DESC:BACKGROUND OF THE INVENTION
Paliperidone palmitate is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives with the chemical name (9RS)-3-[2-[4(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2-a]pyrimadin-9-yl hexadecanoate. Its molecular formula is C39H57FN4O4 and its molecular weight is 664.89 g/mol. The structural formula is:

The injection composition of paliperidone palmitate is available commercially and marketed under the brand name of INVEGA SUSTENNA® in the US market. It is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 25mg, 50mg, 75mg, 100mg, and 150mg of paliperidone. The composition is provided in a prefilled syringe (cyclic-olefin-copolymer) with a plunger stopper and tip cap (bromobutyl rubber).
Impurities in any active pharmaceutical ingredient (“API”) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form of the API. Impurities and degradation products arising from manufacturing process and/or storage of paliperidone palmitate or its composition were reported and characterized. Potential impurities in composition containing them may include product impurities, process impurities and product by process impurities. The excipients used in the preparation of the pharmaceutical composition, milling bodies used during the processing, size reduction and sterilization of active pharmaceutical ingredient may also produce unidentified impurities in the product.
It is well known in the art that, for human administration, safety considerations require the establishment, by national and international regulatory authorities, of very low limits for identified, but toxicologically uncharacterized impurities, before a product is commercialized.
Hence there is an established need for a simple, industrially feasible, inexpensive, scalable and safe-to-handle process for the preparation of pharmaceutical composition comprising API.
The use of highly inert, robust and pure ceramic materials results in minimum contamination from the beads but many parameters affect on metallic impurity such as milling speed, bead volume and beads sterilization. Beads sterilization is important parameter to control the metallic impurity.
Efforts to reduce the level of undesired contaminants introduced into milled particles by milling media have been disclosed.
US Patent No. 5,534,270 discloses a method of preparing sterilized nanoparticulate crystalline drug particles using rigid grinding media having an average particle size less than 3mm. Wet grinding of the drug substance was done to maintain an effective average particle size of less than 400nm using zirconium silicate beads, zirconium oxide stabilized with magnesia, 95% ZrO stabilized with yttrium, or glass beads.
US Patent No. 5,704,556 discloses a media milling process for producing colloidal particles using ceramic beads of zircon, glass, and yttrium toughened zirconium oxide less than 100 microns in diameter in which the diameter of the ceramic milling media beads is no more than about one hundred times the average particle size of the feedstock particles.
The inventors of the invention surprisingly found that by using the novel method for the sterilization of yttrium stabilized zirconium beads, it is possible to control the metallic impurity from beads in the pharmaceutical composition of paliperidone palmitate. In addition, the inventors of the invention found that the pharmaceutical composition comprising paliperidone palmitate prepared by a process, wherein the process yields the composition having less than about 0.2 ppm of zirconium and yttrium impurities.

SUMMARY OF THE INVENTION
The invention provides a pharmaceutical composition comprising paliperidone palmitate having less than about 0.2ppm of zirconium and yttrium impurities prepared by a novel process.
In one general aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising paliperidone palmitate having less than about 0.2 ppm of zirconium and yttrium contaminants, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b).

In another general aspect of the invention, there is provided a process for sterilizing yttrium stabilized zirconium beads comprising the steps of:
i) cleaning the yttrium stabilized zirconium beads using a solvent having temperature of less than about 60°C,
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i) using a solvent having temperature of less than about 60°C,
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) at less than about 60°C for about 1 hr to about 48 hr and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to sterilization.

In another general aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising paliperidone palmitate having less than about 0.2 ppm of zirconium and yttrium contaminants, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b),
wherein the process of sterilizing yttrium stabilized zirconium beads comprises the steps of:
i) cleaning the yttrium stabilized zirconium beads using a solvent having temperature of less than about 60°C,
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i) using a solvent having temperature of less than about 60°C,
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) at less than about 60°C for about 1 hr to about 48 hr and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to sterilization.

In another general aspect of the invention, there is provided a process for sterilizing yttrium stabilized zirconium beads comprising the steps of:
i) cleaning the yttrium stabilized zirconium beads using water for injection or deionized water having temperature of less than about 60°C,
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i) using water for injection or deionized water having temperature of less than about 60°C,
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) at less than about 60°C for about 1 hr to about 48 hr and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to dry heat sterilization.

In another general aspect of the invention, there is provided a process for sterilizing yttrium stabilized zirconium beads comprising the steps of:
i) cleaning the yttrium stabilized zirconium beads using water for injection or deionized water having temperature of less than about 60°C,
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i) using water for injection or deionized water having temperature of less than about 60°C,
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) at less than about 60°C for about 1 hr to about 48 hr and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to steam sterilization.

In another general aspect of the invention, there is provided a process for sterilizing yttrium stabilized zirconium beads comprising the steps of:
i) cleaning the yttrium stabilized zirconium beads using water for injection or deionized water having temperature of less than about 60°C,
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i) using water for injection or deionized water having temperature of less than about 60°C,
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) at less than about 60°C for about 1 hr to about 48 hr and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to dry heat sterilization followed by steam sterilization.

The drying of rinsed yttrium stabilized zirconium beads of step (ii) can be done at less than about 55°C for about 1 hr to about 48 hr. Preferably at less than about 50°C, more preferably at less than about 45°C, more preferably at less than about 40°C for about 1 hr to about 48 hr.

In another general aspect of the invention, there is provided process for preparing a pharmaceutical composition comprising paliperidone palmitate, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b), wherein the process is carried out aseptically.

In another general aspect of the invention, the sterilization of yttrium stabilized zirconium beads is carried out by dry heat sterilization at 120°C to 400°C for about 2 hr to about 10 hr.

In another general aspect of the invention, the sterilization of yttrium stabilized zirconium beads is carried out by dry heat sterilization at 250°C for about 3 hr followed by steam sterilization at 121°C and 15 psi for about 30 min.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a pharmaceutical composition comprising paliperidone palmitate, wherein the composition contains less than 0.2 ppm of zirconium and yttrium contaminants. By using the sterilized yttrium stabilized zirconium beads, it is possible to control the metallic impurity in the pharmaceutical composition.
The terms 'aseptic' and 'sterile' are used herein interchangeably and referes to 'free from micro-organisms'

As used herein, “impurity” and “contaminants” are used interchangeably and refers to undesired metallic contents present in a pharmaceutical composition.

The term “cleaning” as used herein is referes to mean the step in which the dirt, including dust, stains, bad smells, and clutter on surfaces are removed. The cleaning agents include but not limited to liquids (aqueous solvents, organic solvents etc), powders, sprays, granules or combination thereof.

The term “rinsing” as used herein referes to washing with clean aqueous solvents to remove soap, detergent, dirt, or impurities.

The term “sterilization” as refers to a dry heat sterilization or steam sterilization or dry heat sterilization followed by steam sterilization.

The term "wet milling" as used herein refers to the grinding of materials with a sufficient quantity of a liquid to form slurry.

The “milling bodies” in the method of the present invention, preferably are chemically inert and rigid. Preferably, the milling bodies are provided in the form of one or more of beads, balls or spheres.

In one general aspect of the invention, there is provided a sterile pharmaceutical composition comprising paliperidone palmitate, polysorbate, polyethylene glycol, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide and water for injection, wherein the composition comprising less than about 0.2 ppm of zirconium and yttrium contaminants.

In another general aspect of the invention, there is provided a process for preparing pharmaceutical composition comprising paliperidone palmitate having less than about 0.1 ppm of zirconium and yttrium contaminants, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b).

In another general aspect of the invention, there is provided a process for preparing a sterile pharmaceutical composition comprising paliperidone palmitate having less than about 0.05 ppm of zirconium and yttrium contaminants, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b).

In another general aspect of the invention, there is provided a process for preparing pharmaceutical composition comprising paliperidone palmitate having less than about 0.2 ppm of zirconium and yttrium contaminants, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b),
wherein the process of sterilizing yttrium stabilized zirconium beads comprises the steps of:
i) cleaning the yttrium stabilized zirconium beads
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i)
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to sterilization.

In one general aspect of the invention, there is provided a process for preparing a sterile pharmaceutical composition comprising paliperidone palmitate, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b), wherein the process employs two types of milling bodies.

In an embodiment, a process for preparing pharmaceutical composition comprising paliperidone palmitate having less than about 0.2 ppm of zirconium and yttrium contaminants, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
d) subjecting the yttrium stabilized zirconium beads of step (c) to sterilization.

In another embodiment, a process for preparing pharmaceutical composition comprising paliperidone palmitate having less than about 0.2 ppm of zirconium and yttrium contaminants, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b),
wherein the process of sterilizing yttrium stabilized zirconium beads comprises the steps of:
i) cleaning the yttrium stabilized zirconium beads using solvent having temperature of less than about 60 °C,
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i) using solvent having temperature of less than about 60 °C,
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) at less than about 60 °C for about 1 hr to about 48 hr and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to sterilization.

In another embodiment, crystalline paliperidone palmitate used in the composition is in micronised form.

In another embodiment, the solvent used for cleaning or rinsing step is selected from water for injection, deionized water, organic solvent or combination thereof.

In another embodiment, the organic solvent used for cleaning step is isopropyl alcohol.

In another embodiment, the sterilization of yttrium stabilized zirconium beads is carried out by dry heat sterilization at 120 °C to 400 °C for about 1 hr to about 10 hr.

In another embodiment, the sterilization of yttrium stabilized zirconium beads is carried out by dry heat sterilization at 250°C for about 3 hr followed by steam sterilization at 121°C and 15 psi for about 30 min.

In another embodiment, the cleaning of yttrium stabilized zirconium beads is carried out by solvent having temperature of less than about 60°C.

In another embodiment, the cleaning of yttrium stabilized zirconium beads is carried out by water for injection having temperature of less than about 60°C.

In another embodiment, the cleaning of yttrium stabilized zirconium beads is carried out by deionized water having temperature of less than about 60°C.

In another embodiment, the cleaning of yttrium stabilized zirconium beads is carried out by organic solvent having temperature of less than about 60°C.

In another embodiment, the cleaning of yttrium stabilized zirconium beads is carried out by isopropyl alcohol having temperature of less than about 60°C.

In another embodiment, the cleaning of yttrium stabilized zirconium beads is carried out by isopropyl alcohol having temperature of less than about 50°C.

In another embodiment, the cleaning of yttrium stabilized zirconium beads is carried out by isopropyl alcohol having temperature of less than about 30°C.

In another embodiment, the rinsing of yttrium stabilized zirconium beads is carried out by water for injection having temperature of less than about 60°C.

In another embodiment, the rinsing of yttrium stabilized zirconium beads is carried out by deionized water having temperature of less than about 60°C.

In another embodiment, the process yields the composition having less than about 0.2 ppm of zirconium and yttrium contaminants. Preferably, the process yields the contaminants level less than about 0.18 ppm, more preferably less than about 0.16 ppm, more preferably less than about 0.14 ppm, more preferably less than about 0.12 ppm, more preferably less than about 0.10 ppm.

In another embodiment, process yields the composition having less than about 0.20 ppm of yttrium contaminants and less than about 0.20 ppm of zirconium contaminants.

In another embodiment, drying of rinsed yttrium stabilized zirconium beads is carried out at less than about 60°C temperature for about 1 hr to about 48 hr.

In another embodiment, drying of rinsed yttrium stabilized zirconium beads is carried out at less than about 50°C temperature for about 1 hr to about 48 hr.

In another embodiment, drying of rinsed yttrium stabilized zirconium beads is carried out at less than about 40°C temperature for about 1 hr to about 48 hr.

In another embodiment, drying of rinsed yttrium stabilized zirconium beads is carried out at less than about 60°C temperature for about 10 hr to about 24 hr.

In another embodiment, drying of rinsed yttrium stabilized zirconium beads is carried out at less than about 50°C temperature for about 12 hr to about 26 hr.

In another embodiment, drying of rinsed yttrium stabilized zirconium beads is carried out at less than about 40°C temperature for about 15 hr to about 40 hr.

In another embodiment, drying of rinsed yttrium stabilized zirconium beads is carried out at less than about 30°C temperature for about 20 hr to about 48 hr.

In another embodiment, the wet milling for micronizing paliperidone palmitate is done by two types of milling bodies.

In another embodiment, the size of first type of milling bodies ranges from 0.1mm to 2.5mm.

In another embodiment, the size of second type of milling bodies ranges from 150µm to 450µm.

In another embodiment, the size of yttrium stabilized zirconium beads ranges from 0.1mm to 2mm.

In another embodiment, the first milling bodies reduce the particle size of paliperidone palmitate to an effective average particle size of less than about 30µm. Preferably, the particle size is less than about 20µm and more preferably less than about 15µm.

In another embodiment, the particle size of paliperidone palmitate is reduced by the second milling bodies upto less than 5µm. Preferably, the particle size is reduced upto less than 2µm and more preferably reduced upto less than 1.5µm.

In another embodiment, the pharmaceutical composition comprises crystalline form of paliperidone palmitate.

In another embodiment, the pharmaceutical composition comprises less than about 10 µ to less than about 7 µ of crystalline paliperidone palmitate.

In another embodiment, the pharmaceutical composition comprises less than about 1.0 µ to less than about 1.4 µ of crystalline paliperidone palmitate.

In another embodiment, the pharmaceutical composition comprising a paliperidone palmitate in an amount about 150mg/ml to about 160mg/ml, polysorbate in an amount about 6mg/ml to about 18mg/ml, polyethylene glycol in an amount about 20mg/ml to about 40mg/ml, citric acid monohydrate in an amount about 2.5mg/ml to about 7.5mg/ml, disodium hydrogen phosphate anhydrous in an amount about 2.5mg/ml to about 7.5mg/ml, sodium dihydrogen phosphate monohydrate in an amount about 1.25mg/ml to about 7mg/ml, sodium hydroxide in an amount about 1mg/ml to about 6mg/ml, and water for injection, wherein the composition is prepared by a process comprising steps of:
a) mixing paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b), wherein the process yields less than about 0.2 ppm of zirconium and yttrium contaminants.

In another embodiment, the pharmaceutical composition comprising paliperidone palmitate in an amount about 150mg/ml to about 160mg/ml, polysorbate in an amount about 6 mg/ml to about 18mg/ml, polyethylene glycol in an amount about 20mg/ml to about 40mg/ml, citric acid monohydrate in an amount about 2.5mg/ml to about 7.5mg/ml, disodium hydrogen phosphate anhydrous in an amount about 2.5mg/ml to about 7.5mg/ml, sodium dihydrogen phosphate monohydrate in an amount about 1.25mg/ml to about 7mg/ml, sodium hydroxide in an amount about 1mg/ml to about 6mg/ml, and water for injection wherein the composition is prepared by a process comprising steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b),
wherein the process of sterilizing yttrium stabilized zirconium beads comprises the steps of:
i) cleaning the yttrium stabilized zirconium beads
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i)
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to sterilization, wherein the process yields the composition having less than about 0.2 ppm of zirconium and yttrium contaminants.

In another embodiment, the pharmaceutical composition comprising paliperidone palmitate in an amount about 150mg/ml to about 160mg/ml, polysorbate 20 in an amount about 6 mg/ml to about 18mg/ml, polyethylene glycol in an amount about 20mg/ml to about 40mg/ml, citric acid monohydrate in an amount about 2.5mg/ml to about 7.5mg/ml, disodium hydrogen phosphate anhydrous in an amount about 2.5mg/ml to about 7.5mg/ml, sodium dihydrogen phosphate monohydrate in an amount about 1.25mg/ml to about 7mg/ml, sodium hydroxide in an amount about 1mg/ml to about 6mg/ml, and water for injection wherein the composition is prepared by a process comprising steps of:
a) adding polysorbate 20 in water for injection and mixing it until dissolved and further sterilized by filtration to form a polysorbate solution.
b) mixing sterile grade crystalline paliperidone palmitate in step (a) to form a premix,
c) sterilizing the yttrium stabilized zirconium beads, and
d) subjecting the premix of step (b) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (c), milled aseptically in the grinding chamber until the desired particle size reached to form a milled suspension.
e) citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved in water for injection and sterilized by filtration.
f) aseptically transferred sterile vehicle of step (e) into the milled suspension of step (d) and further mixed until homogeneous to form a final suspension.
g) final suspension filled aseptically into sterile syringes, wherein the process of sterilizing yttrium stabilized zirconium beads comprises the steps of:
i) cleaning the yttrium stabilized zirconium beads
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i)
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to sterilization, wherein the process yields the composition having less than about 0.2 ppm of zirconium and yttrium contaminants.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1: Pharmaceutical composition comprising Paliperidone Palmitate
Table 1
Ingredients Qty/mL
(mg)
Paliperidone Palmitate 156.00 mg
Polysorbate 20 NF 12.00 mg
Polyethylene glycol 4000 NF 30.00 mg
Citric acid monohydrate USP 5.00 mg
Disodium hydrogen phosphate anhydrous USP 5.00 mg
Sodium dihydrogen phosphate monohydrate USP 2.50 mg
Sodium hydroxide NF 2.84 mg
Water for Injection USP q.s. to 1.0 mL

Manufacturing Process:
Water for injection was transferred into a SS container. Polysorbate 20 was added and dissolved by mixing. The solution was sterilized by filtration through a sterile 0.2 µm filter into a sterilized SS container. Paliperidone palmitate (micronized, D90 < 10 micron) was dispersed into the solution and mixed until homogeneous. The suspension was milled aseptically in the grinding chamber using sterilized yttrium stabilized Zirconium beads as grinding media until the desired particle size was reached. Several variations were carried out as represented in table 3. Water for injection was transferred into a separate SS container, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved. This solution was sterilized by filtration through a sterile 0.2 µm filter and transferred aseptically into the milled suspension. The final suspension was mixed until homogeneous. The suspension was filled aseptically into sterile syringes. The target dose volume was between 0.25 ml and 1.50 ml depending on the dose needed.

Example 2: Pharmaceutical composition comprising Paliperidone Palmitate
Table 2
Ingredient Qty/mL
(mg)
Paliperidone Palmitate 312.00 mg
Polysorbate 20 NF 10.00 mg
Polyethylene glycol 4000 NF 75.00 mg
Citric acid monohydrate USP 7.50 mg
Sodium dihydrogen phosphate monohydrate USP 6.00 mg
Sodium hydroxide NF 5.40 mg
Water for Injection USP q.s. to 1.0 mL

Manufacturing Process:
Water for injection was transferred into a SS container. Polysorbate 20 was added and dissolved by mixing. The solution was sterilized by filtration through a sterile 0.2 µm filter into a sterilized SS container. Paliperidone palmitate (D90 < 50 micron) was dispersed into the solution and mixed until homogeneous. The suspension was milled aseptically in the grinding chamber using sterilized yttrium stabilized Zirconium beads (Source: TOSOH) as grinding media until the desired required particle size was reached. Water for injection was transferred into a separate SS container, citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved. This solution was sterilized by filtration through a sterile 0.2 µm filter and transferred aseptically into the milled suspension. The final suspension was mixed until homogeneous. The suspension was filled aseptically into sterile syringes

Example 3: Effect of Sterilization: The results for sterilization as obtained are mentioned in Table 3.

Table 3
Example
Milling Parameters
(Feed Volume) Sterilization Mode Elemental Impurities (ppm)
Zirconium Yttrium
Invega Sustenna® NA NA 0.02 0.01
Invega Sustenna® NA NA 0.03 0.01
Example I 500 rpm 60% Bead Dry bead /Dry heat sterilization 0.02 0.01
Example I
500 rpm 60% Bead Dry bead/ Steam Sterilization 0.09 0.01
Example I 500 rpm 60% Bead Wet bead/ Dry heat sterilization 0.46 0.30
,CLAIMS:1. A pharmaceutical composition comprising paliperidone palmitate having less than about 0.2 ppm of zirconium and yttrium contaminants, said composition is prepared by a process comprising steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b), wherein the process yields the composition.

2. The pharmaceutical composition of claim 1, wherein the composition contains less than about 0.12 ppm of zirconium and yttrium contaminants.

3. The pharmaceutical composition of claim 1, wherein the composition further comprises pharmaceutical acceptable excipients selected from the group consisting of citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000, water for injection or combination thereof.

4. A process for preparing pharmaceutical composition comprising paliperidone palmitate having less than about 0.2ppm of zirconium and yttrium contaminants, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b), wherein the process of sterilizing yttrium stabilized zirconium beads comprises the steps of:
i) cleaning the yttrium stabilized zirconium beads using a solvent having temperature of less than about 60°C,
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i) using a solvent having temperature of less than about 60°C,
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) at less than about 60°C for about 1 hr to about 48 hr, and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to sterilization.

5. The process for preparing the pharmaceutical composition of claim 4, wherein the solvent used for the cleaning step is selected from water for injection, deionized water, organic solvent or combination thereof.

6. The process for preparing the pharmaceutical composition of claim 4, wherein the solvent used for rinsing step is selected from water for injection, deionized water or combination thereof.

7. A pharmaceutical composition comprising paliperidone palmitate in an amount about 150mg/ml to about 160mg/ml, polysorbate in an amount about 6mg/ml to about 18mg/ml, polyethylene glycol in an amount about 20mg/ml to about 40mg/ml, citric acid monohydrate in an amount about 2.5mg/ml to about 7.5mg/ml, disodium hydrogen phosphate anhydrous in an amount about 2.5mg/ml to about 7.5mg/ml, sodium dihydrogen phosphate monohydrate in an amount about 1.25mg/ml to about 7mg/ml, sodium hydroxide in an amount about 1mg/ml to about 6mg/ml, and water for injection, wherein the composition is prepared by a process comprising steps of:
a. mixing paliperidone palmitate in a sterile vehicle to form a premix,
b. sterilizing the yttrium stabilized zirconium beads, and
c subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b), wherein the process yields less than about 0.2 ppm of zirconium and yttrium contaminants.

8. A pharmaceutical composition comprising paliperidone palmitate in an amount about 150mg/ml to about 160mg/ml, polysorbate in an amount about 6 mg/ml to about 18mg/ml, polyethylene glycol in an amount about 20mg/ml to about 40mg/ml, citric acid monohydrate in an amount about 2.5mg/ml to about 7.5mg/ml, disodium hydrogen phosphate anhydrous in an amount about 2.5mg/ml to about 7.5mg/ml, sodium dihydrogen phosphate monohydrate in an amount about 1.25mg/ml to about 7mg/ml, sodium hydroxide in an amount about 1mg/ml to about 6mg/ml, and water for injection, wherein the composition is prepared by a process comprising steps of:
a) mixing crystalline paliperidone palmitate in a sterile vehicle to form a premix,
b) sterilizing the yttrium stabilized zirconium beads, and
c) subjecting the premix of step (a) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (b), wherein the process of sterilizing yttrium stabilized zirconium beads comprises the steps of:
i) cleaning the yttrium stabilized zirconium beads
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i)
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to sterilization,
wherein the process yields the composition having less than about 0.2 ppm of zirconium and yttrium contaminants.

9. A pharmaceutical composition comprising paliperidone palmitate in an amount about 150mg/ml to about 160mg/ml, polysorbate 20 in an amount about 6 mg/ml to about 18mg/ml, polyethylene glycol in an amount about 20mg/ml to about 40mg/ml, citric acid monohydrate in an amount about 2.5mg/ml to about 7.5mg/ml, disodium hydrogen phosphate anhydrous in an amount about 2.5mg/ml to about 7.5mg/ml, sodium dihydrogen phosphate monohydrate in an amount about 1.25mg/ml to about 7mg/ml, sodium hydroxide in an amount about 1mg/ml to about 6mg/ml, and water for injection wherein the composition is prepared by a process comprising steps of:
a) adding polysorbate 20 in water for injection and mixing until dissolved and further sterilized by filtration to form a polysorbate solution.
b) mixing sterile grade crystalline paliperidone palmitate in step (a) to form a premix,
c) sterilizing the yttrium stabilized zirconium beads, and
d) subjecting the premix of step (b) to wet milling in the presence of sterilized yttrium stabilized zirconium beads of step (c), milled aseptically in the grinding chamber until the desired particle size reached to form a milled suspension.
e) citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved in water for injection and sterilized by filtration.
f) aseptically transferred sterile vehicle of step (e) into the milled suspension of step (d) and further mixed until homogeneous to form a final suspension.
g) final suspension filled aseptically into sterile syringes, wherein the process of sterilizing yttrium stabilized zirconium beads comprises the steps of:
i) cleaning the yttrium stabilized zirconium beads
ii) rinsing the cleaned yttrium stabilized zirconium beads of step (i)
iii) drying the rinsed yttrium stabilized zirconium beads of step (ii) and
iv) subjecting the yttrium stabilized zirconium beads of step (iii) to sterilization, wherein the process yields the composition having less than about 0.2 ppm of zirconium and yttrium contaminants.