WO2018153925A1

WO2018153925A1 - Stable pharmaceutical compositions comprising macitentan

Info

Publication number: WO2018153925A1
Application number: PCT/EP2018/054290
Authority: WO
Inventors: Jatin GAJJAR; Shreejit MENON; Dhruv SHAH; Nikunj Patel; Jalashri PATADIA
Original assignee: Amneal Pharmaceuticals Company Gmbh
Priority date: 2017-02-22
Filing date: 2018-02-21
Publication date: 2018-08-30

Abstract

The present invention relates to a pharmaceutical composition comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The present invention specifically relates to a surfactant-free pharmaceutical composition of macitentan or a pharmaceutically acceptable salt thereof. Moreover, the present invention further relates to a surfactant-free pharmaceutical composition of macitentan or a pharmaceutically acceptable salt thereof which is used in the treatment of a disease selected from the group consisting of pulmonary arterial hypertension, myocardial infarction, thrombotic stroke, transient ischaemic attack, peripheral vascular disease and angina.

Description

STABLE PHARMACEUTICAL COMPOSITIONS COMPRISING

MACITENTAN

FIELD

The present disclosure relates to a stable pharmaceutical composition comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Specifically, the present disclosure relates to a pharmaceutical composition of macitentan or a pharmaceutically acceptable salt thereof is surfactant-free.

BACKGROUND

Macitentan is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5- bromo-2-pyrimidinyl) oxy]ethoxy]-4- pyrimidinyl]-N'-propylsulfarnide. It has a molecular formula of C₁₉H₂₀Br₂N₆O₄S and a molecular weight of 588.27.

Macitentan is a crystalline powder that is insoluble in water and possess achiral group with following structural Formula -I.

Macitentan is a BCS class II drug substance characterized by low solubility and high permeability. The poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability. It is known that for BCS class II drugs rate limiting step is drug release from the dosage form and solubility in the gastric fluid and not the absorption, so increasing the solubility in turn increases the bioavailability for BCS class II drugs.

Macitentan is the active ingredient in a product being sold as OPSUMIT® for the long-term treatment of pulmonary arterial hypertension. Inactive ingredients are: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A, polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum. Polysorbate 80 is a commonly known surfactant.

US Patent 8,367,685 B2 describes pharmaceutical compositions comprising macitentan or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof and additionally, a filler, a disintegrant, a surfactant, and a lubricant. The '685 patent specifically requires use of surfactant to prepare pharmaceutical composition.

The '685 patent teaches that the pharmaceutical composition would have altered properties if certain components in formulation were missing or replaced by other components even though one skilled in the art would understand this as equivalent substitution. Moreover, the alteration would make the composition less stable and/or unsuitable for certain types of preparations. The recited experiments emphasize that only a particular combination of excipients are suitable for the preparation of storage-stable pharmaceutical compositions of macitentan having a satisfactory dissolution profiles.

PCT Patent Application WO 2014/173805 describes a pharmaceutical composition comprising crystalline macitentan free base and at least one excipient. The '805 patent application discloses a pharmaceutical composition that preferably comprises at least one excipient selected from the group consisting of fillers, disintegrants, lubricants, and surfactants and a method for the preparation thereof.

The above prior art formulations use surfactants to improve the bioavailability and dissolution profile of the poorly soluble drug macitentan, which is a well-known method. It is known by persons skilled in the art that surfactants reduce surface tension and enhance solubility of poorly soluble lipophilic drugs, thereby improving the dissolution of lipophilic drugs in aqueous medium.

However, the use of surfactants in an oral formulation has multiple disadvantages, such as producing gastric irritation and toxicity in humans. Furthermore, while non-ionic surfactants are less toxic than ionic surfactants, non-ionic surfactants may change the permeability of the intestinal lumen, which can cause absorption of toxins that leads to serious medical conditions.

Hence, the present invention is directed to a stable surfactant-free pharmaceutical composition of macitentan.

SUMMARY

The present invention relates to a stable surfactant-free pharmaceutical composition comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention further relates to a process of preparing a stable surfactant- free pharmaceutical composition comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Moreover, embodiments of the pharmaceutical composition are used in the treatment of a disease selected from the group consisting of: pulmonary arterial hypertension, myocardial infarction, thrombotic stroke, transient ischaemic attack, peripheral vascular disease and angina. Methods of treatment include: administering a pharmaceutical formulation comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the formulation does not comprise a surfactant. The pharmaceutical formulation is formulated to deliver an amount of macitentan or a pharmaceutically acceptable salt thereof effective to treat one or more of: pulmonary arterial hypertension, myocardial infarction, thrombotic stroke, transient ischaemic attack, peripheral vascular disease, and angina.

DETAILED DESCRIPTION

Pharmaceutical compositions comprise macitentan or a pharmaceutically acceptable salt thereof in the absence of a surfactant. Processes of preparing the pharmaceutical compositions are provided.

The term "about" refers to any value which lies within a defined range variation of up to ±10% of specified value.

The term "surfactant" means a surface-active agent, a substance such as a detergent that, when added to a liquid, reduces its surface tension, thereby increasing its spreading and wetting properties, and include the following: sodium lauryl sulphate, polysorbates (commercially available as Tween®), polyethylene polyoxypropylene polymers (Pluronic F65), polyoxylethylene stearates (MYRJ), dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters (commercial available from Nikko Chemicals), polyoxyethylene Cl-4-alkyl ethers, sucrose monoesters and lanolin esters and ethers.

A pharmaceutical composition is considered "stable" if, during a certain period of time, 70%, preferably 80% and most preferably 95% of the initial content of a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, is maintained over said period of time. The pharmaceutical compositions are surfactant-free, which excludes any functional (e.g., noncontaminating) amount of surfactant, including any amount that contributes to or has any effect on the stability of the macitentan. Stated differently, the composition may in some embodiments contain surfactant in an amount that is functionally negligible.

A first aspect is a surfactant-free pharmaceutical composition comprising macitentan or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention addresses major problems associated with the use of surfactants in an oral formulation, specifically gastric irritation and toxicity. When a higher amount of a surfactant is used in a formulation to solubilize a poorly soluble drug, it may cause toxicity and lead to gastric irritation.

Non-ionic surfactants are less toxic than ionic surfactants but they may lead to reversible changes in the permeability of the intestinal lumen. The change in the permeability of the membrane may lead to absorption of toxins leading to serious medical conditions.

The present invention has found an approach for solving this problem by formulating a surfactant-free pharmaceutical composition comprising of macitentan, wherein the pharmaceutical composition is free of surfactant without having a substantial impact on stability.

The surfactant-free macitentan composition may be formulated with one or more pharmaceutically acceptable excipients, representative examples of which include diluents, binders, disintegrants and glidants.

Examples of suitable diluents include but are not limited to: inorganic phosphates like dibasic calcium phosphate, or sugars or sugar analogues and derivatives thereof. In particular, diluents may be one or more of: lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbitol, mannitol, saccharose, maltodextrin, isomalt, or celluloses like microcrystalline cellulose (MCC) or powdered celluloses. The diluents may present in an amount from about 10% to about 80% by weight of the composition, preferably from about 40% to about 80% by weight of the composition.

The pharmaceutical composition may further include binders. Representative examples of suitable binders include but are not limited to: polyvinylpyrrolidone (PVP), starch, cellulose derivatives like hydroxypropylmethyl cellulose, sucrose, lactose, xylitol, sorbitol, maltitol, water, alcohol, and the like. A preferred binder includes polyvinylpyrrolidone, which is commercially available as Povidone K30. The binders may present in an amount from about 0.5% to about 5.0% by weight of the composition, preferably from about 1.0% to about 3.0% by weight of the composition.

Disintegrants in the pharmaceutical composition may be selected from the group consisting of: sodium starch glycolate (SSG), alginates, pregelatinized starch, croscarmellose, and the like. Preferable disintegrants include sodium starch glycolate. The disintegrants may present in an amount from about 1.0% to about 10% by weight of the composition, preferably from about 3.0% to about 7.0% by weight of the composition.

Additionally, the pharmaceutical composition may further include lubricants. Representative suitable lubricants include: fatty acids or fatty acid derivatives, such as alkali and earth alkali salts of stearic, lauric and/or palmitic acid. A preferred lubricant is magnesium stearate and may present in amount from about 0.1% to about 10% by weight of the composition.

Glidants present in a pharmaceutical dosage form include but are not limited to: silicon dioxide, talc, magnesium stearate, and the like. A preferred glidant is talc and may present in amount from about 0.1% to about 10% by weight of the composition.

The pharmaceutical composition may be obtained by known conventional methods including but not limited to: dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot-melt extrusion, and the like.

According to another embodiment, a pharmaceutical composition comprises: from about 1% to about 40% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 10% to about 80% w/w of one or more diluents, about 0.5% to about 5% w/w of one or more binders, about 1% to about 10% w/w of one or more disintegrants, about 0.1% to about 10% w/w of one or more lubricants, about 0.0% to about 10% w/w of one or more glidants, and optionally about 1.0% to about 10% w/w of one or more film coating materials.

In one or more embodiments, the amounts of macitentan or a pharmaceutically acceptable salt thereof, diluents, binders, disintegrants, lubricants, glidants, and film coating material total 100% in the pharmaceutical composition.

In an embodiment, the pharmaceutical composition consists of: from about 1% to about 40% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 10% to about 80% w/w of one or more diluents, about 0.5% to about 5% w/w of one or more binders, about 1% to about 10% w/w of one or more disintegrants, about 0.1% to about 10% w/w of one or more lubricants, about 0.0% to about 10% w/w of one or more glidants, and optionally about 1.0% to about 10% w/w of one or more film coating materials.

In a particular embodiment, the pharmaceutical composition comprises: about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 30 to 60 % w/w of lactose monohydrate, about 20 to 30% w/w of microcrystalline cellulose, about 1.0 to 3.0% w/w of polyvinyl pyrrolidone, about 3.0 to 7.0% w/w of sodium starch glycolate, about 0.0 to 2.0% w/w of talc, about 0.1 to 2.0% of magnesium stearate, and about 2.0 to 5.0% w/w of a film coating material. In an embodiment, talc is present in an amount in the range of 0.1 to 2.0% w/w.

In one or more embodiments, the amounts of macitentan or a pharmaceutically acceptable salt thereof, lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone, sodium starch glycolate, talc, magnesium stearate, and film coating material total 100% in the pharmaceutical composition.

In an embodiment, the pharmaceutical composition consists of: about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 30 to 60 % w/w of lactose monohydrate, about 20 to 30% w/w of microcrystalline cellulose, about 1.0 to 3.0% w/w of polyvinyl pyrrolidone, about 3.0 to 7.0% w/w of sodium starch glycolate, about 0 to 2.0% w/w of talc, about 0.1 to 2.0% of magnesium stearate, and about 2.0 to 5.0% w/w of a film coating material.

In another particular embodiment, the pharmaceutical composition comprises: about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 30 to 60 % w/w of lactose monohydrate, about 20 to 30% w/w of microcrystalline cellulose, about 1.0 to 3.0% w/w of polyvinyl pyrrolidone, about 3.0 to 7.0% w/w of sodium starch glycolate, about 0.1 to 2.0% of magnesium stearate, and about 2.0 to 5.0% w/w of a film coating material, preferably a PVA- based film coating material.

In one or more embodiments, the amounts of macitentan or a pharmaceutically acceptable salt thereof, lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone, sodium starch glycolate, magnesium stearate, and the film coating material, preferably a PVA-based film coating material, total 100% in the pharmaceutical composition. In an embodiment, the pharmaceutical composition consists of: about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 30 to 60 % w/w of lactose monohydrate, about 20 to 30% w/w of microcrystalline cellulose, about 1.0 to 3.0% w/w of polyvinyl pyrrolidone, about 3.0 to 7.0% w/w of sodium starch glycolate, about 0.1 to 2.0% of magnesium stearate, and about 2.0 to 5.0% w/w of a film coating material, preferably a PVA-based film coating material.

According to other aspects, the pharmaceutical composition is prepared by a process comprising: (i) preparing a dry mixture comprising macitentan and one or more pharmaceutical excipients; (ii) granulating the dry mixture by addition of binder solution; (iii) sifting and milling of dried granules; (iv) blending of dried and milled granules with one or more pharmaceutical excipients and lubricants; (v) compressing or filling the lubricated blend to form a composition; and (vi) optionally coating the composition. In one or more embodiments, the dry mixture of (i) is prepared in the absence of a surfactant. In one or more embodiments, the blend of dried and milled granules with one or more pharmaceutical excipients and lubricants is in the absence of a surfactant. In one or more embodiments, the process is conducted in the absence of a surfactant.

A second aspect provides a process for the preparation of a pharmaceutical composition, wherein the process comprises: blending macitentan and one or more pharmaceutically acceptable excipients; further lubricating the blend; and directly compressing the lubricated blend into tablets or filling the lubricated blend into capsule dosage form. In one or more embodiments, blending of macitentan and one or more pharmaceutically acceptable excipients is done in the absence of a surfactant. In one or more embodiments, the process is conducted in the absence of a surfactant.

A third aspect provides a process for the preparation of the pharmaceutical composition, wherein the process comprises: blending macitentan and one or more diluents, binders, and disintegrants; compacting the blend to obtain granules or flakes; lubricating the granules/flakes using the additional lubricants; and compressing the lubricated granules into tablets or filling into capsules. In one or more embodiments, blending of macitentan and one or more diluents, binders, and disintegrants is done in the absence of a surfactant. In one or more embodiments, the process is conducted in the absence of a surfactant.

A fourth aspect provides a process for the preparation of a pharmaceutical composition, wherein the process comprises: blending macitentan and one or more hydrophilic polymers in a rapid mixer granulator; loading the granules obtained into a hot melt extruder to form a solid dispersion in the form of extrudates; milling the extrudates and adding one or more diluents, binders, disintegrants, and lubricants; and compressing the granules into tablets or filling into capsules. Non-limiting examples of hydrophilic polymers include: poly(ethylene glycol) (PEG), polyethylene oxide (PEO), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), and polyacrylic acid (PAA).

In one or more embodiments, blending of macitentan and one or more hydrophilic polymers is done in the absence of a surfactant. In one or more embodiments, the process is conducted in the absence of a surfactant.

The pharmaceutical composition may be in a dosage form of minitablets, granules, pellets, tablets, and/or capsules. The pharmaceutical composition may further be film-coated using techniques known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating. Alternatively, coating may also be performed using the hot melt technique. The film coat comprises film-forming polymers, one or more pharmaceutically acceptable excipients and pharmaceutically acceptable solvents.

Examples of film-forming agents include, but are not limited to, cellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose; waxes; fat substances; or mixtures thereof. Alternatively, commercially available coating compositions comprising film forming polymers marketed under various trade names, such as OPADRY®, may be used for coating.

Examples of solvents used for preparing the coating solution are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.

The pharmaceutical composition may be used in the treatment of a disease selected from the group consisting of, pulmonary arterial hypertension, myocardial infarction, thrombotic stroke, transient ischaemic attack, peripheral vascular disease and angina.

The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example 1

Table 1

Procedure:

1) Co-sift API, lactose monohydrate, MCC PH 101, and SSG type A and load in a Rapid mixer granulator.

2) Dissolve Povidone in purified water and stir for 15 minutes.

3) Dry mix the material of step 1.

4) Perform granulation of step 3 by addition of binder solution of step 2.

5) Dry the wet granules in a Fluid bed drier.

6) Sift the dried granules and mill the oversized granules in an Oscillatory granulator.

7) Co-sift MCC PH 101 and SSG and mix with material of step 6 in a blender.

8) Sift magnesium stearate and mix with material of step 7 in a blender.

9) Compress the lubricated granules.

10) Film coat the core tablets using an aqueous dispersion of Opadry® AMB White in a coater.

Dissolution profile study:

Not less than 75% of the labelled amount of Macitentan should be dissolved minutes.

The dissolution profile for Example 1 is depicted in Table 2. USP dissolution studies were performed for both reference and test products. Table 2

The pharmaceutical composition of Example 1 shows more than 95% drug release in 45 minutes in 900 ml of dissolution media containing mixture of pH Phosphate Buffer, pH 6.8 with 0.1% of cetrimonium bromide (CTAB) at 75 RPM using USP dissolution apparatus II.

As per the results depicted in above Table 2, the dissolution profile of pharmaceutical composition of Example 1 is comparable with marketed reference product of macitentan (Opsumit®), which contains surfactant polysorbate 80.

In one or more embodiments, the pharmaceutical composition, preferably the tablet, releases 80% or more of the macitentan after 10 minutes of USP dissolution testing; 90% or more of the macitentan after 20 minutes; and/or 95% or more of the macitentan after 45 minutes. In one or more detailed embodiments, the pharmaceutical composition, preferably the tablet, releases 93% or more of the macitentan after 10 minutes of USP dissolution testing; 97% or more of the macitentan after 15 minutes; 98% or more of the macitentan after 20 minutes; 99% or more of the macitentan after 30 minutes; and/or 99% or more of the macitentan after 45 minutes.

In one or more embodiments, a percentage of the macitentan released after dissolution testing for a time of an inventive tablet that is surfactant-free is within (e.g., ±) 5% (absolute) of a percentage released by a reference tablet comprising macitentan and a surfactant (e.g., polysorbate 80) after dissolution testing for the same time.

In one or more embodiments, the amount of the macitentan released at one or more time points after dissolution testing of an inventive tablet that is surfactant- free in a USP dissolution apparatus 2 (paddle) with 900 mL of phosphate buffer and 0.1% of cetrimonium bromide at pH 6.8 and 75 rpm stirring is within X% of the amount released at the same time points after dissolution testing of a reference tablet comprising macitentan and a surfactant (e.g., polysorbate 80), wherein X% and time points are as follows: about 1% after 10 minutes; about 3% after 15 minutes; about 3% after 20 minutes; about 4% after 30 minutes; and about 4% after 45 minutes.

The stability of the pharmaceutical composition may be tested in a conventional manner, e.g. by measurement of compound of formula I and its degradation or other impurity products, dissolution, friability, disintegration time, appearance and/or microscopy, e.g. after storage at 25° C. and 60% relative humidity, and/or storage at 40° C. and 75% relative humidity for defined periods of time.

In yet another embodiment, the pharmaceutical composition remains stable for longer periods of time in different thermo-hygrostats 25° C/60%+5% RH, 30° C/65%+5% RH, and 40° C/75%+5% RH as per ICH guidelines.

Preferably, the solid compositions will be stable for at least 6 or 12 months when kept at a temperature of 5° to 50° C. More preferably, they will be stable for at least 6 or 12 months when kept at a temperature of 15° to 45° C. Most preferred, they will be stable for at least 6 or 12 months when kept at a temperature of 25° to 40° C. In a more preferred embodiment, the pharmaceutical compositions are stable over a certain period of time such as 1 year, and preferably 2 years. More preferably, the pharmaceutical compositions are stable for 3 years.

The content of compound of formula I and its degradation products in the capsules or tablets can be evaluated via high performance liquid chromatography (HPLC).

Amounts of impurity products in the pharmaceutical compositions should be as follows:

Stage-III-Amino impurity: NMT 0.50 %

Stage-II-Dimer impurity: NMT 0.15 % Any unspecified impurity: NMT 0.20 % Total Impurities: NMT 2.0 %

Table 3 shows results of an accelerated stability study of a pharmaceutical composition with identical makeup and dissolution profile to that of Example 1. The result indicates that the pharmaceutical composition remains stable for at least for 6 months in 40°C/75% RH condition with purity greater than 99% or more preferably greater than 99.5%.

Table 3

In one or more embodiments, the amino impurity increases by no more than a factor of about 5 or no more than about 0.1% (absolute) after 6 months of storage at 40°C and 75% relative humidity. In one or more embodiments, the percentage of dirtier impurity is substantially unchanged relative to the initial percentage of dimer impurity after 6 months of storage at 40°C and 75% relative humidity. In one or more embodiments, the percentage of any unspecified impurity is substantially unchanged relative to the initial percentage of unspecified impurity after 6 months of storage at 40°C and 75% relative humidity. In one or more embodiments, the percentage of total impurity increases no more than a factor of about 2 or no more than about 0.01% (absolute) of the initial percentage of total impurity after 6 months of storage at 40°C and 75% relative humidity.

Claims

What is claimed:

1. A pharmaceutical composition comprising a compound according to Formula-I:

or a pharmaceutically acceptable salt, solvate, hydrate, or morphological form thereof, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is surfactant-free.

2. The pharmaceutical composition according to claim 1, wherein the one or more pharmaceutically acceptable excipients is selected from the group consisting of: diluents, binders, disintegrants, glidants, lubricants, or mixtures thereof.

3. The pharmaceutical composition according to one of claims 1 to 2, wherein a diluent is present in an amount from about 10% to about 80% by weight based on the total weight of the pharmaceutical composition.

4. The pharmaceutical composition according to one of claims 1 to 3, wherein a binder is present in an amount from about 0.5% to about 5.0% by weight based on the total weight of the pharmaceutical composition.

5. The pharmaceutical composition according to one of claims 1 to 4, wherein a disintegrant is present in an amount from about 1.0% to about 10.0% by weight based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to one of claims 1 to 5, wherein each of a lubricant and a glidant is present in an amount from about 0.1% to about 10% by weight based on the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to one of claims 1 to 6, wherein the pharmaceutical composition is in the form of tablets, capsules, pellets, or sachets .

8. The pharmaceutical composition according to one of claims 1 to 7 in the form of a tablet further comprising a film coating material.

9. The pharmaceutical composition according to one of claims 1 to 8, which releases about 95% or more of the macitentan after 45 minutes dissolution testing in a USP dissolution apparatus 2 (paddle) with 900 mL of phosphate buffer and 0.1% of cetrimonium bromide at pH 6.8 and 75 rpm stirring.

10. The pharmaceutical composition according to one of claims 1 to 9, which releases one or more of the following percentages of the macitentan after dissolution testing in a USP dissolution apparatus 2 (paddle) with 900 mL of phosphate buffer and 0.1% of cetrimonium bromide at pH 6.8 and 75 rpm stirring: 80% or more of the macitentan after 10 minutes of USP dissolution testing; 90% or more of the macitentan after 20 minutes; 95% or more of the macitentan after 45 minutes.

11. The pharmaceutical composition according to one of claims 1 to 10, wherein the amount of the macitentan released at one or more time points after dissolution testing in a USP dissolution apparatus 2 (paddle) with 900 mL of phosphate buffer and 0.1% of cetrimonium bromide at pH 6.8 and 75 rpm stirring is within X% of the amount released at the same time points after dissolution testing of a reference tablet comprising macitentan and a surfactant, wherein X% and time points are as follows: about 1% after 10 minutes; about 3% after 15 minutes; about 3% after 20 minutes; about 4% after 30 minutes; and about 4% after 45 minutes.

12. The pharmaceutical composition according to one of claims 1 to 11 comprising a percentage of amino impurity that is no more than about 5 -fold greater than the initial percentage of the amino impurity, a percentage of dimer impurity that is substantially the same as the initial percentage of the dimer impurity, a percentage of any unspecified impurity that is substantially the same as the initial percentage of the unspecified impurity, and/or a percentage of total impurities that is no more than about 2-fold greater than the initial percentage of total impurities, as measured by high performance liquid chromatography following six months of storage at 40°C and 75% relative humidity.

13. The pharmaceutical composition according to one of claims 1 to 12 comprising a purity of 99% or greater as measured by high performance liquid chromatography following six months of storage at 40°C and 75% relative humidity.

14. A pharmaceutical composition comprising :

from about 1% to about 40% w/w of a compound of Formula-I :

or a pharmaceutically acceptable salt, solvate, hydrate, or morphological form thereof,

about 10% to about 80% w/w of diluents,

about 0.5% to about 5% w/w of binders,

about 1% to about 10% w/w of disintegrants,

about 0.1% to about 10% w/w of lubricants, about 0.1% to about 10% w/w of glidants, and

optionally about 1.0% to about 10% w/w of a film coating material, wherein the pharmaceutical composition is surfactant-free.

15. The pharmaceutical composition according to claim 14, wherein the amounts of macitentan or a pharmaceutically acceptable salt thereof, diluents, binders, disintegrants, lubricants, glidants, and film coating material total 100%.

16. The pharmaceutical composition according to one of claims 14 to 15 comprising:

about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof,

about 30 to 60 % w/w of lactose monohydrate,

about 20 to 30% w/w of microcrystalline cellulose,

about 1.0 to 3.0% w/w of polyvinyl pyrrolidone,

about 3.0 to 7.0% w/w of sodium starch glycolate,

about 0 to 2.0% w/w of talc,

about 0.1 to 2.0% of magnesium stearate, and

optionally about 2.0 to 5.0% w/w of a film coating material.

17. The pharmaceutical composition according to claim 16, wherein the amounts of macitentan or a pharmaceutically acceptable salt thereof, lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone, sodium starch glycolate, talc, magnesium stearate, and film coating material total 100%.

18. A pharmaceutical composition consisting of: about 10 to 25% w/w of macitentan or a pharmaceutically acceptable salt thereof, about 30 to 60 % w/w of lactose monohydrate, about 20 to 30% w/w of microcrystalline cellulose, about 1.0 to 3.0% w/w of polyvinyl pyrrolidone, about 3.0 to 7.0% w/w of sodium starch glycolate, about 0.1 to 2.0% of magnesium stearate, and about 2.0 to 5.0% w/w of a film coating material.

19. The pharmaceutical composition of claim 18 consisting of by weight: about 13 to 14% macitentan; about 53 to 54% lactose monohydrate; about 22 to 23% microcystalline cellulose; about 2 to 4% sodium starch glycolate type A; about 1 to 2% polyvinylpyrrolidone; about 0.1 to 1% magnesium stearate, and about 3 to 4% polyvinyl alcohol-based film coating material.

20. A method of producing a pharmaceutical tablet, the method comprising: blending macitentan in the absence of a surfactant with one or more pharmaceutical excipients to form a blend; and

forming the blend into tablets.

21. The method of claim 20, wherein the pharmaceutical excipients are selected from the group consisting of diluents, binders, disintegrants, and lubricants.

22. The method of one of claims 20 to 21, wherein the blend is directly compressed into the tablets.

23. The method of one of claims 20 to 22, wherein the blend is compacted into granules or flakes, lubricating the granules or flakes, and the lubricated granules or flakes are compressed into tablets.