TITLE: NOVEL PROCESS FOR PREPARING DEXIBUPROFEN READY TO COMPRESS GRANULES

TECHNICAL FIELD OF THE INVENTION:

The present invention relates to novel process of preparing dexibuprofen pharmaceutical formulation in the form of granules, which can be directly compressed into tablets.

BACKGROUND OF THE INVENTION:

Ibuprofen [R, S-(±)-2-(4-isobutylphenyl) - propionic acid] has one chiral center, thus there are two enantiomers, S(+)-ibuprofen and R(-)-ibuprofen, the S(+)-ibuprofen is also known as dexibuprofen. Ibuprofen is a poorly water-soluble drug with a melting point of 75°C to 77.5°C, while both enantiomers of ibuprofen, S (+)-ibuprofen and R(-)-ibuprofen, melt at 52°C to 54°C.

Ibuprofen has proved to be difficult to formulate in the form of tablets, and this is believed to be due to its poor compressibility and flowability. The poor compressibility and flowability is believed to be partly due to the fact that ibuprofen itself has a very low bulk density, and partly due to the low melting point.

In the case of dexibuprofen, the above-mentioned problems of poor compressibility and flowability associated with the preparation of tablets containing ibuprofen are considerably more pronounced, owing to the fact that the melting point of dexibuprofen is significantly lower than for the ibuprofen. Furthermore, dexibuprofen has a very low bulk density. The low melting point also causes frequent sticking problem during compression on high speed commercial scale tablet compression machine.

Following is given a brief review of patent literature relating to dexibuprofen formulation and profess of preparing the same:

US patent no US4877620 discloses a pharmaceutical tablet compositions comprising 62.5% w/w S-(+)- ibuprofen, 4.2% w/w insoluble polyvinylpyrrolidone, 31.3% w/w microcrystalline cellulose and 2% w/w magnesium stearate, process of preparing the same is not disclosed.

US patent no US5869102 discloses a solid pharmaceutical composition containing dexibuprofen in the form of tablet comprising of dexibuprofen, macrocrystalline cellulose (30-50 % w/w), colloidal silica (less than 0.3%w/w) and wetting agent (3-6 % w/w) or surfactant (0.01-2 % w/w of sodium lauryl sulfate, Tween, Span), wherein the tablets are prepared by direct compression.

PCT application no WO199410993 discloses a pharmaceutical particulate formulation comprising dexibuprofen, and a water-soluble binder, wherein the particulate formulation comprise of a blend containing i) granulated material incorporating the active drug substance and ii) extragranular excipients in powder form and the granules are prepared by conventional wet granulation process using granulator.

PCT application no W02009084041 discloses a pharmaceutical composition comprising of dexibuprofen or its pharmaceutically acceptable salt and process of preparing the same, having dexibuprofen mean particle size equal to or less than 125 microns with in- vitro dissolution of more than about 90% in 5 minutes, wherein the preferred process involves wet granulation using high shear granulator.

PCT application no WO 1994017793 discloses a process for the preparation of a tablet containing dexibuprofen which rapidly releases the active compound, wherein the tablet consist of dry binder intra and extra granularly and prepared by dry granulation process.

The prior art discloses various process of preparing solid pharmaceutical formulation containing dexibuprofen including direct compression, dry granulation and wet granulation using conventional granulator to overcome the formulation difficulties associated with dexibuprofen due to its low melting point, low density and poor flowability.

Thus there is constant need of developing a robust process of preparing dexibuprofen pharmaceutical formulation in the form of granules which can be directly compressed into tablets and at the same time should also overcome the formulation difficulties associated with dexibuprofen.

SUMMARY OF THE INVENTION:

The present invention relates to a novel process of preparing dexibuprofen pharmaceutical formulation in the form of granules, which can be directly compressed into tablets. It was surprisingly found that the granules prepared by using fluid bed granulation process showed improved compressibility and flowability compared to granules prepared by conventional granulation process using rapid mixer granulator. Also, the granules prepared using fluid bed granulation process showed no signs of sticking when compressed on high speed commercial scale tablet compression machine, whereas the granules prepared by conventional granulation process using rapid mixer granulator showed signs of sticking from the beginning of compression. The compressed tablets of granules prepared by using fluid bed granulation process showed no signs of tablet shape deformation when subjected to the stress stability study at 50°C/90%RH for one month.

DETAILED DESCRIPTION:

The present invention relates to novel process of preparing dexibuprofen pharmaceutical formulation in the form of granules, which can be directly compressed into tablets, more specifically relates to a novel process of preparing dexibuprofen ready-to-compress granules.
One of the objectives of the present invention is to prepare dexibuprofen granules, which can be directly compressed into tablets, wherein the granules comprise of mixture or blend of base granules and compression aid.
Another objective of the present invention is to prepare dexibuprofen ready to compress granules, which can be directly compressed into tablets, wherein the granules comprise of mixture or blend of base granules and compression aid.
Another objective of the present invention is to prepare dexibuprofen granules, which can be directly compressed into tablets, wherein (a) the granules comprise of mixture or blend of base granules and compression aid, and (b) the base granules were prepared by fluid bed granulation process.

Another objective of the present invention is to prepare dexibuprofen granules, which can be directly compressed into tablets, wherein, (a) the granules comprise of mixture or blend of base granules and compression aid and (b) the base granules were prepared by wet granulation process using fluid bed granulator with bottom spray method.
Yet another objective of the present invention is to prepare dexibuprofen granules, which can be directly compressed into tablets, wherein, (a) the granules comprises of a mixture or blend of base granules and compression aid and (b) the base granules were prepared by wet granulation process using fluid bed granulator with top spray method.

According to the present invention the novel process of preparing dexibuprofen granules which can be directly compressed into tablets mainly comprise of two steps: (a) preparation of base granule, and (b) blending of base granules with compression aid, wherein the process of preparing base granules, comprising the steps of: (a) mixing or blending of sifted dexibuprofen, and other pharmaceutically acceptable excipient(s), in fluid bed granulator, (b) granulation of fluidized dry mix obtained in step (a) using binder solution with top spray method to get wet granules, (c) drying of fluidized wet granules at suitable product bed temperature to obtain granules with loss on drying of not more than 0.3% w/w at 50°C, (d) sizing the dried granules of step (c) using suitable method to get base granules, and (e) the blending of base granules with compression aid involves mixing or blinding of base granules with previously sifted super disintegrant(s), glidant(s), lubricant(s) and diluent(s).

According to the present invention compression aid may be comprise of one or more selected from the group of lubricant(s), glidant(s), super disintegrant(s), and diluent(s).
According to the present invention other pharmaceutically acceptable excipient(s) may be comprise of one or more selected from the group of glidant(s), super disintegrant(s), surfactant(s) and diluent(s).

According to the present invention binder solution may be aqueous based or, hydroalcoholic based or alcoholic based, preferably aqueous based.
According to the present invention sizing of dried granules can be done using suitable size sieve and /or multi mill or cone mill.

According to the present invention base granules can be prepared by using fluid bed granulation process with top spray or bottom spray method, preferably with top spray method.

According to the present invention one or more diluent(s) can be selected from the group comprising of saccharides like lactose, sucrose, dextrose, sugar alcohols like mannitol, xylitol, sorbitol, starch, silicates like magnesium silicate, aluminum silicate, microcrystalline cellulose, polyethylene glycols solid grades (PEG average molecular weight greater than 1000) like PEG 1000, PEG 2000, PEG 6000, dibasic calcium phosphate dihydrate, pregelatinized starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin and the like.

According to the present invention one or more binder(s) can be selected from the group comprising of povidone, polyvinyl alcohol, starch, pregelatinized starch, gum acacia, gum tragacanth, guar gum, pectin, copolyvidone, gelatin, sodium alginate, polymethacrylates, carbomer, saccharides like lactose, sucrose, dextrose, sugar alcohols like mannitol, xylitol, sorbitol, and the like.

According to the present invention one or more super disintegrant(s) can be selected from the group comprising of crospovidone, sodium starch glycolate, croscarmellose sodium, calcium carboxymethylcelluose, starch and the like.

According to the present invention one or more lubricant(s) and/ or glidant(s) can be selected from the group comprising of magnesium stearate, stearic acid, calcium stearate, zinc stearate, talc, camauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols, glyceryl behenate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, colloidal silicon dioxide, and the like.

According to the present invention optionally one or more surfactant(s) can be selected from the group comprising of sodium alkyl sulfates such as sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosinates such as sodium N-lauroyl sarcosinate and sodium N-myristoyl sarcosinate, sodium dodecylbenzenesulfonate, sodium hydrogenated coconut fatty acid monoglyceride sulfate, sodium lauryl sulfoacetate, N-acyl glutamates such as N-palmitoyl glutamate, N-methylacyltaurin sodium salt, N-methylacylalanine sodium salt, sodium a-olefm sulfonate, sodium dioctylsulfosuccinate; N-alkylaminoglycerols such as N- lauryldiaminoethylglycerol and N-myristyldiaminoethylglycerol, N-alkyl-N- carboxymethylammonium betaine, sodium 2-alkyl-l-hydroxyethylimidazoline betaine; polyoxyethylenealkyl ether, polyoxyethylenealkylaryl ether, polyoxyethylenelanolin alcohol, polyoxyethyleneglyceryl monoaliphatic acid ester, polyoxyethylenesorbitol aliphatic acid ester, polyoxyethylene aliphatic acid ester, higher aliphatic acid glycerol ester, sorbitan aliphatic acid ester, pluronic type surface active agent, and polyoxyethylenesorbitan aliphatic acid esters such as polyoxyethylenesorbitan monooleate and polyoxyethylenesorbitan monolaurate and the like.
According to the present invention general composition and process of preparing dexibuprofen ready to compress granules is as follows:
TABLE 1: General composition of dexibuprofen ready to compress granules is as follows:

General manufacturing process of dexibuprofen ready to compress granules is as follows:

According to the present invention the novel process of preparing dexibuprofen granules which can be directly compressed in to tablets mainly consists of two steps: (a) preparation of base granule, and (b) blending or mixing of base granules with compression aid, wherein the process of preparing base granules, comprising the steps of: (a) mixing or blending of sifted dexibuprofen, and other pharmaceutically acceptable excipient(s), in fluid bed granulator, (b) granulation of fluidized dry mix obtained in step (a) using aqueous binder solution with top spray method to get wet granules, (c) drying of fluidized wet granules at suitable product bed temperature to obtain granules with loss on drying not more than 0.3% w/w at 50°C, (d) sizing the dried granules of step (c) using suitable method to get base granules, and (e) the blending of base granules with compression aid involves mixing or blending of base granules with previously sifted super disintegrant(s), glidant(s), lubricant(s) and diluent(s).

According to the present invention two sets of experiment were performed to evaluate the effect of granulation process on compressibility and flowability of dexibuprofen granules. In the first set of experiment wet granulation is performed using conventional rapid mixer granulator as described in example 1 and in the second set of experiment wet granulation is performed using fluid bed granulator with top spray method as described in example 2, 3 and 4.

Following examples are illustrative but no way limits the scope of the invention.

TABLE 2: Composition of dexibuprofen ready to compress granules:
Manufacturing process:

Example 1: Dexibuprofen ready to compress granules prepared using rapid mixer granulator:

1. Sift dexibuprofen through #30 mesh sieve, colloidal silicon dioxide and croscarmellose sodium through #60 mesh sieve, load and mix in rapid mixer granulator.

2. Preparation binder solution: disperse maize starch sufficient quantity of purified water to get uniform slurry and separately add lactose in sufficient quantity of purified water, then add starch slurry into boiling water under stirring to get thick paste. Allow the temperature of the paste to decrease to 50°C and then add lactose slurry into paste and mix well.

3. Granulate the dry blend of step 1 using the binder solution prepared in step 2.

4. Dry the wet granules obtained in step 3 using fluid bed dryer (Glatt GPCG 1.1) at product bed temperature 25 °C to 30°C, to get dried granules with loss on drying not more than 0.3%w/w at 50°C.

5. Size the dry granule of step 4 through #24 mesh sieve and pass the retains through 1.0 mm screen using a cone mill.

6. Mix the sized dry granule of step 5 with previously sifted (#60 mesh sieve) blend of half the quantity of microcrystalline cellulose and colloidal silicon dioxide in blender for 3 minutes at 30 rpm.

7. Further add previously sifted (#60 mesh sieve) blend of remaining quantity of microcrystalline cellulose and sodium starch glycolate to step 6 and mix for 5 minutes at 30 rpm.

8. Finally lubricate blend of step 7 using previously sifted (#60 mesh sieve) talc by mixing for 2 minutes at 30 rpm.

9. Compress the blend of step 8 into tablets and pack into blister packs.
Example 2: Dexibuprofen ready to compress granules prepared using fluid bed granulator:

1. Sift dexibuprofen through #30 mesh sieve, colloidal silicon dioxide and croscarmellose sodiimi through #60 mesh sieve, load and mix in fluid bed granulator (Glatt GPCG 1.1).

2. Preparation binder solution: disperse maize starch sufficient quantity of purified water to get uniform slurry and separately add lactose in sufficient quantity of purified water, then add starch slurry into boiling water under stirring to get thick paste. Allow the temperature of the paste to decrease to 50°C and then add lactose slurry into paste and mix well.

3. Granulate the fluidized dry blend of step 1 using the binder solution prepared in step 2 using top spray method.

4. Dry the fluidized wet granules obtained in step 3 at product bed temperature 25°C to 30°C, to get dried granules with loss on drying not more than 0.3%w/w at 50°C.

5. Size the dry granule of step 4 through #24 mesh sieve and pass the retains through 1.0 mm screen using a cone mill.

6. Mix the sized dry granule of step 5 with previously sifted (#60 mesh sieve) blend of half quantity of microcrystalline cellulose and colloidal silicon dioxide in blender for 3 minutes at 30 rpm.

7. Further add previously sifted (#60 mesh sieve) blend of remaining quantity of microcrystalline cellulose and sodium starch glycolate to step 6 and mix for 5 minutes at 30 rpm.

8. Finally lubricate blend of step 7 using previously sifted (#60 mesh sieve) talc by mixing for 2 minutes at 30 rpm.

9. Compress the blend of step 8 into tablets and pack into blister packs.
Example 3: Dexibuprofen ready to compress granules prepared using fluid bed granulation process as followed in example 2.
Example 4: Dexibuprofen ready to compress granules prepared using fluid bed granulation process as followed in example 2 and 3.
The dexibuprofen ready to compress granules prepared according to examples 1, 2, 3, and 4 were evaluated for compressibility index, flowability (Hausner Ratio), suitability for compressed on high speed commercial scale tablet compression machine and stability study at 30°C/65%RH, 40°C/75%RH, and stress stability test at 50°C/90%RH for one month.

TABLE 3: Compressibility index and flowability (Hausner Ratio) of dexibuprofen ready to compress granules is as follows:
Examples Compressibility index Flowability (Hausner Ratio) Examples 1 15.9% 1.19%
Examples 19% 1.11%
2, 3 and 4

The compressibility index of granules prepared by using fluid bed granulation process was found to be excellent (3.9%) compared with compressibility index of granules prepared by conventional granulation process using rapid mixer granulator i.e. fair (15.9%) and the flowability (Hausner Ratio) of granules prepared by using fluid bed granulation was found to be excellent (1.11%) compared with flowability (Hausner Ratio) of granules prepared by conventional granulation process using rapid mixer granulator i.e. fair (1.19%).

As compressibility and flowability of granules depends on surface characteristics of particles, it was surprisingly found that the granules prepared using fluid bed granulation process showed improved compressibility and flowability compared to granules prepared by conventional granulation process using rapid mixer granulator, which may be due to individual particles coating with binder achieved in fluid bed granulation process and hence the surface characteristics of particles get modified in better way compared to conventional rapid mixer granulations process where individual particles coating with binder is not achieved.

The granules prepared using fluid bed granulation process showed no signs of sticking when compressed on high speed commercial scale tablet compression machine, whereas the granules prepared by conventional granulation process using rapid mixer granulator showed signs of sticking from the beginning of compression.

The tablets prepared according to example 2, 3 and 4 showed no changes with respect to hardness, disintegration time, dissolution, assay value, and tablet shape at 40°C/75%RH for six months and at 30°C/65%RH for one year.

A stress stability study was conducted at 50°C/90% RH for one month to check the possibility of tablet shape deformation due to low melting point of dexibuprofen. Tablet softening was observed in blister packs of tablets prepared according to example 1 (using rapid mixer granulator) leading to tablets shape deformation, but the blister packs of tablets prepared according to example 2, 3 and 4 (using fluid bed granulator) showed no signs of tablet softening.

WE CLAIM:

1. A process of preparing dexibuprofen ready to compress granules, comprising the steps of: (i) preparation of base granules using fluid bed granulation process, and (ii) mixing or blending of base granules with compression aid to get dexibuprofen ready to compress granules.

2. A process of preparing dexibuprofen ready to compress granules, comprising the steps of: (i) preparation of base granules using fluid bed granulation process with top spray method, and (ii) mixing or blending of base granules with compression aid to get dexibuprofen ready to compress granules.

3. A process of preparing dexibuprofen ready to compress granules, comprising the steps of: (i) preparation of base granules using fluid bed granulation process with bottom spray method, and (ii) mixing or blending of base granules with compression aid to get dexibuprofen ready to compress granules.

4. A process of preparing dexibuprofen ready to compress granules, comprising the steps of: (i) preparation of base granules using fluid bed granulation process with top spray method, and (ii) mixing or blending of base granules with compression aid, wherein process of preparing base granules, comprising the steps of: (a) mixing or blending of sifted dexibuprofen, and other pharmaceutically acceptable excipient(s), in fluid bed granulator, (b) granulation of fluidized dry mix obtained in step (a) using binder solution with top spray method to get wet granules, (c) drying of fluidized wet granules, (d) sizing the dried granules of step (c) using suitable method to get base granules.

5. A process of preparing dexibuprofen ready to compress granules, comprising the steps of: (i) preparation of base granules using fluid bed granulation process with top spray method, and (ii) mixing or blending of base granules with compression aid, wherein process of preparing base granules, comprising the steps of: (a) mixing or blending of sifted dexibuprofen, and other pharmaceutically acceptable excipient(s), in fluid bed granulator, (b) granulation of fluidized dry mix obtained in step (a) using binder solution with top spray method to get wet granules, ' ) drying of fluidized wet granules at suitable product bed temperature to obtain granules with loss on drying not more than 0.3%w/w at 50°C, (d) sizing the dried granules of step (c) using suitable method to get base granules.

5. A process of preparing dexibuprofen ready to compress granules according to claim 4 and 5, wherein the drying of fluidized wet granules is carried out at product bed temperature of 25°C to 30°C.

6. A process of preparing dexibuprofen ready to compress granules according to claim 4 and 5, wherein the sizing dried granules can be done using suitable size sieve and /or multi mill or cone mill.

7. A process of preparing dexibuprofen ready to compress granules according to any of the preceding claims, wherein the compression aid may be comprise of one or more selected from the group of lubricant(s), glidant(s), super disintegrant(s), surfactant(s) and diluent(s).

8. A process of preparing dexibuprofen ready to compress granules according to claim 4 and 5, wherein the other pharmaceutically acceptable excipients may be comprise of one or more selected from the group of glidant(s), super disintegrant(s), diluent(s) and surfactant(s).