Claims:
We claim,

1) A pharmaceutical oral solution comprises of aripiprazole and malic acid with improved stability, solubility and bioavailability with acidic pH.
2) A pharmaceutical oral solution as claimed in claim 1, wherein pH of formulation is between 3 and 3.5.
3) A pharmaceutical oral solution as claimed in claim 1, wherein other pharmaceutically accepted excipients are selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer and flavoring agent and sweetness/flavor enhancing agent.
4) A pharmaceutical oral solution as claimed in claim 3, wherein vehicle is purified water.
5) A pharmaceutical oral solution as claimed in claim 3, wherein co-solvent system comprises of combination of glycerin and propylene glycol.
6) A pharmaceutical oral solution as claimed in claim 3, wherein chelating agent is disodium edetate.
7) A process for preparation of a pharmaceutical oral solution of aripiprazole
comprises of following steps:
a) Dissolution of aripiprazole, methyl 4-hydroxybenzoate and propyl 4-hydroxybenzoate in co-solvent propylene glycol.
b) Addition of glycerine solution is to solution of step a).
c) Dissolution of fructose, sucrose and malic acid in Purified water.
d) Addition of solution of step b) to solution of step c).
e) Adjusted of pH of solution of step d) between 2.0-4.0
f) Addition of flavoring agent to solution of step e).
g) Adjustment of volume of solution of step f) to up to batch size with purified water.
h) Filling of solution of step g) is in amber colored PET bottles and capped using PP CR closure.
, Description:Field of invention
The present invention pertains to pharmaceutical composition of aripiprazole. In particular, present invention relates to oral solution of aripiprazole improved solubility, stability and bioavailability of active ingredient, aripiprazole and process for preparation of the same.

Background of invention
Atypical antipsychotics are the class of compounds used to treat psychiatric conditions including schizophrenia, bipolar disorder, autism and major depressive disorder and preferred over typical antipsychotics because of fewer chances to cause extrapyramidal and motor control disabilities.
An atypical antipsychotic, aripiprazole act as partial agonist at D2 receptor and used for treatment of schizophrenia, bipolar disorder, depression and autism spectrum disorders.

EP1381367 discloses oral pharmaceutical solution of aripiprazole with suitable solvent system, one or more taste-enhancing/masking agents and one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid, wherein said solution has a pH from 2.5 to 4.5.
EP1933814 discloses stable nanoparticulate formulation of aripiprazole, or salts or derivatives of aripiprazole with improved bioavailability, faster rates of absorption and a faster onset of therapeutic effect, wherein an average effective particle size of aripiprazole is less than about 2000 nm and formulation contain at least one surface stabilizer which is useful for the treatment of diseases and disorders of the central nervous system, including mental diseases and disorders.
EP2170279 discloses an aripiprazole suspension and method of preparation of aripiprazole suspension, wherein mean particle size of aripiprazole is 1 to 10 µm.
EP2299983 discloses a pharmaceutical composition of an atypical antipsychotic drug with succinic acid, fumaric acid or a mixture of succinic acid and fumaric acid.
WO 2011107855 discloses sustained release oral liquid suspension dosage form of aripiprazole and method of its preparation. Oral liquid suspension comprises of sustained release pellets in which inert pellets are surrounded by seal coating. Drug layer comprises of active pharmaceutical ingredient with one or more pharmaceutically acceptable excipients surrounding seal coated inert pellets and this drug layer is surrounded by coating layer comprises of rate controlling polymer These prepared sustained release pellets are suspended with suitable suspending agen and other pharmaceutically acceptable excipients in a suspending media at a suitable pH.
WO2014059363 discloses oral solution formulation of aripiprazole which comprises ofglycerin, propylene glycol, a buffer, a sweetener, and a flavoring agent, wherein said pharmaceutical formulation does not comprise a sugar and preservative The pH of formulation is 4.3 or greater.
Although many dosage form of aripiprazole have been described in prior, present invention provides a stable oral solution of aripiprazole with a malic acid and other pharmaceutically acceptable excipients having improved solubility and bioavailability which further influence patient compliance, wherein pH of solution is 2.0 to 4.0.

Object of invention
The primary object of present invention is to provide oral pharmaceutical solution of aripiprazole with improved stability, solubility and bioavailability of active ingredient comprises of aripiprazole, malic acid and other pharmaceutically acceptable excipients, wherein pH of solution is 2.0 to 4.0. Another object of present invention is to provide oral solution having dose flexibility for patients who need special doses of the drug and have difficulties in swallowing oral dosage forms.
Still another object of present invention is to provide oral solution with improved taste having high patient compliance.
It is yet another object of present invention to provide process of preparation of oral solution of aripiprazole.

Summary of invention
The present invention relates to the oral solution of aripiprazole having improved stability, solubility and bioavaillibity of active ingredient, aripiprazole.
One aspect of present invention relates to oral solution of aripiprazole comprises of an active ingredient, aripiprazole and malic acid and other pharmaceutically acceptable ingredients selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring agent and sweetness/flavor enhancing agent wherein said formulation is with acidic pH, more particularly pH between 3 and 3.5.

Detail description of invention
Schizophrenia is a mental disorder that generally appears in late adolescence or early adulthood, however it can emerge at any time in life. It is one of many brain diseases that may include delusions, loss of personality (flat affect), confusion, agitation, social withdrawal, psychosis, and bizarre behavior.
An imbalance of dopamine, a neurotransmitter is involved in the onset of schizophrenia.
The mainstay of treatment is antipsychotic medication, which primarily suppresses dopamine receptor activity.
Atypical antipsychotics are preferred over typical antipsychotics because of fewer chances to cause severe side-effects such as extrapyramidal and motor control disabilities.
A carbostyril derivative, aripiprazole is an atypical antipsychotic which act as partial agonist at D2 receptor and used for treatment of schizophrenia, bipolar disorder, depression and autism spectrum disorders.
Chemically, aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)piperazine-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one. Aripiprazole has the following chemical structure:

Carbostyril compounds are influenced by temperature, air and humidity conditions, so aripiprazole has stability problems related to environmental and physical conditions when formulated in oral solution form and undergo structural degradation and chemical behaviour changes when get exposed to air and humidity. Because of this reasons stability of aripiprazole is not maintained to desired level when formulated in solution form and shelf life is decreased and requires presence of preservative which further enhances stability of aripiprazole in solution form.
It is an object of present invention is to provide oral pharmaceutical solution of aripiprazole with improved solubility, stability and bioavailability of active ingredient, aripiprazole and improved taste.
In the present invention a preferred embodiment, malic acid is used in formulation of aripiprazole. The main reason of using malic acid is it has characteristic such as low hygroscopicity, easy dissolution, taste enhancement, free flowing, non dusty, even particle size and overall tartness is smoother than other acids. Also malice acid can be used to adjust pH. In a preferred form of present invention with malic acid other excipients used can be selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring agent and sweetness/flavor enhancing agent.
Vehicles used in pharmaceutical formulations are mainly liquid bases which carries drugs and other excipients in dissolved or dispersed state. Pharmaceutical vehicles are of two types:
1) Aqueous vehicles
2) Oily vehicles
Aqueous vehicles can be selected from but not limited to purified water, hydro-alcoholic, polyhydric alcohols and buffers, while oily vehicles can be selected from vegetable oils, mineral oils, organic oily bases or emulsified bases.
Co-solvents are used to increase solubility of drugs that show low solubility in water. It is also used to improve viscosity, taste and flavor. Co-solvent system comprises of solvents selected from but not limited to propylene glycol, glycerin, alcohol, polyhydric alcohol and water for injection which is used alone or in combination.
Preservatives are included in pharmaceutical solutions to control the microbial bioburden of the formulation having broad spectrum of antimicrobial activity, must be chemically and physically stable over the shelf-life of the product and have low toxicity. Preservative can be selected from group but not limited to alcohol, benzyl alcohol, chlorbutol, chlorocresol, alkyl esters of paraben, phenol, phenyl ethanol, sodium benzoate, antimicrobial solvents like propylene glycol, chloroform.
.
Sweetener can be selected from but not limited to sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium and aspartame to impart sweetness to the formulation.
Chelating agent is used for drug stabilization, to maintain potency of active ingredients and to stabilize colors and flavors. Chelating agent can be selected from but not limited to citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid and trisodium edetate.
pH of the formulation can be controlled and optimize the physicochemical performance of the formulation by using base or buffer can be selected from but not limited to sodium acetate, sodium hydroxide, sodium citrate, sodium phosphate and disodium phosphate.
Flavoring agents are mainly use to increase the palatability and enhance the aesthetic qualities of the formulation. Flavoring agent can be selected but not limited to oil based flavoring agent such as essential oils including peppermint oil, orange oil, lemon oil etc.
Sweetness/flavor enhancing agent can be selected from but not limited to monoammonium glycyrrhizinate, fructose, and monosodium glutamate used to reduce the sharp bitter taste of medications.
In aspect of present invention, oral pharmaceutical solution of aripiprazole is formulated which comprises of an active ingredient, aripiprazole, malic acid and other excipients selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring agent and sweetness/flavor enhancing agent, wherein pH of formulation is maintained between 2.0 to 4.0, more particularly between 3 and 3.5.
Examples
The present invention can be described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the description or claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this disclosure.

For the composition of aripiprazole 1mg/ml, drug and excipients with its range are shown below in table:
No. Drug/ Excipients Quantity
(% w/w)
1 Aripiprazole 0.080
2 Propylene glycol 8.019
3 Glycerin 3.256
4 Malic acid 1.123
5 Methyl 4-hydroxybenzoate 0.144
6 Propyl 4-hydroxybenzoate 0.016
7 Fructose 16.038
8 Sucrose 32.077
9 Disodium edetate 0.080
10 Orange flavor 0.080
11 Sodium hydroxide 0.401
12 Purified water QS

The oral pharmaceutical solution of above composition is prepared by following method:-
a) Aripiprazole, methyl 4-hydroxybenzoate and propyl 4-hydroxybenzoate are dissolved in co-solvent propylene glycol.
b) Glycerine solution is added to solution of step a).
c) Fructose, sucrose and malic acid are dissolved in Purified water.
d) Solution of step b) is added to solution of step c).
e) pH of solution of step d) is adjusted between 2.0 to 4.0 using 20 %w/w sodium hydroxide.
f) Flavoring agent (orange flavor) is added to solution of step e).
g) Volume of solution of step f) is made up to batch size with purified water.
h) Solution of step g) is filled in amber colored PET bottles and capped using PP CR closure.