Title of Invention

"A PROCESS FOR THE PREPARATION OF CELECOXIB COMPOSITION WITH IMPROVED AQUEOUS SOLUBILITY"

Abstract The present invention relates to a process for the preparation of a synergistic pharmaceutical composition of celecoxib with improved aqueous solubility containing mixture of celecoxib, a polymeric stabilizer, a non-surfactant solubility enhancer and pharmaceutically acceptable excipients.
Full Text A process for the preparation of celecoxib composition with improved aqueous solubility
Field of the Invention
The present invention relates to a process for the preparation of pharmaceutical composition with an improved aqueous solubility containing a mixture of celecoxib, a polymeric stabilizer, a non-surfactant solubility enhancer, and pharmaceutically acceptable excipients.
Background of the Invention
Celecoxib, chemically is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-1-yl] benzenesulfonamide, and is used for the prophylaxis and treatment of specific COX-2 mediated disorders. It has registered record sales 1.5 billion USD in year 1999 and the figure is expected to go beyond USD 3 billion by the end of year 2002.
Pharmacia Corporation, USA, holds the patent for this molecule and its various polymorphs and pseudo-polymorphs through a series of patents viz. US 5,466,823; WO 00/32189; WO 00/42021.
Poor aqueous solubility of a drug may be a limiting factor in the oral bioavailability of the dosage form. There is a need for improvement in aqueous solubility for rapid-onset of action of such drugs from immediate-release (IR) dosage forms, and achievement of predicted drug release profile from a controlled-release (CR) or sustained-release (SR) dosage from without compromising its oral bioavailability.
A number of approaches like pH modification, co-solvents, complexation etc are available for improvement of aqueous solubility. A particularly useful approach for solid dosage forms is conversion of crystalline form to corresponding amorphous form. However, many times amorphous systems are not inherently stable to provide a meaningful product shelf life. Amorphous systems can be stabilized by inclusion of excipients, especially polymers like polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC) etc.

Yoshioka et al, J. Pharm.Sci. 84(8), August 1995, 983 - 986 describe the stabilization of amorphous indomethacin.
Published PCT Patent application WO 01/41536 entitled "Solid-state form of celecoxib having enhanced bioavailability", provides a novel amorphous form of celecoxib. It provides for amorphous celecoxib per se, celecoxib drug substance that comprises amorphous celecoxib, so as to provide enhanced dissolution. The invention also provides celecoxib - crystallization inhibitor composites using crystallization inhibitors like PVP, HPMC, hydroxypropyl methylcellulose phthalate (HPMCP), ethylcellulose (EC), hydroxyethylcellulose (HEC), sodium carboxymethyl cellulose (Na CMC), calcium carboxymethyl cellulose (Ca CMC), dextran acacia, starches, cyclodextrins, block co-polymers of ethylene oxide and propylene oxide, polyvinyl alcohol (PVA) and polyethylene glycol (PEG). PVP and HPMC are the preferred polymers for the invention. A process for preparation of the amorphous celecoxib drug substance and celecoxib-crystallization inhibitor composite is also provided. The process consists either of quench cooling the melt or dissolving in solvent followed by evaporation of the same. This patent also describes amorphous celecoxib or celecoxib crystallization inhibitor composite, and its process of preparing a formulation using pharmaceutically acceptable excipients to obtain a suitable pharmaceutical composition.
US Patent Nos. 6,387,901; 6,376,519; 6,342,521; 6,329,397; 6,214,870; 6,197,810; 6,156,798; 6,114,361 and 6,110,964 describe different new chemical entities as meglumine salt and it's use in combination therapy with celecoxib. However, celecoxib is not incorporated along with the meglumine salt of new chemical entity to obtain pharmaceutical composition.
The aqueous solubility of drug from stabilized amorphous system can be further improved by inclusion of excipients additional to the one used for stabilizing the amorphous form. This gives advantages in terms of increased aqueous solubility, thus improving functioning of IR and CR formulations.
Celecoxib has poor aqueous solubility and consequently its absorption from the gastrointestinal tract is limited. Improvement in its aqueous solubility will increase its

oral bioavailability and will also help in rapid-onset of action, which provides significant benefits in terms of faster relief from pain.
Objects of the Invention
The main object of the invention is to provide a pharmaceutical composition selected from celecoxib with an improved aqueous solubility.
Another object of the invention is to obtain amorphous celecoxib from crystalline celecoxib.
Yet another object of the invention is to stabilize amorphous celecoxib obtained by using a polymer.
Still another object of the present invention is to provide a pharmaceutical composition having enhanced bioavailability.
Yet another object of the invention is to provide use of less dosage of celecoxib pharmaceutical composition for the treatment.
Yet another object of the invention is to provide solid dosage forms including binders, disintegrants, diluents, lubricants, glidants, anti-adherents, surface active agents, coating polymers, flavors and colors.
Still yet another object of the invention is to provide a SR or CR formulation for celecoxib.
Still yet another object of the invention is to minimize the side effects caused by the drug celecoxib.
Further object of the invention is to provide a stable pharmaceutical composition of celecoxib amorphous.
Summary of the Invention
Accordingly, the present invention provides a synergistic pharmaceutical composition of a mixture containing celecoxib, a polymer, a non-surfactant solubility enhancer and a pharmaceutically acceptable excipient and an efficient and economical process for the preparation of the said pharmaceutical composition.

Detailed Description of the Invention
In accordance, the present invention provides a synergistic pharmaceutical composition of a mixture containing celecoxib with enhanced aqueous solubility, the said composition comprising:
a) Celecoxib,
b) a polymer,
c) a non surfactant solubility enhancer, and
d) one or more pharmaceutical^ acceptable excipient
One embodiment of the present invention provides a composition, wherein the polymer used is selected from PVP, HPMC, hydroxypropyl cellulose (HPC) or HPMCP, EC, Na CMC and preferably PVP.
The composition of the present invention is a synergistic composition exhibiting unexpected properties and the process of the present invention does not involve any chemical reaction between the ingredients.
In another embodiment of the present invention, the polymer used is in the range of 5-50 %, preferably in the range of 10-40 % and more preferably 15-25 %
In still another embodiment of the present invention, the celecoxib used is in the range of 30 to 80 % by weight, preferably in the range of 50 to 70 % by weight.
In still another embodiment of the present invention, the nonsurfactant solubility enhancer used is an amino sugar, which is selected from N-methyl-D-glucamine (meglumine) in the range of 5-25 %, preferably in the range of 5-20 % and more preferably 5-15%.
In yet another embodiment of the present invention, the celecoxib exists at least in detectable amount in amorphous form and preferably more than 90 % in the amorphous form.
In still another embodiment of the present invention, the pharmaceutically acceptable excipients are binders selected from the group consisting of starch, gelatin, (PVP), (HPC), acacia, tragacanth, disintegrants selected from starch, croscarmellose sodium, crospovidone, sodium starch glycoiate, diluents selected from microcrystalhne cellulose, dicalcium phosphate, starch, lactose, mannitol, xylitol, calcium sulphate, lubricants selected from stearic acid, magnesium stearate, hydrogenated vegetable oil, glidants selected from colloidal silicon dioxide, anti-adherents like talc, surface active

agents such as sodium lauryl sulphate, cremophor RH 40, polysorbate 80, coating polymers selected from HPMC, HPC, flavors and coloring agents.
In yet another embodiment of the present invention, the non-surfactant solubility enhancer, enhances the aqueous solubility of celecoxib by at least 1-50 times.
In yet another embodiment the polymer used stabilizes the celecoxib amorphous formed.
In still yet another embodiment, the dosage can be provided in the form of IR, SR, modified release or CR, which can be a tablet, capsule or any other acceptable solid dosage form.
One more embodiment of the present invention provides a process for the preparation of a synergistic pharmaceutical composition of celecoxib with improved aqueous solubility, the said process comprising the steps of:
a) dissolving celecoxib in the range of 30 to 80% by weight, a polymer in the range of 5 to 50% by weight and a non-surfactant solubility enhancer in the range of 5 to 25% by weight in an organic solvent such as herein described,
b) heating with optionally stirring the mixture of step (a) at a temperature range of 50° to 60° C, to obtain a complete solution,
c) removing the organic solvent from step (b) solution, by either evaporating or spray drying or freeze drying to obtain a mixture containing celecoxib,
d) performing, optional heating of the mixture of step (c) for thorough mixing at a temperature range of 150° to 180° C to obtain a melt.
e) cooling immediately the molten mass of step (d) by dipping in a liquid nitrogen or dry ice-acetone mixture to obtain a mixture containing celecoxib, and
f) formulating the mixture of step (c) and/or (d) containing celocoxib with one or more pharmaceutically acceptable excipients such as herein described to obtain the required pharmaceutical, composition
An embodiment provides a process, wherein in celecoxib used is in the range of 30 to 80 % by weight, preferably in the range of 50 to 70 % of total composition.

Another embodiment provides a process, wherein the celecoxib exists at least in detectable amount in amorphous form and preferably more than 90 % in the amorphous form.
In an another embodiment, the nonsurfactant solubility enhancer used is an amino sugar selected from N-methyl-D-glucamine (meglumine).
Yet another embodiment provides a process, wherein meglumine used is in the range of 5-25% by weight, preferably in the range of 5-20% and more preferably 5-15% by weight of total composition.
In another embodiment, the organic solvent used is selected from a group consisting of, methanol, ethanol, isopropanol, tertiary butanol, acetonitrile, acetone, ethyl acetate, dimethyl sulfoxide, cyclohexane, dichloromethane, water or mixtures thereof.
In another embodiment, the polymer used is selected from a group consisting of PVP, HPMC, HPC or HPMCP, EC, NaCMC and preferably PVP.
Another embodiment provides a process, wherein polymer used is in the range of 5-50% by weight, preferably in the range of 10-40% by weight and more preferably 15-25% by weight of total composition.
Yet another embodiment provides a process wherein the spray drying is performed under the condition of liquid flow rate being 5 to 20 ml/minute, at a temperature in the range of 50° C to 200° C and air pressure in the range of 500 to 800 bars.
In another embodiment of the process, the freeze drying is performed under the condition of freezing temperature in the range of -120° C to +25° C. Primary drying in the range of -60° C to 0° C under a reduced pressure of 0.1 to 1.0 torr over the product and 0.05 to 0.10 torr at the condenser. Secondary drying in the range of -40° C to +10°C under a reduced pressure of 0.01 to 0.50 torr over the product and 0.01 to 0.10 torr at the condenser.
In yet another embodiment the process, the heating is performed at a temperature range of 150° to 180° C and preferably in the range of 170 ° to 180 °C.

In still yet another embodiment of the process, the pharmaceutically acceptable excipients are binders selected from group consisting of starch, gelatin, PVP, HPMC, HPMCP, EC, HEC, dextran, HPC, acacia and tragacanth, disintegrants selected from starch, croscarmellose sodium, crospovidone and sodium starch glycolate, diluents selected from microcrystalline cellulose, dicalcium phosphate, starch, lactose, mannitol, xylitol and calcium sulphate, lubricants selected from stearic acid, magnesium stearate and hydrogenated vegetable oil, glidants selected from colloidal silicon dioxide, anti-adherents like talc, surface active agents such as sodium lauryl sulphate, cremophor RH 40, polysorbate 80, coating polymers selected from HPMC, HPC, flavors and coloring agents.
In still another embodiment, the evaporation is carried out by either spray drying, lyophilization or distillation under reduced pressure.
In still another embodiment, the heating is done at a temperature range of 150° to 180° C and preferably in the range of 170 ° to 180 °C.
Still another embodiment provides a process wherein, the pharmaceutically acceptable excipients are selected from group consisting of binders (starch, gelatin, PVP, HPC, acacia and tragacanth), disintegrants (starch, croscarmellose sodium, crospovidone, sodium starch glycolate), diluents (microcrystalline cellulose, dicalcium phosphate, starch, lactose, mannitol, xylitol, calcium sulphate), lubricants (stearic acid, magnesium stearate, hydrogenated vegetable oil), glidants (colloidal silicon dioxide), anti-adherents (talc), surface active agents (sodium lauryl sulphate, cremophor RH 40, polysorbate 80), coating polymers HPMC, HPC), flavors and colors.
In still another embodiment the solubility of poorly aqueous soluble drugs like celecoxib can be improved by converting their crystalline form to amorphous state. Amorphous state is characterized by absence of long-range order in the molecular arrangement in the solid state. Although there may be regions showing short-range order (micro-crystallites/ nano-crystallites), such an order over long range is missing. Such systems give diffused peaks in the X-ray diffractogram.
In another embodiment the aqueous solubility of the drug candidate can be further improved by addition of judiciously chosen excipient to the 'drug-stabilizer' system. This

improvement may be provided due to specific interactions between the drug and the excipient.
Yet another embodiment provides an important aspect to be considered during development of such systems, is that the percentage of the excipients used as stabilizer and solubilizer should be kept to a minimum to maintain flexibility in the formulation approaches.
Still yet another embodiment provides a synergistic mixture exhibiting unexpected/surprising property. In this composition, celecoxib is present in the range of 30 to 80% by weight, the polymer is in the range of 10 to 40% by wt, non-surfactant solubility enhancer in the range of 5 to 25% by wt. and remaining one or more pharmaceutically acceptable additives/excipient.
The percentage values indicated in the synergistic composition are expressed in weight percentage basis unless otherwise specified.
In the present invention exemplified by celecoxib amorphous system, the solubility of drug was significantly improved by addition of meglumine (N-methyl-aD-glucamine) to celecoxib-PVP mixture. As is reported earlier (WO 0141536), polymers like PVP, HPMC, HPMCP, EC, NaCMC, etc. are able to stabilize the amorphous form of celecoxib and provide improved solubility of celecoxib.
In an another embodiment the maximum solubility achieved with celecoxib-PVP binary system is about 20 mcg/ml which is achieved when the system consists of 20% PVP. Any increase in PVP beyond 20% concentration does not provide any further improvement in solubility (Refer Table 1 for solubility data). PVP concentration of 20% and above is also able to retard the conversion of amorphous celecoxib to crystalline form.
Table 2 provides the solubility of celecoxib achieved from a celecoxib-meglumine binary mixture. Peak solubility values of about 15 mcg/ml are achieved using 25 and 50 % of meglumine.
Surprisingly, it was found that the peak solubility values achieved with a 'celecoxib-PVP-meglumine' ternary mixture is higher as compared to the values achieved with corresponding binary systems of 'celecoxib-PVP' and 'celecoxib-

meglumine'. As is shown in Table 3 a composition consisting of celecoxib:PVP:meglumine 70:10:20 gives a peak solubility of 47 mcg/ml as compared to solubility of 14.83 and 16.59 mcg/ml obtained with celecoxib:PVP 90:10 and celecoxib:meglumine 80:20 binary systems, respectively.
The composition of the ternary mixture of this embodiment can consist 5-60% of PVP and 5-30% of meglumine, preferably 10-40% of PVP and 5-20% of meglumine, and still more preferably 15-25% of PVP and 5-15% of meglumine. Celecoxib in such a system exists at least in detectable amount in amorphous form and preferably more than 90% celecoxib present is in the amorphous form.
The system of the present embodiment on exposure to 40°C / 75% RH, in an open dish for a period of 14 days, maintains celecoxib in amorphous state. The transformation of amorphous celecoxib to crystalline form was not more than 50%, preferably not more than 25% and still more preferably no more than 10% of the initial amorphous content.
It is sometimes difficult to achieve the desired release kinetics from the SR/CR dosage form prepared using poorly aqueous soluble drug. In such cases, the ternary system of the present embodiment can help in achieving the desired release kinetics from the formulation. Illustrative non-limiting example of excipients in such cases would be rate-controlling polymers (cellulosic polymers like HPMC, HPC, EC, carrageenan, xanthan gum), diluents, polymers, binders, and coating polymers, etc.
The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention:
EXAMPLES Example I
To dichloromethane (25 ml), added celecoxib (7 gms), PVP (2 gm) and
meglumine (1 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C
to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally,
adopting further heating of the mixture containing Celecoxib to obtain a molten mass.
Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry
ice acetone to also obtain the required mixture containing Celecoxib.

Example II
To dichloromethane (18 ml), added celecoxib (5 gms), PVP (3 gm) and meglumine (2 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Then cooling the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing celecoxib.
Example III
To dichloromethane (18 ml), added celecoxib (5 gms), PVP (4 gm) and meglumine (1 gm) and dissolved. Heated the mixture to a temperature around 50 to 60 ° C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Then cooling the molten mass immediately using liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Examples IV:
To dichloromethane (18 ml), added celecoxib (7.5 gm), PVP (1.5 gm) and meglumine (1 gm) and dissolved. Heated the mixture to a temperature around 50 to 60 ° C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally,adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Example V
To dichloromethane (18 ml), added celecoxib (6 gms), PVP (2.5 gm) and meglumine (1.5 gm) and dissolved. Heated the mixture to a temperature around 50 to 60° C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a

molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Example VI
To dichloromethane (25 ml), added celecoxib (7 gms), HPMC (2 gm) and meglumine (1 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Example VII
To dichloromethane (18 ml), added celecoxib (5 gms), HPMC (3 gm) and meglumine (2 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Example VIII
To dichloromethane (18 ml), added celecoxib (5 gms), HPMC (4 gm) and meglumine (1 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Examples IX
To dichloromethane (18 ml), added celecoxib (7.5 gm), HPMC (1.5 gm) and meglumine (1 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally,

adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Example X
To dichloromethane (18 ml), added celecoxib (6 gms), HPMC (2.5 gm) and meglumine (1.5 gm) and dissolved. Heated the mixture to a temperature around 50 to 60° C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Example XI
To dichloromethane (25 ml), added celecoxib (7 gms), sodium CMC (2 gm) and meglumine (1 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C to evaporate completely the solvent to obtain a mixture containing Celecoxib.. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Example XII
To dichloromethane (18 ml), added celecoxib (5 gms), sodium CMC (3 gm) and meglumine (2 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally,adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Example XIII
To dichloromethane (18 ml), added celecoxib (5 gms), sodium CMC (4 gm) and meglumine (1 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C

to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally,adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Examples XIV
To dichloromethane (18 ml), added celecoxib (7.5 gm), sodium CMC (1.5 gm) and meglumine (1 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.

Example XV
To dichloromethane (18 ml), added celecoxib (6 gms), sodium CMC (2.5 gm) and meglumine (1.5 gm) and dissolved. Heated the mixture to a temperature around 50 to 60°C to evaporate completely the solvent to obtain a mixture containing Celecoxib. Optionally, adopting further heating of the mixture containing Celecoxib to obtain a molten mass. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to also obtain the required mixture containing Celecoxib.
Removal of solvents in Examples I to XV can also be performed by employing spray drying, freeze drying or any other suitable method.
Example XVI
The mixture containing Celecoxib obtained from any of the examples I to XV mentioned above can be further formulated using one or more conventionally acceptable pharmaceutical excipient to obtain the required pharmaceutical composition containing Celecoxib.

Example XVII; SOLUBILITY DATA
Table 1
Solubility data for Celecoxib-PVP binary systems
(Table Removed)

Crystalline celecoxib has solubility of 3.36 10.16 mcg/ml and amorphous celecoxib has a solubility of 4.66 10.62 mcg/ml.
Table 2
Solubility data of Ceiecoxib-Meglumine binary systems
(Table Removed)



Table 3
Solubility data for Celecoxib-PVP-Meglumine ternary systems
(Table Removed)


* Percent improvement over solubility of crystalline celecoxib ** Percent improvement over solubility of celecoxib-PVP binary mixture containing identical percentage of PVP *** Stored at 40 C / 75 % RH
The main advantages of the invention are:
1. The present invention provides a pharmaceutical composition containing celecoxib with enhanced aqueous solubility.
2. The present invention provides enhanced bio-availability of celecoxib.
3. The present invention also provides the possibility of minimizing the side effects caused by the drug.
4. The present invention provides the use of less quantity of drug in the treatment of disease.
5. The present invention provides a pharmaceutical composition with improved release kinetic in SR or CR dosage forms.






We claim
1. A process for the preparation of a synergistic pharmaceutical composition of
celecoxib with improved aqueous solubility, the said process comprising the steps of.
a) dissolving celecoxib in the range of 30 to 80% by weight, a polymer in the range of 5 to 50% by weight and a non-surfactant solubility enhancer in the range of 5 to 25% by weight in an organic solvent such as herein described,
b) heating with optionally stirring the mixture of step (a) at a temperature range of 50° to 60° C, to obtain a complete solution,
c) removing the organic solvent from step (b) solution, by either evaporating or spray drying or freeze drying to obtain a mixture containing celecoxib,
d) performing, optional heating of the mixture of step (c) for thorough mixing at a temperature range of 150° to 180° C to obtain a melt.
e) cooling immediately the molten mass of step (d) by dipping in a liquid nitrogen or dry ice-acetone mixture to obtain a mixture containing celecoxib, and
f) formulating the mixture of step (c) and/or (d) containing celocoxib with one or more pharmaceutically acceptable excipients such as herein described to obtain the required pharmaceutical composition

2. A process as claimed in claim 1, wherein in step (a) celecoxib used is preferably in the range of 50 to 70 % of total composition.
3. A process as claimed in claim 1, wherein the celecoxib exists at least in detectable amount in amorphous form and preferably more than 90 % in the amorphous form.
4. A process as claimed in claim 1, wherein in step (a), the non-surfactant solubility enhancer used is an amino sugar.
5. A process as claimed in claim 4, wherein the amino sugar used is N-methyl-D-glucamine (meglumine).
6. A process as claimed in claim 5, wherein the meglumine used is preferably in the range of 5-20% and more preferably 5-15% by weight of total composition.
7. A process as claimed in claim 1, wherein in step (a), the organic solvent used is selected from a group consisting of, methanol, ethanol, isopropanol, tertiary butanol,

acetonitrile, acetone, ethyl acetate, dimethyl sulfoxide, cyclohexanc, dichloromethane, water or mixtures thereof.
8. A process as claimed in claim 1, wherein in step (a), the polymer used is selected from a group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose phthalate (HPMCP), ethyl cellulose (EC), sodium carboxymethyl cellulose (NaCMC), polyethylene glycol block copolymers of ethylene oxide and propylene oxide, polyvinyl alcohol and preferably PVP.
9. A process of claim 8, wherein the polymer used is preferably in the range of 10- 40% by weight and more preferably 15-25% by weight of total composition.
10. A process as claimed in claim 1, wherein in step (b) the evaporation of solvent is performed at a temperature range of 40° to 100° C under reduced pressure.
11. A process of claim 1, wherein in step(c), the spray drying is performed under the condition of liquid flow rate being 5 to 20 ml/minute, at temperature in the range of 50°C to 200°C and air pressure in the range of 500 to 800 bars.
12. A process of claim 1, wherein in step (c) freeze drying is performed under the condition of freezing temperature in the range of-120° C to +25° C under a reduced pressure in the range of 0.1 to 1.0 torr.
13. A process as claimed in claim 1, wherein in step (d), the heating is done at a temperature range of 150° -180° and preferably in the range of 170 ° - 180 °C.
14. A process as claimed in claim 1, wherein the pharmaceutically acceptable excipients may be binders selected from a group consisting of starch, gelatin, polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose phthalate (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), ethylcellulose (EC), hydroxyethyl cellulose (HEC), dextran, hydroxypropyl cellulose (HPC), acacia and tragacanth.
15. A process as claimed in claim 1, wherein the pharmaceutically acceptable excipients may be disintegrants selected from starch, croscarmellose sodium, crospovidone and sodium starch glycolate.

16. A process as claimed in claim 1, wherein the pharmaceutically acceptable excipients may be diluents selected from microcrystalline cellulose, dicalcium phosphate, starch, lactose, mannitol, xylitol and calcium sulphate.
17. A process as claimed in claim 1, wherein the pharmaceutically acceptable excipients may be lubricants selected from stearic acid, magnesium stearate and hydrogenated vegetable oil.
18. A process as claimed in claim 1, wherein the pharmaceutically acceptable excipients may be glidant selected from colloidal silicon dioxide.
19.A process as claimed in claim 1, wherein the pharmaceutically acceptable excipients may be anti-adherents like talc, surface active agents such as sodium lauryl sulphate, cremophor RH 40, polysorbate 80, coating polymers selected from HPMC, HPC, flavors and coloring agents.
20.A process for preparation of a synergistic pharmaceutical composition of a mixture containing celecoxib with enhanced aqueous solubility substantially as herein described with reference to the foregoing examples.

Documents:

1165-del-2002-abstract.pdf

1165-del-2002-claims.pdf

1165-del-2002-complete specification (granted).pdf

1165-DEL-2002-Correspondence-Others-(22-06-2010).pdf

1165-del-2002-correspondence-others.pdf

1165-del-2002-correspondence-po.pdf

1165-del-2002-description (complete).pdf

1165-del-2002-form-1.pdf

1165-del-2002-form-2.pdf

1165-del-2002-form-26.pdf

1165-del-2002-form-3.pdf

1165-del-2002-form-5.pdf

1165-del-2002-petition-138.pdf


Patent Number 243294
Indian Patent Application Number 1165/DEL/2002
PG Journal Number 41/2010
Publication Date 08-Oct-2010
Grant Date 04-Oct-2010
Date of Filing 18-Nov-2002
Name of Patentee NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER),
Applicant Address SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA
Inventors:
# Inventor's Name Inventor's Address
1 ARVING KUMAR BANSAL NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIJPER), PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA
2 PIYUSH GUPTA NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIJPER), PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA
3 VASU KUMAR KAKUMANU NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIJPER), PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA
PCT International Classification Number A61K 31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA