FORM 2
The Patents Act 1970 Complete Specifications Section 10
A process for preparation of pharmaceutical composition containing a non-steroidal anti-inflammatory substance (NSAID) and a cyclodextrin.
Applicant: Macleods Pharmaceuticals Ltd., an Indian company, having office at 304-310 Atlanta Arcade, Church Road, Andheri-Kurla Road, Andheri (E), Mumbai 400059 Maharashtra State, India.
Inventor : DR. SHRUTI UMESH BHAT, an Indian National, C/o Macleods Pharmaceuticals Ltd.,304 - 310 Atlanta Arcade, Church Road, Andheri- Kurla Road, Andheri (E), Mumbai 400 059 , Maharashtra State, India.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed :-


The present invention relates to a process for the preparation of pharmaceutical composition containing a non-steroidal anti-inflammatory drug (NSAID) belonging to the category of cyclooxygenase -2 (COX-2) inhibitor such as valdecoxib and a cyclodextrin.
Background of invention: -
NSAID treatment is prescribed primarily for pain management and represents nearly 60 % of the total sales in the Indian market. Intrinsically, COX-2 inhibitors viz. Celecoxib, rofecoxib, valdecoxib, parecoxib, atoricoxib etc. are relatively insoluble insoluble in water. As the bioavailability of a drug is dependent on its solubility in biologic fluid, there is a need to prepare a dosage form of NSAID such as valdecoxib with improved solubility in water or biological fluid, which would provide improved absorption and consequently better therapeutic management. Use of cyclodextrin as a carrier for preparation of inclusion complexes with pharmaceutically active agents has been well-listed in literature. [Chemical Abstracts 116 (16); 158718p (1992); Int. J. Pharmaceutics 79; 289-299 (1992); J. Pharm. Pharmacology 46(6); 470-80; Pharmceutical Research vol. 10; No. 5, p.682-86 (1993); US Patent 6485706, 6482830, 6479467, 64724486, 6469989, 6468521, 6465012, 6465425, 6462237, 6458383, 6455533,6451339, 6436442, 6423344, 6423342, 6407079, 6403110, 6383471, 6376550, 6379697, 6372402, 6368629, 6358530, 6358469, 6355269, 6436414]. Several scientific articles document compositions of

COX-2 inhibitor NSAID drug substances e.g .Chemical Abstract Vol.137, No.5, 2002, No.57443y, Chemical Abstract Vol.137, No. 12, 2002, No.163184, PCT Applications WO0215884, WO0215885, WO0215886, WO0217923, WO 0205815, WO0205799, WO0141761, WO0145698, WO0145706, WO0053149, WO0051685, W09729776, W09729775, WO96625,WO9641626,WO9625405 ].
4-( 5- methyl -3- phenyl- 4- isoxazolyl) benzene sulfonamide , a diaryl substituted isoxazole that is Valdecoxib inhibits the activity of the enzyme cyclooxygenase -2 resulting in a decreased formation of precurssors of prostaglandins. Valdecoxib exists in two known polymorphic forms both active in vivo and is relatively insoluble in water.
The present invention relates to a process for preparation of pharmaceutical composition of a NSAID such as COX-2 inhibitor and a cyclodextrin .
Scope of invention:
The objective of the present invention is to develop a process for preparing
a stable pharmaceutical composition of NSAID or a pharmaceutically
accepted salt thereof, with a cyclodextrin.
The NSAID may be for example valdecoxib or celecoxib or atoricoxib or
parecoxib or a pharmaceutically acceptable salt thereof..
The cyclodextrin may be any suitable cyclodextrin such as alfa, beta or
gamma cyclodextrin which may be suitable for example with
dimethyl betacyclodextrin, 2-hydroxyethyl betacyclodextrin, 2-hydroxy

Propyl betacyclodextrin, 3-hydroxypropyl betacyclodextrin, trimethyl betacyclodextrin or any substituted or unsubstituted beta-cyclodextrin.
The further objective of the present invention is to improve patient compliance to the said NSAID composition containing cyclodextrin by providing the composition in a pharmaceutically effective and acceptable dosage form. The pharmaceutical composition of the present invention may be preferably formulated as a tablet, capsule, granules, pellets, spansules, pulvule, dermatological, opthalmic as well as a parenteral.
The further objective of the present invention is to develop a process of preparing formulation containing a COX-2 inhibitor NSAID or a pharmaceutically acceptable salt there of with cyclodextrin in a composition which provides the medicament at the desired site of action.
The further objective of the present invention is to develop a process of preparing formulation containing a COX-2 inhibitor NSAID or a pharmaceutically acceptable salt there of with cyclodextrin in a composition which can be manufactured on an industrial scale and consequently commercialized.
Several drug + cyclodextrin complexation techniques such as kneading, milling and trituration as well as combination thereof may be attempted.

However, ball-milling technique followed by spray or tray drying of liquid dispersion being preferred for complexation of the NSAID.
The process involves use of the NSAID- cyclodextrin complex
along with binder, disintegrating agents, lubricants, levigating agent and
other additives.
The formulation may or may not contain at least one further active
ingredient.
An inclusion complex for use in the process of preparation of
pharmaceutical composition of the present invention may be prepared as
follows:
1. Premixture of the required ratios of pre-screened Cox-2 inhibitor and cyclodextrin.
2. Transfer to a ball-mill containing balls made either of porcelain or stainless steel. Ball milling the blend for a definite period of time for e.g. 2-8 hours with occasional scraping of the blend from the sides of the mill until the complex is formed.
3. Screening the complex solid through 60#.
4. Adding formulation additives such as binders, bulking agents, levigating agents, surfactants, etc. and granulating the mass to form a dough.

5. Wet screening of the above dough of step (4) through 8 mesh and drying the granules obtained at 60°C in a fluidized bed drier for 1-4 hours or in a tray drier for upto 12 hours until granules with moisture content between 2.5 - 3.0% w/w are obtained.
6. Blending the dried granules of step (5) with suitable excipients such as lubricants, disintegrants and glidants to form a suitable oral dosage form such as tablets or capsules.
7. The dough from step (4) may also be extruded through an extruder to form rods which may be then spheronized through a marumerizer to form beads or pellets.
8. The beads or pellets from step (7) may be then either encapsulated into a hard gelatin capsule or compressed into tablets after incorporating suitable excipients such as lubricants, disintegrants and glidants.
9. The powder from step 4 may also be sterilized and filled aseptically in vials along with other ingredients such as pH modifiers, stabilizers, tonicity adjusters etc. The powder may be reconstituted with water for injection prior to administration parenterally.
10. The powder from step 4 may also be sterilized and suspended in sterile water along with other ingredients such as pH modifiers, stabilizers, osmolality and tonicity adjusters to be administered as an opthalmic preparation.

The preferred active component of the pharmaceutical composition of the invention is an inclusion complex of valdecoxib or a pharmaceutically acceptable salt thereof and an un-substituted beta-cyclodextrin or atoricoxib or parecoxib or a pharmaceutically accepted salt thereof and an unsubstituted or substituted beta- or gamma-cylcodextrin. The Cox-2 inihibitor NSAID and cyclodextrin may be premixed at ratios between 1:1 upto 1:25, but preferably at a ratio of 1:4. The cyclodextrin being incorporated may be either substituted or unsubstituted gamma or beta- cyclodextrin but preferably an unsubstituted betacyclodextrin. The NSAID and cyclodextrin may be complexed either by simple addition, phase coeservation, trituration, kneading or ball milling using stainless steel or porcelain balls, but preferably by ball milling technique followed by aqueous dispersion and spray or tray drying.
Several formulation additives viz. binders for example acacia, cellulose, sugars, starches, polyvinyl pyrrolidone, gelatin, pre-gelatinised starch, liquid glucose, sorbitol, maltol etc. may be used; but preferably polyvinyl pyrollidone may be used. Bulking agents for example calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, dextrose, mannitol, hydroxypropyl cellulose, lactose, starch, magnesium carbonate, magnesium oxide, sugars etc., may be incorporated but preferably microcrystalline cellulose and lactose may be used. Levigating agents such as water, isopropyl alcohol, water-isopropanol mixture, ethyl alcohol etc may be used, but preferably isopropyl alcohol may be used.

Surfactants such as sodium lauryl sulfate, polysorbate 80, polyethylene glycol (PEG) 6000, chremophore RH, poloxamer etc. may be incorporated into the formulation, but polysorbate 80 and PEG 6000 may be used. Disintegrants amongst crospovidone, microcrystalline cellulose, colloidal silicon dioxide,starch, cros-linked sodium carboxymethyl cellulose, partially pre-gelatinised starch etc. may be used but preferably crospovidone and colloidal silicon dioxide are used.
The NSAID such as valdecoxib as a cyclodextrin complex granules after addition of suitable fillers may be compressed into either a conventional, effervescent, chewable or a dispersible tablet or encapsulated into a hard gelatin capsule or filled as dry powder into bottle to be reconstituted with water prior to use. Suitable chemical and microbial preservatives such as sodium benzoate, parahydroxy benzoates and soluble salts thereof, butylated hydroxy anisole, butylated hydroxy toluene, ascorbic acid, tocopherol, edetates, sodium chloride, propyl gallate, sodium ascorbate, sodium metabisulfite, sorbic acid, tartaric acid, citric acid, triacetin, bronopol, sodium bicarbonate etc. may be incorporated into the formulation. Several ratios of 1:0 to 1: 25 of flavoring agents such as cherry, butterscotch, mango, pineapple, orange, peppermint, mixed fruit, blackcurrant, raspberry, vanilla, spearmint etc. shall be added to the formulation. In addition, soluble or lake colours such as sunset yellow,

quinoline yellow, tartrazine yellow, ponceau red, erythrosme pink, iron oxides etc. may be incorporated into the formulation. The pharmaceutical composition of cyclodextrin with COX-2 inhibitor NSAID such as valdecoxib has been evaluated for the in vitro performance such as disintegration time, uniformity of dispersion, assay and rate of dissolution in water medium. When studied for drug availability for absorption with respect to time using the in vitro dissolution rate test the formulation containing complex, according to the invention showed a superior extent of drug solubility measured as amount of drug dissolved in water vs time when compared with commercially available valdecoxib tablets used as reference products. The dissolution efficiency of the formulation which is measured as the ratio of area under the dissolution rate curve at time point to the area at 100% dissolution at the same time point has been calculated. Due to enhanced dissolution, oral formulations according to the invention containing valdecoxib exhibit increased drug availability than that observed with reference products when tested in healthy human volunteers in a cross - over plasma study.
The pharmaceutical composition for oral use, so developed by the process of the present invention has been evaluated for stability at several combinations of temperature and relative humidity, viz. 25 deg.C - 60% RH, 30 deg. C -70% RH, 40 deg.C - 75% RH, 40 deg.C, Ambient room

temperature - RH, 70 deg. C, 100% RH as well as under ultraviolet and fluorescence light etc. for a period between 1 - 36 months.
The pharmaceutical composition for oral use, so developed by the process of the present invention has been analysed by HPLC and was found to be stable and the quantity of the medicament well within specified limits.
The pharmaceutical composition for oral use, so developed by the process of the present invention was found to be safe. It could be employed on the industrial scale for the purpose of commercialization as was indicated by the encouraging results of the pilot scale-up batches.
The above specified specification can be better understood with the help of examples. However, these examples do not in any way restrict the broad scope of the invention.
Example 1 :
(1) Tablets :
1. Conventional Tablets : valdecoxib with beta-cyclodextrin complex may be admixed with additives such as microcrystalline cellulose and lactose, granulated with a binder solution containing povidone or starch in solvent such as water or isopropyl alcohol or methylene chloride. The granules may be dried using a fluidised bed or a tray drier and admixed with materials such as colloidal

silicon dioxide, sodium lauryl sulphate , talcum , disintegrants viz. Ac-di-sol or cros-povidone and magnesium stearate and compressed into a tablet.
2) Dispersible Tablet : valdecoxib with beta-cyclodextrin complex
may be admixed with additives such as microcrystalline cellulose and lactose, granulated with a binder solution containing povidone or starch in solvent such as water or isopropyl alcohol or methylene chloride. The granules may be dried using a fluidised bed or a tray drier and admixed with materials such as colloidal silicon dioxide, sodium lauryl sulphate , talcum , disintegrants viz. Ac-di-sol, cros-povidone etc., flavoring and coloring and sweetening agents and magnesium stearate and compressed into a tablet.
3) Chewable Tablet: valdecoxib with beta-cyclodextrin complex may
be admixed with additives such as sucrose cellulose and lactose, granulated with a binder solution containing povidone or starch in solvent such as water or isopropyl alcohol or methylene chloride. The granules may be dried using a fluidised bed or a tray drier and admixed with materials such as colloidal silicon dioxide, talcum , disintegrants viz. Ac-di-sol, cros-povidone etc., flavoring and coloring agents and magnesium stearate and compressed into a tablet.

4) Effervescent Tablet : valdecoxib with beta-cyclodextrin complex may be admixed with additives such as microcrystalline cellulose and lactose, granulated with a binder solution containing povidone or starch in solvent such as water or isopropyl alcohol or methylene chloride. The granules may be dried using a fluidised bed or a tray drier and admixed with materials such as sodium citrate, citric acid , colloidal silicon dioxide, sodium lauryl sulphate , talcum , disintegrants viz. Ac-di-sol, cros-povidone etc., stabilizers, flavoring ,coloring and sweetening agents and magnesium stearate and compressed into a tablet. (2) Liquid dosage forms :
1. The valdecoxib + betacyclodextrin complex powder is admixed with lactose or mannitol or sucrose. Flavoring, coloring agents, viscosity builders, buffering agents, stabilizers etc. may be added. The product is reconstituted using water prior to use.
2. The powder containing the valdecoxib + betacyclodextrin complex is admixed into a syrup base. Sweenteners, flavors, coloring stabilizing agents, viscosity builders etc. may be added to the liquid dosage form.
3. Following sweeteners such as sucrose, mannitol, sorbitol, xylitol, aspartame, saccharin, saccharin sodium, glycyrrhizin, sodium monoamino glutamate etc. may be added to the tablet or liquid

composition. However, it is not intended that the scope of the invention be limited by these examples. 4. Following flavors such as orange, peppermint, pineapple, mango, raspberry, strawberry, tutti-frutti, cola etc. may be added to the tablet or liquid composition for oral use. However, it is intended that the scope of this invention may not be limited by these examples.
5. Following disintegr anting agents such as cross-linked polyvinyl
pyrrolidone, cross-carmellose sodium, sodium starch glycollate,
starch etc. may be added to the composition. However, it is not
intended that the scope of this invention be limited by these
examples.
6. Following stabilizing agents such as butylated hydroxy anisole,
butylated hydroxy toluene, ascorbic acid, tocopherol, sodium meta
bisulphite, disodium edetate, methyl, butyl, propyl paraben and its
sodium salt etc. may be added to the composition. However, it is
not intended that the scope of this invention be limited by these
examples.
The above specified specification can be better understood with the help of the following illustrations. However, these illustrations do not in any way restrict the broad scope of the invention.

Illustration 1:
Valdecoxib and betacyclodextrin as 1: 4 ratio were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added lactose , microcrystalline cellulose and polyvinyl pyrrolidone , Polysorbate 80 and PEG 6000 was added to isopropyl alcohol and the above powder mixture was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for these dried granules was checked to be between 2.5 - 3% w/w. The dried granules were rasped through 20 mesh. Crospovidone , colloidal silicon dioxide, were screened through 40 mesh and added to the dried granules Finally talcum and magnesium stearate were added and the lubricated granules were compressed into tablets with a compression pressure at 4-5 kg/cm2. The tablets obtained at an average weight of 290 mg/tablet contained 20.0 mg of valdecoxib. The tablets were compressed at half dose proportionate weight to get tablets containing valdecoxib 10 mg per tablet. The tablets were film coated in a conventional coating pan using hydroxy propyl methyl cellulose, talc, titanium dioxide in a non-aqueous solution The tablets were evaluated for all parameters as per the general pharmacopoeial requirements of monograph for tablet preparations as well as the rate of dissolution and disintegration time in water medium. More than 98% of the labeled amount of drug dissolved in 5 minutes. The product had a disintegration time of less than 5 minutes.

Illustration 2:
Valdecoxib and betacyclodextrin in 1: 4 ratio were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added lactose, microcrystalline cellulose and polyvinyl pyrrolidone. Polysorbate 80 and PEG 6000 was added to isopropyl alcohol and the above powder mixture was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for these dried granules was checked to be between 2.5 - 3% w/w. The dried granules were rasped through 20 mesh. Crospovidone , colloidal silicon dioxide, aspartame, approved flavors and color, were screened through 40 mesh and added to the dried granules Finally talcum and magnesium stearate were added and the lubricated granules were compressed into tablets with a compression pressure at 4-5 kg/cm2. The tablets obtained at an average weight of 290 mg/tablet contained 20.0 mg of valdecoxib. The tablets were compressed at half dose proportionate weight to get tablets containing valdecoxib 10 mg per tablet.
The tablets were evaluated for all parameters as per the general pharmacopoeial requirements of monograph for dispersible tablet preparations as well as the rate of dissolution and disintegration time in water medium. More than 98% of the labeled amount of drug dissolved in 5 minutes. The product had a disintegration time 30 seconds.

Illustration 3:
Valdecoxib and betacyclodextrin in 1: 4 ratio were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added lactose, microcrystalline cellulose and polyvinyl pyrrolidone. Polysorbate 80 and PEG 6000 was added to isopropyl alcohol and the above powder mixture was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for these dried granules was checked to be between 2.5 - 3% w/w. The dried granules were rasped through 20 mesh. Crospovidone , colloidal silicon dioxide, aspartame, color and flavor agents, sodium citrate, citric acid were screened through 40 mesh and added to the dried granules Finally talcum and magnesium stearate were added and the lubricated granules were compressed into tablets with a compression pressure at 4-5 kg/cm". The tablets obtained at an average weight of 290 mg/tablet contained 20.0 mg of valdecoxib. The tablets were compressed at half dose proportionate weight to get tablets containing valdecoxib 10 mg per tablet. The tablets were evaluated for all parameters as per the general pharmacopoeial requirements of monograph for effervescent tablet preparations as well as the rate of dissolution and disintegration time in water medium. More than 95 % of the labeled amount of drug dissolved in 5 minutes. The product had a disintegration 10 seconds.

Illustration 4:
Valdecoxib and betacyclodextrin 1:4 ratio were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added sucrose, microcrystalline cellulose and polyvinyl pyrrolidone. Polysorbate 80 and PEG 6000 was added to water or isopropyl alcohol and the above powder mixture was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for these dried granules was checked to be between 2.5-3% w/w. The dried granules were rasped through 20 mesh. Crospovidone , colloidal silicon dioxide, color and flavoring agent, preservatives such as parabens and disodium edetate were screened through 40 mesh and added to the dried granules Finally talcum and magnesium stearate were added and the lubricated granules were compressed into tablets with a compression pressure at 4-5 kg/cm". The tablets obtained at an average weight of 290 mg/tablet contained 20.0 mg of valdecoxib. The tablets were compressed at half dose proportionate weight to get tablets containing valdecoxib 10 mg per tablet. The tablets were evaluated for all parameters as per the general pharmacopoeial requirements of monograph for chewable tablet preparations as well as the rate of dissolution time in water medium. More than 96% of the labeled amount of drug dissolved in 5 minutes. Illustration 5:
Valdecoxib and betacyclodextrin in 1: 4 ratio were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch

radius, 3.5 kg) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. The complex was added under stirring to a syrup base containing microcrystalline cellulose ,polysorbate 80, PEG 6000, glycerine, sorbitol, parabens, disodium edetate , potassium sorbate, colloidal silicon dioxide. The syrup obtained contained valdecoxib 20 mg and 10 mg per 5 ml. The syrup was filled into bottles and sealed. The liquid was analysed for tests as per the pharmacopoeia liquid reparations as well as the rate of dissolution and disintegration time in water medium. More than 98% of the labeled amount of drug dissolved in 5 minutes. Illustration 6 :
Valdecoxib and betacyclodextrin in 1: 4 ratio were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added lactose, microcrystalline cellulose and polyvinyl pyrrolidone. Polysorbate 80 and PEG 6000 was added to isopropyl alcohol and the above powder mixture was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for these dried granules was checked to be between 2.5 - 3% w/w. The dried granules were rasped through 20 mesh. Crospovidone , colloidal silicon dioxide, were screened through 40 mesh and added to the dried granules Finally talcum and magnesium stearate were added and the lubricated granules were filled into hard gelatin capsules so as to get valdecoxib 20 and 10 mg per capsule. The capsules were evaluated for all parameters as per the general pharmacopoeial requirements of monograph for capsule preparations as well

as the rate of dissolution and disintegration time in water medium. More than 98% of the labeled amount of drug dissolved in 5 minutes. The product had a disintegration 12 minutes. Illustration 7:
Valdecoxib and betacyclodextrin in 1: 4 ratio were screened (60 mesh) and tumble mixed. The mixture was transferred into a ball mill containing porcelain balls (1 inch radius, 3.5 kg) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added lactose, microcrystalline cellulose and polyvinyl pyrrolidone. Polysorbate 80 and PEG 6000 was added to isopropyl alcohol and the above powder mixture was granulated in a planetary mixer for 20 minutes. The wet mass was screened through 8 mesh and dried in a fluidized bed drier at 60°C for 2 hours. The loss on drying for these dried granules was checked to be between 2.5 - 3% w/w. The dried granules were rasped through 30 mesh. Crospovidone , colloidal silicon dioxide,aspartame, disodium edetate, parabens, color and flavors were screened through 40 mesh and added to the dried granules The powder was fillied into bottles. On reconstitution with water the product would administer valdecoxib 20 and 10 mg per 5 ml of reconstituted suspension. The product was evaluated for all parameters as per the general pharmacopoeial requirements of monograph for powders for reconstitution as well as the rate of dissolution and disintegration time in water medium. More than 90% of the labeled amount of drug dissolved in 5 minutes.

We Claim,
1. A process for the preparation of a pharmaceutical composition
containing a cyclooxygenase-2 (COX-2) inhibitor NSAID comprising; mixing the required ratios of pre-screened (COX-2) inhibitor NSAID and cyclodextrin; milling the mixture in a ball-mill containing balls made either of procelein or stainless steel; ball milling the blend for a definite period of time for e.g. 2-8 hours with occasional scraping of the blend from the sides of the mill until the complex is formed; screening the complex solid through mesh; adding formulation additives such as binders, bulking agents, levigating agents, surfactants, etc. and granulating the mass to form a dough; wet screening of the dough through 8 mesh and drying the granules obtained at 60°C in a fluidized bed drier for 11-4 hours or in a tray drier for up to 12 hours until granules with moisture content between 2.5-3.0% w/w are obtained; blending the dried granules with suitable excipients such as lubricated, disintegrants and glidants to form a suitable oral dosage form; extruding the aforementioned dough through an extruder to form rods which may be spheronized through a marumerizer to form beads or pellets; encapsulating the beads or pellets into a hard gelatin capsule; compressing the beads or pellets or granules into tablets after incorporating suitable excipients such

as lubricants, disintegrants, flavor, colors and glidants; mixing the beads after passing through screen 40 mesh and adding sweetner, colors, flavors to form a formulation ready to reconstitute with water before administration.
2. A process for the preparation of pharmaceutical composition containing a (COX-2) inhibitor NSAID as claimed in claim 1, where in, the (COX-2) inhibitor NSAID drug is either valdecoxib or parecoxib or atoricoxib or pharmaceutically acceptable salt there of.
3. A process for the preparation of pharmaceutical composition containing a (COX-2) inhibitor NSAID as claimed in claim 1 or 2, where in, the cyclodextrin used is an unsubstituted beta cyclodextrin in ratios of 1:1 upto 1:25 of drugxyclodextrin.
4. A process for the preparation of pharmaceutical composition containing a (COX-2) inhibitor NSAID as claimed in claims 1 to 3, where in, the inclusion complex may be formed using the ball milling technique followed by dispersing the milled powder in a solvent such as water to form a slurry and spray drying the slurry to form a free flowing powder of the drug inclusion complex.

5. A process for the preparation of pharmaceutical composition containing a (COX-2) inhibitor NSAID as claimed in claims 1 to 4 , where in, the formulation additives incorporated may be microcrystalline cellulose, lactose, polyvinyl pyrolidone, polysorbate 80, polyethylene glycol 6000, crospovidone, colloidal silicon dioxide, talcum and magnesium stearate.
6. A process for the preparation of pharmaceutical composition containing a (COX-2) inhibitor NSAID as claimed in claims 1 to 5, where in, the formulation may contain flavour such as orange, strawberry, raspberry, mixed fruit or cola flavor.
7. A process for the preparation of pharmaceutical composition containing a (COX-2) inhibitor NSAID as claimed in claims 1 to 6, where in, the formulation may contain color such as erythrosine pink, sunset yellow, tartrazine or quinoline yellow.
8. A process for the preparation of pharmaceutical composition containing a (COX-2) inhibitor NSAID as claimed in claims 1 to 7, where in, the formulation may contain chemical and microbial preservatives such as sodium benzoates, parahydroxy benzoates and alkali metal salts there of, citric acid, sodium bicarbonate,

triacetin, butylated hydroxy anisole, butylated hydroxy toluene, sodium chloride, disodium edetate and sodium metabisulfite.
A process for the preparation of pharmaceutical composition containing a (COX-2) inhibitor NSAID as claimed in claims in claims 1 to 8 , substantially as described herein before with reference to Illustrations 1 - 7.