WO2017072714A1

WO2017072714A1 - Stable ledipasvir premix and process of preparation thereof

Info

Publication number: WO2017072714A1
Application number: PCT/IB2016/056509
Authority: WO
Inventors: Girij Pal Singh; Himanshu Madhav Godbole; Adinath Murlidhar Jain; Manoj Kunjabihari Agrawal; Swapnil Sudhakar DESHMUKH
Original assignee: Lupin Limited
Priority date: 2015-10-30
Filing date: 2016-10-28
Publication date: 2017-05-04

Abstract

The present invention provides premix of ledipasvir comprising Ledipasvir and at least one pharmaceutically acceptable excipient, process for preparation of premix and pharmaceutical composition thereof and their use as medicaments.

Description

STABLE LEDIPASVIR PREMIX AND PROCESS OF

PREPARATION THEREOF

Field of the Invention:

The present invention relates to premix of anti-HCV compound Ledipasvir, having the chemical name (l-{3-[6-(9, 9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl- butyryl)-5-aza-spiro[2.4]hept-6-yl ]-3H -imidazol-4-yl} -9H-fluoren-2-yl)-lH- benzoimidazol-2-yl] -2-aza-bicyclo[2.2.1 ]heptane-2-carbonyl } -2-methylpropyl)-carbamic acid methyl ester, is known to be an effective anti-HCV agent, process for their preparation and pharmaceutical composition thereof. Background of the Invention:

Hepatitis C is recognized as a chronic viral disease of the liver which is characterized by liver disease. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness. Inhibitors of hepatitis C virus (HCV) are useful to limit the establishment and progression of infection by HCV as well as in diagnostic assays for HCV.

The hepatitis C virus (HCV) is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family. The enveloped HCV virion contains a positive stranded RNA genome encoding all known virus-specific proteins in a single, uninterrupted, open reading frame. The open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids. The polyprotein comprises a core protein, envelope proteins El and E2, a membrane bound protein p7, and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C may be treated with peginterferon-alpha in combination with ribavirin. Substantial limitations to efficacy and tolerability remain as many users suffer from side effects, and viral elimination from the body is often inadequate. Therefore, there is a need for new drugs to treat HCV infection. Ledipasvir is described in US 8,088,368 B2, and is a HCV NS5A inhibitor that has demonstrated potent anti-HCV activity against genotype (la and lb) HCV infection. Ledipasvir has the following chemical formula:

Extensive study is carried out in pharmaceutical industry for development of different polymorphs of various drug substances, to obtain suitable polymorphs that possess improved performance characteristics such as aqueous solubility, improved bioavailability, chemical stability, shelf life etc.

Literature survey reveals that Ledipasvir can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties and pharmacokinetics. The reported polymorphs of Ledipasvir are incorporated here by way of reference.

PCT publication WO2013184698 by Gilead Al discloses various polymorphs and/or solvates including amorphous form of Ledipasvir.

PCT publication WO2013101550 Al by Abbvie discloses solid dispersion of various HCV inhibitors using hydrophilic polymer.

PCT publicationWO2014120982Al by Gilead discloses solid dispersion of Ledipasvir within polymer matrix formed by a pharmaceutically acceptable polymer.

Polymorphs often improve physical and biological characteristics of mother compounds without modifying primary pharmacological activity, based on mechanism of action. Thus there is a continuing need to obtain new polymorphs of Ledipasvir having improved physical and/or chemical properties.

The amorphous premix of ledipasvir shows benefits over other formulations of Ledipasvir. For example, amorphous premix enhances flow property, stability and solubility in water or aqueous media as an essential property of active pharmaceutical ingredients determining the performance of pharmaceutical formulation.

Description of drawings:

Figure 1 : Illustrates X-ray powder diffraction(XRPD) pattern of Ledipasvir premix with syloid.

Summary of the Invention:

In one aspect, the present invention provides a stable ledipasvir premix having enhanced stability and dissolution properties.

In another aspect, the present invention provides a process for the preparation of a stable Ledipasvir premix.

In another aspect, the invention provides a pharmaceutical composition comprising said stable ledipasvir premix and at least one pharmaceutically acceptable excipient or carrier.

Detail Description of the Invention:

The term "premix" is used herein to describe combinations of Ledipasvir and at least one pharmaceutically acceptable excipient, wherein individual particles of the components cannot be distinguished using techniques such as optical microscopy. In embodiments, the drug is considered as being uniformly or non-uniformly distributed over surfaces of excipient particles. In other embodiments, the premixes are considered to be in the nature of molecular dispersions, or solid solutions. Simple mixtures of powdered ingredients will not constitute premixes.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.

The term "stable" herein means Ledipasvir that substantially does not convert to any other solid form and fulfill the standard stability criteria given in USP/EP monograph. In another embodiment of the invention, the present invention provides a stable Ledipasvir premix having enhanced flow property, stability, dissolution properties that can be easily formulated into pharmaceutical compositions. In another embodiment of the invention, the present invention provides a stable ledipasvir premix comprising crystalline or amorphous Ledipasvir and at least one pharmaceutically acceptable excipient.

Any of the pharmaceutically acceptable excipient described in the specification can be used in the process of preparing stable Ledipasvir premix.

The pharmaceutically acceptable excipients used in the process of preparing stable Ledipasvir premix may also be termed as "premixing agents". The stable premix can further be mixed with other pharmaceutically acceptable excipients to prepare a pharmaceutical formulation or composition of the present invention.

The suitable premixing agent(s) or pharmaceutically acceptable excipient(s) discussed in the specification includes but is not limited to diluents, lubricants, disintegrants, glidants, stabilizers & surface active agents or mixtures thereof. Preferably the premixing agents or pharmaceutically acceptable excipients used in the process of preparing stable Ledipasvir premix can be selected from the group consisting of polyvinyl alcohol (PVA); poly aery lie acid (PA A), poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), copovidone, hypromellose acetate succinate (AQOAT), polyacrylates, polyvinylpyrrolidone, corn starch and mixtures thereof; gums; polymers of carboxymethyl celluloses, sodium carboxymethyl cellulose, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, polyoxyethylene derivatives, propylene glycol derivatives, Zeolite, cross-linked cellulose acetate phthalate, cross-linked, microcrystalline cellulose, polyethylene oxides, polyethylene/polyvinyl alcohol copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolate, and cross-linked styrene divinyl benzene, divinylbenzene copolymers, colloidal silicon dioxide, Amberiite IRP-69, Amberiite XAD16HP. XAD4, and XAD7HP, styrene- divinylbenzene copolymers, ethylhydroxy ethyl cellulose, polyimides, polyarylonitrile, phenolic resins, regenerated cellulose, and rayon, hydroxypropyl methyl cellulose phthalate (HPMCP), polyvinyl acetate hydroxyethylcellulose, methyl cellulose, cellulose acetate trimellitate (CAT), methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, and carboxymethyl ethyl cellulose, Aerosil like but not limited to Aerosil 200, Aerosil 380 and Syloid like but not limited to Syloid AL1 , Syloid 72 FP and Syloid 244 FP and combinations comprising one or more of the foregoing agents.

In another embodiment, the invention provides a stable Ledipasvir premix with Syloid and aerosil.

In another embodiment, the present invention provides a stable Ledipasvir premix with Syloid, which is characterized by XRPD (X-ray powder diffractogram) as depicted in Figure 1.

In another embodiment, the invention provides a process for preparation of stable Ledipasvir premix comprising the steps of:

(i) providing a solution of Ledipasvir in a solvent;

(ii) adding suitable premixing agent(s); and

(iii) substantially removing the solvents from the solution to afford stable Ledipasvir premix.

The term "substantially removing" the solvent refers to at least 80%, specifically greater than about 85%, more specifically greater than about 90%, still more specifically greater than about 99%, and most specifically essentially complete (100%), removal of the solvent from the reaction mixture.

The solvent employed in step (i) is selected from halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol, isopropyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and t-butyl alcohol; ketones such as acetone, ethyl methyl ketone, diethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; water; and mixtures thereof;

The reaction of step (i) is carried out at a temperature of about 20 to about 100°C, preferably at about 50 to about 90°C and more preferably at a temperature of about 25 to about 50°C.

The suitable premixing agent of step (ii) can be any pharmaceutically acceptable excipient(s) discussed in the specification includes but not limited to diluents, Bulking agents, lubricants, disintegrants, glidants, stabilizers & surface active agents or mixtures thereof.

Preferably the premixing agents or pharmaceutically acceptable excipients used in the process of preparing stable Ledipasvir premix can be selected from the group consisting of polyvinyl alcohol (PVA); poly aery lie acid (PA A), poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), copovidone, hypromellose acetate succinate (AQOAT), poly aery lates, polyvinylpyrrolidone corn starch and mixtures thereof; gums; polymers of carboxymethyl celluloses, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, polyoxyethylene derivatives, propylene glycol derivatives, Zeolite, cross-linked cellulose acetate phthalate, cross-linked, microcrystalline cellulose, polyethylene oxides, polyethylene/polyvinyl alcohol copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene, divinylbenzene copolymers, colloidal silicon dioxide, Amberiite IRP-69, Amberiite XAD16HP. XAD4, and XAD7HP, styrene- divinylbenzene copolymers, ethylhydroxy ethyl cellulose, polyimides, polyarylonitrile, phenolic resins, regenerated cellulose, and rayon, hydroxypropyl methyl cellulose phthalate (HPMCP), polyvinyl acetate, hydroxyethylcellulose, cellulose acetate trimellitate (CAT), methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, methyl cellulose, cellulose acetate terephthalate, cellulose acetate isophthalate, and carboxymethyl ethyl cellulose, sodium carboxymethyl cellulose, Aerosil like but not limited to Aerosil 200, Aerosil 380 and Syloid like but not limited to Syloid AL1 , Syloid 72 FP and Syloid 244 FP and combinations comprising one or more of the foregoing agents, Preferably selected from corn starch and microcrystalline cellulose. Removal of solvent in step (iii) is accomplished, for example, by filtration, substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent, under inert atmosphere to obtain the stable Ledipasvir premix.

In another embodiment, the solvent is removed by evaporation. Evaporation can be achieved at sub-zero temperatures by lyophilisation or freeze-drying techniques. The solution may also be completely evaporated in, for example, a pilot plant rotavapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer ("ATFD"), or evaporated by spray drying to obtain a dry crystalline powder.

The distillation process can be performed at atmospheric pressure or reduced pressure. Specifically, the solvent is removed at a pressure of about 760 mm Hg or less, more specifically at about 400 mm Hg or less, still more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.

Solvents can also be removed by spray-drying, in which a solution comprising of Ledipasvir and a premixing agent is sprayed into the spray drier at the flow rate ranging from about 10 to about 300 ml/hr, specifically about 40 to about 200ml/hr. The air inlet temperature to the spray drier used may range from about 30° C to about 150° C, specifically from about 65 ° C to about 110 ° C and the outlet air temperature used may range from about 30 ° C to about 90 ° C. Another suitable method is vertical agitated thin-film drying (or evaporation). Agitated thin film evaporation technology involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled conditions. In vertical agitated thin-film drying (or evaporation) (ATFD-V), the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor rotation agitates the downside-flowing solution while the heating jacket heats it. The Ledipasvir premix with the premixing agent obtained by process disclosed herein may be further dried, preferably spin dried, in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.

In another embodiment, the present invention provides a pharmaceutical composition comprising Ledipasvir premix and at least one pharmaceutically acceptable excipient or carrier.

The Ledipasvir premix can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

The pharmaceutical composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like. The composition or formulation may be coated or uncoated. Coating of compositions such as tablets and caplets is well known in the art.

Although for many pharmaceutical compounds oral administration in the form of a tablet or capsule is preferred, some patients, for example elderly and paediatric patients, may have difficulties in swallowing such formulations. Therefore, liquid formulations such as oral solutions may offer a suitable alternative, avoiding the need of swallowing tablets or capsules. An oral solution further provides the possibility of a more flexible dosing regimen. In order to limit the volume of an oral solution it is necessary to have a high concentration of the active ingredient in the solution, which again requires a high solubility of the active ingredient. Hence the superior solubility of Ledipasvir premix of the present invention makes this particular solid state form especially suitable for the preparation of liquid pharmaceutical formulations such as oral solutions Pharmaceutically acceptable excipients may be utilized as required for conversion of the Ledipasvir premix into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations.

The present invention includes administration of an effective amount of Ledipasvir premix (either alone or as the active component of a pharmaceutical composition), in particular for use in the treatment of hepatitis C virus.

In a further embodiment, the present invention relates to a method for the treatment hepatitis C virus, in a subject in need of such treatment, which method comprises administering to such subject a therapeutically effective amount of Ledipasvir premix. The present invention includes the use of Ledipasvir premix in combination with other antiviral agents used in the treatment of Hepatitis C virus.

The diluents, binders, bulking agents, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations includes

Diluents:

Various useful fillers or diluents include but are not limited to starches, lactose, mannitol (Pearlitol™ SD200), cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™, Pharmatose™ and others. Different starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and starch 1500, starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch and others. Different cellulose compounds that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™ PHlOl, PH102, PH301, PH302 and PH-F20, PHI 12 microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol (Pearlitol™ SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Binders:

Various useful binders include but are not limited to hydroxypropylcelluloses, also called HPC (Klucel™ LF, Klucel EXF) and useful in various grades, hydroxypropyl methylcelluloses, also called hypromelloses or HPMC (Methocel™) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP-K29, PVP- K30, and PVP-K90), Plasdone™ S-630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (Carbopol™), methylcelluloses, polymethacrylates, and starches.

Bulking agents:

Bulking agents are ingredients which may provide bulk to a pharmaceutical composition. Various useful binders include but are not limited to PEGs, mannitol, trehalose, lactose, sucrose, polyvinyl pyrrolidone, sucrose, glycine, cyclodextrins, dextran and derivatives and mixtures thereof. Disintegrants:

Various useful disintegrants include but are not limited to carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, Kollidon™ CL, Polyplasdone™ XL, XI- 10, and INF- 10 and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33. Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches. Stabilizers:

Various useful stabilizers include basic inorganic salts, such as but not limited to basic inorganic salts of sodium, potassium, magnesium and calcium. Examples of basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like. Examples of basic inorganic salts of magnesium are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6Al₂(OH)i6.C03.4H₂0] , aluminum hydroxide-magnesium [2.5MgO.Al₂03.xH₂0], and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, and the like.

Surf ace- Active Agents:

Useful surface-active agents include non-ionic, cationic and anionic surface-active agents. Useful non-ionic surface-active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPAN™) and polyhydroxyethylenically treated sorbitan esters (TWEEN™), aliphatic alcohols and PEG ethers, phenol and PEG ethers. Useful cationic surface-active agents include quaternary ammonium salts (e.g. cetyltrimethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethenolamine stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate. Natural surface-active agents may also be used, such as for example phospholipids, e.g. diacylphosphatidyl glycerols, diaceylphosphatidyl cholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as for example soybean lecithin and egg yolk.

Lubricants:

An effective amount of any pharmaceutically acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof. Glidants:

One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variations can be used. Useful glidants include but are not limited to silicone dioxide, talc and combinations thereof.

Coloring Agents:

Coloring agents can be used to color code the compositions, for example, to indicate the type and dosage of the therapeutic agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, combinations thereof, and the like.

Useful additives for coatings include but are not limited to plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.

Plasticizers:

Various useful plasticizers include but are not limited to substances such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. An opacifier like titianium dioxide may also be present, typically in an amount ranging from about 10% to about 20% based on the total weight of the coating.

Instrument settings for XRPD

The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X'pert PRO diffractogram with Cu K radiation (λ=1.54060 A°), running at 45 kv and 40ma. To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

Examples:

Example 1:

5g of Ledipasvir was dissolved in 50ml dichloro methane (DCM) and stirred at 25-30°C. 5g colloidal silica (Syloid) was added to above solution. Reaction mass was stirred for 45 min. Reaction mass was distilled under vacuum to get solid. Obtained solid was dried under vacuum at 40°C to afford Ledipasvir adsorbed on silica particles.

Example 2:

5g of Ledipasvir was dissolved in 50ml dichloro methane (DCM) and stirred at 25-30°C. 5g colloidal silica (Aerosil) was added to above solution. Reaction mass was stirred for 45 min. Reaction mass was distilled under vacuum to get solid. Obtained solid was dried under vacuum at 40°C to afford Ledipasvir adsorbed on silica particles.

Example 3:

5g of Ledipasvir was dissolved in 50ml methanol and stirred at 25-30°C. 5g colloidal silica (Syloid) was added to above solution. Reaction mass was stirred for 45 min. Reaction mass was distilled under vacuum to get solid. Obtained solid was dried under vacuum at 40°C to afford Ledipasvir adsorbed on silica particles.

Claims

1. A stable amorphous Ledipasvir premix comprising Ledipasvir and at least one pharmaceutically acceptable excipient.

2. The stable amorphous Ledipasvir premix of claim 1, wherein the pharmaceutically acceptable excipient can be amorphous colloidal silicon dioxide or colloidal silicon dioxide.

3. The stable amorphous Ledipasvir premix of claim 2, wherein the pharmaceutically acceptable excipient is selected from syloid and aerosil.

4. The stable amorphous Ledipasvir premix of claim 3, wherein the pharmaceutically acceptable excipient is syloid.

5. The stable amorphous Ledipasvir premix of claim 4 has XRPD as depicted in figure 1.

6. A process for preparing stable amorphous Ledipasvir premix comprising the steps of: (i) providing a solution of Ledipasvir in a solvent; (ii) adding suitable premixing agent(s); and

(iii) substantially removing the solvents from the solution to afford stable amorphous Ledipasvir premix.

7. The process of claim 6, wherein a solvent of step i) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, methanol, ethanol, isopropyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and t- butyl alcohol, acetone, ethyl methyl ketone, diethyl ketone, and methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate and t-butyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether and 1,4-dioxane, acetonitrile, propionitrile, water and mixtures thereof.

8. The process of claim 6, wherein the premixing agent of step ii) is selected from amorphous colloidal silicon dioxide or colloidal silicon dioxide.

9. The process of claim 6, wherein the removal of the solvent in step iii) is accomplished by complete evaporation of the solvent, concentrating the solution or distillation, spray drying, vacuum drying, lyophilisation or freeze drying, agitated thin-film (ATFD) drying, or a combination thereof.

10. A pharmaceutical formulation comprising stable amorphous Ledipasvir premix of claim 1 and at least one pharmaceutically acceptable excipient.

11. The pharmaceutical formulation of claim 10, is in the form of a tablet, capsule, powder, granules, pellets, pellets in capsule, powder in capsule and granules in capsule.

12. A method for treating Hepatitis C comprising administering a pharmaceutical composition that comprises a therapeutically effective amount of the stable amorphous ledipasvir premix of claim 1 , along with additional pharmaceutically acceptable excipient and optionally combine with other anti-HCV agent.