Field of the invention
The present invention relates to stable ropinirole compositions and process of preparation thereof. The compositions are useful for the treatment of the signs and symptoms of idiopathic Parkinson's disease and for treatment of moderate-to-severe primary Restless Legs Syndrome.
Background of the invention
Ropinirole hydrochloride {4-[2-(dipropylamino) ethyl]-1,3-dihydro-2H-indol-2-one
monohydrochloride} disclosed in US 4452808 is an orally administered anti-Parkinsonian drug and is a non-ergoline dopamine agonist.
Parkinson's disease is a debilitating disease characterized by disturbance of voluntary movement in which muscles become stiff and sluggish, movement becomes clumsy and difficult, and uncontrollable rhythmic twitching of groups of muscles produces characteristic shaking or tremor. The condition is believed to be caused by the degeneration of dopaminergic neurons in the nigral striatal system of the brain, leading to inadequate release of the neurotransmitter dopamine.
Ropinirole, an indolone derivative, alleviates the deficiencies of conventional anti-parkinsonian drugs like L-DOPA and ergot alkaloids, and has particularly minimum liability to cause dyskinesia. Furthermore, it has additional beneficial effects on the central nervous system, namely anti-depressant and anxiolytic effects, which are considered to be particularly advantageous, considering that patients requiring current therapies often need to take separate anti-depressant medication. Presence of such qualities in a single compound obviates the need for separate therapy. Ropinirole is believed to act by stimulation of post- synaptic dopamine D2-type receptors within the caudate putamen of the brain, leading to an increase in the activity of the neurotransmitter dopamine.
Ropinirole used in tablets is in the form of the hydrochloride salt. Ropinirole hydrochloride has been provided previously as immediate release formulation or a 24-hours controlled release formulation.
PCT application WO91/16306 discloses the process for the preparation of ropinirole.
PCT application WO01/78688 discloses a multi-layer controlled-release tablet comprising a mixed matrix of hydrophilic or lipophilic components to control the release rate of one or more therapeutically active agents from the tablets.

PCT application WO05018605 discloses controlled release oral dosage form of ropinirole for oral administration and to their use in the treatment of diseases which can prevent or disturb sleep, particularly Restless Legs Syndrome (RLS).
Stability of a drug is of paramount importance and is required to demonstrate that the drug product meets its acceptance criteria throughout the lifetime and also to gain regulatory approval.
It was observed that optimization of certain parameters in the composition and its process of preparation has varied effects on the stability of ropinirole composition.
Prior art does not acknowledge the criticality of any parameters for the stability of ropinirole compositions and there is a need to prepare stable ropinirole compositions that exhibits enhanced/comparable stability relative to existing ropinirole compositions.
We have surprisingly observed that particle size of ropinirole that is used to formulate the composition plays a major role in the stability of the composition. Further, selection of particular pharmaceutically acceptable excipients and the selection of the process of preparing the composition was found to be critical for the stability.
Micronization involves reducing the size of the solid drug particles to microns and is done commonly by spray drying or by use of air attrition methods. It leads to increase in surface area causing greater interaction with the excipients. It was observed that compositions having unmicronised ropinirole are comparatively stable when compared to the compositions having micronised ropinirole.
Direct compression is advantageous over wet granulation as being simple and economical and it was observed that ropinirole compositions prepared by direct compression were effectively more stable when compared with compositions prepared by wet granulation.
Further, we have surprisingly found that addition of certain pharmaceutically acceptable excipients adversely affects the stability of the composition.
Thus the present invention relates to stable ropinirole compositions and process of preparing thereof. The compositions have acceptable stability in terms of related substances, even after storage at accelerated conditions. Further, the compositions are cost effective and easy to manufacture on a commercial scale without requiring complex processing steps.

Summary of the invention
According to one embodiment there is provided a stable ropinirole composition comprising unmicronised ropinirole and one or more pharmaceutically acceptable excipients.
According to another embodiment there is provided a stable ropinirole composition comprising ropinirole and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by direct compression.
According to another embodiment there is provided a stable ropinirole composition comprising unmicronised ropinirole and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by direct compression.
According to another embodiment there is provided a stable ropinirole composition comprising ropinirole and one or more pharmaceutically acceptable excipients wherein the composition is devoid of colloidal silicon dioxide.
According to another embodiment there is provided a stable ropinirole composition comprising unmicronised ropinirole and one or more pharmaceutically acceptable excipients wherein the composition is devoid of colloidal silicon dioxide.
According to another embodiment there is provided a stable ropinirole composition comprising ropinirole and one or more pharmaceutically acceptable excipients wherein the composition is devoid of colloidal silicon dioxide and talc.
According to another embodiment there is provided a stable ropinirole composition comprising unmicronised ropinirole and one or more pharmaceutically acceptable excipients wherein the composition is devoid of colloidal silicon dioxide and talc.
According to another embodiment there is provided a stable ropinirole composition comprising unmicronised ropinirole and one or more pharmaceutically acceptable excipients wherein the composition is prepared by direct compression and is devoid of colloidal silicon dioxide and talc.
According to another embodiment there is provided a process for the preparation of stable ropinirole composition, the process comprising the steps of: (a) preparing a dry blend of ropinirole and one or more pharmaceutically acceptable excipients, and b) directly compressing the blend of step (a) to obtain stable ropinirole composition.

According to another embodiment there is provided a process for the preparation of stable ropinirole composition, the process comprising the steps of: (a) preparing a dry blend of unmicronised ropinirole and one or more pharmaceutically acceptable excipients, and b) directly compressing the blend of step (a) to obtain stable ropinirole composition.
Detailed Description of the Invention The present invention provides for a stable ropinirole composition.
According to one embodiment the stable ropinirole composition comprises unmicronised ropinirole and one or more pharmaceutically acceptable excipients. It was observed that compositions containing unmicronised ropinirole provided better stability in terms of related substance when compared to compositions containing micronised ropinirole.
The term "ropinirole" as used herein refers to ropinirole or salts thereof. Preferably, ropinirole is in the form of ropinirole hydrochloride.
The term "unmicronised ropinirole" refers to particles of ropinirole wherein the D90 value ranges from 50 to 200 microns, the D50 value ranges from 20 to 80 microns and the D10 value ranges from 5 to 30 microns.
The term "composition" refers to any oral dosage form such as tablet or capsule. Stability of the composition is measured in terms of total related substances determined using HPLC or TLC.
The pharmaceutically acceptable excipients may be selected from one or more of binders, diluents, disintegrants and lubricants/glidants.
Suitable binders include polymeric substances having sufficient elasticity and structural stability as a film. Generally the binders may be selected from one or more of cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums such as xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers such as polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate; sugars such as sorbitol and mannitol.
Suitable diluents may be selected from one or more of sugars such as dextrose, glucose and lactose; sugar alcohols such as sorbitol, xylitol and mannitol; cellulose derivatives such as powdered cellulose and microcrystalline cellulose; starches such as corn starch, pregelatinized starch and maize starch.

Suitable disintegrants may be selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone and corn starch.
The lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate and colloidal silicon dioxide.
The compositions in the form of tablets or capsule may be prepared by conventional processes known to a person skilled in the art such as by wet granulation, dry granulation or direct compression. Preferably, the process involves direct compression. Surprisingly, it was observed that compositions prepared by direct compression were stable in terms of related substances when compared to compositions prepared by wet granulation. Direct compression is a dry process, which avoids the use of water.
According to one embodiment there is provided a process for the preparation of stable ropinirole composition, the process comprising the steps of: (a) preparing a dry blend of ropinirole and one or more pharmaceutically acceptable excipients, and b) directly compressing the blend of step (a) to obtain stable ropinirole composition.
Further, it was observed that ropinirole compositions comprising unmicronised ropinirole and prepared by direct compression provided a stable composition.
Thus, according to another embodiment there is provided a process for the preparation of stable ropinirole composition, the process comprising the steps of: (a) preparing a dry blend of unmicronised ropinirole and one or more pharmaceutically acceptable excipients, and b) directly compressing the blend of step (a) to obtain stable ropinirole composition.
Further, it was observed that the presence of certain pharmaceutically acceptable excipients e.g. talc and colloidal silicon dioxide have adverse effect on the stability of the composition.
Thus according to another embodiment there is provided a stable ropinirole composition comprising unmicronised ropinirole and one or more pharmaceutically acceptable excipients wherein the composition is prepared by direct compression and is devoid of colloidal silicon dioxide.
According to further embodiment there is provided a stable ropinirole composition comprising unmicronised ropinirole and one or more pharmaceutically acceptable excipients wherein the composition is prepared by direct compression and is devoid of colloidal silicon dioxide and talc.

The stable composition of ropinirole may optionally be coated with non-functional layers comprising film-forming polymers, if desired.
Suitable film-forming polymers include one or more of ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit RL and RS; and the like. Alternatively, commercially available coating compositions may be used for the coating including film-forming polymers marketed under various names, such as, Opadry.
The following non-limiting example illustrates the stable ropinirole composition disclosed in various embodiments of the specification.
Examples 1 - 2:
(Table Removed)
* D90 = 6μm, D50 = 3μm, D10= 1μm **D90 = 108μm, D50 = 40μm, D10=16μm
Brief Manufacturing Process
1. Ropinirole, lactose (lactose 200M), microcrystalline cellulose, croscaramellose sodium,
lactose (DCL 11) and colloidal anhydrous silica are sifted and mixed to obtain a blend.
2. Magnesium stearate and talc are mixed with the blend obtained in step 1 and final
blend is compressed to obtain tablets.
3. Tablets obtained in step 2 are then coated with Opadry film coating to obtain coated
tablets.
The compositions of Example 1 and Example 2 were evaluated for total related substances (both at initial time point and after storage). The result is provided in Table 1 below.
Table 1:
(Table Removed)
As evident from the above data, example 1 having micronised ropinirole showed high total related substances in comparison to example 2 having unmicronised ropinirole. Thus example 2 shows better stability compared to Example 1.
Examples 3 - 4:
(Table Removed)
* Dgo = 21μm, D50 =10μm, D10= 2μm ** D90 = 67μm, D50 =30μm, D10= 9μm
Brief Manufacturing Process
1. Ropinirole hydrochloride, lactose monohydrate (pharmatose 200M), microcrystalline cellulose, lactose (DCI 11) and croscaramellose sodium are sieved and mixed to obtain a blend
2. Magnesium stearate is then mixed with the blend obtained in step 1 and final blend is
then compressed to obtain tablets.
3. Tablets obtained in step 2 are then coated with opadry film coating.
The compositions of Example 3 and Example 4 were evaluated for total related substances (both at initial time point and after storage). The result is provided in Table 2 below.
Table 2:
(Table Removed)
The above results further show that composition having micronised ropinirole has higher amount of total related substances in comparison to composition with unmicronised ropinirole. Thus example 4 shows better stability when compared to example 3. Moreover composition without talc and colloidal silicon dioxide show better stability in comparison to tablet with these, though both have unmicronised API (Example 4 & 2).
The composition of example 4 was also subjected to longer periods of storage. The related substances amount after storage is provided in Table 3 below:
Table 3 (Table Removed)
The above results show that composition having unmicronised ropinirole show stability even after storage at accelerated conditions for a period of 6 months.
Examples 5-7
(Table Removed)
* D90 = 21 μm, D50 =10μm, D10= 2μm
Brief Manufacturing Process for Example 5 and 6
1. Ropinirole, lactose (pharmatose 200M), microcrystalline cellulose, lactose (DCI 11),
croscaramellose sodium and colloidal anhydrous silica are sifted and mixed to obtain a
blend.
2. Magnesium stearate and talc are mixed with the blend obtained in step 1 and final
blend is compressed to obtain tablets.
Brief Manufacturing Process for Example 7
1. Ropinirole, lactose (lactose 200M), microcrystalline cellulose, lactose (DCI 11) and
croscaramellose sodium are sifted and mixed to obtain a blend.
2. Magnesium stearate is mixed with the blend obtained in step 1 and final blend is
compressed to obtain tablets.
The compositions of Example 5, Example 6 and Example 7 were evaluated for total related substances (both at initial time point and after storage). The result is provided in Table 4 below.
Table 4:
(Table Removed)
The above results show the effect of talc and colloidal silicon dioxide on the stability of the composition. Example 7, without talc and colloidal silicon dioxide, shows lower total related substances when compared with example 6 (with talc) and example 5 (with talc and colloidal silicon dioxide).
Example 8 and Example 2
(Table Removed)
• D90 = 108μm, D50 = 40μm, D10= 16μm

Example 8 - Brief Manufacturing Process
1. Ropinirole hydrochloride, lactose and microcrystalline cellulose are sifted and mixed in a
rapid mixer granulator to obtain a blend.
2. The blend obtained in step 1 is granulated with purified water to obtain granules.
3. The granules obtained in step 2 are dried in fluidized bed drier and sifted to obtain dry
granules.
4. Croscaramellose sodium and colloidal silicon dioxide are sifted and mixed with the dry
granules of step 3 to obtain a mixture.
5. Talc is sifted and added to mixture obtained in step 4 to obtain final blend.
6. The final blend obtained in step 5 is then compressed to obtain tablets.
The compositions of Example 8 and Example 2 were evaluated for total related substances (both at initial time point and after storage). The result is provided in Table 5 below.
Table 5:
(Table Removed)
The above result shows that in compositions comprising unmicronised ropinirole if we change the formulation process from direct compression to wet granulation there is increase in the total related substances.
Example 9 & Example 4
(Table Removed)
*D9071 μm, D50 = 35 μm, D10= 9μ **D90 = 67μm, D50 = 30μm, D10= 9μ
Example 9: Brief Manufacturing Process
1. Ropinirole, lactose (lactose 200M), microcrystalline cellulose, croscaramellose sodium and
lactose (DCI 11) are sifted and mixed in a rapid mixer granulator to obtain a blend
2. The blend obtained in step 1 is then granulated with purified water to obtain granules.
3. The granules of step 2 are dried and milled to desired size.
4. Microcrystalline cellulose, lactose monohydrate and magnesium stearate are sifted through
suitable sieve and mix with the granules obtained in step 3 to obtain a blend.
5. The blend obtained in step 4 is compressed using appropriate toolings to obtain tablets.
6. The tablets obtained in step 5 are coated with 12%w/v dispersion of Opadry to obtain
coated tablets.
The compositions of Example 9 and Example 4 were evaluated for total related substances (both at initial time point and after storage). The result is provided in Table 6 below.
Table 6:
(Table Removed)
The above results further shows that compositions prepared by direct compression have lower total related substances than compositions prepared by wet granulation.
The API (Ropinirole hydrochloride), both micronised and Unmicronised, was evaluated for total related substances (both at initial time point and after 6 months storage). The results are provided in Table 7 below:
Table 7:
(Table Removed)
* D90 = 6 urn, D50= 3 urn, D10= 1 urn ** D90 = 108 urn, D50= 40 urn, D10= 16um
As evident from the above data, the API as such is quite stable in both micronised and Unmicronised state with respect to the total related substances.
Further, it was observed that the stable ropinirole composition according to the present invention had better stability when compared to marketed Requip® tablets from GlaxoSmithKline. The amount of impurities (at initial time point and after 6 months) is provided in Table 8 below:
Table 8:
(Table Removed)
The above results further show that composition having unmicronised ropinirole and prepared by direct compression has lesser amount of impurity in comparison to Requip® tablets.

WE CLAIM:
1. A stable ropinirole composition comprising unmicronised ropinirole and one or more
pharmaceutically acceptable excipients.
2. A stable ropinirole composition comprising ropinirole and one or more pharmaceutically
acceptable excipients, wherein the composition is devoid of colloidal silicon dioxide.
3. The composition according to claim 2, wherein the composition is devoid of talc.
4. The composition according to any of claims 2 or 3, wherein the ropinirole is
unmicronised ropinirole.
5. The composition according to any of claims 1 or 4, wherein the unmicronised ropinirole
has a particle size wherein, the D90 value ranges from 50 to 200 microns, the D50 value
ranges from 20 to 80 microns and the D10 value ranges from 5 to 30 microns.
6. The composition according to any of the preceding claims, wherein the pharmaceutically
acceptable excipient is selected from one or more of binders, diluents, disintegrants and
lubricants.
7. The composition according to any of the preceding claims, wherein the composition is
prepared by direct compression.
8. The composition according to claim 1, wherein the composition is devoid of colloidal
silicon dioxide and talc; and the composition is prepared by direct compression.
9. A process for the preparation of stable ropinirole composition, the process comprising
the steps of: (a) preparing a dry blend of ropinirole and one or more pharmaceutically
acceptable excipients, and b) directly compressing the blend of step (a) to obtain stable
ropinirole composition.
10. A stable ropinirole composition and process of preparation thereof as substantially
described and exemplified herein.