FORM 2
THE PATENTS ACT l970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"TITLE OF THE INVENTION:
"STABILIZED DONEPEZIL FORMULATIONS" 2. APPLICANT(S)
(a) NAME: FDC Limited
(b) NATIONALITY: Indian company incorporated under the Companies
Act, 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102,
Maharashtra, India.
PREAMBLE OF THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed

Technical field:
The present invention relates to stabilized formulations of Donepezil where the said formulation is stabilized using inorganic stabilizer.
Background and prior art:
Alzheimer's disease (AD) is the most common form of dementia. This incurable, degenerative and terminal disease is generally diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. Although the course of Alzheimer's disease is unique for every individual, there are many common symptoms. The earliest observable symptoms are often mistakenly thought to be 'age-related' concerns or manifestations of stress. The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain.
Donepezil is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. It has an oral bioavailability of 100% and easily crosses the blood-brain barrier. Because it has a half life of about 70 hours, it can be taken once a day. Initial dose is 5 mg per day which can be increased to 10 mg per day after an adjustment period of at least 4 weeks. While the drug is currently indicated for mild to moderate Alzheimer's, there is also evidence from trials that it may be effective for moderate to severe diseases, therefore many neurologists, psychiatrists and primary-care physicians use Donepezil in patients with Alzheimer's disease.
US20080063705 by Krka discloses solid pharmaceutical composition comprising Donepezil hydrochloride in the form of a hydrate along with excipients, and having a water content of 3 to 10% by weight. The application also discloses the physical instability of polymorphic form I and its conversion into polymorphic form III during heating and/or storage.
US20080311202 by Julia Schulze Nahrup et al. discloses a pharmaceutical composition which is suited for the production of comprimates by direct compression, wherein said

composition contains Donepezil hydrochloride of polymorphic form I, having water content of less than 6%.
WO2008012495 by Pliva discloses a pharmaceutical composition comprising Donepezil or a pharmaceutically acceptable salt thereof in the form of a hydrate and the pharmaceutical composition having a content of water of less than 3% by weight (determined by Karl-Fischer).
US6372760 by Kato et al. provides a stable composition comprising Donepezil hydrochloride and an organic acid.
Thus, the above mentioned prior art documents do not address the stabilization of pharmaceutical composition containing Donepezil hydrochloride using inorganic stabilizer, wherein the Donepezil hydrochloride is highly stable and does not convert into any other polymorphic forms.
Object of the invention:
Accordingly, the main objective of the present invention is to provide a stable oral composition comprising Form I of Donepezil hydrochloride along with at least one . pharmaceutically acceptable excipient, wherein the stabilization of the said composition is done using inorganic stabilizer.
Another objective of the present invention is to provide a process for preparing the said composition.
Summary of the invention:
In accordance with the above objectives, the present invention discloses a stabilized pharmaceutical composition comprising Form I of Donepezil hydrochloride, and a process for preparing the same.
According to the present invention, the composition comprises Donepezil in an amount ranging from 10%w/w to 25% w/w, preferably more than 10% w/w of Donepezil, along with at least one pharmaceutically acceptable excipient.

Particularly the present invention relates to the composition, wherein the Donepezil hydrochloride retains its polymorphic form without conversion into other polymorphic forms and is therefore highly stable, by use of an inorganic stabilizer.
Description of drawings:
Fig 1 depicts XRD of Donepezil HC1 Form I API
Fig 2 shows XRD of Donepezil HC1 Tablets without any inorganic stabilizer, before charging for stability
Fig 3 shows XRD of Donepezil HCl Tablets without any inorganic stabilizer after exposure for 3 months at 40°C/75%RH
Fig 4 shows XRD of Donepezil HC1 Tablets prepared by example 1 before charging for stability
Fig 5 shows XRD of Donepezil HC1 Tablets prepared by example 1 after exposure for 3 months at 40°C/75%RH
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
In one embodiment, the present invention provides a stable oral composition comprising Form I of Donepezil hydrochloride along with at least one pharmaceutically acceptable excipient. The term "Donepezil" as used herein alone also denotes Form I of Donepezil hydrochloride salt, and the term can be used interchangeably for the purpose of this invention.
The present invention provides a stabilized pharmaceutical composition of Donepezil hydrochloride which comprises donepezil in an amount ranging from 10%w/w to 25%

w/w, together with an inorganic stabilizer in amount of 0.5 to 10%w/w. along with at least one pharmaceutically acceptable excipient. The Donepezil content in the said dosage forms is preferably more than 10% w/w. Water content in the said pharmaceutical composition would be less than 3% and the amount of disintegrant employed is below 5%.
Donepezil Form I gets converted to other polymorphic forms under certain conditions such as moisture content of composition, light and heat. In order to overcome such conversion, the present invention employs an inorganic stabilizer. Thus, by using inorganic stabilizer, required polymorphic form viz., Form I of Donepezil can be retained. The formulation so formed by using inorganic stabilizer exhibits significant increase in the stability.
In a preferred embodiment, the composition of present invention can be formulated into various solid oral dosage forms such as tablets, capsules, granules and powders for oral suspensions.
In another embodiment, the stable oral composition of Donepezil of present invention may be provided in solid oral dosage forms such as in immediate release, delayed release and sustained release forms and tablets for oral disintegration.
The said dosage forms such as tablets, capsules, granules and powders for oral suspensions comprising Donepezil, are prepared by direct blending followed by compression wherever applicable. The said dosage forms can also be prepared by non aqueous granulation processes and compression into tablets wherever applicable.
The said dosage forms do not contain any binder. The compressed tablets mentioned in the invention are optionally coated.
The pharmaceutically acceptable excipients used in the present invention include disintegrants, glidants, lubricants, diluents, sweetener and preservatives.

Suitable inorganic stabilizer selected from the group consisting of but not limited to sulfates such as magnesium sulfate, calcium sulfate, zinc sulfate, sodium sulfate, potassium sulfate and ammonium sulfate, and phosphates such as monobasic sodium phosphate and monobasic potassium phosphate, is present either alone or in combination in the range of about 0.5% to 10% by weight.
Suitable disintegrants selected from the group consisting of but not limited to cellulose or cellulose derivatives such as croscarmellose sodium, crospovidone, sodium starch glycolate and starch, is present either alone or in combination below 5% by weight.
Suitable gJidants selected from the group consisting of but not limited to colloidal silicon dioxide, starch and talc, is present either alone or in combination in the range of about 0.1% to 5%by weight.
Suitable lubricants selected from the group consisting of but not limited to magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmito stearate, stearic acid, zinc stearate, magnesium lauryl sulfate, sodium stearyl fumarate and glyceryl behenate, is present either alone or in combination in the range of about 0.25% to 5% by weight.
Suitable diluents selected from a group consisting of but not limited to lactose, sucrose, glucose, dextrose, xylitol, mannitol, sorbitol, erythritol, dulcitol, ribitol, sorbitol, powdered cellulose, microcrystalline cellulose, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, kaolin, magnesium oxide and magnesium carbonate, is present either alone or in combination in the range of about 10% to 95% by weight.
Suitable sweeteners selected from a group consisting of but not limited to sucrose, aspartame, sucralose, sodium saccharine and acesulfame potassium, is present either alone or in combination in the range of about 0.1 % to 3% by weight.
Suitable preservatives selected from a group consisting of but not limited to sodium benzoate, methyfparaben, propylparaben and sodium metabisulfite, is present either alone or in combination in the range of about 0.1 % to 3% by weight.

The present invention is exemplified by the following examples which are provided for illustration only and should not be construed to limit the scope of the invention.
EXAMPLES: Example 1:
10 mg tablets containing Donepezi! more than 10% by weight

Sr.
No. Ingredient mg/tablet
1 Donepezil Form 1 10.0
2 Mannitol 70.0
3 Monobasic sodium phosphate 0.5
4 Sodium starch glycolate 4.5
5 Colloidal Silicon Dioxide 3.0
6 Talc 3.0
7 Sodium Stearyl Fumarate 3.0
8 Coating premix 3.0
9 Water* q.s.
Total 97.0
* processing solvent, present in traces
Example 2:
10 mg tablets containing Donepezil more than 10% by weight

Sr. No. Ingredient mg/tablet
1 Donepezil Form I 10.0
2 Microcrystalline cellulose 70.0
3 Monobasic sodium phosphate 0.5
4 Sodium starch glycolate 4.5
5 Colloidal Silicon Dioxide 3.0
6 Talc 3.0
7 Sodium Stearyl Fumarate 2.0

8 Coating premix 3.0
9 Water* q.s.
Total 96.0
* processing solvent, present in traces
Brief manufacturing process for example 1 and 2:
1. Sifting all ingredients through mesh no. 40 (ASTM, 425 microns);
2. Mixing donepezil hydrochloride, monobasic sodium phosphate, colloidal silicon dioxide, sodium starch glycoiate, mannitol (Example 1)/microcrystalline cellulose (Example 2) and talc in a suitable blender;
3. Adding sodium stearyl fumarate in step 2 and mixing the same in the suitable blender;
4. Compressing the blend into tablets of desired shape; and
5. Preparing aqueous coating dispersion and applying coating to the compressed tablets.
Example 3:
10 mg tablets containing Donepezil more than 10% by weight

Sr.
No. Ingredient mg/tablet
1 Donepezil Form I 10.0
2 Lactose anhydrous 78.5
3 Monobasic sodium phosphate 0.5
4 Sodium starch glycoiate 4.0
5 Magnesium stearate 1.0
6 Coating premix 3.0
7 Water q.s.
Total 97.0
* processing solvent, present in traces

Brief manufacturing process ;
1. Sifting all ingredients through mesh no. 40 (ASTM, 425 microns);
2. Mixing donepezil hydrochloride, Lactose anhydrous, monobasic sodium phosphate and sodium starch glycolate (Example 3)/starch (Example 4) in a suitable blender;
3. Adding Magnesium stearate in step 2 and mixing the same in the suitable blender;

4. Compressing the blend into tablets of desired shape; and
5. Preparing aqueous coating dispersion and applying coating to the compressed tablets.
Example 4:
10 mg orally disintegrating tablets containing Donepezil more than 10% by weight

Sr. No. Ingredient mg/tablet
1 Donepezil Form I 10.0
2 Mannitol 81.8
3 Monobasic sodium phosphate 0.5
4 Crospovidone 2.7
5 Magnesium stearate 2.0
Total 97.0
Brief manufacturing process:
1. Sifting all ingredients except crospovidone through mesh no. 40 (ASTM, 425 microns);
2. Sifting crospovidone through mesh no. 30 (ASTM 600 microns);
3. Mixing donepezil hydrochloride, mannitol, monobasic sodium phosphate (Example 5)/monobasic potassium phosphate (Example 6) and crospovidone in a suitable blender;
4. Adding Magnesium stearate in step 2 and mixing the same in the suitable blender and
5. Compressing the said blend into tablets of desired shape.

Example 5:
10 mg orally disintegrating tablets containing Donepezil more than 10% by weight

Sr. No. Ingredient mg/tablet
1 Donepezil Form I 10.0
2 Mannitol 81.8
3 Monobasic sodium phosphate 0.5
4 Crospovidone 2.7
' 5 Sodium stearyl fumarate 2.0
Total 97.0
Brief manufacturing process:
1. Sifting all ingredients except crospovidone through mesh no. 40 (ASTM, 425 microns);
2. Sifting crospovidone through mesh no. 30 (ASTM, 600 microns);
3. Mixing donepezil hydrochloride, mannitol, monobasic sodium phosphate and crospovidone in a suitable blender;
4. Adding Sodium Stearyl fumarate in step 3 and mixing the same in the suitable blender; and
5. Compressing the blend into tablets of desired shape.

We claim:
1. A stabilized pharmaceutical composition of Donepezil hydrochloride comprising donepezil in an amount ranging from 10%w/w to 25% w/w, together with an inorganic stabilizer in amount of 0.5 to 10%vv/w. along with at least one pharmaceutically acceptable excipient.
2. The stabilized pharmaceutical composition as claimed in claim 1, wherein Donepezil hydrochloride is in polymorphic form I.
3. The stabilized pharmaceutical composition as claimed in claim 1, wherein water content in the said pharmaceutical composition is less than 3% and the amount of disintegrant employed is below 5%.
4. The stabilized pharmaceutical composition as claimed in claim 1, wherein the composition exists in solid oral dosage forms such as tablets, capsules, granules and powders for oral suspensions in immediate-release, delayed-release, sustained-re lease forms and tablets for oral disintegration.
5. The stabilized pharmaceutical composition as claimed in claim 4 wherein the solid oral dosage forms are prepared by direct blending followed by compression, or by non-aqueous granulation followed by compression into tablets.
6. The stabilized pharmaceutical composition as claimed in claim 1, wherein the inorganic stabilizers are sulfates such as magnesium sulfate, calcium sulfate, zinc sulfate, sodium sulfate, potassium sulfate and ammonium sulfate, and phosphates such as monobasic sodium phosphate and monobasic potassium phosphate, present either alone or in combination.
7. The stabilized pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from disintegrants, glidants, lubricants, diluents, sweetener and preservatives.

8. The stabilized pharmaceutical composition as claimed in claim 7, wherein the disintegrants are selected from cellulose or cellulose derivatives such as croscarmellose sodium, crospovidone. sodium starch glycolate and starch, present either alone or in combination in an amount of below 5% by weight.
9. The stabilized pharmaceutical composition as claimed in claim 7, wherein the glidants are selected from colloidal silicon dioxide, starch and talc, present either alone or in combination in an amount of 0.1% to 5% by weight.
10. The stabilized pharmaceutical composition as claimed in claim 7, wherein the lubricants are selected from magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmito stearate, stearic acid, zinc stearate, magnesium lauryl sulfate, sodium stearyl fumarate and glyceryl behenate, present either alone or in combination in an amount of 0.25% to 5% by weight.
11. The stabilized pharmaceutical composition as claimed in claim 7, wherein the diluents are selected from lactose, sucrose, glucose, dextrose, xylitol, mannitol, sorbitol, erythritol, dulcitol, ribitol, sorbitol, powdered cellulose, microcrystalline cellulose, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, kaolin, magnesium oxide and magnesium carbonate, present either alone or in combination in an amount of 10% to 95% by weight.
12. The stabilized pharmaceutical composition as claimed in claim 7, wherein the sweeteners are selected from sucrose, aspartame, sucralose, sodium saccharine and acesulfame potassium, present either alone or in combination in an amount of 0.1 % to 3% by weight.
13. The stabilized pharmaceutical composition as claimed in claim 1, wherein the preservatives are selected from sodium benzoate, methylparaben, propylparaben and sodium metabisulfite, present either alone or in combination in an amount of 0.1 % to 3% by weight.

14, The stabilized pharmaceutical composition as claimed in claim 1, wherein the formulation is devoid of binder.