FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"PROCESS OF MAKING DOSAGE UNIT BY NOVEL HIGH SHEAR WET GRANULATION"
Centaur Pharmaceutical Pvt Ltd. an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Vakola, Santacruz (East) Mumbai -400055
1. The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS OF MAKING DOSAGE UNIT BY NOVEL HIGH SHEAR WET GRANULATION
FIELD OF INVENTION:
The present invention relates to modified release formulation of active pharmaceutical ingredient(s), which involves (a) addition of a granulating fluid into the powder dry mixture of API with or without additives to prepare a semisolid mass; (b) addition of release retarding polymer to the semisolid mass obtained in step (a) and further kneading of resulting semisolid mass into uniform granules.
BACKGROUND OF THE INVENTION:
U. S. Patent No. 6,509,037 discloses a sustained release preparation of diclofenac and wet granulation process for the preparation of the same, the said process comprises 1) intimately blending a pharmaceutically acceptable salt of diclofenac with a sustained release polymer (hydroxy ethyl cellulose), channeling agent and glidant in a high shear mixer 2) granulating the homogeneous blend from step 1 a with solution of polyvinylpyrrolidone (PVP) in isopropyl alcohol in high shear mixer to obtain a granules.
U.S. Patent No. 7,090,867 discloses a sustained release formulation, which is being prepared by wet granulation process wherein said process comprises i) an intimate blending of API, sustained release polymer like xanthum gum and hydroxy propyl methyl cellulose and diluent in high shear mixture ii) granulating a homogeneous blend from step i with a granulation fluid (preferably isopropyl alcohol) in high shear mixture to obtain a granules.
U.S. Patent Publication No. 20080242642 discloses a modified release formulation of minocycline hydrochloride and method of preparing the same, wherein said method involve a mixing of minocycline hydrochloride with the hydroxy propyl methyl cellulose and lactose monohydrate in high shear granulator to prepare a uniform blend and wet granulation of said blend using a purified water in high shear granulator to produce a granule which is then dried

further in fluidized bed dryer. The resultant granule again mixed with lactose monohydrate, colloidal silicon dioxide and magnesium stearate which are then compressed to obtain tablets.
Conventional high shear wet granulation process disclosed in Handbook of Pharmaceutical Granulation Technology Third Edition Volume 198 Drugs and the Pharmaceutical Sciences involve following steps:
Loading all ingredients including release retarding polymer into mixing bowl by either of
the following methods: manually charging the bowl, gravity feeding with manual or
pneumatic valve, and vacuum feeding.
Mixing of dry ingredients such as API, other excipients, and disintegrant (optional),
with an impeller and chopper at high-speed settings for a short period of time
(2-5 minutes).
Addition of a liquid binder (either binder solution or solvent) into the powder mixture,
while both the impeller and the choppers are running at a low speed.
Wet massing when both impeller and the chopper running at a high speed.
A typical power consumption profile obtained from a commercially available high-shear granulator during conventional high shear granulation process is depicted in Figure no. 1

Wherein
Phase I: Liquid Bridge formation (Granulation Fluid Addition) (Power consumption does not
increase)
Phase II: Granule Formation (Power Consumption increases dramatically)

Phase III: Coarser Granules (Usable Granules) (Power Consumption relatively constant) Phase IV: More Coarser Granules (liquid saturation) (Power Consumption increases) Phase V: Droplet stage (Suspension form) (Power Consumption Decline)
As mentioned above in patents / patent applications, a conventional high-shear wet granulation process involves dry mixing of API with or without additives and release retarding polymer in high shear granulator and addition of granulating fluid in this dry mix to yield granules. There are many limitations with this process, especially in modified release formulation where release retarding polymer is in added in dry mix stage such as sufficiently large quantity of release retarding polymer is required which in turn significantly increases drug product cost. Furthermore granules obtained are non uniform in particle size thus increases processing time during milling and drying operations during manufacturing.
Accordingly, there is need in the art for the development of novel process of wet granulation which is cost efficient by employing minimum quantity of modified release polymer and also produce a uniform size granules to improve flowability which thereby achieve lesser processing time during manufacturing operation like drying, milling and compaction.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process of preparing pharmaceutical granules containing an active ingredient or a salt thereof comprising the step of:
(a) addition of a granulating fluid into the powder dry mixture of API with or without additives other than release retarding polymer, to prepare a semisolid mass;
(b) addition of release retarding polymer to the semisolid mass obtained in step (a) and further kneading of resulting semisolid mass into uniform granules.
Second aspect of present invention is to provide modified release formulation of active ingredients comprising granules prepared by a novel high shear wet granulation method

Another aspect of present invention is to provide a process of converting granules prepared by novel high shear wet granulation method into tablets, capsules or sachets.
DETAILED DESCRIPTION OF THE INVENTION:
Novel high shear wet granulation process described in present invention is advantageous over conventional process in following aspect:
• Efficient use of release retarding polymer.
• Granulation end point determination made easy, as
Extra quantity of granulating fluid addition not required.
Granulating fluid quantity fixed during product development phase, if RMG occupancy
and torque of impeller kept constant during scale up can give reproducible granulation. Mixing time fixed during product development phase if RMG occupancy and torque of impeller kept constant during scale up can give reproducible granulation. Granulation end can be determined when Ampere reading for granulation show similar value as that of Ampere reading observed for dry mixing. When granulating fluid added to dry mixed material to form semisolid mass, ampere reading is increased. While after addition of polymer/ release retardant material with wet mixing starts ampere reading shows maximum value, which then gets decreased and reaches to ampere value similar to amperage value during dry mixing.
• Yield granules with uniform particle size
• Effectively Reproducible & Scalable Process.
• Cost Effective Formulation as it require less time for drying and milling and requires
sufficiently less quantity of functional ingredient to achieve desired drug release profile.
The pharmaceutical active ingredient (API) used in the present invention may be water insoluble drugs, which may be BCS class II or BCS class IV.
The pharmaceutical active ingredient (API) used in the present invention may be water soluble drugs, which may be BCS class I or BCS class III.

The nonlimiting examples of a pharmaceutical active ingredient(API) suitable for use herein may include Metformin hydrochloride, Potassium Chloride, Ibuprofen, Gliclazide, Zolpidem Tartrate, Alprazolam, Methylphenidate, Doxazocin, Mesalazine, Torsemide, Zopiclone, or Acetazolamide and salt thereof.
In the method of the present invention, a granulating liquid is defined as a liquid which, when mixed with the API, and optional excipient particles, promotes adherence, or agglomeration of the particles to form granules.
A granulating amount of a granulating liquid is an amount of liquid sufficient to permit particle adherence, or agglomeration, without significant dissolution of the API.
The granulating fluid incorporated in the wet granulation in present invention may be aqueous or organic solvent or a solution of binder prepared in said solvent or other combination thereof.
The aqueous solvent used in the wet granulation may include water.
Suitable examples of organic solvents may include, but are not limited to, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichlorethane, dichloromethane, 1,2-dimethoxyethane, N,N,-dimethylacetamide, N,N-dimethylformamide, 1,4 dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methyl-pyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,2-trichlorethane, xylene, acetic acid, acetone, anisole, butyl acetate, tert-butylethylether, cumene, dimethyl sulfoxide, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, methyl ethyl ketone, methylisobutyl ketone, pentanal, propyl acetate, tetrahydrofuran, C1-C6 alcohols, and mixtures thereof.
The preferred organic solvent used as granulation fluid is ethanol, isopropyl alcohol, acetone and methylene chloride.

The present invention may also employ combination of aqueous and organic solvent include water, water/ethanol, water/isopropyl alcohol, and water/acetone.
The quantity of granulating liquid used in preparing granulation will vary depending on the granulating liquid and drug form.
The composition of the present invention can be formulated into granules or fine granules. Also, it can be encapsulated to give capsules or tabletted to give tablets.
The modified release polymer incorporated in present invention may be hydrophilic or hydrophobic.
The examples of suitable modified release polymer may include but not limited to polyethylene oxide (polyox), gum Arabic, xanthan gum, polyvinyl pyrrolidone, pullulan, hydroxyl propyl cellulose, hydroxy propyl methyl cellulose, hydroxyl ethyl cellulose, polyvinyl acetal diethyl amino acetate, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymers, macrogol, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; natural substances such as shellac or mixture(s) thereof.
Furthermore, the composition of the present invention may contain additive like diluent, binder, disintegrant, glidant and lubricant, a coloring agent, a flavor, stabilizer , antioxidant, taste masking agent, fillers or the like which are all well known in the art, if necessary.
The examples of diluent may include but not limited to mannitol, sucrose, lactose, glucose, sorbitol, calcium carbonate, calcium phosphate, microcrystalline cellulose, starch or mixture(s) thereof.
The examples of binder may include but not limited to hydroxyl propyl cellulose, hydroxy propyl methyl cellulose, polyvinyl pyrrolidone, macrogol, starch derivatives such as corn starch,

potato starch, a-starch and dextrin or mixture(s) thereof added in dry mix or in the form of solution or dispersion.
The examples of disintegrant may include but not limited to cellulose derivatives such as low substituted hydroxyl propyl cellulose, carboxy methyl cellulose, calcium carboxy methyl cellulose or internally cross-linked sodium carboxy methyl cellulose; cross-linked polyvinyl pyrrolidone; and chemically modified starches/celluloses such as carboxy methyl starch, sodium carboxy methyl starch, sodium starch glycolate, pregelatinized starch, croscarmellose sodium or mixture(s) thereof.
The examples of glidant may include but not limited to talc, colloidal silicon dioxide or mixture(s) thereof.
The examples of lubricant may include but not limited to stearic acid, stearic acid metal salts such as calcium stearate and magnesium stearate, talc, colloidal silica, waxes such as beeswax or spermaceti, boric acid, adipic acid, sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate, silicates such as silicic anhydride and silicate hydrate, starch derivatives such as corn starch, potato starch, a-starch and dextrin or mixture(s) thereof.
The examples of coloring agent may include but not limited to titanium oxide, talc, ferric oxide, yellow ferric oxide, black iron oxide, copper chlorophyll, copper chlorophylline sodium, carbon black, carbon for medical use, various edible colorants, glycyrrhiza extract, green tea powder, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, octyldodecyl myristate and the like.
The examples of flavor may include but not limited to fennel powder, fennel oil, ethyl vanillin, orange extract, orange oil, orange essence, capsicum flavor, glycyrrhiza extract, cinnamon bark powder, cinnamon oil, cherry flavor, clove oil, turpentine oil, bitter orange peel powder, peppermint oil, vanilla flavor, vanillin, bitter essence, bergamot flavor, menthol, eucalyptus oil, borneol, rosin and the like.

Examples of stabilizers may include but not limited to acids, bases or buffer salts, preferably selected from group of sodium carbonate, sodium bicarbonate, calcium carbonate, sodium citrate, magnesium oxide, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, and disodium hydrogen phosphate.
Antioxidants can be divided in two groups: the free radical capturing agents, such as tocopherol, butyl hydroxy anisole, butyl hydroxy toluene, and easily oxidizable substances, such as ascorbic acid, its fatty acid esters, sulfite and hydrogen sulfite, which will be oxidized faster than the drug substance.
The process flow of novel high shear wet granulation in RMG may be depicted in Figure no. 2.

Figure No. 2
The power consumption profile obtained from a commercially available high-shear granulator during novel high shear granulation process may be depicted in Figure no. 3.


Wherein
Phase I: (S1-S2) Granulation Fluid Addition (Power consumption does not increase)
Phase II: (S2-S3) Start of wet mixing (Drastic increase in Power consumption)
Phase III: (S3-S4) Uniform granules with desired properties (Power consumption decline and
similar to when granulation fluid addition)
DETAILED DESCRIPTION OF FIGURES:
Figure I depicted power consumption profile obtained from a commercially available high-shear granulator during conventional high shear granulation process. Figure II depicted process flow of novel high shear wet granulation in RMG Figure III depicted power consumption profile obtained from a commercially available high-shear granulator during novel high shear granulation process.
EXAMPLES
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1:
Novel high shear wet granulation process for pharmaceutical composition containing Metformin hydrochloride.

Name of Material Quantity
Dry Mix
Metformin HC1 500*
Colloidal Silicon Dioxide 6.8**
Binder
Hypromellose(Methocel K100M) 3.4**
Purified water 150**
Hypromellose(Methocel K100M) 262.8"

* Quantity given in milligrams per tablet, ** Quantity given in grams for batch.
Manufacturing process:
1. Metformin hydrochloride and colloidal silicon dioxide were dry mixed in Rapid Mixer Granulator.
2. Hypromellose K100 M (3.4 g) was dissolved in 150 g of water to prepare granulating fluid.
3. Granulating fluid was added to the material of step no. 1 with impeller & chopper at fast speed. Semisolid mass was formed.
4. Hypromellose K 100 M (262.8 g) was added to semisolid mass and further kneaded to yield desired granules.
Example 2:
Novel high shear wet granulation process for pharmaceutical composition containing Metformin hydrochloride.

Name of Material Quantity
Dry Mix
Metformin HC1 1000*
Colloidal Silicon Dioxide 10.4**
Magnesium Stearate 20.8**
Binder
Ethocel 20cps 31.5**
Isopropyl alcohol 283.5**
Hypromellose(Methocel K100M) 209.3**
* Quantity given in milligrams per tablet, ** Quantity given in grams for batch.
Manufacturing process:
1. Metformin hydrochloride and colloidal silicon dioxide were dry mixed in Rapid Mixer Granulator.

. 2. Ethocel 20 cps (31.5 g) dissolved in 283.5 g of isopropyl alcohol to prepare granulating fluid.
3. Granulating fluid and extra quantity of isopropyl alcohol were added to the dry mixed material of step no. 1, with impeller at slow speed & chopper off, semisolid mass was formed.
4. Hypromellose K 100 M (209.3 g) was added to semisolid mass of step no. 3 and further kneaded to yield desired granules.
Example 3:
Novel High shear granulation process for pharmaceutical composition containing potassium
chloride:

Name of Material Quantity
Intragranular
Potassium Chloride 750"
Colloidal Silicon Dioxide 6.375 **
Magnesium Stearate 6.375**
Binder
PVP K30 31.875**
Purified water 150+*
Hypromellose(Methocel K100M) 205.125**
* Quantity given in milligrams per tablet, ** quantity given in grams for batch. Manufacturing process:
1. Potassium chloride was milled and sized.
2. Colloidal silicon dioxide and magnesium stearate were dry mixed with material of step no. 1 in RMG.
3. PVP K30 was dissolved in 150 ml of purified water to prepare granulating fluid.
4. Granulating fluid was added to the material of step no. 2 with impeller and chopper at fast speed, semi solid mass formed.
5. Hypromellose (205.125 g) was added to semisolid mass of step no. 4 and further kneaded to yield desired granules

WE CLAIM:
1. Process for preparing pharmaceutical granules containing an active ingredient or a salt, said process comprising the step of: (a) addition of a granulating fluid into the powder dry mixture of API with or without additives other than release retarding polymer, to prepare a semisolid mass; (b) addition of release retarding polymer to the semisolid mass obtained in step (a) and further kneading to yield uniform granules.
2. The process of claim 1, wherein said process is carried out in a high shear wet granulator.
3. The process of claim 1, wherein the granulation liquid is solution or dispersion of binding agents in water, ethanol, methanol, isopropanol or and mixtures thereof.
4. Pharmaceutical granules containing an active ingredient or a salt, said granule being obtained by a process comprising the steps of (a) addition of a granulating fluid into the powder dry mixture of API with or without additives other than release retarding polymer, to prepare a semisolid mass; (b) addition of release retarding polymer to the semisolid mass obtained in step (a) and further kneading to yield uniform granules.
5. The granules of claim 4, comprising additives selected from the group of diluents, binders, disintegrants, glidant, coloring agents, sweeteners, flavors , stabilizers and antioxidants.
6. The granules of claim 4, comprising an active ingredient selected from the group of Metformin Hcl, Potassium Chloride, Ibuprofen, Gliclazide, Zolpidem Tartrate, Alprazolam, Methyl Phenidate, Doxazocin, Mesalazine, Torsemide, Zopiclone, and Acetazolamide and salt thereof.
7. A pharmaceutical composition, comprising granules are prepared according to claim 4.

8. The pharmaceutical composition of claim 7, exhibit release of active ingredient for extended period of time from 2 hr to 24 hr.
9. The pharmaceutical composition of claim 7, constituting a tablet prepared by compressing the granules and, optionally, further excipients.
10. The pharmaceutical composition of claim 7, constituting a hard capsule filled with the granules and, optionally, further excipients.