Field of The Invention
The present invention relates to solid dosage forms of quetiapine. In particular, the invention relates to solid dosage forms comprising quetiapine fumarate having defined particle size distribution.
The present invention also relates to a process for the preparation of solid dosage forms comprising quetiapine fumarate having defined particle size distribution.
Background Of The Invention
Quetiapine fumarate is chemically known as 2-[2-{4-dibenzo[b,f|[l,4] thiazepin-ll-yl-l-piperazinyl)ethoxy]ethanol fumarate (2:1) and is disclosed in US 4,879,288. Quetiapine fumarate is an antipsychotic drug belongs to benzothiazapine derivatives and clinically effective for the treatment of schizophrenia and bipolar mania.
Quetiapine fumarate is marketed under the trade name Seroquel® as an oral tablet and also Seroquel XR® as an extended release tablet in the United State.
Quetiapine fumarate is moderately soluble in water and rapidly absorbed after the oral administration. The rate of dissolution of the drug from a dosage form depends on the particle size distribution and also the choice of excipient in the formulation. Also the particle size distribution of a drug may significantly affect the processing behavior and characteristics of a composition mainly when it is prepared by wet granulation process. For example, granule formation in a wet granulation process is due to particle agglomeration behavior, which may ultimately depend on the particle size distribution of the active ingredient. Compressibility may also be affected by factors like bulk density which may be functionally related to particle size. Moreover, the use of defined particle size distribution may resuh in tablet with adequate hardness, disintegration and friability and also overcome the problems such as sticking and picking.
The marketed composition of quetiapine fumarate tablet is composed of povidone, dibasic calcium phosphate dihydrate, microcrystalline cellulose, sodium

starch glycolate, lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycol and titanium dioxide.
Given below are patents/patent publications, which disclose various compositions of quetiapine.
US 5,948,437 discloses a sustained release formulation comprising quetiapine or pharmaceutically acceptable salts thereof and methods of treating psychotic states and hyperactivity utilizing the sustained release formulations.
US 6,372,734 discloses quetiapine and pharmaceutical compositions comprising crystalline quetiapine and pharmaceutical acceptable diluent.
US 6,599,897 discloses a granule formulation comprising quetiapine or a pharmaceutical ly acceptable salt thereof and a freely or very water soluble binder, wherein granules have a bulk density of 0.J5 g/cc to 0.60 g/cc and a tap density range of 0.20 g/cc to 0.70 g/cc and 80% of the granules are in the size range of 75 to 850 microns.
US 2003/0216376 discloses micronized crystalline form II quetiapine hemifumarate including a plurality of quetiapine hemifumarate particles wherein the mean particle size (d0.05) is about 2^m to about 7)j.m and 10 volume percent or less of the plurality of particles have a particle diameter equal to or greater than about 30pm, preferably 20 fim.
US 2005/0003001 discloses a granulated product of poorly dispersible medicament to enhance its dissolution properties, which comprises poorly dispersible medicament including quetiapine and a floating agent. This patent publication further discloses the granulated products may be fine granules or granules, where the fine granules particle size is not more than 850ja-m in which the particles of 500pm or more are 5% or less and those of 75|im or less are 10% or less, while the granules particle size is not more than 1,700pm in which the particles of 1,400pm or more are 5% or less and those of 355pm or less are 15% or less.
WO 05/041935 discloses dosage form of quetiapine comprising an easily openable capsule enclosing a plurality of micropellets, where each of the micropellets

comprises a seed coated with a first coating mixture of quetiapine or a pharmaceutically acceptable salt thereof and a water soluble polymer and coated thereon with a second coating mixture of about 90% to about 70% by weight of a non-hydrophilic polymer and about 10% to about 30% of a hydrophilic polymer. This patent publication further discloses the micropellets have a mean diameter of about 0.5 to about 0.7 mm.
WO 06/117700 discloses pharmaceutical compositions comprising quetiapine fumarate having a particle size distribution wherein approximately 10% by volume of the particles have a diameter below approximately 5|mi, approximately 50% by volume of the particles have a diameter below approximately 20|mi and approximately 90% by volume of the particles have a diameter below approximately 35^m.
The above prior art references disclose various solid dosage forms of quetiapine fumarate. In view of the importance of quetiapine fumarate, as a potential agent for the treatment of schizophrenia, the inventors of the present invention have developed composition having higher particle size distribution, thereby reducing sticking and picking problems during compression.
Objective Of The Present Invention
Accordingly, the main objective of the present invention is to provide solid dosage forms comprising quetiapine fumarate having defined particle size distribution.
Yet another objective of the present invention is to provide solid dosage forms comprising quetiapine fumarate having defined particle size distribution in such a way that it will comply with the reference product in terms of in vivo parameters for bioequivalence such as Cma*:. AUC, Tmax and m vitro parameters like dissolution, disintegration etc.
Yet another objective of the present invention is to provide a process for the preparation of solid dosage forms comprising quetiapine fumarate having defined particle size distribution.

Summary Of The Invention
Accordingly, the present invention provides a solid dosage form comprising quetiapine fumarate having defined particle size distribution such that at least 50% of the particles have size in the range from 40nm to 100|im and at least 90% of the particles have size less than 200gm.
Detailed Description Of The Invention
The solid dosage form of quetiapine fumarate of the present invention, further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants and the like.
In another embodiment of the present invention, the solid dosage form ma>' be in the form of tablet or capsule.
The desired particle size distribution is obtained by sieving or air jet milling. The particle size distribution is measured either by sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, disk centrifugation, laser beam diffraction (Malvern mastersizer) or by other techniques.
Suitable diluents used according to the present invention are selected from lactose, dibasic calcium phosphate dihydrate, calcium silicate, microcrystalline cellulose, sucrose, starch, polyols such as mannitol, sorbitol, xylitol, mahitol and the like or combinations thereof. The diluent may be used in the range of about 40 to 70% by weight of the composition.
Suitable binders used according to the present invention are selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelatin, alginates, starch, povidone, copolyvidone, microcrystalline cellulose, pre gelatinized starch and the like or combinations thereof. The binder may be used in the range of about 1 to 5% by weight of the composition.
Suitable disintegrants used according to the present invention are selected from sodium starch glycolate, carboxymethylcellulose and its salts, cross linked polyvinylpyrrolidone, croscarmellose sodium and the like. The disintegrant may be used in the range of about 3 to 10% by weight of the composition.

Suitable lubricants used according to the present invention are selected from magnesium stearate, calcium stearate, sodium stearyi ftimarate, colioidai silicon dioxide, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like. The lubricant may be used in the range of about 0.1 to 5% by weight of the composition.
Suitable glidants includes talc, colloidal silicon dioxide, cornstarch and the like.
In a preferred embodiment of the present invention, a solid dosage form comprising quetiapine fumarate having defined particle size distribution such that at least 50% of the particles have size in the range from 40|im to 100pm and at least 90% of the particles have size ISOpm.
In a preferred embodiment of the present invention, a solid dosage form comprises quetiapine fumarate having defined particle size distribution such that at least 50% of the particles have size in the range from 40nm to 100|4m and at least 90% of the particles have size less than 200^m, 40 to 70% by weight of diluents selected from lactose, dibasic calcium phosphate dihydrate, calcium silicate; 1 to 5% by weight of binders selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, starch, povidone; 3 to 10% by weight of disintegrants selected from sodium starch glycolate, carboxymethylcellulose and its salts and 0.1 to 5% by weight of lubricants selected from magnesium stearate, calcium stearate, talc and colloidal silicon dioxide.
In another embodiment of the present invention, the solid dosage form comprising quetiapine fumarate having defined particle size distribution and one or more pharmaceutic ally acceptable excipients, may be prepared by direct compression, dry granulation using slugging or compaction and wet granulation.
In yet another embodiment of the present invention, this is provided a process for the preparation of solid dosage form comprising quetiapine fumarate having defined particle size distribution such that at least 50% of the particles have size in

the range from 40!im to 100|im and at least 90% of the particles have size less than 200|im, using wet granulation, which comprises the following steps: i). sifting and mixing of quetiapine fumarate and intragranular diluent and disintegrant in a rapid mixer granulator,
ii). granulating the materia! obtained in step (i) using binder solution, iii). drying the wet granules obtained in step (ii) and blending with extragranular excipients such as diluent and disintegrant, iv). lubricating the blend obtained in step (iii) and
v). compressing the lubricated blend of step (iv) into tablets or filled into capsules.
In yet another embodiment, there is provided a method for the treatment of schizophrenia, bipolar mania including acute manic episodes associated with bipolar I disorder, by administering tablet composition of quetiapine fumarate of the present invention.
The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.



The processing steps involved in manufacturing solid dosage form of quetiapine fumarate are given below:
1. quetiapine fumarate, dibasic calcium phosphate dihydrate, lactose
monohydrate, microcrystalUne cellulose and sodium starch glycolate were sifted and
mixed in granulator,
2. binder solution of povidone in purified water was prepared,
3. granulated the dry mix obtained in step (1) with a binder solution of step (2),

4. dried the granules obtained in step (3) and blended with extragranular microcrystalUne cellulose and sodium starch glycolate,
5. lubricated the blend of step (4) with magnesium stearate, colloidal silicon dioxide and talc,
6. compressed the lubricated blend of step (5) into tablet.
The solid dosage forms of quetiapine fumarate disclosed in example 2 and 3 were prepared by similar procedure as described in example 1.

We claim:
1. A solid dosage form comprising quetiapine fumarate having defined particle size distribution such that at least 50% of the particles have size in the range from 40|im to lOO^m and at least 90% of the particles have size less than 200gm.
2. The dosage form as claimed in claim 1, fiarther comprises one or more pharmaceutically acceptable excipients such as diluents, binders, disintegrants, lubricants and glidants.
3. The dosage form as claimed in claim 2, wherein the diluent is selected from lactose, dibasic calcium phosphate dihydrate, calcium silicate, microcrystalline cellulose, sucrose, starch, polyols such as mannitol, sorbitol, xylitol and maltitol or a combination thereof.
4. The dosage form as claimed in claim 2, wherein the binder is selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelatin, alginates, starch, povidone, copolyvidone, microcrystalline cellulose and pregelatinized starch or a combination thereof
5. The dosage form as claimed in claim 2, wherein the disintegrant is selected from sodium starch glycolate, carboxymethylcellulose and its salts, cross-linked polyvinylpyrrolidone and croscarmellose sodium or a combination thereof.
6. The dosage form as claimed in claim 2, wherein the lubricant is selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, colloidal silicon dioxide, talc, vegetable oils, stearic acid, ftimaric acid and glyceryl behenate or a combination thereof.
7. The dosage form as claimed in claim 2, wherein the glidant is selected from talc, colloidal silicon dioxide or cornstarch.
8. The dosage form as claimed in claim 1, is in the form of tablet or capsule.
9. A process for the preparation of solid dosage form comprising quetiapine fumarate having defined particle size distribution such that at least 50% of the particles have size in the range from 40)im to lOOjim and at least 90% of the particles

have size less than 200m, using wet granulation, which comprises the following
steps:
i). sifting and mixing of quetiapine fumarate and intragranular diluent and
disinlegrant in a rapid mixer granulator,
ii). granulating the material obtained in step (i) using binder solution,
iii). drying the wet granules obtained in step (ii) and blending with extragranular
excipients such as diluent and disintegrant,
iv). lubricating the blend obtained in step (iii) and
v). compressing the lubricated blend of step (iv) into tablets or filled into
capsules.