Crystalline prostacyclin (IP) receptor agonists and uses thereof

Abstract

Described herein are crystalline forms of prostacyclin (IP) receptor agonist compounds and pharmaceutical compositions thereof, as well as methods of their use in treating diseases or disorders that benefit from treatment with prostacyclin (IP) receptor agonist compounds.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 310,469, filed February 15, 2022, the entirety of which is incorporated herein by reference.

[0002] Described herein are solid state forms of the prostacyclin (IP) receptor agonist ralinepag and pharmaceutical compositions thereof, as well as methods of their use in the treatment of diseases or conditions that would benefit from treatment with ralinepag. [Background technology]

[0003] Prostacyclin (IP) receptors are expressed on platelets and on smooth muscle cells of several tissues, including the lungs, heart, aorta, liver, kidneys, and blood vessels. Activation of IP receptors leads to an increase in cellular cyclic adenosine monophosphate (cAMP), which subsequently leads to arterial vasodilation and inhibition of platelet aggregation. For example, PGI2 replacement therapy for the treatment of pulmonary arterial hypertension (PAH) has been demonstrated to improve hemodynamics, exercise capacity, and survival. Summary of the Invention

[0004] The present disclosure relates to various solid state forms of the prostacyclin (IP) receptor agonist ralinepag, which are useful for modulating prostacyclin (IP) receptor agonist activity in mammals that may benefit from such activity.

[0005] In one aspect, described herein is a crystalline form of lalinepag characterized by having an X-ray powder diffraction (XRPD) pattern, when measured using Cu Kα radiation, substantially the same as that shown in FIG. 1, or an X-ray powder diffraction (XRPD) pattern, when measured using Cu Kα radiation, substantially the same as that shown in FIG. 2, or an X-ray powder diffraction (XRPD) pattern, when measured using Cu Kα radiation, substantially the same as that shown in FIG. 3, or an X-ray powder diffraction (XRPD) pattern, when measured using Cu Kα radiation, substantially the same as that shown in FIG. 4.

[0006] In another aspect, described herein is a crystalline form of Ralinepag (Form 1), characterized by having an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1, when measured using Cu Kα radiation, i.e., an XRPD pattern having peaks at 8.8±0.2°2-Θ, 11.7±0.2°2-Θ, 16.2±0.2°2-Θ, 21.3±0.2°2-Θ, and 33.8±0.2°2-Θ, when measured using Cu Kα radiation.

[0007] In some embodiments, described herein is a crystalline form of Ralinepag (Form 1), characterized by having an X-ray powder diffraction (XRPD) pattern substantially the same as shown in any one of Figures 12a, 12b, 12c, 12d, 12e, 12f, 13a, 13b, 13c, 13d, 13e, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 15a, 15b, 15c, 16, 17a, or 17b, when measured using Cu Kα radiation.

[0008] In some embodiments, the crystalline form of ralinepag (Form 1) is further characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in FIG. 6 or a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 7.

[0009] In some embodiments, the crystalline form of Ralinepag (Form 1) is further characterized by having a differential thermal analysis (DTA) thermogram that exhibits a sharp endothermic event with an onset at about 127.2°C and a differential scanning calorimetry (DSC) thermogram that has a sharp endothermic event with an onset at about 127.5°C.

[0010] In some embodiments, the crystalline form of Lalinepag (Form 1) is further characterized by having a reversible water uptake of 0.1% (w / w) at 0%-90% relative humidity (RH).

[0011] In some embodiments, crystalline Form 1 of ralinepag is further characterized by having an invariant XRPD following dynamic vapor sorption (DVS) analysis at RH between 0% and 90%.

[0012] In another aspect, described herein is a crystalline form of Ralinepag (Form 1), characterized in that it has unit cell parameters at 100K approximately equal to the following:

[0013] [Table 1]

[0014] In yet another aspect, described herein is a crystalline form of Lalinepag (Form 2), characterized by having an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 2, when measured using Cu Kα radiation, i.e., an XRPD pattern having peaks at 4.1±0.2°2-Θ, 15.5±0.2°2-Θ, 16.9±0.2°2-Θ, 17.9±0.2°2-Θ, 22.8±0.2°2-Θ, and 23.7±0.2°2-Θ, when measured using Cu Kα radiation.

[0015] In some embodiments, the crystalline form of Lalinepag (Pattern 2) is further characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in FIG. 8. In some embodiments, the crystalline form of Lalinepag (Pattern 2) is further characterized by having a differential thermal analysis (TGA / DTA) thermogram that exhibits weak endothermic and exothermic events at 81-89° C., as well as a broad endothermic event with an onset at about 124.7° C. In some embodiments, the crystalline form of Lalinepag (Pattern 2) is further characterized by having an XRPD that converts upon heating to a crystalline form of Lalinepag (Form 1). In some embodiments, the crystalline form of Lalinepag (Pattern 2) is further characterized as being a dimethylsulfoxide solvate.

[0016] In yet another aspect, described herein is a crystalline form of Ralinepag (Form 3), characterized by having an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 3, when measured using Cu Kα radiation, i.e., an XRPD pattern having peaks at 3.6±0.2°2-Θ, 18.7±0.2°2-Θ, 22.2±0.2°2-Θ, 24.2±0.2°2-Θ, and 24.3±0.2°2-Θ, when measured using Cu Kα radiation.

[0017] In some embodiments, the crystalline form of Lalinepag (Form 3) is further characterized in that it has a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in Figure 9. In some embodiments, the crystalline form of Lalinepag (Form 3) is further characterized in that it has a thermogravimetric analysis (TGA) trace that exhibits a weight loss of about 17.8% from the onset of heating to approximately 238°C. In some embodiments, the crystalline form of Lalinepag (Form 3) is further characterized in that it has a differential thermal analysis (DTA) thermogram that exhibits a sharp endothermic event with an onset at about 74.6°C. In some embodiments, the crystalline form of Lalinepag (Form 3) is further characterized in that it is a hydrate.

[0018] In yet another aspect, described herein is a crystalline form of Ralinepag (Form 4), characterized by having an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 4, when measured using Cu Kα radiation, i.e., an XRPD pattern having peaks at 15.0±0.2°2-Θ, 16.7±0.2°2-Θ, 18.0±0.2°2-Θ, 18.7±0.2°2-Θ, and 18.9±0.2°2-Θ, when measured using Cu Kα radiation.

[0019] In some embodiments, the crystalline form of Lalinepag (Pattern 4) is further characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in Figure 10. In some embodiments, the crystalline form of Lalinepag (Pattern 4) is further characterized by having a differential thermal analysis (DTA) thermogram exhibiting a broad endothermic event with an onset at about 29.0°C, a sharp endothermic event with an onset at about 127.8°C, or both. In some embodiments, the crystalline form of Lalinepag (Pattern 4) is further characterized by having an XRPD that converts to a crystalline form of Lalinepag (Form 1) when dried. In some embodiments, the crystalline form of Lalinepag (Pattern 4) is further characterized by having an XRPD that converts to amorphous Lalinepag when dried.

[0020] In yet another aspect, described herein is amorphous larinepag, characterized by having an X-ray powder diffraction (XRPD) pattern indicative of a lack of crystallinity. In some embodiments, the amorphous larinepag is further characterized by converting to a crystalline form of larinepag (Form 1) upon drying.

[0021] Also described herein is a pharmaceutical composition comprising crystalline ralinepag as described herein and at least one pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated in the form of a solid form pharmaceutical composition suitable for administration to a subject by oral administration, intranasal administration, or inhalation. In some embodiments, the pharmaceutical composition is formulated in the form of a solid form pharmaceutical composition for oral administration to a mammal. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule. In some embodiments, the pharmaceutical composition is administered using a dry powder inhaler (DPI) or a metered dose inhaler (MDI).

[0022] Also described herein is a pharmaceutical composition comprising amorphous ralinepag and at least one pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated in the form of a solid form pharmaceutical composition suitable for administration to a subject by oral administration, intranasal administration, or inhalation. In some embodiments, the pharmaceutical composition is formulated in the form of a solid form pharmaceutical composition for oral administration to a mammal. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule. In some embodiments, the pharmaceutical composition is administered using a dry powder inhaler (DPI) or a metered dose inhaler (MDI).

[0023] In one aspect, described herein is a method of treating pulmonary arterial hypertension (PAH) in a subject in need thereof, the method comprising administering crystalline or amorphous lalinepag, or a pharmaceutical composition comprising crystalline or amorphous lalinepag. In some embodiments, the PAH is selected from idiopathic PAH, familial PAH, scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis, PAH associated with congenital heart disease in patients with atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus, PAH associated with portal hypertension, PAH associated with HIV infection, PAH associated with drug or toxin intake, PAH associated with hereditary hemorrhagic telangiectasia, PAH associated with splenectomy, PAH associated with significant venous or capillary involvement, PAH associated with pulmonary veno-occlusive disease (PVOD), and PAH associated with pulmonary capillary hemangiomatosis (PCH) in patients. In some embodiments, the PAH is World Health Organization (WHO) Group 1 PAH. In some embodiments, the subject has symptoms of WHO / NYHA functional class II-IV.

[0024] In one aspect, described herein are methods for synthesizing amorphous ralinepag, characterized by having an X-ray powder diffraction (XRPD) pattern indicative of no crystallinity, comprising converting ralinepag in Form 1, Form 3, Pattern 2, or Pattern 4 to an amorphous form. In some embodiments, the method comprises drying crystalline Pattern 4 ralinepag. In some embodiments, the method comprises lyophilizing a solution of ralinepag in an organic solvent. In some embodiments, the organic solvent is 1,4-dioxane. In some embodiments, the concentration of the ralinepag solution is up to 5 mg / mL. In some embodiments, the concentration of the ralinepag solution is up to 3 mg / mL.

[0025] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description, but it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. [Brief description of the drawings]

[0026] The features of the invention are set forth with particularity in the appended claims. For a better understanding of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments in which the principles of the invention are utilized and the accompanying drawings.

[0027] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline form 1 of ralinepag. [Diagram 2] 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline pattern 2 of lalinepag. [Diagram 3] 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline form 3 of larinepag. [Figure 4] 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline pattern 4 of lalinepag. [Diagram 5] 1 shows the X-ray powder diffraction (XRPD) pattern of amorphous larinepag. [Figure 6] 1 shows a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram of crystalline form 1 of larinepag. [Figure 7] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form 1 of ralinepag. [Figure 8] 1 shows a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram of crystalline pattern 2 of larinepag. [Figure 9] 1 shows a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram of crystalline form 3 of lalinepag. [Figure 10] 1 shows a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram of crystalline pattern 4 of larinepag. [Figure 11] 1 shows an overlay of the simulated XRPD diffraction pattern (top) of crystalline form 1 of lalinepag with the experimental XRPD diffraction pattern (bottom). [Figure 12a]

[0036] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of ralinepag obtained from screening by solvent solubility test in Example 3. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientations. [Figure 12b]

[0036] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of ralinepag obtained from screening by solvent solubility test in Example 3. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientations. [Figure 12c]

[0036] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of ralinepag obtained from screening by solvent solubility test in Example 3. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientations. [Figure 12d]

[0036] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of ralinepag obtained from screening by solvent solubility test in Example 3. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientations. [Figure 12e]

[0036] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of ralinepag obtained from screening by solvent solubility test in Example 3. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientations. [Figure 12f]

[0036] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of ralinepag obtained from screening by solvent solubility test in Example 3. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientations. [Figure 13a] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from the experiment after thermal cycling in Example 4. All figures show the reference XRPD pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 13b] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from the experiment after thermal cycling in Example 4. All figures show the reference XRPD pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 13c] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from the experiment after thermal cycling in Example 4. All figures show the reference XRPD pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 13d] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from the experiment after thermal cycling in Example 4. All figures show the reference XRPD pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 13e] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from the experiment after thermal cycling in Example 4. All figures show the reference XRPD pattern of Form 1 at the top. The XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 14a]FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from drying in a vacuum oven at 40° C. after thermal cycling in Example 4. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 14b] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from drying in a vacuum oven at 40° C. after thermal cycling in Example 4. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 14c] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from drying in a vacuum oven at 40° C. after thermal cycling in Example 4. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 14d] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from drying in a vacuum oven at 40° C. after thermal cycling in Example 4. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 14e] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained from drying in a vacuum oven at 40° C. after thermal cycling in Example 4. All figures show the reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 14f] Figure 1 shows X-ray powder diffraction (XRPD) patterns of crystalline Form 1 of Lalinepag after thermal cycling. After drying, only Form 1 was precipitated in all samples. [Figure 14g]Figure 1 shows the X-ray powder diffraction (XRPD) patterns of crystalline Form 1 of Lalinepag after thermal cycling. Three of the five solids precipitated after thermal cycling yielded Form 1. Upon drying, this form was retained. Amorphous solids from DMA / water and NMP / water were found to dry to Form 1. [Figure 15a] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained after evaporation of the mother liquor in Example 4. (The last sample shown was obtained after anti-solvent addition of the mother liquor in Example 4.) All figures show a reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 15b] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained after evaporation of the mother liquor in Example 4. (The last sample shown was obtained after anti-solvent addition of the mother liquor in Example 4.) All figures show a reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 15c] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained after evaporation of the mother liquor in Example 4. (The last sample shown was obtained after anti-solvent addition of the mother liquor in Example 4.) All figures show a reference X-ray powder diffraction (XRPD) pattern of Form 1 at the top. XRPD patterns marked with (PO) correspond to preferred orientation. [Figure 16] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of isolated crystalline Form 1 of Lalinepag obtained after crash cooling of the mother liquor in Example 4. All figures show at the top a reference X-ray powder diffraction (XRPD) pattern of Form 1. The XRPD patterns marked with (PO) correspond to preferred orientations. [Figure 17a]FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained after antisolvent addition of the mother liquor in Example 4. All figures show at the top a reference X-ray powder diffraction (XRPD) pattern of Form 1. The XRPD patterns marked with (PO) correspond to preferred orientations. [Figure 17b] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of Lalinepag obtained after antisolvent addition of the mother liquor in Example 4. All figures show at the top a reference X-ray powder diffraction (XRPD) pattern of Form 1. The XRPD patterns marked with (PO) correspond to preferred orientations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Small molecule inhibitors are often first evaluated for their activity when dissolved in solution, but solid-state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance can differ in physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct impact on the ability to process or manufacture the drug substance and drug product. Furthermore, differences in these properties can, and often do, result in different pharmacokinetic profiles for different polymorphic forms of the drug product. Thus, polymorphism is often an important factor in regulatory review of the "identity" of drug products from various manufacturers.

[0029] Pulmonary Arterial Hypertension (PAH), PGI2, and IP Receptor Agonists Pulmonary hypertension (PH) is a rare progressive disease characterized by elevated pulmonary vascular resistance (PVR) that can lead to right ventricular enlargement, hypertrophy, heart failure, and ultimately death. There are five different groups of PH based on different causes according to the current World Health Organization (WHO) classification. These are referred to as the WHO PH Groups. The first group is pulmonary arterial hypertension (PAH), which is characterized by thickening and stiffening of the pulmonary blood vessels. Although management of PAH has improved significantly over the past 15 years, mortality remains unacceptably high, with a median life expectancy of 7 years after diagnosis. The second WHO group includes PH due to left heart disease. In these patients, cardiac problems, rather than the pulmonary vasculature, are the primary cause of the condition. The third WHO group includes PH due to chronic lung disease and / or hypoxia (low oxygen levels). The third group includes pulmonary hypertension associated with interstitial lung disease (PH-ILD) and PH associated with pulmonary fibrosis. WHO group 4 is called chronic thromboembolic pulmonary hypertension (CTEPH). WHO group 5 is when PH occurs secondary to other, unspecified diseases. Treatment is determined by the form of PH; for example, PAH is often treated with prostacyclin. Regardless of classification, PH is a severe and often fatal disease.

[0030] The severity of PH, including PAH, is graded by four functional classes according to a system originally developed for heart failure by the New York Heart Association (NYHA) and then modified by the WHO for PAH patients. Patients are usually asymptomatic in the early stages of the disease (i.e., functional class I), but as the disease progresses, symptoms of the disease, including exertional dyspnea, fatigue, peripheral edema, and syncope, may be indistinguishable from other cardiorespiratory diseases. Many patients are never diagnosed until they develop symptoms of WHO / NYHA functional class II or III.

[0031] Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology. Vasoconstriction, remodeling of the pulmonary vascular wall, and thrombosis lead to increased pulmonary vascular resistance in PAH (Humbert et al., J. Am. Coll. Cardiol., 2004, 43:13S-24S).

[0032] The compounds disclosed herein are useful for treating pulmonary arterial hypertension (PAH) and its symptoms. PAH should be understood to include all forms of pulmonary arterial hypertension described in the World Health Organization (WHO) 2003 clinical classification of pulmonary arterial hypertension. These forms include idiopathic PAH (IPAH), familial PAH (FPAH), other disease-associated PAH (APAH), such as collagen vascular disease-associated PAH, congenital systemic-to-pulmonary shunt-associated PAH, portal hypertension-associated PAH, HTV infection-associated PAH, drug or toxin-associated PAH, or other, and venous or capillary-associated PAH.

[0033] Idiopathic PAH refers to PAH with an unknown cause.

[0034] Familial PAH refers to PAH with suspected or proven genetic inheritance.

[0035] PAH associated with collagen vascular disease should be understood to include PAH associated with scleroderma, PAH associated with CREST (calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, digital sclerosis, and telangiectasia) syndrome, PAH associated with systemic lupus erythematosus (SLE), PAH associated with rheumatoid arthritis, PAH associated with Takayasu's arteritis, PAH associated with polymyositis, and PAH associated with dermatomyositis.

[0036] PAH associated with congenital systemic-to-pulmonary shunts should be understood to include PAH associated with atrial septal defect (ASD), PAH associated with ventricular septal defect (VSD), and PAH associated with patent ductus arteriosus.

[0037] PAHs associated with drugs or toxins should be understood to include PAHs associated with ingestion of Aminorex, PAHs associated with ingestion of fenfluramine compounds (e.g., PAHs associated with ingestion of fenfluramine or PAHs associated with ingestion of dexfenfluramine), PAHs associated with ingestion of certain toxic oils (e.g., PAHs associated with ingestion of rapeseed oil), PAHs associated with ingestion of pyrrolizidine alkaloids (e.g., PAHs associated with ingestion of bush tea), and PAHs associated with ingestion of monocrotaline.

[0038] Other associated PAH should be understood to include PAH associated with thyroid disorder, PAH associated with glycogen storage disease, PAH associated with Gaucher disease, PAH associated with hereditary hemorrhagic telangiectasia, PAH associated with hemochromatosis, PAH associated with myeloproliferative disorders, and PAH associated with splenectomy.

[0039] PAH associated with significant venous or capillary involvement should be understood to include PAH associated with pulmonary veno-occlusive disease (PVOD) and PAH associated with pulmonary capillary hemangiomatosis (PCH). (See, e.g., Simonneau et al., J. Am. Coll. Cardiol., 2004, 43:5S-12S; McGoon et al., Chest, 2004, 126:14S-34S; Rabinovitch, Annu. Rev. Pathol. Mech. Dis., 2007, 2:369-399; McLaughlin et al., Circulation, 2006, 114:1417-1431; Strauss et al., Clin. Chest. Med., 2007, 28:127-142; Taichman et al., Clin. Chest. Med., 2007, 28:1-22).

[0040] Evidence for the association of PAH with scleroderma and the beneficial effect of PGI2 receptor agonists on PAH has been shown by Badesch et al. (Badesch et al., Ann. Intern. Med., 2000, 132:425-434). Evidence for the association of PAH with collagen vascular disease mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE), Sjogren's syndrome, and CREST syndrome, as well as the beneficial effect of PGI2 receptor agonists on PAH, have been demonstrated by Humbert et al. (Eur. Respir. J., 1999, 13:1351-1356). Evidence for the association of PAH with CREST syndrome and the beneficial effect of PGI2 receptor agonists on PAH have been shown by Miwa et al. (Int. Heart J., 2007, 48:417-422). Evidence for an association between PAH and SLE and the beneficial effect of PGI2 receptor agonists on PAH is presented by Robbins et al. (Chest, 2000, 117:14-18). Evidence for an association between PAH and HIV infection and the beneficial effect of PGI2 receptor agonists on PAH is presented by Aguilar et al. (Am. J. Respir. Crit. Care Med., 2000, 162:1846-1850). Evidence for an association between PAH and congenital heart defects (including ASD, VSD, and patent ductus arteriosus) and the beneficial effect of PGI2 receptor agonists on PAH is presented by Rosenzweig et al. (Circulation, 1999, 99:1858-1865). Evidence for an association between PAH and fenfluramine or dexfenfluramine or anorectic agents is provided by Archer et al. (Am. J. Respir. Crit. Care Med., 1998, 158:1061-1067). Evidence for an association between PAH and hereditary hemorrhagic telangiectasia is documented by McGoon et al. (Chest, 2004, 126:14-34). Evidence for an association between PAH and splenectomy is provided by Hoeper et al. (Ann. Intern. Med., 1999, 130:506-509).Evidence for an association between PAH and portal hypertension and the beneficial effects of PGI2 receptor agonists on PAH has been presented by Hoeper et al. (Eur. Respir. J., 2005, 25:502-508).

[0041] Symptoms of PAH include dyspnea, angina, syncope, and edema (McLaughlin et al., Circulation, 2006, 114:1417-1431). The compounds disclosed herein are useful for treating the symptoms of PAH.

[0042] In some embodiments, the pulmonary arterial hypertension (PAH) is selected from idiopathic PAH, familial PAH, PAH associated with collagen vascular disease selected from scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis, PAH associated with congenital heart disease selected from atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus in patients, PAH associated with portal hypertension, PAH associated with HIV infection, PAH associated with drug or toxin ingestion, PAH associated with hereditary hemorrhagic telangiectasia, PAH associated with splenectomy, PAH associated with significant venous or capillary involvement, PAH associated with pulmonary veno-occlusive disease (PVOD), and PAH associated with pulmonary capillary hemangiomatosis (PCH) in patients.

[0043] Studies have shown that patients with PAH have altered prostacyclin and thromboxane A2 activity in the pulmonary arterial system, including increased synthesis of endothelin and decreased expression of nitric oxide synthase, all of which contribute to vasoconstriction / vasodilation imbalance, thrombosis, cellular proliferation, and remodeling of the pulmonary arterial wall.Currently available pharmacologic therapies for PAH target the prostacyclin (also called prostaglandin I2 [PGI2]), endothelin, and nitric oxide pathways.

[0044] Treatment guidelines for PAH support the use of oral endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5-I), or soluble guanylate cyclase (sGC) stimulators as monotherapy or in combination for PAH patients with WHO / NHYA functional class III. ERAs target the endothelin pathway, while PDE5-I and sGC stimulators target the nitric oxide pathway. There are three commercially available ERAs, ambrisentan, bosentan, and macitentan, two commercially available PDE5-Is, sildenafil and tadalafil, and one commercially available sGC stimulator, riociguat, that are approved for the treatment of PAH. These agents can improve exercise capacity, symptoms, and / or cardiopulmonary hemodynamic variables in symptomatic PAH patients. There is uncertainty as to whether they extend survival time in this group.

[0045] PGI2 is a metabolic product of arachidonic acid and is formed via the cyclooxygenase pathway. Endothelial cells are the major source of PGI2. The vascular effects of PGI2 and its mimetics are largely mediated by activation of the PGI2 (IP) receptor, which includes vasodilation, inhibition of smooth muscle cell proliferation, and inhibition of platelet aggregation. IP receptors are expressed on platelets and on smooth muscle cells of several tissues, including the lung, heart, aorta, liver, kidney, and blood vessels. Activation of IP receptors leads to an increase in cellular cyclic adenosine monophosphate (cAMP), which subsequently leads to arterial vasodilation and inhibition of platelet aggregation. Replacement therapy with PGI2 has been clearly demonstrated to improve hemodynamics, exercise capacity, and survival.

[0046] Epoprostenol, a synthetic PGI2 analogue, is a potent vasodilator and platelet aggregation inhibitor and was the first therapeutic agent approved for PAH therapy. Epoprostenol improves the prognosis of PAH patients compared with conventional therapy and validates the IP receptor as a target for PAH therapy. However, epoprostenol requires continuous infusion by ambulatory pumps, is unstable at room temperature, and is associated with intravenous catheter-associated infections and thrombosis. According to the treatment algorithm presented by the 5th World Symposium and the European Society of Cardiology / European Respiratory Society (ESC / ERS) guidelines, injectable prostacyclin analogues should be administered in patients with PAH severity classified as WHO / NYHA functional class III-IV.

[0047] Subsequent PGI2 analogues, such as treprostinil (continuous subcutaneous and intravenous infusion, intermittent inhalation, and oral) and iloprost (intermittent inhalation), have demonstrated efficacy by improving exercise capacity and / or delaying clinical deterioration. These prostacyclins are prescribed to patients with PAH of WHO / NYHA functional class II-IV. Although these prostacyclin analogues address some of the limitations associated with epoprostenol, they have drawbacks with regard to frequent administration (iloprost) and pain at the injection site (subcutaneous treprostinil), in addition to typical prostacyclin-related side effects such as headache, nausea, flushing, diarrhea, and jaw pain.

[0048] Selexipag is an oral selective IP receptor agonist approved for the treatment of PAH in the United States and elsewhere to slow disease progression and reduce the risk of hospitalization for PAH. The ESC / ERS guidelines recommend the use of selexipag to treat patients with PAH whose severity is WHO / NYHA functional class II-III. Selexipag and its active metabolites have a mode of action similar to that of endogenous prostacyclin (IP receptor agonism), but they are chemically distinct from prostacyclin analogues that have different pharmacological properties. Selexipag has been shown to reduce PVR after 17 weeks of treatment, with a 40% reduction in the composite morbidity and mortality endpoint. However, the short effective half-life (3-4 hours) of selexipag's active metabolites results in relatively large fluctuations between peak and trough plasma concentrations following BID administration.

[0049] Despite the availability of numerous treatments, functional limitations and survival of PAH patients remain poor. The success of selexipag in delaying disease progression and reducing the risk of hospitalization for PAH supports the utility of oral prostacyclin therapy and paves the way for further optimization of non-prostanoid IP receptor agonists. Research efforts are focused on optimizing non-prostanoid IP receptor activation, bioavailability, and PK with the goal of providing unremitting and potent target association with oral formulations that provide similar clinical efficacy as parenteral prostacyclin.

[0050] As described herein, ralinepag and its crystalline and amorphous phases, pharmaceutical compositions thereof may be an attractive oral alternative to currently approved oral prostacyclin analogs and non-prostanoid IP receptor agonists for treating PAH. In some embodiments, the compounds disclosed herein are useful for treating PH other than PAH. For example, the compounds disclosed herein may be useful for treating Group 3 forms of PH, such as PH-ILD or PH associated with pulmonary fibrosis.

[0051] The disclosed methods and compositions may also be suitable for treating other diseases such as platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clot formation in individuals who have had angioplasty or coronary artery bypass surgery or who suffer from atrial fibrillation, atherothrombosis, asthma or symptoms thereof, diabetes-related disorders such as diabetic peripheral neuropathy, diabetic nephropathy, or diabetic retinopathy, glaucoma or other eye diseases with abnormal intraocular pressure, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis, and chronic obstructive pulmonary disorder (COPD).

[0052] In some embodiments, the methods and compositions disclosed herein are useful for treating chronic thromboembolic pulmonary hypertension (CTEPH). In some embodiments, the methods and compositions disclosed herein are useful for treating CTEPH (WHO group 4) that persists / recurs after surgical treatment. In some embodiments, the methods and compositions disclosed herein are useful for treating inoperable CTEPH to improve exercise capacity and / or WHO functional class.

[0053] Laline Pug Ralinepag may be referred to as "2-([(1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)-cyclohexyl]methoxy)acetic acid", "Acetic acid,2-((trans-4-((((4-chlorophenyl)phenylamino)-carbonyl)oxy)methyl)cyclohexyl)methoxy)-", "2-((trans-4-((((4-chlorophenyl)(phenyl)carbamoyl)-oxy)methyl)cyclohexyl)methoxy)acetic acid", or "APD-811". It may be known by other names.

[0054] Lalinepag has the following chemical structure:

[0055] [ka] has.

[0056] Ralinepag is an oral, potent, and selective IP receptor agonist developed to treat PAH. Ralinepag has been characterized in both single- and multiple-dose studies in healthy volunteer populations. Ralinepag has a longer t 1 / 2 and exhibits low plasma concentration fluctuations during dosing (peak:trough ratio). Selexipag has a relatively short half-life, giving rise to the need for BID dosing.

[0057] The safety profile suggests that dose-related pharmacological effects occur at the IP receptor within the low dose range of 0.01 mg to 0.2 mg, with adverse effects consistent with those reported for IP receptor agonists.Head-to-head in vitro studies demonstrated that ralinepag was more potent and effective than selexipag in increasing cellular cAMP levels, resulting in improved pulmonary artery vasodilation and better inhibition of human pulmonary artery smooth muscle cell (PASMC) proliferation.

[0058] Because ralinepag produces improved vasodilation and inhibition of smooth muscle proliferation, it may be an attractive oral alternative to the currently available oral prostacyclin analogues and non-prostanoid IP receptor agonists for treating PAH.

[0059] One embodiment herein provides a method of stimulating an IP receptor, the method comprising contacting the IP receptor with ralinepag or a solid state form thereof disclosed herein.

[0060] The preparation of ralinepag has been previously described (see WO2009 / 117095, US8,895,776, US10,668,033, and US2020 / 0375930, each of which is incorporated by reference in its entirety).

[0061] In some embodiments, ralinepag is amorphous. As used herein, the term "amorphous" or "amorphous solid form" or "amorphous phase" refers to a solid form that lacks crystallinity.

[0062] In some embodiments, ralinepag is crystalline. In some embodiments, crystallinity is determined by methods known in the art.

[0063] In some embodiments, the crystallinity of the solid form is determined by X-ray powder diffraction (XRPD). In some embodiments, the crystallinity of the solid form is determined by solid-state NMR. In some embodiments, the crystallinity of the solid form is determined by Fourier transform IR spectroscopy (FTIR).

[0064] If multiple diffraction patterns are available, particle statistics (PS) and / or preferred orientation (PO) can be assessed. Consistency in relative intensities between XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern can be compared to a calculated XRPD pattern based on a single crystal structure, if available. Two-dimensional scattering patterns using an area detector can also be used to assess PS / PO. If both PS and PO contributions are determined to be negligible, the XRPD pattern represents the powder average intensity for the sample, and prominent peaks can be identified as "representative peaks." Typically, the more data collected to determine representative peaks, the more confidence there is in the classification of those peaks.

[0065] "Diagram peaks", to the extent they exist, are a subset of the representative peaks used to distinguish one crystalline polymorph from another (a polymorph of a crystalline form having the same chemical composition). The characteristic peaks are determined by assessing which representative peaks, if any, are present in one crystalline polymorph of a compound relative to all other known crystalline polymorphs of the compound, to within ±0.2°2Θ. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

[0066] As used herein, the term "preferred orientation" refers to an extreme case of non-random distribution of crystallites in a solid-state morphology. In XRPD, an ideal sample is homogeneous, with crystallites randomly distributed in the bulk solid. In a truly random sample, each possible reflection from a given set of planes has an equal number of crystallites contributing to it. However, this is not the case when the solid-state morphology is in a preferred orientation. Thus, comparing the intensities between a randomly oriented and a preferentially oriented diffraction pattern can appear completely different. Quantitative analysis according to intensity ratios is heavily distorted by preferred orientation. Careful sample preparation is important to reduce the occurrence of preferred orientation.

[0067] Amorphous Laline Pug Amorphous ralinepag is provided herein, in some embodiments, compositions comprising amorphous ralinepag are provided.

[0068] In some embodiments, amorphous ralinepag is characterized by having an X-ray powder diffraction (XRPD) pattern indicative of no crystallinity.

[0069] In one aspect, described herein are methods of synthesizing amorphous lalinepag, characterized by having an X-ray powder diffraction (XRPD) pattern indicative of no crystallinity, the methods comprising converting lalinepag in Form 1, Form 3, Pattern 2, or Pattern 4 to an amorphous form. In some embodiments, the methods comprise drying lalinepag in crystalline Pattern 4. In some embodiments, the methods comprise drying lalinepag in crystalline Form 1. In some embodiments, the methods comprise lyophilizing a solution of lalinepag in an organic solvent. In some embodiments, the organic solvent is 1,4-dioxane. In some embodiments, the concentration of the lalinepag solution is up to 10 mg / mL. In some embodiments, the concentration of the lalinepag solution is up to 5 mg / mL. In some embodiments, the concentration of the lalinepag solution is up to 4 mg / mL. In some embodiments, the concentration of the lalinepag solution is up to 3 mg / mL. In some embodiments, the concentration of the lalinepag solution is up to 2 mg / mL. In some embodiments, the concentration of the Lalinepag solution is up to 1 mg / mL. In some embodiments, the concentration of the Lalinepag solution is from about 0.1 mg / mL to about 5 mg / mL. In some embodiments, the concentration of the Lalinepag solution is from about 0.1 mg / mL to about 3 mg / mL. In some embodiments, the concentration of the Lalinepag solution is from about 0.1 mg / mL to about 4 mg / mL.

[0070] Crystalline Laline Pug Also provided herein is crystalline ralinepag.

[0071] In some embodiments, the crystalline ralinepag is unsolvated.

[0072] In some embodiments, the crystalline ralinepag is solvated, hi some embodiments, the crystalline ralinepag is a dimethylsulfoxide solvate.

[0073] In some embodiments, the crystalline ralinepag is a hydrate.

[0074] Crystalline form of Lalinepag 1 In some embodiments, the crystalline Ralinepag is Ralinepag crystalline Form 1. In some embodiments, described herein are compositions comprising Ralinepag crystalline Form 1. In some embodiments, Ralinepag crystalline Form 1 is referred to as Ralinepag crystalline Pattern 1.

[0075] In some embodiments, crystalline Form 1 of Ralinepag is anhydrous. In some embodiments, crystalline Form 1 of Ralinepag is non-solvated. In some embodiments, crystalline Form 1 of Ralinepag is non-hydrated.

[0076] In some embodiments, crystalline Form 1 of Ralinepag is formed from other solid state forms described herein, in some embodiments, crystalline Form 1 of Ralinepag is the thermodynamically favored solid state form of Ralinepag.

[0077] In some embodiments, crystalline Form 1 of ralinepag is characterized by having an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 1, measured using Cu Kα radiation.

[0078] In some embodiments, crystalline Form 1 of ralinepag is characterized by an XRPD pattern with peaks at 8.8±0.2° 2-Θ, 11.7±0.2° 2-Θ, 16.2±0.2° 2-Θ, 21.3±0.2° 2-Θ, and 33.8±0.2° 2-Θ when measured using Cu Kα radiation.

[0079] In some embodiments, crystalline Form 1 of ralinepag is characterized by an XRPD pattern with peaks at 8.8±0.2° 2-Θ, 11.7±0.2° 2-Θ, and 16.2±0.2° 2-Θ when measured using Cu Kα radiation.

[0080] In some embodiments, crystalline Form 1 of ralinepag is characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in FIG.

[0081] In some embodiments, crystalline Form 1 of ralinepag is characterized by having a differential thermal analysis (DTA) thermogram that exhibits a sharp endothermic event with an onset at about 127.2°C.

[0082] In some embodiments, crystalline Form 1 of ralinepag is characterized by having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

[0083] In some embodiments, crystalline Form 1 of ralinepag is characterized by having a DSC thermogram with a sharp endothermic event having an onset at about 127.5°C.

[0084] In some embodiments, crystalline Form 1 of ralinepag is characterized by having a reversible water uptake of 0.1% (w / w) at relative humidity (RH) between 0% and 90%.

[0085] In some embodiments, crystalline Form 1 of ralinepag is characterized by having an invariant XRPD following dynamic vapor sorption (DVS) analysis at RH between 0% and 90%.

[0086] In some embodiments, crystalline Form 1 of Ralinepag is characterized by having unit cell parameters at 100K approximately equal to the following:

[0087] [Table 2]

[0088] In some embodiments, the crystalline Form 1 of ralinepag is An X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, substantially the same as that shown in FIG. 1; and a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in FIG. 6, or a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 7, or both. The present invention is characterized by having the following.

[0089] In some embodiments, the crystalline Form 1 of ralinepag is An XRPD pattern with peaks at 8.8±0.2° 2-Θ, 11.7±0.2° 2-Θ, 16.2±0.2° 2-Θ, 21.3±0.2° 2-Θ, and 33.8±0.2° 2-Θ when measured using Cu Kα radiation; and A differential thermal analysis (DTA) thermogram showing a sharp endothermic event with an onset at about 127.2°C, or a DSC thermogram showing a sharp endothermic event with an onset at about 127.5°C, or both. The present invention is characterized by having the following.

[0090] In some embodiments, the crystalline Form 1 of ralinepag is An XRPD pattern with peaks at 8.8±0.2° 2-Θ, 11.7±0.2° 2-Θ, and 16.2±0.2° 2-Θ, measured using Cu Kα radiation; and A differential thermal analysis (DTA) thermogram showing a sharp endothermic event with an onset at about 127.2°C, or a DSC thermogram showing a sharp endothermic event with an onset at about 127.5°C, or both. The present invention is characterized by having the following.

[0091] In some embodiments, crystalline Form 1 of Lalinepag is characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in FIG. 6. In some embodiments, crystalline Form 1 of Lalinepag is characterized by having a DTA thermogram that exhibits a sharp endothermic event with an onset at about 127.2° C. In some embodiments, crystalline Form 1 of Lalinepag is characterized by having a DTA thermogram that exhibits a sharp endothermic event with an onset at about 127.2° C. and a peak at about 129.5° C. In some embodiments, DTA thermograms of other solid state forms exhibit an endothermic event with an onset at 125-128° C., which may be attributable to the formation of crystalline Form 1 of Lalinepag in DTA experiments. In some embodiments, crystalline Form 1 of Lalinepag is characterized by having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 7. In some embodiments, crystalline form 1 of Lalinepag is characterized by having a DSC thermogram with a sharp endothermic event with an onset at about 127.5° C. In some embodiments, crystalline form 1 of Lalinepag is characterized by having a DSC thermogram with a sharp endothermic event with an onset at about 127.5° C. and a peak at about 129.2° C. In some embodiments, DSC thermograms of other solid state forms show an endothermic event with an onset at 125-128° C., which may be attributed to the formation of crystalline form 1 of Lalinepag in DSC experiments. In some embodiments, crystalline form 1 of Lalinepag is characterized by having a reversible water uptake of 0.1% (w / w) at 0%-90% relative humidity (RH). In some embodiments, crystalline form 1 of Lalinepag is characterized by having an XRPD that does not vary after dynamic water vapor sorption (DVS) analysis at 0%-90% RH.

[0092] In some embodiments, crystalline Form 1 of Ralinepag is characterized by having unit cell parameters at 100K approximately equal to the following:

[0093] [Table 3]

[0094] In some embodiments, crystalline Form 1 of Ralinepag has an XRPD pattern that exhibits a preferred orientation. In some embodiments, crystalline Form 1 of Ralinepag has an XRPD pattern that exhibits several peaks with greater intensity than would be observed in a sample not in a preferred orientation. In some embodiments, crystalline Form 1 of Ralinepag has an XRPD pattern that exhibits only one or two peaks that correspond to a preferred orientation.

[0095] Laline Pug Crystal Pattern 2 In some embodiments, the crystalline ralinepag is ralinepag crystalline pattern 2. In some embodiments, described herein are compositions comprising ralinepag crystalline pattern 2.

[0096] In some embodiments, crystalline pattern 2 is formed from lyophilization. In some embodiments, crystalline pattern 2 is formed from lyophilization alone. In some embodiments, crystalline pattern 2 of ralinepag is poorly crystalline.

[0097] In some embodiments, crystalline pattern 2 of Ralinepag is anhydrous. In some embodiments, crystalline pattern 2 of Ralinepag is non-solvated. In some embodiments, crystalline pattern 2 of Ralinepag is non-hydrated.

[0098] In some embodiments, crystalline pattern 2 of ralinepag is characterized by having an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 2, when measured using Cu Kα radiation.

[0099] In some embodiments, crystalline pattern 2 of lalinepag is characterized by an XRPD pattern with peaks at 4.1±0.2°2-Θ, 15.5±0.2°2-Θ, 16.9±0.2°2-Θ, 17.9±0.2°2-Θ, 22.8±0.2°2-Θ, and 23.7±0.2°2-Θ when measured using Cu Kα radiation. In some embodiments, crystalline pattern 2 of lalinepag is characterized by an XRPD pattern with peaks at 4.1±0.2°2-Θ, 15.5±0.2°2-Θ, and 16.9±0.2°2-Θ when measured using Cu Kα radiation.

[0100] In some embodiments, crystalline pattern 2 of Ralinepag is further characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in Figure 8. In some embodiments, crystalline pattern 2 of Ralinepag is further characterized by having a differential thermal analysis (TGA / DTA) thermogram exhibiting weak endothermic and exothermic events at 81-89°C, and a broad endothermic event with an onset at about 124.7°C. In some embodiments, crystalline pattern 2 of Ralinepag is further characterized by having an XRPD that converts to Form 1 upon heating. In some embodiments, crystalline pattern 2 of Ralinepag is further characterized as being a dimethylsulfoxide solvate.

[0101] In some embodiments, crystalline pattern 2 of ralinepag is An X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, substantially the same as that shown in FIG. 2; and Thermogravimetric / differential thermal analysis (TGA / DTA) thermograms substantially similar to those shown in FIG. The present invention is characterized by having the following.

[0102] In some embodiments, crystalline pattern 2 of ralinepag is An XRPD pattern with peaks at 4.1±0.2° 2-Θ, 15.5±0.2° 2-Θ, 16.9±0.2° 2-Θ, 17.9±0.2° 2-Θ, 22.8±0.2° 2-Θ, and 23.7±0.2° 2-Θ when measured using Cu Kα radiation, as well as Differential thermal analysis (TGA / DTA) thermogram showing weak endothermic and exothermic events between 81-89°C and a broad endothermic event with an onset at approximately 124.7°C. In some embodiments, crystalline pattern 2 of ralinepag is characterized by having: It is characterized by an XRPD pattern with 4.1±0.2° 2-Θ, 15.5±0.2° 2-Θ, and 16.9±0.2° 2-Θ when measured using Cu Kα radiation, and a differential thermal analysis (TGA / DTA) thermogram showing weak endothermic and exothermic events between 81-89 °C, and a broad endothermic event with an onset at approximately 124.7 °C.

[0103] In some embodiments, crystalline pattern 2 of lalinepag is characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in FIG. 8. In some embodiments, crystalline pattern 2 of lalinepag is characterized by having a DTA thermogram showing weak endothermic and exothermic events at 81-89°C, and a broad endothermic event with an onset at about 124.7°C. In some embodiments, crystalline pattern 2 of lalinepag is characterized by having a DTA thermogram showing weak endothermic and exothermic events at 81-89°C, and a broad endothermic event with an onset at about 124.7°C and a peak at about 127.3°C. In some embodiments, the weak endothermic and exothermic events at 81-89°C may be due to crystalline pattern 2 recrystallizing and crystalline form 1 being formed. In some embodiments, the broad endothermic event with an onset at about 124.7°C may be due to crystalline form 1. In some embodiments, crystalline pattern 2 of ralinepag is characterized by having an XRPD that converts to form 1 upon heating.

[0104] Crystalline form of Lalinepag 3 In some embodiments, the crystalline Ralinepag is Ralinepag crystalline Form 3. In some embodiments, described herein are compositions comprising Ralinepag crystalline Form 3. In some embodiments, Ralinepag crystalline Form 3 is referred to as Ralinepag crystalline Pattern 3.

[0105] In some embodiments, crystalline Form 3 of Ralinepag is highly crystalline. In some embodiments, crystalline Form 3 of Ralinepag is partially crystalline. In some embodiments, crystalline Form 3 of Ralinepag is poorly crystalline.

[0106] In some embodiments, crystalline Form 3 of Ralinepag is precipitated only from samples containing dimethylsulfoxide. In some embodiments, crystalline Form 3 of Ralinepag is solvated. In some embodiments, crystalline Form 3 of Ralinepag is a dimethylsulfoxide solvate.

[0107] In some embodiments, crystalline Form 3 of ralinepag is characterized by having an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 3, when measured using Cu Kα radiation.

[0108] In some embodiments, crystalline Form 3 of Ralinepag is characterized by an XRPD pattern with peaks at 3.6±0.2°2-Θ, 18.7±0.2°2-Θ, 22.2±0.2°2-Θ, 24.2±0.2°2-Θ, and 24.3±0.2°2-Θ when measured using Cu Kα radiation. In some embodiments, crystalline Form 3 of Ralinepag is characterized by an XRPD pattern with peaks at 3.6±0.2°2-Θ, 18.7±0.2°2-Θ, and 22.2±0.2°2-Θ when measured using Cu Kα radiation.

[0109] In some embodiments, crystalline Form 3 of Lalinepag is further characterized in that it has a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in Figure 9. In some embodiments, crystalline Form 3 of Lalinepag is further characterized in that it has a thermogravimetric analysis (TGA) trace that exhibits a weight loss of 17.8% from the onset of heating to approximately 238°C. In some embodiments, crystalline Form 3 of Lalinepag is further characterized in that it has a differential thermal analysis (DTA) thermogram that exhibits a sharp endothermic event with an onset at about 74.6°C. In some embodiments, crystalline Form 3 of Lalinepag is further characterized in that it is a hydrate.

[0110] In some embodiments, the crystalline Form 3 of ralinepag is An X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, substantially the same as that shown in FIG. 3; and Thermogravimetric / differential thermal analysis (TGA / DTA) thermograms substantially similar to those shown in FIG. The present invention is characterized by having the following.

[0111] In some embodiments, the crystalline Form 3 of ralinepag is An XRPD pattern with peaks at 3.6±0.2° 2-Θ, 18.7±0.2° 2-Θ, 22.2±0.2° 2-Θ, 24.2±0.2° 2-Θ, and 24.3±0.2° 2-Θ when measured using Cu Kα radiation; and A TG trace showing a weight loss of 17.8% from the start of heating to approximately 238°C, or A DTA thermogram showing a sharp endothermic event with an onset at approximately 74.6°C, or both In some embodiments, crystalline Form 3 of ralinepag is characterized by having an XRPD pattern with peaks at 3.6±0.2° 2-Θ, 18.7±0.2° 2-Θ, and 22.2±0.2° 2-Θ, as measured using Cu Kα radiation, and a TG trace that exhibits a 17.8% weight loss from the onset of heating to approximately 238° C., or a DTA thermogram that exhibits a sharp endothermic event with an onset at about 74.6° C., or both.

[0112] In some embodiments, crystalline Form 3 of Lalinepag is characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in Figure 9. In some embodiments, crystalline Form 3 of Lalinepag is characterized by having a TGA trace exhibiting a 17.8% weight loss from the onset of heating to approximately 238°C. In some embodiments, crystalline Form 3 of Lalinepag is characterized by having a DTA thermogram exhibiting a sharp endothermic event with an onset at about 74.6°C. In some embodiments, crystalline Form 3 of Lalinepag is characterized by having a DTA thermogram exhibiting a sharp endothermic event with an onset at about 74.6°C and a peak at about 78.9°C.

[0113] In some embodiments, crystalline Form 3 of ralinepag has an XRPD pattern that shows additional unknown peaks.

[0114] Laline Pug Crystal Pattern 4 In some embodiments, the crystalline ralinepag is ralinepag crystalline pattern 4. In some embodiments, described herein are compositions comprising ralinepag crystalline pattern 4.

[0115] In some embodiments, crystalline pattern 4 of Ralinepag is highly crystalline. In some embodiments, crystalline pattern 4 of Ralinepag is partially crystalline. In some embodiments, crystalline pattern 4 of Ralinepag is poorly crystalline.

[0116] In some embodiments, crystalline pattern 4 of Ralinepag is anhydrous. In some embodiments, crystalline pattern 4 of Ralinepag is non-solvated. In some embodiments, crystalline pattern 4 of Ralinepag is non-hydrated.

[0117] In some embodiments, crystalline pattern 4 of ralinepag precipitates only from samples containing water as an antisolvent. In some embodiments, crystalline pattern 4 of ralinepag is solvated. In some embodiments, crystalline pattern 4 of ralinepag is a hydrate.

[0118] In some embodiments, crystalline pattern 4 of ralinepag is characterized by having an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 4, when measured using Cu Kα radiation.

[0119] In some embodiments, crystalline Form 4 of Lalinepag is characterized by an XRPD pattern with peaks at 15.0±0.2°2-Θ, 16.7±0.2°2-Θ, 18.0±0.2°2-Θ, 18.7±0.2°2-Θ, and 18.9±0.2°2-Θ when measured using Cu Kα radiation. In some embodiments, crystalline Form 4 of Lalinepag is characterized by an XRPD pattern with peaks at 15.0±0.2°2-Θ, 16.7±0.2°2-Θ, and 18.0±0.2°2-Θ when measured using Cu Kα radiation.

[0120] In some embodiments, crystalline pattern 4 of Lalinepag is further characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially the same as that shown in Figure 10. In some embodiments, crystalline pattern 4 of Lalinepag is further characterized by having a differential thermal analysis (DTA) thermogram that exhibits a broad endothermic event with an onset at about 29.0°C, a sharp endothermic event with an onset at about 127.8°C, or both. In some embodiments, crystalline pattern 4 of Lalinepag is further characterized by having an XRPD that converts to Form 1 when dried. In some embodiments, crystalline pattern 4 of Lalinepag is further characterized by an XRPD that converts to amorphous Lalinepag when dried.

[0121] In some embodiments, the crystalline pattern 4 of ralinepag is: An X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, substantially the same as that shown in FIG. 4; and Thermogravimetric / differential thermal analysis (TGA / DTA) thermograms substantially similar to those shown in FIG. The present invention is characterized by having the following.

[0122] In some embodiments, the crystalline pattern 4 of ralinepag is: An XRPD pattern with peaks at 15.0±0.2° 2-Θ, 16.7±0.2° 2-Θ, 18.0±0.2° 2-Θ, 18.7±0.2° 2-Θ, and 18.9±0.2° 2-Θ when measured using Cu Kα radiation, as well as DTA thermogram showing a broad endothermic event with an onset at about 29.0° C. and a sharp endothermic event with an onset at about 127.8° C. The present invention is characterized by having the following.

[0123] In some embodiments, the crystalline pattern 4 of ralinepag is: An XRPD pattern with peaks at 15.0±0.2° 2-Θ, 16.7±0.2° 2-Θ, and 18.0±0.2° 2-Θ, measured using Cu Kα radiation, and a DTA thermogram showing a broad endothermic event with an onset at about 29.0° C. and a sharp endothermic event with an onset at about 127.8° C. The present invention is characterized by having the following.

[0124] In some embodiments, crystalline pattern 4 of Lalinepag is characterized by having a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in FIG. 10. In some embodiments, crystalline pattern 4 of Lalinepag is characterized by having a TG trace that exhibits significant weight loss (21.6%) prior to melting. In some embodiments, this weight loss may be due to loss of residual solvent and water. In some embodiments, crystalline pattern 4 of Lalinepag is characterized by having a DTA thermogram that exhibits a broad endothermic event with an onset at about 29.0° C. and a sharp endothermic event with an onset at about 127.8° C. In some embodiments, crystalline pattern 4 of Lalinepag is characterized by having a DTA thermogram that exhibits a broad endothermic event with an onset at about 29.0° C. and a peak at about 64.0° C., as well as a sharp endothermic event with an onset at about 127.8° C. and a peak at about 130.4° C. In some embodiments, a broad endothermic event with an onset of about 29.0° C. may be due to loss of residual solvent and water and recrystallization of crystalline pattern 4 to form crystalline form 1. In some embodiments, a sharp endothermic event with an onset of about 127.8° C. may be due to crystalline form 1. In some embodiments, crystalline pattern 4 of Lalinepag is characterized by having an XRPD that converts to form 1 when dried. In some embodiments, crystalline pattern 4 of Lalinepag is characterized by having an XRPD that converts to form 1 when dried in air at ambient conditions. In some embodiments, crystalline pattern 4 of Lalinepag is characterized by having an XRPD that converts to amorphous Lalinepag when dried.

[0125] Lalinepag salt In one embodiment, pharma- ceutically acceptable salts of ralinepag are prepared, including solvates, hydrates, and unsolvated forms thereof.

[0126] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms. In some embodiments, solvates include either stoichiometric or non-stoichiometric solvents and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds and crystalline forms thereof described herein are conveniently prepared or formed during the process described herein. In addition, the compounds and crystalline forms thereof provided herein optionally exist in solvated and unsolvated forms.

[0127] "Pharmaceutically acceptable," as used herein, refers to a relatively non-toxic substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound, i.e., the substance may be administered to an individual without causing any unwanted biological effects or interacting in any deleterious manner with any of the components of the composition in which it is contained.

[0128] The term "pharmaceutical acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. PHStahl and CGWermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are useful in solid dosage forms because they are typically more soluble than non-ionic species and dissolve more rapidly in gastric and intestinal fluids. Furthermore, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the digestive tract, and this ability can be manipulated as an aspect of delayed- and sustained-release behavior.Furthermore, salt-forming molecules can be in equilibrium with neutral forms, allowing for regulated passage through biological membranes.

[0129] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting the compounds disclosed herein with an acid. In some embodiments, the compounds disclosed herein (i.e., in the form of a free base) are basic and are reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptan-1,2-disulfonic acid, ethylhexanoic ... The acidic acids include sucrose, glycerol, glyceryl, stearate, sorbitol, sorbitolsulfonic ...

[0130] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting ralinepag with a base. Under such circumstances, the acidic proton of ralinepag is exchanged with a metal ion, such as a lithium ion, a sodium ion, a potassium ion, a magnesium ion, a calcium ion, or an aluminum ion. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.

[0131] In some cases, larinepag is coordinated with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc. In other cases, larinepag forms salts with amino acids, such as, but not limited to, arginine, lysine, etc.

[0132] In some embodiments, ralinepag is prepared as a sodium salt, a calcium salt, a potassium salt, a magnesium salt, a meglumine salt, an N-methylglucamine salt, or an ammonium salt.

[0133] In another embodiment, cocrystals of ralinepag are prepared, including its solvates, hydrates, and non-solvates. Salts are formed by complete proton transfer from one compound to another. Salts and cocrystals can be differentiated based on the proton transfer from acid to base. Complete proton transfer occurs between acid-base pairs, and no proton transfer occurs during the formation of cocrystals.

[0134] Therapeutic agents that can be administered to mammals, such as humans, such as ralinepag, must be prepared according to regulatory guidelines. Such government regulatory guidelines are referred to as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvents in the final product. Preferred solvents are those that are suitable for use by GMP organizations and consistent with industry safety considerations. Solvent classifications are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005).

[0135] Solvents are divided into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are those whose use should be restricted in the manufacture of therapeutic agents. Class 3 solvents are those with low toxicity potential and pose lower risks to human health. Data on Class 3 solvents indicates that this class of solvents has low toxicity in acute or short-term studies and negative genotoxicity tests.

[0136] Class 1 solvents, which are those to be avoided, include benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0137] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0138] Class 3 solvents, which are less toxic, include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0139] Residual solvents in active pharmaceutical ingredients (APIs) originate from the preparation of the APIs. In some cases, the solvents are not completely removed by the actual manufacturing techniques. The appropriate selection of solvents used in the synthesis of APIs can improve the yield or determine characteristics such as crystal morphology, purity, and solubility. Thus, the solvent is an important parameter in the synthesis process.

[0140] In some embodiments, compositions comprising ralinepag or a pharma- ceutically acceptable salt thereof contain organic solvent(s). In some embodiments, compositions comprising ralinepag or a pharma- ceutically acceptable salt thereof contain a residual amount of organic solvent(s).

[0141] In some embodiments, the composition comprising ralinepag or a pharma- ceutically acceptable salt thereof contains a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0142] In some embodiments, the composition comprising lalinepag or a pharma- ceutically acceptable salt thereof comprises a detectable amount of an organic solvent. In some embodiments, the pharma- ceutically acceptable salt of lalinepag is a tosylate salt (i.e., lalinepag-tosyl). In some embodiments, the organic solvent is a Class 3 solvent (i.e., 1-butanol).

[0143] In another embodiment, a composition comprising lalinepag or a pharma- ceutically acceptable salt thereof, the composition comprising less than about 1% detectable amount of solvent, the solvent being selected from acetone, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, and 2-propanol. In another embodiment, a composition comprising lalinepag or a pharma-ceutically acceptable salt thereof, the composition comprising less than about 5000 ppm detectable amount of solvent. In yet another embodiment, a composition comprising lalinepag, the composition comprising less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm detectable amount of solvent.

[0144] definition Unless otherwise specified, the following terms used in this application have the following definitions. Use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. The paragraph headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0145] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting deleterious effects on the general health of the subject being treated.

[0146] As used herein, the term "modulate" means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0147] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. The interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0148] As used herein, the terms "administer", "administering", "administration" and the like refer to methods that can be used to enable delivery of a compound or composition to the site where a biological effect is desired. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), and topical administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. In some embodiments, the compounds and compositions described herein are administered intranasally or by inhalation.

[0149] "Concomitant administration," and the like, as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include therapeutic regimens in which agents are administered by the same or different routes of administration or at the same or different times.

[0150] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound being administered that relieves to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to clinically significantly reduce the symptoms of the disease. The appropriate "effective" amount in any individual case is optionally determined using techniques such as dose escalation studies.

[0151] The terms "enhance" or "enhancing," as used herein, mean to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0152] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other ape and monkey species, farm animals such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0153] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition.

[0154] The term "about" means within a statistically meaningful range of values, such as a stated concentration range, time frame, molecular weight, particle size, temperature, or pH. Such a range may be within an order of magnitude, typically within 10%, more typically within 5%, and even more typically within 3% of the indicated value or range. Sometimes such a range may be within the experimental error typical of the standard method used to measure and / or determine a given value or range. The acceptable deviation encompassed by the term "about" will depend on the particular system being tested and can be readily recognized by one of ordinary skill in the art. Whenever a range is stated within this application, all integers within the range are also contemplated as embodiments of the invention.

[0155] The term "substantially the same" as used herein with reference to the drawings is intended to mean that the drawings are considered to represent the type and variety of characteristic data obtained by one of ordinary skill in the art in terms of deviations acceptable in the art. Such deviations may arise from factors related to variations in sample size, sample preparation, the particular instrument used, operating conditions, and other experimental conditions known in the art. For example, one of ordinary skill in the art may recognize that the temperature of the endothermic onset and the temperature of the peak may vary significantly from experiment to experiment as measured by differential scanning calorimetry (DSC). For example, one of ordinary skill in the art may readily recognize whether two X-ray diffraction patterns or two DSC thermograms are substantially the same. In some embodiments, X-ray diffraction patterns are considered to be substantially the same if the characteristic peaks of the two X-ray diffraction patterns do not vary by more than ±0.2° 2-Θ.

[0156] Pharmaceutical Compositions In some embodiments, the compound and solid state forms described herein are formulated into pharmaceutical compositions.The pharmaceutical compositions are formulated in a conventional manner using one or more pharma-ceutical acceptable inactive ingredients that facilitate the processing of active compound into pharmaceutical preparations.The appropriate formulation depends on the route of administration selected. Summary summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0157] In some embodiments, the compounds and solid state forms described herein are administered alone or in combination with a pharma- ceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition.Administration of the compounds and compositions described herein can be accomplished by any method that allows delivery of the compound to the site of action.

[0158] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, hi some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0159] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surface active agent, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide a delayed or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compound may be dissolved or suspended in suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different combinations of doses of active compound.

[0160] It will be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0161] In some embodiments, the formulations described herein are suitable for oral or nasal inhalation. The inhalable formulations described herein include those capable of rapid delivery of ralinepag to the circulatory system and / or target organs (e.g., lungs) of a mammal in need thereof.

[0162] In certain embodiments, the inhalable formulation is in the form of a dry powder. In some embodiments, the dry powder is delivered with a propellant. In some embodiments, the dry powder is delivered without a propellant. In some cases, the dry powder is a one-phase mixture of solid particles. In some cases, when actuated, the dry powder is a two-phase gas-solid system in which the dry powder is dispersed into the air.

[0163] In some embodiments, the dry powder contains at least one pharma- ceutically acceptable excipient selected from a pH adjusting agent, a tonicity agent, a propellant, a preservative, and a surfactant.

[0164] In some embodiments, the dry powder comprises micronized and / or nanosized particles of a prostacyclin (IP) receptor agonist mixed with larger carrier particles that prevent agglomeration. The excipients and / or carriers in the dry powder are endogenous to the lungs and are readily metabolized or eliminated.

[0165] In some cases, the dry powder contains lactose as a carrier. In some cases, the dry powder includes starch, mannitol, or glucose as a carrier. In some cases, the dry powder is formulated as a liposome including phospholipids (e.g., phosphatidylcholine), cholesterol, etc. The carrier particles have low hygroscopicity (e.g., lactose), which prevents aggregation or caking due to moisture absorption.

[0166] In some cases, the dry powder inhalable formulations described herein comprise nanoparticulate ralinepag. In some cases, the dry powder inhalable formulations described herein comprise crystalline particles. In some embodiments, the dry powder inhalable formulations described herein comprise amorphous particles.

[0167] In some embodiments, the inhalable formulation is administered using a dry powder inhaler (DPI) or a metered dose inhaler (MDI).

[0168] In some cases, the dry powder inhalable formulations described herein are administered using a dry powder inhaler (DPI). The drug is typically loaded into the chamber of the inhaler as a capsule and then delivered by the patient's inhalation, preferably a forced deep inhalation.

[0169] In some embodiments, the inhalable formulations described herein are administered using a metered dose inhaler (MDI). In some embodiments, the inhalable formulations described herein contain a propellant and are pressurized and packaged to administer ralinepag using a pressurized aerosol. In some embodiments, the metered dose inhaler includes three main components: a canister, a regulating valve, and an actuator. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve that regulates and delivers the amount. In some cases, depressing the top of the canister and actuating the MDI releases a metered dose of the drug in the propellant, creating an aerosol that is then inhaled by the patient.

[0170] In some cases, the dry powder inhalable formulations described herein are administered using an inhaler. The dry powder is placed in the inhaler and the inhaler is pressed. A portion of the powder is released into the air through the nozzle and inhaled. By way of example only, capsules and cartridges such as gelatin for use in inhalers or insufflators may be formulated to contain the dry powder formulations described herein.

[0171] Dosage and Treatment Regimens In one embodiment, the compounds and solid state forms disclosed herein, or pharmaceutically acceptable salts thereof, are used to prepare a medicament for the treatment of a disease or condition in a mammal that would benefit from the modulation of prostacyclin (IP) receptor agonist activity. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0172] In certain embodiments, compositions comprising the compounds and solid state forms described herein are administered for preventive and / or therapeutic treatment.In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or illness in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or illness.The amount effective for this use depends on the severity and course of the disease or illness, previous treatments, the patient's health status, weight, and response to drugs, and the judgment of the treating physician.Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0173] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0174] However, the doses used for treating adults in general are typically in the range of 0.01 mg to 0.6 mg per day. In one embodiment, the desired dose is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example, as two or more subdoses per day. In some embodiments, the daily dose or amount of the active ingredient in the dosage form will be lower or higher than the ranges set forth herein, based on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including but not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the physician's judgment.

[0175] Any of the foregoing aspects are further embodiments in which an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to the mammal, and / or (b) administered orally to the mammal, and / or (c) administered by inhalation to the mammal.

[0176] In some embodiments, ralinepag or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.21 mg, about 0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg, about 0.26 mg, about 0.27 mg, about 0.28 mg, about 0.29 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 40 mg, about 41 mg, about 42 mg, about g, about 0.31 mg, about 0.32 mg, about 0.33 mg, about 0.34 mg, about 0.35 mg, about 0.36 mg, about 0.37 mg, about 0.38 mg, about 0.39 mg, about 0.4 mg, about 0.41 mg, about 0.42 mg, about 0.43 mg, about 0.44 mg, about 0.45 mg, about 0.46 mg, about 0.47 mg, about 0.48 mg, about 0.49 mg, about 0.5 mg, about 0.51 mg, about 0.52 mg, about 0.53 mg, about 0.54 mg, about 0.55 mg, about 0.56 mg, about 0.57 mg, about 0.58 mg, about 0.59 mg, or about 0.6 mg of larinepag. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.05 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.10 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.15 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.20 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.25 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.30 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.35 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.40 mg per day. In some embodiments, ralinepag or a pharma- ceutically acceptable salt thereof is administered at 0.45 mg per day.In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.5 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.55 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.60 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.65 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.70 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.75 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.80 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.85 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.9 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 0.95 mg per day. In some embodiments, lalinepag or a pharma- ceutically acceptable salt thereof is administered at 1 mg per day. In some embodiments, it is dosed once per day. In some embodiments, it is dosed twice per day.

[0177] Other embodiments and uses will be apparent to those skilled in the art in light of the present disclosure. The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way. EXAMPLES

[0178] Abbreviation: HPLC-UV = High performance liquid chromatography with ultraviolet detection NMR=nuclear magnetic resonance RH = relative humidity v / v = volume ratio w / w=weight ratio 2-MethylTHF = 2-Methyltetrahydrofuran tBME = tert-butyl methyl ether t-BuOH = tert-butanol DCM = dichloromethane, methylene chloride DIPE = Diisopropyl Ether DMA = N,N-Dimethylacetamide DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide DIPE = Diisopropyl Ether EtOAc = ethyl acetate EtOH = ethanol iPrAc = isopropyl acetate MEK = methyl ethyl ketone MeOH = methanol MIBK = methyl isobutyl ketone NMP = N-methyl-2-pyrrolidone THF = tetrahydrofuran tol = toluene mL = milliliters μL = microliter

[0179] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0180] Example 1: Preparation of Lalinepag The preparation of ralinepag has been previously described (see WO2009 / 117095, US8,895,776, US10,668,033, and US2020 / 0375930, each of which is incorporated by reference in its entirety).

[0181] Example 2: Preparation of amorphous Ralinepag from Ralinepag crystalline Form 1 Example 2a: First attempt. To prepare amorphous material for primary polymorph screening, 1.2 g of lalinepag was dissolved in 336 mL of 1,4-dioxane and divided into 24 vials (approximately 50 mg of lalinepag per sample). These solution vials were frozen at -50°C and then lyophilized overnight. An aliquot of the lyophilized solid was analyzed by XRPD and confirmed to be the less crystalline Form 1.

[0182] Example 2b: Second attempt. The solid from Example 2a was redissolved in 100 mL of methanol and the solvent removed by rotary evaporation. An aliquot of the solid was analyzed by XRPD and confirmed to be Form 1.

[0183] Example 2c: Third attempt. The solid from Example 2b was redissolved in 100 mL of DCM and the solvent was removed by rotary evaporation. An aliquot of the solid was analyzed by XRPD and confirmed to be Form 1. Example 2d: Fourth attempt. The solid from Example 2c was dissolved in 240 mL of tert-butanol, and the solution was divided among 24 vials and lyophilized as described in Example 2a. An aliquot of the solid was analyzed by XRPD and confirmed to be Form 1.

[0184] Example 2e: 5th attempt. The solid from one vial from Example 2d was dissolved in 200 pL of DCM, followed by the addition of 2 mL of heptane as anti-solvent all at once to precipitate the solid. A small amount of precipitate was observed on the side of the vial. The solution was decanted and the solid was removed using a spatula for XRPD analysis. Form 1 was observed.

[0185] Example 2f: Sixth attempt. All solids from Examples 2d and 2e were combined and redissolved in 336 mL of 1,4-dioxane, then divided into 24 vials and lyophilized as described in Example 2a. An aliquot of the solid was analyzed by XRPD and confirmed to be amorphous lalinepag and was used for the primary polymorph screening.

[0186] Example 2g: 7th attempt. To generate additional amorphous material, 300 mg of lalinepag was dissolved in 84 mL of 1,4-dioxane, divided equally among six vials, and lyophilized as above. An aliquot of the solid was analyzed by XRPD, which confirmed the new pattern 2.

[0187] Example 2i: 8th attempt. Six vials of lyophilized lalinepag from Example 2g were each dissolved in 16 mL of 1,4-dioxane and lyophilized as described above. An aliquot of the solid was analyzed by XRPD, which confirmed Pattern 2. A sample was dried under vacuum at 40° C. for approximately 21 hours, and an aliquot of the solid was analyzed by XRPD, which showed that Pattern 2 was retained, and analyzed by TGA / DTA.

[0188] Summary of results As seen in trials 1 to 8, form 1 was produced by fast evaporation of MeOH or DCM, addition of heptane to DCM solutions, and lyophilization of t-BuOH or 1,4-dioxane solutions. However, amorphous lalinepag was successfully prepared by lyophilizing a more dilute solution of lalinepag in 1,4-dioxane.

[0189] Amorphous material was used for the primary polymorph screen to eliminate the possibility of any seed material being present in the experiment.

[0190] Example 3: Solvent solubility studies of Ralinepag To prepare amorphous material for solubility testing, 330 mg of lalinepag was dissolved in 33 mL of tert-butanol (with gentle heating via a heat gun) and then divided equally into 33 vials (approximately 10 mg of lalinepag per sample). These solution vials were frozen at -50°C and then lyophilized overnight. The solid from one vial was analyzed by XRPD, confirming that the lalinepag had become amorphous. However, similar to Example 2g, low crystallinity Pattern 2 was observed.

[0191] Thirty-two solvents and solvent systems were added to 32 vials containing 10 mg lyophilized Lalinepag in 50 μL aliquots, initially to a volume of 300 μL or until complete dissolution was observed. If complete dissolution was not observed, then 100 μL aliquots were added up to a total solvent volume of 1 mL. Between each addition, the mixture was shaken manually for a few seconds, and if complete dissolution was not apparent, the mixture was heated to approximately 40°C and rechecked.

[0192] Once complete dissolution had occurred, the solvent was allowed to evaporate at ambient temperature. If complete dissolution was not observed, the solids were separated using centrifugal filtration. The precipitated solids were analyzed by XRPD.

[0193] The results of the solvent screening are summarized in Table 1.

[0194] [Table 4]

[0195] Poorly crystalline larinepag was found to be soluble in 29 of 32 solvent systems at concentrations of 10 mg / mL or greater.

[0196] No solids were obtained from 1-butanol, benzyl alcohol, or N-methylpyrrolidone.

[0197] Upon evaporation of the dimethylsulfoxide, a new pattern was generated from the precipitated solid (Form 3).

[0198] Evaporation of 1,1-dimethoxymethane, acetone, and water precipitated the less crystalline Form 1.

[0199] The remaining solvent systems produced Form 1.

[0200] The following samples produced crystalline Form 1 of lalinepag in a preferred orientation as described herein: 1,4-dioxane, 1-propanol, 2-ethoxyethanol, 2-methyltetrahydrofuran, 2-methyl-1-propanol, ethanol / water (93:7% v / v), ethanol / water (98.5:1.5% v / v), acetonitrile, butyl acetate, ethanol, ethyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, tert-butyl methyl ether, tetrahydrofuran, and toluene.

[0201] Example 4: Polymorphism Screening of Lalinepag Using the amorphous material prepared in Example 2f above, various solvent systems were added in an attempt to form slurries (where possible). The slurries / solutions were thermally cycled (with stirring) for 72 hours between ambient temperature and 40° C. (4 hour cycles) (no specified heating / cooling rates).

[0202] The solid material remaining after temperature cycling was isolated using centrifugal filtration and the isolated material was analyzed by XRPD. The solid was dried in a vacuum oven at 40° C. for 2 hours and then analyzed again by XRPD.

[0203] The separated mother liquor was divided equally into three portions and the following experiments were carried out. (a) Evaporation at ambient temperature. (b) First rapid cooling at 5°C, then rapid cooling at −20°C if no solids were observed. (c) Addition of antisolvent: 2 mL of antisolvent was added and the sample was left at ambient temperature overnight.

[0204] If no solids precipitated after thermal cycling, anti-solvent was added and the resulting slurry was thermal cycled as above. Any precipitated solids were analyzed by XRPD, dried as above, and analyzed again by XPRD. All patterns were analyzed by TGA / DTA and NMR, where the amount of material permitted.

[0205] The results of the polymorphism screening are seen in Tables 2 and 3.

[0206] [Table 5]

[0207] [Table 6-1]

[0208] [Table 6-2]

[0209] Thermal cycling Only Form 1 (or amorphous material containing a Form 1 peak) was precipitated, except for the N,N-dimethylacetamide / water and N-methyl-2-pyrrolidone / water mixtures, where amorphous material was produced after thermal cycling. See Figures 14f and 14g. All Form 1 solids appeared to be highly crystalline, although a slight decrease in crystallinity was observed in solids precipitated from N,N-dimethylformamide, tert-butyl methyl ether, and water.

[0210] After drying, only Form 1 precipitated in all samples. Some solids that were amorphous / predominantly amorphous when wet, e.g., solids obtained from 2-methyl-tetrahydrofuran, benzyl alcohol, toluene, N,N-dimethylacetamide / water, and N-methyl-2-pyrrolidone / water, were dried to Form 1.

[0211] evaporation All samples that produced a solid after evaporation gave Form 1, except for dimethyl sulfoxide, which gave Form 3.

[0212] rapid cooling Only 2-ethoxyethanol (Form 1) and acetone (amorphous with some Form 1 peaks) gave solids after rapid cooling.

[0213] Addition of antisolvent Form 1 was obtained in solids isolated from 1,4-dioxane / heptane, 1-propanol / heptane, 2-ethoxyethanol / heptane, dimethylsulfoxide / water, methyl isobutyl ketone / heptane, N,N-dimethylformamide / water, tert-butyl methyl ether / heptane, tetrahydrofuran / heptane, toluene / heptane, and chloroform / heptane. Amorphous material was obtained from 2-methyl-tetrahydrofuran / heptane, ethanol / water, acetone / heptane, acetonitrile / water, butyl acetate / heptane, ethanol / heptane, and ethyl acetate / heptane.

[0214] When water was added as an antisolvent, a new pattern was precipitated from N,N-dimethylacetamide and N-methyl-2-pyrrolidone (Pattern 4). Upon drying, Pattern 4 produced Form 1. To perform the analysis of Pattern 4, another sample was prepared from N-methyl-2-pyrrolidone / water.

[0215] The method of sample preparation can affect the relative intensities of the peaks: many of the sample preparations of crystalline form 1 exhibited preferred orientations, including: Samples prepared by thermal cycling of acetone, All samples prepared by evaporation of the solvent, as well as • Samples prepared by adding antisolvents: 1-propanol / heptane, 2-ethoxyethanol / heptane, and methyl isobutyl ketone / heptane.

[0216] Example 5: X-ray Powder Diffraction (XRPD) The following diffractometer was used, but other types of diffractometers may be used. Additionally, other wavelengths may be used with Cu Kα conversion. In some embodiments, synchrotron radiation X-ray powder diffraction (SR-XRPD) may be used to characterize the crystalline form.

[0217] "Diagram peaks", to the extent they exist, are a subset of the observed peaks that are used to distinguish one crystalline polymorph from another (a polymorph of a crystalline form having the same chemical composition).Diagram peaks are determined by assessing which observed peaks, if any, are present in one crystalline polymorph of a compound relative to all other known crystalline polymorphs of the compound, to within ±0.2°2Θ.

[0218] XRPD analysis was performed on a PANalytical X'pert pro equipped with a pixelated detector (128 channels) and samples were scanned from 3 to 35°2Θ. The material was gently ground to release any aggregates and loaded into 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 (α1 λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; ratio of α1:α2 = 0.5) running in transmission mode (step size 0.0130°2Θ, step time 18.87 s) using a generator setting of 40 kV / 40 mA. Data were visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0219] For samples with only one XRPD pattern and no other means of assessing whether the sample provides a good approximation of the powder average, the peak table contains data identified only as "prominent peaks." These peaks are a subset of the entire observed peak list. Prominent peaks are preferably selected from the observed peaks by identifying non-overlapping, low angle peaks with strong intensity.

[0220] Characterization of crystalline form 1 of larinepag The X-ray powder diffraction pattern of crystalline Form 1 of Lalinepag is shown in Figure 1. Representative peaks include those listed in the table below.

[0221] [Table 7]

[0222] Characteristic peaks for crystalline form 1 of Lalinepag may include 8.8±0.2°2-Θ, 11.7±0.2°2-Θ, 16.2±0.2°2-Θ, 21.3±0.2°2-Θ, and 33.8±0.2°2-Θ. Characteristic peaks for crystalline form 1 of Lalinepag may include 8.8±0.2°2-Θ, 11.7±0.2°2-Θ, and 16.2±0.2°2-Θ.

[0223] The method of sample preparation may affect the relative intensities of the peaks. For example, all of the samples prepared by evaporating the solvent as described in Example 4, as well as many of the samples prepared by other methods, exhibited preferred orientation. Additional X-ray powder diffraction patterns obtained from crystalline Form 1 isolated from Lalinepag throughout the Examples described herein are shown in Figures 12a-12f, 13a-13e, 14a-14e, 15a-15c, 16, 17a and 17b. These additional patterns show variations in the XRPD pattern of crystalline Form 1 of Lalinepag obtained throughout the Examples herein.

[0224] If multiple diffraction patterns are available, particle statistics (PS) and / or preferred orientation (PO) can be assessed. Consistency in relative intensities between XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern can be compared to a calculated XRPD pattern based on a single crystal structure, if available. Two-dimensional scattering patterns using an area detector can also be used to assess PS / PO. If both PS and PO contributions are determined to be negligible, the XRPD pattern represents the powder average intensity for the sample, and prominent peaks can be identified as "representative peaks."

[0225] As used herein, the term "preferred orientation" refers to an extreme case of non-random distribution of crystallites in a solid-state morphology. In XRPD, an ideal sample is homogeneous, with crystallites randomly distributed in the bulk solid. In a truly random sample, each possible reflection from a given set of planes has an equal number of crystallites contributing to it. However, this is not the case when the solid-state morphology is in a preferred orientation. Thus, comparing the intensities between a randomly oriented and a preferentially oriented diffraction pattern can appear completely different. Quantitative analysis according to intensity ratios is highly distorted by preferred orientation.

[0226] Characterization of the crystal pattern of Lalinepag 2 The X-ray powder diffraction pattern of crystalline pattern 2 of lalinepag is shown in Figure 2. Representative peaks include those listed in the table below.

[0227] [Table 8]

[0228] Pattern 2 was precipitated from tert-butanol and 1,4-dioxane only after lyophilization and is a less crystalline form.

[0229] Pattern 2 transforms into Form 1 when heated.

[0230] Characterization of crystalline form 3 of larinepag The X-ray powder diffraction pattern of crystalline Form 3 of Lalinepag is shown in Figure 3. Representative peaks include those listed in the table below.

[0231] [Table 9]

[0232] Form 3 is precipitated only from DMSO and is highly crystalline.

[0233] Characterization of the crystal pattern of Lalinepag 4 The X-ray powder diffraction pattern of crystalline pattern 4 of ralinepag is shown in Figure 4. Representative peaks include those listed in the table below.

[0234] [Table 10]

[0235] Pattern 4 was observed only in the wet solids obtained from N,N-dimethylacetamide (DMA) and N-methyl-2-pyrrolidone (NMP) with water as a co-solvent.

[0236] Pattern 4 made from NMP / water converts to Form 1 upon drying (even air drying).

[0237] Pattern 4 made from DMA / water converts to a predominantly amorphous form with some Form 1 peaks present.

[0238] Characterization of amorphous larinepag The X-ray powder diffraction pattern of the amorphous ralinepag prepared in Example 2f is shown in Figure 5. The XRPD shows no crystallinity.

[0239] Example 6: Thermogravimetric / Differential Thermal Analysis (TGA / DTA) Approximately 5 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TGA / DTA) and held at room temperature. The sample was then heated at a rate of 10°C / min from 20°C to 350°C while recording the change in sample weight along with all differential thermal events (DTA). Nitrogen was used as the purge gas at 300 cm 3 A flow rate of 1 / min was used.

[0240] The TGA / DTA thermogram of crystalline form 1 of Lalinepag is shown in Figure 6. The TGA / DTA thermogram of crystalline pattern 2 of Lalinepag is shown in Figure 8. The TGA / DTA thermogram of crystalline form 3 of Lalinepag is shown in Figure 9. The TGA / DTA thermogram of crystalline pattern 4 of Lalinepag is shown in Figure 10.

[0241] The thermogravimetric / differential thermal analysis (TGA / DTA) patterns of the solid state forms of Lalinepag are set forth in the table below.

[0242] [Table 11]

[0243] Example 7: Differential Scanning Calorimetry (DSC) To assess the possibility of recrystallization, crystalline Form 1 of Lalinepag was heated above its melting point, cooled back to 20° C., and subsequently reheated.

[0244] Approximately 1-5 mg of material was weighed into an aluminum DSC pan and non-hermetically sealed with an aluminum lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 Differential Scanning Calorimeter equipped with an RC90 cooler. The sample and reference were heated above their melting temperatures at a scan rate of 10°C / min and the resulting heat flow response was monitored. The sample was re-cooled to 20°C and then re-heated again above melting at 10°C / min. 50 cm of nitrogen was used as the cell purge gas. 3 A flow rate of 1 / min was used.

[0245] The DSC thermogram of crystalline Form 1 of Lalinepag is shown in Figure 7. A sharp endothermic event was observed in the first heating step, consistent with the onset of melting in the TGA / DTA (onset at about 127.5°C; peak at about 129.2°C). No further events were observed in the first heating step. No thermal events were observed upon cooling after melting. A weak thermal event was observed in the second heating step at approximately 193°C, potentially due to the onset of decomposition.

[0246] Example 8: Dynamic Vapor Sorption (DVS) Approximately 10 mg of sample was placed into a mesh vapor sorption balance pan and loaded into a DVS-1 / DVS Intrinsic / DVS Advantage dynamic vapor sorption balance by Surface Measurement Systems. The sample was subjected to a ramping profile from 40 to 90% relative humidity (RH) in 10% increments, maintaining the sample at each step until a stable weight was achieved (dm / dt 0.004%, minimum step length 30 min, maximum step length 500 min) at 25 °C. After the sorption cycle was completed, the sample was dried to 0% RH using the same procedure and then returned to 40% RH using a second sorption cycle. The cycle was performed twice. The change in weight during the sorption / desorption cycle was plotted, allowing the hygroscopicity of the sample to be determined.

[0247] Crystalline Form 1 of ralinepag is non-hygroscopic. The reversible water uptake of crystalline Form 1, as determined by DVS, was 0.1% (w / w) from 0% to 90% RH.

[0248] XRPD analysis was then performed on all retained solids, which showed that the material was unchanged after DVS analysis and remained as crystalline Form 1.

[0249] Example 9: High-performance liquid chromatography with ultraviolet detection (HPLC-UV) Purity analysis was performed using HPLC, the full method is given below.

[0250] [Table 12]

[0251] Crystalline Form 1 of ralinepag was determined to be 99.7% pure by relative area.

[0252] Example 10: Single Crystal X-Ray Diffraction (SXRD) of Crystalline Form 1 of Lalinepag Crystalline Form 1 of lalinepag obtained from isopropyl acetate with heptane as the antisolvent consisted of very large lath-like particles that exhibited birefringence under polarized light, consistent with crystalline material.

[0253] A suitable crystal was selected and mounted using paratone oil on a loop. Data were collected using Cu-Kα radiation (1.54178 Å) on a Bruker D8 Venture diffractometer with a Photon III detector operating in shutterless mode at 100(2) K. The structure was solved with the Olex2 software package (Dolomanov, OV, Bourhis, LJ, Gildea, RJ, Howard, JAK & Puschmann, HJ Appl. Cryst., 2009, 42, 339-341.) using the ShelXT (intrinsic phase) (Sheldrick, GM Acta Cryst., 2015, A71, 3-8.) structure solution program and refined with the ShelXL (Sheldrick, GM Acta Cryst., 2015, C71, 3-8.) refinement package using Least Squares minimisation. The data were collected, analyzed and refined in the triclinic space group P-1.

[0254] All non-hydrogen atoms were placed in a Fourier map and their positions were anisotropically refined before describing the thermal movements of all non-hydrogen atoms. One complete Lalinepag formula unit was refined in the asymmetric unit. All hydrogen atoms were placed in positions calculated using the riding model with fixed Uiso at 1.2 times for all CH and CH2 groups and 1.5 times for all OH groups.

[0255] The highest residual Fourier peak is 0.79 e.Å -3 , Cl(1A) was found to be approximately 0.68 Å, and the deepest Fourier hole was found to be -0.43 e.Å. -3 , found to be approximately 0.52 Å from Cl(1A).

[0256] The asymmetric unit was found to contain only one complete molecule of ralinepag.

[0257] The crystallographic parameters and refinement indices were found to be as follows:

[0258] [Table 13]

[0259] [Table 14]

[0260] [Table 15]

[0261] The structure has efficient packing with a calculated density of 1.330 g / cm 3It was observed that the crystals had no regions of spurious electron density that could be attributed to solvent, nor any large voids or channels where solvent or water could reside. Packing can be confirmed by looking along the unit cell axes a, b, and c. Strong hydrogen bonding interactions were observed between the opposing terminal carboxylic acids, driving the crystallization of lalinepag: O(1)...H(2)-O(2)=1.78355(16) Å.

[0262] The simulated XRPD2Θ was calculated and compared to the experimental diffractogram of Lalinepag crystalline Form 1, with excellent overlap as shown in Figure 11. Any deviations in the diffractograms may be attributed to differences in the temperatures at which the data sets were collected.

[0263] [Table 16]

[0264] Example A-1: ​​Oral Capsule (Immediate Release Formulation) To prepare a pharmaceutical composition for oral delivery, 0.01-0.4 mg of a form of ralinepag disclosed herein or a pharma- ceutically acceptable salt thereof is dissolved in Kolliphor® RH4 or another suitable dissolving agent, optionally thickened with silicon dioxide or another suitable thickening agent, and / or stabilized with dibutylhydroxytoluene (BHT) or another suitable stabilizing agent, and the liquid mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, suitable for oral administration.

[0265] Example A-2: Oral Capsule (Sustained Release Formulation) To prepare a pharmaceutical composition for sustained release oral delivery, 0.01-0.4 mg of ralinepag or a pharma- ceutically acceptable salt thereof is mixed with poloxamer P188 or another suitable solubilizer and / or glycerol monostearate or another suitable emulsifier. This liquid mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, suitable for oral administration. The ratio of excipients may be varied to control the rate of drug release.

[0266] Example A-3: Oral tablet (extended release formulation) Tablets are prepared by mixing 0.05-0.4 mg of ralinepag or a pharma- ceutically acceptable salt thereof with 20-50% by weight microcrystalline cellulose, 40-60% by weight modified release excipients such as a blend of hydroxypropyl methylcellulose (HPMC) K4M and HPMC K100LV, and 20-40% by weight mannitol, silicon dioxide, magnesium stearate, or other suitable excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-200 mg.

[0267] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. When measured using Cu Kα radiation, the X-ray powder diffraction (XRPD) pattern was substantially the same as that shown in FIG. an XRPD pattern having peaks at 8.8±0.2° 2-Θ, 11.7±0.2° 2-Θ, and 16.2±0.2° 2-Θ, when measured using Cu Kα radiation; or When measured using Cu Kα radiation, it gave an XRPD pattern substantially the same as that shown in FIG. an XRPD pattern having peaks at 4.1±0.2° 2-Θ, 15.5±0.2° 2-Θ, and 16.9±0.2° 2-Θ, when measured using Cu Kα radiation; or When measured using Cu Kα radiation, it gave an XRPD pattern substantially the same as that shown in FIG. an XRPD pattern having peaks at 3.6±0.2° 2-Θ, 18.7±0.2° 2-Θ, and 22.2±0.2° 2-Θ, when measured using Cu Kα radiation; or When measured using Cu Kα radiation, it gave an XRPD pattern substantially the same as that shown in FIG. An XRPD pattern having peaks at 15.0±0.2° 2-Θ, 16.7±0.2° 2-Θ, and 18.0±0.2° 2-Θ when measured using Cu Kα radiation.

2. A crystalline form of Lalinepag, characterized in that it has:

2. When measured using Cu Kα radiation, the X-ray powder diffraction (XRPD) pattern was substantially the same as that shown in FIG. an XRPD pattern having peaks at 8.8±0.2° 2-Θ, 11.7±0.2° 2-Θ, and 16.2±0.2° 2-Θ, when measured using Cu Kα radiation; or When measured using Cu Kα radiation, the XRPD pattern is substantially the same as that shown in any one of Figures 12a, 12b, 12c, 12d, 12e, 12f, 13a, 13b, 13c, 13d, 13e, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 15a, 15b, 15c, 16, 17a, or 17b. A crystalline form of Lalinepag (Form 1), characterized in that it has:

3. 3. The crystalline form of ralinepag according to claim 2, characterized in that it has an XRPD pattern with peaks at 8.8±0.2° 2-Θ, 11.7±0.2° 2-Θ, and 16.2±0.2° 2-Θ when measured using Cu Kα radiation.

4. an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1, measured using Cu Kα radiation; or When measured using Cu Kα radiation, the XRPD pattern is substantially the same as that shown in any one of Figures 12a, 12b, 12c, 12d, 12e, 12f, 13a, 13b, 13c, 13d, 13e, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 15a, 15b, 15c, 16, 17a, or 17b.

3. The crystalline form of Ralinepag according to claim 2, characterized in that it has the formula:

5. a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially similar to that shown in FIG. 6; or a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 7; or A differential thermal analysis (DTA) thermogram showing a sharp endothermic event with an onset at about 127.2° C., or DSC thermogram with a sharp endothermic event with an onset at approximately 127.5° C. The crystalline form of Ralinepag according to any one of claims 2 to 4, further characterized by having:

6. A reversible water uptake of up to 0.2% (w / w) at 0% to 90% relative humidity (RH) as determined by dynamic vapor sorption (DVS); or XRPD pattern remains constant after DVS analysis from 0% to 90% RH The crystalline form of Ralinepag according to any one of claims 2 to 5, further characterized by having:

7. i) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1, measured using Cu Kα radiation; or and an XRPD pattern substantially the same as shown in any one of Figures 12a, 12b, 12c, 12d, 12e, 12f, 13a, 13b, 13c, 13d, 13e, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 15a, 15b, 15c, 16, 17a, or 17b, when measured using Cu Kα radiation; and ii) a thermogravimetric / differential thermal analysis (TGA / DTA) thermogram substantially the same as that shown in FIG. 6; or Differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

6. The crystalline form of Ralinepag according to claim 5, characterized in that it has the following structure:

8. i) an XRPD pattern having peaks at 8.8±0.2° 2-Θ, 11.7±0.2° 2-Θ, and 16.2±0.2° 2-Θ, when measured using Cu Kα radiation; and ii) a differential thermal analysis (DTA) thermogram that exhibits a sharp endothermic event with an onset at about 127.2°C; or Differential Scanning Calorimetry (DSC) thermogram with a sharp endothermic event with an onset at about 127.5° C.

6. The crystalline form of Ralinepag according to claim 5, characterized in that it has the following structure:

9. A crystalline form of Ralinepag (Form 1), characterized in that it has unit cell parameters at 100K approximately equal to: 【Table 1】

10. When measured using Cu Kα radiation, the X-ray powder diffraction (XRPD) pattern was substantially the same as that shown in FIG. An XRPD pattern having peaks at 4.1±0.2° 2-Θ, 15.5±0.2° 2-Θ, and 16.9±0.2° 2-Θ when measured using Cu Kα radiation. A crystalline form of ralinepag (Pattern 2), characterized in that it has:

11. Thermogravimetric / differential thermal analysis (TGA / DTA) thermograms substantially similar to those shown in FIG. TGA / DTA thermogram showing weak endothermic and exothermic events between 81-89° C. and a broad endothermic event with an onset at approximately 124.7° C. The crystalline form of Ralinepag according to claim 10 (Pattern 2), further characterized by having:

12. An X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, substantially the same as that shown in FIG. 2; and Thermogravimetric / differential thermal analysis (TGA / DTA) thermograms substantially similar to those shown in FIG.

12. The crystalline form of Ralinepag according to claim 11, characterized in that it has the formula:

13. an XRPD pattern having peaks at 4.1±0.2° 2-Θ, 15.5±0.2° 2-Θ, and 16.9±0.2° 2-Θ, as measured using Cu Kα radiation; and TGA / DTA thermogram showing weak endothermic and exothermic events between 81-89° C. and a broad endothermic event with an onset at approximately 124.7° C.

12. The crystalline form of Ralinepag according to claim 11, characterized in that it has the formula:

14. A crystalline form of Lalinepag according to any one of claims 10 to 13, further characterized by having an XRPD which upon heating converts to the crystalline form of Lalinepag according to any one of claims 2 to 9.

15. The crystalline form of Ralinepag according to any one of claims 10 to 14, further characterized in that the crystalline pattern 2 of Ralinepag is a dimethylsulfoxide solvate.

16. When measured using Cu Kα radiation, it gave an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. An XRPD pattern having peaks at 3.6±0.2° 2-Θ, 18.7±0.2° 2-Θ, and 22.2±0.2° 2-Θ when measured using Cu Kα radiation. A crystalline form of Lalinepag (Form 3), characterized in that it has:

17. Thermogravimetric / differential thermal analysis (TGA / DTA) thermograms substantially similar to those shown in FIG. A thermogravimetric analysis (TGA) trace showing a weight loss of about 17.8% from the start of heating to approximately 238°C; or Differential thermal analysis (DTA) thermogram showing a sharp endothermic event with an onset at approximately 74.6° C.

17. The crystalline form of Ralinepag according to claim 16, further characterized by having:

18. When measured using Cu Kα radiation, it gave an XRPD pattern substantially the same as that shown in FIG. Thermogravimetric / differential thermal analysis (TGA / DTA) thermograms substantially similar to those shown in FIG.

18. The crystalline form of Ralinepag according to claim 17, characterized in that it has the formula:

19. an XRPD pattern having peaks at 3.6±0.2° 2-Θ, 18.7±0.2° 2-Θ, and 22.2±0.2° 2-Θ, as measured using Cu Kα radiation; and A thermogravimetric analysis (TGA) trace showing a weight loss of about 17.8% from the onset of heating to approximately 238°C, or a differential thermal analysis (DTA) thermogram showing a sharp endothermic event with an onset at about 74.6°C.

18. The crystalline form of Ralinepag according to claim 17, characterized in that it has the formula:

20. The crystalline form of Ralinepag according to any one of claims 16 to 19, further characterized as being a hydrate.

21. When measured using Cu Kα radiation, it gave an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. An XRPD pattern having peaks at 15.0±0.2° 2-Θ, 16.7±0.2° 2-Θ, and 18.0±0.2° 2-Θ when measured using Cu Kα radiation. A crystalline form of Lalinepag (Pattern 4), characterized in that it has:

22. Thermogravimetric / differential thermal analysis (TGA / DTA) thermograms substantially similar to those shown in FIG. Differential thermal analysis (DTA) thermograms showing a broad endothermic event with an onset at about 29.0° C., a sharp endothermic event with an onset at about 127.8° C., or both.

22. The crystalline form of Ralinepag according to claim 21, further characterized by having:

23. When measured using Cu Kα radiation, it gave an XRPD pattern substantially the same as that shown in FIG. Thermogravimetric / differential thermal analysis (TGA / DTA) thermograms substantially similar to those shown in FIG.

23. The crystalline form of Ralinepag according to claim 22, characterized in that it has the formula:

24. an XRPD pattern having peaks at 15.0±0.2° 2-Θ, 16.7±0.2° 2-Θ, and 18.0±0.2° 2-Θ, as measured using Cu Kα radiation; and Differential thermal analysis (DTA) thermograms showing a broad endothermic event with an onset at about 29.0° C., a sharp endothermic event with an onset at about 127.8° C., or both.

23. The crystalline form of Ralinepag according to claim 22, characterized in that it has the formula:

25. A crystalline form of Lalinepag according to any one of claims 21 to 24, further characterized by having an XRPD that upon drying converts to the crystalline form of Lalinepag according to any one of claims 2 to 9.

26. 25. The crystalline form of Lalinepag according to any one of claims 21 to 24, further characterized by having an XRPD that converts to an amorphous form of Lalinepag when dried.

27. Amorphous ralinepag, characterized by having an X-ray powder diffraction (XRPD) pattern indicative of no crystallinity.

28. 25. Amorphous lalinepag according to claim 24, further characterized in that upon drying it converts to a crystalline form of lalinepag according to any one of claims 2 to 9.

29. A pharmaceutical composition comprising crystalline ralinepag according to any one of claims 1 to 26, and at least one pharma- ceutically acceptable excipient.

30. 29. A pharmaceutical composition comprising the amorphous form of claim 27 or 28 and at least one pharma- ceutically acceptable excipient.

31. 31. The pharmaceutical composition of claim 29 or 30, formulated in the form of a solid form pharmaceutical composition suitable for administration to a subject orally, intranasally, or by inhalation.

32. 32. The pharmaceutical composition of claim 29, 30, or 31, in the form of a tablet, pill, or capsule.

33. 32. The pharmaceutical composition of claim 29, 30, or 31, which is administered to a subject using a dry powder inhaler (DPI) or a metered dose inhaler (MDI).

34. 36. A method of treating pulmonary arterial hypertension (PAH) in a subject in need of such treatment, comprising administering ralinepag as defined in any one of claims 1 to 28, or a pharmaceutical composition as defined in any one of claims 29 to 33.

35. The PAH is (a) Idiopathic PAH, (b) familial PAH; (c) PAH associated with collagen vascular disease selected from scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis; (d) Takayasu's arteritis, polymyositis, and dermatomyositis, (e) PAH associated with congenital heart disease selected from atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus in patients; (f) PAH associated with portal hypertension; (g) PAH associated with HIV infection; (h) PAH associated with ingestion of drugs or toxins, PAH associated with hereditary hemorrhagic telangiectasia; (i) PAH associated with splenectomy; (j) PAH associated with significant venous or capillary involvement; (k) PAH associated with pulmonary veno-occlusive disease (PVOD); and (l) PAH associated with pulmonary capillary hemangiomatosis (PCH) in patients 35. The method of claim 34, wherein said compound is selected from:

36. 35. The method of claim 34, wherein the PAH is a World Health Organization (WHO) Group 1 PAH.

37. 37. The method of any one of claims 34 to 36, wherein the subject has World Health Organization (WHO) / New York Heart Association (NYHA) functional class II to IV symptoms.

38. A method for synthesizing amorphous lalinepag, characterized by having an X-ray powder diffraction (XRPD) pattern indicating no crystallinity, comprising a step of converting a crystalline form of lalinepag to an amorphous form of lalinepag.

39. 39. The method of claim 38, comprising drying the crystalline form of Ralinepag of any one of claims 21 to 24.

40. 39. The method of claim 38, comprising lyophilizing a solution of ralinepag in an organic solvent.

41. The method of claim 40, wherein the organic solvent is 1,4-dioxane.

42. 42. The method of claim 40 or 41, wherein the concentration of the lalinepag solution is up to 5 mg / mL.

43. 42. The method of claim 40 or 41, wherein the concentration of the lalinepag solution is up to 3 mg / mL.

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