FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
PHARMACEUTICAL COMPOSITIONS
OF ESCITALOPRAM AND PROCESS
FOR PREPARATION THEREOF
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 invention:
1

FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of escitalopram. More particularly, the present invention relates to a pharmaceutical composition comprising escitalopram particles having a specific particle size distribution; and process for preparing such composition.
BACKGROUND OF THE INVENTION
Citalopram is a selective, centrally active serotonin reuptake inhibitor, having antidepressant activity. Citalopram was first disclosed in US 4,136,193 patent. This patent also describes the manufacture of tablets containing salts of citalopram. The S-enantiomer of citalopram, escitalopram was shown to have better activity profile.
Escitalopram is chemically known as (+)-1-(3-Dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile. Escitalopram and its
pharmaceutical^ acceptable salts are disclosed in US 4,943,590 patent, reissued as US RE 34,712. It also describes the manufacture of tablets containing salts of escitalopram. Escitalopram is an orally administered selective serotonin reuptake inhibitor (SSRI), and is indicated for the treatment of depression. Escitalopram is marketed as oral tablets comprising escitalopram oxalate, under the trade name LEXAPRO®.
US 6,916,941 patent discloses crystalline particles of escitalopram oxalate having median particle size of at least 40 ^m. It is described therein that the escitalopram oxalate product prepared by crystallization from acetone as outlined in US 4,943,590 has a very small particle size of around 2-20 ^m which results in poor flow properties. Active substances with such small particle size when mixed with excipients having a larger particle size typically segregate or de-mix during the tableting process. In view of this fact, US 6,916,941 patent discloses crystallisation process producing larger crystalline particles of escitalopram oxalate and preparing tablets by direct compression using such large particles.
2

US 2005/0147674, which is a continuation of US 6,916,941 patent discloses crystalline particles of escitalopram oxalate having median particle size of at least 20 urn, method for the manufacture of said crystalline particles and pharmaceutical compositions comprising the crystalline particles.
US 2005/197388 discloses crystalline particles of escitalopram oxalate having a ratio between the median particle size and the particle size at the 95% quantile less than 0.42. It discloses a solid dosage form comprising crystalline escitalopram oxalate having the median particle size in the range of 50-200 urn.
WO 2006/123243 discloses a granulation technique to improve the flow properties of escitalopram oxalate having smaller particle size. The pharmaceutical dosage form comprising escitalopram oxalate prepared by a dry granulation technique is also disclosed. It discloses the particle size of the escitalopram oxalate, which is less than 20 μm. It also discloses the particle size distribution of escitalopram oxalate such that at least 50% of the particles are less than 15 microns and 95% of the particles are less than 20 microns. The patent application also discusses compositions prepared by wet granulation process.
It is known in the art that particle size of escitalopram plays an important role in achieving appropriate dosing of escitalopram during tabletting. Thus there is a need in the art for alternative dosage forms, more particularly tablets, of escitalopram having improved flow properties, homogeneous distribution, uniform content and desirable tableting parameters. We have surprisingly found that such characteristics can be achieved by careful selection of particle size of escitalopram.
SUMMARY OF THE INVENTION
One embodiment discloses a pharmaceutical composition comprising
(i) crystalline escitalopram particles having d2o more than 6 microns, d50 less than 18 microns, d90 more than 23 microns and d95 less than 40 microns; and
3

(ii) at least one pharmaceutical^ acceptable excipient.
Another embodiment discloses a process for preparing the composition of escitalopram, wherein the process comprises
(i) mixing escitalopram particles having d2o more than 6 microns, d50 less than 18 microns, d9o more than 23 microns and d95 less than 40 microns and at least one pharmaceutical^ acceptable excipient; (ii) lubricating the mixture of step (i); and (iii) compressing the mixture of step (ii) into tablets.
Another embodiment discloses a process for the preparation of the composition of escitalopram, wherein the process comprises
(i) mixing escitalopram oxalate particles having d2o more than 6 microns, d5o less than 18 microns, d90 more than 23 microns and d95 less than 40 microns and at least one pharmaceutical^ acceptable excipient, (ii) granulating the mixture obtained in step (i), (iii) drying the granules obtained in step (ii), (iv) lubricating the mixture of step (iii); and (v) compressing the mixture of step (iv) into tablets.
Yet another embodiment discloses a method of treating a neurotic disorder
comprising administration of a pharmaceutical composition of escitalopram to a patient in need thereof, wherein the composition comprises
(i) crystalline escitalopram particles having d2o more than 6 microns, d5o less than 18 microns, d90 more than 23 microns and d95 less than 40 microns;
and (ii) at least one pharmaceutically acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION
The term" escitalopram" as used herein refers to escitalopram free base or pharmaceutically acceptable salts, hydrates, solvates and enantiomers thereof or mixtures thereof. The preferred salt of escitalopram is escitalopram oxalate.
4

Escitalopram may be present in amorphous form, crystalline form or mixtures
thereof. Escitalopram typically comprises from about 0.1% to about 50% by
weight of the composition.
The term "d95n, "d90", "d5o" and "d20" as described herein denotes respectively that 95 %, 90 %, 50 % and 20 % volume of particles are smaller than the specified value.
The term "neurotic disorder" used herein refers to designate a group of mental disorders, including major depressive disorder, generalized anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder and panic attacks.
The pharmaceutical compositions as described herein may comprise of one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder or glidant / lubricant.
Diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol or erythritol; and mixtures thereof. The diluent may be present in an amount ranging from 1 % to 90 % by weight of the composition.
Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and mixtures thereof. The disintegrant may be present in an amount ranging from 1 % to 10 % by weight of the composition.
Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, gelatin, polymethacrylates, polyvinylpyrrolidone, pregelatinized
5

starch, sodium alginate, gums, synthetic resins and the like. The binder may be present in an amount ranging from 0.1 % to 8 % by weight of the composition.
Lubricant / glidant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate; and mixtures thereof. The lubricant / glidant may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
Escitalopram oxalate is a sticky material. The use of micronized particles of escitalopram oxalate resulted in difficulty in direct compression process due to sticking to the punches. When larger particle size of escitalopram was used, the formulation showed demixing and segregation problems, particularly when the formulation contained excipient(s) with smaller particle size. Alternatively, escitalopram may be blended with an excipient, for example colloidal silicon dioxide, to obtain pre-mix with superior flow properties and reduced stickiness, which may be used further to prepare tablets.
The pharmaceutical composition of escitalopram may be in the form of a tablet, a capsule, powder or granules. Tablet dosage form may be prepared by direct compression, dry granulation or wet granulation method.
One embodiment discloses a pharmaceutical composition comprising
(i) crystalline escitalopram particles having d2o more than 6 microns, d50 less
than 18 microns, d90 more than 23 microns and d95 less than 40
microns; and (ii) at least one excipient selected from a diluent, a disintegrant, a binder or
a lubricant / glidant.
Another embodiment discloses a process for the preparation of pharmaceutical composition comprising escitalopram, wherein the process comprises:
6

(i) mixing escitalopram oxalate with at least one pharmaceutically acceptable
excipient, (ii) lubricating the mixture of step (i); and (iii) compressing the mixture of step (iii) into tablets.
Another embodiment discloses a process for the preparation of pharmaceutical composition comprising escitalopram, wherein the process comprises:
(i) mixing escitalopram oxalate with at least one pharmaceutically acceptable excipient,
(ii) granulating the mixture obtained in step (i),
(iii) drying the granules obtained in step (ii),
(iv) optionally mixing the granules of step (iii) with at least one pharmaceutically acceptable excipient,
(v) lubricating the mixture of step (iii) or (iv); and
(vi) compressing the mixture of step (v) into tablets.
Yet another embodiment discloses a process for the preparation of pharmaceutical composition comprising escitalopram, wherein the process comprises:
(i) mixing escitalopram oxalate with at least one pharmaceutically acceptable excipient,
(ii) compacting the mixture of step (i),
(iii) optionally milling and sieving the compacts to obtain granules,
(iv) mixing the granules of step (ii) or (iii) with at least one pharmaceutically acceptable excipient, and
(iv) compressing the mixture of step (iv) into tablets.
The tablets may be coated with polymers selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, ethyl cellulose, polyethylene oxide and the like.
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:
7

COMPARATIVE EXAMPLE 1

Sr. No. INGREDIENTS QUANTITY (Mg/Tablet)
CORE
1 Escitalopram oxalate* 25.55
2 Microcrystalline cellulose 190.95
3 Croscarmellose sodium 12
4 Colloidal silicon dioxide 4
5 Talc 3
6 Magnesium stearate 4.5
COATING
7 Hydroxypropyl methylcellulose 3.2
8 Titanium dioxide 0.6
9 Polyethylene glycol 0.4
10 Purified water q.s.
* d2o= 5 μm; d5o= 9-27 μm ; d»= 22.6μm
[Particle size distribution measured by Malvern™ Mastersizer; Dispersant=Toluene]
PROCEDURE: Escitalopram oxalate, microcrystalline cellulose, colloidal silicon dioxide and croscarmellose sodium were mixed. The mixture was lubricated by addition of magnesium stearate and talc and compressed into tablets using appropriate punches and dies. Hydroxypropyl methylcellulose, titanium dioxide and polyethylene glycol were mixed and dispersed in purified water and the dispersion was coated on the tablets. Tablets of Comparative Example 1 exhibited sticking problems.
EXAMPLE 1

Sr. No. INGREDIENTS QUANTITY (mg/tablet)
CORE
8

1 Escitalopram oxalate* 25.55
2 Microcrystalline cellulose 182.05
3 Croscarmellose sodium 12
4 Colloidal silicon dioxide 4.8
5 Talc 6
6 Magnesium stearate 9.6
COATING
7 Hydroxypropyl methylcellulose 3.0
8 Titanium dioxide 0.6
9 Polyethylene glycol 0.4
10 Purified water q.s.
* d2o= 9.20 μm ; dso= 14.97 μm ; dM= 28.36 μm ; d95=33.06 μm [Particle size distribution measured by Malvern™ Mastersizen Dispersant=Toluene]
Tablets of EXAMPLE 1 were prepared by process as described in Comparative Example 1.
EXAMPLE 2

Sr. No. INGREDIENTS QUANTITY (mg/tablet)
CORE
1 Escitalopram oxalate* 25.55
2 Microcrystalline cellulose 147.45
3 Croscarmellose sodium 12
4 Polyvinyl pyrrolidone 5
5 Isopropyl alcohol q.s.
6 Colloidal silicon dioxide 4
7 Talc 2
8 Magnesium stearate 4
COATING
9 Hydroxypropyl methylcellulose 3.2
9

10 Titanium dioxide 0.6
11 Polyethylene glycol 0.4
12 Purified water q.s.
*d2o= 9.20 μm, d5o= 14.97 μm; dw= 28.36 μm ; do5=33.06 μm
[Particle size distribution measured by Malvern™ Mastersizen Dispersant=Toluene]
PROCEDURE: Escitalopram oxalate, microcrystalline cellulose, croscarmellose sodium were mixed and granulated by solution of polyvinyl pyrrolidone in isopropyl alcohol. The granules were dried, sieved and mixed with croscarmellose sodium, magnesium stearate, colloidal silicon dioxide and talc, and compressed into tablets using appropriate punches and dies. Hydroxypropyl methylcellulose, titanium dioxide and polyethylene glycol were mixed and dispersed in purified water and the dispersion was coated on the tablets.
It would be appreciated by person skilled in the art that any of the above examples may be prepared using dry granulation process. The mixture of drug and excipients may be compacted using a roller compacter and the compacts may be milled and sieved to obtain uniform sized granules. The granules may be mixed with disintegrant and lubricant before compressing into tablets.
Particle size distribution of escitalopram particles was measured by Malvern™ Mastersizer laser diffraction instrument. Sample of Escitalopram oxalate (50 mg) was suspended in toluene (dispersant) with 3 minutes sonication with external sonicator. The sample unit was filled with about 80 ml of Toluene (dispersant medium) and the stirrer was operated at 2500 RPM speed before measuring the particle size.
Dated This 9th Day of March, 2007

10

ABSTRACT
The present invention relates to pharmaceutical compositions of escitalopram.
More particularly, the present invention relates to a pharmaceutical composition comprising escitalopram particles having a specific particle size distribution; and
process for preparing such composition.