FORM 2
THE PATENTS ACT 1970 (39 OF 1970)
COMPLETE SPECIFICATION (SECTION 10)
"IMPROVED & STABLE PHARMACEUTICAL COMPOSITION OF PRAMIPEXOLE OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS"
UNICHEM LABORATORIES LIMITED
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN,
PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI (WEST), MUMBAI - 400102,
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed

"IMPROVED & STABLE PHARMACEUTICAL COMPOSITION OF PRAMIPEXOLE OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS"
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an directly compressible, stable, easily dissolving immediate release solid oral pharmaceutical composition comprising Pramipexole or its pharmaceutically acceptable salt or solvates or enantiomers or mixtures and its preparation thereof. Pramipexole is a selective dopamine D2 receptor agonist used in the treatment of Schizophrenia, Parkinson's disease and Alzheimer's disease. More specifically, the present invention is relates an stable pharmaceutical composition and its methods of manufacturing for potent or low dose active pharmaceutical ingredient like pramipexole or its pharmaceutically acceptable salt or solvates or enantiomers or mixtures thereof.
BACKGROUND OF THE INVENTION:
Pramipexole is a selective dopamine D2 receptor agonist. An (S)-enantiomer of Pramipexole dihydrochloride salt is used for the treatment of Schizophrenia and Parkinson's disease and Alzheimer's disease. Chemical name of Pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole dihydrochloride monohydrate. It has a molecular formula of C10H17N3S2HCl-H20 with a molecular weight of 302.27.
Pramipexole dihydrochloride monohydrate occurs as white to off-white powder. Pramipexole is highly crystalline in nature and remains unaltered even under milling. Melting occurs in the range of 296°C to 301 °C, with decomposition. It is a highly soluble compound. Water solubility is more than 20 mg/mL and solubility in buffer media is generally above 10 mg/mL between pH 2 and pH 7.4. It is soluble in methanol, slightly

soluble in ethanol and insoluble in dichloromethane. At relative humidity above 92% pramipexole liquefies but at lower relative humidity no absorption of water occurs.
Pramipexole dihydrochloride is currently marketed by Boehringer Ingelheim in the form of immediate release tablets under the trade name MIRAPEX® tablets in 0.125 mg, 0.25 mg, 0.5 mg, 1 mg and 1.5 mg strengths and it was first authorized in the USA in the year 1997. US patent application US20080254117 reports that Pramipexole immediate release tablets has marketing authorizations in the European Union (EU), Switzerland, Canada, South America, in Eastern Europe, Near East and Asian countries
US2008/0254118 Al (Hans-Werner Wernersbach; October, 2008) discloses the process of preparing pramipexole dihydrochloride tablets by wet granulation method. According the disclosed procedure, granules are prepared by spray granulation technique using pramipexole-PVP solution as granulating agent. Wet granulation involves more number of unit operations. There is a possibility for the loss of active pharmaceutical ingredient during various processing steps like granulation, drying & milling and active pharmaceutical ingredient will also be exposed to harsh conditions like heat, and moisture or granulating fluid, which may increase the impurities in the formulation. In addition, wet granulation by spray granulation requires costlier equipment like Fluid Bed Granulator leading to increased manufacturing time and manufacturing cost.
US2008/0254117 Al (Cotton Noel; October, 2008) describes the process of preparing pramipexole dihydrochloride tablets by wet granulation method. According the disclosed procedure, granules are prepared by using pramipexole solution and binder solution as granulating agent. Wet granulation technique involves more number of unit operations this leads to increased manufacturing time. During the preparation of granules by wet granulation method, there is a possibility for the loss of active pharmaceutical ingredient during various processing steps and in addition, active pharmaceutical ingredient will also be exposed to harsh conditions like heat, and moisture or granulating fluid, which may increase the impurities in the formulation.

WO 2007/072497 A2 (Kshirsagar et al; June, 2007) and US 2007/0129329 Al (Kshirsagar et al.; June, 2007) disclosed pharmaceutical compositions of pramipexole and their process of preparation. Disclosed pharmaceutical compositions are immediate release tablets prepared by wet granulation method wherein, pramipexole-PVP solution or pramipexole-cyclodextrin inclusion complexes were used as binders for granulation. As per the disclosed pharmaceutical composition, pramipexole-cyclodextrin inclusion complex can be directly compressed into tablets. Even though the disclosed pharmaceutical composition utlilizes direct compression, it includes preparation of pramipexole-cyclodextrin inclusion complexes, which increases number of unit operations. In addition, the disclosed pharmaceutical composition utilizes oxygen absorbers in the packaging and packaging activity was carried out under inert atmosphere. Furthermore, excipients like cyclodextrins are expensive. Granulation by wet granulation technique, usage of costlier excipients like cyclodextrins, usage of oxygen absorbers in the packaging and carrying out packaging activity under inert atmosphere leads to increased manufacturing time and manufacturing cost and therefore increases the cost of the drug product.
Even though, wet granulation method is widely used in the manufacture of various pharmaceutical dosage forms, it suffers from disadvantages like, loss of active pharmaceutical ingredient during various processing steps like granulation, drying and milling. In addition, active pharmaceutical ingredient will be exposed to harsh conditions like heat, and moisture or granulating fluid, which may increase the impurities in the formulation. Hence, there is a necessity for the development of simple, cost effective, solvent-free method for the preparation of stable formulations of Pramipexole, which can eliminate all the above mentioned disadvantages.
OBJECT OF THE INVENTION
An object of the present invention is to provide a stable pharmaceutical composition comprising Pramipexole or its pharmaceutically acceptable salt or solvate or enantiomers or mixtures thereof.

Another object of invention is to provide a stable, immediate release solid oral pharmaceutical composition comprising Pramipexole or its pharmaceutically acceptable salt or enantiomers or mixtures thereof by direct compression.
Another object of invention is to provide simple and cost effective method of manufacturing a stable pharmaceutical composition comprising Pramipexole or its pharmaceutical ly acceptable salt or enantiomers or mixtures thereof.
SUMMARY OF THE INVENTION
The present invention relates to an immediate release solid pharmaceutical composition comprising pramipexole or its pharmaceutically acceptable salt(s), or enantiomer(s) or mixture(s) thereof along with one or more pharmaceutically acceptable excipients, prepared by mixing of the active pharmaceutical ingredient with one or more pharmaceutical ly acceptable excipients in geometric and/or non-geometric proportions and prepared by direct compression technique.
Further, the present invention discloses the method of manufacturing of the pharmaceutical composition as given below-A. Preparation of lubricated blend by non-geometric dilution method:
1. Sifting of active pharmaceutical ingredient and 25% of diluent through ASTM # 60 mesh.
2. Sifting of the remaining 75% quantity of diluent and disintegrant through ASTM #40 mesh.
3. Step-1 blend was sandwiched with step-2 blend and mixing for 20 mins.
4. Sifting of step-3 blend twice through ASTM # 60 mesh and then mixing for 3 mins.
5. Sifting of lubricant through ASTM # 60 mesh and mixing with step-4 blend for 3 mins.
6. Lubricated blend of step-5 is then compressed into tablets or filled into capsules or filled in a sachet

B. Preparation of lubricated blend by geometric dilution method:
1. Mixing active pharmaceutical ingredient with diluent in geometric dilution technique.
2. Addition of pharmaceutically acceptable excipients other than lubricants and glidants to step- 1 blend and then mixing
3. Sifting of step-2 blend twice through ASTM # 60 mesh.
4. Sifting of lubricants and glidants through ASTM # 60 mesh and mixing with step-3 blend.
5. Lubricated blend of step-5 is then compressed into tablets or filled into capsules or filled in a sachet.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Comparative dissolution profile of Pramipexole tablets 0.125mg of Example-3
and Mirapex® tablets 0.125 mg in 0.023 M Citrate/0.155 M Phosphate Buffer.
Figure 2: Comparative dissolution profile of Pramipexole tablets 0.250mg of Example-3
and Mirapex® tablets 0.250 mg in 0.023 M Citrate/0.155 M Phosphate Buffer.
Figure 3: Comparative dissolution profile of Pramipexole tablets 1.50mg of Example-3
and Mirapex® tablets 1.50 mg in 0.023 M Citrate/0.155 M Phosphate Buffer.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides stable, simple and cost effective immediate release solid oral pharmaceutical compositions and process thereof for pramipexole or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof. In particular, the present invention is directly compressible, immediate release solid oral pharmaceutical composition comprising, pramipexole or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures, more preferably pramipexole dihydrochloride and one or more of pharmaceutically acceptable excipients.

According to the present invention, pharmaceutical composition may be manufactured by
direct compression of active ingredient with at least one or more of pharmaceutically
acceptable excipients. Method of manufacturing includes mixing of pramipexole with
excipients in geometric and/or non-geometric dilution techniques.
In accordance with the present invention term "solid pharmaceutical composition" refers
to tablets, capsule, sachets.
In accordance with the present invention, the phrase "pharmaceutically acceptable
excipients," includes all physiologically inert additives used in pharmaceutical dosage
forms.
In accordance with the present invention, pharmaceutical composition of Pramipexole
dihydrochloride is in the form of solid dosage form i.e., either a tablet or capsule or
sachet of powder blend.
In accordance with the present invention, the pharmaceutically acceptable excipients are
those inert additives, which are required in the tablet capsule dosage forms. Examples of
such excipients include but are not limited to diluents, disintegrants, lubricants, glidants
and the like, or mixtures thereof
Further, pramipexole used as an active ingredient in developed composition is
pramipexole or its pharmaceutically acceptable salt(s), solvate(s), enantiomer(s) or
mixture(s) thereof, preferably pramipexole used in disclosure is pramipexole
dihydrochloride
One aspect of the present invention is to prepare a simple, cost-effective, stable solid oral
pharmaceutical composition by comprising mixing one or more diluents with active
pharmaceutical ingredient in geometric dilution technique, and addition of
pharmaceutical excipients other than lubricants and glidants and mixing, followed by
addition of lubricants and/or glidants and mixing, compression of the lubricated blend
into tablets or filling of lubricated blend into capsules or sachets.
Another aspect of the present invention is to prepare a simple, cost-effective, stable solid
oral pharmaceutical composition which comprises mixing the one or more diluents with
active pharmaceutical ingredient in non-geometric ratios, addition of pharmaceutical
excipients other than lubricants and glidants and mixing, addition of lubricants and

glidants and mixing, compression of the lubricated blend into tablets or filled into
capsules or filled in a sachet.
In accordance with the present invention, tablets prepared by this method are simple and
cost effective. The developed method of manufacturing helps in the distribution of drug
more uniformly throughout the blend, which ensures uniformity of drug among the final
dosage forms.
In accordance with the present invention, pharmaceutical composition comprises active
pharmaceutical ingredient and at least one or more of pharmaceutically acceptable
excipients. Pharmaceutically acceptable excipients include one or more of diluents,
disintegrants, glidants and lubricants.
In accordance with the present invention, the term 'active ingredient' refers to
pramipexole or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures
thereof.
In accordance with the present invention, pharmaceutical composition utilizes high
moisture grades or low moisture grades, directly compressible or non-directly
compressible grades of pharmaceutically acceptable excipients.
In accordance with the present invention, diluents used include one or more of cellulose,
co-processed celluloses and cellulose derivatives; starch and starch derivatives; sugars
and sugar alcohols; inorganic salts or mixture thereof.
In accordance with the present invention, cellulose, co-processed celluloses and cellulose
derivatives used include cellulose powder, carboxymethyl cellulose, silicified
microcrystalline cellulose (SMCC), microcrystalline cellulose-lactose (Microlac),
microcrystalline cellulose-guar gum (Avicel CE15), Microcrystalline cellulose-calcium
phosphate (Celocal), carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl
cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl
cellulose, hyroxyethyl cellulose, cellulose acetate.
In accordance with the present invention, starch and starch derivatives like pregelatinized
starch, corn starch, maize starch, starch glycollate, hydroxyethyl starch, sodium
carboxymethyl starch, hydroxypropylated pea starch, starch borate.
In accordance with the present invention, sugars and sugar alcohols like dextrose,
fructose, sucrose, maltose, glycerol, mannitol xylitol and lactose; inorganic salts like

calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate or
mixture thereof.
Preferred diluents used in the present invention includes one or more of co-processed
celluloses and cellulose derivatives like silicified microcrystalline cellulose (SMCC),
microcrystalline cellulose-lactose (Microlac), microcrystalline cellulose-guar gum
(Avicel CE15), Microcrystalline cellulose-calcium phosphate (Celocal) & low substituted
hydroxypropyl cellulose; starch and starch derivatives like pregelatinized starch and corn
starch; sugars and sugar alcohols like mannitol; inorganic salts like calcium phosphate
(dibasic/tribasic) or mixture thereof.
More preferred diluents includes one or more of co-processed celluloses like silicified
microcrystalline cellulose (SMCC); starch and starch derivatives like pregelatinized
starch.
Silicified microcrystalline cellulose grades used in the present invention has the particle
size distribution d(0.9) in the range of 25 μrn to 500 μm; preferably particle size
distribution d(0.9) is in the range of 50 μm to 400 μm; more preferably particle size
distribution d(0.9) is in the range of 75 μm to 300 μm.
Silicified microcrystalline cellulose grades used in the present invention has the moisture
content of less than 10%; preferably a moisture content of less than 8%; more preferably
a moisture content of less than 6%.
Disintegrants used in the present invention includes one or more of croscarmellose
sodium, crospovidone, microcrystalline cellulose, emcosoy (Soya polysaccharide),
potassium polacrilin, sodium starch glycolate, low-substituted hydroxypropyl cellulose,
starch, pregelatinized starch or mixture thereof.
Preferred disintegrants used in the present invention includes one or more of
croscarmellose sodium, microcrystalline cellulose, Emcosoy (Soya polysaccharide),
sodium starch glycolate, starch, pregelatinized starch or mixture thereof.
More preferred disintegrants used in the present invention includes one or more of
croscarmellose sodium, sodium starch glycolate, pregelatinized or mixture thereof.
Glidants used in the present invention includes one or more of colloidal silicon dioxide,
silicon dioxide, calcium silicate, magnesium silicate, calcium phosphate tribasic, talc,
pregelatinized stach and starch.

Preferred glidants used in the present invention includes one or more of colloidal silicon
dioxide, silicon dixode, calcium silicate, magnesium silicate and talc.
More preferred glidant in the present invention one or more of colloidal silicon dioxide
and silicon dioxide.
The lubricants used in the present invention includes one or more of magnesium stearate,
calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils,
magnesium lauryl sulfate, talc, wax, polyethylene glycol, glyceryl behenate, glyceryl
palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate.
Preferred lubricants used in the present invention includes one or more of magnesium
stearate, calcium stearate, stearic acid, sodium stearyl fumerate, talc, glyceryl behenate
and glyceryl palmito stearate.
More preferred lubricants used in the present invention includes one or more of
magnesium stearate, stearic acid and sodium stearyl fumerate.
According to the present invention, the pharmaceutical composition contains from about
0.01% to 20% of active pharmaceutical ingredient, from about 10% to 99.99% of diluents
from about 0.25% to 10% of disintegrants, from about 0.2% to 5% of glidants and from
about 0.1% to 5% of lubricants. Preferably from about 0.05% to 10% of active
pharmaceutical ingredient, from about 50% to 99.99% of diluents, from about 0.5% to
7.5% of disintegrants, from about 0.2% to 4% of glidants and from about 0.1% to 2%
of lubricants. More preferably from about 0.1% to 5% of active pharmaceutical
ingredient, from about 85% to 99.9 % of diluents, from about 1% to 5% of disintegrants,
from about 0.2% to 3% of glidants and from about 0.1% to 3% of lubricants.
The pharmaceutical composition of the present invention contains the active ingredient in
the range of about 0.1 mg to about 20 mg; preferably from about 0.1 mg to 11.0 mg;
More preferably from about 0.1 mg to 2.0 mg.
In accordance with the present invention, wherein pramipexole dihydrochloride is
micronized having a particle size distribution d(0.9) of less than 90 microns, preferably
particle size distribution d(0.9) of less than 60 microns, more preferably particle size
distribution d(0.9) of less than 30 microns.

In accordance with the present invention, wherein total degradation products (related substances) in pharmaceutical composition even after storage at accelerated storage condition of 40°C/75%RH is less than 1.0%.
In accordance with present invention, direct compression of active ingredient with at least one or more of excipients is preferred method of preparation. Method of preparation of pharmaceutical composition includes mixing of pramipexole with excipients in geometric and/or non-geometric proportion. Geometric mixing helps in ensuring blend uniformity of drug throughout the blend. Process of Preparation of Pharmaceutical Composition by non-geometric mixing:
1. Sift active pharmaceutical ingredient and 25% of diluent through ASTM # 60 mesh.
2. Sift the remaining 75% quantity of diluent and disintegrant through ASTM # 40 mesh.
3. Sandwich the blend of step 1 with blend of step-2 and mix.
4. Sift step-3 blend twice through ASTM # 60 mesh and then mix.
5. Sift lubricant through ASTM # 60 mesh and mix with step-4 blend.
6. Compress lubricated blend of step-5 into tablets or fill into capsules or sachet.
Process of Preparation of Pharmaceutical Composition by geometric mixing:
1. Mix active pharmaceutical ingredient with diluent in geometric proportion.
2. Add excipients other than lubricants and glidants to step-1 blend and then mix.
3. Sift blend of step-2 twice through ASTM # 60 mesh.
4. Sift of lubricants and glidants through ASTM # 60 mesh and mix with step-3 blend.
5. Compress lubricated blend of step-5 into tablets or fill into capsules or fill in a sachet.
An immediate release solid pharmaceutical composition of present disclosure is used in the treatment of schizophrenia, Parkinson's disease and Alzheimer's disease.
Schizophrenia is a serious mental illness characterized by a disintegration of the process of thinking and of emotional responsiveness. It is characterized by auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking with significant social or occupational dysfunction.

Parkinson's disease is a progressive disorder of the central nervous system, which is characterized by a decrease in spontaneous movements, gait difficulty, postural instability, rigidity and tremor. Parkinson's disease is caused by the degeneration of the pigmented neurons in the Substantia Nigra of the brain, resulting in decreased dopamine availability.
Alzheimer's disease, is the most common form of dementia. This neurological disorder attacks the brain and results in cognitive problems, such as memory loss, impaired thinking, difficulty performing familiar tasks, disorientation to time and place, poor or decreased judgment, problems with language, changes in mood or behaviour and personality. Advancing age is the single greatest risk factor for Alzheimer's, a disease that strikes 10 percent of individuals by the time they reach age 65 and up to 50 percent by age 85. Part of this increased risk seems to occur because brain cells become increasingly vulnerable to stress as they age.
Although the present invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
EXAMPLES:
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example 1:
Table 1: Formulations of Example-1

s. Ingredients Quantity per tablet (in mg)

No.
I II III IV V
1 Pramipexole 0.125 0.250 0.500 1.000 1.500
2 Silicified Microcrystalline cellulose (Prosolv SMCC90) 84.025 103.700 207.400 206.900 354.900
3 Magnesium stearate 0.850 1.050 2.100 2.100 3.600
Tablet weight (mg) 85.000 105.000 210.00 210.00 360.00
Manufacturing process:
1. Mixed pramipexole with silicified microcrystalline cellulose (Prosolv SMCC90) in geometric dilution technique.
2. Sifted step-1 blend twice through ASTM # 60 mesh.
3. Sifted lubricants through ASTM # 60 mesh and mixed with step-2 blend.
4. Lubricated blend of step-3 is then compressed into tablets or filled into capsules or filled in a sachet.
Example 2:
Table 2: Formulations of Example-2

S.
No. Ingredients Quantity per tablet (in mg)

I II III IV V
1 Pramipexole 0.125 0.250 0.500 1.000 1.500
2 Silicified Microcrystalline cellulose (Prosolv SMCC90) 83.175 102.650 205.300 204.800 351.300
3 Croscarmellose sodium 0.850 1.050 2.100 2.100 3.600
4 Magnesium stearate 0.850 1.050 2.100 2.100 3.600
Tablet weight 85.000 105.000 210.00 210.00 360.00
Manufacturing process:

1. Sifted of Pramipexole and 25% of Silicified Microcrystalline cellulose (Prosolv SMCC90) through ASTM#60 mesh,
2. Sifted of the remaining 75% quantity of Silicified Microcrystalline cellulose (Prosolv SMCC90) and croscarmellose sodium through ASTM#40 mesh.
3. Step-1 blend was sandwiched with step-2 blend and mixed for 20 mins.
4. Sifted step-3 blend twice through ASTM # 60 mesh and then mixed for 3 mins.
5. Sifted lubricant through ASTM # 60 mesh and mixed with step-4 blend for 3 mins.
6. Lubricated blend of step-5 is then compressed into tablets or filled into capsules or filled in a sachet.
Example 3:
Table 3: Formulations of Example-3

s.
No. Ingredients Quan tity per tablet in mg

I II III IV V
1 Pramipexole 0.125 0.250 0.500 1.000 1.500
2 Silicified Microcrystalline cellulose (Prosolv SMCC90LM) 83.175 J 02.650 205.300 204.800 351.300
3 Croscarmellose sodium 0.850 1.050 2.100 2.100 3.600
4 Magnesium stearate 0.850 1.050 2.100 2.100 3.600
Tablet weight (in mg) 85.000 105.000 210.000 210.000 360.000
Manufacturing process:
1. Sifted of Pramipexole and 25% of Silicified Microcrystalline cellulose (Prosolv SMCC90LM) through ASTM#60 mash.
2. Sifted of the remaining 75% quantity of Silicified Microcrystalline cellulose (Prosolv SMCC90LM) and croscarmellose sodium through ASTM#40 mesh.

3. Step-1 blend was sandwiched with step-2 blend and mixed for 20 mins.
4. Sifted step-3 blend twice through ASTM # 60 mesh and then mixed for 3 mins.
5. Sifted lubricant through ASTM # 60 mesh and mixed with step-4 blend for 3 mins.
6. Lubricated blend of step-5 is then compressed into tablets or filled into capsules or filled in a sachet.
Dissolution studies of pramipexole tablets 0.125mg/0.25mg/1.5mg of Example-3 and MIRAPEX tablets 0.125mg/0.25mg/1.5mg were performed in 500 ml of 0.023M Citrate/0.155M Phosphate Buffer by using a USP Type II apparatus at the paddle speed of 50 rpm, at 37± 2°C. Comparative dissolution profiles are shown in Table: 4 to 6 and Figures 1 to 3.
Table 4: Comparative dissolution profiles Pramipexole tablets 0.125 mg of Example-3 and MIRAPEX® tablets 0.125 mg in 0.023M Citrate/0.155M Phosphate Buffer

Time (minutes) Percent Pramipexole Released

MIRAPEX® Tablets 0.125 mg Pramipexole diHCl
Tablets 0.125 mg of
Example-3
5 81.4 93.4
10 94.1 96.0
15 97.1 95.8
30 99.1 95.2
45 100.0 93.0
Table 5: Comparative dissolution profiles Pramipexole tablets 0.250 mg of Example-3 and MIRAPEX® tablets 0.250 mg in 0.023M Citrate/0.155M Phosphate Buffer

Time (minutes) Percent Pramipexole Released

MIRAPEX® Tablets 0.250 mg Pramipexole diHCl
Tablets 0. 250 mg of
Example-3
5 67.6 86.5
10 92.1 96.3
15 93.8 98.1
30 93.4 98.7
45 94.2 98.9
Table 6: Comparative dissolution profiles Pramipexole tablets 1.50 mg of Example-3 and MIRAPEX® tablets 1.50 mg in 0.023M Citrate/0.155M Phosphate Buffer

Time (minutes) Percent Pramipexole released

MIRAPEX®
Tablets 1.50 mg Pramipexole diHCl
Tablets 1.50 mg of
Example-3
5 43.5 95.4
10 86.1 96.6
15 93.9 97.0
30 94.7 97.2
45 94.5 97.0
Chemical analysis was performed for the manufactured Pramipexole tablets 0.125mg/0.250mg/1.50mg. Studies were conducted for assay and related substances in these tablets. The results of these studies are shown in Tables 7 to 9. Table 7: Physicochemical parameters of Pramipexole tablets 0.125 mg of Example-3.

S.No. Parameters Results
1. Assay (%) 101.1

2. Related substances

IMP A BRT

IMP B BRT

IMP C BDL

IMP E BDL

Unknown impurities (%) 0.05

Total impurities (%) 0.05
3. Hardness (N) 80.3
BDL: Below detection limit; BRT: Below reporting threshold.
Table 8: Physicochemical parameters of composition of Pramipexole tablets 0.25 mg of Example-3

S.No. Parameters Results
1. Assay (%) 101.2
2. Related substances

IMP A BRT

IMP B BRT

IMP C 0.06

IMP E BDL

Unknown impurities (%) 0.05

Total impurities (%) 0.11
3. Hardness (N) 90.3
BDL: Below detection limit; BRT: Below reporting threshold.
Table 9: Physicochemical parameters of composition of Pramipexole tablets 1.5 mg of Example-3

S.No. Parameters Results
1. Assay (%) 103.3
2. Related substances

IMP A BRT

IMP B BRT

IMP C BDL

IMP E BDL

Unknown impurities (%) 0.05

Total impurities (%) 0.05
3. Hardness (N) 177.1
BDL: Be ow detection limit; BRT: Below reporting threshold.
Pramipexole tablets 0.125mg/0.250mg/1.50mg of Example-3 were packed in HDPE bottles and subjected for stability studies at accelerated storage condition (40°C/75%RH). Results of chemical analysis of the Pramipexole tablets (0.125mg/0.250mg/1.50mg ) stability samples are reported in Tables 10 to 12. Table 10: Accelerated stability study results of Pramipexole tablets 0.125 mg of Example-3

S.
No. Parameters Initial Accelerated storage condition (40°C/75% RH)

1 month 2 months 3 months
1. Assay (%) 101.1 95.9 94.3 95.1
2. Related subs tarn :es

IMP A BRT BDL BRT 0.05

IMP B BRT BDL BDL BRT

IMP C BDL BDL BDL BDL

IMP E BDL BRT BDL BRT

Unknown impurities (%) 0.05 0.07 0.05, 0.05 0.05, 0.05

Total Impurities (%) 0.05 0.07 0.10 0.15
BDL: Below detection limit; BRT: Below reporting threshold.

Table 11: Accelerated stability study results of Pramipexole tablets 0.25 mg of Example-3

BDL: Below detection limit; BRT: Below reporting threshold Table 12: Accelerated stability study results of Pramipexole tablets 1.5 mg of Example-3

S.No. Parameters Initial Accelerated conditions (40°C/75% RH)

1 month 2 month2 3 months
1. Assay (%) 101.2 99.0 98.0 97.0
2. Related substances

IMP A BRT BRT BRT BRT

IMP B BRT BDL 0.08 0.09

IMP C 0.06 0.05 0.05 0.07

IMP E BDL BDL BRT BRT

Unknown Impurities (%) 0.05 0.06, 0.07, 0.05 0.06, 0.05, 0.11, 0.05,0.14,0.05,0.06, 0.07,0.10,0.08

Total impurities (%) 0.11 0.23 0.35 0.71

S.No. Parameters Initial Accelerated conditions (40°C/75% RH)

1 month 2months 3 months
1. Assay (%) 103.3 99.0 99.9 98.2
2. Related substances

IMP A BDL BRT BRT BRT

IMP B BDL BDL BRT BRT

IMP C BDL BDL BDL BDL

IMP E BDL BDL BDL BRT

Unknown Impurities (%) 0.05 0.06 0.06, 0.07 0.05, 0.06, 0.07, 0.08

Total impurities (%) 0.05 0.06 0.13 0.26
BDL: Below detection limit; BRT: Below reporting threshold.

CLAIMS:
We claim-
1. Immediate release solid pharmaceutical composition comprising pramipexole or its pharmaceutically acceptable salt(s), or enantiomer(s) or mixture(s) thereof along with one or more pharmaceutically acceptable excipients, prepared by mixing of the active pharmaceutical ingredient with one or more pharmaceutically acceptable excipients in geometric and/or non-geometric proportions.
2. Immediate release solid pharmaceutical composition of claim 1, wherein the dosage forms comprises tablets, capsules, sachets, preferably tablets.
3. Immediate release solid pharmaceutical composition of claim 1, wherein immediate release tablets prepared by direct compression method.
4. Immediate release solid pharmaceutical composition of claim 1, wherein pharmaceutically acceptable excipients comprises diluents, disintegrants, glidants and lubricants.
5. Immediate release solid pharmaceutical composition claim of 4, wherein the diluent comprises one or more of cellulose, co-processed celluloses and cellulose derivatives, starch and starch derivatives sugars and sugar alcohols inorganic salts or mixture thereof.
6. Immediate release solid pharmaceutical composition of claim 5, wherein the diluent comprises one or more of cellulose , co-processed celluloses and cellulose derivatives like cellulose powder, carboxymethyl cellulose, silicified microcrystalline cellulose (SMCC), microcrystalline cellulose-lactose (Microlac), microcrystalline cellulose-guar gum (Avicel CE15), microcrystalline cellulose-calcium phosphate (Celocal), carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hyroxyethyl cellulose, cellulose acetate; preferably silicified microcrystalline

cellulose (SMCC), microcrystalline cellulose-lactose (Microlac), micro crystalline cellulose-guar gum (Avicel CE15), Microcrystalline cellulose-calcium phosphate (Celocal) & low substituted hydroxypropyl cellulose; more preferably silicified microcrystalline cellulose (SMCC); starch and starch derivatives like pregelatinized starch, corn starch, maize starch, starch glycollate, hydroxyethyl starch, sodium carboxymethyl starch, hydroxypropylated pea starch , starch borate; preferably pregelatinized starch and corn starch; more preferably pregelatinized starch; sugars and sugar alcohols like dextrose, fructose, sucrose, maltose, glycerol, mannitol, xylitol and lactose; preferably mannitol; inorganic salts like calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate or mixture thereof; preferably calcium phosphate (dibasic/tribasic) or mixture thereof.
7. Immediate release solid pharmaceutical composition of claim 6, wherein the silicified microcrystalline cellulose grades used in the present invention has the particle size distribution d(0.9) is in the range of 25 μm to 500 urn; preferably in the range of 50 μm to 400 μm; more preferably in the range of 75 μm to 300 μm.
8. Immediate release solid pharmaceutical composition of claim 6, wherein the moisture content of silicified microcrystalline cellulose is less than 10%; preferably a moisture content less than 8%; and more preferably a moisture content less than 6%.
9. Immediate release solid pharmaceutical composition of claim 4, wherein disintegrant comprises one or more of croscarmellose sodium, crospovidone, microcrystalline cellulose, emcosoy (Soya polysaccharide), potassium polacrilin, sodium starch glycolate, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch or mixture thereof.
10. Immediate release solid pharmaceutical composition of claim 9, wherein preferred disintegrant comprises one or more of croscarmellose sodium, microcrystalline cellulose, emcosoy (Soya polysaccharide), sodium starch glycolate, starch, pregelatinized starch or mixture thereof & more preferred disintegrant comprises one or more of croscarmellose sodium, sodium starch glycolate, pregelatinized or mixture thereof.
11. Immediate release solid pharmaceutical composition of claim 4, wherein lubricant includes one or more of magnesium stearate, stearic acid, sodium stearyl fumerate,

hydrogenated vegetable oils, talc, glyceryl behenate and glyceryl palmitostearate, preferably magnesium stearate.
12. Immediate release solid pharmaceutical composition of claim 4, wherein glidant includes one or more of colloidal silicon dioxide, silicon dioxide, calcium silicate, magnesium silicate, calcium phosphate tribasic, talc, pregelatinized starch and starch, preferably colloidal silicon dioxide.
13. Immediate release solid pharmaceutical composition of claim 1, wherein the solid oral pharmaceutical composition comprises from about 0.01% to 20% of active pharmaceutical ingredient, from about 10% to 99.99% of diluents from about 0.25% to 10% of disintegrants, from about 0.2% to 5% of glidants and from about 0.1% to 5% of lubricants. Preferably from about 0.05% to 10% of active pharmaceutical ingredient, from about 50% to 99.99% of diluents, from about 0.5% to 7.5% of disintegrants, from about 0.2% to 4% of glidants and from about 0.1% to 2% of lubricants. More preferably from about 0.1% to 5% of active pharmaceutical ingredient, from about 85% to 99.9 % of diluents, from about 1% to 5% of disintegrants, from about 0.2% to 3% of glidants and from about 0.1% to 3% of lubricants.
14. Immediate release solid pharmaceutical composition of claim 1, wherein active ingredient in the range of about 0.1 mg to about 20 mg; preferably from about 0.1 mg to 11.0 mg; more preferably from about 0.1 mg to 2.0 mg.
15. Immediate release solid pharmaceutical composition of claim 1, wherein active ingredient is pramipexole dihydrochloride.
16. Immediate release solid pharmaceutical composition of claim 15, wherein pramipexole dihydrochloride micronized and having particle size distribution d(0.9) of less than 90 microns, preferably less than 60 microns, more preferably less than 30 microns.
17. Immediate release solid pharmaceutical composition of claim 1, wherein preparation of lubricated blend by non-geometric dilution, comprises the steps of,

i. Sifting of active pharmaceutical ingredient and 25% of diluent through ASTM
# 60 mesh. ii. Sifting of the remaining 75% quantity of diluent and disintegrant through
ASTM # 40 mesh. iii. Step-i blend was sandwiched with step-2 blend and mixing for 20 mins. iv. Sifting of step-3 blend twice through ASTM # 60 mesh and then mixing for
3 mins. v. Sifting of lubricant through ASTM # 60 mesh and mixing with step-4 blend
for 3 mins. vi. Lubricated blend of step-5 is then compressed into tablets or filled into
capsules or filled in a sachet.
18. Immediate release solid pharmaceutical composition of claim 1, wherein preparation
of lubricated blend by geometric dilution, comprises the steps of,
a) Mixing active pharmaceutical ingredient with diluent in geometric dilution technique.
b) Addition of pharmaceutically acceptable excipients other than lubricants and glidants to step-1 blend and then mixing
c) Sifting of step-2 blend twice through ASTM # 60 mesh.
d) Sifting of lubricants and glidants through ASTM # 60 mesh and mixing with step-3 blend.
e) Lubricated blend of step-5 is then compressed into tablets or filled into capsules or filled in a sachet.

19. Immediate release solid pharmaceutical composition of claim 1, wherein the total degradation products (related substances) in pharmaceutical composition even after storage at accelerated storage condition at 40°C/75% RH is less than 1.0%.
20. Immediate release solid pharmaceutical composition of claim 1, wherein the dosage form is used in the treatment of schizophrenia, Parkinson's disease and Alzheimer's disease.

21. The stable, immediate release, solid oral pharmaceutical composition substantially as herein described and illustrated with reference to the accompanying examples.