FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
STABLE PHARMACEUTICAL COMPOSITION OF DONEPEZIL
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the nature of the invention

STABLE PHARMACEUTICAL COMPOSITION OF DONEPEZIL
FIELD OF THE INVENTION
The invention relates to a directly compressed stable solid oral tablet dosage form comprising of donepezil hydrochloride form - I and a pharmaceutically acceptable carrier, characterized in that said carrier comprises a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75 : 25) as a diluent, and a process of preparing such dosage form.
BACKGROUND OF THE INVENTION
Donepezil is chemically known as 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl] methyl piperidine has the formula (I).

(I)
Donepezil hydrochloride shows the acetylcholinesterase inhibitory action and is useful for the treatment of all kinds of senile dementia, in particular being useful for prevention, treatment and amelioration of Alzheimer Disease. Donepezil's unique chemical structure makes it more specifically effective on Alzheimer disease than other drugs.
Alzheimer's disease is the most common form of dementia among older people. Dementia is a collective name for progressive degenerative brain syndromes which affect memory, thinking, behaviour and emotion.
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Alzheimer's disease involves the parts of the brain that control thought, memory, and language. The primary symptoms include memory loss, disorientation, confusion and problems with reasoning and thinking. These symptoms worsen as brain cells die and the connections between cells are lost.
The crystalline form of the active ingredient in a solid oral dosage form may play a significant role in the behavior of the drug and may influence its therapeutical effect. The crystalline form may modify the dissolution and thus bioavailability of the drug.
Donepezil hydrochloride exhibits polymorphism. In such a case it is very important that the formulation of donepezil hydrochloride should contain the same crystalline form in formulation throughout the shelf life in order to ensure the same therapeutical activity of the drug on the patients.
One way to resolve the problem and to retain the same polymorphic form of donepezil is to use direct compression process.
The other advantages of using direct compression process are as below:
1. Direct compression is more efficient and economical process as compared to other processes, because it involves only dry blending and compaction process.
2. Direct compression process needs reduced processing time, reduced labor costs, fewer manufacturing steps, less number of equipments, less process validation, and reduced consumption of power.
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3. In direct compression, there is minimum effect of heat and moisture, thus may improve the stability of the dosage form.
4. The chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is less.
Hence the skilled person in the art will prefer a direct compression in order to resolve the above mentioned problems. Although, there are many disadvantages of the direct compression process, which needs to be resolved in order to develop the desired formulation. The disadvantages of the direct compression process are discussed as below:
1. Direct compression blends may lead to demixing because of difference in density of drug and excipients. Similarly the lack of moisture may give rise to static charges, which may lead to demixing.
2. In case of low dose drugs, the problem of content uniformity is relatively high.
3. The selection of excipients is critical in direct compression process and should be such that the blend has compressibility and good flowability.
Further, WO 200404100857 A2 discloses tablet composition capable of melting rapidly in buccal cavity comprising of plurality of highly plastic granules, wherein these granules comprises of porous plastic substance, a water penetration enhancer and a binder. All the examples in the application disclose that wet granulation is preferred for preparing highly plastic granules. Further in one of the example (Example 3), it is mentioned that composition
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which is manufactured by direct compression process, did not yield tablets with desirable strength.
Hence, there exist a need to develop pharmaceutical composition including tablet dosage form of Donepezil or its pharmaceutically acceptable salts, prepared by direct compression which is substantially free from conversion to different polymorphic form, easy to manufacture having acceptable dissolution profile and substantially free of above discussed disadvantages including the teaching of prior art.
In addition to the need as discussed herein above the selection of excipients in direct compression process thus becomes critical and further complicates the matter. It was surprisingly found in the instant invention that a particular diluent (spray-dried mixture of lactose monohydrate and microcrystalline cellulose, 75:25) had resolved the problems.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to a stable solid oral tablet dosage form comprising of donepezil hydrochloride form - I and a pharmaceutically acceptable carrier, characterized in that said carrier comprises a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75: 25) as a diluent.
In another aspect, the invention relates to a stable solid oral tablet dosage form comprising of donepezil hydrochloride form - I and a pharmaceutically acceptable carrier, characterized in that said carrier comprises a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75: 25) as a diluent and a disintegrant.
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In another aspect, the solid oral tablet dosage form comprising of donepezil hydrochloride form - I is substantially free from conversion to different polymorphic form.
In another aspect, the invention relates to a stable solid oral tablet dosage form comprising of donepezil hydrochloride form - I and a pharmaceutically acceptable carrier, characterized in that said carrier comprises a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75: 25) as a diluent and a disintegrant, wherein the said solid oral dosage form have a dissolution of at least 75 % after 30 minutes, Apparatus 2 (paddle, 30 rpm) in 900 mL of 0.1 NHCI.
In another aspect there is provided a direct compression process for preparing a stable solid oral tablet dosage form comprising of donepezil hydrochloride form -1. The tablets may optionally include a film coating.
DETAILED DESCRIPTION OF THE INVENTION
Initial experiments of direct compression were carried out using lactose and microcrystalline cellulose as diluent, and starch as disintegrant. A particular problem which occurred during compression of dry blend into the tablet press by direct compression was poor flow and higher disintegration time at high tablet hardness. In order to develop a rugged manufacturing process, it is desirable by formulation scientist that the tablet should have satisfactory disintegration time even at high tablet hardness. It was surprisingly found by inventor that, in order to solve the percieved problems, the diluent was substituted for a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), (Microcelac® 100). In addition to having
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satisfactory disintegration time at high hardness during feeding into the tablet press, the dry blend comprising the above diluent was further found to have excellent rheological properties (flowability), as well as to be easily miscible with the active ingredient and other tablet excipients.
The term "solid oral tablet dosage form" or "pharmaceutical composition" or "dosage form" as used herein refers to the tablet composition of predetermined quantity of active substance in association with at least one pharmaceutical^ acceptable excipient.
The term "stable" as used herein refers to dosage form which is physically, or polymorphically stable. The dosage form according to present invention may remain physically stable that is there are no substantial change with respect to physical attributes like colour etc. The dosage form according to present invention may remain polymorphically stable that is the polymorph (crystalline or amorphous) in the dosage form does not rearranges into another form upon storage.
The term "drug" or "active substance" or "donepezil" as used herein includes donepezil free base, or pharmaceutically acceptable acid addition salts thereof or mixtures thereof, more preferably donepezil hydrochloride Form-I. It also covers anhydrous form, hydrous form, different crystalline forms, amorphous form or pharmaceutically acceptable acid addition salts thereof or mixtures thereof. Donepezil may be present in an amount ranging from 1 % to 15 % by weight of the composition.
The pharmaceutical compositions as described herein may comprise one or more pharmaceutically acceptable excipients selected from carrier / diluent, disintegrant, binder, film forming agent, lubricant, opacifiers, plasticizers,
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stabilizers, colouring agent, anti-tacking agent, organoleptic additives such as flavoring agent, sweetener or coloring agent and others known to the skilled person in the art.
Diluent / Carrier may be selected from anhydrous lactose, lactose monohydrate, dicalcium phosphate dihydrate, microcrystalline cellulose, modified (spray processed) lactose, spray dried mixture of lactose and microcrystalline cellulose (Microcelac 100®, Manufacturer: Meggle Pharma), starch, starch derivatives, mannitol, Spray dried Mannitol (Pearlitol SD 200), sorbitol and the like known to the skilled person in the art. The other coprocessed excipients which may be used in the instant invention are Ran Explo-C (Microcrystalline cellulose, Colloidal silicon dioxide, Crospovidone), Ran Explo-S (Microcrystalline cellulose, Colloidal silicon dioxide and Sodium starch glycollate). The filler may be used in a concentration of about 50 % to about 95 % by weight of the tablet, particularly about 80 % to about 95 % by weight of the tablet.
Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, partially pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, Low - substituted hydroxy propyl cellulose and the like known to the skilled person in the art. The disintegrant may be present in an amount ranging from 1 % to 20 % by weight of the tablet particularly about 5% to 17% by weight of the tablet. Starch is preffered disintegrant in the instant invention.
Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl
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pyrrolidone, starch, pregelatinized starch, sodium alginate, gums, synthetic resins. The binder may be present in an amount ranging from 0.0 % to 10 % by weight of the composition.
Lubricant / glidant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; sodium stearyl fumarate, colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, starch, sodium stearyl fumarate, mineral oil, magnesium trisilicate; or mixtures thereof. The lubricant / glidant may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
The sweetener is selected from aspartame, saccharin sodium, acesulfame potassium, dried invert sugar, dextrose, glucose, fructose, galactose, levulose, maltose, neotame, sucralose or mixture thereof. Preferred sweetener is aspartame.
The flavoring agent is selected from cherry, black current, pineapple, orange, strawberry, banana, vanilla, mint, menthol, citric acid, fumaric acid, tartaric acid, and their mixture thereof.
Film forming agent may be selected from hydroxypropyl methylcellulose (hypromellose), polyvinylpyrrolidone, gelatin, hydroxypropyl cellulose, polyethylene oxide, hydroxyethyl cellulose, sodium alginate and such like. The film forming agent may be used in seal coat, drug coat, separating coat, film coat and such like.
Tablets of donepezil are optionally conveniently film-coated following art known coating procedures. Film-coated tablets are easier to swallow than
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uncoated tablet cores, are usually easier to distinguish from other tablets - in particular when the film-coat contains a dye or a pigment, and may furthermore have an improved stability. Of particular importance, it is the requirement that the film-coat should not adversely affect the disintegration and dissolution of the active substance from the tablet.
Donepezil pharmaceutical composition as disclosed in instant invention may additionally include other active pharmaceutical ingredients, which may be selected from Rivastigmine, Memantine, Selegiline, Ondansetron, Creatinine or their pharmaceutically acceptable salts in single layer tablet or multiple layered tablets.
Donepezil pharmaceutical composition as disclosed in instant invention additionally include other active pharmaceutical ingredients, which may be selected from the group of cognition improving drugs, Acetyl choline esterase inbitiors, HMG CoA reductase inhibitors, 5-HT receptor agonists \ antagonists in single layer tablet or multiple layered tablets.
In place of Donepezil other active pharmaceutical ingredients can be incorporated, which may be selected from Oxazepam, Lorazepam, Loperamide, Enalapril, Loratadine, Piroxicam, Rizatriptan, Famotidine, Olanzapine, Risperidone, Ondanseteron, Mirtazepine, Zolmitriptan or their pharmaceutically acceptable salts thereof or the active pharmaceutical ingredients, which are sensitive to wet granulation, thermo labile, and prone to change their polymorphic form can be replaced with donepezil.
The term "immediate release" as used herein refers to the release of an active substance from a pharmaceutical composition or dosage form in which the active substance is released according to a desired dissolution profile (Not less than 75% in thirty minutes).
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The term "substantial" as used herein refers that more than ninety five percent of the selected polymorphic form remain in original form.
The disintegration time of the instant invention must be less than 10 minutes, more preferably less than 5 minutes in 37°C of purified water.
The dissolution of the present invention was determined by following method:
Instrument Apparatus II (Paddle)
RPM : 30
Dissolution Medium 900ml_, 0.1 N HCI
Temperature 37° ± 0.5°C
The present invention is also concerned with a process of preparing solid oral tablet dosage form of donepezil hydrochloride form - I by direct compression, comprising the steps of:
(i) Dry blending the active substance, carrier / diluent and optionally
with at least one pharmaceutically acceptable excipient.
(ii) Mixing the lubricant with the mixture obtained in step (i);
(iii) Compressing the mixture obtained in step (i) or in step (ii) in the dry
state into a tablet; and
(iv) Optionally film-coating the tablet obtained in step (iii).
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
BRIEF DESCRIPTION OF THE DRAWING
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Figure 1: Comparative XRPD (X-Ray Powder Diffraction) data of Donepezil Tablet at Initial stage, placebo and Donepezil Tablet at 2 month 40°C-75% relative humidity
EXAMPLES
Table 1

S.No. Ingredients Mg / Tablet
B.No : 01 B.No : 02
1 Donepezil Hydrochloride (Form-I) 10.00 10.00
2 * Spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) 224.00
3 Lactose Monohydrate 168.00 -
4 Microcrystalline Cellulose 56.00 -
5 Maize Starch 42.00 42.00
6 Magnesium Stearate 4.00 4.00
Weight of Core Tablet 280.00 280.00
Lubricated Blend Analysis
1 Bulk Density (g/ml) 0.55 0.55
2 Tap Density (g/ml) 0.80 0.72
3 Carr's Index 32 22
4 Hausner's Ratio 1.47 1.30
5 Angle of Repose (°) 29 21
*Microcelac100®
$ Evaporated during coating
In above compositions, lactose monohydrate is preferably Pharmatose DCL 11; microcrystalline cellulose is preferably Avicel® PH 102.
PROCEDURE:
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1. Donepezil HCI, Lactose monohydrate, Microcrystalline cellulose,
Microcelac 100® (B.No:01), Maize starch & Magnesium Stearate was sifted
through appropriate sieve.
2. The material from step 1 was blended.
3. The blend from step 2 was compressed.
Table 2

Physical parameters of uncoated tablets at different hardness
# Parameters B.No: 01 B.No: 02
Low Hardness Optimum Hardness High Hardness Low Hardness Optimum Hardness High Hardness
1 Avg.Wt (mg) 279 282 280 280 280 283
2 Thickness (mm) 4.88 4.66 4.54 5.12 5.05 4.83
3 Hardness (N) 40 67 67 47 68 96
4 DT (min:sec) 02:00 04:05 05:15 00:20 01:00 03:00
5 Friability (%) 0.48 0.28 Capping 0.26 0.16 0.07
Table 3

Dissolution Profile: % Drug release in 900 ml of 0.1 N HCI @ 30 RPM, Paddle
S.No Time (Min) Aricept 10 B.No: 6034203 B.No: 01 B.No: 02
1 10 58.9 61.5 62.4
2 15 72.7 80.9 71.7
3 20 83.3 85.5 77.3
4 30 91.8 87.9 82.0
5 45 94.2 89.7 86.8
6 60 95.5 93.0 90.3
In B.No: 01, where the ratio of lactose monohydrate and microcrystalline cellulose was 75:25, capping was observed at higher hardness and the powder flow was poor. In B.No: 02, where spray-dried mixture of lactose
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monohydrate and microcrystalline cellulose (75:25) was used, all the tableting parameters were satisfactory. Also the tablets manufactured with spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) doesn't show polymorphic changes even after 2 months (Figure 1). Aricept® 10 Tablets is marketed preparation of Donepezil hydrochloride manufactured by Eisai.

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ABSTRACT
The invention relates to a stable solid oral tablet dosage form comprising of donepezil hydrochloride form - I and a pharmaceutically acceptable carrier, characterized in that said carrier comprises a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75 : 25) as a diluent, and with a direct compression process of preparing such dosage form.