FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)

1. TITLE OF THE INVENTION:
"NOVEL AND IMPROVED PROCESS FOR THE PREPARATION OF
TABLET DOSAGE FORM
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED.
Companies ACT, 1956
(c) ADDRESS: Indoco House, 166 C. S. T. Roaq, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.


FIELD OF THE INVENTION
The present invention relates to a novel and an improved process for the preparation of tablet dosage form.
BACKGROUND OF THE INVENTION
Tablets are the most common and popular oral solid dosage form accounting for over two-third of the total number and cost of the medicines produced all over the world. Their advantages like ability to maintain accurate dose, ability to achieve tailor made release profile, longer expiry period and minimum microbial spillage owing to lower moisture content, ease of packaging (blister or strip) and ease in transport in bulk, greater patient compliance and finally ability to improve organoleptic properties (taste, appearance and odor) by coating ascertains its supremacy over other dosage forms.
Tablets are usually made by either of the three ways viz., dry granulation, wet granulation and direct compression. Wet granulation technique, which is one of the most common techniques, involves the steps of weighing, blending, granulating, sieving and screening, drying, sizing, lubricating, blending and finally compressing to get the tablets. Even though the number of steps involved in the tablets may not be of much significance in the small scale/lab production; however, this plays a very vital role during the large scale production as the reduction in each step would consequently indicate reduction in cost of production.
Further, although the tablets are compressed solid dosage form containing mainly the medicament; however, in addition, they contain a number of inactive materials; also known as excipients or additives.
Also, USP 29-NF 24 includes more than 40 functional categories of excipients in pharmaceuticals, and many more may be added over time to meet the needs of new drug delivery systems and biotechnology-derived products. Excipients affect the critical quality attributes of the actives, including modulating solubility and bioavailability of APIs, increasing the stability of active ingredients in dosage forms, helping active ingredients maintain preferred polymorphic forms or conformations, maintaining the pH and/or osmolarity of liquid formulations, acting as

antioxidants, emulsifying agents, preventing aggregation or dissociation (e.g., of protein and polysaccharide actives), modulating immunogenic responses of active ingredients (e.g. adjuvants), and more.
An excipient is selected and used because it contributes one or more functional attributes to the product characteristics. These also influence the safety and effectiveness of drugs depending on the route of administration.
Some of the widely used excipients in the tablet dosage formulation include diluents, lubricants, binders, glidant, disintegrants. coloring agent, flavoring agent, sweeteners etc.
Lubricants are intended to decrease friction at the interface between a tablet's surface and the die wall during ejection, reduce wear and tear on punches & dies, prevent sticking to punch faces or in the case of encapsulation, prevent sticking to machine dosators, tamping pins. etc. and finally enhance the product flow by reducing interparticulate friction. Of all the lubricants in use, "magnesium stearate" is the most widely used lubricant in the pharmaceutical industry. Although it is used in low concentrations, it is often the cause of many problems experienced in solid oral dosage forms. To name a few, the hydrophobic nature of magnesium stearate interferes with "wetting", leading to increases in the time required for the tablet to disintegrate and/or the drug to become dissolved. Additionally, a complete coating of lubricant may affect tablet hardness by interfering with the interparticle bonding required by formulations where tablets are formed with components that bond by plastic deformation. The use of Magnesium Stearate as a lubricant has further complications in that a variety of commercial samples have been known to exhibit significant batch-to-batch variation in their lubricant properties. Many studies and attempts have been made to address this issue of drawbacks of magnesium stearate. For example: US 3,577,492 by Welsch et al discloses that the combination of corn oil and siloxane polymer when mixed with tabletting material provides the necessary lubricating effect. Hoss et al in US 3,506,756 discloses the use of adipic acid as a lubricant in the tabletting process. US 5,922,351 by Daher Lawrence claims the use of potassium sorbate, calcium sorbate, a comicronized mixture of polyethylene glycol 8000 with a co-agent like anhydrous trisodium citrate and calcium ascorbate as

suitable lubricant in the tablets which circumvents the above-mentioned problems. Also, Sangekar et al in US 3,957,662 advocates the use of finely divided magnesium or calcium stearate coated with surfectant like sodium lauryl sulfate, polyoxyethylene (20) sorbitan mono-oleate and dioctyl sodium which overcomes the problems which are associated with magnesium stearate. In spite of all the disadvantages of magnesium stearate, it is still one of the most effective and commonly utilized lubricants in the tablet dosage form.
The present inventors have surprisingly found that the addition of magnesium stearate to the wet mass trounces the problem of hydrophobicity of the magnesium stearate. Also, addition of lubricant i.e. magnesium stearate to the wet mass reduces the step of lubrication and blending; which ultimately results in substantial reduction both in terms of time and money during large-scale production and meeting the regulatory process .
DETAILED DESCRIPTION OF THE INVENTION
As mentioned herein before, the wet granulation technique for the preparation of tablets involve the steps like mixing of the drug(s) and excipients, preparation of binder solution, mixing of binder solution with powder mixture to form wet mass., coarse screening of wet mass using a suitable sieve to get the granules, drying of moist granules, screening of dry granules through a suitable sieve, blending of screened granules with lubricant, and finally compressing the material to get the tablets.
It has been found by the present inventors that the lubricant can be added directly to the wet mass before the granulation stage and this process holds true for both Fluidized bed processor (FBP) as well as Rotary mixer granulator (RMG). This not only reduces the no. of steps involved in production but also contributes many other advantages like,
• Since the lubricant is added to the wet mass, it increases the contact surface area and thus results in effective lubrication.
• As the mixing of the lubricant to the wet mass is very effective, the quantity of lubricant can be reduced, which results in reduction of product cost.

• As mentioned above, addition of lubricant i.e. magnesium stearate, glyceryl
behenate, sodium stearyl fumarate, hydrogenated vegetable oil. hydrogenated
castor oil, hydrogenated cottonseed oil, stearic acid and calcium stearate, high
molecular weight Polyethylene glycols like PEG 6000, colloidal silicon
dioxide and the like to the wet mass eliminates the step of lubrication and
blending; which saves time and ultimately results in the cost effective process
during large-scale production.
• Lubricants such as magnesium stearate are hydrophobic in nature. Thus, when
they are further added at the last stage of the tabletting process to the
hydrophobic drug, the dissolution and disintegration time of hydrophobic drug
is normally hindered. However, when they are added to the wet mass, the
dissolution and disintegration time of drug remains unaffected. This is
because, lubricant rapidly distributes over the wet mass due to the shear action
and provides adequate lubrication desired for action.
In one embodiment, the examples of drugs that can be selected for the preparation of tablets include ace-inhibitors, antianginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, anti¬diabetic agents, anti-diarrhea preparations, antidotes, anti-histamines, anti¬hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplastics, anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators, cardiovascular agents, central nervous system stimulates, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis management agents, enzymes, erectile dysfunction therapies, fertility agents, gastrointestinal agents, homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments, muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives, smoking cessation aids, sympatholytics, tremor

preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents, anti¬ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti¬tumor drugs, anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, antispasmodics, terine relaxants, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof.
In another embodiment, both the hydrophobic and hydrophillic pharmaceutical!)' active agent can be used for the preparation of tablets.
In a preferred embodiment, the hydrophobic drug used is selected from allopurinol, azithromycin, carbamazepine, clarithromycin, ketoprofen, carprofen, ciprofloxacin hydrochloride, erythromycin,, griseofulvin, oxcarbamzepine and paracetamol and the hydrophilic drug used is selected from metformin .dextromethorphan, , metoprolol and nortryptaline.
Various excipients that could be employed for the preparation of the tablets are disintegrants, fillers, binders, glidants, surfactants and lubricants.
The disintegrant that can be used is selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmeilose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polyacrilin potassium, powdered cellulose, pregelatinized starch, sodium or calcium alginate and starch.
The filler that can be used in the present invention is selected from calcium carbonate, calcium sulfate, compressible sugars, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil (type I), kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose,


pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate.
The binder that can be used in the present invention is selected from acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylceliulose, gelatin, guar gum, hydrogenated vegetable oil (type I), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminaum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, corn starch, and zein.
The surfactant is selected from anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide).
The lubricant is selected from stearate acid metal salt (magnesium stearate or calcium stearate), sodium stearyl fumarate, hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated cottonseed oil, high molecular weight polyethylene glycols like PEG 6000, stearic acid and colloidal silicon dioxide.
Optionally, the composition may further comprise a coloring agent.
Some typical examples illustrating the embodiments of the present invention are provided; however, these are exemplary only and should not be regarded as limitations of the present invention.


Example 1:
Sr.No. Ingredients Quantities (mg/tablet)
1. Paracetamol 500.00
2. Pregelatinised Starch 65.00
3. Magnesium Stearate 3.00
4. Purified Water q.s
Procedure
1. Weigh the required quantity of ingredients.
2. Sieve the ingredients Paracetamol BP through 20# sieve & Pregelatinised Starch BP through 60# sieve.
3. Transfer, Paracetamol BP & Pregelatinised starch BP into the Rapid Mixer Granulator (RMG) and mix for around 10 minutes at slow speed of impeller & chopper in OFF position.
4. Add gradually Purified Water (50°C) over a period of 10 min. After completion of water additions, continue kneading for 10 minutes with impeller on slow speed and chopper in OFF position.
5. Spread magnesium stearate over granulated mass of step 5 and knead further with impeller at fast speed for 30 sec.

7. Discharge the Wet granules into the Fluid Bed Drier (FBD) bowl
8. Place the FBD bowl containing the wet granules in position for drying. Dry the granules at 55°+ 3°C (inlet temperature) for 25-30 min till the outlet temperature reaches 33°+ 2°C, to a moisture content of 2.5 - 3.0 %.
9. Remove the FBD bowl with the dry granules from the FBD
10. Feed the lubricated granules into the hopper of the Compression machine and compress the lubricated granules to get suitable tablets.


Example 2:
Sr.No. Ingredients Quantities (mg/tablet)
1. Metformin 1000.00
2. PVP-K 55.00 mg
3. Magnesium Stearate 10.00
4. Purified Water q.s
Procedure
1. Weigh the required quantity of ingredients.
2. Sieve the ingredients Metformin through 20# sieve & PVP-K through 60# sieve.
3. Transfer, Metformin and PVP-K into the Rapid Mixer Granulator (RMG) and mix for around 10 minutes at slow speed of impeller & chopper in OFF position.
4. Add gradually Purified Water (50°C) over a period of 10 min. After completion of water additions, continue kneading for 10 minutes with impeller on slow speed and chopper in OFF position.
5. Spread magnesium stearate over granulated mass of step 5 and knead further with impeller at fast speed for 30 sec.
6. Discharge the Wet granules into the Fluid Bed Drier (FBD) bowl
7. Place the FBD bowl containing the wet granules in position for drying. Dry the granules at 55°+ 3°C (inlet temperature) for 25-30 min till the outlet temperature reaches 33°± 2°C, to a moisture content of 2.5 - 3.0 %.
8. Remove the FBD bowl with the dry granules from the FBD
9. Feed the lubricated granules into the hopper of the Compression machine and compress the lubricated granules to get suitable tablets.


Example 3:

Sr.No. Ingredients Quantities, (mg/tablet)
1. lbuprofen 600.00
2. Microcrystalline cellulose (Avicel PH 102) 82.50
3. Silica Colloidal Anhydrous (Aerosil 200) 6.00
4. Crospovidone Type A (Kollidon CL) 15.00
5. Povidone (PVP K-25) 25.50
6. 96 % Ethanol q.s
7. Water, Purified q.s
8. Macrogol 6000 (Polyglykol 6000 P) 4.50
9. Sodium stearyl fumarate 16.50
Procedure
1. Weigh the required quantity of ingredients.
2. Sieve the ingredients lbuprofen, Microcrystaliine cellulose, Silica Colloidal Anhydrous and Crospovidone Type A
3. Transfer, Ibuprofen, Microcrystaliine cellulose, Silica Colloidal Anhydrous and Crospovidone Type A into the Rapid Mixer Granulator (RMG) and mix for around 10 minutes at slow speed of impeller & chopper in OFF position.
4. Dissolve Povidone (PVP K-25) in the ethanol and water.
5. Add gradually the solution of Povidone-ethanol- Purified Water (50°C) over a period of 10 min. After completion of solution additions, continue kneading for 10 minutes with impeller on slow speed and chopper in OFF position.
6. Spread macrogol and Sodium stearyl fumarate over granulated mass of step 5 and knead further with impeller at fast speed for 30 sec.
7. Discharge the Wet granules into the Fluid Bed Drier (FBD) bowl
8. Place the FBD bowl containing the wet granules in position for drying. Dry the granules at 55°+ 3°C (inlet temperature) for 25-30 min till the outlet temperature reaches 33°+ 2°C, to a moisture content of 2.5 - 3.0 %.
9. Remove the FBD bowl with the dry granules from the FBD
10. Feed the lubricated granules into the hopper of the Compression machine and compress the lubricated granules to get suitable tablets.


Example 4:

Sr. Ingredients Quantities (mg/tablet)
20 mg 40 mg 80 mg
tablet tablet tablet
20 40 80
No.
10 mg tablet
36.92 273.84 547.68 6 12 24
20 40 80
1. Simvastatin 10
2. Lactose Monohydrate 68.46
(Pharmatose 200 M)
3. Pregelatinized starch 3
(Starch 1500)
4. Microcrystalline Cellulose 10
(AvicelPH 101)
5 10 20
2.5 5 10
q.s. q.s. q.s.
0.08 0.16 0.32
q.s. q.s. q.s.
5. Ascorbic acid 2.5
6. Citric acid monohydrate 1.25
7. Water q.s.
8. Butylated hydroxy I anisole 0.04
9. Isopropanol q.s.
8 16 32
1.5 3 6
10. Croscarmallose sodium 4
(Ac-di-sol)
11. Magnesium Stearate 0.75

Procedure
1. Weigh the required quantity of ingredients.
2. Sieve the ingredients Simvastatin, Lactose Monohydrate. Pregelatinized starch, Microcrystalline Cellulose
3. Transfer Simvastatin, Lactose Monohydrate, Pregelatinized starch, Microcrystalline Cellulose into the Rapid Mixer Granulator (RMG) and mix for around 10 minutes at slow speed of impeller & chopper in OFF position.
4. Dissolve Ascorbic acid and Citric acid monohydrate in water and Butylated hydroxyl anisole in Isopropanol.
5. Add gradually the solution of ascorbic acid- citric acid monohydrate -water and Butylated hydroxyl anisole- Isopropanol over a period of 10 min into the Rapid Mixer Granulator. After completion of solution additions, continue kneading for 10 minutes with impeller on slow speed and chopper in OFF position.


6. Spread Croscarmallose sodium and magnesium stearate over granulated mass of step 5 and knead further with impeller at fast speed for 30 sec.
7. Discharge the Wet granules into the Fluid Bed Drier (FBD) bowl
8. Place the FBD bowl containing the wet granules in position for drying. Dry the granules at 55°+ 3°C (inlet temperature) for 25-30 min till the outlet temperature reaches 33°+ 2°C, to a moisture content of 2.5 - 3.0 %.
9. Remove the FBD bowl with the dry granules from the FBD
10. Feed the lubricated granules into the hopper of the Compression machine and compress the lubricated granules to get suitable tablets.


We Claim,
!. A cost effective process for the preparation of pharmaceutical tablets that circumvents issues of hydrophobicity of hydrophobic lubricants characterized in that a hydrophobic lubricant is added to the wet mass, in a process comprising
a. Mixing of the drug(s) and excipients,
b. Preparing binder solution,
c. Mixing of binder solution with powder mixture to form wet mass.,
d. Adding hydrophobic lubricant to the wet mass of step c;
e. Coarse screening of wet mass using a suitable sieve to get the granules,
drying of moist granules, screening of dry granules through a suitable
sieve, and
f. compressing the dry granules into tablets.
2. A novel process according to claim 1, wherein hydrophobic lubricant is magnesium stearate, glyceryl behenate, sodium stearyl fumarate. hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated cottonseed oil, stearic acid and calcium stearate, high molecular weight polyethylene glycols like PEG 6000, colloidal silicon dioxide and sucrose esters..
3. A novel process according to claim ] wherein, pharmaceutical!}' active agents are selected from hydrophobic and hydrophilic pharmaceutically active agents.
4. A novel process according to claims 1 to 4 wherein, hydrophobic active agent is allopurinol, azithromycin, carbamazepine, clarithromycin, ketoprofen, carprofen, ciprofloxacin hydrochloride, erythromycin. , griseofulvin, oxcarbamzepine and paracetamol.
5. A novel process according to claims I to 3 wherein, hydrophilic active agent is dextromethorphan,, metformin, metoprolol and nortryptaline.
6. A novel process according to claim 1, wherein said tablet further comprises pharmaceutically known excipients selected from disintegrants. fillers, binders, glidants, surfactants and lubricants.
Dated this the 2nd day of April 2009

Dr. Gopakumar G. Nair Agent for the applicant