Two-Step Aripiprazole Pulverization for Sterile Suspensions
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Solution Overview
Problem
Existing methods for producing aripiprazole suspensions face challenges such as contamination risks from bead friction in ball milling, difficulty in achieving desired particle sizes without special crystallization techniques, and the need for vacuum mixing, which complicates commercial-scale aseptic production.
Innovation Solution
A two-step pulverization process using high shear and high-pressure jet type emulsifying dispersion machines to reduce aripiprazole particle size from bulk powder with larger mean sizes, eliminating the need for vacuum mixing and enabling in-line sterilization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If ball milling method is used for pulverization, then particle size reduction is achieved, but contamination occurs due to bead friction
Solution Approach 1:
The patent replaces the mechanical ball milling system with a high-pressure homogenizer system that uses hydraulic pressure and cavitation effects to achieve particle size reduction without mechanical contact and bead friction, thereby eliminating contamination
Solution Approach 2:
The patent changes the pulverization parameters by using high pressure (up to 200 MPa) and temperature control during homogenization to achieve particle size reduction without the mechanical wear and contamination associated with traditional ball milling
2Manufacturing precision
If bulk aripiprazole with mean particle size of 100 μm or less is used, then desired suspension properties are achieved, but special crystallization techniques are required
Solution Approach 1:
The patent performs pulverization as a preliminary action after crystallization, using high-pressure homogenization to reduce particle size to the desired range, thereby avoiding the need for complex crystallization techniques and simplifying the overall manufacturing process
Solution Approach 2:
The patent separates the particle size control function from the crystallization process by extracting it as a subsequent pulverization step, allowing standard crystallization methods to be used followed by high-pressure homogenization to achieve the required particle size distribution
3Stability of the object's composition
If vacuum mixing is used to prepare homogeneous suspension, then mixing quality is improved, but contamination risk increases due to outside air introduction
Solution Approach 1:
The patent replaces vacuum mixing with high-pressure homogenization that creates homogeneous suspension through high-shear forces and cavitation without requiring vacuum conditions, thereby eliminating the risk of contamination from outside air introduction
Solution Approach 2:
The patent changes the mixing parameters by using high pressure and high shear rate during homogenization to achieve uniform suspension distribution without creating the vacuum conditions that would require contamination control measures
4Manufacturing precision
If high-pressure homogenizer is used on 10% suspension with mean particle size more than 100 μm, then particle size reduction is achieved, but clogging occurs in the line
Solution Approach 1:
The patent performs a preliminary pulverization step using a high shear mixer or ultrasonic disperser before high-pressure homogenization to reduce particle size to a range that will not cause clogging in the homogenizer line, ensuring continuous operation
Solution Approach 2:
The patent segments the pulverization process into multiple stages: initial coarse pulverization followed by fine pulverization in the high-pressure homogenizer, allowing each stage to operate within optimal parameters without clogging
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method produces aripiprazole suspensions with desired particle sizes of 1 to 10 μm efficiently, reduces contamination risks, and allows for sterile production without special crystallization techniques, facilitating commercial-scale aseptic processing.
Implementation Method 1
pulverizing means, and in particular, a high-pressure homogenizer
Implementation Method 2
first pulverization using a high shear pulverizing machine
Implementation Method 3
The present invention also provides a method for producing a freeze-dried formulation
Data Source
AI summary
Disclosed are a method for producing an aripiprazole suspension, wherein the aripiprazole has a mean particle size of 1 to 10 ?m, the method comprising the steps of: (a) combining bulk aripiprazole and a vehicle to form a primary suspension; (b) subjecting the primary suspension to first pulverization using e.g., a high shear pulverizing machine, a dispersion machine that applies shear force to a material to be processed, a colloid mill, an ultrasonic dispersion machine, or a high-pressure jet type emulsifying dispersion machine to form a secondary suspension; and (c) subjecting the secondary suspension to second pulverization using e.g., a high pressure jet type emulsifying dispersion machine to form a sterile final suspension; and a method for producing a freeze dried formulation from the aripiprazole suspension.