Technical Field of the Invention
The present invention relates to solid oral dosage forms containing ziprasidone and salts thereof having reproducible dissolution profiles and process for the preparation thereof.
Background of the Invention
Ziprasidone is an antipsychotic used in the treatment of schizophrenia. Chemically, it is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one. It is available as capsule under the brand name Geodon® sold by Pfizer. The capsules contain ziprasidone hydrochloride, lactose, pregelatinized starch, and magnesium stearate. These are available in dosage strengths of 20, 40, 60 and 80mg.
Ziprasidone free base or its hydrochloride salt has very poor solubility. In addition to this, ziprasidone is difficult to wet which is problematic when formulating its dosage form. Ziprasidone tends to form agglomerates when it comes in contact with an aqueous liquid. The agglomerates would slow the dissolution of ziprasidone when the dosage form is in contact with gastrointestinal fluids.
US Patent No. 6,150,366 discloses ziprasidone containing formulations which use ziprasidone of mean particle size equal to or less than 85μm and are shown to exhibit good dissolution properties at physiological pH. The patent also discloses that rate of dissolution in vitro does not correlate with particle size. Ziprasidone dissolution rate in aqueous media, at least at or below 85um, does not vary substantially with the particle size, and therefore appears to be largely independent of it. It is further disclosed that ziprasidone of this particle size can be formulated in a composition which is easily manageable using conventional formulations methodology and equipment, it is not necessary to use extreme measures or specialized technology to maintain relatively tiny particles to facilitate dissolution.
US Patent No. 4,831,031 discloses preparation of ziprasidone and salts thereof. By following the process for the production of hydrochloride salt as generally disclosed in US 4,831,031, ziprasidone hydrochloride is obtained in a very fine particle size. It would be advantageous to use ziprasidone in as obtained form for formulating a dosage form as it reduces a process step. However, we have found that ziprasidone of small particle size is fluffy and tends to agglomerate due to surface charge which decreases the effective available surface area. The decreased available /exposed surface area results in slowed dissolution of ziprasidone contrary to the expectation that decreased particle size would enhance the solubility. The agglomerates

further contribute to handling problems while formulating a dosage form. This also leads to problems of content uniformity in the dosage forms and reproducibility of dissolution profile.
Therefore, the present invention provides a method of preparing solid oral dosage forms of ziprasidone with finer particle size which exhibit good dissolution properties at physiological pH.
Summary of the Invention
In one general aspect, it relates to a solid oral dosage form comprising ziprasidone having a particle size D90 less than or equal to 10 urn and colloidal silicon dioxide in a weight ratio 1: 0.1 to 1:1.
In another general aspect, it relates to a process for preparing a solid oral dosage form comprising ziprasidone having a particle size D90 less than or equal to 10 urn and colloidal silicon dioxide in a weight ratio 1: 0.1 to 1:1; wherein the process comprises blending ziprasidone with colloidal silicon dioxide; optionally with other pharmaceutically acceptable excipient, optionally granulating the blend and formulating into a solid oral dosage form.
In another general aspect, it relates to a method of treating a psychotic condition in a human wherein the method comprises administering to the human in need thereof a solid oral dosage form comprising ziprasidone having a particle size D90 less than or equal to 10 urn and colloidal silicon dioxide in a weight ratio 1: 0.1 to 1:1.
In another general aspect, it relates to a solid oral dosage form comprising ziprasidone having a particle size D90 less than or equal to 3 urn and colloidal silicon dioxide in a weight ratio of 1:1.
In another general aspect, it relates to a process for preparing a solid oral dosage form comprising ziprasidone having a particle size D90 less than or equal to 10μm and colloidal silicon dioxide in a weight ratio 1: 0.1 to 1:1; wherein the process comprises blending ziprasidone with colloidal silicon dioxide; optionally with other pharmaceutically acceptable excipient, optionally granulating the blend by wet or dry granulation and formulating into a solid oral dosage form.
Detailed Description of the Invention
The term "ziprasidone" as used herein includes ziprasidone free base and pharmaceutically acceptable salts arid hydrates thereof. Suitable salt include hydrochloride salt and hydrates thereof. The amount of ziprasidone in the solid oral dosage form is intended to provide a unit therapeutic dose which can be from about 5mg to about 500mg; particularly about 10mg to about 100mg.

The notation D90 as used herein means that 90% of the particles have particle size less than a particular range mentioned. D90 less than 10 urn means 90% of the particles have particle size less than 10 urn. The particle size analysis has been measured by Malvern light scattering. Ziprasidone particles have particle size D90 less than 10 urn; particularly less than 5 urn; more particularly less than 3 urn.
Ziprasidone having these defined particle size is found to be very fluffy and tends to form agglomerate which are difficult to break into unit particles. Without wishing to be bound by theory, the agglomeration of Ziprasidone particles can be due to surface charges. Colloidal silicon dioxide when mixed with these agglomerate tends to neutralize the surface charges from the particles which then de-segregate into individual particles, with colloidal sillicon dioxide acting as a drug carrier. The high surface area of colloidal sillicon dioxide is an added advantage in its role as a drug carrier. The ziprasidone-colloidal silicon dioxide mixture can then be easily processed into desired dosage form following conventional formulation methodology.
Colloidal silicon dioxide is generally used as a glidant to improve the flow of powders while making dosage forms like tablets or granules. Colloidal silicon dioxide is usually added to a final blend prior to compression. It is available under several brand names like AEROSIL® and CAB-O-SIL®. When mixed with Ziprasidone, the ratio by weight of Ziprasidone to colloidal silicon dioxide is 1:0.1 to 1:1. Within the ratio, it has been found that on increasing the amount of colloidal silicon dioxide w.r.t. Ziprasidone, a graded enhancement in dissolution is observed. Further increasing the amount of colloidal silicon dioxide to more than 1:1 by weight of Ziprasidone results in handling problems due to significant decrease in bulk density.
In addition to Ziprasidone and colloidal silicon dioxide, the solid oral dosage form may contain other pharmaceutical excipients such as fillers, binders, disintegrants, glidant and lubricant.
The filler may be selected from microcrystalline cellulose, mannitol, sucrose, lactose, dextrose, calcium carbonate, sorbitol and their combinations and the like. The filler may be present in an amount of about 15% to about 80%, particularly form about 30% to 70% by weight of the solid oral dosage form.
The binder may be selected from polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch and starch based binders, gelatin, gums and the like. The binder may be mixed with other excipients or added as granulating liquid dissolved or dispersed in a suitable solvent. The binder solution/dispersion can be prepared in aqueous or non-aqueous solvents such as water, ethanol, isopropyl alcohol or mixtures thereof. The binder may

be present in an amount of about 0.1% to about 10%, particularly from about 1% to about 5% by weight of the solid oral dosage form.
The disintegrant may be selected from crospovidone, croscarmellose sodium, starch, hydroxypropylcellulose, gums, sodium starch glycolate and the like. The disintegrant may be present in an amount of about 1% to about 40%, particularly from about 2% to about 20% by weight of the dosage form.
The lubricants and glidants may be selected from talc, colloidal silicon dioxide, magnesium stearate, stearic acid and sodium stearyl fumarate. These may be present in an amount of about 0.1% to about 2% by weight of the dosage form.
The solid oral dosage form as defined herein may be in the form of tablets, caplets and granules that can be filled in capsules or sachets. Particularly suitable are granules as these can be easily processed into other dosage forms like tablets and capsules.
The granules may be prepared by conventional procedures like wet granulation and dry granulation. In wet granulation ziprasidone may be mixed with colloidal silicon dioxide and then mixed with one or more of other pharmaceutical excipients like filler, binder, disintegrant and granulated with a granulating liquid or a binder solution, drying and sizing the granules. Optionally, the granules may be compressed into tablets using appropriate tooling. Alternatively, the dried granules can be filled into hard gelatin capsules.
Dry granulation would involve mixing ziprasidone with colloidal silicon dioxide. The resultant blend is subsequently transferred to a roller compactor for compaction in a known manner. The roller speed, roller gap width and force of compaction are then adjusted and the blend is fed through the roller compactor. The typical force and other conditions can be easily adjusted by the skilled in the art. For example, the compaction pressure may be between 25 to 120 bar or typically between 80 to 120 bar. For maintaining the steady output of the compact material from the roller compactor, the rollers may be rotated at a speed of between 1 to 20 rpm, particularly between 2 to 15 rpm or more particularly between 3 to 9 rpm. When in contact with the counter rotating rollers of the roller compactor, the compression force imparted on the blend by rollers converts the powdered form into a ribbon or compaction sheet. This compact sheet is fed to a mill, such as an oscillating mill, fitted with a screen. The screen can be selected with variable hole diameters depending upon the size of the granules required. After passing through the mill and the screen, the compact is converted into granules of the desired particle size distribution. The granules can also be recompacted to attain desired bulk density and processed again. The granules obtained as above may be filled into capsules or packed in sachet. The granules can

also be mixed with one or more of pharmaceutically acceptable excipients and compressed into tablets.
In one aspect of the process, direct compression may be followed for preparing a tablet by mixing ziprasidone and colloidal silicon dioxide, further mixing the blend with one or more of filler, binder, disintegrant, lubricant and glidant and compressing into tablet using appropriate tooling.
In one embodiment, the solid oral dosage form comprising ziprasidone may be prepared by blending ziprasidone and colloidal silicon dioxide in a non-shear blender; lubricating the above blend with a lubricant; compacting the blend using a roller compactor; milling the compacts into granules of appropriate size using oscillating granulator; lubricating the sized granules with a lubricant and filling into hard gelatin capsules.
In another embodiment, the solid oral dosage form comprising ziprasidone may be prepared by blending ziprasidone and colloidal silicon dioxide in a non-shear blender; lubricating the above blend with a lubricant; compacting the blend using a roller compactor; milling the compacts into granules of appropriate size using oscillating granulator; mixing the sized granules with filler and further lubricating the blend with a lubricant and filling into hard gelatin capsules.
In still another embodiment, the solid oral dosage form comprising ziprasidone may be prepared by blending ziprasidone and colloidal silicon dioxide in a suitable blender; optionally mixing one or more of pharmaceutically acceptable excipients; and granulating with a binder solution; drying the granules; lubricating the dried granules and filling into hard gelatin capsules.
In another embodiment, the solid oral dosage form comprising ziprasidone may be prepared by blending ziprasidone and colloidal silicon dioxide in a suitable blender and granulating with a binder solution; drying the granules; mixing the sized granules with filler and further lubricating the blend with a lubricant and filling into hard gelatin capsules.
In one embodiment, the solid oral dosage form comprising ziprasidone may be prepared by blending ziprasidone and colloidal silicon dioxide in a non-shear blender; lubricating the above blend with a lubricant; compacting the blend using a roller compactor; milling the compacts into granules of appropriate size using oscillating granulator; lubricating the sized granules with a lubricant and compressing into a tablet using appropriate tooling.
In another embodiment, the solid oral dosage form comprising ziprasidone may be prepared by blending ziprasidone and colloidal silicon dioxide in a non-shear blender; lubricating the above

blend with a lubricant; compacting the blend using a roller compactor; milling the compacts into granules of appropriate size using oscillating granulator; mixing the sized granules with one or more of filler, disintegrant and glidant and further lubricating the blend with a lubricant and compressing into a tablet.
In another embodiment, the solid oral dosage form comprising ziprasidone may be prepared by blending ziprasidone and colloidal silicon dioxide in a suitable blender and granulating with a binder solution; drying the granules; mixing the sized granules with one or more of filler; disintegrant, glidant and further lubricating the blend with a lubricant and compressing into tablet using appropriate tooling.
In yet another embodiment, the solid oral dosage form comprising ziprasidone may be prepared by blending ziprasidone and colloidal silicon dioxide in a suitable blender; lubricating the above blend with a lubricant; compacting the blend by slugging; milling the compacts into granules of appropriate size using oscillating granulator; lubricating the sized granules with a lubricant and filling into hard gelatin capsules.
The invention described herein is further illustrated by the following examples but these should not be construed as limiting the scope of the invention.
EXAMPLES
(Table Removed)

Procedure:
Ziprasidone hydrochloride and magnesium stearate were blended in a non-shear blender. The blend was compacted with a roller compactor. The compacts were milled into granules using oscillating granulator. The granules were recompacted with a roller compactor and the compacts thus formed were milled using Quadro Comill. The granules were filled in hard gelatin capsules.
EXAMPLES 2-4
(Table Removed)

Procedure:
Ziprasidone hydrochloride and colloidal silicon dioxide were sifted and blended in a non-shear blender. The blend was lubricated with magnesium stearate. The lubricated blend was compacted using a roller compactor. The compacts were milled into granules using oscillating granulator. The granules were recompacted with a roller compactor and the compacts thus formed were milled into granules of appropriate size using Quadro Comill. The granules were filled in hard gelatin capsules.
Alternatively, examples 2-4 can have extragranular excipients, either compacted or uncompacted, for improvement in flow and other process parameters. An example to this effect is given below as Example 5.
EXAMPLE 5
(Table Removed)

Procedure:
Ziprasidone hydrochloride and colloidal silicon dioxide were sifted and blended in a non-shear blender. The blend was lubricated with magnesium stearate. The lubricated blend was compacted using a roller compactor. The compacts were milled into granules using oscillating granulator. The granules were recompacted with a roller compactor and the compacts thus formed were milled into granules of appropriate size using Quadro Comill. Separately, Lactose, and a portion of microcrystalline cellulose were blended in a non-shear blender and lubricated with magnesium stearate. The lubricated blend was compacted using a roller compactor. The compacts were milled into granules using oscillating granulator. The granules were mixed with Ziprasidone containing granules and blended with remaining microcrystalline cellulose and magnesium stearate and filled into hard gelatin capsules.
Table 1: Dissolution profiles of the capsules was measured in a USP type II dissolution apparatus, at 75 rpm in 900ml of 0.05M Phosphate buffer with 2% sodium lauryl sulphate.
(Table Removed)

As it can be seen form comparative example and example 1, in which ziprasidone hydrochloride has particle size D90 16 μm and D90 3 urn respectively, there is appreciable decrease in the % drug release of ziprasidone hydrochloride in spite of using finer particle size. However, from examples 2-5, it can be appreciated that the dissolution is markedly improved when colloidal silicon dioxide is mixed with ziprasidone hydrochloride.

WE CLAIM:
1. A solid oral dosage form comprising ziprasidone having a particle size D90 less than or
equal to 10 urn and colloidal silicon dioxide in a weight ratio 1: 0.1 to 1:1 optionally
other pharmaceutical excipients selected from filler, binder, disintegrant, glidant and
lubricant.
2. The solid dosage form according to claim 1 wherein ziprasidone has D90 less than or
equal to 3 urn.
3. The solid dosage form according to claim 1 wherein ziprasidone and colloidal silicon
dioxide are present in a weight ratio of 1:1.
4. The solid oral dosage form according claims 1 wherein the solid oral dosage form is
selected from tablet, capsule, caplet and granules.
5. The solid dosage form according to claim 1 wherein the dosage form is prepared by a
process comprising the steps of:

a) blending ziprasidone with colloidal silicon dioxide;
b) optionally blending the blend with other pharmaceutically acceptable excipient,
c) optionally granulating the blend by wet or dry granulation,
d) formulating into a solid oral dosage form.

6. The solid dosage form according to claim 5 wherein the wet granulation is done by a
binder solution or with solvent.
7. The solid dosage form according to claim 5 wherein dry granulation is done by roller
compaction

8. The solid dosage form according to claim 5 wherein dry granulation is done by
slugging.
9. The solid dosage form according to claim 1 for treatment of a psychotic condition in a
human.
10. The solid dosage form comprising Ziprasidone as herein described and illustrated.