The present invention relates to a new process for the preparation of fast dissolving tablets, which disintegrate quickly in saliva or water.
With the increase in the average human life span, drug administration for elderly patients has become more important. Old age is normally accompanied by the onset of degenerative pathologies involving difficulties in coordination and in swallowing the conventional dosage forms such as tablets or capsules. Swallowing problems are also present, in other population groups, such as children.
Need for dosage forms having quick onset of action is particularly felt even for those patients who do not have swallowing problems.
Similarly in cases of motion sickness and sudden episodes of allergic attack or coughing, the swallowing becomes difficult.
Fast dissolving or disintegrating tablets provides the solution to such problems. These tablets disintegrate quickly in saliva or water.
Different techniques are used to prepare fast dissolving tablets. Most of these techniques aim at making porous particles / granules or tablets, so that mouth dissolving time can be reduced. Freeze drying (Zydis technology), spray drying, sublimation, disintegrant addition, shearform (Fuisz) technology and tablet molding are examples of such techniques.
US Pat. Nos. 4,305,502; 4,371,516 and 5,738,875 describe the use of freeze-drying process to prepare an amorphous porous structure, which dissolves rapidly. However, such formulations are very expensive and require sophisticated technologies and methods from the production point of view. The tablets prepared by this method are difficult to handle and require special packaging.
US Patent Nos. 5,587,180; 5,635,210; 5,595,761; 5,807,576 describe spray drying technique to prepare highly porous particulate support matrix, which is mixed with active and compressed to form a tablet. This technique is quite expensive and cannot be used for drugs, which become unstable on losing their crystalline structure.

Sublimation technique described in US Pat. Nos. 3,885,206; 4,134,943; 5,762,961 use mannitol and camphor as pore forming agents. The tablets prepared by this method dissolved in 10 to 20 seconds.
US Pat. Nos. 4,134,943; 5,720,974 describe the use of water as pore forming agent. A mixture containing an active ingredient and a carbohydrate is moistened with water and compressed into tablets. The removal of water yielded highly porous tablets. However, this process is not practically feasible. The high water content in the granules makes the compression difficult.
US 6,149,938 describes that mouth soluble tablets can be prepared by fluidized bed granulating an aqueous solution of a water soluble or water dispersible polymer in a polyalcohol, optionally in mixture with other solid components. Granulates prepared by this process have high porosity.
Disintegrant addition is another method of making fast dissolving tablets. Use of effervescent mixture, which generally consists of an acid and a gas-generating base as a disintegrant for preparation of porous granulates, or particles is also known.
Different processes have been used to prepare porous granulates of effervescent mixture suitable to the preparation of fast dissolving tablets.
US Pat. No. 3,207,824 describes a process for preparing effervescent granules which involves mixing the dry powders together to form a dry mix, adding a small amount of water which starts the effervescence reaction so that a workable mass is obtained; quickly drying the mass in ovens or heated dishes to stop the reaction; and grinding the mass under the dry conditions to form powder or granules.
The effervescent reaction can obviously be permitted to proceed only to a very limited extent. Thus it is important to be able to accurately control the amount of water added. US Pat. No. 3,401,216 describes an improved technique consisting essentially of suspending a dry mixture of the acid and the base in powder form in the stream of gas, thereby forming a constantly agitated "fluidized bed" and introducing into this bed just so much of a fluid which causes said chemical ingredient to react to only a limited extent.

French Patent Nos. 7112175 & 7135069 describe a technique which involves the careful humidification of sodium bicarbonate by a very small quantity of demineralized water, then addition of citric acid and optionally a binding agent, in a mixture, which starts off the reaction of the bicarbonate on the citric acid. This mixture is pre-dried in fluid bed dryer by blowing hot air, which interrupts the reaction. The final drying is again done in fluid bed dryer by blowing hot air.
This technique has the draw back of necessitating the transfer of the filler, from the mixer to the drier. Consequently, the effervescent reaction triggered off in the mixer cannot be mastered with total precision as its interruption, in the drier, depends on the time for emptying and transferring the filler towards the drier, the time varies from one batch to the another. The variation in time has a considerable repercussion on the quality of the grain at the end of granulation.
US Pat. No. 5,437,873 describes a process for the preparation of superior tasting pharmaceutical composition having porous particles. Stiochiometeric amounts of an appropriate base and an appropriate acid are mixed and compressed in a press to form a compact. The compact is then milled to form an evenly distributed Stiochiometeric mixture of the base and the acid. A pharmacologically active is then added to the mixture and wet granulated. The wet granulated material is then dried whereby the applied heat and the water cause the acid and the base to react releasing gas from the wet granulation to form porous particles. The porous particles are then milled to form powder, which is then compressed to form a tablet.
EP 494972 patent describes effervescent tablets suitable to the direct oral administration, i.e. without a previous development of the effervescence in water, consisting of microcapsules containing the active ingredients and an amount of effervescent agents sufficient to promote the release of the microgranules when ingested and to give a "fizzing" sensation when in contact with the buccal mucosa to the patient. Such a preparation technique yields tablets having friability values higher than those involving the humid granulation of the mixture to be pressed. Tablets prepared by this technique have higher dissolution time.
All the above mentioned prior art processes, except the Zydis and sublimation techniques describe the preparation of porous particles or granules, which are then compressed to

form the fast dissolving tablets. However, due to compression pressure these porous particles / granules undergo the rearrangement to form a less porous structure. This decrease in porosity results in increased dissolution / disintegration time. So the whole purpose of making fast dissolving tablets by using porous particles / granules gets defeated once the compression pressure is applied to them.
We have now found that above difficulties of making fast dissolving tablets may be overcome and mouth soluble tablets having fast dissolution / disintegration can be prepared by a new novel process.
Therefore, the present invention relates to a process for the preparation of fast dissolving / disintegrating tablets characterised by the step that the porosity in the tablet is produced by in-situ gas generation through moisture activation of the effervescent mixture comprising acid and a base in a tablet by exposing tablet to controlled humidity of 20 to 100% in a relative humidity chamber at a temperature of about 25° to 90°C for upto 2 weeks and wherein the amount of effervescent mixture is upto 35% by weight of the total composition.
The present invention has the advantage of short dissolution / disintegration time as porosity is achieved in the final tablet rather than making the porous particles or granules. When such tablets are placed in the oral cavity, saliva quickly penetrates into the pore to cause rapid disintegration / dissolution. The tablets prepared by the process of present invention dissolves in saliva in less than 20 seconds. The present process has the further advantage as markedly lower amounts of effervescent mixture than those usually employed in the conventional effervescent tablets may be used. The use of lower effervescent mixture concentration gives the advantage of better taste and pleasant mouth feel against the abrasiveness and burning sensation experienced with the higher concentrations.
Furthermore, the present process is simple and cost effective, as it does not require any extra steps or special equipments. It can easily be carried out in the normal effervescent tablet plant. The tablets prepared by the process of present invention maintain its structural integrity and can be handled and packed as conventional effervescent tablets.
The term "moisture activation" means activating the acid base reaction by providing moisture. The moisture causes the acid and the base present in the tablet to effervesce, the gas produced tries to escape forming pores in the tablets. The moisture activation can

be done by subjecting the tablets comprising the effervescent mixture to either controlled humidity or controlled heating.
The moisture activation by controlled humidity can be achieved by subjecting the final tablets containing effervescent mixture to careful humidification, which starts off the reaction of the base and acid.
This can easily be done by keeping the tablets in relative humidity chamber at a percentage relative humidity of 20 to 100% depending on the temperature.
An alternative process for moisture activation is by controlled heating. In this method, tablets containing effervescent mixture are heated to liberate water of crystallization. The water thus liberated initiates the acid and base reaction, giving carbon dioxide which when tries to escape the tablet generates pores.
For this method, presence of at least one ingredient having water of crystallization is must. Heating can be done as such or under vacuum. Heating temperature would vary according to the ingredient from which water of crystallization is to be liberated.
The tablets comprising effervescent mixture can be prepared by any method known in the art. The effervescent mixture can consist of acid and bases.
The acid source can consist of citric, tartaric, malic, fumaric, adipic, succinic, alginic acids, anhydrides and acid salts such as dihydrogen phosphate, disodium dihydrogen phosphate, citric acid salts.
The bases can be : solid carbonates of salts such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L- lysine carbonate, arginine carbonate and amorphous calcium.
The amount of the effervescent mixture is preferably lower than 35% by weight of the total composition, most preferably lower than 20%.
The process of the present invention comprises the following steps.

Step 1: Preparing the tablets comprising effervescent mixture by any method known
in the art.
Step 2: subjecting these tablets to moisture activation, by either exposing the tablets to controlled humidity or heating the tablets at controlled temperature,
Step 3: optionally, interrupting the reaction by subjecting the tablets to vacuum to remove the moisture.
Since the tablets of the present invention consists of an intimate mixture of components which are highly reactive in the presence of moisture, it is apparent that the control of humidity is an extremely important factor in the production of commercially acceptable and stable tablets. Uncontrolled humidity or prolonged exposure to moisture, or even excessive moisture content, will cause the base and the acid to react. Since this reaction not only forms salt and carbon dioxide but water as well, the decomposition reaction is progressive. Therefore, preferably the acid base reaction is interrupted by applying vacuum.
The vacuum can be applied until the complete moisture is removed.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of this invention in any way.
EXAMPLE 1
Rofecoxib mouth soluble tablets (50 mg strength)

(Table Removed)

Method
1. Rofecoxib (granulated), mannitol, sodium bicarbonate (preheated at 80°C for 1
hour), L-hydroxypropyl cellulose, microcrystalline cellulose, Aspartame, colloidal
silicon dioxide, Mango flavour, Banana flavour are sifted through 44 BSS sieve.
2. The blend is mixed for 10 minutes in a double cone blender.
3. Citric acid (preheated at 80°C for 1 hour) is sifted through 100 (BSS) sieve and
added to step 2.
4. The blend is mixed again for 10 minutes in double cone blender.
5. Magnesium stearate is passed through 44 (BSS) sieve and the final blending was
done for 5 minutes.
6. Lubricated blend of step 5 is compressed on 11 mm flat round punch, on 16-station
rotary compression machine.
7. The tablets of step 5 are subjected to relative humidity.
8. The tablets of step 7 are vacuum dried.
These tablets had mouth-dissolving time of less than 20 seconds.
EXAMPLE 2
Simvastatin mouth soluble tablets (5mg strength)

(Table Removed)

Process:
1. Simvastatin (BHA-treated), directly compressible lactose, L-hydroxypropyl
cellulose, mannitol, pineapple flavour, aspartame, sodium bicarbonate (preheated
at 80°C for 1 hour), are sifted through 44 BSS sieve.
2. The blend of step 1 is mixed for 10 minutes in double cone blender.
3. Citric acid (anhydrous) is sifted through 100 BSS sieve (preheated at 80°C for 1
hour) and mixed with the blend of step 2; the blend is then mixed for 10 minutes in
a double cone blender.
4. The blend of step 3 is lubricated with magnesium stearate (sifted through sieve 44
BSS) by mixing for five minutes in a double cone blender.
5. The blend of step 4 is compressed using 7mm standard concave punch.
6. The tablets of step 5 are subjected to relative humidity.
7. These tablets are then vacuum dried.
These tablets had a mouth dissolving time of less than 20 seconds.
EXAMPLE 3
Olanzapine mouth soluble tablets (5mg strength)

(Table Removed)
Process:

1. Olanzapine, directly compressible lactose, croscarmellose sodium, mannitol, orange
flavour, aspartame, sodium bicarbonate (preheated at 80°C for 1 hour), are sifted
through 44 BSS sieve.
2. The blend of step 1 is mixed for 10 minutes in double cone blender.
3. Citric acid anhydrous (preheated at 80°C for 1 hour) is sifted through 100 BSS sieve
and mixed with the blend of step 2; the blend is then mixed for 10 minutes in a double
cone blender.
4. The blend of step 3 is lubricated with magnesium stearate (sifted through sieve 44
BSS) by mixing for five minutes in a double cone blender.
5. The blend of step 4 is compressed using 6.4 mm flat round punch.
6. The tablets of step 5 are subjected to relative humidity.
7. These tablets are then vacuum dried.
These tablets had a mouth dissolving time of less than 20 seconds.
EXAMPLE 4 Rofecoxib mouth soluble tablets (5mg strength)

(Table Removed)
Method
1. Rofecoxib (granulated), mannitol, sodium bicarbonate (preheated at 80°C for 1 hour), L-hydroxypropyl cellulose, microcrystalline cellulose, Aspartame, colloidal silicon dioxide, Mango flavour, Banana flavour are sifted through 44 BSS sieve.

2. The blend is mixed for 10 minutes in a double cone blender.
3. Citric acid bicarbonate (preheated at 80°C for 1 hour) is sifted through 100 (BSS)
sieve and added to step 2.
4. The blend is mixed again for 10 minutes in double cone blender.
5. Magnesium stearate is passed through 44 (BSS) sieve and the final blending was
done for 5 minutes.
6. Lubricated blend of step 5 is compressed on 11 mm flat round punch, on 16-station
rotary compression machine.
7. The tablets of step 6 are subjected to a temperature of 80°C for 30 minutes and the
kept at ambient temperature for 8 hours.
8. The tablets of step 7 are vacuum dried.
These tablets had mouth-dissolving time of less than 20 seconds.
Scanning Electron micrographs (Fig. 1 & 2) of the rofecoxib tablets prepared using composition of Example 1 clearly show the pore formation in the tablets after the moisture activation.

WE CLAIM:
1. A process for the preparation of fast dissolving / disintegrating tablets characterised
by the step that the porosity in the tablet is produced by in-situ gas generation
through moisture activation of the effervescent mixture comprising acid and a base
in a tablet by exposing tablet to controlled humidity of 20 to 100% in a relative
humidity chamber at a temperature of about 25° to 90°C for upto 2 weeks and
wherein the amount of effervescent mixture is upto 35% by weight of the total
composition.
2. The process according to claim 1 wherein the tablets are exposed to controlled
heating under vacuum.
3. The process according to claim 1 wherein the acid is selected from the group
consisting of citric, tartaric, malic, fumaric, adipic, succinic, alginic acids; anhydrides
and acid salts.
4. The process according to claim 3 wherein the acid salts are selected from
dihydrogen phosphate, disodium dihydrogen phosphate and citric acid salts.
5. The process according to claim 1 wherein the base is selected from the group
comprising of solid carbonate.
6. The process according to claim 5 wherein the solid carbonates are selected from
the group consisting of sodium carbonate, sodium bicarbonate, potassium
carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine
carbonate, L-Lysine carbonate, arginine carbonate and amorphous calcium.
7. The process according to claim 1 wherein the amount of effervescent mixture is 15-
20% by weight of the total composition.

8. A process for the preparation of fast dissolving / disintegrating tablets according to
claim 1 wherein the porosity is produced in-situ by subjecting the tablets comprising
citric acid and sodium bicarbonate mixture to 50 - 75% relative humidity at 30 -
50°C for upto 24 hours.
9. A process for preparing fast dissolving / disintegrating tablets as described and
illustrated by the examples herein.