WO2023214433A1

WO2023214433A1 - Stable parenteral compositions of parecoxib

Info

Publication number: WO2023214433A1
Application number: PCT/IN2023/050429
Authority: WO
Inventors: Vaibhavi SHAH; Mayurbhai SANKALIA; Pradnya BORHADE
Original assignee: Inventia Healthcare Limited
Priority date: 2022-05-05
Filing date: 2023-05-04
Publication date: 2023-11-09

Abstract

The present invention relates to stable, lyophilized compositions comprising parecoxib, for parenteral administration. The lyophilized compositions are capable of being reconstituted in a suitable reconstitution diluent to obtain liquid parecoxib compositions, the said liquid compositions having an in-use stability of at least 48 hours. The invention provides a process for preparation of the said compositions.

Description

STABLE PARENTERAL COMPOSITIONS OF PARECOXIB

FIELD OF THE INVENTION

The present invention relates to stable, lyophilized compositions of parecoxib for parenteral administration. The invention provides a process for preparation of the said compositions.

BACKGROUND OF THE INVENTION

Parecoxib is an amide prodrug of the cyclooxygenase II (COX-2) selective, non-steroidal anti-inflammatory drug (NSAID) valdecoxib, with anti-inflammatory, analgesic, and antipyretic activity. Upon administration, parecoxib is hydrolyzed by hepatic carboxyesterases to its active form, valdecoxib. Valdecoxib selectively binds to and inhibits COX-2. This prevents conversion of arachidonic acid into prostaglandins, which are involved in the regulation of pain, inflammation, and fever.

Parecoxib, commercially available as an injection (Dynastat®), is used for the short-term treatment of postoperative pain in adults. The recommended dose is 40 mg administered intravenously (IV) or intramuscularly (IM), followed by 20 mg or 40 mg, every 6 to 12 hours, as required. Dynastat® is reconstituted with commonly used reconstitution diluents before use, using an aseptic process. Dynastat®, after reconstitution with sodium chloride solution, provides a pH of 7.5 - 8.5. Physical and chemical in-use stability, of Dynastat® reconstituted solution, is upto 24 hours, and the reconstituted solution should be used within 24 hours of reconstitution.

Parecoxib is susceptible to heat, and over a period of time, undergoes conversion to a sulphonamide impurity (valdecoxib), which being relatively insoluble in water tends to precipitate out of solution, resulting in a formulation unsuitable for parenteral administration. Hence it is desirable to minimize such conversion, to ensure complete dissolution of the parecoxib, with no particulates or precipitates.

European Patent Publication No. 1372645 relates to a pharmaceutical composition in powder form comprising water-soluble selective cyclooxygenase-2 (COX-2) inhibitory drug (in particular parecoxib sodium), a parenterally acceptable buffering agent, and not more than 10% by weight of other pharmaceutically acceptable excipient(s). The said powder is reconstitutable in a parenterally acceptable solvent liquid to form an injectable solution. EP1372645 discloses that said compositions, comprising no more than 10% by weight of bulking agents such as mannitol, reduced or eliminated conversion of parecoxib to valdecoxib. The said compositions exhibited chemical stability of parecoxib, with individual impurities not more than 1 % and total impurities not more than 5% (Example 1 of EP1372645), when compared to compositions having higher levels (> 10% of composition) of excipients (Example 2 of EP1372645). The lyophilization cycle, used to prepare such compositions, involved temperatures ranging from -60°C in the freezing phase to 45°C in the secondary drying phase, and the lyophilization cycle time was 36 hours.

US Patent Publication No. 2004/0127537 relates to a ready-to-use parenterally deliverable, liquid pharmaceutical composition, comprising water soluble parecoxib salt dissolved in a solvent liquid comprising water and a non-aqueous solubilizer. Nonaqueous solubilizer(s) solubilized the valdecoxib that was formed due to conversion of parecoxib, and inhibited precipitation of valdecoxib. Less than 5% of parecoxib was converted to valdecoxib, when composition of the invention was stored in a closed container.

European Patent Publication No. 3932397 relates to parenterally administered compositions comprising non-steroidal anti-inflammatory drugs or salts thereof. Patent publication discloses that the formation of valdecoxib from parecoxib occurs in the presence of water by a reaction catalysed by a nucleophile such as phosphate anion (PO4^3-) (commonly found in buffering agents such as phosphate buffer). Hence, formulations of EP3932397, comprising parecoxib sodium and a pH corrector, were free of buffering agents. The said buffering-agent free compositions had a pH in the range of 8.5 and 9.5, and content of sulphonamide impurity (valdecoxib) of not above 0.2%. The formulations were prepared by freeze-drying using temperatures ranging from -45°C in the freezing cycle to 50°C in the secondary drying cycle.

Prior art uses the following strategies to obtain stable parecoxib compositions for parenteral administration (with reduced impurities, in particular reduced sulphonamide impurity/valdecoxib): i. Using non-aqueous solubilizers ii. Eliminating the use of buffering agents iii. Maintaining the pH of the liquid composition in the range of 8.5 and 9.5 iv. Reducing or eliminating the use of excipients such as bulking agents (e.g. mannitol)

Parenteral compositions of the present invention, comprising parecoxib, exhibit the desired storage stability and in-use stability, despite not using prior art strategies.

It has surprisingly been found that when compositions comprising parecoxib were prepared by a lyophilization process wherein the temperatures in the lyophilization cycle did not exceed 35°C, more preferably did not exceed 30°C, and when the lyophilization cycle time was less than 30 hours, the said compositions exhibited the desired storage stability, photostability, thermal excursion stability, and freeze-thaw stability. The lyophilized parecoxib compositions exhibited physical and chemical stability, with sulphonamide impurity (valdecoxib) content not more than 0.2% by weight.

Further, it has surprisingly been found that when the said lyophilized parecoxib compositions (prepared by a lyophilization process with temperatures not exceeding 35°C, and cycle time less than 30 hours) were reconstituted to obtain a liquid parecoxib composition, the said liquid compositions had a higher in-use stability of at least 48 hours, when compared to commercially available DYNAST AT® which has an in-use stability of 24 hours. The sulphonamide impurity (valdecoxib) content was found to be not more than 0.05% by weight at the end of 48 hours.

The said liquid compositions when further diluted with infusion fluids, provided an in-use stability of upto 2 hours. The sulphonamide impurity (valdecoxib) content was found to be not more than 0.05% by weight at the end of 2 hours.

Thus, process for manufacture of the parecoxib compositions of the present invention, which use reduced processing temperatures and reduced processing time as compared to the cited prior art, result in parecoxib compositions with improved storage stability and in-use stability.

OBJECTS OF THE INVENTION

Principal object of the present invention is to provide stable, lyophilized compositions comprising parecoxib, for parenteral administration. Another objective of the present invention is to provide a process for the manufacture of the stable, lyophilized compositions comprising parecoxib.

Yet another objective of the present invention is to provide stable, lyophilized parecoxib compositions, the said compositions being stable and storable, at room temperature conditions for at least 24 months, and a process for manufacture of the said compositions.

Yet another objective of the present invention is to provide stable, lyophilized parecoxib compositions, the said compositions being photostable, and a process for manufacture of the said compositions.

Yet another objective of the present invention is to provide stable, lyophilized parecoxib compositions, the said compositions being stable to temperature excursion cycles and freeze-thaw cycles, and a process for manufacture of the said compositions.

Yet another objective of the present invention is to provide stable, lyophilized parecoxib compositions, the said compositions being reconstitutable in reconstitution diluents to obtain liquid parecoxib compositions, wherein the said liquid compositions have an in-use stability of at least 48 hours.

Yet another object of the present invention is to provide stable parecoxib compositions free of stabilizers.

SUMMARY OF THE INVENTION

The present invention relates to stable, lyophilized compositions, comprising parecoxib, for parenteral administration. The present invention also provides a process for the preparation of such compositions.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides stable, lyophilized compositions comprising parecoxib for parenteral administration.

“Solid composition” or “solid parecoxib composition” or “lyophilized composition” as used to herein refers to the lyophilized parecoxib composition which may be form of powder, cake, flakes, or granules. “Liquid composition” or “liquid parecoxib composition” as used to herein refers to the liquid that is obtained, after reconstitution of solid parecoxib composition with a suitable reconstitution diluent.

“Room temperature storage conditions” as used herein refers to temperatures of 25°C ± 2°C to 30°C ± 2°C, and relative humidities of 60% ± 5% to 75% ± 5% relative humidity (RH). Room temperature refers to the temperature and/or humidity conditions prevailing in a work area, which range from 25°C ± 2°C and 60% ± 5% relative humidity for Mediterranean and subtropical climatic regions (Zone II of the ICH Stability Climatic Zone), to 30°C ± 2°C and 75% ± 5% relative humidity for hot and highly humid regions (Zone IVB of the ICH Stability Climatic Zone). These temperature and/or humidity ranges encompass the usual and customary working environment and temperatures that are generally experienced in pharmacies, hospitals, and warehouses, and during shipping, in these regions. ICH guidelines recommend conducting long-term storage stability studies at the “room temperature conditions” of the various zones to establish its stability and shelf-life.

“Accelerated storage conditions” as used herein refers to 40°C ± 2°C and 75% ± 5% relative humidity.

“Physical stability” or “physical stable” as used herein means that the physical characteristics of the composition, such as appearance, moisture content, pH, osmolality, and reconstitution time, are within the acceptance criteria.

“Chemical stability” or “chemically stable” as used herein means that chemical characteristics of the composition, such as content of parecoxib, content of sulphonic acid impurity, content of sulphonamide impurity, and content of total impurities, are within the acceptance criteria.

“Reconstitution” as used herein refers to the process of adding a reconstitution diluent to a solid parecoxib composition to prepare a liquid parecoxib composition, suitable for parenteral administration. “Reconstitution Diluent” as used herein refers to the solvent(s) or solution(s) used for reconstitution.

“Stable, solid, lyophilized compositions” as used herein refers to solid parecoxib compositions that are physically and chemically stable, for at least 24 months at roomtemperature storage conditions, and for at least 6 months at accelerated storage conditions.

“Stable liquid compositions” or “in-use stable liquid compositions” or “in-use stability” as used herein refers to liquid parecoxib compositions that are physically and chemically stable, immediately after reconstitution of solid parecoxib compositions, and for at least at least 48 hours (2 hours) after reconstitution.

“Photostable” or “photostability” as used herein refers to parecoxib compositions that are physically and chemically stable, on exposure to light (in accordance with the photostability study).

“Infusion administration” as used herein refers to the process of further diluting liquid parecoxib compositions, by mixing the said liquid compositions with infusion fluids. Injecting the reconstituted liquid composition into an infusion bag comprising infusion fluids is a preferred process of “infusion administration”.

“Infusion Fluid” as used herein refers to fluids/solutions that are used for further diluting liquid parecoxib compositions for infusion administration.

“Dissolved Oxygen” as used herein refers to the content of oxygen dissolved in a vehicle or liquid composition.

“Headspace Oxygen” as used herein refers to the content of oxygen in the headspace of a closed container filled with a composition. It refers to the oxygen content in the gas mixture present in the volume of the closed container unoccupied by the composition.

“Parecoxib” as used herein includes parecoxib, and its pharmaceutically acceptable salts, hydrates, derivatives or solvates thereof. Parecoxib can be in crystalline and/or amorphous form. Parecoxib sodium is the preferred salt. The present invention relates to a stable, solid, lyophilized composition comprising parecoxib, for parenteral administration.

The stable, solid, lyophilized parecoxib composition is capable of being reconstituted with a suitable reconstitution diluent(s) to give a stable liquid parecoxib composition, for parenteral administration.

Liquid parecoxib compositions, for parenteral administration, can be in the form of solutions, suspensions, colloids, or emulsions. The preferred form is the solution form.

Liquid parecoxib compositions can be parenterally administered, as a bolus, by intravenous, subcutaneous, intra-dermal, intra-muscular, or intra-arterial route. The intravenous route is the preferred route.

In an aspect, stable liquid parecoxib compositions are further diluted with an infusion fluid for infusion administration. Infusion administration of parecoxib can be intermittent or continuous, and can be through the intravenous, subcutaneous, intra-dermal, intramuscular, or intra-arterial route. The intravenous route is the preferred route.

Stable, solid, lyophilized compositions comprise parecoxib in concentrations ranging from about 50% to about 99%, preferably from about 60% to about 99%, more preferably from about 70% to about 95%, and most preferably from about 80% to about 95% by weight of the solid composition.

Stable liquid compositions comprise parecoxib in concentrations ranging from about 0.1 mg/ml to about 100 mg/ml, preferably from about 0.5 mg/ml to about 80 mg/ml, more preferably from about 0.5 mg/ml to about 75 mg/ml, and most preferably from about 1 mg/ml to about 50 mg/ml.

Stable parecoxib compositions of the present invention, comprise excipients selected from buffering agents, pH-adjusting agents, tonicity adjusting agents, diluents, preservatives, vehicles, reconstitution diluents, and/or infusion fluids.

In an embodiment, the stable parecoxib compositions comprise parecoxib and a buffering agent. In another embodiment, the stable parecoxib compositions comprise parecoxib, a buffering agent, and a pH-adjusting agent.

In yet another embodiment, the stable parecoxib compositions consist of parecoxib and a buffering agent.

In yet another embodiment, the stable parecoxib compositions consist of parecoxib sodium and phosphate buffer.

In yet another embodiment, the stable compositions of the present invention consist of parecoxib sodium, phosphate buffer, and a pH-adjusting agent.

Buffering agents, in stable parecoxib compositions comprising parecoxib, can be salts of an acid or a base. Buffering agents are selected from those known in the art and can be citrates, glycine, acetates, phosphates, carbonates, other organic buffers, and the like. Suitable buffering agents can illustratively be selected from sodium and potassium phosphates, sodium and potassium citrates, mono-, di- and triethanolamines, 2-ammo- 2-(hydroxymethyl)-l,3-propanediol (tromethamine), and mixtures thereof. Preferred buffering agents are selected from dibasic sodium phosphate, dibasic potassium phosphate, and tromethamine. An especially preferred buffering agent is dibasic sodium phosphate, for example dibasic sodium phosphate heptahydrate.

Lyophilized parecoxib compositions comprise buffering agent(s) in concentrations ranging from about 1 % to about 50%, or from about 1 % to about 40%, or from about 5% to about 30%, or from about 5% to about 20%, by weight of the composition.

Liquid parecoxib compositions comprise buffering agent(s) in concentrations ranging from 0.01 mg/ml to about 100 mg/ml, or from about 1 mg/ml to about 60 mg/ml, or from about 1 mg/ml to about 40 mg/ml of the said liquid composition, or from about 1 mg/ml to about 30 mg/ml. pH-adjusting agents in stable parecoxib compositions comprising parecoxib can be acid or base. The base can be oxides (such as calcium oxide, magnesium oxide), hydroxides of alkali metals or alkaline earth metals (such as sodium hydroxide, potassium hydroxide, calcium hydroxide), carbonates (such as sodium carbonate, sodium bicarbonates, potassium carbonates, potassium bicarbonates), bicarbonates, or mixtures thereof. The acid can be mineral acids or organic acids such as hydrochloric, nitric, phosphoric, acetic, citric, sulfuric, fumaric, maleic, malic, tartaric, methanesulfonic, naphthalenesulfonic, p- toluenesulfonic, lactic, ascorbic acid, and glycine hydrochloride.

Tonicity agents can be selected from sodium chloride, potassium chloride, mannitol, glycerol, sorbitol, glucose, xylitol, trehalose, maltose, maltitol, or mixtures thereof.

Diluents can be selected from mannitol, sucrose, maltose, xylitol, glucose, starches, sorbitol, and the like, and are present in amounts ranging from 1 % to 20% by weight of the composition.

Preservatives are present in concentrations of about 0.5% by weight of the composition. Suitable preservatives include methylparaben, propylparaben, phenol, and benzyl alcohol.

Stabilizers in the stable parecoxib compositions can be selected from antioxidants, chelating agents, and mixtures thereof.

In a preferred embodiment, the stable parecoxib compositions are free of stabilizers.

Vehicles, used in the manufacture of solid, lyophilized parecoxib compositions can be selected from aqueous vehicles such as water for injection, alcohols (such as ethyl alcohol), or glycols (such as propylene glycol, butylene glycol, glycerol, polyethylene glycol), and non-aqueous vehicles like polyoxyethylated castor oils, oils (such as corn oil, cottonseed oil, sesame oil, peanut oil), fixed oils, ethyl oleate, isopropyl myristate, and benzyl benzoate. Preferred vehicle is water for injection.

Stable, solid, lyophilized parecoxib compositions are reconstituted with reconstitution diluent(s), to obtain stable liquid parecoxib compositions. The lyophilized compositions are preferably, aseptically reconstituted.

Reconstitution diluents are selected from those known in the art such as 0.9% w/v sodium chloride solution for injection, bacteriostatic 0.9% w/v sodium chloride solution for injection, 5% w/v glucose (dextrose) solution for injection, Ringer-Lactate solution for injection, 0.45% w/v sodium chloride and 5% w/v glucose solution for injection, Ringer- Lactate solution and 5% w/v glucose solution for injection, and 5% w/v glucose and 0.45% w/v sodium chloride solution for injection.

In a preferred embodiment, the reconstitution diluent is selected from 0.9% w/v sodium chloride solution for injection, bacteriostatic 0.9% w/v sodium chloride solution for injection, 5% w/v glucose solution for injection, and 0.45% w/v sodium chloride and 5% w/v glucose solution for injection.

Volume of the reconstitution diluent may range from about 0.25 ml to about 10 ml, preferably from about 0.25 ml to about 5 ml, and more preferably from about 0.5 ml to 2 ml.

In an embodiment, solid composition equivalent to 20 mg dose of parecoxib is reconstituted in about 1 ml of reconstitution diluent.

In another embodiment, solid composition equivalent to 40 mg dose of parecoxib is reconstituted in about 2 ml of reconstitution diluent.

Liquid parecoxib compositions, obtained on reconstitution, have an in-use stability for at least about 12 hours, preferably for at least 24 hours (1 day), and more preferably for at least 48 hours (2 days).

Liquid parecoxib compositions, obtained after reconstitution, can be further diluted with infusion fluids for parenteral administration, such that the liquid compositions are physically and chemically stable, on immediate dilution and for at least 1 hour, preferably for at least 2 hours, when stored at 25°± 2°C after dilution.

In an aspect, liquid parecoxib compositions comprising parecoxib, are aseptically diluted with infusion fluids for infusion administration.

In another aspect, liquid parecoxib compositions comprising parecoxib, are administered through infusion by injecting the liquid compositions into an infusion bag comprising infusion fluids.

Infusion fluids are selected from those known in the art such as 0.9% w/v sodium chloride solution in water, 5% w/v glucose (dextrose) solution in water, 0.45% w/v sodium chloride solution, ringer’s solution, ringer-lactate solution, ringer-lactate solution in 5% w/v glucose solution in water, and mixtures thereof.

Liquid compositions comprising parecoxib, are diluted with infusion fluids such that the concentration of parecoxib after dilution is 10 mg/ml or 5 mg/ml or 2 mg/ml.

Process for manufacture of stable, lyophilized, parecoxib compositions comprise one or more steps selected from dissolving/dispersing parecoxib in a vehicle, dissolving/dispersing excipients in a vehicle, homogenization, pH adjustment, sparging with non-oxygen containing inert gas, adding vehicle to obtain the final volume, filtration, filling of a container, sealing of the container, spray-drying, fluid bed drying, freeze drying (lyophilization), and/or sterilization.

Process for manufacture of stable, lyophilized, parecoxib compositions comprises the step of lyophilization, wherein the temperature during the lyophilization cycle does not exceed 35°C, preferably does not exceed 30°C

In an embodiment, the process for manufacture of the stable, solid, lyophilized parecoxib compositions comprises the steps of:

• preparing a parecoxib solution;

• filling the parecoxib solution in a suitable container;

• partially stoppering the container;

• subjecting the sealed container to a lyophilization cycle. wherein the temperature during the lyophilization cycle does not exceed 35°C, preferably does not exceed 30°C.

The lyophilization cycle, used in the manufacture of solid, parecoxib compositions of the present invention, comprises a freezing phase, a primary drying phase, and a secondary drying phase.

The minimum temperature used in the freezing phase (first phase) of the lyophilization cycle can be in the range of about -30°C to about -60°C, or about -30°C to about -50°C, or about -40°C to about -50°C. The temperature, during the primary drying phase (second phase) of the lyophilization cycle, is increased from about -50°C or about -45°C to about -10°C or about -5°C or about 0°C.

The temperature during the secondary drying phase (third phase) of the lyophilization process does not exceed 35°C, preferably does not exceed 30°C.

In an aspect, in the secondary drying phase (third phase) of the lyophilization cycle, the temperature is increased from about -10°C or about -5°C or about 0°C to about 35°C or about 30°C.

The total duration of the lyophilization cycle (lyophilization cycle time) ranges from 20 hours to 35 hours, preferably from 20 hours to 30 hours, and more preferably from 22 hours to 30 hours.

In an embodiment, the lyophilization cycle time ranges from about 22 hours to about 25 hours.

The process for manufacture of parecoxib solution for lyophilization comprises steps selected from:

• sparging vehicle with a non-oxygen containing inert gas;

• dissolving parecoxib and/or excipient(s) in a vehicle with continuous stirring or homogenization to give parecoxib solution;

• adjusting the pH of parecoxib solution using pH-adjusting agents;

• sparging parecoxib solution with non-oxygen containing inert gas;

• adding vehicle to obtain the final volume of the parecoxib solution;

• filtering the parecoxib solution;

• filling the parecoxib solution in a container;

• flushing container headspace with non-oxygen inert gas; and

• sealing the container.

Non-oxygen containing inert gas, used in sparging, is selected from nitrogen, argon, helium, and neon. Nitrogen is the preferred non-oxygen containing inert gas.

In a preferred embodiment, the vehicle is water for injection. In an aspect, the vehicle is sparged with a non-oxygen containing inert gas till the dissolved oxygen content is not more than 3 ppm, preferably not more than 2 ppm and more preferably not more than 1 ppm;

In another aspect, during the process of manufacture the headspace in the container is overlayed with non-oxygen containing inert gas till the oxygen content in the headspace gas is not more than 5%, preferably not more than 4%, more preferably not more than 3%, and most preferably not more than 2% by volume.

In an embodiment, the process for manufacturing the solid, lyophilized composition of parecoxib sodium comprises the steps of:

(i) preparing a solution comprising parecoxib sodium, phosphate buffer and a vehicle,

(ii) filling the parecoxib solution in a container, and partially stoppering the container;

(iii) subjecting the container from step (ii) to a lyophilization cycle of less than 30 hours, wherein, the temperature during the lyophilization cycle does not exceed 35°C.

In an aspect of the embodiment, the solution of parecoxib sodium is prepared using the steps of:

(i) sparging vehicle with a non-oxygen containing inert gas till the dissolved oxygen content is not more than 1 ppm;

(ii) dissolving phosphate buffer in the vehicle from step (i), and adding pH-adjusting agents to adjust the pH of the solution from about 8 to about 8.5;

(iii) dissolving parecoxib sodium in the vehicle from step (ii), and adding pH adjusting agents to adjust the pH of the solution from about 8 to about 8.5;

(iv) adding vehicle to the solution from step (iii) and mixing it, to obtain the final batch volume of the parecoxib sodium solution; and

(v) filtering the parecoxib sodium solution from step (iv) through at least two filters.

Solid, lyophilized parecoxib compositions when reconstituted with a suitable reconstitution diluent, provide liquid compositions which are parenterally administered. The process of reconstitution is an aseptic reconstitution process, comprising one or more steps selected from:

• removing the cap/seal, of the container containing solid compositions of parecoxib, to expose the rubber stopper; • withdrawing the required quantity of a reconstitution diluent with a sterile syringe and needle;

• inserting the needle through the rubber stopper;

• injecting and transferring the reconstitution diluent into the container;

• dissolving the solid, lyophilized parecoxib composition completely using a gentle swirling motion to give a liquid composition in the form of a solution.

Stable parecoxib compositions can be sterilized through autoclaving, dry-heat sterilization, or filtration using filters such as nylon, polycarbonate, cellulose acetate, polyvinylidene fluoride (PVDF), and polyethersulfone (PES). Pore sizes of the filters may range from about 0.1 microns to about 0.25 microns, preferably 0.22 microns.

In an aspect the liquid parecoxib compositions are sterilized by filtration through at least two filters, which may have the same or different pore sizes.

In an embodiment, the liquid parecoxib compositions are sterilized by filtration through at least two filters, one filter having a pore size 0.45 microns and the second filter of pore size 0.22 microns.

Stable parecoxib compositions of the present invention are packed in containers such as vials, bottles, ampoules, cartridges, flexible bags and pre-filled syringes. The said containers maybe made of glass or plastic, or any other suitable material. The containers may be clear, colorless or amber coloured (for light protection).

Evaluation of solid and liquid parecoxib compositions was carried out by analysing the physical characteristics such as appearance, water content, reconstitution time, pH, and osmolality, and the chemical characteristics such as parecoxib content, sulphonic acid impurity content, sulphonamide impurity content, and total impurities content.

Storage stability studies of lyophilized parecoxib compositions was conducted in one or more of the following conditions: i) 40°C ± 2°C and 75% ± 5 % relative humidity (40°C/75%RH) ii) 30°C ± 2°C and 75% ± 5 % relative humidity (30°C/75%RH) iii) 25°C ± 2°C and 60% ± 5% relative humidity (25°C/60%RH) Storage stability studies were conducted in an upright orientation or inverted orientation of the container.

Photostability (Light Exposure) studies of the solid, lyophilized parecoxib compositions was conducted by exposing lyophilized vials of parecoxib compositions to light providing an overall illumination of not less than 1.2 million lux hours, and an integrated near ultraviolet energy of not less than 200 watt hours/square meter as per the guidelines of ICH Q1 B (Photostability testing of New Drug Substances and Products), by placing them horizontally in the Photostability Chamber at 25°C (room temperature condition) against the light source.

Thermal excursion studies were conducted by subjecting solid, lyophilized parecoxib compositions to a temperature cycle of -20°C ± 5°C for 2 days followed by 60 ± 2°C for 2 days (total study time 4 days).

Freeze-thaw studies were conducted by subjecting solid, lyophilized parecoxib compositions to a temperature cycle of -20°C ± 5°C for 2 days followed by 40° ± 2°C for 2 days, and continuing the study for three such cycles (total study time 12 days).

In-use stability studies was conducted by reconstituting solid, lyophilized composition of parecoxib with a reconstitution diluent to obtain a liquid solution composition of concentration of 20 mg/ml of parecoxib and swirled gently to ensure the complete dissolution of all the contents of the vial. Immediately after reconstitution, the liquid solution was evaluated for physical and chemical characteristics (initial time-point). The said liquid solution composition was stored at 25°± 2°C and analysed for physical and chemical characteristics at 12 hours, 24 hours, and 48 hours of storage.

At the end of each study (storage stability, photostability, thermal excursion, or freezethaw), the solid parecoxib composition was analysed for appearance, moisture content, and/or reconstitution time, and after reconstituted with a reconstitution diluent it was analysed for appearance, pH, osmolality, parecoxib content, sulphonic acid impurity content, sulphonamide impurity content, and/or total impurities content. At the end of the in-use stability study the liquid parecoxib composition was analysed for appearance, pH, osmolality, parecoxib content, sulphonic acid impurity content, sulphonamide impurity content, and/or total impurities content.

Solid, lyophilized parecoxib composition should appear as white to off-white lyophilized cake/powder, and the liquid parecoxib composition should be a clear colorless liquid, free from visible particulates.

Water content of solid compositions of parecoxib was determined by the Karl Fischer Titration method. The acceptable limit (acceptance criteria) of water content of the solid compositions of parecoxib is not more than 5.0% w/w, preferably not more than 4.0% w/w.

Reconstitution time is evaluated by determining the time required for the solid, lyophilized parecoxib composition to completely dissolve in the reconstitution diluent, to give a liquid parecoxib composition. Acceptable limit (acceptance criteria) for reconstitution time is not more than 120 seconds, preferably not more than 90 seconds, more preferably not more than 60 seconds, and most preferably not more than 30 seconds. pH of the liquid parecoxib compositions, was evaluated using a suitable pH meter. The acceptable limits (acceptance criteria) of pH are from 6.5 to 9.5, preferably from 7.0 to 9.0, and more preferably from 7.5 to 8.5.

Tonicity/osmolality of the liquid parecoxib compositions was evaluated for using a Freezing Point Osmometer (Osmomat 3000) using 0.9% w/v sodium chloride solution as the standard. The acceptable limit (acceptance criteria), of osmolality of liquid parecoxib compositions, is from about 100 mOsmol/kg to about 800mOsmol/kg, preferably from about 200 mOsmol/kg to about 700 mOsmol/kg.

Content of parecoxib (assay) in parecoxib compositions is determined by liquid chromatography, and the acceptable limit (acceptance criteria) of parecoxib content is from about 90% to about 1 10%, preferably from about 95% to about 1 10%, more preferably from about 97% to about 110%, and most preferably from about 99% to about 1 10%, by weight of the label claim. Content of sulphonic acid impurity, in parecoxib compositions, is determined by liquid chromatography. The acceptable limit (acceptance criteria) of sulphonic acid impurity content is not more than 0.25%, or not more than 0.2%, or not more than 0.15%, or not more than 0.1 %, by weight, or not more than 0.05%, or not more than 0.01%, by weight.

Content of sulphonamide impurity, in parecoxib compositions, is determined by liquid chromatography. The acceptable limit (acceptance criteria) of sulphonamide impurity content is not more than 0.5%, or not more than 0.4%, or not more than 0.3%, or not more than 0.2%, by weight.

In preferred compositions, sulphonamide impurity content, in parecoxib compositions, is not more than 0.18%, or not more than 0.15%, or not more than 0.13%, or not more than 0.08%, or not more than 0.1 %, or not more than 0.05%, by weight.

Content of total impurities in parecoxib compositions is determined by liquid chromatography. The acceptable limit (acceptance criteria) of total impurity content is not more than 3%, or not more than 2.5%, or not more than 2%, or not more than 1 %, or not more than 0.75%, or not more than 0.5%, or not more than 0.25%, or not more than 0.2%, by weight.

The invention is now illustrated with non - limiting examples.

Example 1 : Solid Compositions of Parecoxib

Water for injection was purged with nitrogen gas till dissolved oxygen level was not more than 1 ppm. Water for injection (52 liters) was taken in a manufacturing tank and disodium hydrogen phosphate heptahydrate (174.2 g) was added and continuously stirred till a clear solution was obtained. pH of the solution was adjusted to about 8.5 ± 0.1 using 0.1 M phosphoric acid. Parecoxib sodium (1 .38 kg) was added to the solution and continuously stirred till a clear solution was obtained. pH of the solution was adjusted to pH 8-8.5 using 0.1 N sodium hydroxide solution or 0.1 M phosphoric acid. The volume of the solution was made up to 65 liters by adding Water for Injection under continuous stirring. The manufacturing process was carried out under carried out under an overlay of nitrogen gas such that dissolved oxygen content was not more than 2 ppm. The bulk solution was filtered through Dual Layer Asepticap® KS PES Membrane Capsule Filter (0.45 micron and 0.2 micron), under 0.2 micron filtered nitrogen gas blanket. The solution was filled into sterilized 5 ml clear glass vials such that each vial had 2.05 ± 0.3 ml of fill volume. The vials were partially stoppered using sterilized, 13 mm Bromobutyl igloo type lyophilization rubber stopper. The partially stoppered vials were loaded into the Epsilon 2-6D LSC Plus Lyophilizer and lyophilized using following parameters.

Table 1 : Lyophilization cycle parameters

On completion of the lyophilization cycle, vacuum was released with 0.2 micron filtered nitrogen gas at 750 torr pressure, and the vials capped. The capped vials were unloaded from the lyophilizer and sealed using 13mm aluminium flip-off seals, to prevent reabsorption of moisture from the atmosphere and to maintain sterility.

Parecoxib solid compositions prepared in accordance with example 1 showed water content of about 1 .95% and about 2.09 %w/w.

Example 2: Liquid compositions of Parecoxib

Solid composition (lyophilized powder) of parecoxib was prepared in accordance with Example 1 . Flip-off caps of vials from Example 1 were removed to expose the central portion of the rubber stopper of vials. The required volume of reconstitution diluent was withdrawn and injected through the central portion of the rubber stopper into the vials of Example 1 , to give a 20 mg/ml liquid composition of parecoxib. The vial was mixed by gentle swirling motion.

In-Use Stability Study: The reconstituted vials were stored at 25° ± 2°C, and samples withdrawn after 12 hours, 24 hours, and 48 hours for evaluation, the results of which are provided in Table 2. At the initial time point, liquid composition was a clear, colorless solution, free from visible particulates. No change in the appearance of the liquid composition was observed after reconstitution and storage for 24 hours and 48 hours.

Table 2: In-use stability of Liquid compositions of Example 2

Storage Stability

Parecoxib solid compositions (Batch size 0.35 liters), prepared in accordance with Example 1 , was studied for storage stability at room temperature and accelerated stability conditions, in upright and inverted positions, the results of which are given in Table 3. The lyophilized composition was in the form of a white to off-white cake, and there was no change in the appearance of the composition during the storage stability study.

Lyophilized compositions, which were subjected to storage stability studies, were reconstituted, and evaluated, the results of which are given in Table 4. The liquid composition, at the initial time point, was a clear, colorless solution, free from visible particulates. There was no change in the appearance of the liquid composition during the storage stability study. Table 3: Storage stability of lyophilized parecoxib compositions

M: Month(s); ‘f: Upright orientation of vial; Inverted orientation of vial

Table 4: Storage stability of lyophilized parecoxib compositions

M: Month(s); ‘f: Upright orientation of vial;

Inverted orientation of vial; ND: Not detected

Lyophilized parecoxib compositions (Batch size 65 litres), prepared in accordance to Example 1 , were subjected to storage stability studies. The results are given in Table 5. Lyophilized compositions, which were subjected to storage stability studies, were reconstituted and the resultant liquid compositions evaluated, the results of which are given in Table 6.

Table 5: Storage stability of lyophilized parecoxib compositions

M: Month(s); ‘f: Upright orientation of vial; Inverted orientation of vial

Table 6: Storage stability of lyophilized parecoxib compositions

M: Month(s); ‘f: Upright orientation of vial; Inverted orientation of vial; ND: Not detected Photostability Study (Light Exposure Study)

Lyophilized parecoxib composition was prepared using a composition and process similar to Example 1 . Vials, containing the solid composition were subjected to Photostability Study.

After light exposure, the lyophilized composition was evaluated for appearance. The composition was then reconstituted with 0.9% w/v sodium chloride solution for injection (reconstitution diluent) to give a liquid composition of strength of 20 mg/ml of parecoxib. Results of the evaluation of the liquid composition are provided in Table 7.

Table 7: Photostability study evaluation

Thermal excursion studies:

Solid compositions prepared in accordance to Example 1 were subjected to a thermal excursion study. At the end of 4 days of exposure, the solid composition was analysed for appearance. The composition was reconstituted with 0.9% w/v sodium chloride solution for injection (reconstitution diluent) to give a liquid composition of strength of 20 mg/ml of parecoxib. Results of the evaluation of the liquid composition are provided in Table 8.

Table 8: Temperature Excursion Study evaluation

ND: Not detected

Freeze-thaw studies:

Solid compositions prepared in accordance to Example 1 were subjected freeze-thaw study. At the end of 3 cycles, the lyophilized composition was analysed for appearance. The composition was reconstituted with 0.9% w/v sodium chloride solution for injection (reconstitution diluent) to give a liquid composition of strength of 20 mg/ml of parecoxib. Results of the evaluation of the liquid composition are provided in Table 9.

Table 9: Freeze-thaw Study evaluation

ND: Not detected

Example 3: Liquid Infusion Composition of Parecoxib

Lyophilized compositions were reconstituted in accordance with Example 2 using three reconstitution diluents - 0.9% w/v sodium chloride solution for injection, 5% w/v glucose solution, and 0.45% w/v sodium chloride and 5% w/v glucose solution for injection, such that the concentration of parecoxib in the liquid composition was 20 mg/ml. After reconstitution, the required volume of liquid composition was withdrawn and injected into the infusion bags containing infusion fluids, such that the concentration of parecoxib after dilution with the infusion fluids was 2 mg/ml. The solutions were thoroughly mixed by gentle manual rotation. The compatibility of the liquid compositions with infusion fluids was studied by storing the admixture at 25°± 2°C and analysing the admixtures after 2 hours. The results are provided in Table 10. Table 10: Infusion fluid compatibility study evaluation

Tables 3-5 show that lyophilized parecoxib compositions of the present invention, on storage both in an upright orientation or inverted orientation, are stable at room temperature storage conditions for at least 24 months and at accelerated storage conditions for at least 6 months, with sulphonamide impurity content not more than 0.15% by weight. Tables 7-9 show that lyophilized parecoxib compositions of the present invention, are stable to thermal excursion cycles, freeze-thaw cycles, and light exposure studies, with sulphonamide impurity content not more than 0.1 % by weight. Table 2 shows that liquid compositions comprising parecoxib, obtained by reconstitution of stable lyophilized compositions, show an in-use stability of at least 48 hours. Table 10 shows that liquid compositions when further diluted with infusion fluids show a stability of at least 2 hours.

Thus, the process of manufacture of lyophilized parecoxib compositions, wherein the temperature during the lyophilization cycle did not exceed 35°C, and wherein the lyophilization cycle time was less than 30 hours, resulted in compositions that exhibited acceptable storage stability, photostability, thermal excursion stability, freeze-thaw stability, and enhanced in-use stability of liquid parecoxib compositions obtained after reconstitution.

Claims

WE CLAIM . A process for manufacturing a stable, solid, lyophilized composition of parecoxib sodium, wherein the composition comprises not more than 0.2% by weight of sulphonamide impurity, the said process comprising the steps of:

(iii) subjecting the container from step (ii) to a lyophilization cycle of less than 30 hours, wherein, the temperature in the lyophilization cycle does not exceed 35°C. . The process as claimed in claim 1 , wherein the lyophilization cycle time ranges from 20 hours to 30 hours. . The process as claimed in claim 2, wherein the lyophilization cycle time ranges from 22 hours to 25 hours. . The process as claimed in claim 1 , wherein temperature in the lyophilization cycle does not exceed 30°C. . The process as claimed in claim 1 , wherein the lyophilization cycle comprises a freezing phase, a primary drying phase, and a secondary drying phase, wherein the temperature in the secondary drying phase does not exceed 35°C. . The process as claimed in claim 1 , wherein the solution of parecoxib sodium is prepared using the steps of:

(i) sparging a vehicle with a non-oxygen containing inert gas till the dissolved oxygen content is not more than 1 ppm;

(iii) dissolving parecoxib sodium in the vehicle from step (ii), and adding pH adjusting agents to adjust the pH of the solution from about 8 to about 8.5; (iv) adding vehicle to the solution from step (iii) and mixing it, to obtain the final batch volume of the parecoxib sodium solution; and

7. The process as claimed in claim 6, wherein the process steps (ii) to (v) are carried out under an overlay of a non-oxygen containing inert gas such that the dissolved oxygen content of the parecoxib liquid composition is from about 0.1 ppm to about 2 ppm.

8. The process as claimed in claim 6 or claim 7, wherein the non-oxygen containing inert gas is selected from nitrogen, argon, helium, and neon.

9. The process as claimed in claim 1 , wherein the concentration of parecoxib sodium, in the lyophilized composition, ranges from about 60% to about 99% by weight of the composition.

10. The process as claimed in claim 1 , wherein the concentration of buffer, in the lyophilized composition, ranges from about 1 % to about 40% by weight of the composition.

1 1 . The process as claimed in claim 1 , wherein the vehicle is water for injection.

12. The process as claimed in claim 1 , wherein the lyophilized composition is reconstituted by adding a reconstitution diluent, to obtain a stable liquid parecoxib composition containing 1 mg/ml to about 50 mg/ml of parecoxib sodium.

13. The process as claimed in claim 12, wherein the reconstitution diluent is selected from 0.9% w/v sodium chloride solution for injection, bacteriostatic 0.9% w/v sodium chloride solution for injection, 5% w/v glucose solution for injection, and 0.45% w/v sodium chloride and 5% glucose solution for injection.

14. The process as claimed in claim 12, wherein the liquid parecoxib composition has an in-use stability of at least 48 hours, wherein the content of sulphonamide impurity is not more than 0.05% by weight. The process as claimed in claim 12, wherein the pH of the liquid parecoxib composition ranges from pH 7 to pH 8.5. The process as claimed in claim 12, wherein the osmolality of the liquid parecoxib composition ranges from about 200 mOsmol/kg to about 700 mOsmol/kg. The process as claimed in claim 12, wherein the liquid parecoxib composition when further diluted with an infusion fluid to a concentration of 2 mg/ml of parecoxib, has a pH of from pH 7 to pH 8.5, and is stable for at least 2 hours. The process as claimed in claim 1 , wherein the solid composition when stored at room temperature storage conditions for at least 24 months, in containers in an upright orientation or inverted orientation, or when stored at accelerated storage conditions for at least 6 months, in containers in an upright orientation or inverted orientation, contains parecoxib not less than 95% by weight of the label claim, and sulphonamide impurity not more than 0.15% by weight, at the end of the time period. The process as claimed in claim 1 , wherein the solid composition, when subjected to a temperature cycle of -20°C ± 5°C for 2 days followed by 60 ± 2°C for 2 days, contains parecoxib not less than 95% by weight of the label claim, and sulphonamide impurity not more than 0.1 % by weight, at the end of the cycle. The process as claimed in claim 1 , wherein the solid composition when subjected to three temperature cycles of -20°C ± 5°C for 2 days followed by 40° ± 2°C for 2 days, contains parecoxib not less than 95% by weight of the label claim, and sulphonamide impurity not more than 0.1 % by weight, at the end of the cycle. The process as claimed in claim 1 , wherein the solid composition, after exposure to light at an intensity of not less than 350 lux for at least 21 days, contains parecoxib not less than 95% by weight of the label claim, and sulphonamide impurity not more than 0.1 % by weight.