Stable selexipag liquid formulations and method of its use

Abstract

Stable liquid pharmaceutical formulation of selexipag or its pharmaceutically acceptable salt thereof is provided. The stable liquid formulation of selexipag comprises selexipag or its suitable salt, a vehicle, and one or more optional pharmaceutically acceptable excipients. The method of preparing the stable liquid selexipag formulation and the use of such formulation for the treatment of diseases treatable by selexipag is described.

Description

TITLE OF THE INVENTIONSTABLE SELEXIPAG LIQUID FORMULATIONS AND METHOD OF ITS USE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 711,044 filed on October 23, 2024, and U.S. Provisional Application No. 63 / 817,985 filed on June 4, 2025, the disclosures of which are incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The present invention relates to stable liquid pharmaceutical formulations of selexipag or its pharmaceutically acceptable salt thereof and its method of use.BACKGROUND OF THE INVENTION

[0003] Selexipag is a prostacyclin receptor agonist. The chemical name of selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N-(methyl sulfonyl) acetamide. It has a molecular formula of C26H32N4O4S and a molecular weight of 496.62. Selexipag has the following structural formula:

[0004] Selexipag is a pale-yellow crystalline powder that is practically insoluble in water. In the solid state selexipag is very stable, is not hygroscopic, and is not light sensitive.

[0005] Selexipag is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

[0006] Selexipag is marketed as UPTRAVI® tablets since 2015. Depending on the dose strength, each round film-coated tablet for oral administration contains 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg (microgram) of selexipag. The tablets include the following inactive ingredients: corn starch, D-mannitol, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, and magnesium stearate. The tablets are film coated with a coating material containing carnauba wax, hypromellose, propylene glycol, titanium dioxide, along with mixtures of iron oxide black, iron oxide red or iron oxide yellow.

[0007] Moreover, manufacturing seven different strengths of tablets pose significant overhead cost of manufacturing, risk of mixing up strengths in manufacturing, packaging, dispensing and administration by end user. It also cause confusion during dose titration and results in medication error, while single strength of liquid formulation where the dose can be titrated using different dose volume will simplify manufacturing process, and reduce the risk of dosing error for dose titration.

[0008] Solid dosage forms of selexipag, for e.g. UPTRAVI® tablets, lack the ease of administration in people with dysphagia (difficulty in swallowing). Such patients with dysphagia may delay taking medication or skipping the medication entirely, and thus, there is a need for alternate methods of administration.

[0009] There is need for oral liquid formulation of selexipag for administration to the pediatrics and adults with dysphagia.

[0010] Selexipag is also marketed as UPTRAVI® (selexipag) for injection. It contains 1800 mcg of selexipag per vial. UPTRAVI® for injection includes the following inactive ingredients: glycine (180 mg), phosphoric acid (3.53 mg), polysorbate 20 (10.8 mg) and sodium hydroxide (for pH adjustment). UPTRAVI® for injection is provided in 10 mL Type I clear glass vials closed by a stopper and tear-off aluminum seal. UPTRAVI for injection vials are single dose, for single administration. All remaining reconstituted product must be discarded.

[0011] According to prescribing label of UPTRAVI® for injections, reconstitution and further dilution is required prior to intravenous infusion following aseptic procedures, Moreover, dosing regiments suggest that after pulling required dose of reconstituted solution, remaining reconstituted product must be discarded which is significant waste of product and require waste handling.

[0012] According to reconstitution and dilution procedure of UPTRAVI® (selexipag) for injection, the infusion must be completed within 4 hours of first puncture. This indicate that the reconstituted and or diluted liquid product is highly unstable and cannot be commercially viable.

[0013] Selexipag is classified as practically insoluble in water. According to the United States Pharmacopeia (USP), this classification indicates that dissolving one part of the solute requires 10,000 parts or more of the solvent. Consequently, the aqueous solubility of selexipag is at or below 100 mcg / mL. This low intrinsic solubility presents a significant technical challenge for developing a stable aqueous liquid formulation, particularly at concentrations approaching or exceeding this limit, such as 100 mcg / mU or 1000 mcg / mL. Even in an aqueous suspension, the processes of solubilization anddegradation exist in a state of equilibrium. As the small fraction of dissolved selexipag degrades over time, the equilibrium shifts, causing more of the suspended drug to dissolve to maintain saturation. This newly dissolved drug is then also subject to degradation, creating a cycle that can lead to a significant loss of potency over the product's shelf life. This instability mechanism may explain why the commercial selexipag for injection, which is reconstituted to a concentration of 225 mcg / mL prior to further dilution, is provided as a lyophilized powder stored at 2-8°C rather than a ready-to-use liquid and has a limited in-use stability of only four hours after reconstitution.

[0014] U.S. Patent No. 7,205,302 discloses the compound selexipag itself among a class of heterocyclic derivatives and its use as a PG12 receptor agonist. However, this patent does not describe specific formulations and does not teach how to overcome the challenges of creating a stable liquid product.

[0015] U.S. Patent Nos. 8,791,122 and 9,284,280 are directed to specific crystalline forms (Form-I, Form-II, and Form-Ill) of selexipag. The identification of stable polymorphs is a common strategy to improve the handling, purity, and stability of a drug substance for incorporation into a solid dosage form, but it does not resolve the inherent instability of the molecule in an aqueous solution.

[0016] U.S. Patent Nos. 10,821,108 and 10,828,298 describe stabilized solid preparations of selexipag. These patents teach that the stability of solid formulations can be improved by using D-mannitol with a specific surface area as a diluent. The need to develop such specialized solid formulations underscores the inherent stability issues of the compound, which would be even more pronounced in a liquid environment. These patents do not disclose a stable liquid formulation.

[0017] U.S. Patent No. 9,173,881 discloses combination therapies of the endothelin receptor antagonist macitentan with a prostacyclin receptor agonist, listing selexipag as an example. It does not provide any enabling disclosure for a specific liquid formulation of selexipag.

[0018] U.S. Patent No. 12,121,516 represents the most relevant prior art, disclosing an aqueous pharmaceutical composition of selexipag for intravenous administration. However, this composition is not a ready-to-use, long-term stable liquid. Instead, it is a lyophilized (freeze-dried) powder containing selexipag, glycine, polysorbate 20, and a phosphate buffer, which must be reconstituted with a diluent (e.g., water or saline) before administration. Lyophilization is a process used to stabilize drugs that are unstable in aqueous solutions by removing the water. While this approach provides aninjectable form of selexipag, it requires a complex manufacturing process and an extra reconstitution step before use, highlighting the significant challenge of achieving long-term stability in a liquid state.

[0019] Therefore, despite the recognized clinical need, the prior art does not disclose a commercially viable, ready-to-use liquid formulation of selexipag that is stable for long-term storage without the need for lyophilization and reconstitution. A significant need remains for a liquid selexipag product with sufficient solubility and chemical stability to ensure accurate dosing, patient safety, and a practical shelflife.SUMMARY OF THE INVENTION

[0020] The present invention relates generally to pharmaceutical compositions, and more specifically to stable liquid formulations of selexipag, or a pharmaceutically acceptable salt thereof, suitable for oral or injectable administration. The invention further relates to processes for manufacturing said formulations and methods of using said formulations for the treatment of diseases responsive to selexipag therapy, including pulmonary arterial hypertension (PAH).

[0021] An object of the present invention is to provide a stable liquid pharmaceutical formulation comprising selexipag, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, wherein said formulation overcomes challenges related to the low aqueous solubility and / or hydrolytic instability of selexipag.

[0022] In some embodiments, the stable liquid formulation of selexipag of the present invention is suitable for oral administration. In other embodiments of the present invention, the liquid formulation of selexipag is suitable for injectable route of administration. In yet another embodiment, the liquid formulation of selexipag is suitable for depot injection via subcutaneous and / or intramuscular administration.

[0023] In one embodiment, the stable liquid pharmaceutical formulation comprises selexipag, or a pharmaceutically acceptable salt thereof, at a concentration ranging from about 1 microgram per milliliter (mcg / mL) to about 2000 mcg / mL. In certain embodiments, the concentration ranges from about 10 mcg / mL to about 1000 mcg / mL. In further embodiments, the concentration ranges from about 50 mcg / mL to about 500 mcg / mL.

[0024] In another embodiments, the stable liquid pharmaceutical formulation of selexipag or a pharmaceutically acceptable salt thereof suitable for depot injectable formulations as long actinginjectable, comprising selexipag, or a pharmaceutically acceptable salt thereof, at a concentration ranging from about 1 mg / mL to about 200 mg / mL, optionally from about 10 mg / mL to about 100 mg / mL.

[0025] In an embodiment of the present invention, stable liquid pharmaceutical formulation is provided in the form of solution, suspension, or emulsion. In another embodiment, the stable liquid pharmaceutical formulation of the present invention is provided in the form of solution containing at least one non-aqueous solvent or aqueous suspension.

[0026] In a further embodiment, the formulation comprises one or more pharmaceutically acceptable excipients selected from the group consisting of solvents, co-solvents, suspending agents, wetting agents, flavoring agents, sweetening agents, preservatives, buffering agents, stabilizers, antioxidants, viscosity modifiers, chelating agents, pH adjusting agents, and combinations thereof.

[0027] According to one embodiment, the stable liquid pharmaceutical formulation is a solution comprising selexipag dissolved in a pharmaceutically acceptable vehicle, wherein the vehicle comprises at least one non-aqueous solvent. Said non-aqueous solvent is selected from the group consisting of polyethylene glycol (PEG), propylene glycol (PG), glycerin (glycerol), ethanol, sorbitol solutions, and combinations thereof. In specific embodiments, the polyethylene glycol is selected from PEG 200, PEG 300, or PEG 400. Higher molecular weight PEG could be used in combination with solvent like water. The total concentration of the non-aqueous solvent or mixture of non-aqueous solvents in this embodiment may range from about 10% to about 99.99% by weight or volume of the total formulation.

[0028] According to another embodiment, the stable liquid pharmaceutical formulation is a solution comprising selexipag dissolved in a pharmaceutically acceptable vehicle, wherein the vehicle is an aqueous co-solvent system. Said co-solvent system comprises water and at least one non-aqueous cosolvent selected from the group consisting of polyethylene glycol (PEG), propylene glycol (PG), glycerin (glycerol), ethanol, and combinations thereof. The non-aqueous co-solvent is present in an amount sufficient to maintain selexipag in solution, typically ranging from about 10% to about 90% by weight or volume of the total formulation.

[0029] According to yet another embodiment, the stable liquid pharmaceutical formulation is an aqueous suspension comprising particles of selexipag dispersed in an aqueous vehicle. A critical feature of this embodiment is that the pH of the aqueous vehicle is maintained below 7.5 to enhancethe chemical stability of selexipag against hydrolysis. In preferred embodiments, the pH is maintained below 7.0. In preferred embodiments, the pH is maintained within the range of about 2 to about 5.

[0030] In the embodiment wherein the formulation is an aqueous suspension with controlled pH, the formulation comprises at least one pH adjusting agent or buffer system capable of establishing and maintaining the pH within the desired range. Suitable pH adjusting agents include, but are not limited to, pharmaceutically acceptable acids (e.g., citric acid, acetic acid, hydrochloric acid, phosphoric acid), pharmaceutically acceptable bases (e.g., sodium hydroxide, potassium hydroxide, sodium bicarbonate), and pharmaceutically acceptable buffer systems (e.g., citrate buffer, acetate buffer, phosphate buffer).

[0031] In the embodiment wherein the formulation is an aqueous suspension, the formulation may further comprise one or more excipients selected from suspending agents (e.g., xanthan gum, hypromellose, microcrystalline cellulose, carboxymethylcellulose sodium), wetting agents (e.g., polysorbate 80, pol oxamer 188), preservatives (e.g., sodium benzoate, potassium sorbate, methylparaben, propylparaben), sweeteners (e.g., sucralose, sorbitol, xylitol), and flavoring agents to improve physical stability, microbiological quality, and patient acceptability. Selexipag used in suspensions may optionally be micronized to improve dispersion uniformity and dissolution characteristics.

[0032] Another aspect of the present invention provides a process for preparing a stable liquid pharmaceutical formulation of selexipag as a solution. Said process comprises the steps of: (a) providing a pharmaceutically acceptable vehicle comprising at least one non-aqueous solvent or an aqueous co-solvent system as defined herein; (b) dissolving selexipag, or a pharmaceutically acceptable salt thereof, in said vehicle, optionally along with other desired excipients; (c) mixing until a homogenous solution is formed; and (d) filling the resulting solution into a primary packaging container suitable for liquid formulations and sealing said container.

[0033] Another aspect of the present invention provides a process for preparing a stable liquid pharmaceutical formulation of selexipag as an aqueous suspension. Said process comprises the steps of: (a) providing an aqueous vehicle containing at least one pH adjusting agent or buffer system to achieve a pH below 7.5, preferably below 7.0; (b) incorporating other desired excipients such as suspending agents, wetting agents, and preservatives into the aqueous vehicle; (c) dispersing selexipag particles, optionally micronized, into the vehicle using suitable mixing or homogenization techniquesuntil a uniform suspension is formed; and (d) filling the resulting suspension into a primary packaging container suitable for liquid formulations and sealing said container.

[0034] A further aspect of the present invention provides a method for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in a patient in need thereof, comprising orally administering to said patient a therapeutically effective amount of a stable liquid pharmaceutical formulation of selexipag according to any of the embodiments described herein. Said administration may delay disease progression and reduce the risk of hospitalization for PAH.

[0035] In some embodiments of the present invention, without wishing to be bound by any theory, the liquid formulation of selexipag of the present invention is bioequivalent to the solid dosage form (UPTRAVI® tablet) approved in the market.BRIEF DESCRIPTION OF DRAWINGS

[0036] FIG. 1 describes process flow diagram for method of preparing stable liquid selexipag formulation for oral administration.

[0037] FIG. 2 describes process flow diagram for method of preparing stable liquid selexipag formulation for oral administration.

[0038] FIG. 3 describes process flow diagram for method of preparing stable liquid selexipag formulation for oral administration.

[0039] FIG. 4 describes process flow diagram for method of preparing stable liquid selexipag formulation for injectable or parenteral administration.

[0040] FIG. 5 describes process flow diagram for method of preparing stable liquid suspension formulation of selexipag for oral route of administration.DETAILED DESCRIPTION OF THE INVENTION

[0041] As used herein, the terms “selexipag” refers to selexipag free form or its pharmaceutically acceptable salts (such as selexipag calcium, magnesium, sodium, potassium, etc ), solvates, or hydrates thereof. In principle, any crystalline or amorphous form of selexipag may be used to manufacture inventive pharmaceutical compositions of the present invention. It is understood that if the active ingredient or a portion thereof is provided as a salt, the concentration of active ingredient salt may be higher than the concentration of active ingredient. It is also understood that the concentration of active ingredient salt may be selected to provide active ingredient concentration as described herein.

[0042] As used herein, the terms “about” or “approximately” or symbolrefer to within a range of ±20%, optionally within ±10%, optionally within ±5%, optionally within ±3%, optionally within ±2%, optionally within ±1%, optionally within ±0.5%, optionally within ±0.1%, or optionally within ±0.01% of the stated value, except where such number would be less than 0% or exceed 100% of a possible value. As used herein, reference to “approximately” or “about” a value or parameter includes (and describes) embodiments that are directed to that value or parameter. For example, description referring to “about X” includes description of “X”.

[0043] As used herein, the term “or” means “and / or.” The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0044] The term “purity” describes the proportion of selexipag or its salt in its original form, expressed as a percentage (%). Purity is determined by calculating the area percentage of the selexipag peak (main peak or parent peak) when analyzed using an appropriate chromatographic method such as HPLC. The terms "impurity" or "degradation impurity" or "selexipag -related impurity" used herein refer to any chemical compound that is undesired and generated from the degradation of selexipag during the formulation process or storage of the formulation. The concentrations of these compounds are reported as a percentage (%), representing the area percentage of the impurity peak relative to the selexipag peak when analyzed by a suitable chromatographic method such as HPLC. Such impurities may be reported individually or in total. The term "highest single impurity" or “maximum singleimpurity” or “maximum individual impurity” or “highest individual impurity” refers to any individual impurity with the highest percent peak area. The term “total impurities” refers to the combined amount of all impurities separated from selexipag peak when analyzed using HPLC and concentration of total impurities is reported in percentage (%) area. An alternative method for determining total impurities is to subtract the percentage of purity from 100.

[0045] The United States Pharmacopoeia (USP) defines stability as the ability of a product to retain its characteristics that it possessed during its manufacturing within specified limits throughout its period of storage and use. According to the ICH guidelines, pharmaceutical stability testing is defined as systematic experiments conducted on pharmaceutical products to understand and provide evidence how the quality of a drug product varies under the influence of a variety of environmental factors such as temperature, and to set a re-test period for the drug, or a shelf life for the drug product and recommend good storage conditions. In view of these, degradation products / impurities in a drug product are required to be evaluated and reported to the regulatory agencies. The term “stable” used herein refers to the invented composition that has less 10%, preferably less than 8%, preferably less than 5%, preferably less than 3%, preferably less than 2% of the total degradation impurities after extended period at room temperature (15-25°C), or at refrigerated condition, i.e. 2-8°C. In some embodiments, the invented composition that has less than 10%, preferably less than 8%, preferably less than 5%, preferably less than 3% of the total degradation impurities after shorter period at accelerated conditions such as about 25°C (for 2-8°C long term storage), about 40°C, about 60°C, about 70°C, or about 120°C (such as terminal sterilization for about 5 to 15 minutes) may also be considered stable.

[0046] As used herein, the term “shelf life” refers to the length of time that a formulation may be stored without becoming unfit for medical use. Examples of compositions which are unfit for medical use include, but are not limited to, compositions with unacceptably high impurity levels (such as more than 10% total impurities or less than 90% purity), and / or the presence of physical changes such as precipitation or discoloration.

[0047] As used herein, the term “step” is not particularly limiting. For example, each step as described herein may be a discrete step such that steps are performed sequentially upon completion of a preceding step. Alternatively, at least a portion of the method may be continuous, or the steps may be performed out of the order stated.

[0048] As used herein, the terms “micron”, or “microns” or “micrometer” or “pm” refer to one millionth of a meter, while “microgram” or “mcg” or “pg” refer to one millionth of a gram.

[0049] The present invention relates to stable liquid pharmaceutical compositions of selexipag or its pharmaceutically acceptable salt, wherein selexipag is present at a concentration of about 1 mcg / mL or more.

[0050] In one aspect, the pharmaceutical composition of the present invention comprises selexipag, wherein the concentration of selexipag in the composition is about 1 mcg / mL to about 2000 mcg / mL.

[0051] In another aspect, the pharmaceutical composition of the present invention comprises selexipag, wherein the concentration of selexipag in the composition is about 1 mg / mL to about 200 mg / mL.

[0052] In an embodiment, concentration of selexipag in the presented stable liquid formulation may be about 1 mcg / mL, about 10 mcg / mL, about 15 mcg / mL, about 30 mcg / mL, about 40 mcg / mL, about 50 mcg / mL, about 100 mcg / mL, about 150 mcg / mL, about 200 mcg / mL, 225 mcg / mL, about 300 mcg / mL, about 400 mcg / mL, about 500 mcg / mL, about 800 mcg / mL, about 1000 mcg / mL, about 1600 mcg / mL, or about 2000 mcg / mL. The concentration of selexipag may be from about 1 mcg / mL to about 2000 mcg / mL, from about 10 mcg / mL to about 1600 mcg / mL, from about 50 mcg / mL to about 800 mcg / mL, from about 100 mcg / mL to about 600 mg / mL, from about 200 mcg to about 600 mcg / mL, from about 350 mcg / mL to about 450 mcg / mL.

[0053] In an embodiment, the liquid pharmaceutical composition may be provided in a dosage form suitable for oral administration, including but not limited to a solution, suspension, or emulsion. The preferred liquid formulation of selexipag suitable for oral administration is the solution or suspension.

[0054] In another embodiment, the liquid pharmaceutical composition such as solution or suspension may be provided in a dosage form suitable for injectable route of administration.

[0055] Another aspect relates to methods of treatment for pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH by orally administering a therapeutic effective amount of liquid pharmaceutical formulation of selexipag.

[0056] As used herein, the term “ready-to-dilute” refers to formulation that does not require reconstitution prior to dilution. For example, a lyophilized product (such as UPTRAVI® for injection) is not ready-to-dilute since it requires reconstitution using diluent before final dilution. While ready-to-dilute product is liquid concentrate that can be further diluted using suitable diluents prior to administration.

[0057] As used herein, the term “ready-to-use” refers to formulation that does not require reconstitution or dilution prior to administration to patient. For example, a lyophilized product is not ready-to-use since it requires reconstitution using diluent before dilution or administration. Ready-to-dilute product is liquid concentrate that requires further dilution using suitable diluents prior to administration. While ready-to-use product can be administered to patient without need of reconstitution or dilution.

[0058] In an embodiment, the present invention provides a stable liquid pharmaceutical formulation suitable for oral administration, wherein the composition comprises (i) selexipag at a concentration of about 100 mcg / mL to about 2000 mcg / mL, and (ii) at least one solubilizer; and (iii) one or more optional pharmaceutically acceptable excipients.

[0059] In an embodiment of the present invention, the stable liquid formulation of selexipag comprises selexipag at concentration from about 20 mcg / mL to about 1600 mcg / mL.

[0060] In an embodiment of the present invention, the stable liquid formulation of selexipag comprises selexipag at concentration from about 10 mg / mL to about 100 mg / mL.

[0061] In an embodiment of the present invention, the stable liquid formulation of selexipag is provided as solution containing at least one non-aqueous vehicle or solvent.

[0062] In an embodiment of the present invention, the stable liquid formulation of selexipag is provided as solution containing at least one pH adjusting and / or buffering agent.

[0063] In an embodiment of the present invention, the stable liquid formulation of selexipag is provided as suspension containing at least water as vehicle.

[0064] In an embodiment of the present invention, the stable liquid formulation of selexipag is provided as suspension containing at least one pH adjusting and / or buffering agent.

[0065] In an embodiment of the present invention, the stable liquid formulation of selexipag comprises one or more pharmaceutically acceptable excipients selected from group comprising vehicles, preservatives, sweeteners, flavors, pH adjusting agents, buffering agents, viscosity adjusting agents, antioxidants, tonicity adjusting agents, chelating agents, stabilizers, complexing agents, crystallization inhibitors, suspending agents, surfactants, anti-foaming agents, dispersing agents, wetting agents, and combinations thereof.

[0066] In an embodiment, the present invention provides a ready -to-use stable liquid pharmaceutical formulation suitable for oral route of administration without need for reconstitution or dilution.

[0067] In an embodiment, the present invention provides a ready -to-use stable liquid pharmaceutical formulation suitable for injectable route of administration without need for reconstitution or dilution.

[0068] In an embodiment, the present invention provides a stable liquid pharmaceutical formulation suitable for oral administration, wherein the composition comprises (i) selexipag at a concentration of about 100 mcg / mL to about 1600 mcg / mL; (ii) at least one vehicle selected from polyethylene glycol, propylene glycol, water, and combination thereof; and (iii) one or more optional pharmaceutically acceptable excipients.

[0069] In an embodiment, the present invention provides a stable liquid pharmaceutical formulation suitable for oral administration, wherein the composition comprises (i) selexipag at a concentration of about 100 mcg / mL to about 1600 mcg / mL; (ii) at least one vehicle selected from group comprising polyethylene glycol, propylene glycol, glycerin, water, and combination thereof; (iii) at least one pH adjusting agent and / or buffering agent; and (vi) one or more optional pharmaceutically acceptable excipients.

[0070] In an embodiment, the present invention provides a ready-to-dilute stable liquid pharmaceutical formulation suitable for injectable route of administration, wherein the composition comprises (i) selexipag at a concentration of about 100 mcg / mL to about 1600 mcg / mL; (ii) at least one solubilizer and / or complexing agent; and (iii) one or more optional pharmaceutically acceptable excipients.

[0071] In an embodiment, the present invention provides a stable, ready-to-dilute, multiple dose liquid pharmaceutical formulation suitable for injectable route of administration, wherein the composition comprises (i) selexipag at a concentration of about 200 mcg / mL to about 400 mcg / mL; (ii) at least one solubilizer; (iii) at least one preservative; and (iii) one or more optional pharmaceutically acceptable excipients.

[0072] In an embodiment, the present invention provides a stable, ready-to-dilute, multiple dose liquid pharmaceutical formulation suitable for injectable route of administration, wherein the composition comprises (i) selexipag at a concentration of about 225 mcg / mL; (ii) at least one solubilizer; (iii) at least one preservative; and (iii) one or more optional pharmaceutically acceptable excipients.

[0073] In an embodiment, the present invention provides a stable, ready-to-use liquid pharmaceutical formulation suitable for injectable route of administration, wherein the composition comprises (i) selexipag at a concentration of about 2 mcg / mL to about 20 mcg / mL; (ii) at least one solubilizer; and (iii) one or more optional pharmaceutically acceptable excipients.

[0074] In an embodiment, the present invention provides a stable, ready-to-use liquid pharmaceutical formulation suitable for injectable route of administration, wherein the composition comprises (i) selexipag at a concentration of about 15 mcg / mL; (ii) at least one solubilizer; and (iii) one or more optional pharmaceutically acceptable excipients.

[0075] In some embodiments of the present invention, the liquid formulation of selexipag comprises one or more vehicle(s). As used herein, the term "vehicle" refers to a pharmaceutically acceptable medium used as a carrier for delivering an active pharmaceutical ingredient. In certain embodiments, the vehicle is a liquid used to dissolve, suspend, or dilute selexipag or a pharmaceutically acceptable salt thereof. The vehicle may comprise a single component or a mixture of components. For example, in one embodiment, the vehicle is water, wherein the selexipag is formulated as a suspension. In another embodiment, the vehicle is a non-aqueous solvent, such as polyethylene glycol, wherein the selexipag is formulated as a solution. In an embodiment of the present invention, vehicles are added in sufficient quantity (quantum satis or q.s.) to achieve the target concentration of the liquid formulation of selexipag, after accounting for the amount of all other ingredients.

[0076] In some embodiments of the present invention, the liquid formulation of selexipag comprises one or more solubilizer(s). As used herein, the term "solubilizer" or "solvent" refers to a pharmaceutically acceptable excipient incorporated into the formulation to increase the solubility of selexipag or a pharmaceutically acceptable salt thereof within the vehicle to a desired concentration. In some embodiments, a component may function as both a vehicle and a solubilizer; for example, polyethylene glycol may serve as the primary medium and may also dissolve the selexipag. In other embodiments, a solubilizer is an agent distinct from the primary vehicle. For instance, where the solubility of selexipag in an aqueous vehicle is insufficient, a solubilizer, such as a co-solvent like polyethylene glycol or a surfactant, may be added to achieve the target concentration. Examples of solubilizer include, without limitation surfactant, hydrophilic polymer, ethanol, polyhydric alcohol, polyethylene glycol, carbohydrate, glycerin, propylene glycol, polyethylene glycol (or PEG such as PEG 200, PEG 300, PEG 400, PEG 600, or PEG 1000), polysorbate (or PS such as PS 20, PS 40, PS60 or PS 80), polyvinylpyrrolidone (PVP, such as PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, or PVP KI 20), sodium lauryl sulfate, copovidone, pol oxamer, fructose, sucrose, sorbitol, etc. In some embodiments, the concentration of solubilizer may range from about 0.001% to about 99.99% depending on function, for example, surfactant may be used at very low concentrations such as 0.001% to about 5%, while polyethylene glycol may require higher concentrations when used with water such as from about 5% to about 99.99% or up to make up the batch size.

[0077] In one aspect of the invention, the formulation is stable for at least 1 month, preferably for at least 3 months, preferably for at least 6 months, preferably for at least 9 months, preferably for at least 12 months, preferably for at least 15 months, preferably for at least 18 months, preferably for at least 24 months, preferably for at least 30 months at 2-8°C.

[0078] In another aspect of the invention, the formulation is stable for at least 1 month, preferably for at least 3 months, preferably for at least 6 months, preferably for at least 9 months, preferably for at least 12 months, preferably for at least 15 months, preferably for at least 18 months, preferably for at least 24 months, preferably for at least 30 months at room temperature (about 15 - 25°C).

[0079] In some embodiments of the present invention, the liquid pharmaceutical composition of the present invention comprises one or more tonicity adjusting agent. As used herein, the term “tonicity adjusting agent” refers to any ingredient or combination of ingredients added to the pharmaceutical formulation to adjust or contributing to its osmotic pressure, thereby ensuring that the formulation is isotonic or near-isotonic with physiological fluids, such as nasal mucosa, when administered intranasally, or to a soft tissue or muscle when administered by intramuscular route, or into the blood when administered intravenously. Tonicity adjusting agents contribute to patient comfort, prevent irritation, and help maintain the stability and efficacy of the formulation upon administration. Nonlimiting examples of tonicity adjusting agents that may be used in the pharmaceutical compositions of the present invention include alanine, arginine, betaine, boric acid, calcium chloride (CaCk), calcium lactate, dextran, dextrose, fructose, glycerin, glycine, glucose, histidine, hydroxyethyl starch, lactose, lysine, magnesium chloride, magnesium sulfate (MgSCE), maltose, mannitol, polyethylene glycol (PEG), potassium chloride (KC1), potassium citrate, proline, propylene glycol, raffinose, ribose, sodium acetate, sodium benzoate, sodium bicarbonate (NaHCOs), sodium citrate, sodium chloride (NaCl), sodium gluconate, sodium lactate, sodium phosphate (NaHzPCh or Na2HPO4), sodium sulfate (Na2SC>4), sodium tartrate, sodium thiosulfate (Na2S20s), sorbitol, sucrose, taurine, trehalose,tromethamine (Tris), xylitol, etc., as well as mixtures thereof. In some embodiments, the concentration of tonicity adjusting agents ranges from about 0.1% to about 10%, from about 0.2% to about 8%, from about 0.5% to about 5% by weight based on the total composition, with the precise amount selected to achieve the desired osmolality, for example, from about 100 mOsmol / Kg to about 1000 mOsmol / Kg, preferably from about 250 mOsmol / kg to about 350 mOsmol / kg. The specific selection, combination, and concentration of tonicity adjusting agents is tailored according to the overall composition and intended route of administration to ensure optimal therapeutic performance and patient tolerability.

[0080] In some embodiments, pharmaceutically acceptable excipients for stable liquid formulation of selexipag suitable for oral administration includes, without limitation, vehicles, preservatives, sweeteners, flavors, pH adjusting agents, buffering agents, viscosity adjusting agents, antioxidants, tonicity adjusting agents, chelating agents, stabilizers, complexing agents, crystallization inhibitors, suspending agents, surfactants, anti-foaming agents, dispersing agents, wetting agents, and combinations thereof.

[0081] According to some aspects, the liquid pharmaceutical composition of the present invention comprises one or more complexing agent(s). The term “complexing agent,” as used herein, refers to a compound or mixture of compounds that interacts with an active pharmaceutical ingredient to form a stable complex, thereby enhancing solubility, stability, palatability (taste masking) or bioavailability within the formulation. In the context of selexipag liquid pharmaceutical compositions, suitable complexing agents may include, but are not limited to, Cyclodextrins (such as a-cyclodextrin, 0-cyclodextrin, y-cyclodextrin, and their derivatives like hydroxypropyl-0-cyclodextrin, sulfobutyl ether-0-cyclodextrin), ethylenediaminetetraacetic acid (EDTA), citric acid, tartaric acid, or other pharmaceutically acceptable agents capable of forming inclusion or coordination complexes. The concentration of complexing agents in compositions of present invention typically ranges from about 0.01% to about 70% by weight of the total formulation, optionally from about 1% to about 40%, optionally from about 1% to about 20%, depending on the nature and binding affinity of the selected agent, and the desired solubility and / or stability and / or taste masking properties. In some embodiments of the present invention, the complexing agent may be used in a mole ratio from about 1 : 1 to about 15:1 (complexing agent: selexipag), preferably from about 1:1 to about 5:1, optionally from about 1:1 to about 2:1, optionally about 1 : 1. In some other embodiments of the present invention, the mole ratioof complexing agent: selexipag is <1:1, for example, about 0.5:1 to about 1:1, about 0.8:1 to about 1:1. In some embodiments of the present invention, when complexing agent is used, selexipag is used as free base or its poorly soluble salt to achieve concentration higher than saturated concentration in absence of complexing agent. In some embodiments, primary purpose of complexation is to mask the taste or improve solubility or both. In some embodiments, salts with higher aqueous solubility may be used with complexing agent to achieve the said benefits of the complexing agents.

[0082] In some embodiments, the stable liquid formulation of selexipag is preservative-free.

[0083] In some other embodiments, the stable liquid formulation of selexipag is sterile.

[0084] In an embodiment, the liquid formulation of selexipag may contain suitable surfactants such as ionic or non-ionic surface-active agents. Suitable ionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include potassium, sodium, ammonium salts of long chain alkyl sulfonates, and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate; quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene. In an embodiment, the concentration of ionic surfactant ranges from about 0.01% to 3%, based on the total weight of the composition.

[0085] Suitable nonionic surfactants optionally used include, but are not limited to, glycol stearates such as ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, polyethylene glycol dilaurate, polyethylene glycol monolaurate, polysorbates, polyoxyethylene octylphenylether, polyethylene glycol cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, stearoyl monoisopropanolamide, polyoxyethylene hydrogenated tallow amide, polyoxyl-ethylated castor oils (CREMOPHOR®), polyoxyethylene esters of 12-hydroxy stearic acid (SOLUTOL®) and PEGylated glycerides (LABRASOL®). In another embodiment, the concentration of non-ionic surfactant ranges from about 0.02% to 2%, based on the total weight of the composition. In another embodiment, polysorbate is the non-ionic surfactant at a concentration of less than 7% (w / w) of the total composition, less than 6% (w / w) of the total composition, less than 5% (w / w) of the total composition,less than 4% (w / w) of the total composition, less than 3% (w / w) of the total composition, less than 2% (w / w) of the total composition, less than 1% (w / w) of the total composition.

[0086] A polyhydric alcohol, as referred to herein, is a compound with more than one hydroxyl group. Non-limiting examples of polyhydric alcohol that can be used are glycerin, propylene glycol, polyethylene glycol, sucralose, sorbitol, xylitol, dextrose, and mannitol. In some embodiments, the concentration of polyhydric alcohol ranges from about 0.1% to 10%, based on the total weight of the composition.

[0087] According to some aspects, the liquid pharmaceutical composition of the present invention comprises one or more anti-foaming agent(s). As used herein, the term “anti-foaming agent” or “defoamers” refers to ingredients suitable to be used in the formulation of the present invention that disrupt the stability of the foam or prevent the foaming by destabilizing the thin liquid films or lamellae that form the bubble walls, causing them to rupture and collapse. Non-limiting examples of antifoaming agents are simethicone, polydimethylsiloxane, organomodified silicones, mineral oil, vegetable oil, polypropylene glycol, fatty alcohols, aliphatic esters, triglycerides or combination thereof. In an embodiment of the present invention, the concentration of anti-foaming agent is from about 0.001%w / v to about 5%w / v, optionally from about 0.001%w / v to about l%w / v, optionally from about 0.01%w / v to about 0.5%w / v.

[0088] According to some aspects, the liquid pharmaceutical composition of the present invention comprises one or more dispersing agent(s). As used herein, the term “dispersing agent” refers to any substance that facilitates the uniform distribution of solid particles within a liquid medium, thereby preventing aggregation or clumping and ensuring homogeneity of the formulation of the present invention. Dispersing agents improve the stability and consistency of suspensions by enhancing the separation of individual particles and maintaining their even distribution throughout storage and dosing. Non-limiting examples of dispersing agents include polysorbates (PS, such as PS 20, PS 40, PS 60, PS 80), lecithin, polyvinylpyrrolidone (PVP, such as PVP K12, PVP K30, PVP K90), poloxamers, sodium lauryl sulfate, sodium citrate, sodium carboxymethyl cellulose, and phospholipids, as well as certain surfactants and amphiphilic polymers. In some embodiments of the present invention, the concentration of dispersing agent ranges from about 0.01% to about 5%, preferably from about 0.05% to about 2%.

[0089] According to some aspects, the liquid pharmaceutical composition of the present invention comprises one or more wetting agent(s). As used herein, the term “wetting agent” refers to any substance that facilitates the dispersion and penetration of solid particles by reducing the interfacial tension between the solid and the liquid medium in a formulation. Wetting agents play a crucial role in enhancing the ability of the liquid to spread across the surface of solids, thereby improving uniformity and consistency in pharmaceutical suspensions and other liquid formulations. Non-limiting examples of wetting agents suitable for use in the present invention include, but are not limited to, polysorbates (such as polysorbate 20, Polysorbate 40, Polysorbate 60, or Polysorbate 80), sodium lauryl sulfate, poloxamers, lecithin, polyoxyethylene sorbitan monolaurate, polyvinylpyrrolidone (PVP), sorbitan esters, cetyl alcohol, stearyl alcohol, glycerol monostearate, polyethylene glycol (such as PEG 200, 300, 400, 600, or 1000), and sodium dioctyl sulfosuccinate. In some embodiments of the present invention, the concentration of wetting agent ranges from about 0.01% to about 5% based on the total weight of the composition, preferably from about 0.05% to about 2%, and more preferably from about 0.1% to about 1%.

[0090] The pharmaceutical composition of the present invention may contain a “stability enhancing agent” or “stabilizer”. The terms “stability enhancing agent” or “stabilizer” are used herein to inhibit, prevent, slow down, or reduce the degradation of selexipag. More specifically, stability-enhancing agents include amino acids such as alanine, glycine, lactic acid, glutamate, sodium glutamate, L-arginine, lysine, L-cysteine or methionine; sodium chloride or sodium sulfate salts; ethylenediaminetetraacetic acid (EDTA), metal ions such as zinc, magnesium and calcium or mixtures thereof; natural or synthetic gums, cellulosic derivatives such as carboxy methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, hydroxyl propyl methylcellulose, methyl cellulose, polyanionic cellulose; cyclodextrins; sugars; sugar alcohols; monosaccharides, disaccharides or polysaccharides or combinations thereof. The concentration of the stabilizer ranges from 0.001% to 20%, based on the total weight of the composition.

[0091] According to some aspects, the liquid pharmaceutical composition of the present invention comprises one or more preservative(s). The term “preservative” used herein refers to any ingredient or mixture or combination of ingredients added to prevent or inhibit the growth of microorganisms, thereby ensuring the safety and shelf-life of the product. Preservatives are especially important in multi-dose preparations, where repeated access can introduce contaminants, and their inclusion helpsmaintain the sterility and integrity of the formulation throughout its intended use. In an embodiment, the pharmaceutical composition of the liquid formulation of selexipag comprises one or more preservative(s) selected from the group comprising of benzoic acid and the sodium or potassium salts thereof, ethanol, isopropanol, methanol, butyl alcohol, benzalkonium chloride, benzyl alcohol, benzethonium chloride, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, propylparaben sodium, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol, or combinations thereof.

[0092] In some embodiments of the present invention, the concentration of preservatives ranges from 0.001% to about 10%, preferably from about 0.01% to about 5%, preferably from about 0.01% about 2%, preferably from about 0.01% to about 1%, preferably from about 0.01% to about 0.5% based on the total weight of the composition.

[0093] In some other embodiments of the present invention, the concentration of preservatives ranges from 0.1% to about 10%, preferably from about 0.1% to about 5%, preferably from about 0.1% about 2%, preferably from about 0.1% to about 1%, preferably from about 0.1% to about 0.5% based on the total weight of the composition.

[0094] In some embodiments, liquid formulation of the present invention may contain an ingredient or a group of ingredients at concentration that is sufficient to prevent microbial growth by generating higher osmotic pressure. Non-limiting examples for such ingredients are sugars (sorbitol, mannitol, xylitol, dextrose, sucrose, lactose, etc.) at concentration from about 5% to about 90%, preferably from about 10% to about 70%, preferably from about 40%; and salts (such as sodium chloride, potassium chloride, etc.) at concentration from about 0.5% to about 10%, preferably from about 1% to about 5%. In some other embodiments, selexipag or its pharmaceutically acceptable salt may be present at a concentration that prevents microbial growth and act as self-preservative and it is still within the scope of the present invention. In yet other embodiments of the present invention, non-aqueous solvent used as vehicle, such as polyethylene glycol, propylene glycol, glycerin, ethanol or combination thereof at quantity enough (for example from about 5 - 99%, preferably from about 50 - 99%, preferably more than about 50% of the total weight of the composition) preventing microbial growth acting as preservative and it is still within the scope of the invention.The term “sweetening agents” refers toboth bulk (caloric) and intense (non-caloric) sweeteners, which impart a sweet taste to the preparation. Examples of sweeteners include acesulfame, alitame, aspartame, cyclamate, saccharin, sucralose, acesulfame, potassium or sodium cyclamate, and mixtures thereof. In particular, the sweetening agent is sucralose. The concentration of sweeteners range from 0.001% to 5%, based on the total weight of the composition.

[0095] The term “flavoring agent,” as used herein, refers to an agent or a mixture of agents that adds flavor to a mixture. A flavoring agent is selected from the group consisting of a natural flavor, an artificial flavor, and mixtures thereof. Flavoring agents include, but are not limited to, mint, peppermint, cola, apple, vanilla, orange, peach, apricot, raspberry, cherry, honey, lemon, coconut, pineapple, strawberry banana, mixed berry, mixed red fruit, and cream flavors and mixture thereof. In particular, the flavoring agent is strawberry flavor or cherry flavor. The concentration of flavoring agent ranges from 0.001% to 5%, based on total weight of the composition.

[0096] According to some aspects, the liquid pharmaceutical composition comprises one or more pH adjusting agent(s). As used herein, the term “pH adjusting agent” refers to a component or combination of components sufficient to adjust a pharmaceutical composition's pH. According to some aspects, the pH adjusting agent is sufficient to raise or lower the pharmaceutical composition's initial pH to a pharmaceutically acceptable range (i.e., not toxic or producing unacceptable side effects). Additionally, or alternatively, the pH adjusting agent may be sufficient to maintain the pharmaceutical composition's pH in a pharmaceutically acceptable range over a certain period of shelflife. Example of pH adjusting agents includes without limitation, acetic acid, adipic acid, ammonia, ascorbic acid, barium hydroxide, benzoic acid, calcium hydroxide, carbonic acid, cesium hydroxide, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrochloric acid, isothionic acid, lactic acid, lithium hydroxide, malic acid, maleic acid, mandelic acid, methane sulfonic acid, monopotassium phosphate, monosodium phosphate, mucic acid, nitric acid, oxalic acid, p-toluenesulfonic acid, pantothenic acid, phosphoric acid, phthalic acid, potassium hydroxide, pyrophosphoric acid, rubidium hydroxide, sodium hydroxide, strontium hydroxide, succinic acid, sulfuric acid, tartaric acid., or combination thereof. In one example, the pharmaceutical composition comprises hydrochloric acid, sodium hydroxide, or a combination thereof.

[0097] In some other embodiments of the present invention, the concentration of pH adjusting agent may depends on the pH of formulation and quantity to be used is generally considered as “quantity sufficient (q.s.) to target pH”.

[0098] According to some aspects, each of the pH adjusting agents may together or independently have a concentration in the range from about 0.0001 N to about 20 N, preferably from about 0.01 N to about 1 N.

[0099] In some embodiments of the present invention, without wishing to be bound by any theory, the presence of glycerin as a co-solvent may be detrimental to the stability of selexipag. Therefore, the stable formulations of the present invention may essentially free from glycerin. As used herein, 'essentially free from' means that glycerin is not intentionally added as a co-solvent or vehicle, and is present, if at all, only in amounts that do not materially affect the stability of the formulation. In a preferred embodiment, the formulation contains less than 10%v / v of glycerin, more preferably less than 5% v / v, more preferably less than 2% v / v, more preferably less than 1% v / v of glycerin, and most preferably is free from glycerin.

[0100] The term “buffering agent”, also known as buffer system, refers to ingredients that helps maintaining the pH of formulation. Examples of buffering agents include, without limitation, salts of citric acid, tartaric acid, ascorbic acid, phosphoric acid, acetic acid, carbonic acid, phthalic acid, succinic acid, glutamic acid, benzoic acid, gluconic acid, formic acid, fumaric acid, lactic acid, isothionic acid, malic acid, maleic acid, mandelic acid, nitric acid, mucic acid, oxalic acid, pantothenic acid, p-toluenesulfonic acid, methane sulfonic acid, sulfuric acid, hydrochloric acid, or combination thereof. Additionally, pharmaceutically acceptable amino acids such as methionine, cysteine, glycine, etc. can also be used as buffering agent. The concentration of buffering agent ranges from 0.0001% to 10%, based on total weight of the composition.

[0101] In some embodiments of the present invention, the liquid pharmaceutical composition of the present invention comprises one or more antioxidants. The term “antioxidant” refers to agents that protect any ingredients of the composition from oxidative degradation. Examples include, without limitation, methionine, sodium / potassium bisulfite, sodium metabisulfite, potassium metabisulfite, sodium ascorbate, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, cysteine, glutathione, monothioglycerol, propyl gallate, sodium / potassium sulfite, tocopherol (such as alpha-tocopherol) or its salt and esters (such as D-alpha-tocopheryl polyethylene glycol 1000 succinate), or combination thereof.

[0102] In some embodiments of the present invention, the concentration of antioxidants ranges from about 0.001% to about 5%, optionally from about 0.01% to about 2%, optionally from about 0.01% to about 1%, optionally from about 0.01% to about 0.5%, optionally from about 0.01% to about 0.1% based on total weight of the composition.

[0103] In some embodiments of the present invention, the concentration of antioxidants ranges from about 0.05% to about 2%, optionally from about 0.1% to about 2%, optionally from about 0.1% to about 2%, optionally from about 0.1% to about 1%, optionally from about 0.1% to about 0.5% based on total weight of the composition.

[0104] According to some aspects, the liquid pharmaceutical composition of the present invention comprises one or more crystallization inhibitor(s). As used herein, the term “crystallization inhibitors” refers to ingredients that prevent or reduce the formation and / or growth of crystals and / or amorphous particles of selexipag or its pharmaceutically acceptable salt within a liquid formulation, thereby stabilizing the active ingredient in a supersaturated or amorphous state and improving the clarity and homogeneity of the final product. Suitable crystallization inhibitors include, without limitation, hydrophilic polymers such as polyvinylpyrrolidone (PVP, including PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, or PVP K120), polyethylene glycol (PEG 200, PEG 300, PEG 400, PEG 600, or PEG 1000), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, poloxamers, povidone, copovidone, cyclodextrins, and polysorbates (such as Polysorbate 20, Polysorbate 40, Polysorbate 60, or Polysorbate 80). In some embodiments of the present invention, the concentration of crystallization inhibitor ranges from about 0.01% to about 10% based on the total weight of the composition.

[0105] The term “chelating agent” refers to compounds that helps to stabilize the formulation by means of chelating undesired compounds or elements or ions. Suitable chelating agents which may be used in the present invention include, but not limited to edetate di sodium (EDTA); edetate trisodium, edetate tetrasodium, calcium edetate disodium; and diethylene amine pentaacetate or derivatives thereof, citric acid, tartaric acid. In certain preferable embodiments, the formulations comprise disodium edetate. The concentration of chelating agents ranges from 0.001% to 5%, based on total weight of the composition.

[0106] According to some aspects, the liquid pharmaceutical composition of the present invention comprises one or more suspending agent(s). As used herein, the term “suspending agent” refers to a substance that helps keep the solid particle dispersed and prevent or slow down the settling to the bottom of the liquid. Suspending agents suitable for use in the liquid oral suspensions of the present invention include, cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone (PVP, such as PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, or PVP K120), alginate, guar gum, xanthan gum, carrageenan, acacia gum, tragacanth, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene and polyoxypropylene ether.

[0107] In an embodiment of the present invention, the concentration of suspending agent ranges from about 0.01% to 5%, preferably from about 0.05% to about 5%, preferably from about 0.1% to about 4%, preferably from about 0.1% to about 3%, preferably from about 0.1% to about 2% based on the total weight of the composition.

[0108] In an embodiment, the stable liquid formulation of selexipag is filled into a suitable pharmaceutically acceptable container selected from the group consisting of bottles, bags, sprayers, ampules (plastic or glass), blisters, sachets, syringes, cartridges, and vials.

[0109] In another embodiment, the stable liquid formulation of selexipag is filled into a pharmaceutically acceptable container suitable for single or multiple-dose delivery for oral, nasal or injectable administration.

[0110] In an embodiment, the stable liquid formulation of selexipag is filled into a suitable pharmaceutically acceptable container that reasonably protects the composition from air and light that otherwise may degrade selexipag or any vehicle or excipient within the container.

[0111] In an embodiment, the stable liquid formulation of selexipag is administered via oral route to the patient as a fluid stream, droplet(s), spray, or combination thereof.

[0112] In an embodiment, the stable liquid formulation of selexipag is administered to patients using syringe and delivery tube, for example nasogastric tube, gastrostomy tube, jejunostomy tube, or gastrojejunal tube.

[0113] In an embodiment, the pharmaceutically acceptable container for the liquid selexipag containers may be a bottle, wherein the bottle is selected from a group consisting of glass bottles orplastic bottles, wherein glass bottle is selected from a group consisting of Type I, II, III, soda lime or borosilicate glass bottles, wherein the glass bottle may be amber color glass bottle or clear glass bottle.

[0114] In another embodiment, the pharmaceutically acceptable container for the stable liquid selexipag formulations may be a bottle, wherein the bottle is selected from a group consisting of high-density polyethylene (HDPE) bottle, polyethylene terephthalate (PET) and polypropylene (PP), wherein the plastic bottle may be without limitation, amber color, white color, opaque or translucent plastic bottle.

[0115] In an embodiment, the ready-to-use, stable, liquid formulation of selexipag is packaged in flexible polymeric bag contained in secondary outer packaging.

[0116] In an embodiment, the glass and HDPE bottles for the liquid selexipag formulations may be available in range from about 2, 3, 5, 10, 30, 60, 100, 120, 150, 250 or up to 500 mL fill volumes.

[0117] In another embodiment, the pharmaceutical composition of the present application may be packed in a kit comprising a bottle with a child-resistant cap, adapter, and dosing syringe.

[0118] In another embodiment, the liquid selexipag formulations may be packaged in a metered device that protects the composition from air, light, and microbial contamination during storage and use.

[0119] In an embodiment, the stable liquid formulation of selexipag for oral administration is prepared by solubilizing selexipag in solubilizer and one or more pharmaceutical ingredients, optionally filtering the formulation, filling the formulation into a primary packaging container, and closing the container using closure with optional inert gas overlay. In some embodiments, the nitrogen can be overlayed before closing the container.

[0120] In an embodiment, the stable liquid formulation of selexipag for injection route of administration is prepared by solubilizing selexipag in solubilizer and one or more pharmaceutical ingredients, sterile filtering the formulation using 0.2p filter, filling the formulation into a primary packaging container, and closing the container using closure. In some embodiments, the nitrogen can be overlayed before closing the container.

[0121] In an embodiment, the stable liquid formulation of selexipag is prepared by suspending selexipag in oil or a mixture of oil and one or more pharmaceutical ingredients, filling formulated selexipag liquid into the primary packaging container, and closing the container.

[0122] In an embodiment, the present invention provides a liquid pharmaceutical formulation suitable for oral route of administration, wherein the composition comprises (i) selexipag; (ii) oil or a mixture of oil, and (iii) one or more optional pharmaceutically acceptable excipients.

[0123] The term “oil,” as used herein, is a liquid medium that may not be miscible with water to form a clear homogenous solution but may remain as a separate phase.

[0124] In an embodiment, oil used in a liquid formulation of selexipag is selected from the group of, without limitation, olive oil, almond oil, fish oil, avocado oil, sesame oil, canola oil, sunflower oil, castor oil, soybean oil, coconut oil, anise oil, apricot kernel oil, cinnamon oil, corn oil, cottonseed oil, rapeseed oil, mustard oil, palm oil, peanut oil, macadamia oil, beechnut oil, brazil nut oil, cashew oil, hazel nut oil, pecan oil, pine nut oil, pistachio oil, walnut oil, pumpkin seed oil, rice-bran oil, grapefruit seed oil, lemon oil, orange oil, bitter gourd oil, bottle gourd oil, buffalo gourd oil, butternut squash seed oil, edusi seed oil, watermelon seed oil, acai seed oil, black seed oil, blackcurrent seed oil, borage seed oil, evening primrose oil, flaxseed oil, amaranth oil, apricot oil, apple seed oil, argan oil, babassu oil, ben oil, borneo tallow nut oil, cape chestnut oil, citrus Sinensis flower oil, clove oil, coriander oil, eucalyptus oil, lanolin oil, mineral oil, nutmeg oil, peppermint oil, spearmint oil, vegetable oil, animal oil, hydrogenated vegetable oil, polyoxyl vegetable oil, apricot kernel oil PEG-6 esters, citrus sinensis flower oil, palm kernel oil glycerides (hydrogenated), corn oil mono- and di- glycerides (cl 8), hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, lanolin alcohol - mineral oil, lavender oil, light mineral oil, lime oil, natural oil, orange oil terpeneless, PEG-40 castor oil, PEG-60 hydrogenated castor oil, pine needle oil (pinus sylvestris), polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, sassafras oil, thyme oil, turpentine oil, hydrogenated vegetable oil glyceride, or combination thereof. The concentration of oil in the disclosed liquid formulation of selexipag ranges from about 30% to 99.99%, based on the total weight of the composition.

[0125] In another embodiment, oil used in a liquid formulation of selexipag is selected from the group of, without limitation, Miglyol® 818, Miglyol® 812, Miglyol® 840, Labrafac®, Captax® 385, Capmul®, Imwitor® 988, Imvitor® 948, oleic acid, linoleic acid, Maisine® 35-1, Capryol® 90, Maisine® CC, PeceolTM, other similar oils from different manufacturer, or combination thereof. The concentration of oil in the disclosed liquid formulation of selexipag ranges from about 30% to 99.9%, based on the total weight of the composition.

[0126] In some other embodiment, an oil may be mixed with water using a surfactant to form an emulsion, microemulsion, or nanoemulsion.

[0127] In an embodiment, an oil may be of natural or synthetic origin. In other embodiments, the oil may be hydrogenated or non-hydrogenated. In an embodiment, the oil may be extracted using the coldpress method, solvent extraction method, heat-aided extraction method, or another method.

[0128] The present invention is further illustrated by, but is by no means limited to, the following examples.

[0129] In some embodiments of the present invention, the pH of the selexipag liquid formulation of the present invention is between about 1 and about 7, optionally between about 2 and about 6.5, optionally between about 2 and about 6, optionally between about 2 and about 5.5, optionally between about 2 and about 5, optionally between about 3 and about 5, optionally between about 3 and about 6, optionally between 3 and about 6.5, optionally between about 4 and about 6.5, optionally between about 5 and 6.5, optionally between about 5.5 and 6.5, optionally between about 3.5 and about 6.5, optionally between about 3.5 and about 5.5, optionally about 2.5, optionally about 3, optionally about 3.5, optionally about 4.0, optionally about 4.5, or optionally about 5.0, optionally about 5.5, optionally about 6, optionally about 6.5, optionally less than about 7, optionally less than about 6.5, optionally less than about 5. In one example, pH of the formulation is from about 3 to about 5.

[0130] In some other embodiments of the present invention, the pH of the formulation is from about 7 to about 9, optionally from about 7 to about 8, optionally about 7, optionally about 7.5, optionally about 8.

[0131] In some embodiments, the selexipag liquid formulation of the present invention has water like viscosity such as about 5 cP to about 2000cP. Optionally from about lOcP to about 500cP, optionally about lOOcP, optionally about 200cP.

[0132] In some embodiments, the selexipag liquid formulation of the present invention has osmolality from about 100 mOsmol / kg to about 2000 mOsmol / kg, from about 200 mOsmol / Kg to about 1000 mOsmol / Kg, from about 250 mOsmol / Kg to about 800 mOsmol / Kg, from about 250 mOsmol / Kg to about 550 mOsmol / Kg, from about 250 mOsomol / Kg to about 350 mOsoml / Kg. In yet other embodiments, the osmolality of the selexipag liquid formulation is about 280 to 320 mOsmol / Kg. In one example, the osmolality of the selexipag liquid formulation is about 270 to about 330 mOsmol / Kg.

[0133] In some embodiments, the particle size distribution (PSD) of selexipag in pharmaceutical suspension formulation of the present invention comprises at least 10% of particles smaller than about 30 microns, and / or at least 50% of particles smaller than about 70 microns, and / or at least 90% of particles smaller than about 150 microns.

[0134] In some embodiments of the present invention, the particle size distribution (PSD) of selexipag in pharmaceutical suspension formulation of the present invention comprises at least 10% of particles smaller than about 10 microns, and / or at least 50% of particles smaller than about 50 microns, and / or at least 90% of particles smaller than about 100 microns.

[0135] In some embodiments of the present invention, the particle size distribution (PSD) of selexipag in pharmaceutical suspension formulation of the present invention comprises at least 10% of particles smaller than about 10 microns, and / or at least 50% of particles smaller than about 25 microns, and / or at least 90% of particles smaller than about 50 microns.

[0136] In some embodiments of the present invention, the particle size distribution (PSD) of selexipag in pharmaceutical suspension formulation of the present invention comprises at least 10% of particles smaller than about 2 microns, and / or at least 50% of particles smaller than about 5 microns, and / or at least 90% of particles smaller than about 10 microns.

[0137] In some embodiments of the present invention, the particle size of selexipag in suspension formulation comprises at least 90% of particles smaller than about 300 microns, preferably smaller than about 200 microns, more preferably smaller than about 100 microns, more preferably smaller than about 90 microns, more preferably smaller than about 80 microns, more preferably smaller than about 70 microns, more preferably smaller than about 60 microns, more preferably smaller than about 50 microns, more preferably smaller than about 45 microns, more preferably smaller than about 40 microns, more preferably smaller than about 35 microns, more preferably smaller than about 33 microns, more preferably smaller than about 30 microns, more preferably smaller than about 28 microns, more preferably smaller than about 25 microns, more preferably smaller than about 23 microns, more preferably smaller than about 20 microns, more preferably smaller than about 18 microns, more preferably smaller than about 16 microns, more preferably smaller than about 15 microns, more preferably smaller than about 14 microns, more preferably smaller than about 13 microns, more preferably smaller than about 12 microns, more preferably smaller than about 11 microns, more preferably smaller than about 10 microns, more preferably smaller than about 9microns, more preferably smaller than about 8 microns, more preferably smaller than about 7 microns, more preferably smaller than about 6 microns, or more preferably smaller than about 5 microns. In some other embodiments, the particle size of selexipag in suspension formulation comprises at least 90% of particles are within the range from about 5 microns to about 10 microns.

[0138] According to some aspects, the pharmaceutical composition of the present invention may have an initial total impurity concentration of no more than about 10%, more preferably no more than about 5%, more preferably no more than about 3%, more preferably no more than about 3.5%, more preferably no more than about 3%, more preferably no more than about 2.5%, more preferably no more than about 2%, more preferably no more than about 1.5%, more preferably no more than about 1%, and most preferably no more than about 0.5%.

[0139] According to some aspects, the pharmaceutical composition of the present invention may have a total impurity concentration after a certain period of shelf life of no more than about 15%, more preferably no more than about 10%, more preferably no more than about 8%, more preferably no more than about 5%, more preferably no more than about 3%, more preferably no more than about 2.5%, more preferably no more than about 2%, more preferably no more than about 1.5%, more preferably no more than about 1%, and most preferably no more than about 0.5%.

[0140] In one embodiment, the present invention relates to a liquid pharmaceutical composition comprising about 200mcg to about 1600 mcg of selexipag in a volume ranging from about 1 mb to about 20 mb. Following single-dose administration to healthy human subjects, this liquid composition could demonstrate bioequivalence to an oral reference tablet, as evidenced by a single-dose geometric mean Area Under the Curve from time zero to infinity (AUCo-co) and a geometric mean Maximum Plasma Concentration (Cmax). Bioequivalence is established when the 90% confidence interval for the ratio of geometric means for both AUCo-co and Cmax falls entirely within the range of about 80% to about 125%.

[0141] The following example illustrates the use of the liquid formulation of the present invention at an equivalent required dose; it is provided for demonstration purposes and is not intended to be restrictive.Dose volume of selexipag liquid formulation of the present invention Strength 0.2 mg 0.4 mg 0.6 mg 0.8 mg 1.0 mg 1.2 mg 1.4 mg 1.6 mg dose dose dose dose dose dose Dose dose 0.10 mg / mL 2 mL 4 mL 6 mL 8 mL 10 mL 12 mL 14 mL 16 mL 0.16 mg / mL 1.25 mL 2.5 mL 3.75 mL 5 mL 6.25 mL 7.5 mL 8.75 mL 10 mL 0.20 mg / mL 1 mL 2 mL 3 mL 4 mL 5 mL 6 mL 7 mL 8 mL 0.25 mg / mL 0.8 mL 1.6 mL 2.4 mL 3.2 mL 4 mL 4.8 mL 5.6 mL 6.4 mL 0.40 mg / mL 0.5 mL 1 mL 1.5 mL 2 mL 2.5 mL 3 mL 3.5 mL 4 mL 0.50 mg / mL 0.4 mL 0.8 mL 1.2 mL 1.6 mL 2 mL 2.4 mL 2.8 mL 3.2 mL 0.80 mg / mL 0.25 mL 0.5 mL 0.75 mL 1 mL 1.25 mL 1.5 mL 1.75 mL 2 mL 1.00 mg / mL 0.2 mL 0.4 mL 0.6 mL 0.8 mL 1 mL 1.2 mL 1.4 mL 1.6 mL 1.60 mg / mL 0.125 mL 0.25 mL 0.375 mL 0.5 mL 0.625 mL 0.75 mL 0.875 mL 1 mL 2.00 mg / mL 0.1 mL 0.2 mL 0.3 mL 0.4 mL 0.5 mL 0.6 mL 0.7 mL 0.8 mLWORKING EXAMPLES

[0142] The present invention is further illustrated by, but is by no means limited to, the following examples. It will be appreciated that where typical or preferred process conditions are given, other process conditions can also be used unless otherwise stated. Materials used in the examples set forth below were provided by commercial suppliers. It is preferred and recommended that ingredients, used in selexipag liquid formulations, comply with the compendial monograph such as USP, Ph. Eur., and / or JP, and ICH guidelines for residual process related impurities (elemental impurities and residual solvents).

[0143] Example 1 - 5 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 1. Required quantity of selexipag was dissolved in about 80% of the required quantity of, where applicable, polyethylene glycol 400 (PEG 400) or propylene glycol. Required quantity of glycerin was added and mixed to homogeneity. Volume of the batch was made to the batch size using PEG 400 or propylene glycol and optionally filtered to remove foreign particulates. The filteredsolution was filled in glass container, sealed using closure with nitrogen overlay. Stability test result for example 1-5 are provided in table 2.Table 1. Composition of example 1-5.Example No. (Quantity per mL)Ingredients1 2 3 4 5 Selexipag 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg Propylene Glycol — q.s. to 1 mL — 0.25 mL q.s. to 1 mL Glycerin — — 0.5 mL 0.25 mL — Polyethylene Glycol 400 q.s. to 1 mL — q.s. to 1 mL q.s. to 1 mL 0.5 mLTable 2. Stability test results for example 1-5.% Maximum Example No. Sample Details Visual Description %Purity Single %Total Impurity2-8°C / 3M Clear, colorless solution 99.7 0.34 0.3 RT / 3M Clear, colorless solution 99.7 0.30 0.3 1 RT / 1 IM Clear, colorless solution 90.1 2.94 9.940°C / 2M Clear, colorless solution 84.7 4.12 15.3 40°C / 3M Clear, colorless solution 76.6 7.62 23.4 2-8°C / 3M Clear, colorless solution 100.0 0.00 0.0 RT / 3M Clear, colorless solution 99.7 0.29 0.3 2 RT / 1 IM Clear, colorless solution 97.8 1.58 2.240°C / 2M Clear, colorless solution 96.5 2.44 3.5 40°C / 3M Clear, colorless solution 96.0 2.96 4.0 2-8°C / 2M Clear, colorless solution 99.4 0.58 0.6 3 RT / 1 IM Clear, colorless solution 63.3 29.82 36.740°C / 2M Clear, colorless solution 41.7 39.91 58.3 4 2-8°C / 3M Clear, colorless solution 99.3 0.56 0.7% Maximum Example No. Sample Details Visual Description %Purity Single %Total ImpurityRT / 3M Clear, colorless solution 93.8 4.28 6.2 40°C / 3M Clear, colorless solution 41.7 35.06 58.3 2-8°C / 2M Clear, colorless solution 99.7 0.27 0.3 2-8°C / 3M Clear, colorless solution 99.7 0.36 0.4 RT / 3M Clear, colorless solution 97.0 2.25 3.0 5RT / 11M Clear, colorless solution 82.6 9.34 17.4 40°C / 2M Clear, colorless solution 76.2 12.98 23.8 40°C / 3M Clear, colorless solution 67.8 18.10 32.3

[0144] Example 6 - 10 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 3. Required quantity of selexipag was dissolved in the required quantity of, where applicable, polyethylene glycol 400 (PEG 400) or propylene glycol. Required quantity of glycerin was added and mixed to homogeneity. Buffer solution was prepared by dissolving di-sodium hydrogen phosphate dihydrate and sodium dihydrogen phosphate monohydrate in required quantity of water in separate vessel and then added to vessel containing drug solution with mixing. Volume of the batch was made up to the batch size using water and optionally fdtered to remove foreign particulates. The filtered solution was filled in 2 mL USP type I amber glass vial and 10CC HDPE bottles and sealed using closure with nitrogen overlay. Stability test results for example 6-10 are provided in table 4. Table 3. Composition of example 6-10.Example No. (Quantity per mL) Ingredients6 7 8 9 10 Selexipag 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg Polyethylene glycol 400 0.8 mL 0.8 mL — 0.5 mL 0.5 mL Propylene glycol — — 0.8 mL — — Glycerin — — — 0.25 mL 0.25 mLExample No. (Quantity per mL) Ingredients6 7 8 9 10 Di-sodium hydrogen phosphate— 0.3 mg 0.3 mg — 0.38 mg dihydrateSodium dihydrogen phosphate— 0.06 mg 0.06 mg — 0.08 mg monohydratePurified water q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL q.s. to 1 mLTable 4. Stability test results for example 6-10.% MaximumExample % % Total Sample Details Visual Description Single PH No. Purity Impurities ImpurityRT / 3M Clear, colorless solution 99.7 0.15 0.3 7.6 RT / 6M, HDPE Bottle Clear, colorless solution 98.3 0.24 1.7 — 6 RT / 6M, Glass vial Clear, colorless solution 98.7 0.23 1.4 — RT / 1 IM, HDPE Bottle Clear, colorless solution 95.8 0.61 4.2 7.7 RT / 1 IM, Glass vial Clear, colorless solution 97.8 0.39 2.2 7.7 RT / 3M Clear, colorless solution 100.0 0.00 0.0 8.1 RT / 6M, HDPE Bottle Clear, colorless solution 98.9 0.36 1.1 — 7RT / 6M, Glass vial Clear, colorless solution 98.9 0.38 1.1 — RT / 1 IM, HDPE Bottle Clear, colorless solution 96.1 0.83 3.6 8.1 RT / 3M Clear, colorless solution 96.7 1.43 3.3 7.5 RT / 6M, HDPE Bottle Clear, colorless solution 93.1 3.30 6.9 — 8RT / 6M, Glass vial Clear, colorless solution 93.2 3.31 6.9 — RT / 1 IM, HDPE Bottle Clear, colorless solution 85.6 10.06 14.4 7.6 RT / 3M Clear, colorless solution 97.2 2.37 2.8 7.3 9RT / 6M, HDPE Bottle Clear, colorless solution 92.5 4.99 7.5 —% MaximumExample % % Total Sample Details Visual Description Single PH No. Purity Impurities ImpurityRT / 6M, Glass vial Clear, colorless solution 92.5 5.08 7.5 — RT / 1 IM, HDPE Bottle Clear, colorless solution 84.2 10.2 15.8 7.3 RT / 3M Clear, colorless solution 96.4 2.23 3.6 — 10 RT / 6M, HDPE Bottle Clear, colorless solution 90.8 3.86 9.2 — RT / 6M, Glass vial Clear, colorless solution 90.9 3.89 9.1 —

[0145] Example 11 - 14 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 5. Where applicable, required quantity of sucralose, methylparaben, propylparaben, strawberry flavor, polysorbate 80, and all-rac-alpha-tocopherol were added one-by-one in about 80% of the batch required quantity of polyethylene glycol 400 or propylene glycol and mixed until dissolved. Required quantity of selexipag was added and mixed until dissolved. Volume of the batch was made up to the batch size using PEG 400 or propylene glycol and optionally filtered to remove foreign particulate matters. The solution was filled into glass containers and sealed using closure with nitrogen overlay. Stability test results for example 11-14 are provided in table 6.Table 5. Composition of example 11-14.Example No. (Quantity per mL)Ingredients11 12 13 14 Selexipag 0.4 mg 0.4 mg 0.4 mg 0.4 mg Sucralose 5 mg 5 mg 5 mg 5 mg Methylparaben 2.5 mg 2.5 mg 2.5 mg 2.5 mg Propylparaben 0.25 mg 0.25 mg 0.25 mg 0.25 mg Strawberry flavor 1 mg 1 mg 1 mg 1 mg Polysorbate 80 0.5 mg 0.5 mg 0.5 mg 0.5 mg a-Tocopherol 1 mg — 1 mg —Example No. (Quantity per mb) Ingredients11 12 13 14 Polyethylene Glycol 400 q.s. to 1 mL q.s. to 1 mL — — Propylene Glycol — -- q.s. to 1 mL q.s. to 1 mLTable 6. Stability test results for example 11-14.% Maximum%Example No. Sample Details Visual Description Single %Total PurityImpurity2-8°C / 3M Clear, colorless solution 99.7 0.31 0.3 2-8°C / 6M Clear, colorless solution 99.6 0.27 0.4 11 RT / 3M Clear, colorless solution 99.9 0.13 0.1RT / 6M Clear, colorless solution 97.2 0.44 2.8 40°C / 3M Clear, colorless solution 92.1 1.90 7.9 2-8°C / 3M Clear, colorless solution 100.0 0.00 0.0 2-8°C / 6M Clear, colorless solution 99.7 0.13 0.3 12 RT / 3M Clear, colorless solution 99.8 0.23 0.2RT / 6M Clear, colorless solution 94.9 0.87 5.1 40°C / 3M Clear, colorless solution 79.0 5.55 21.0 2-8°C / 3M Clear, colorless solution 100.0 0.00 0.0 2-8°C / 6M Clear, colorless solution 99.8 0.11 0.2 13 RT / 3M Clear, colorless solution 99.8 0.25 0.3RT / 6M Clear, colorless solution 99.1 0.61 0.9 40°C / 3M Clear, colorless solution 96.7 2.40 3.3 2-8°C / 3M Clear, colorless solution 100.0 0.00 0.0 2-8°C / 6M Clear, colorless solution 99.8 0.11 0.2 14RT / 3M Clear, colorless solution 99.8 0.25 0.3 RT / 6M Clear, colorless solution 99.1 0.59 1.0% Maximum%Example No. Sample Details Visual Description Single %Total PurityImpurity40°C / 3M Clear, colorless solution 97.1 2.18 3.0

[0146] Example 15 - 22 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 7. Where applicable, required quantity of sucralose, methylparaben, propylparaben, cherry flavor, lactic acid, and all-racemic-alpha-tocopherol were added, one-by-one, in polyethylene glycol 400 or about 80% of the batch required quantity of propylene glycol and mixed until dissolved. Required quantity of selexipag was added and mixed until dissolved. Volume of the batch was made up to the batch size using propylene glycol and optionally filtered to remove foreign particulate matters. The solution was filled into glass containers and sealed using closure with nitrogen overlay. Stability test results for example 15-22 are provided in table 8.Table 7. Composition of example 15-22.Example No. (Quantity per mL)Ingredients15 16 17 18 19 20 21 22 Selexipag 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg Sucralose 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg Methylparaben 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg Propylparaben 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg Cherry flavor 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg Lactic acid -- 0.5 mg 1 mg — 0.5 mg 1 mg 2 mg 1 mg a-Tocopherol -- -- — — -- — — 1 mg PEG 400 -- — — 0.5 mL 0.5 mL 0.5 mL 0.5 mL 0.5 mL Propylene q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 Glycol mL mL mL mL mL mL mL mLTable 8. Stability test results for example 15-22.%Maximum Example Sample %Total Visual Description %Purity SingleNo. Details Impurities ImpurityInitial Clear, colorless solution 99.9 0.09 0.09 RT / 3M Clear, colorless solution 99.4 0.45 0.64 154O°C / 1M Clear, colorless solution 98.4 1.17 1.60 40°C / 3M Clear, colorless solution 95.8 2.99 4.24 Initial Clear, colorless solution 99.7 0.10 0.28 RT / 3M Clear, colorless solution 99.3 0.41 0.66 164O°C / 1M Clear, colorless solution 98.8 0.72 1.22 40°C / 3M Clear, colorless solution 96.6 1.70 3.40 Initial Clear, colorless solution 99.6 0.11 0.37 RT / 3M Clear, colorless solution 99.0 0.59 0.97 174O°C / 1M Clear, colorless solution 98.4 0.93 1.60 40°C / 3M Clear, colorless solution 95.8 2.15 4.16 Initial Clear, colorless solution 99.9 0.08 0.08 RT / 3M Clear, colorless solution 94.3 3.62 5.70 184O°C / 1M Clear, colorless solution 85.6 8.05 14.37 40°C / 3M Clear, colorless solution 65.0 18.77 34.97 Initial Clear, colorless solution 99.9 0.06 0.06 RT / 3M Clear, colorless solution 98.3 1.27 1.67 194O°C / 1M Clear, colorless solution 95.2 3.24 4.82 40°C / 3M Clear, colorless solution 86.4 7.58 13.60 Initial Clear, colorless solution 100.0 0.05 0.05 RT / 3M Clear, colorless solution 99.0 0.80 1.04 204O°C / 1M Clear, colorless solution 96.8 2.11 3.20 40°C / 3M Clear, colorless solution 89.9 5.08 10.13 Initial Clear, colorless solution 100.0 0.05 0.05 21RT / 3M Clear, colorless solution 99.3 0.53 0.74%MaximumExample Sample %Total Visual Description %Purity SingleNo. Details Impurities Impurity4O°C / 1M Clear, colorless solution 97.8 1.40 2.20 40°C / 3M Clear, colorless solution 78.2 10.70 21.86 Initial Clear, colorless solution 100.0 0.05 0.05 RT / 3M Clear, colorless solution 99.1 0.70 0.92 224O°C / 1M Clear, colorless solution 97.2 1.86 2.80 40°C / 3M Clear, colorless solution 92.9 4.60 7.10

[0147] Example 23 - 24 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 9. Where applicable, required quantity of sucralose, methylparaben, propylparaben, cherry flavor, and all-rac-alpha-tocopherol were added, one-by-one, in required quantity of polyethylene glycol 400 and mixed until dissolved. Required quantity of selexipag was added and mixed until dissolved. In separate container, required quantity of sodium lauryl sulfate was dissolved in about 70% of required quantity of water and added to the drug solution. Volume of the batch was made up to the batch size using water and optionally filtered to remove foreign particulate matters. The solution was filled into 10CC glass containers and 10CC HDPE containers, sealed using closure without nitrogen overlay. Stability test results for example 23-24 are provided in table 10.Table 9. Composition of example 23-24.Example No. (Quantity per mL) Ingredients23 24 Selexipag 0.4 mg 0.4 mg Sucralose 5 mg 5 mg Methylparaben 2.5 mg 2.5 mg Propylparaben 0.25 mg 0.25 mg Cherry flavor 1 mg 1 mga-Tocopherol 1 mg 1 mgExample No. (Quantity per mL) Ingredients23 24Sodium Lauryl Sulfate — 1 mgPEG 400 0.8 mL 0.8 mLWater q.s. to 1 mL q.s. to 1 mLTable 10. Stability test results for example 23-24.% Maximum Example % %Total Sample Details Visual Description SingleNo. Purity Impurities ImpurityInitial Clear, colorless solution 99.9 0.13 0.1 23 RT / 3M, glass bottle Clear, colorless solution 99.4 0.13 0.6 RT / 3M, HDPE bottle Clear, colorless solution 99.5 0.13 0.5 Initial Clear, colorless solution 100.0 0.00 0.0 24 RT / 3M, glass bottle Clear, colorless solution 99.3 0.13 0.7 RT / 3M, HDPE bottle Clear, colorless solution 99.4 0.12 0.6

[0148] Example 25 - 31 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 11. Where applicable, required quantity of sucralose, methylparaben, propylparaben, cherry flavor, all-rac-alpha-tocopherol, lactic acid, and water were added, one-by-one, in required quantity of polyethylene glycol 400 and mixed until dissolved. Required quantity of selexipag was added and mixed until dissolved. Volume of the batches were made up to the batch size using PEG 400 and optionally filtered to remove foreign particulate matters. The solution was filled into glass containers and sealed using closure with nitrogen overlay. Stability test results for example 23-24 are provided in table 12.Table 11. Composition of example 25-31.Example No. (Quantity per mL)Ingredients25 26 27 28 29 30 31 Selexipag 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg Sucralose 10 mg 10 mg 10 mg 10 mg 10 mg 10 mg 10 mg Methylparaben 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg Propylparaben 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg Cherry flavor 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg a-Tocopherol 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg Lactic acid — 1 mg 2.5 mg 5 mg 7.5 mg 10 mg 5 mg Water — — — — — — 0.2 mL q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 PEG 400 q.s. to 1 mLmL mL mL mL mL mLTable 12. Stability test results for example 25-31.%MaximumExample Sample %Total Visual Description %Purity SingleNo. Details Impurities ImpurityInitial Clear, colorless solution 100.0 0.00 0.0 25 RT / 3M Clear, colorless solution 97.5 0.40 2.540°C / 2M Clear, colorless solution 91.5 1.48 8.5 Initial Clear, colorless solution 100.0 0.00 0.0 26 RT / 3M Clear, colorless solution 99.3 0.12 0.740°C / 2M Clear, colorless solution 96.1 0.58 3.9 Initial Clear, colorless solution 100.0 0.00 0.0 27 RT / 3M Clear, colorless solution 98.6 0.25 1.440°C / 2M Clear, colorless solution 96.5 0.56 3.5 Initial Clear, colorless solution 100.0 0.00 0.0 28 RT / 3M Clear, colorless solution 98.4 0.28 1.640°C / 2M Clear, colorless solution 95.9 0.72 4.1%MaximumExample Sample %Total Visual Description %Purity SingleNo. Details Impurities ImpurityInitial Clear, colorless solution 100.0 0.00 0.0 29 RT / 3M Clear, colorless solution 97.8 0.33 2.240°C / 2M Clear, colorless solution 95.5 0.87 4.5 Initial Clear, colorless solution 100.0 0.00 0.0 30 RT / 3M Clear, colorless solution 97.7 0.38 2.340°C / 2M Clear, colorless solution 93.7 0.96 6.3 Initial Clear, colorless solution 99.9 0.12 0.1 31 RT / 3M Clear, colorless solution 99.6 0.16 0.440°C / 2M Clear, colorless solution 94.9 4.15 5.1

[0149] Example 32 - 39 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 13. Where applicable, required quantity of sucralose, methylparaben, propylparaben, cherry flavor, all-rac-alpha-tocopherol, and lactic acid were added, one-by-one, in required quantity of polyethylene glycol 400 or 80% of the required quantity of propylene glycol and mixed until dissolved. Required quantity of selexipag was added and mixed until dissolved. Volume of the batches were made up to the batch size using propylene glycol and optionally filtered to remove foreign particulate matters. The solution was filled into glass containers and sealed using closure with nitrogen overlay. Stability test results for example 32-39 are provided in table 14.Table 13. Composition of example 32-39.Example No. (Quantity per mL)Ingredients32 33 34 35 36 37 38 39 Selexipag 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg Sucralose 10 mg 10 mg 10 mg 10 mg 10 mg 10 mg 10 mg 10 mg Methylparaben 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mgExample No. (Quantity per mL)Ingredients32 33 34 35 36 37 38 39 Propylparaben 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg 0.25 mg Cherry flavor 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg Lactic acid — 1 mg 2.5 mg 5 mg 7.5 mg 10 mg 5 mg 10 mg a-Tocopherol — -- — -- — — 1 mg 1 mg PEG 400 — -- — -- — — 0.5 mL 0.5 mL q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 Propylene GlycolmL mL mL mL mL mL mL mLTable 14. Stability test results for example 32-39.%Maximum Example %Total Sample Details Visual Description %Purity SingleNo. Impurities ImpurityInitial Clear, colorless solution 100.0 0.00 0.0 32 RT / 3M Clear, colorless solution 89.9 7.97 10.1 40°C / 2M Clear, colorless solution 69.0 25.07 31.0 Initial Clear, colorless solution 100.0 0.00 0.0 33 RT / 3M Clear, colorless solution 98.6 0.54 1.6 40°C / 2M Clear, colorless solution 98.1 1.30 1.9 Initial Clear, colorless solution 100.0 0.00 0.0 34 RT / 3M Clear, colorless solution 98.3 0.86 1.7 40°C / 2M Clear, colorless solution 96.8 2.02 3.2 Initial Clear, colorless solution 100.0 0.00 0.0 35 RT / 3M Clear, colorless solution 97.9 1.20 2.1 40°C / 2M Clear, colorless solution 95.7 2.85 4.3 Initial Clear, colorless solution 100.0 0.00 0.0 36 RT / 3M Clear, colorless solution 98.0 1.44 2.0 40°C / 2M Clear, colorless solution 94.8 3.36 5.2 37 Initial Clear, colorless solution 100.0 0.00 0.0%Maximum Example %Total Sample Details Visual Description %Purity SingleNo. Impurities ImpurityRT / 3M Clear, colorless solution 97.7 1.63 2.3 40°C / 2M Clear, colorless solution 94.0 3.83 6.0 Initial Clear, colorless solution 100.0 0.00 0.0 38 RT / 3M Clear, colorless solution 99.1 0.47 0.9 40°C / 2M Clear, colorless solution 98.0 1.60 2.0 Initial Clear, colorless solution 100.0 0.00 0.0 39 RT / 3M Clear, colorless solution 98.8 0.58 1.2 40°C / 2M Clear, colorless solution 97.7 1.78 2.3

[0150] Example 40 is an experiment conducted to determine the approximate solubility of selexipag using vehicles and / or various pH adjusting agents provided in table 15. The samples were prepared by suspending selexipag in vehicle and adjusting pH to target (where applicable) followed by mixing for 24 hours. The supernatant was collected for each sample followed by centrifugation and tested using HPLC for approximate concentration. Results are provided in table 15.Table 15. Approximate solubility of selexipag in various solvent systemExample No. Vehicle pH Adjusting agent Adjusted pH Solubility (mg / mL) 40A Water Sodium hydroxide 7.5 -1.509 40B Water Tromethamine 8.2 -0.515 40C Water Hydrochloric acid 2.5 -0.006 40D Water Lactic acid 3.7 -0.005 40E Water Phosphoric acid 2.3 -0.002 40F Water Citric acid 3.1 -0.003

[0151] Example 41 - 45 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 16. Where applicable, required quantity of sodium hydroxide or lactic acid were added in about 80% of required quantity of water, propylene glycol or PEG 400. Selexipag was added and mixed until dissolved. Volume was made up to the batch size. The solutions were optionallyfiltered and filled into glass containers and closed with closure. Stability test results for example 41-45 are provided in table 21.Table 16. Composition of example 41-45.Example No. (Quantity per mL)Ingredients41 42 43 44 45 Selexipag 1.6 mg 1.6 mg 1.6 mg 1.6 mg 1.6 mg Sodium Hydroxide (IN) 3.2pL 3.2pL 3.2pL 3.2pL 3.2pL Lactic acid (90%) — — — — 2.3pL Tocopherol — -- -- 1 mg 1 mg Water q.s. to 1 mL -- — — — Propylene Glycol — q.s. to 1 mL — — — PEG 400 — -- q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL Clear, Clear, Clear, Clear, Clear, Description colorless colorless colorless colorless colorless solution solution solution solution solution

[0152] Example 46 - 51 describe the liquid formulations of selexipag prepared as suspension using ingredients detailed in Table 17. Where applicable, required quantity of hydrochloric acid, lactic acid, phosphoric acid, citric acid, disodium edetate, and polysorbate 80 were added one-by-one in about 80% of required quantity of water. Selexipag was suspended and mixed to obtain a suspension. The prepared suspension was filled into containers and closed with closure. Minimal ingredients were used to prepare the suspension. Stability test results for example 46-51 are provided in table 21.Table 17. Compositions of example 46-51.Example No. (Quantity per mL)Ingredients46 47 48 49 50 51 Selexipag 1.6 mg 1.6 mg 1.6 mg 1.6 mg 1.6 mg 1.6 mg Polysorbate 80 1 mg Img Img Img Img Img q.s. to pHHydrochloric acid (IN) — — — — —2.7 (3.2pL)Example No. (Quantity per mL)Ingredients46 47 48 49 50 51 q.s. to pHLactic acid (9%) — — — — —3.4 (3.2pL)q.s. to pHPhosphoric acid (8.5%) — — — — —2.6 (3.7pL)q.s. to pHCitric acid (5%) — — — — —3.5 (6.2pL)Di sodium edetate 0.1 mg — — — — —dihydrate (2% in water) (5pL) q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 Water q.s. to 1 mLmL mL mL mL mL White White White White White White Descriptionsuspension suspension suspension suspension suspension suspension

[0153] Example 52 - 57 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 18. Where applicable, required quantity of hydrochloric acid, lactic acid, phosphoric acid, citric acid, disodium edetate, and tocopherol were added one-by-one in about 80% of required quantity of PEG 400. Selexipag was added and mixed until dissolved. The prepared solution was filled into containers and closed with closure. The acid quantities were chosen arbitrarily (following examples 47-50) to observe their effects and could be further optimized. Stability test results for example 52-57 are provided in table 21.Table 18. Compositions of example 52-57.Example No. (Quantity per mL)Lot# 1252 53 54 55 56 57 Selexipag 1.6 mg 1.6 mg 1.6 mg 1.6 mg 1.6 mg 1.6 mg a-Tocopherol 1 mg Img Img Img Img Img Hydrochloric acid (IN) — 3.2pL — -- — — Lactic acid (9%) — — 3.2pL — — — Phosphoric acid (8.5%) — -- — 3.7pL — — Citric acid (5%) — — — — 6.2pL —Example No. (Quantity per mL)Lot# 1252 53 54 55 56 57 Di sodium edetate dihydrate 0.25 mg — — — — —(2% in water) (1.25pL) q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 PEG 400mL mL mL mL mL mL Clear, Clear, Clear, Clear, Clear, Clear, Description colorless colorless colorless colorless colorless colorless Solution Solution Solution Solution Solution Solution

[0154] Example 58 - 63 describe the liquid formulations of selexipag prepared using ingredients detailed in Table 19. Where applicable, required quantity of hydrochloric acid, lactic acid, phosphoric acid, citric acid, and disodium edetate were added one-by-one in about 80% of required quantity of propylene glycol. Selexipag was added and mixed until dissolved. The prepared solution was fdled into containers and closed with closure. The acid quantities were chosen arbitrarily (following examples 47-50, based on selexipag used) to observe their effects and could be further optimized. Selexipag concentration was lower than PEG 400 due to limited solubility in propylene glycol (<1 mg / mL). Stability test results for example 58-63 are provided in table 21.Table 19. Compositions of example 58-63.Example No. (Quantity per mL)Ingredients58 59 60 61 62 63 Selexipag 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg 0.4 mg Hydrochloric acid (IN) — 0.81pL — -- -- — Lactic acid (9%) — — 0.81pL -- -- — Phosphoric acid (8.5%) — — — 0.93pL -- — Citric acid (5%) — — — — 1.55pL — Di sodium edetate 0.1 mg — — — — —dihydrate (2% in water) (5pL)Example No. (Quantity per mL)Ingredients58 59 60 61 62 63 q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 Propylene Glycol q.s. to 1 mL q.s. to 1 mLmL mL mL mL Clear, Clear, Clear, Clear, Clear, Slight Clear, Description colorless colorless yellow color colorless yellow color colorless Solution Solution solution solution solution solution

[0155] Example 64 describes the liquid formulations of selexipag prepared using ingredients detailed in Table 20. This composition is very similar to described in patent number US12121556, without use of polysorbate 20. 80% of batch required quantity of water was collected in vessel, required quantity of sodium hydroxide was added and mixed, required quantity of selexipag was added in absence of light and mixed until dissolved, required quantity of glycine was added and mixed until dissolved, required quantity of phosphoric acid was added and mixed until dissolved. pH was adjusted to 7.54. Weight was made up to 15.2 g and fdled into glass containers and closed with closure. Stability test results for example 64 are provided in table 21.Table 20. Compositions of example 64.Ingredients Quantity per batchSelexipag 7.60 mgGlycine 760 mgSodium hydroxide, (15%w / w) 48 mgOrtho-phosphoric acid (85%w / w) 17.52 mgSodium hydroxide (l%w / v) q.s. to pH 7.54Water for Injection q.s. to 15.2 gDescription: Clear colorless solutionTable 21. Stability test results for example 41-64 after 6 days at 60°C.%Example Maximum % Total Visual Description % Purity PH No. Single Impurities Impurity41 Clear, colorless solution 96.9 2.99 3.1 — 42 Clear, colorless solution 75.1 15.19 24.9 — 43 Clear, colorless solution 94.6 0.89 5.4 — 44 Clear, colorless solution 93.8 1.17 6.2 — 45 Clear, colorless solution 97.1 0.53 2.9 —White color suspension (after46 99.4 0.40 0.6 7.7 shaking for 30 seconds)White color suspension (after47 99.0 0.45 1.0 2.7 shaking for 30 seconds)White color suspension (after48 99.6 0.17 0.4 3.5 shaking for 30 seconds)White color suspension (after49 99.6 0.34 0.4 2.6 shaking for 30 seconds)White color suspension (after50 99.8 0.21 0.2 3.5 shaking for 30 seconds)White color suspension (after51 99.6 0.40 0.4 6.4 shaking for 30 seconds)52 Clear, colorless solution 95.6 0.78 4.4 — 53 Clear, colorless solution 98.2 0.32 1.8 — 54 Clear, colorless solution 96.3 0.65 3.7 — 55 Clear, colorless solution 97.6 0.41 2.4 — 56 Clear, colorless solution 97.0 0.53 3.0 — 57 Clear, colorless solution 96.0 0.68 4.0 — 58 Clear, colorless solution 97.0 2.27 3.0 —%Example Maximum % Total Visual Description % Purity pH No. Single Impurities Impurity— 59 Clear, yellow color solution 44.3 12.88 55.760 Clear, colorless solution 98.5 1.09 1.5 — 61 Clear, colorless solution 98.2 1.10 1.8 — 62 Clear, colorless solution 99.2 0.53 0.8 — 63 Clear, colorless solution 90.9 6.65 9.1 — 64 Clear, colorless solution 86.6 8.90 13.4 —

Claims

CLAIMS1. A stable liquid pharmaceutical formulation comprising:(a) selexipag or its pharmaceutically acceptable salt;(b) at least one pharmaceutically acceptable excipients selected from the group comprising vehicles, preservatives, sweeteners, flavors, pH adjusting agents, buffering agents, viscosity adjusting agents, antioxidants, tonicity adjusting agents, chelating agents, stabilizers, complexing agents, crystallization inhibitors, suspending agents, surfactants, anti-foaming agents, dispersing agents, wetting agents, and combinations thereof;wherein upon storage for at least three months at room temperature, the formulation has:(i) at least about 90% pure selexipag,(ii) less than about 10% of total degradant impurities.

2. The formulation according to claim 1, wherein the selexipag concentration is about 100 mcg / mL to about 2000 mcg / mL.

3. The formulation according to claim 2, wherein the selexipag concentration is about 160 mcg / mL to about 1600 mcg / mL.

4. The formulation according to claim 2, wherein the selexipag concentration is from about 400 mcg / mL to about 800 mcg / mL.

5. The formulation according to claim 1, wherein upon storage for at least three months at room temperature, the formulation contains less than about 5% total degradation impurities.

6. The formulation according to claim 5, wherein upon storage for at least three months at room temperature, the formulation contains less than about 3% total degradation impurities.

7. The formulation according to claim 5, wherein upon storage for at least three months at room temperature, the formulation contains less than about 2% total degradation impurities.

8. The formulation according to claim 1, wherein upon storage for at least three months at room temperature, the formulation contains less than about 1% of maximum single impurity.

9. The formulation according to claim 8, wherein upon storage for at least three months at room temperature, the formulation contains less than about 0.5% of maximum single impurity.

10. The formulation according to claim 1, wherein the formulation contains stability-enhancing amount of one or more acid ingredient(s).

11. The formulation according to claim 1, wherein the acid ingredients are selected from lactic acid, hydrochloric acid, phosphoric acid, citric acid, and combination thereof.

12. The formulation according to claim 1, wherein the pH of formulation is less than about 7.

13. The formulation according to claim 12, formulated at pH between about 2 to about 6.

14. The formulation according to claim 1, wherein the formulation is solution or suspension.

15. The formulation according to claim 14, wherein the formulation is solution.

16. The formulation according to claim 1 , wherein the formulation is essentially from glycerin as a vehicle.

17. The formulation according to claim 15, wherein at least one solubilizer is polyethylene glycol or propylene glycol.

18. The formulation according to claim 15, wherein the formulation contains at least one vehicle from water, polyethylene glycol, propylene glycol, and combination thereof.

19. The formulation according to claim 18, wherein at least one vehicle is polyethylene glycol.

20. The formulation according to claim 18, wherein at least one vehicle is polyethylene glycol 400.

21. The formulation according to claim 18, wherein the vehicle is a mixture of water and polyethylene glycol.

22. The formulation according to claim 1, formulated as an oral liquid comprising:(a) selexipag at about 100 mcg / mL to about 1600 mcg / mL;(b) at least one sweetener at concentration of about 0.01% to about 5%;(c) at least one preservative at concentration from about 0.01% to about 2%; and(d) at least one vehicle selected from water, polyethylene glycol, propylene glycol, and combination thereof.

23. The formulation according to claim 1, wherein the formulation is filled in a multi-dose container suitable for oral liquid administration.

24. The formulation according to claim 23, wherein the container is a glass or polymeric bottle of about 5-500 mL fill volume.

25. The formulation according to claim 23, wherein the container is provided with a flow-restrictor and / or dosing syringe.

26. A method of treatment one or more conditions selected from pulmonary arterial hypertension (PAH, WHO Group I- VI), chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension due to lung disease (PH-ILD), and systemic sclerosis (SSc) vasculopathy, comprising administering a therapeutically effective amount of the formulation according to any of claims 1- 25.

27. The method according to claim 26, wherein the condition is pulmonary arterial hypertension (PAH, WHO Group I- VI).

28. The method according to claim 26, wherein the condition is pulmonary arterial hypertension (PAH,WHO Group I) to delay disease progression and reduce the risk of hospitalization.

29. The method according to claim 26, wherein the condition is pulmonary arterial hypertension (PAH, WHO Group II-III).

30. A method of preparing the liquid pharmaceutical formulation according to claim 15, the method comprising the steps of: (i) solubilizing selexipag or its pharmaceutically acceptable salt in a vehicle and / or solubilizer; (ii) solubilizing one or more optional pharmaceutically acceptable excipients; (iii) optionally filtering the formulated liquid; (iv) filling the filtered liquid into a primary packaging container; and (v) sealing the container with an optional inert gas overlay.

31. The formulation according to claim 1, wherein the formulation is suspension.

32. A method of preparing the liquid pharmaceutical formulation according to claim 31, the method comprising the steps of: (i) adding one or more pharmaceutically acceptable excipients in vehicle; (ii) suspending selexipag and mixing to achieve homogenous suspension; (ii) optionally filtering the formulated suspension; (iii) filling the suspension into a suitable primary packaging container, such as a glass or polymeric bottle; and (vi) sealing the container with an optional inert gas overlay.

33. The formulation according to claim 32, wherein the formulation comprises a surfactant and viscosity adjusting agent.

34. A stable liquid pharmaceutical formulation comprising:(a) Selexipag at a concentration from about 100 mcg / mL to about 1600 mcg / mL; and(b) at least one excipient selected from group of comprising of vehicles, surfactants, viscosity enhancing agents, sweeteners, flavoring agents, preservatives, pH adjusting agents, buffering agents, antioxidants, or combination thereof,wherein the formulation is suspension and formulated at pH below about 7, preferably from about 2 to about 6.

35. The formulation according to claim 1, wherein the formulation is suitable for parenteral administration, and pH of the formulation is from about 7 to about 8.

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