DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

STABLE LIQUID DOSAGE FORM OF EDARAVONE AND ITS PREPARATION THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION

The present invention relates to storage-stable liquid edaravone formulations for parenteral use in a glass vial.

The present invention relates to process of making stable liquid edaravone formulations for parenteral use and packaging such storage-stable liquid formulations for a desired time duration in a glass vial.

BACKGROUND OF THE INVENTION

The US generic injectable market reached a value of US$ 13.7 Billion in 2020.
The rise of injectable generics show that the importance of this segment is still on the rise. Vials, Ampoules, Premix, Pre-filled syringes are primary packaging containers for modern injectables. The container of a product intended for parenteral use has to ensure the functionality, drug delivery accuracy and comply with the specifications throughout the product shelf life. Several factors have to be considered when choosing the right packaging / container for an injectable product, such as drug product formulation properties, dosage, type of application, stability, storage condition and duration, and end-user friendliness. Currently, vials account for the majority of the total market share as they are flexible, easy to dispose of and cost-effective. They are followed by premix, prefilled syringes and ampoules.

Edaravone, a member of the substituted 2-pyrazolin-5-one class, has the chemical name 3-methyl-1-phenyl-2-pyrazolin-5-one. U.S. Pat. No. 6,933,310 describes method of treatment of amyotrophic lateral sclerosis (ALS) by administering effective amount of Edaravone of physiologically acceptable salt thereof. Edaravone was first approved in 2001 in Japan, under the trade name of RADICUT, for the treatment of acute ischemic stroke (AIS) using intravenous (IV) infusion of 30 mg edaravone administered twice daily over 30 minutes for up to 14 days of treatment. In Japan, Edaravone Injection 30 mg/20 ml provided in 20 ml ampoule as RADICUT Injection 30 mg. Edaravone was also approved in Japan in June 2015 and in South Korea in December 2015 for the treatment of ALS based upon a series of clinical studies completed in Japan for ALS with the following indication: “Inhibition on progression of functional disorder in patients with amyotrophic lateral sclerosis (ALS)”. Edaravone was approved in the US in May 2017 for the broad indication “for the treatment of ALS”, under the tradename of Radicava®. Radicava® (Edaravone) injection is available as a clear, colorless liquid solution supplied for intravenous (IV) infusion in a polypropylene bag containing 30 mg edaravone in 100 mL of isotonic solution. Radicava® inactive ingredients include L-cysteine hydrochloride hydrate, sodium bisulfite, sodium chloride for isotonicity, and phosphoric acid and sodium hydroxide to adjust the solution to a pH of 4. Radicava® (Edaravone) injection is also supplied as infusion in single-dose polypropylene bags, each overwrapped with polyvinyl alcohol (PVA) secondary packaging containing an oxygen absorber and oxygen indicator, which should be pink to reflect appropriate oxygen levels. The oxygen indicator will turn blue or purple if the oxygen has exceeded acceptable levels.

However, there is a significant problem with the use of edaravone- its instability in solution. In aqueous solution edaravone is present as edaravone anions, this anion donates an electron to free radicals including oxygen to become edaravone radical. These edaravone radicals acts as a precursor to produce edaravone dimer and trimer. In order to overcome these problems, special packaging of edaravone is attempted, to ensure the storage of the solution with unchanged drug concentration. Numerous attempts were made earlier with the use of different packaging materials, for e.g. the U.S. Pat. No. 9,956,203 describes a plastic container containing edaravone solution wherein the container comprises multilayered film having six or more layers, JP2016022092 discloses plastic container formed by an outer and intermediate polypropylene layer, and an inner layer of cyclic polyolefin. It discloses that when enclosing the Edaravone-containing aqueous solution in a plastic container, it is preferable to exhaust the aqueous solution or oxygen inside the plastic container by bubbling the aqueous solution with an inert gas. Examples of the inert gas include nitrogen gas and helium gas. Nitrogen gas is preferable from the viewpoint of being inexpensive. By exhausting the Edaravone-containing aqueous solution or oxygen inside the plastic container, the oxygen concentration inside the plastic container can be lowered, so that decomposition of Edaravone can be prevented. Furthermore, in these arbitrary processes, you may sterilize as needed. JP2016022092 also discloses that it is preferable to accommodate the plastic container of the present invention in a gas barrier container, so that inside and the outside of the container do not easily transmit gas, for example, oxygen.

US20210353538A1 discloses method of producing parenteral dosage of Edaravone which are stable during storage, transportation which involves preparing a solution containing Edaravone and excipients, packaging it in pre-sterilized glass bottle with lid coated with anti-adhesive coatings which inhibit adhesion of molecules of the edaravone on the surface of the vial lid. Table 1 of US20210353538A1 disclosed the results of edaravone compositions packed in different packages and concluded that when edaravone compositions were packed in bottle of borosilicate glass, sealed with a rubber cover and stored at 250C for 3,6,12 & 24 months, the drug assay of edaravone is acceptable only for 6 months. Thus, the use of glass packages is not meeting the quality characteristics of stable edaravone liquid formulations for parenteral use.

Also U.S. publication number 20220105000 discloses a bottle or vial filled with a parenteral dosage form of edaravone and pharmaceutically accepted excipients, wherein the bottle is closed with uncoated lid. It also discloses Thermal Stability Study Results of Edaravone Injection 30 mg/100 mL with Head space oxygen more than 1% at 40o C/75% RH & 25o C/60% RH respectively.

Numerous attempts were made earlier with the use of Nitrogen and/or deaeration of water for manufacture of liquid edaravone formulations. For e.g. JP2082773B discloses edaravone aqueous solution with bisulfite and cysteine which are stabilized by deaeration of the water to be used in composition and replacing the air in container (for example, ampoule, vial, etc.) with an inert gas such as nitrogen, CN101933899 describes edaravone composition in ampoules wherein nitrogen is added before welding ampoules, CN110090225 patent discloses edaravone sodium chloride injections comprising cosolvents and antioxidant, filled in bottle under nitrogen and sterilized by moist heat at 126°C for 6-8 minutes, CN107823128 discloses preparation method of the oxygen-removing from WFI which involves heating water, vacuuming under stirring and purging nitrogen. CN108324683 discloses process of preparation of Edaravone injection which uses inert gas selected from nitrogen, carbon dioxide and helium.

Also, numerous attempts were made earlier with the use of different sterilization methods to sterilize aqueous liquid edaravone formulations but still there is a need to select an optimal sterilization method to meet the desired quality characteristics of stable edaravone liquid formulations for parenteral use. However, each of these have several disadvantages, for example, when ampoule is used for packaging, only a fixed volume of the drug can be used. Also, while opening the ampoule, small glass particles may enter solution. When glass vial is used, there is a problem due to adhesion of substance molecules to the surface of the lid. This problem can be overcome by coating the vial lid with anti-adhesive coating, but this leads to increase in the production cost. Also, when glass vial is used there are high chances of oxidation due to dissolved oxygen levels (DO) & Head space oxygen levels which were not controlled despite application of Nitrogen during several processing steps. When plastic container is used, oxygen can enter solution as the container is not tight enough. To overcome the problem of tightness with respect to plastic container, the multilayer plastic containers could be used. Although, once opened, the pack loses its integrity and impurity levels increases. This form of packaging is not cost-effective and complicates the large-scale production. Further, process of sterilization becomes tedious as plastics do not withstand high process temperature. Thus, there is a long felt need to develop a process and/or identify critical process parameters for making a storage stable aqueous liquid edaravone formulations in a glass pack which is cost-effective.

SUMMARY OF INVENTION

Aspects of the present invention relate to a storage-stable liquid dosage form for parenteral administration comprising of edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients in a glass pack.

Aspects of the present invention relate to a process of making a storage-stable liquid dosage form for parenteral administration comprising of edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients in a glass pack.

Aspects of the present invention relate to a critical process parameters for making a storage-stable liquid dosage form for parenteral administration comprising of edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients in a glass pack.

DETAILED DESCRIPTION OF THE INVENTION

The detailed description and the examples provided herein are exemplary and any modification or variation within the scope of the invention will be apparent to a person skilled in the art. Further, unless otherwise defined, all the technical and scientific terms used herein shall bear the meaning as understood by a person who is ordinarily skilled in the art. Any ranges given herein include both the lower and the upper endpoints of the range. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

The term "about," as used herein, generally refers to a range of values +/- 10% of a specified value. The term "about," also refers within the pharmaceutically acceptable limits found in the United States Pharmacopeia (USP-NF 21), 2003 Annual Edition, or available at www.usp.org, for amount of active pharmaceutical ingredients. With respect to blood levels, “about” means within FDA acceptable guidelines”.

In embodiments, the present invention provides a storage-stable liquid dosage form for parenteral administration comprising of edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients in a glass pack. The term “parenteral” in the present invention means sterile solutions or suspension of drug in aqueous or oily vehicle that are given by other than oral routes. Parenteral drugs are administered directly into the veins (i.e. intravenous), muscles (i.e. intramuscular) or under the skin (i.e. subcutaneous) or more specialized tissues such as spinal cord (intra-spinal) or spinal fluid (intra-thecal), by means of syringe and needles. The term “liquid dosage form” in the present invention means solution, suspension, emulsion or infusion fluid which are administered via parenteral route by means of syringe and needles.

The term “edaravone” in the present invention means [3-methyl-1-phenyl-2-pyrazolin-5-one] having molecular formula C10H10N2O and the molecular weight is 174.20 g/mol. The chemical structure is:

The term “pharmaceutically acceptable” in the present invention means salt, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical ingredients of a composition and are not deleterious to an individual treated with composition. The term "total impurities” in the present invention means an unwanted chemical substance which differs from the chemical composition of the drug substance. Total impurities in drug substance are the sum of all specified and unspecified impurities above the reporting threshold. The term "identified impurity” in the present invention means an impurity for which structural characterization has been achieved. The term "unidentified impurity” in the present invention means an impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (for example, relative retention). The term "specified impurity” in the present invention means an impurity that is individually listed and limited with a specific acceptance criterion in a monograph. A specified impurity can be either identified or unidentified. The term "unspecified impurity” in the present invention means an impurity that is limited by a general acceptance criterion and not individually listed with its own specific acceptance criterion. The term "edaravone dimer” in the present invention means 5,5’-dimethyl-2,2’-diphenyl-2,2’,4,4’-tetrahydro-3H,3’H-[4,4’-bipyrazole]-3,3’-dione. The term "edaravone trimer” in the present invention means 5,5’,5”-trimethyl-2,2’,2”-triphenyl-2,2’,4,4”-tetrahydro-3H,3”H-[4,4’,4”-terpyrazole]-3,3’,3”(2’H)-trione. The term “glass pack” in the present invention means Type I, Type II, or Type III container used for packaging of parenteral pharmaceutical composition, wherein said glass pack is glass ampoule, glass vial or glass bottle used for packaging of parenteral pharmaceutical composition. The term “pharmaceutically acceptable excipient” (also named as “excipients”) refers to a substance formulated alongside with the active pharmaceutical ingredient of a medicinal product and includes all kind of pharmaceutically acceptable compounds commonly used in pharmaceutical compositions and in particular parenteral liquid dosage form. The term “pharmaceutically acceptable excipient” comprise an antioxidant, a antimicrobial agent, a chelating agent, a stabilizer, a solubilizing agent, flocculating / suspending agents, a pH adjusting agent/ buffer, a tonicity modifying agent, a vehicle or a combination thereof.

In another embodiment of the present invention provides a storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition comprising an antioxidant, a antimicrobial agent, a chelating agent, a stabilizer, a solubilizing agent, flocculating / suspending agents, a pH adjusting agent / buffer, a tonicity modifying agent, a vehicle or mixture thereof. In another embodiment the present invention is a pharmaceutical composition with antioxidants wherein antioxidants are selected from the group consisting of alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, erythorbic acid, fumaric acid, malic acid, methionine, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium formaldehyde sulfoxylate, , sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, thymol, vitamin e polyethylene glycol succinate or mixture thereof. The said antioxidants are present in a concentration of at least about 0.01% w/w to about 10% w/w of the said pharmaceutical composition. In another embodiment the present invention is a pharmaceutical composition with antimicrobial agents wherein antimicrobial agents are selected from the group consisting of benzalkonium chloride, benzyl alcohol, chlorobutanol, m-cresol, myristyl gammapicolinium chloride, paraben methyl, paraben propyl, phenol, 2-penoxyethanol, phenyl mercuric nitrate, thimerosal or mixture thereof. The said antimicrobial agents are present in a concentration of at least about 0.001% w/w to about 5% w/w of the said pharmaceutical composition.

In another embodiment the present invention is a pharmaceutical composition with chelating agents wherein chelating agents are selected from the group consisting of calcium disodium EDTA (Ethylenediaminetetra acetic acid), disodium EDTA, sodium EDTA, calteridol, DTPA (Diethylenetriaminepenta acetic acid) or mixture thereof. The said chelating agents are present in a concentration of at least about 0.001% w/w to about 5% w/w of the said pharmaceutical composition.

In another embodiment the present invention is a pharmaceutical composition with stabilizer wherein stabilizers are selected from the group consisting of Aminoethyl sulfonic acid, L-arginine, asepsis sodium bicarbonate, butylhydroxyanisol, l-cysteine, cysteine hydrochloride, diethanolamine, ferric chloride, human serum albumin, hydrolyzed gelatin, inositol, d,l-methionine, polyoxyethylene castor, polyoxyethylene hydrogenated castor oil base, potassium pyrosulite, potassium thiocyanate, sodium acetate, anhydrous, sodium gluconate, sodium pyrophosphate, anhydrous, sodium sulite, sodium thioglycolate, sorbitan esters of fatty acids, trienthanolamine, zinc chloride solution or mixture thereof. The said stabilizers present in a concentration of at least about 0.01% w/w to about 10% w/w of the said pharmaceutical composition.

In another embodiment the present invention is a pharmaceutical composition with solubilizing agents wherein solubilizing agents are selected from the group consisting of polyoxyethylene sorbitan monooleate (tween 80), sorbitan monooleate polyoxyethylene sorbitan monolaurate (tween 20), lecithin, polyoxyethylene polyoxypropylene copolymers (pluronics), propylene glycol, glycerin, ethanol, polyethylene glycol (300 and 400), sorbitol, dimethylacetamide, cremophor el, benzyl benzoate, castor oil, cottonseed oil, n,n dimethylacetamide, ethanol/ethanol dehydrated, glycerin (glycerol), n-methyl-2- pyrrolidone, peanut oil, poppyseed oil, propylene glycol, saflower oil, seasme oil, soybean oil, vegetable oil or mixture thereof. The said solubilizing agents are present in a concentration of at least about 0.001% w/w to about 80% w/w of the said pharmaceutical composition.
In another embodiment the present invention is a pharmaceutical composition with flocculating / suspending agents wherein flocculating / suspending agents are selected from electrolytes, surfactant, hydrophilic colloids, viscosity building agents or mixture thereof, wherein electrolytes, surfactant, hydrophilic colloids, viscosity building agents, are selected from the group consisting of potassium/sodium chloride, potassium/sodium citrate, potassium/sodium acetate, polysorbates, polyvinylpyrrolidone, sodium carboxymethyl cellulose, acacia, gelatin, methyl cellulose or mixture thereof. The said flocculating / suspending agents are present in a concentration of at least about 0.001% w/w to about 50% w/w of the said pharmaceutical composition.

In another embodiment the present invention is a pharmaceutical composition with pH adjusting agents or buffers wherein pH adjusting agents or buffers are selected from the group consisting of acetate (sodium, acetic acid, glacial acetic acid, ammonium), ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzene sulfonic acid, benzoate sodium/acid, sodium bicarbonate, boric acid/sodium, sodium carbonate, carbon dioxide, citrate (acid, sodium, disodium, trisodium), diethanolamine, glucono delta lactone, glycine/glycine HCl, histidine HCl, hydrochloric acid, hydrobromic acid, lysine (L), maleic acid, meglumine, methanesulfonic acid, monoethanolamine, phosphoric acid, monobasic potassium, dibasic potassium, monobasic sodium, dibasic sodium, tribasic sodium, sodium hydroxide, succinate sodium/disodium, sulfuric acid, tartarate sodium/acid, tromethamine (tris) or mixture thereof.

In another embodiment the present invention is a pharmaceutical composition with tonicity modifying agents where in tonicity modifying agents are selected from the group consisting of dextrose, glycerol, Mannitol, sodium chloride or mixture. The said tonicity modifying agents present in a concentration of at least about 0.001% w/w to about 10% w/w of the said pharmaceutical composition.

In another embodiment the present invention is a pharmaceutical composition with vehicles wherein vehicles are selected from the group consisting of aqueous or non-aqueous or mixture thereof, wherein said aqueous or non-aqueous vehicles are selected from water for injection, ethanol, glycerin, propylene glycol, n–lactamide, polyethylene glycol, aminoethyl sulfonic acid, inositol, castor oil, sodium gluconate, sorbitan esters of fatty acids or mixture thereof.

In another embodiment of the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, have edaravone dimer or edaravone trimer or both the impurity content not more than 0.70%w/w, preferably not more than 0.50%w/w, more preferably not more than 0.35%w/w.

In another embodiment of the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said process utilized at least 450 mmHg vacuum during manufacturing of said storage-stable liquid dosage form.

In another embodiment, the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has dissolved oxygen content less than 1.0 ppm or 1 mg/liter.

In another embodiment, of the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, is sterilized at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes.

In another embodiment of the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has edaravone dimer or edaravone trimer or both the impurity content not more than 0.70%w/w, preferably not more than 0.50%w/w, more preferably not more than 0.35%w/w; wherein in said composition is sterilized at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes; wherein said process utilizes at least 450 mmHg vacuum during manufacturing of said storage-stable liquid dosage form, wherein said process maintains dissolved oxygen content less than 1.0 ppm or 1 mg/liter.

In another embodiment of the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition comprising an antioxidant, a antimicrobial agent, a chelating agent, a stabilizer, a solubilizing agent, flocculating / suspending agents, a pH adjusting agent / buffers, a tonicity modifying agent, a vehicle or mixture thereof, wherein said process provides composition having edaravone dimer or edaravone trimer or both the impurity content not more than 0.70%w/w, preferably not more than 0.50%w/w, more preferably not more than 0.35%w/w, wherein said composition has dissolved oxygen content less than 1.0 ppm or 1 mg/liter, wherein in said composition is sterilized at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes, wherein said process utilizes at least 450 mmHg vacuum during manufacturing of said storage-stable liquid dosage form.

In another embodiment the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said process comprises following step:
A) Adding one or more vehicle to vessel;
B) Maintaining dissolved oxygen content less than 1.0 ppm or 1 mg/liter to the solution of step A;
C) Dissolving one or more antioxidant, antimicrobial agent, chelating agent, stabilizer, solubilizing agent, flocculating / suspending agents, pH adjusting agent, tonicity modifying agent to the solution of step A with continuous stirring;
D) Maintaining the pH of solution of step C by adding one or more buffer or pH adjusting agent with continuous stirring;
E) Dissolving the edaravone or pharmaceutically acceptable salt thereof in the solution of step E with continuous stirring;
F) Adding one or more vehicle to the solution of step E to makeup the desired volume;
G) Filtering the solution of step F;
H) Filling the solution of step G to the glass pack with vacuum;
I) Sterilizing the glass pack of step H at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes,
wherein said process provides composition having edaravone dimer or edaravone trimer or both the impurity content not more than 0.70%w/w.

In another embodiment of the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients wherein said pharmaceutically acceptable excipients are selected from sodium chloride, L-cystine hydrochloride, sodium bisulfite, sodium hydroxide, phosphoric acid, water for injection or mixture thereof, wherein said process provides composition having edaravone dimer or edaravone trimer or both the impurity content not more than 0.70%w/w, preferably not more than 0.50%w/w, more preferably not more than 0.35%w/w, wherein said composition has dissolved oxygen content less than 1.0 ppm or 1 mg/liter, wherein in said composition is sterilized at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes, wherein said process utilizes at least 450 mmHg vacuum during manufacturing of said storage-stable liquid dosage form..

In another embodiment of the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said process comprises following step:
A) Adding water for injection to vessel;
B) Maintaining dissolved oxygen content less than 1.0 ppm or 1 mg/liter to the solution of step A;
C) Dissolving L-cystine hydrochloride, sodium bisulfite and sodium chloride to the solution of step B with continuous stirring;
D) Maintaining the pH of solution of step C to about pH 3-5 by adding sodium hydroxide or phosphoric acid or both with continuous stirring;
E) Dissolving the edaravone or pharmaceutically acceptable salt thereof in the solution of step D with continuous stirring;
F) Adding water for injection to the solution of step E to makeup the desired volume;
G) Optionally, adding sodium hydroxide or phosphoric acid or both to the solution of step F for maintaining about pH 3-5 with continuous stirring;
H) Filtering the solution of step F or step G for one or more time with 0.22 µm filter;
I) Filling the solution of step G to the glass pack with vacuum,
wherein vacuum used in said process is at least 450 mmHg;
wherein said process provides composition having edaravone dimer or edaravone trimer or both the impurity content not more than 0.70%w/w, preferably not more than 0.50%w/w, more preferably not more than 0.35%w/w;
wherein the composition of said process is sterilized at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes.

In another embodiment the present invention provides a process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients wherein said pharmaceutically acceptable excipients are selected from sodium chloride, L-cystine hydrochloride, sodium bisulfite, sodium hydroxide, phosphoric acid, water for injection or mixture thereof, wherein said process comprises following step:
A) Adding water for injection to vessel;
B) Maintaining dissolved oxygen content less than 1.0 ppm or 1 mg/liter to the solution of step A;
C) Dissolving L-cystine hydrochloride, sodium bisulfite and sodium chloride to the solution of step B with continuous stirring;
D) Maintaining the pH of solution of step C to about pH 3-5 by adding sodium hydroxide or phosphoric acid or both with continuous stirring;
E) Dissolving the edaravone or pharmaceutically acceptable salt thereof in the solution of step D with continuous stirring;
F) Adding water for injection to the solution of step E to makeup the desired volume;
G) Optionally, adding sodium hydroxide or phosphoric acid or both to the solution of step F for maintaining about pH 3-5 with continuous stirring;
H) Filtering the solution of step F or step G for one or more time with 0.22 µm filter;
I) Filling the solution of step H to the glass pack with vacuum,
wherein vacuum used in said process is at least 450 mmHg;
wherein said process provides composition having edaravone dimer or edaravone trimer or both the impurity content not more than 0.70%w/w, preferably not more than 0.50%w/w, more preferably not more than 0.35%w/w;
wherein said glass pack is vial;
wherein the composition of said process is sterilized at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes.

In another embodiment, the present invention provides a process and/or critical process parameters of making a storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in a glass pack.

In another embodiment,the present invention provides a storage-stable liquid dosage form for parenteral administration comprising of edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the said composition is prepared by a process comprising the following steps: (a) preparing a solution containing edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients under nitrogen purging till dissolved oxygen reaches to less than 1.0 ppm or 1 mg/liter; (b) filter the bulk solution of step (a) through a sterilized 0.22 µm; (c) filling the filtered bulk solution of step (b) in a glass vial with pre and post nitrogen blanketing and stopper with a rubber stopper under vacuum (no less than 450 mm of Hg of vacuum is applied) and sealing; (d) sterilize the vacuum stoppered vials at 1150C for 30 minutes.

The inventors of this invention unexpectedly found that, to ensure the stability and potency of oxygen-sensitive drug like Edaravone, the headspace oxygen level below 1% needs to be maintained, dissolved oxygen content less than 1.0 ppm or 1 mg/liter needs to be maintained, at least 450 mm of Hg of vacuum is applied while stoppering the vial, sterilizing the Edaravone composition at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes.

Usually, it is the general practice in vial stoppering, the headspace oxygen is 1-10% when no vacuum is applied.

The inventors of this invention unexpectedly found that, application of vacuum while stoppering the vials is critical step to ensure the headspace oxygen level below 1%, preferably below 0.5%, when no less than 450 mm of Hg of vacuum is applied while stoppering the vial. Use of vacuum and maintaining the headspace oxygen level below 1%, preferably below 0.5% produced stable compositions. The invention also uses 0.22 µm PVDF (polyvinyl difluoride) cartridge filter for microfiltration to exclude microbes and the filtrate is stored under nitrogen blanketing. The filtrate is again filtered with sterilized 0.22 µm PVDF cartridge filter for enhanced stability to produce sterile compositions. Usage of 0.22 µm PVDF cartridge filter, storing the filtrate under nitrogen blanketing and maintaining head space oxygen below 1% by application of vacuum are the important aspects of present invention.

The inventors of this invention have achieved enhanced stability of solution by combining the steps of Nitrogen purging till the dissolved oxygen reaches less than 1 ppm and application of vacuum i.e. not less than 450 mm of Hg of vacuum while stoppering the vials which reduces the head space oxygen level to below 1% preferably below 0.5%.

The term "stable" and/or “storage-stable” as used herein refers to a composition and/or a pharmaceutical formulation that retains its physical stability when stored at 40°C / 75% RH for 6 months or 25°C / 60%RH for 24 months. The term "stable" as used herein also refers to a composition and/or a pharmaceutical formulation that retains its chemical stability [i.e. Assay & RS (Related substances/ impurities)] when stored at stored at 40°C / 75% RH for 6 months or 25°C / 60%RH for 24 months.

In embodiments, the present invention provides a storage-stable liquid dosage form for parenteral administration comprising of edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient is packed in a glass vial made of borosilicate glass. In preferred embodiments, at least one pharmaceutically acceptable excipient are selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has not more than 0.70%w/w, preferably not more than 0.50%w/w, more preferably not more than 0.35%w/w of edaravone dimer, edaravone trimer or both impurities.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has not more than 0.40%w/w, preferably not more than 0.30%w/w, more preferably not more than 0.20%w/w of specified unidentified impurities.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has not more than 0.40%w/w, preferably not more than 0.30%w/w, more preferably not more than 0.20%w/w of unspecified degradation impurities.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has not more than 2.5%w/w, preferably not more than 2.0%w/w, more preferably not more than 1.5 %w/w of total degradation impurities.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has not more than 40%w/w, preferably not more than 35%w/w, more preferably not less than 30%w/w of sodium bisulfite content.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has about 200 mOsmol/Kg to about 400 mOsmol/Kg, preferably about 225 mOsmol/Kg to about 375 mOsmol/Kg, more preferably about 250 mOsmol/Kg to about 330 mOsmol/Kg of osmolarity.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has about 90%w/w to about 110%w/w of edaravone content.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has not more than 5 units of endotoxin content per 1 mg of Edaravone i.e. 5 units/mg of edaravone.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has pH of about 3.0 to about 5.0.

In another embodiment of the present invention provides a process, described in examples and above, for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein said composition, prepared by said process, has particulate matter having size = 10µm is not more than 6000 particles/vial or particulate matter having size = 25 µm is not more than 600 particles/via or both.

In embodiments, the present invention provides a storage-stable liquid dosage form for parenteral administration comprising of edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients, wherein the said parenteral liquid dosage form is stable at 250C/ 60% RH for at least 24 months.

The present invention provides Edaravone compositions with carcinogenic impurity Phenyl hydrazine content in the range of 0.0001%w/w and 0.15% w/w. 0.13989 % w/w, preferably in the range of 0.009%w/w and 0.14% w/w.

In embodiments, the present invention provides a storage-stable liquid dosage form for parenteral administration comprising of edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients, wherein the said parenteral liquid dosage form is stable at 250C / 60% RH for at least 24 months wherein the assay of edaravone is between 90% to 110% of labelled amount. The following examples are intended to serve as illustrations of the present invention only and do not restrict the scope of the invention in any manner whatsoever. The modifications in present invention falling within the scope and spirit of the appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention.

EXAMPLE 1

The formulation according to present invention was prepared as follows.

Table 1: General composition
Sr. No. Ingredients Quantity (w/w)
1 Antioxidant 0.01-10
2 Antimicrobial agent 0.001-5
3 Chelating agent 0.001-5
4 Stabilizer 0.01-10
5 Solubilizing agent 0.001-80
6 Flocculating / suspending agents 0.001-50
7 Tonicity modifying agent 0.001-10
8 pH adjusting agent q.s.
10 Vehicle q.s.

Manufacturing process:
A) Adding one or more vehicle to a vessel;
B) Dissolving one or more antioxidant, antimicrobial agent, chelating agent, stabilizer, solubilizing agent, flocculating / suspending agents, pH adjusting agent, tonicity modifying agent to the solution of step A with continuous stirring;
C) Maintaining the pH of solution of step B by adding one or more buffer or pH adjusting agent with continuous stirring;
D) Dissolving the edaravone or pharmaceutically acceptable salt thereof in the solution of step C with continuous stirring;
E) Adding one or more vehicle to the solution of step D to makeup the desired volume;
F) Filtering the solution of step E;
G) Filling the solution of step F to the glass pack with vacuum.

Table 2: Edaravone Composition
Sr. No. Ingredients Quantity
1 Edaravone 0.3 mg/mL
2 L-cysteine hydrochloride monohydrate 0.1 mg/mL
3 Sodium bisulfite 0.2 mg/ml
4 Sodium chloride 8.55 mg/ml
5 Water for injection q.s to 1 mL
6 Sodium hydroxide q.s. to adjust pH
7 Phosphoric acid q.s. to adjust pH
q.s. – Quantity sufficient.

Step-1: Hot water for injection (WFI) was collected in SS316 l preparatory vessel. The WFI was cooled to temperature 20°C-25°C and purged with nitrogen till the Dissolved Oxygen (DO) level reached to less than 1ppm. Then WFI was transferred from the preparatory vessel to the SS 316L Makeup vessel such that WFI approximately equivalent to 80% of the batch size remained in the preparatory vessel.
Step-2: To WFI in the preparatory vessel, L-cysteine Hydrochloride monohydrate was added gradually under continuous stirring. The L-cysteine Hydrochloride monohydrate container was rinsed with cooled WFI from Makeup vessel and added to the bulk solution in the preparatory vessel.
Step-3: Sodium bisulfite was added gradually to step-2 under continuous stirring. The residual was rinsed with cooled WFI from Makeup vessel and added to the bulk solution in the preparatory vessel and stirring continued till clear solution obtained.
Step-4: Sodium chloride was added gradually to step-3 under continuous stirring. The sodium chloride container was rinsed with cooled WFI from Makeup vessel and added to the bulk solution in the preparatory vessel and stirring continued till clear solution obtained.
Step-5: pH of the bulk solution was checked and adjusted if required using 0.5N Sodium Hydroxide and/or 0.1N Phosphoric acid solution. Stir the solution for 5 minutes after each addition of 0.5 N Sodium Hydroxide and/or 0.1 N Phosphoric acid solution. Record the quantity of 0.5 N Sodium Hydroxide and/or 0.1 N Phosphoric acid solution used for pH adjustment. Ensure that bulk solution Dissolved Oxygen should be < 1.0 ppm or mg/liter.
Step-6: Edaravone was added gradually to step-4 under continuous stirring. The sodium chloride container was rinsed with cooled WFI from Makeup vessel and added to the bulk solution in the preparatory vessel and stirring continued till clear solution obtained.
Step-7: The weight of solution was made upto 100% of batch size using WFI.
Step-8: pH of the solution was adjusted (3.8-4.5) and check the bulk solution clarity and Dissolved oxygen (Limit: <1.0 ppm or mg/Liter), if require purge with nitrogen. Store the bulk solution at temperature of 20°-25°C under nitrogen blanketing and protect from light till taken for further processing.
Step-9: The formulation of step 8 was filtered through 0.22 µm PVDF cartridge filter and collected into SS 316L vessel. This solution is stored under nitrogen blanketing.
Step-10: The bulk solution of step-9 was filtered using sterilized 0.22 µm PVDF cartridge filter and collect in aseptic area buffer thank
Step-11: Target fill volume was filled in 100mL clean and depyrogenated clear glass pack/vial and stoppered with bromobutyl rubber stopper under following conditions
A. without nitrogen purging; without vacuum or
B. with nitrogen; without vacuum or
C. with vacuum not less than 450 mm of Hg
and sealed with aluminium seals with PP disks.
Step-12: Stoppered glass vials of step-11 were autoclaved at 1150C for 30 minutes.

Stability of Edaravone formulation in glass vial stoppered with bromobutyl rubber stopper prepared according to example 1, was evaluated over a time period of 3 months (3 M) and 6 months (6 M) at 40°C/75%RH. Physical stability, Assay and RS (related substances/ impurities) study was conducted on the composition for example 1.

Table 2: Physical stability, pH, RS and Assay study results of edaravone formulation of example 1 at 40°C/75%RH

Test parameters specification Initial Example 1 (A) Example 1 (B) Example 1 (C)
3M 6M 3M 6M 3M 6M
Description CCS CCS CCS NA CCS CCS CCS CCS
Assay (%) 90.0 – 110.0 98.0 97.0 99.0 98.7 99.1 94.2
Related Substances
Edaravone Dimer NMT 0.33 0.03 0.09 NA 0.02 0.03 Below LOD Below LOQ
Edaravone Trimer NMT 0.33 0.01 0.17 NA 0.01 0.01 Below LOD Below LOQ
Specified unidentified impurity at RRT0.44 NMT 1.0 0.04 0.43 NA 0.18 0.17 0.25 0.24
Specified unidentified impurity at RRT0.59 NMT 0.2 0.02 0.06 NA 0.02 ND 0.03 0.03
Any unspecified degradation product NMT 0.2 0.01 0.05 NA 0.04 0.06 ND ND
Total degradation products NMT 2.5 0.11 1.06 NA 0.32 0.38 0.280 0.270

LOD: Limit of Detection (0.027 for dimer, 0.017 for trimer); LOQ: Limit of Quantification (0.083 for dimer, 0.05 for trimer); ND = Not Detected; NMT = Not More Than; CCS = Clear colourless solution; RRT=Relative Retention Time

The results of the Assay indicate that there was no substantial drop in drug potency at initial and during the storage period. The drug potency values were well within the specified limits i.e. acceptance criteria. The RS result of vials of example 1 (A) i.e. vials filled without nitrogen purging and without vacuum as well as example 1(B) i.e. vials filled with nitrogen purging and without vacuum exhibited higher impurities in accelerated conditions at 40°C/75%RH. The RS results of vials of example 1 (C) i.e. vials filled under vacuum indicate impurities were well within the specified limits i.e. acceptance criteria at accelerated conditions of 40°C/75%RH. Edaravone formulations in glass vial stoppered with bromobutyl rubber stopper were prepared with vaccum, nitrogen purging, total dissolved oxygen less than 1ppm or 1mg/L and sterilization at 115°C for 30 minutes according to example 1. Stability of these batches of formulations - 1(C), 1(D), 1(E), 1(F), 1(G), 1(H) was evaluated over a time period upto 24 Months at 25°C/60%RH. Various parameters of Physical stability, Assay, related substances, impurities were studied and are described in the table 3, table 4 and table 5.

Table 3: Physical stability, RS and Assay study results of edaravone formulation of Example 1(C) & Example 1(D) at 25°C/60%RH
Test parameters specification Initial Example 1(C) Initial Example 1 (D)
3M 6M 9M 12M 18M 24M 3M 6M 9M 12M 18M 24M
Description CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS
Assay (%) 90.0 – 110.0 99.2 98.9 98.4 94.6 93.8 97.2 97.5 99.5 100 98.6 98 96.2 99.9 97.4
Related substances (%W/W, By HPLC)
Edaravone Dimer (%) NMT 0.33 0.015 0.012 0.015 0.025 0.011 0.022 0.024 0.012 0.01 0.015 0.012 0.011 0.024 0.023
Edaravone Trimer (%) NMT 0.33 0.007 0.005 0.013 0.051 0.026 0.029 0.039 0.004 0.005 0.011 0.019 0.018 0.023 0.034
Specified unidentified impurity at RRT0.44 NMT 2.0% 0.07 0.24 0.17 0.20 0.19 0.31 0.23 0.06 0.28 0.22 0.23 0.23 0.30 0.27
Specified unidentified impurity at RRT0.59 NMT 0.2% 0.02 0.02 0.02 0.03 0.02 0.02 0.03 0.02 0.02 0.02 0.03 0.03 0.04 0.03
Any unspecified degradation product NMT 0.2% ND ND ND ND ND ND ND ND ND ND ND ND ND ND
Total degradation products NMT 4.0 0.090 0.260 0.190 0.281 0.210 0.330 0.260 0.080 0.300 0.240 0.260 0.260 0.330 0.300
Particulate matter in injections (Number of particles/vial, By light obscuration method) =10µm: NMT 6000 127 2573 627 47 813 240 627 140 673 400 47 540 160 427
=25µm: NMT 600 0 13
7
0
0
0
0 0 0 0 0 0 0 0
Sterility Should meet the USP <71> requirement Complies - - - Complies -- Complies Complies - - - Complies -- Complies

LOD: Limit of Detection (0.027 for dimer, 0.017 for trimer); LOQ: Limit of Quantification (0.083 for dimer, 0.05 for trimer); ND = Not Detected; NMT = Not More Than; CCS = Clear colourless solution.

Table 4: Physical stability, RS and Assay study results of edaravone formulation of Example 1(E) & Example 1(F) at 25°C/60%RH
Test parameters specification Initial Example 1(E) Initial Example 1 (F)
3M 6M 9M 12M 18M 24M 3M 6M 9M 12M 18M 24M
Description CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS
Assay (%) 90.0 – 110.0 100.1 99.9 98.7 97.5 95.5 99.9 97.6 98.3 99.9 98.9 96.8 94.7 99.6 96.9
Related substances (%W/W, By HPLC)
Edaravone Dimer (%) NMT 0.33 0.015 0.014 0.015 0.011 0.010 0.018 0.022 0.014 0.013 0.013 0.011 0.009 0.02 0.023
Edaravone Trimer (%) NMT 0.33 0.004 0.006 0.012 0.020 0.018 0.029 0.041 0.003 0.006 0.011 0.018 0.016 0.029 0.039
Specified unidentified impurity at RRT0.44 NMT 2.0% 0.07 0.25 0.17 0.18 0.19 0.28 0.22 0.04 0.21 0.17 0.18 0.17 0.27 0.22
Specified unidentified impurity at RRT0.59 NMT 0.2% 0.01 0.01 0.02 0.02 0.02 0.03 0.03 0.02 0.01 0.02 0.02 0.02 0.02 0.02
Any unspecified degradation product NMT 0.2% ND ND ND ND ND ND ND ND ND ND ND ND ND ND
Total degradation products NMT 4.0 0.080 0.260 0.190 0.200 0.210 0.310 0.250 0.060 0.220 0.190 0.200 0.190 0.290 0.240
Particulate matter in injections (Number of particles/vial, By light obscuration method) =10µm: NMT 6000 160 533 500 40 1773 180 173 133 1620 253 20 627 287 260
=25µm: NMT 600 7 0 0 0 80 7 0 0 27 0 0 7 0 0
Sterility Should meet the USP <71> requirement Complies - - - Complies -- Complies Complies - - - Complies Complies Complies

LOD: Limit of Detection (0.027 for dimer, 0.017 for trimer); LOQ: Limit of Quantification (0.083 for dimer, 0.05 for trimer); ND = Not Detected; NMT = Not More Than; CCS = Clear colourless solution.

Table 5: Physical stability, RS and Assay study results of edaravone formulation of Example 1(G) & Example 1 (H) at 25°C/60%RH

Test parameters specification Initial Example 1(G) Initial Example 1 (H)
3M 6M 9M 12M 18M 24M 3M 6M 9M 12M 18M 24M
Description CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS
Assay (%) 90.0 – 110.0 99.2 100.1 98.8 98.2 96.6 100.1 97.8 100.7 100.1 98.6 98.3 97.7 100.3 97.6

Edaravone Dimer (%) NMT 0.33 0.008 0.009 0.009 0.006 0.007 0.012 0.018 0.011 0.012 0.013 0.015 0.011 0.026 0.021
Edaravone Trimer (%) NMT 0.33 0.004 0.005 0.011 0.016 0.018 0.030 0.044 0.004 0.009 0.012 0.016 0.021 0.035 0.041
Specified unidentified impurity at RRT0.44 NMT 2.0% 0.04 0.23 0.18 0.19 0.19 0.31 0.24 0.03 0.23 0.16 0.18 0.29 0.29 0.24
Specified unidentified impurity at RRT0.59 NMT 0.2% 0.01 0.01 0.02 0.02 0.02 0.02 0.03 0.02 0.02 0.02 0.02 0.03 0.03 0.03
Any unspecified degradation product NMT 0.2% ND ND ND ND ND ND ND ND ND ND ND ND ND ND
Total degradation products NMT 4.0 0.050 0.240 0.200 0.210 0.210 0.330 0.270 0.050 0.250 0.180 0.200 0.320 0.320 0.270
Particulate matter in injections (Number of particles/vial, By light obscuration method) =10µm: NMT 6000 107 480 427 67 467 153 213 240 333 727 33 927 380 527
=25µm: NMT 600 0 0 0 0 0 0 0 0 0 20 0 13 0 7
Sterility Should meet the USP <71> requirement Complies - - - Complies Complies Complies Complies - - - Complies Complies Complies

LOD: Limit of Detection (0.027 for dimer, 0.017 for trimer); LOQ: Limit of Quantification (0.083 for dimer, 0.05 for trimer); ND = Not Detected; NMT = Not More Than; CCS = Clear colourless solution.

The Description, Assay & RS results of vials of Example 1 (C), 1 (D), 1 (E), 1(F), 1(G), 1(H) i.e. vials filled under vacuum, with nitrogen purging, total dissolved oxygen less than 1ppm or 1mg/L and sterilization at 115°C for 30 minutes indicate that the impurities were well within the specified limits i.e. acceptance criteria at 25°C/60%RH. Based on the above studies, it can be concluded that the stability of the drug product was maintained when filled in the glass vial and stoppered with bromobutyl rubber closure under vacuum, with nitrogen purging, total dissolved oxygen less than 1ppm or 1mg/L and sterilization at 115°C for 30 minutes. ,CLAIMS:We claim,

1. A process for preparation of storage-stable liquid composition for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein said composition has edaravone dimer or edaravone trimer or both the impurity content not more than 0.70%w/w.
2. The process as claimed in claim 1 provides pharmaceutical composition wherein said composition comprising of an antioxidant, a antimicrobial agent, a chelating agent, a stabilizer, a solubilizing agent, flocculating / suspending agents, a pH adjusting agent, a tonicity modifying agent, a vehicle or mixture thereof.
3. The process as claimed in claim 2 provides pharmaceutical composition wherein said composition comprising of sodium chloride, L-cystine hydrochloride, sodium bisulfite, sodium hydroxide, phosphoric acid, water for injection or mixture thereof.
4. The process as claimed in claim 3 wherein said process utilized at least 450 mmHg vacuum during manufacturing process.
5. The process as claimed in claim 3 wherein said process comprising the steps:
A) Adding water for injection to vessel and maintaining dissolved oxygen content less than 1.0 ppm or 1 mg/liter;
B) Dissolving L-cystine hydrochloride, sodium bisulfite and sodium chloride to the solution of A with continuous stirring;
C) Maintaining the pH of solution of B to about pH 3-5 by adding sodium hydroxide or phosphoric acid or both with continuous stirring;
D) Dissolving the edaravone or pharmaceutically acceptable salt thereof in the solution of C with continuous stirring;
E) Adding water for injection to the solution of D to makeup the desired volume;
F) Optionally, adding sodium hydroxide or phosphoric acid or both to the solution of E for maintaining about pH 3-5 with continuous stirring;
G) Filtering the solution of E or F for one or more time with 0.22 µm filter;
H) Filling the solution of G to the glass pack with vacuum;
I) Sterilizing the glass pack of H at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes.
6. The process as claimed in claim 5 wherein said process provides composition wherein said composition has pH about 3 – 5 and phenyl hydrazine content in the range of 0.0001%w/w and 0.15% w/w.
7. The process as claimed in claim 5 wherein said process provides composition wherein said composition has not more than 1.5 %w/w of total degradation impurities.
8. The process as claimed in claim 5 wherein said process provides composition wherein said composition has not less than 30%w/w of sodium bisulfite content.
9. The process as claimed in claim 5 wherein said process provides composition wherein said composition has about 250 mOsmol/Kg to about 330 mOsmol/Kg of osmolarity and not more than 5 unit/mg of edaravone of endotoxin content.
10. A process for preparation of storage-stable liquid dosage form for parenteral administration comprising edaravone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein said process comprising the steps:
A) Dissolving L-cystine hydrochloride, sodium bisulfite and sodium chloride in water for injection with continuous stirring;
B) Maintaining dissolved oxygen content less than 1.0 ppm or 1 mg/liter to the solution of A;
C) Maintaining the pH of solution of B to about pH 3 to 5 by adding sodium hydroxide or phosphoric acid or both with continuous stirring;
D) Dissolving edaravone or pharmaceutically acceptable salt thereof in the solution of C with continuous stirring;
E) Adding sodium hydroxide or phosphoric acid or both to the solution of D for maintaining about pH 3-5 with continuous stirring;
F) Filtering the solution of D or E for one or more time with 0.22 µm filter;
G) Filling the solution of E to the glass pack with vacuum;
H) Sterilizing the glass pack of G at about 110 ºC to 121 ºC for about 20 minutes to 45 minutes, preferably about 25 minutes to 40 minutes, more preferably about 30 minutes.
wherein said composition has edaravone dimer or edaravone trimer or both at concentration not more than 0.70%w/w and phenyl hydrazine content in the range of 0.0001%w/w and 0.15% w/w.