FIELD OF THE INVENTION

The present invention relates to a method of making aripiprazole pharmaceutical composition by wet granulation using organic solvent as granulating liquid.

BACKGROUND OF THE INVENTION

Aripiprazole is an atypical antipsychotic agent useful in the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar disorder and is disclosed in US 4,734,416 and US 5,006,528.

Aripiprazole is a carbostyril derivative and is chemically known as 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydrocarbostyril. It is marketed under the trade name Abilify® in the form of tablets, oral solution, orally disintegrating tablets and injection for intramuscular use.

Aripiprazole exist in multiple crystal forms. For example, PCT publication WO 03/026659 describes at least nine crystal forms such as B, C, D, E, F, or G including a hydrate form A and anhydrous forms such as Type - I and Type - II. According to WO 03/026659, the procedures disclosed in proceedings of the 4th Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996) yield significantly hygroscopic crystalline forms. Type-I crystals of aripiprazole anhydride are prepared by recrystallizing from an ethanol solution of aripiprazole, or by heating aripiprazole hydrate at 80°C. Type-II crystals of aripiprazole anhydride can be prepared by heating Type-I crystals of aripiprazole anhydride at 130°C to 140°C for 15 hours. In addition to Type-I and Type-II crystals, several additional anhydrous crystal forms are known.

As reported in WO 03/026659, multiple polymorphs may interconvert from one to the other. For instance if the anhydrous form is exposed to moisture, then it may take water and convert into hydrous form, although the anhydrate Form B is not hygroscopic, it suffers from being unsuitable for milling. Specifically, if milling is attempted in order to create small particle sizes such as 50 microns or less, the milled substance tends to adhere to the milling machine making an industrial process difficult. To overcome this problem, WO 03/26659 teaches forming hydrate Form A aripiprazole, milling the hydrate Form A to the desired size and then heat converting to anhydrate Form B.

WO 03/026659 further discloses aqueous wet granulation of aripiprazole anhydride crystals; drying the granules at 70°C to 100°C and sizing the granules followed by drying the granules for second time at a temperature of 70°C to 100°C.

WO 05/058835 discloses novel crystalline aripiprazole Form I, II, VI, VIII, X, XI, XII, XIV, XIX, and XX.

WO 2008/020820 discloses a method of making high-hygroscopic anhydrous aripiprazole tablets comprising, at least a filler selected from the group consisting of mannitol, isomalt and sorbitol, at least a disintegrant selected from the group consisting of crosspovidone, crosscarmellose sodium and sodium starch glycollate, a pharmaceutical acceptable binder and a pharmaceutical acceptable lubricant, prepared by aqueous wet granulation method.

US 2006/0257471 encompasses a method of making aripiprazole Type II tablets by wet granulation using aqueous solvents comprising unmilled aripiprazole Type II having a particle size distribution such that the dw is not greater than 50 microns, one or more polyol fillers, one or more binders, one or more disintegrants and a lubricant. This method discloses a drying temperature of 70°C.

US 2007/0154544 encompasses a method of making aripiprazole anhydride Type I, Type II and Form II tablets by wet granulation using water as a granulating liquid and involves a single drying step at a temperature less than 70°C, with the proviso that the wet granulate is not milled prior to drying.

US 2007/0154545 encompasses a method of making aripiprazole anhydride Type I, Type II and Form II tablets by dry compression comprising providing a mixture of aripiprazole, at least one diluent, at least one tablet binder, and at least one tablet disintegrant; blending the mixture to obtain a homogeneous mixture; optionally adding at least one tablet lubricant to the homogeneous mixture; and dry compressing the homogeneous mixture into tablet.

WO 2010/079506 discloses a stable composition comprising aripiprazole manufactured by wet granulation using water as granulating liquid, wherein intragranular stage is devoid of diluent.

The above prior art references disclose various methods for preparing compositions of anhydrous aripiprazole by wet granulation using water and different drying temperatures of about 70°C and/or two drying steps at a temperature above 70°C which provide resistant to hydration/ and or possible polymorphic interconversion. However, the process is rather expensive and time consuming.

Formulation methods such as spray drying and solvent evaporation have also been suggested to make tablet formulations of aripiprazole. These methods need specialized equipment and heating at high temperatures.

In our continuous efforts to develop stable solid dosage form of aripiprazole, we found that stable aripiprazole composition can be obtained by eliminating the need of water in granulation. The present invention employed non-aqueous wet granulation technique using organic solvents as granulating liquids. Organic solvents are volatile in nature and requires less time and low temperature to eliminate them from formulation and thus make the process rapid and energy saving.

OBJECTIVE OF THE INVENTION

The main objective of present invention is a method of making aripiprazole pharmaceutical composition by wet granulation comprising the steps of: blending aripiprazole, at least one diluent, at least one binder and organic solvent to form wet granulate; drying the wet granulate to obtain a dried granulate.

Yet another objective of the present invention is to provide a stable solid dosage form comprising aripiprazole, at least one tablet diluent and/or at least one tablet binder prepared by wet granulation using organic solvent as granulating liquid.

Yet another objective of the present invention is to provide stable solid dosage form comprising aripiprazole in such a way that it will comply with the reference product in terms of in vivo parameters for bioequivalence such as Cmax, AUC, Tmax and in- vitro parameters like dissolution, disintegration etc.

SUMMARY OF THE INVENTION

The main embodiment of the present invention is a method of making aripiprazole pharmaceutical composition by wet granulation comprising the steps of; blending aripiprazole, at least one diluent, at least one binder and organic solvent to form wet granulate; drying the wet granulate to obtain a dried granulate.

In another embodiment of the present invention is to provide a stable solid dosage form comprising aripiprazole, at least one tablet diluent and/or at least one tablet binder prepared by wet granulation, using organic solvent as granulating liquid.

DETAILED DESCRIPTION OF THE INVENTION

The process of wet granulation includes aqueous or non-aqueous granulation. The wet granulation process comprises admixing of the active ingredient with pharmaceutical excipient(s), and granulation of the blend with granulating liquid or the binder solution prepared by dissolving the binder in aqueous or non-aqueous solvent to form the wet mass followed by drying and sizing. The binder may optionally be admixed with the dry blend and/or dissolved in the aqueous or rion-aqueous solvent.

The present invention provides a method of making aripiprazole pharmaceutical composition by wet granulation comprising the steps of: blending aripiprazole, at least one diluent, at least one binder and organic solvent to form wet granulate; drying the wet granulate to obtain a dried granulate.

In another embodiment, the present invention relates to aripiprazole pharmaceutical composition prepared by wet granulation using organic solvent as granulating liquid.

Organic solvents are volatile in nature and requires less time and low temperature to eliminate them from formulation making the process rapid and energy saving.

In yet another embodiment, the present invention relates to a method of making
aripiprazole pharmaceutical composition by wet granulation comprises the steps of:

i) sifting aripiprazole, at least one diluent and optionally one or more
pharmaceutical acceptable excipients,

ii) granulating the blend of step

(i) with a solution of binder in organic solvent, iii) drying wet granules at a temperature of less than about 70°C, iv) the dried granules of step (iii) are blended with extra granular excipients, and v) compressing the blend of step (iv) into tablets or filling into capsules.

In yet another embodiment, the method of making aripiprazole pharmaceutical composition by wet granulation comprises the steps of

i) shifting aripiprazole, at least one diluent, at least one binder and optionally one or
more pharmaceutically acceptable excipients, ii) granulating the blend of step (i) with organic solvent, iii) drying wet granules at a temperature of less than about 70°C, iv) the dried granules of step (iii) are blended with extra granular excipients, and v) compressing the blend of step (iv) into tablets or filling into capsules.

In another embodiment the pharmaceutical acceptable excipients comprise diluents/fillers, disintegrants, binders, lubricants, glidants, stabilizer, surfactant, coloring agents, sweetening agents, flavouring agents and the like.

Suitable diluents or fillers used according to the present invention are selected from calcium carbonate, calcium phosphate (dibasic and/or tribasic), calcium sulfate, powdered cellulose, dextrates, dextrin, fructose, lactitol, anhydrous lactose, lactose monohydrate, maltose, mannitol, microcrystalline cellulose, sorbitol, sucrose, starch and combinations thereof. Typically, the diluent is present in an amount of about 60 % to 97 % by weight of the tablet.

Suitable binder used according to the present invention is selected from acacia, alginic acid, carbomer, ethylcellulose, gelatin, glucose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, methylcellulose, polyethylene oxide, povidone and combinations thereof. Preferably, the binder is present in an amount of about 0.5% to about 5 % by weight of the tablet.

Binder can be used as a dry binder or as a wet binder dissolved in granulating liquid. Incase of wet binder, the binder may be dissolved in granulating liquid in concentration of about 2 % w/w to 20 % w/w.

Suitable disintegrant used according to the present invention is selected from pregelatinized starch, starch, maize starch, sodium starch glycolate, carboxymethylcellulose and its salts, crospovidone, croscarmellose sodium and combinations thereof. Preferably, the disintegrant is present in an amount of about 0.5% to about 15 % by weight of the tablet.

Suitable lubricant used according to the present invention is selected from calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, zinc stearate and combinations thereof. The lubricant is present in an amount of about 0.5% to about 2% by weight of the tablet.

Suitable glidants used according to the present invention include talc, colloidal silicon dioxide, cornstarch and combinations thereof and the like. Preferably, the glidant is present in an amount of about 0.1 % to about 2 % by weight of the tablet Suitable organic solvents used according to the present invention are selected from ethanol, isopropyl alcohol, dimethylene chloride, acetone, and mixtures thereof.

The wet granulation process is carried out in rapid mixing granulator (RMG) or fluid bed granulator. The process parameters are optimized such that the formed granulate is of a size that does not require wet milling prior to the drying. The drying is carried out at a temperature of less than about 70°C; preferably, in a fluidized bed dryer at an inlet temperature of less than about 60°C.

The drying is continued to obtain a loss on drying of about 1 - 2 %. The dried granules are subjected to sizing or milling. The milled dried granulate has excellent flowability and compressibility.

The term "aripiprazole" used according to the present invention includes but not limited to aripiprazole, its salts, esters and polymorphs thereof, preferably is anhydrous aripiprazole, and more preferably, anhydrous aripiprazole Type - I. Preferably, aripiprazole is present in an amount of about 0.5% to about 15 % by weight of the tablet.

The pharmaceutical composition according to present invention contains aripiprazole in an amount of about lmg to about 50 mg.

Type-I aripiprazole may be prepared by the methods described in WO 2005/058835 and WO 03/026659.

In a preferred embodiment, the method of making aripiprazole pharmaceutical composition by wet granulation comprises the steps of:

i). sifting aripiprazole and at least one pharmaceutically acceptable excipient selected from diluent / filler, disintegrant and binder,

ii). granulating the blend of step (i) with organic solvent/binder solution in organic solvent,

iii). drying wet granules at a temperature of less than about 70°C,

iv). the dried granules of step (iii) are blended with one or more extra granular excipient selected from diluent / filler, disintegrant, glidant and lubricant,

v). compressing the blend of step (iv) into tablets or filling into capsules.

The pharmaceutical composition according to the present invention can be formulated into solid dosage form such as granules, tablets, capsules, preferably tablets.
The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry-.

Example 1: Preparation of l0mg tablets.

Aripiprazole, lactose monohydrate, starch and microcrystalline cellulose were sifted and dry mixed in RMG for 10 min. A 10% w/w solution of hydroxypropyl cellulose in isopropyl alcohol was prepared and slowly added to the blend in RMG to obtain granules.
The wet granules were removed and dried for 30 min with an inlet temperature of 40°C in fluidized bed dryer. The dried granulates were milled or sized and lubricated for 5 min with magnesium stearate. This lubricated blend was then compressed into tablets.
Tablets prepared according Example-1 were subjected to dissolution using an USP II apparatus (paddle) at 60 rpm with 900ml of 1.2 pH buffer at a temperature of 37°C. The samples of the media were periodically withdrawn and spectrophotometrically analyzed for aripiprazole content. The release profile (% of drug released in minutes) is given in table-1.

Table-l; Dissolution Data Comparison for Aripiprazole tablets (l0 mg) prepared according to Example - 1 with Abilify® Tablets.

Example 2: Preparation of 10, 15,20 and 30 mg tablets.

Aripiprazole, lactose monohydrate, starch and microcrystalline cellulose were sifted and dry mixed in RMG for 10 min. A solution of hydroxypropyl cellulose in isopropyl alcohol was prepared and slowly added to the blend in RMG to obtain granules. The wet granules were dried for 15 min with an inlet temperature of 55°C ± 5°C in fluidized bed dryer. The dried granulates were milled or sized and lubricated with magnesium stearate. This lubricated blend was then compressed into tablets.

Example 3: Preparation of 2 mg tablets.

The tablets of Example -3 were prepared according the manufacturing process of
Example-2.

Example 4: Preparation of 5 mg tablets.

The tablets of Example -4 were prepared according the manufacturing process of Example-2.

Tablets prepared according to the Examples 2 to 4 were subjected to dissolution using USP II apparatus (paddle) at 60 rpm with 900ml at a temperature of 37°C at 4.5 pH. The samples of the media were periodically withdrawn and spectrophotometrically analyzed for aripiprazole content. The release profile (% of drug released in minutes) is given in
Table-2 and 3.

Table - 2: Dissolution Data Comparison for Aripiprazole tablets (10, 15, 20 and 30mg) prepared according to Example - 2 with Ability® Tablets.

Table - 3; Dissolution Data Comparison for Aripiprazole tablets (2 and 5mg) prepared according to Example - 3 and 4 with Ability® Tablets.

We claim:

1. A method of making aripiprazole pharmaceutical composition by wet granulation comprising the steps of: blending aripiprazole, at least one diluent, at least one binder and organic solvent to form wet granulate; drying the wet granulate to obtain a dried granulate.

2. The method according to claim 1, wherein the drying is carried out at a temperature of less than about 70°C.

3. The method according to claim 1, wherein diluent is selected from the group consisting of calcium carbonate, calcium phosphate (dibasic and/or tribasic), calcium sulfate, powdered cellulose, dextrates, dextrin, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, maltose, mannitol, microcrystalline cellulose, sorbitol, sucrose, starch and combinations thereof.

4. The method according to claim 1, wherein the diluent is present in an amount of about 60 % to 97 % by weight of the tablet.

5. The method according claim 1, wherein the binder is selected from the group consisting of acacia, alginic acid, carbomer, ethylcellulose, gelatin, glucose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, methylcellulose, polyethylene oxide, povidone and combinations thereof.

6. The method according to claim 1, wherein binder is present in an amount of about 0.5% to about 5 % by weight of tablet

7. The method according to claim 1, wherein organic solvent is selected from ethanol, isopropyl alcohol, dimethylene chloride, acetone and mixtures thereof.

8. The method according to claim 1, further comprises the steps of blending the dried granulates with a lubricant and/or glidant; and compressing the granulates into tablet.

9. The method according to claim 9, wherein the lubricant is selected from the group consisting of calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, zinc stearate and combinations thereof.

10. A method of making aripiprazole pharmaceutical composition, as described and illustrated in the examples herein.