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Process for making sterile aripiprazole of desired mean particle size

a technology of aripiprazole and aripiprazole, which is applied in the field of making sterile aripiprazole of desired particle size distribution and mean particle size, and can solve the problems of undesirable batch aripiprazole milling

Inactive Publication Date: 2005-07-14
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0031] Prior to step (d) ultasonic energy may be provided, by means of a sonication probe, as described above, the tip of which is positioned within a gap defined between the two jet streams, to cause the impinging jet streams to achieve high intensity micromixing of fluids prior to nucleation.

Problems solved by technology

Milling of batch aripiprazole is undesirable, as a broad particle size distribution will be obtained.

Method used

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  • Process for making sterile aripiprazole of desired mean particle size
  • Process for making sterile aripiprazole of desired mean particle size
  • Process for making sterile aripiprazole of desired mean particle size

Examples

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Effect test

example 1

[0067] Sterile bulk active pharmaceutical ingredient (API) aripiprazole was prepared using impinging crystallization with sonication employing an apparatus set up as shown in the attached Figure.

[0068] The following procedure was employed to form a sterile bulk aripiprazole.

[0069] 1. Charge 100 g of aripiprazole in a 4 L flask 34.

[0070] 2. Add 2 L of 95% ethanol.

[0071] 3. Heat the suspension to 80° C. until it becomes a clear solution.

[0072] 4. Transfer the hot aripiprazole solution to a 2 L jacketed vessel 12 and maintain at 75-80° C.

[0073] 5. Charge 2 L of deionized (DI) water to a 2 L jacketed vessel 14.

[0074] 6. Cool the DI water to 2° C.

[0075] 7. Add 100 mL of 95% ethanol and 100 mL of DI water to the impinging vessel 10 and cool to 2° C.

[0076] 8. Initiate sonication (Sonication is provided by a 0.5 inch probe with 120 W power output employed as described in U.S. Pat. No. 6,302,958).

[0077] 9. Pump the aripiprazole solution through a 0.02 inch diameter nozzle 16 at 0.2...

example 2

[0083] Sterile bulk API aripiprazole was prepared using impinging jet crystallization and an apparatus set up as shown in the accompanying figure.

[0084] The following procedure was employed to form a sterile bulk aripiprazole:

[0085] 1. Suspend 100 g of aripiprazole in 2000 mL of 95% ethanol. Heat the suspension to 80° C. until it becomes a clear solution.

[0086] 2. Polish filter the aripiprazole solution into a holding vessel 12 and maintain at 80° C.

[0087] 3. Polish filter 2000 mL water to another holding vessel 14 and heat to 80° C.

[0088] 4. Pump the aripiprazole solution through a 0.02 inch diameter nozzle 16 at 0.25 kg / min and impinge it with the 30° C. water pumped at 0.25 kg / min through a 0.02 inch diameter nozzle 18 to form a crystal slurry which is collected in an impingement vessel 10.

[0089] 5. Agitate the newly formed crystal slurry in the impingement vessel 10 while continuously transferring it to a receiver 32 to maintain a constant volume in the impingement vessel ...

example 3

[0093] An aripiprazole injectable aqueous suspension (200 mg aripiprazole / 2 mL, 200 mg / vial) was prepared as follows.

[0094] The following ingredients were added to a 3L glass jacketed vessel maintained at 15° C. (±5° C.) to form a sterile primary suspension:

Aripiprazole (prepared by impinging jet 100 gcrystallization as described in Example 2):Carboxymethylcellulose, Sodium Salt 7L2P 9.0 gMannitol  45 gSodium Phosphate, Monobasic 0.8 gSodium Hydroxide Solution, 1Nq.s. to adjust pH to 7.0Water, USPq.s. to 1000 g

[0095] The sterile suspension was mixed at 500-1000 rpm for about 0.5 hour and then at 300-500 rpm for an additional 1 hour under 20 ″Hg (+5″Hg) vacuum.

[0096] 2.5 mL of the above suspension were aseptically filled into sterilized vials which were then aseptically partially stoppered with sterilized stoppers. The vials were aseptically transferred to a freeze dryer and lyophilized according to the following cycle:

[0097] (a) thermal treatment: freeze product at −40° C. over...

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Abstract

A process is provided for making sterile aripiprazole having an average particle size less than 100 microns but preferably greater than 25 microns employing an impinging jet crystallization procedure. The resulting bulk aripiprazole of desired particle size may be used to form a sterile freeze-dried aripiprazole formulation, which upon constitution with water and intramuscular injection releases aripiprazole over a period of at least about one week and up to about eight weeks.

Description

FIELD OF THE INVENTION [0001] This application claims a benefit of priority from U.S. Provisional Application No. 60 / 513,886, the entire disclosure of which is herein incorporated by reference. [0002] The present invention related to a process for making sterile aripiprazole of desired particle size distribution and mean particle size which is especially adapted for use in preparing a controlled release formulation which releases aripiprazole over at least one week or more. BACKGROUND OF THE INVENTION [0003] U.S. provisional application No. 60 / 513,618, discloses a controlled release sterile injectable aripiprazole formulation in the form of a sterile suspension, and a method for preparing a sterile freeze-dried aripiprazole formulation (employed in forming the injectable formulation) which includes the steps of: [0004] (a) preparing sterile bulk aripiprazole preferably having a desired particle size distribution and mean particle size within the range from about 5 to about 100 micro...

Claims

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Application Information

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IPC IPC(8): B01D9/00C07D215/22C07D215/227
CPCB01D9/0009B01D9/0054B01D9/0081B01J2/06C07D215/227A61J3/02B01D9/005B01D9/0063A61K31/496C07D401/00
Inventor GLEESON, MARGARET M.KIM, SOOJINKIENTZLER, DONALD C.KIANG, SAN
Owner BRISTOL MYERS SQUIBB CO
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