Cross-Flow Hollow Fiber Membrane Crystallization for API Nanocrystals
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing crystallization techniques for active pharmaceutical ingredients (APIs) face challenges in producing nanocrystals efficiently with controlled size distribution, as they often result in broad crystal size distributions and require high capital investments, and existing methods like impinging jet crystallization have limitations in scalability and mixing efficiency.
Innovation Solution
A cross-flow configuration using a compact hollow fiber membrane module with porous hollow fibers arranged perpendicular to the incoming fluid flow, where the anti-solvent is injected through the fibers to mix with the API solution, achieving a short residence time and high mixing efficiency for continuous nanocrystal production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional batch processing or traditional continuous crystallization methods are used, then API crystallization can be performed, but broad crystal size distribution and high capital investment are observed
Solution Approach 1:
The patent employs a porous hollow fiber membrane as the core component of the crystallization device. The membrane has controlled porosity (30-70%) with pore sizes of 0.01-10 μm, allowing anti-solvent to be injected through the pores into the solvent stream. This porous structure enables efficient mixing at the micro-scale while maintaining a compact device configuration, producing narrow crystal size distribution (10-50 μm) without requiring large-scale complex equipment
Solution Approach 2:
The patent transitions from conventional batch or simple continuous crystallization to a cross-flow configuration where solvent and anti-solvent flow in perpendicular directions through the hollow fiber membrane. This dimensional change creates extended contact time and surface area for mixing, achieving superior crystal size control (10-50 μm) in a compact footprint with reduced capital investment
2Manufacturing precision
If impinging jet crystallization is used, then narrow crystal size distribution is achieved, but limitations in scalability and mixing efficiency occur
Solution Approach 1:
The patent utilizes hydraulic flow through the hollow fiber membrane to achieve efficient mixing. The solvent containing API flows through the membrane at controlled rates (0.1-10 mL/min), and anti-solvent is injected through the porous walls. This hydraulic approach replaces the jet-based mechanical mixing with flow-driven mixing, enabling scalable operation while maintaining narrow crystal size distribution (10-50 μm) and overcoming the scalability limitations of impinging jet methods
Solution Approach 2:
The patent divides the crystallization process into multiple stages along the length of the hollow fiber membrane (1-100 cm). The cross-flow configuration creates segmented mixing zones where anti-solvent is continuously injected through pores along the membrane length. This segmentation allows for controlled, progressive mixing and crystal formation, achieving narrow size distribution while enabling scalability by simply extending or replicating the membrane module
3Manufacturing precision
If anti-solvent is injected through hollow fiber membrane pores, then high mixing efficiency is achieved, but residence time must be controlled to prevent crystal growth
Solution Approach 1:
The patent carefully controls multiple parameters to achieve the desired balance: membrane porosity (30-70%), pore size (0.01-10 μm), solvent flow rate (0.1-10 mL/min), anti-solvent flow rate (0.1-5 mL/min), and membrane length (1-100 cm). By adjusting these parameters, the system achieves high mixing efficiency (Kolmogorov scale mixing) while maintaining short residence time (seconds to minutes) to prevent excessive crystal growth, producing consistent nanocrystal size distribution
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 effectively produces nanocrystals with controlled size distribution and high yield, overcoming limitations of conventional methods by reducing residence time and enhancing mixing efficiency, suitable for continuous manufacturing of APIs.
Implementation Method 1
An anti-solvent is flowed through a tube side of the hollow fibers. The anti-solvent is permeated through pores of the hollow fibers into the shell-side, thereby mixing with the API solution.
Implementation Method 2
The high level of mixing achieved in this design leads to a mixing scale close to the Kolmogorov scale (10-50 μm) for low viscosity liquids.
Implementation Method 3
the solvent containing the solute flows on one side of a porous hollow fiber membrane parallel to the length of the hollow fiber membrane in laminar flow, and the anti-solvent-which flows on the other side of the hollow fiber membrane under laminar flow conditions—is injected through numerous membrane pores into the solvent containing the solute to be crystallized
Implementation Method 4
Crystallization of the API is induced to form nanocrystals
Data Source
AI summary
A porous hollow fiber membrane based anti-solvent crystallization (AsCr) process is disclosed. The process involves injecting an anti-solvent from a bore of a hollow fiber membrane into a shell side where a feed solution containing a solution containing a material, e.g., an API, is flowing. The shell-side feed solution flows perpendicular to the hollow fiber length; the shell side liquid is in cross flow across the hollow fiber membranes. Multiple HFM modules may be positioned in series with nanocrystal suspension product from one module fed to the next module that is independently fed with an anti-solvent. The crossflow HFM based continuous AsCr technique disclosed herein could result in continuous nanocrystal production of APIs.