WO2007102038A1

WO2007102038A1 - Ziprasidone formulations

Info

Publication number: WO2007102038A1
Application number: PCT/IB2005/003754
Authority: WO
Inventors: Girish Kumar Jain; Mohan Kumar Kondapaturu
Original assignee: Wockhardt Ltd
Current assignee: Wockhardt Ltd
Priority date: 2005-12-05
Filing date: 2005-12-05
Publication date: 2007-09-13
Anticipated expiration: 2008-06-05

Abstract

The present invention provides an oral pharmaceutical composition comprising therapeutically effective amount of ziprasidone hydrochloride hydrate or it's salt or pharmaceutically acceptable derivative thereof having a mean particle size in the range of 100 - 300 gm alongwith other suitable pharmaceutical excipients such as diluents, binders, disintegrants, surfactants, solubilizers, glidants, lubricants and the like. The said oral composition comprising ziprasidone can be prepared by simple manufacturing process.

Description

ZIPRASIDONE FORMULATIONS

PARENT CASE TEXT

This application is a continuation of PCT application No. PCT/IB03 /05479 filed 28^th November 2003, published as WO05054235 on 16^th June 2005: the entire contents of the aforementioned application being incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to an oral pharmaceutical formulation of antipsychotic such as Ziprasidone, in particular, ziprasidone hydrochloride hydrate particles having a maximum size cutoff, and to a method of treating psychosis and related disorders with such formulation.

BACKGROUND OF THE INVENTION

The most important attribute of drug substance that determines its performance in formulation is its particle characteristics. This is particularly true in those cases where the drug is poorly soluble or a free acid form with poor solubility at low pH values. Such drugs are likely to exhibit dissolution-rate-limited absorption, and if dissolution does not take place rapidly enough, a therapeutic concentration in body fluids may never be achieved, the peak plasma concentration may be significantly delayed, or much of the drug may bypass that region of the gastrointestinal tract where absorption is best. Particle size reduction (e.g. Micronization) is often utilized to enhance dissolution rate. Small particles present a larger surface area per unit weight to the dissolution media and hence dissolve more rapidly than large particles. Particle size and surface area are two of the most important properties determining the solubility rate of a drug and thus potentially its bioavailability. There are numerous examples of bioavailability problems and bioequivalence due to inappropriate particle size of the drug substance. Most drugs are passively absorbed and their rates of absorption are dependent upon the concentration gradients in each case; by increasing the dissolution rate in the GI tract, the absorption rate is necessarily increased so long as the dissolution rate is still the limiting step. If a drug is not absorbed enough to be systemically active and if the drug is not soluble enough to be used for its local action in the gut, the reduction of particle size may improve its therapeutic efficacy.

Particle size and shape also play an extremely important role in the homogeneity of powder blend and the unblending of powders in a mixer. Segregation in handling or during the compaction process has a significant effect on the content uniformity of the finished products. Particle size can also affect the stability of a drug substance in that it governs the surface area available for oxidation and hydrolysis. Surface area is critical for interaction with excipients in tablet dosage forms and can greatly affect stability.

Ziprasidone is an antipsychotic agent with the following chemical name: 5-[2-[4-(l,2- benzisothiazol-3-yl)-l-piρerazinyl] ethyl]-6- chloro-l,3-dihydro-2 H -indol-2-one. Ziprasidone is disclosed in U.S. Patent no. 4,831,031 and 5,312,925 (assigned to Pfizer). Ziprasidone inhibits synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor.

The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D ₂ ) and serotonin type 2 (5HT ₂ ) antagonism. Ziprasidone's antagonism of histamine H ] receptors may explain the somnolence observed with this drug.

It is typically administered as the hydrochloride acid addition salt. Ziprasidone is well absorbed after oral administration, reaching peak plasma concentrations in 6 to 8 hours. The absolute bioavailability of a 20 mg dose under fed conditions is approximately 60%. The absorption of ziprasidone is increased up to two-fold in the presence of food. Yet, the hydrochloride salt possesses relatively poor aqueous solubility, a factor that affects bioavailability. Several formulations of Ziprasidone have been reported in the literature. The dosage forms thus far include immediate release dosage forms, depot formulations, parenteral delivery, etc. Examples of patents describing such formulations are as follows.

US 5,312,925 (Pfizer Inc.) describes a process for the synthesis of monohydrate of 5-(2- (4-l,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-l,3-dihydro-2H-indol-2-one hydrochloride and its characterization based on IR, XRD and moisture content. The '925 patent also discloses that the hemihydrate may be obtained by the process described in Example 16 of US Patent No. 4,831,031 and their characterization by IR, XRD and moisture content. It also discloses the IR, XRD and moisture content of anhydrous Ziprasidone hydrochloride. According to the invention in the '925 patent, water content having 3.97, 2.55 and 0.37 % were used for the IR and XRD study of Ziprasidone hydrochloride monohydrate, hemihydrate and anhydrous. In this invention, the monohydrate of Ziprasidone hydrochloride was prepared by reacting anhydrous 5- (2-(4-l,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-l,3-dihydro-2H-indol-2-one with aqueous hydrochloric acid. The temperature range of the reaction was maintained between 60 to 65 °C and aqueous hydrochloride used for salt formation was around 0.7 M. Depending on the reaction temperature and other conditions, the reaction times were set around 3 to 24 hours. The final product thus obtained was dried carefully monitored conditions to make certain that water content was from about 3.8 % to about 4.5 % to obtain the stable monohydrate.

US Patent No. 6,150,366, discloses a manufacturing process of ziprasidone hydrochloride monohydrate, which states:

1) dissolving ziprasidone free base in a solvent comprising THF and water, in a volume ratio of about 22-35 unit volumes of THF to about 1.5-8 volumes of water;

2) heating the solution resulting from step (1);

3) adding HCl to the solution resulting from step (2); and

4) cooling the solution resulting from step (3) and crystals were collected by filtration and drying. The patent also describes ziprasidone composition comprising ziprasidone free base or crystalline ziprasidone hydrochloride particles having a mean particle size equal to or less than about 85 μm alongwith a diluent or carrier. The prosecution file history of the '366 patent describes the significance of particle size of ziprasidone as mentioned below. As known in the prior art, with increase in particle size, surface area decreases and consequently dissolution and bioequivalence are also expected to decrease. This can be applied easily to drugs falling under BCS classification II (poorly soluble, highly permeable). Ziprasidone belongs to this class so it is anticipated that formulations using higher particle size will show poor solubility and hence poor availability. However, the invention as claimed in the '366 patent, shows that ziprasidone with mean particle size of equal to or less than about 85 μm show same solubility (in contrast, to what is anticipated theoretically) and hence are bioequivalent with a formulation having a particle size of about 20 μm. A perusal of file wrapper reveals that, though a composition is claimed, what it transcends to is the bioequivalence of a capsule formulation made with ziprasidone of mean particle size about 20 μm is equivalent to a capsule formulation made with ziprasidone of mean particle size of 85 μm.

However, micronised drug powders are extremely cohesive due to high energy milling processes causing significant dislocation of cystal structure on the particle surface. These particles tend to agglomerate during the solid state processing and unless properly formulated can lead to poor dissolution performance.

WO 04050655A1 (Dr. Reddy's Laboratories, Inc.) describes amorphous form of ziprasidone hydrochloride and a composition comprising the same.

WO 2005/020929 (Ahmed et. al) describes a sustained release solid oral dosage form comprising ziprasidone alongwith suitable pharmaceutically acceptable carrier. The said dosage form releases ziprasidone from about 4 to about 24 hours. The said dosage form further comprises of bi or multiplayer tablets comprising one active layer and the other layer comprised of swelleble material. Micronised Ziprasidone is used in this sustained release dosage form i.e. having a mean particle size of less than about 5 μm. Jet milling is done to micronize the drug. US application no. 2005/0163858 assigned to Alpharma describe a formulation of ziprasidone or its pharmaceutically acceptable salts having a mean particle size greater than 85 μm alongwith a pharmaceutical carrier.

Despite the availability of different technologies for Ziprasidone formulations, there is a clinical need for better preparations that are simple, stable and can confer an unswerving dissolution profile provide improved patient compliance, better and more uniform clinical effects and possible enhanced bioavailability and are manufactured by an expedient manufacturing process.

To this end, it is surprisingly found that a pharmaceutical composition for ziprasidone hydrochloride hydrate according to the present invention provides good therapeutic effect in the treatment of psychotropic and related disorders.

The said composition exhibits good dissolution properties at physiological pH. The invention is surprising in this respect, however in that the rate of dissolution in vitro does not correlate with particle size. i.e. ziprasidone dissolution rate in aqueous media (from the composition according to present invention) does not vary substantially with particle size, and therefore appears to be largely independent of it. Thus ziprasidone free base or ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof can be formulated in a composition having a reasonable particle size (which is easily manageable using conventional formulations methodology and equipment). Therefore, surprisingly, the invention provides a formulation of ziprasidone providing enhanced invitro and invivo performance independent of particle size of ziprasidone or it's salt or solvate or derivatives thereof.

The said composition is made up of ziprasidone hydrochloride hydrate salt with specific particle size together with suitable pharmaceutical excipients. The said composition is prepared using dry granulation process and therefore provides a stable composition with homogeneity of drug content in the formulation. SUMMARY OF THE INVENTION

The present invention provides an oral pharmaceutical composition comprising therapeutically effective amount of ziprasidone hydrochloride hydrate or it's salt or pharmaceutically acceptable derivative thereof having a mean particle size in the range of 100 - 300 μm alongwith other suitable pharmaceutical excipients such as diluents, binders, disintegrants, surfactants, solubilizers, glidants, lubricants and the like to enhance stability and dissolution properties at physiologic pH. The said oral composition comprising ziprasidone can be prepared by simple manufacturing process for solid orals known in the art. Hence, the present invention yields a stable oral composition comprising ziprasidone hydrochloride hydrate or it's salt or pharmaceutically acceptable derivative thereof having a mean particle size in the range of 100 - 300 μm alongwith other suitable pharmaceutical excipients.

Accordingly, it is an object of the present invention to provide an oral pharmaceutical composition comprising ziprasidone of mean particle size in the range of 100-300 μm and a process for preparing the same for administration of ziprasidone to patients suffering from psychotropic and related disorders.

The present invention therefore also provides a pharmaceutical composition comprising ziprasidone hydrochloride hydrate or it's salt or pharmaceutically acceptable derivative thereof having a mean particle size in the range of 100-300 μm along with suitable excipients.

Another aspect of the present invention is a solid pharmaceutical composition adapted for oral administration. The said composition comprises ziprasidone, particularly, ziprasidone hydrochloride hydrate of mean particle size in the range of 100-300 μm alongwith suitable pharmaceutical excipients. It is still further object of the present invention to provide an orally deliverable solid formulation of ziprasidone hydrochloride hydrate that exhibit good stability and dissolution properties at physiological pH.

The present invention further provides a method of administering to a subject in need of treatment a pharmaceutical product or formulation substantially as hereinbefore described and in particular a solid composition which can be administered orally and as such is particularly suited for the treatment of depression and other related psychotropic disorders.

The present invention further provides use of ziprasidone in the manufacture of a medicament for the treatment of psychotropic and other related disorders. Such a medicament according to the present invention comprises a formulation substantially as herein described, and in particular a solid formulation, typically a capsule formulation substantially as hereinafter described.

The present formulation provides noticeable benefits being simple operational process of manufacturing said stable oral solid pharmaceutical composition.

Yet another object of this present invention is to provide for an oral solid composition comprising an antipsychotic, that is bioequivalent to the reference composition.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates comparative dissolution profile of Ziprasidone from ziprasidone capsules (Example- 1) in pH 7.5 Buffer

Figure 2 illustrates comparative dissolution profile of Ziprasidone from ziprasidone capsules (Example-2) in pH 7.5 Buffer

Figure 3 illustrates comparative dissolution profile of Ziprasidone from ziprasidone capsules (Example-3) in pH 7.5 Buffer DETAILED DESCRIPTION OF THE INVENTION

Before the subject invention is described further, it is to be understood that the invention is not limited to the particular embodiments of the invention described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present invention will be established by the appended claims.

In this specification and the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs. Although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preffered methods, devices and materials are now described.

All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the subject components of the invention that are described in the publications, which components might be used in connection with the presently described invention.

The information below is not admitted to be prior art to the present invention, but is provided solely to assist the understanding of the reader.

The details of one or more embodiments of the invention are set forth in the description and the examples below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. The present invention provides an oral pharmaceutical composition comprising therapeutically effective amount of ziprasidone hydrochloride hydrate or it's salt or pharmaceutically acceptable derivative having a mean particle size in the range of 100 - 300 μm alongwith other suitable pharmaceutical excipients such as diluents, binders, disintegrants, surfactants, solubilizers, glidants, lubricants and the like to enhance stability and dissolution properties at physiologic pH. The said oral composition comprising ziprasidone can be prepared by simple manufacturing process for solid orals known in the art. Hence, the present invention yields a stable oral composition comprising ziprasidone hydrochloride hydrate or it's salt or pharmaceutically acceptable derivative thereof having a mean particle size in the range of 100 - 300 μm alongwith other suitable pharmaceutical excipients.

The term "pharmaceutically acceptable derivative" means various pharmaceutical equivalent isomers, enantiomers, complexes, hydrates, polymorphs, etc of ziprasidone hydrochloride hydrate.

The term composition includes but not limited to solutions and/or suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro-tablets, capsules, pellets, comprising ziprasidone hydrochloride hydrate or its pharmaceutically acceptable derivative thereof in a core constituted by drug having a mean particle size in the range of 100-300 μm alongwith suitable pharmaceutical excipients.

The term "therapeutically effective amount" means an amount of the drug, which is capable of eliciting a physiological response in a human patient. More specifically, the term "therapeutically effective amount" means the amount of drug, which is capable of treating depression and related psychotropic disorders.

The said medicament according to the present invention comprises a formulation substantially as herein described, and in particular a capsule or a tablet or micro-tablets or granules or pellets filled in capsule formulation, typically an oral capsule formulation substantially as hereinafter further described. Suitably a formulation according to the present invention provides a novel capsule dosage form comprising ziprasidone hydrochloride hydrate or its pharmaceutically acceptable derivatives thereof having a mean particle size of 100-300 μm alongwith suitable pharmaceutical excipients.

In a preferred embodiment of the present invention, ziprasidone hydrochloride hydrate or its salts or pharmaceutically acceptable derivatives thereof may be prepared as crystalline particles of various sizes as described under the our original PCT application no. WO05054235, filed on 28^th November 2003. In one embodiment, the particles have a mean particle size greater than 100 m, preferably having a mean particle size about 100 m to about 300 m, and more preferably about 100 m to about 250 m and most preferably about 100 to about 200 m. As used herein with regard to crystalline ziprasidone hydrate or its salt or pharmaceutically acceptable derivative thereof, the term "particles" refers to individual particles regardless of whether the particles exist singly or are agglomerated. Reference to ziprasidone or ziprasidone hydrochloride hydrate particles having "a mean particle size" is defined herein as "volume mean diameter" based on the assumption that the particles are of a spherical shape. Particle size distribution can be measured by techniques known in the art, such as Malvern light scattering.

Of the foregoing particles of ziprasidone, the active is preferably ziprasidone hydrochloride hydrate.

The particles may be combined with pharmaceutically acceptable carriers to provide pharmaceutical formulations, particularly formulations that provide bioequivalence with that of the reference product Geodon^R Capsules. Suitable carriers are described further herein.

In another embodiment of the present invention, the particles having a mean particle size of greater than 100 μm is combined with a pharmaceutically acceptable carrier or other excipients resulting in formulation that provides an AUC that is greater than 80% and less than 120% of the mean AUC observed for an equivalent formulation of Geodon^R. hi a further embodiment, a formulation comprising particles having mean particle size of 100 μm to 300 μm provides a maximum ziprasidone plasma concentration (Cmax) that is greater than 80 % and less than 120% of the Cmax observed for an equivalent formulation of Geodon^R.

In a preferred embodiment of the present invention, an oral pharmaceutical capsule dosage form may be formulated by mixing the active agent with suitable diluents, binders, disintegrants, wetting agents, surfactants, lubricants and the like and compacting it using suitable roller compactor. Excipients are usually added in a specified order to increase the rate of dissolution and to facilitate a rapid approach to equilibrium. The slugs such produced, are milled to the required particle size, mixed with glidants and lubricants and filled into the suitable size capsules.

The above materials are combined in specific concentration with therapeutically effective amount of active agent to achieve the desired characteristics of the said capsule formulation according to the present invention.

In general, the present invention provides a pharmaceutical product manufactured by using suitable process and comprising of active agent with specific particle size distribution as hereinbefore described.

Another aspect of the present invention relates to oral capsule composition of antidepressant such as ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof comprising ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof as pharmaceutically active agent having a mean particle size of 100-300 μm and having been made with the simple manufacturing process. The capsule composition contains a pharmaceutically effective amount of ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof, for treating psychotropic and other related disorders. In a preferred embodiment of the present invention, the oral capsule composition is comprised of pharmaceutically effective amount of at least one antidepressant such as ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof mixed together with other pharmaceutically acceptable excipients for treating depression and other related psychotropic disorders.

"Pharmaceutically acceptable excipient," as used herein means a pharmacologically inactive ingredient which is used to formulate a drug product and which is readily known and available in the pharmaceutical arts. Examples of such excipients are given below:

Suitable excipients employed in a pharmaceutical formulation according to the present invention, may include commonly used pharmaceutical excipients such as diluents, binders, disintegrants, wetting agents, surfactants, glidants, lubricants and the like. Wetting agents and/or surfactants are used to improve the solubility of the active agent in the solution. The artisan can select appropriate wetting agents and/or surfactants in order to get good solubility of active agents.

When formulated with appropriate carriers, any one of the foregoing ziprasidone particle- containing formulations preferably provides a mean maximum plasma concentration of ziprasidone of about 120 ng/ml in the fed mode. Furthermore, the formulations preferably provide a mean time to maximum plasma concentration of ziprasidone of about 3-9 hours in the fed mode.

Formulations prepared from the foregoing particle-size distributions preferably provide a dissolution profile such that at least 70% of the ziprasidone therein dissolves within 45 minutes using a USP-II apparatus containing 900 ml of aqueous sodium phosphate buffer, pH 7.5, containing 2 % (w/v) sodium lauryl sulphate, and equipped with paddles stirring at 75 rpm.

The present invention further comprises a process of preparing a pharmaceutical product, or a pharmaceutical formulation, or a medicament as substantially as hereinbefore described. Suitably such a process comprises providing at least one antipsychotic along with suitable pharmaceutical excipients, wherein preferably the formulation comprises an orally deliverable pharmaceutical formulation, typically in capsule form.

The present invention will now be illustrated by the following examples, which do not limit the scope of the invention in any way.

EXAMPLES

Example-1

A capsule formulation was prepared using the following excipients:

Procedure:

Sift ingredients 1,2,3 and 4 through sieve of suitable mesh size. Mix and blend the contents in a suitable blender. The blend is then compacted using suitable roll compactor. The resultant slugs are milled to suitable size and blended with talc in a suitable blender. The resultant granules are filled in suitable size capsule shells.

Figure - 1 shows the comparative dissolution profiles of the said invented capsule formulation and the reference formulation (Geodon^R Capsules). Example-2

A capsule formulation was prepared using the following excipients:

Procedure:

Figure - 2 shows the comparative dissolution profiles of the said invented capsule formulation and the reference formulation (Geodon^R Capsules).

Example-3

A capsule formulation was prepared using the following excipients:

Procedure:

Figure - 3 shows the comparative dissolution profiles of the said invented capsule formulation and the reference formulation (Geodon^R Capsules).

A randomized, two period, two treatment, single dose crossover comparative bioavailability study was performed between the test ziprasidone hydrochloride hydrate capsules with reference product (Geodon^R capsules) in healthy, adult human subjects under fed conditions. A total of 12 subjects were enrolled in the study and all of them completed the study. The investigations included two treatment phases and were separated by washout period of three days between the treatments. All the treatment phases were of 24 hours duration each.

A randomized three-period, three treatment, three sequence single dose crossover comparative bioavailability study was also performed between the test ziprasidone hydrochloride hydrate capsules with reference product (Geodon^R capsules) in healthy, adult human subjects under fasting conditions. A total of 12 subjects were enrolled in the study and all of them completed the study. The investigations included three treatment phases and were separated by washout period of three days between the treatments

It was observed that mean plasma ziprasidone concentrations following single dose oral administration of Test capsule formulation (performed under both-fasting and fed conditions) were comparable to the mean plasma concentrations of ziprasidone following administration of reference ziprasidone capsule formulation.

The area under the time curve concentrations (AUC_0-t) following test formulation was found to be comparable to the AUC following reference ziprasidone capsule formulation. With respect to mean AUC, the relative bioavailability of ziprasidone from Test ziprasidone formulation was found to be equivalent when compared with reference ziprasidone capsule formulation under fasting and fed conditions as mentioned in table- 1 and 2. Time to achieve the maximum plasma concentration (T-max) was also comparable between the two formulations during both the studies.

Tab Ie-I. Pharmacokinetic Parameters for Ziprasidone under Fed conditions

Table-2. Pharmacokinetic Parameters for Ziprasidone under Fasting conditions

Therefore, oral capsule formulation was found to be bioequivalent to the Reference ziprasidone capsule formulation.

Claims

We Claim:

1. A pharmaceutical composition comprising a therapeutically effective amount of ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof having a mean particle size preferably in the range from about 100 to about 300 μm alongwith other suitable pharmaceutical excipients for oral administration.

2. A pharmaceutical composition of claim 1, wherein the said composition comprises ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof.

3. A pharmaceutical composition of claim 1, wherein the said composition comprises ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof having a mean particle size preferably in the range from about 100 to about 300 μm

4. A pharmaceutical composition of claim 1, wherein the said mean particle size is preferably in the range of about 100 to about 300 μm

5. A pharmaceutical composition of claim 4, wherein the said mean particle size more preferably is in the range of about 100 to about 250 μm

6. A pharmaceutical composition of claim 5, wherein the said mean particle size most preferably is in the range of about 100 to about 200 μm

7. A pharmaceutical composition of claim 1, wherein the said composition comprises suitable pharmaceutical excipients such as diluents, binders, disintegrants, wetting agents, surfactants, glidents, lubricants and the like.

8. A pharmaceutical composition of claim 1, wherein the composition is the oral solid dosage form.

9. A pharmaceutical composition of claim 8, wherein the composition is capsule, tablet, granules, pills, granules in capsule, micro-tablets in capsules or combinations thereof

10. A pharmaceutical composition of claim 9, wherein the formulation is capsule dosage form

11. An oral capsule composition of claim 1 , wherein mean plasma concentrations of the antidepressant, following single dose oral administration of capsule formulation, are comparable to the mean plasma concentrations of antidepressant, following the administration of pharmaceutically acceptable dosage of an antidepressant capsule composition.

12. A pharmaceutical composition comprising therapeutically effective amount of at least one antidepressant such as ziprasidone hydrochloride hydrate or its salt or its pharmaceutically acceptable derivatives thereof having a mean particle size preferably in the range from about 100 to about 300 μm alongwith other suitable pharmaceutical excipients, said composition exhibiting a mean AUC and/or Cmax which is at least 80 % of the mean AUC exhibited by a composition equivalent thereof.

13. A pharmaceutical composition of claim 12, wherein the said composition comprises ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof.

14. A pharmaceutical composition of claim 12, wherein the said composition comprises ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof having a mean particle size preferably in the range from about 100 to about 300 μm

15. A pharmaceutical composition of claim 12, wherein the said mean particle size is preferably in the range of about 100 to about 300 μm

16. A pharmaceutical composition of claim 15, wherein the said mean particle size more preferably is in the range of about 100 to about 250 μm

17. A pharmaceutical composition of claim 5, wherein the said mean particle size most preferably is in the range of about 100 to about 200 μm

18. A pharmaceutical composition of claim 1, wherein the said composition comprises suitable pharmaceutical excipients such as diluents, binders, disintegrants, wetting agents, surfactants, glidents, lubricants and the like.

19. A process for preparation of an orally administered solid composition, which comprises mixing/blending at least one antidepressant such as ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof having a mean particle size preferably in the range from about 100 to about 300 μm with suitable pharmaceutical excipients such as diluents, binders, disintegrants, wetting agents, surfactants and the like and compacting the blend using suitable roll compactor and milling and sizing the resultant slugs and mixing the granules thus obtained with suitable glidants and lubricants and filling the resultant granules in appropriate capsule size shells using suitable capsule filling machine.

20. A process of claim 19, wherein the said composition comprises ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof.

21. A process of claim 19, wherein the said composition comprises ziprasidone hydrochloride hydrate or its salt or pharmaceutically acceptable derivative thereof having a mean particle size preferably in the range from about 100 to about 300 μm

22. A process of claim 19, wherein the said mean particle size of active is preferably in the range of about 100 to about 300 μm

23. A process of claim 22, wherein the said mean particle size of active is more preferably in the range of about 100 to about 250 μm

24. A process of claim 23, wherein the said mean particle size of active is most preferably in the range of about 100 to about 200 μm

25. A process of claim 19, wherein the composition is the oral solid dosage form.

26. A process of claim 19, wherein the composition is capsule, tablet, granules, pills, granules in capsule, micro-tablets in capsules or combinations thereof

27. A process of claim 26, wherein the formulation is capsule dosage form

28. A process of claim 19, wherein said composition comprising therapeutically effective amount of at least one antidepressant such as ziprasidone hydrochloride hydrate or its salt or its pharmaceutically acceptable derivatives thereof having a mean particle size preferably in the range from about 100 to about 300 μm alongwith other suitable pharmaceutical excipients, said composition exhibits a mean AUC and/or Cmax which is at least 80 % of the mean AUC exhibited by a composition equivalent thereof.

29. A method of treating depression and other related psychotropic disorders in a subject in need of treatment, which method comprises administering to the subject a pharmaceutical composition of claim 1.

30. Use of at least one antidepressant such as ziprasidone hydrochloride hydrate or its salt or its pharmaceutically acceptable derivatives thereof having a mean particle size preferably in the range from about 100 to about 300 μm, in the manufacture of an oral liquid composition for the treatment of depression and other related psychotropic disorders.