately 5 mg of crystalline Form A of Compound 1 was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA) and held at room temperature. The sample was then heated at a rate of 10°C / min from 20°C to 350°C, during which the change in sample weight was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas at 300 cm. 3 A flow rate of 1000 s / min was used. The TG / DTA thermogram of crystalline form A of compound 1 is shown in Figure 29. Thermogravimetric analysis (top trace) showed no significant loss of mass before decomposition. The differential thermogram (bottom trace) showed an endothermic event due to melting (onset about 134°C). Thus, the onset of melting of compound 1 was about 134°C. A slight mass increase (about 0.3%) was observed near the melting temperature.

[0165] VI Differential Scanning Calorimetry (DSC) Approximately 5 mg of crystalline form A of compound 1 was weighed into an aluminum DSC pan and non-hermetically sealed with a perforated aluminum lid. The sample pan was then loaded into a Seiko DSC6200 (equipped with a condenser) that was cooled and held at 20°C. Once a stable heat flow response was obtained, the sample and reference were heated to melt at a scan rate of 10°C / min and the resulting heat flow response was monitored. Nitrogen was used as the purge gas at 50 cm 3A flow rate of 1000 sq. m / min was used. DSC thermograms are shown in Figure 30: (a) the first heating step, (b) the cooling step, and (c) the second heating (20-200°C). The sample was heated to melting (approximately 200°C), cooled to 20°C, and then reheated to melting again. A sharp endotherm due to melting was observed during the first heating step with an onset of approximately 133°C, coinciding with the onset of melting observed by TG / DTA. No thermal events were observed upon cooling, indicating that the material remained amorphous upon cooling. A weak thermal event at approximately 83°C, possibly due to a glass transition, was observed in the second heating step (b).

[0166] VII Gravimetric Vapor Sorption (GVS) Approximately 10-20 mg of crystalline form A of compound 1 was placed in a mesh vapor sorption balance pan and loaded onto an IGASorp moisture sorption analyzer balance by Hiden Analytical. The sample was subjected to a ramp profile from 40 to 90% relative humidity (RH) in 10% increments, maintaining the sample at each step until a stable weight was achieved at 25 °C (98% step completion, minimum step length 30 min, maximum step length 60 min). After completion of the sorption cycle, the sample was dried to 0% RH using the same procedure and finally returned to the starting point of 40% RH. Two cycles were performed. The weight change during the sorption / desorption cycle was plotted to determine the hygroscopicity of the sample. Figure 31 shows the GVS isotherm (dual cycle) and Figure 32 shows the GVS kinetics. The mass increase of approximately 0.7% up to 90% relative humidity suggests that the material was slightly hygroscopic. The material exhibited a Langmuir Type I isotherm. No evidence of recrystallization or morphology change occurred. (Note that an artifact at about 300 minutes during the first desorption step is likely due to experimental error.)

[0167] VIII Lyophilization Crystalline Form A of Compound 1 (180 mg) was dissolved in 1,4-dioxane (18 mL). 1 mL (10 mg) of the solution was transferred to a vial, which was then frozen at -50°C and lyophilized overnight. The starting material and the lyophilized product were analyzed by XRPD. The resulting XRPD 2θ diffractogram is shown in Figure 33 and demonstrates that lyophilization converts crystalline Form A of Compound 1 into an amorphous form.

[0168] IX Physical stability Compound 1 crystalline form A (10 mg) was weighed into a vial. Then, two vials were stored for one week under various conditions of temperature and relative humidity, respectively. HPLC analysis was performed to evaluate the change in purity, and the results are shown in Table 19, which show that no significant decrease in purity was observed under any of the conditions tested.

[0169] [Table 23]

[0170] XRPD analysis was performed to detect changes in crystallinity. The XRPD diffractograms are shown in Figure 34 and show that the crystalline form A of Compound 1 was maintained (i.e., did not convert to amorphous form) under the conditions tested, i.e., upon storage for 1 week under various conditions of temperature (ambient, 25°C, 40°C, 80°C) and relative humidity (ambient, 60%, 75%).

[0171] X thermodynamic solubility Compound 1 crystalline form A (10 mg) was weighed into a vial and 1 mL of the following was added: pH 3 buffer (0.2 M sodium citrate and 0.2 M citric acid), pH 4.5 buffer (0.2M sodium acetate and 0.2M acetic acid), pH 6.8 buffer (0.2 M KH2PO4 and 0.2 M NaOH), and Deionized water.

[0172] The pH was measured after the addition of the buffer. The material was kept at ambient temperature with stirring for about 24 hours and the pH was measured again. The pH values ​​are shown in Table 20, which shows that no significant changes were observed.

[0173] [Table 24]

[0174] The remaining solid was isolated by filtration and analyzed by XRPD. The XRPD diffractograms are shown in Figure 35 and show that Form A was isolated from all buffer systems and water. HPLC analysis of the filtered mother liquor showed that the concentration of Compound 1 was low (<0.05 mg / mL) in all buffers and water.

[0175] Example 7 Single crystal X-ray structure of Form B of compound 1 Single crystal diffraction data collection was carried out using a Rigaku diffractometer with a MicroMax-007HF Microfocus rotating anode X-ray generator using Mo Kα radiation, equipped with a Pilatus 200K hybrid pixel array detector and an Oxford Cryosystems cryodevice Cryostream 700 plus (T=-173°C). Global data collection was carried out using a 100mV diffractometer with ...

[0176]

number

[0177] The resulting ORTEP plot (50%) along with atomic numbering is shown in Figure 36. The absolute structure shown in the figure was chosen randomly and has an R value of 6.7%. Form B of compound 1 crystallizes in the chiral space group P212121 with symmetry manipulation. 1'x, y, z' 2'-x+1 / 2,-y,z+1 / 2' 3'-x,y+1 / 2,-z+1 / 2' 4'x+1 / 2, -y+1 / 2, -z'

[0178] Figure 37 shows a comparison of the actual form B pattern with a simulated pattern from single crystal X-ray diffraction (SCXRD) data. Both correspond to the same crystalline phase. The small shift observed is due to the different measurement temperatures.

[0179] Table 21 shows the crystal data and structure refinement for crystalline form B of compound 1. Table 22 shows the bond lengths [Å] for crystalline form B of compound 1. Table 22 shows the bond angles [°] for crystalline form B of compound 1. Table 23 shows the torsion angles [°] for crystalline form B of compound 1.

[0180] [Table 25]

[0181] [Table 26]

[0182] [Table 27-1]

[0183] [Table 27-2]

[0184] [Table 28]

[0185] Example 8 Micronization of crystalline compound 1 For inhalation formulation purposes, it is desirable to obtain Compound 1 with a small particle size, preferably a Dv50 of 2-3 μm. To this end, various particle engineering techniques were evaluated to produce stable micronized Compound 1 that retained its crystalline morphology and starting material purity. The processes evaluated included: Jet milling - involves feeding powder into a milling chamber where compressed nitrogen promotes interparticle collisions in a vortex motion, thereby reducing particle size; Wet milling - including microfluidization of suspensions by high pressure homogenization (HPH); and Wet grinding - involves the combination of wet milling of the suspension followed by isolation by spray drying, i.e. (i) preparing a feed suspension; (ii) a step of microfluidization of the suspension by high pressure homogenization (HPH); and (iii) spray drying the suspension to isolate the micronized particles.

[0186] Advantages of wet grinding compared to jet milling include precise control of particle size distribution and a smoother final surface area, potentially allowing for high dose / neat material formulations.

[0187] I. Particle Size Reduction - Jet Mill Crystalline Compound 1 Form A was crushed under pressurized nitrogen (grinding pressure P grind Venturi pressure P exceeds ventThe grinding chamber was fed tangentially by a vacuum created by a Venturi system using a 1000 psi (0.01 mm diameter) gas. Compressed nitrogen was also used for jet nozzles in the wall of the chamber. The feed flow rate was set and controlled automatically (by a gravimetric feeder) or manually. Once inside the grinding chamber, the particles were accelerated in a spiral motion by a series of peripheral jets. The compressed fluid leaving the nozzles was P grind The gas expands from the helical path, imparting a very high rotational velocity into the chamber. The atomizing effect occurs when the slower entering particles collide with the faster particles in the helical path. Centrifugal force keeps the larger particles at the periphery of the grinding chamber, while the smaller particles exit with the exhaust gases from the center of the chamber. Five 20 g trials were run in a 1.5 inch jet mill at various feed rates (F feed,JM ) and pressure. The optimal conditions were used for the sixth large scale 50 g trial. The conditions for each run and the analysis of the resulting micronized material are shown in Table 24.

[0188] [Table 29] P=crystalline form A = amorphous

[0189] II Particle size reduction - Wet grinding (wet milling + spray drying) Step 1 - Wet Milling Aqueous suspensions of crystalline Compound 1 Form A in water (5% w / w or 10% w / w) were processed by microfluidization using a HPH18 (M-110EH-30 Microfluidics Pilot) wet grinding device equipped with an auxiliary processing module (200 μm) and an interaction chamber (Z-type, 100 μm). The unit was started at a given pressure for the first 5 cycles to perform pre-grinding of the suspension using only the auxiliary processing module (200 μm). The interaction chamber (100 μm) was then introduced and the suspension was processed at a specified pressure. The temperature was controlled and recorded using the reactor jacket. To address clogging of the micronization chamber (observed after about 25 cycles), the pressure was increased from 25 to 60 bar. The analysis of the resulting micronized material is shown in Tables 25 and 26.

[0190] [Table 30]

[0191] [Table 31]

[0192] Step 2 - Spray Drying The wet-milled material was then spray dried using a SD48 BUCHI model B-290 Advanced spray dryer equipped with a two-fluid nozzle and one high-performance cyclone to collect the dried product. The unit was operated in a closed cycle with the aspirator blowing nitrogen at 100% capacity (flow rate of dry nitrogen at full capacity F drying is approximately 20 kg / hr). The atomizing nitrogen flow rate was adjusted to a value of 40 mm with a rotameter. Before feeding the stock suspension, the spray dryer was stabilized with water and the flow rate was adjusted. The inlet temperature was adjusted to achieve the target outlet temperature. Samples were subjected to various process conditions to determine the feed mixture flow rate (F feed,SD ), the drying gas temperature at the outlet of the spray drying chamber T out The impact of was evaluated.

[0193] The material isolated from the initial run 1A was split into three (1BI, 1BII and 1BIII). Runs 2A and 3A were spray dried to produce samples 2B and 3B, respectively. The resulting materials were characterized for PSD, XRPD, amorphous content, water content, and assay and related materials. Runs 2B and 3B were further characterized for specific surface area (SSA). See Table 27 (Runs 1BI, 1BII and 1BIII) and Table 28 (Runs 2B and 3B) for conditions and product characterization.

[0194] [Table 32]

[0195] [Table 33]

[0196] III Capsule filling Micronized material prepared by jet milling or wet grinding as described above in Sections I or II, respectively, was filled into clear Hydroxypropyl Methylcellulose (HPMC) size #3 capsules. More specifically, clear HPMC size #3 capsules were filled using an auger-filled Quantos unit with 100% net weight check and a nominal throughput of approximately 100 caps / hour. The Quantos was placed in a climatically controlled enclosure (CTS ClimateZone unit) set at 20-25°C and 40±5% relative humidity (exact conditions were recorded). Micronized crystalline Compound 1 Form A was sieved through a 250 μm mesh and then conditioned at 20-25°C and 40±10% relative humidity for at least 2 hours. The conditioned material was loaded into the Quantos dosator head. Capsules were filled at 10.0 and 20.0 mg with rejection limits of ±5% of the fill weight. The fill weight of each capsule was automatically recorded and classified as pass or fail. After each filling cycle, failing capsules were discarded and passing capsules were manually closed. The cycle was repeated until 60 capsules had been filled. Notably, the wet-ground powder appeared to have a lower density than the jet-milled powder based on the space the same amount of powder (20 mg) occupied in a capsule. A total of eight batches were prepared using: three jet milled powders from runs 1, 4 and 6; 2B of wet abrasive powder; Three different HPMC size #3 capsules from three different suppliers: Capsugel, Ravago and Qualicaps; Two fill weights (10mg and 20mg).

[0197] The materials used, manufacturing parameters, and capsule characterization for each trial are summarized in Table 29.

[0198] [Table 34] JM = jet mill, WP = wet grinding Capsules: C=Capsugel, Q=Qualicaps, R=Ravago AC = amorphous content

[0199] Example 9 Effect of adding a force control agent (L-leucine) Step 1: Micronization Crystalline Compound 1 Form A (100 g) suspended in water (1900 g) (5.0% w / w) was micronized by wet milling according to step I above. The suspension was pre-milled for 5 cycles using only the auxiliary processing module (200 μm) followed by 40 cycles using the interaction chamber, both at a pressure of 50 bar. The conditions are shown in Table 30. PSD samples were taken after various cycles and the results after 45 cycles are shown in Table 31.

[0200] [Table 35]

[0201] [Table 36]

[0202] Step 2: Spray drying with L-leucine The above micronized material was divided into three approximately equal batches and coated with increasing leucine content by spray drying using a BUCHI SD41 spray dryer with settings similar to those described in Step 2-Spray Drying of Example 8 to obtain three batches (2A, 2B and 2C) with different leucine concentrations. The material was evaluated for PSD, SEM, assay and XRPD. The spray drying process parameters and product characterization are shown in Table 32. XRPD showed characteristic peaks of crystalline Compound 1 Form A but not crystalline L-leucine, suggesting that L-leucine is in amorphous form in the spray dried material.

[0203] [Table 37]

[0204] Step 3: Capsule filling The micronized, spray dried material was filled into capsules according to step III above. Three capsule batches were prepared from the three spray dried products using #3 HMPC Capsugel capsule shells. The capsules were filled with the following (capsules had exclusion limits of ±5% of the fill weight): 20mg of 2A powder in 3A capsule, 15 mg of 2B powder in a 3B capsule, or 15mg of 2C powder in 3C capsule.

[0205] Filled capsules were analyzed for NGI (n=3) and DUSA (n=10), and the manufacturing data and capsule characterization are shown in Table 33. Notably, powder flow during the capsule filling process was significantly worse with added L-leucine compared to Compound 1 alone, especially for the higher leucine content formulations. As a result, the fill weight was reduced from 20 mg to 15 mg due to powder adhesion to the capsule shell inner wall.

[0206] [Table 38] FPD: Particulate dose ED: emitted dose (from an inhaler) NGI: Next Generation Impactor DUSA: Dose Unit Sampling Device MMAD: Mass Median Aerodynamic Diameter FPF ED,DUSA : Fine particle fraction (fine particle dose relative to the emitted dose by DUSA) FPF ED,NGI : Fine particle fraction (fine particle dose relative to the dose emitted by NGI) GSD: Geometric standard deviation

[0207] Example 10 Carrier-Based Formulations To investigate the optimization of aerodynamic performance, formulations based on six carriers were tested using three mixing mechanisms: two low shear mixing by Turbula, two high shear mixing by Diosna, and two milling by jet mill. The blending and capsule filling parameters are shown in Table 35 and the characterization of the capsules filled with the blends is shown in Table 36. L-leucine or lactose was used as the carrier. Two grades of lactose were used: Respitose SV003 - sieved lactose crystals with a smooth surface and an average particle size of >50 μm (Dv10=19-43 μm / Dv50=53-66 μm / Dv90=75-106 μm); bulk density=630 g / L, and Tablettose 80 - granular lactose with particle size 0-630 μm (NMT 20% <63 μm, 40-75% <180 μm, NLT 85% <400 μm, NLT 97% <63 μm, average about 300 μm); bulk density = 620 g / L.

[0208] High Shear Mixing High shear mixing was performed using a Diosna high shear mixer equipped with a 0.5L bin. Lactose was sieved (Respitose SV003=500 μm sieve, Tablettose 80=850 μm sieve) and charged. Crystalline Compound 1 Form A was sieved (same sieve as lactose) and charged and the combined materials were mixed for 5 minutes at 450 RPM in the main impeller and 500 RPM in the chopper. Batch size was 20-30g and contained 60% micronized Compound 1 and 40% lactose.

[0209] Low Shear Mixing Low shear mixing was performed using a Glen Mills T2F Turbula equipped with a 0.5L flask. Lactose was sieved (Respitose SV003=500 μm sieve, Tablettose 80=850 μm sieve) and charged. Crystalline Compound 1 Form A was sieved (same sieve as lactose) and charged and the combined materials were mixed for 15 minutes at 96 RPM. The batch size was 15g and contained 60% micronized Compound 1 and 40% lactose.

[0210] Co-grinding Crystalline Compound 1 Form A and excipients (lactose or leucine) were blended using a Turbula low shear mixer at 96 RPM for 15 minutes. The blended material was fed to a MZ0502 jet mill at 60 g / hr and micronized (grinding pressure = 4-5.5 bar, aeration pressure = 6-7 bar). Compound 1 (60%) with lactose (7711.01) and Compound 1 (96%) with L-leucine (7603.02) were obtained.

[0211] Capsule filling The six mixtures were filled into capsules using the Quantos auger filler according to the procedure described above. No significant differences were observed during capsule filling for the different formulations. The filled capsules were analyzed for NGI (n=3) and DUSA (n=10). The results are summarized in Tables 34 and 35.

[0212] [Table 39] R=Respitose SV003 T=Tablet Tose 80 HS = high shear LS = Low Shear JM = Jet mill

[0213] [Table 40]

[0214] Example 11 High-dose crystalline dry powder inhaler (DPI) formulation I. Wet polishing - Compound 1 alone Two 250 g batches of crystalline Compound 1 Form A were each suspended in water (5 L) and wet-ground in a wet-grinding HPH18 (M-110EH-30 Microfluidics Pilot) apparatus equipped with an auxiliary processing module (200 μm) and an interaction chamber (Z-type, 100 μm). The unit was started at 50 bar for the first 5 cycles to perform pre-grinding of the suspension using only the auxiliary processing module (200 μm). The interaction chamber (100 μm) was then introduced and the suspension was processed at 50 bar (increased to 60 or 70 bar if the system was clogged). The temperature was maintained between 18 and 28 °C using the reactor jacket. The reactor agitation speed was 280 RPM (batch 1) and 390 RPM (batch 2). The first batch was micronized for 25 cycles and analyzed for particle size distribution after 5, 15 and 20 cycles, and the second batch was micronized for 3525 cycles and analyzed for particle size distribution after 15, 20, 25 and 35 cycles. The particle size distribution analysis is shown in Table 36.

[0215] [Table 41]

[0216] Next, both batches were spray-dried (separately) using a Buchi spray dryer that uses an open-loop system. This unit is equipped with a two-fluid nozzle, and the diameters of the cap and orifice are 1.5 mm and 0.7 mm, respectively, and it was operated with nitrogen. The aspirator for blowing in nitrogen was set to 100% capacity (about 40 kg / h). The suspension feed flow was set high at 8 ml / min, and the drying outlet temperature was set at 75 ± 1 °C. The final blend of the spray-dried powder was characterized for particle size distribution (PSD), water content by KF, XRPD, and amorphous content (DSC), and the details are shown in Table 37. The total yield (both batches combined) was 267 g (53%).

[0217]

Table 42

[0218] As shown in Table 38, both batches showed little difference between the two batches and exhibited a particle size distribution of 0.5 < Dv50 < 3 μm.

[0219]

Table 43

[0220] The final product showed a Dv50 of 0.6 μm and had the expected amorphous content, water content, and XRPD peaks, as shown in Table 39.

[0221]

Table 44

[0222] II Wet milling - Compound 1 coated with L-leucine Two 250 g batches (250 g and 238 g, total 488 g) of crystalline Compound 1 Form A coated with about 2% L-leucine were each suspended in water (5 L) and wet-ground in a wet-grinding HPH18 (M-110EH-30 Microfluidics Pilot) apparatus under the same process as described in the previous examples. The first batch was micronized for 25 cycles and the second batch for 30 cycles. Samples were taken before the grinding process, after 5, 10, 15, 20 and 25 cycles for the first batch, and after 30 cycles for the second batch. Clogging of the micronization chamber was minimized by using a pressure of 50 bar for the first 5 cycles (200 μm chamber) and 70 bar for the remaining cycles (200 μm and 100 μm chambers). The suspension was weighed at the beginning and end of the process to determine the process yield. The yields were 99 and 97% for the first and second batches, respectively. The conditions are summarized in Table 40 and the PSD analysis is summarized in Table 41.

[0223] [Table 45]

[0224] [Table 46]

[0225] Both batches were then spray dried as described in the previous examples and are summarized in Table 42. The final spray dried product was characterized for assay and related substances, PSD, moisture content by KF, and XRPD with the results shown in Table 43. The two sub-batches were blended to give the final product with an overall final yield of 137 g (68%) (see Table 44).

[0226] [Table 47]

[0227] [Table 48]

[0228] The final product exhibited a Dv50 of 0.6 μm and had the expected amorphous content, water content and XRPD peaks (see Table 44).

[0229] [Table 49]

[0230] III Capsule filling Capsule filling trials were conducted using the micronized material (crystalline Compound 1 Form A alone and with L-leucine) prepared in steps I and II. HPMC size #3 capsules (Capsugel) were filled using an MG2 FlexaLab unit (500-3000 caps / hr), a fully automated dosator-nozzle filling device, where powder was filled into a rotating product container creating a powder bed through which the dosator moved to collect the desired volume of powder. In this process, the dosator creates a powder plug by applying compaction to the powder bed. The dosed powder volume and compaction are adjusted by varying the powder bed depth in the rotating container, the dosator chamber height, and the dosator diameter. The capsule filling process included the following steps: Filling the powder hopper with the blend and forming a powder bed in the rotating vessel: A vibration system distributed the powder from the hopper into the rotating vessel until a uniform bed of powder was formed. The rotating vessel was equipped with levellers to prevent the formation of powder holes due to immersion of the dosator during filling. The machine was run for at least 30 minutes to allow the product to settle into the rotating vessel.

[0231] Dosator adjustment: The machine was run without the MultiNETT (MG2) system and the fill weight was checked by the empty weight difference. Successive adjustments were made to the dosator height until the target fill weight was reached.

[0232] After the batch started, the filled capsules were collected and a fill weight IPC was performed approximately every 100 capsules by weight difference in emptying 5 capsules.

[0233] A summary of the capsule filling parameters is given in Table 45 (Runs 1-5) and Table 46 (Runs 6-9).

[0234] [Table 50]

[0235] [Table 51]

[0236] The batches were analyzed and the results are summarized in Tables 47 and 48.

[0237] [Table 52] LC=Labeling DUSA = Dose Unit Sampling Device ED = emitted dose (from an inhaler device) FPD=fine particle dose FPF ED = Fine particle fraction (fine particle dose relative to the emitted dose by the NGI) MMAD=Mass Median Aerodynamic Diameter NGI = Next Generation Impactor RSD = relative standard deviation GSD=geometric standard deviation

[0238] [Table 53]

[0239] Example 12 Scale-up of a high-dose crystalline dry powder inhaler (DPI) formulation 90% of the purified water was added to the mixing vessel. 1.86 Kg of crystalline Compound 1 Form B was added to the mixing vessel followed by the remaining portion of the purified water to achieve a 5% w / w suspension. The mixture was stirred at 200-600 rpm for at least 2 hours until a homogenous suspension was observed. The suspension was pre-micronized using a high pressure homogenizer equipped with a 400 μm micronization chamber at a pressure of 70 bar. The temperature of the suspension was maintained at 15-25°C and the particle size distribution of Compound 1 was monitored by laser diffraction. The suspension was further micronized using a 100 μm micronization chamber at a pressure of 70 bar until the particle size Dv50 of Compound 1 in the suspension was less than 1 μm. 0.14 kg of L-leucine was added to the micronized Compound 1 in the suspension while mixing. The L-leucine was allowed to dissolve for at least 30 minutes until the suspension was homogenous.

[0240] A PSD-1 spray dryer was assembled and configured with the appropriate cyclone and collection vessel for the spray dried powder of Compound 1. Following the start-up procedure, the micronized suspension was spray dried with nitrogen drying gas using the following target (set point) conditions: Process gas inlet temperature: 125℃ Process gas outlet temperature: 75℃ Process gas flow rate: 100 kg / hour Liquid supply flow rate: 1.2Kg / hour Atomizing gas flow rate: 3.3 kg / hour

[0241] Process parameters were recorded approximately every 30 minutes and the cyclone collection vessel was changed approximately every 4 hours.

[0242] Capsules were hand filled and tested for aerosol performance as summarized in Table 49 below.

[0243] [Table 54]

[0244] Example 13 High-dose amorphous dry powder inhaler (DPI) formulations 3.25 kg of crystalline Compound 1 Form A and 3.25 kg of L-leucine were dispensed. Sufficient water and ethanol were dispensed to obtain a 1.26% w / w solution. L-leucine was added to the water in a stainless steel process tank with mixing. L-leucine was allowed to dissolve in the water for a minimum of 1 hour until a visually clear solution was obtained. The process tank was purged with nitrogen and dehydrated alcohol was added to the L-leucine solution. Compound 1 was added and the contents were mixed for a minimum of 1 hour until a visually clear to slightly hazy solution was obtained.

[0245] A PSD-1 spray dryer was assembled and configured with the appropriate cyclone and collection vessel for spray-dried powder of Compound 1. Two 0.2 μm filters were installed in-line in the feed line between the solution tank and the spray dryer nozzle. Filter integrity (i.e., bubble point) was determined after the process was completed. Following the start-up procedure, the solution was spray-dried with nitrogen drying gas using the following target (set point) conditions: Process gas inlet temperature: 160℃ Process gas outlet temperature: 60℃ Process gas flow rate: 2870g / min Liquid supply flow rate 110g / min Atomizing gas pressure 22psig

[0246] Process parameters are recorded approximately every 10 minutes and the cyclone collection vessel is changed approximately every 16 hours.

[0247] A Harro Hoflinger Modu-C capsule filler, capsule polisher, and metal detector were assembled and prepared with all process consumables. The hopper was loaded with spray-dried powder of Compound 1 and stirred with an angled two-blade agitator. Encapsulation was performed utilizing automatic mass verification (AMV) sorting limits of + / - 7.5% of the target fill weight. Capsule fill weight and closure length were measured throughout the encapsulation process to ensure that the average capsule weight was within 0.5 mg of the AMV system and that the capsules were properly closed. The capsules were tested for aerosol performance as summarized in Table 50 below.

[0248] [Table 55]

[0249] Example 14 Solubility of various forms of compound 1 The solubility of crystalline Compound 1 Form A, amorphous Compound 1, L-leucine and Compound 1 / L-leucine spray dried powder (SDP) mixtures in phosphate buffer and ethanol / water mixtures was tested.

[0250] Sample preparation Samples of crystalline Compound 1 Form A, amorphous Compound 1, Compound 1 / L-leucine SPD (70:30), Compound 1 / L-leucine SPD (50:50), and L-leucine were tested in the following test solutions and the results are shown in Tables 51 and 52.

[0251] The phosphate buffer contained NaH2PO4·H2O (0.345 g), aqueous sodium hydroxide (0.2 M, 10.001 mL), sodium chloride (0.576 g), and water (sufficient to make 100.0 mL). Ethanol / water (30 / 70) contains ethanol (30.0 g) and water (70.0 g); Ethanol / water (40 / 60) contains ethanol (40.0 g) and water (60.0 g); Ethanol / water (50 / 50) contains ethanol (50.0 g) and water (50.0 g), and Ethanol / water (45 / 55) contained ethanol (4.50 g) and water (5.51 g).

[0252] [Table 56]

[0253] Solubility results in ethanol / water at 22° C. are shown in Table 52.

[0254] [Table 57] T Top layer after centrifugation B Bottom layer after centrifugation * Results outside the calibration curve

[0255] Example 15 In vivo studies Three in vivo PKPD studies were used to evaluate the pharmacology of the test formulation (i.e., capsules containing crystalline Compound 1 Form B of Example 12 vs. the reference formulation) vs. the reference formulation (i.e., capsules containing amorphous Compound 1 of Example 13). These head-to-head studies showed that passive inhalation delivery (once a day for 3 days) of the test formulation resulted in significantly higher lung exposure compared to the reference formulation. Overall, the lung exposure of the test formulation was approximately twice that of the reference formulation. The test formulation inhibits PDGFB and SCF-induced phosphorylation of PDGFR and cKIT. The test formulation showed more potent inhibition of phosphorylation of PDGFR and cKIT immediately after administration. This target engagement was sustained 8 hours after administration for the test formulation, while there was a reversal of inhibition for the reference formulation, which corresponds to the lung levels. The results of these studies are shown in Table 53.

[0256] [Table 58]

[0257] Example 16 Clinical trial results A phase 1 study to evaluate the bioavailability of the test formulation (crystalline Compound 1 Form B) compared to the reference formulation (amorphous Compound 1) identified in Example 15 was conducted in a crossover study. The study design is described below. Briefly, it was a two-part, two-treatment, two-period, randomized, open-label, crossover design. Participants were required to participate in both parts 1 and 2 and received a single oral inhalation dose of the two formulations.

[0258] 1st period On Day 1, enrolled subjects received, under fasting conditions, a single oral inhalation dose of either the test formulation of crystalline Compound 1 (1 x 40 mg capsule of a 93% w / w formulation) or a single oral inhalation dose of the reference formulation of the amorphous form of Compound 1 (3 x 15 mg capsules of a 50% w / w formulation), followed by a 3-day washout period.

[0259] 2nd term Subjects were crossed over on day 4. Subjects who received the test formulation in period 1 received the reference formulation in period 2, and subjects who received the reference formulation in period 1 received the test formulation in period 2. Dosing was again performed under the same fasting conditions. Each dose was followed by a 72-hour pharmacokinetic (PK) assessment. After dosing in period 2, subjects were held until day 7 for safety and PK assessments.

[0260] result: Twenty-two subjects were enrolled, and 21 completed Periods 1 and 2. Both formulations were well tolerated, with no significant abnormalities in vital signs, ECGs, or laboratory results.

[0261] Dosage The amount of Compound 1 administered per capsule was determined by gravimetric analysis of the amount of powder dispensed from the device to confirm the actual dose dispensed (devices were weighed before and after administration). For each formulation, the administered weight was multiplied by the Compound 1 content to determine the amount released for each subject.

[0262] PK analysis Figures 38A and 38B show the mean concentration-time profiles (±SD) of Compound 1 over 4 and 72 hours, respectively (Treatment A = test formulation, Treatment B = reference formulation).

[0263] As shown in Figures 38A and 38B, the concentration-time profile of the test formulation was found to differ from the reference formulation. The rate and extent of availability of Compound 1 in the systemic circulation was altered. max was reduced by approximately 10-fold. When the amount of Compound 1 was normalized to the fine particle dose, the AUC of the test formulation was 82% of the reference formulation. The test formulation was found to prolong lung exposure and, when matched to systemic exposure, resulted in a more favorable PK profile with a lower Cmax and prolonged AUC.

[0264] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or listed in the Application Data Sheets are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, as necessary, to use concepts from the various patents, applications, and publications to provide still further embodiments.

[0265] These and other changes can be made to the embodiments in light of the above Detailed Description. Generally, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure herein.

[0266] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0267] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 185,996, filed May 7, 2021, which is incorporated herein by reference in its entirety.

Claims

1. A solid crystalline form of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide.

2. 2. The solid crystalline form of claim 1, wherein the crystalline form is Form A.

3. 3. The crystalline form of claim 2, characterized by an XRPD pattern with peaks at 5.5, 7.8, 11.0, 12.3, and 15.6±0.2 degrees two-theta.

4. 4. The crystalline form of claim 3, further characterized by an XRPD pattern substantially as shown in Figure 9.

5. 3. The solid crystalline form of claim 2, comprising at least 80% of Form A.

6. 6. The solid crystalline form of claim 5, comprising at least 90% of Form A.

7. 2. The solid crystalline form of claim 1, wherein the crystalline form is Form B.

8. 8. The crystalline form of claim 7, characterized by an XRPD pattern with peaks at 5.2, 6.1, 7.6, 11.5, and 12.3±0.2 degrees two-theta.

9. 10. The solid crystalline form of claim 8, further characterized by an XRPD pattern substantially as shown in FIG.

10. 8. The solid crystalline form of claim 7, comprising at least 80% form B.

11. 11. The solid crystalline form of claim 10, comprising at least 90% of Form B.

12. 3. The solid crystalline form of claim 2, wherein the crystalline form is substantially pure Form A.

13. 8. The solid crystalline form of claim 7, wherein the crystalline form is substantially pure Form B.

14. 2. The solid crystalline form of claim 1, wherein the crystalline form is a mixture of Form A and Form B.

15. A pharmaceutical composition comprising the solid crystalline form of any one of claims 1 to 14 in combination with one or more pharma- ceutically acceptable carriers.

16. 16. The pharmaceutical composition of claim 15, comprising an additional therapeutically active compound.

17. 16. The pharmaceutical composition of claim 15, wherein the composition is formulated for administration to the respiratory tract.

18. 16. The pharmaceutical composition of claim 15, wherein the composition is in the form of an inhalable powder.

19. 16. The pharmaceutical composition of claim 15, wherein the composition is in the form of a dry powder.

20. 19. The pharmaceutical composition of claim 18, wherein the inhalable powder comprises particles having a Dv50 of 2-3 um.

21. 19. The pharmaceutical composition of claim 18, wherein the inhalable powder has a mass median aerodynamic diameter of 0.9 to 4.0 um.

22. 19. The pharmaceutical composition according to claim 18, wherein the inhalable powder is obtained by wet-milling micronization in an aqueous solution.

23. 19. The pharmaceutical composition according to claim 18, wherein the inhalable powder is obtained by jet mill micronization.

24. 20. The pharmaceutical composition of claim 18, wherein the inhalable powder has more than 90% of the starting crystalline form.

25. 19. The pharmaceutical composition of claim 18, wherein the inhalable powder has more than 75%% of the starting crystalline form.

26. 16. The pharmaceutical composition of claim 15, wherein the one or more pharma- ceutically acceptable carriers comprise lactose.

27. 16. The pharmaceutical composition of claim 15, further comprising leucine.

28. 28. The pharmaceutical composition of claim 27, wherein leucine coats the solid crystalline form.

29. 29. The pharmaceutical composition of claim 28, wherein the leucine coated solid crystalline form is obtained by adding leucine to a wet-milled crystalline form suspension prior to spray drying.

30. 16. A pharmaceutical dosage form comprising the pharmaceutical composition of claim 15.

31. 31. The pharmaceutical dosage form of claim 30, wherein the dosage form is a capsule for administration by a dry powder inhaler.

32. 31. The pharmaceutical dosage form of claim 30, wherein the dosage form is a blister for administration by a dry powder inhaler.

33. 31. The pharmaceutical dosage form of claim 30, wherein the dosage form is a powder for administration by a dry powder inhaler.

34. A solid unit dosage form comprising the solid crystalline form of any one of claims 1 to 14.

35. 35. The solid unit dosage form of claim 34, wherein the dosage form is formulated for administration to the respiratory tract.

36. 35. The solid unit dosage form of claim 34, wherein the dosage form is in the form of an inhalable powder.

37. 35. The solid unit dosage form of claim 34, wherein the dosage form is in the form of a dry powder.

38. 37. A solid unit dosage form according to claim 36, wherein the inhalable powder comprises particles having a Dv50 of 2-3 um.

39. 37. The solid unit dosage form of claim 36, wherein the inhalable powder has a mass median aerodynamic diameter of 0.9 to 4.0 um.

40. 37. A solid unit dosage form according to claim 36, wherein the inhalable powder is obtained by wet milling micronization in an aqueous solution.

41. 37. The solid unit dosage form of claim 36, wherein the inhalable powder is obtained by jet mill micronization.

42. 37. A solid unit dosage form according to claim 36, wherein the inhalable powder has more than 90% of the starting crystalline form.

43. 37. A solid unit dosage form according to claim 36, wherein the inhalable powder has more than 75%% of the starting crystalline form.

44. 35. The solid unit dosage form of claim 34, further comprising leucine.

45. 45. The solid unit dosage form of claim 44, wherein leucine coats the solid crystalline form.

46. 46. ​​The solid unit dosage form of claim 45, wherein the leucine coated solid crystalline form is obtained by adding leucine to a wet-milled crystalline form suspension prior to spray drying.

47. 35. The solid unit dosage form of claim 34, wherein the dosage form is a capsule for administration by a dry powder inhaler.

48. 35. The solid unit dosage form of claim 34, wherein the dosage form is a blister for administration by a dry powder inhaler.

49. 35. The solid unit dosage form of claim 34, wherein the dosage form is a powder for administration by a dry powder inhaler.

50. 15. A method for treating a disease or condition modulated by kinase inhibition, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising the solid crystalline form of any one of claims 1 to 14.

51. 51. The method of claim 50, wherein the kinase is a tyrosine kinase.

52. 52. The method of claim 51, wherein the tyrosine kinase is platelet-derived growth factor receptor (PDGFR).

53. 51. The method of claim 50, wherein the disease or condition is PAH, primary PAH, idiopathic PAH, hereditary PAH, refractory PAH, drug-induced PAH, toxin-induced PAH, or PAH with secondary disease.

54. 54. The method of claim 53, wherein the disease or condition is PAH.

55. A process for preparing a solid crystalline form of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide by crystallization from a solvent containing ethyl acetate.

56. 56. The process of claim 55, wherein the solvent further comprises n-heptane.

57. 56. The process of claim 55, wherein the crystalline form is Form A.

58. 56. The process of claim 55, wherein the crystalline form is form B.

59. A process for preparing a solid crystalline form of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide by crystallization from a solvent containing ethanol.

60. 60. The process of claim 59, wherein the crystalline form is form B.

61. The process of any one of claims 55 to 60, wherein the solvent further comprises water.

62. 1. A process for preparing form B of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide comprising slurrying form A of N-{3-[(1S)-1-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide in ethyl acetate and maintaining the temperature at about 10° C. to about 45° C. for a period of about 1 minute to 90 hours.

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