Microreactor Particle Size Control via Jet Collision
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for producing pharmaceutically active particles with small particle sizes are limited in achieving sizes below the nanoscale for poorly soluble active ingredients, as they often require high temperatures or prolonged processes that can be inefficient and damaging to thermosensitive compounds.
Innovation Solution
A method combining solvent-nonsolvent precipitation with in-situ spray evaporation in the presence of a surface modifier, where the active pharmaceutical ingredient is dispersed in a water-miscible solvent and injected under high pressure through a nozzle into a microreactor, colliding with a nonsolvent jet to form fine particles quickly, avoiding Ostwald ripening and thermal damage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Length of moving object
If conventional precipitation methods are used to produce small particles, then particle size is reduced to nanoscale, but further reduction below nanoscale is limited and requires high temperatures or prolonged processes
Solution Approach 1:
The precipitation process is segmented into two distinct stages: first, rapid precipitation to form nuclei, then controlled growth phase. This segmentation allows achieving sub-nanoscale particles without requiring high temperatures or prolonged processing, as each stage is optimized independently for its specific function.
Solution Approach 2:
The invention applies preliminary action by pre-forming nuclei through rapid precipitation before controlled growth occurs. This preliminary formation of small particle cores enables subsequent size control without requiring extreme temperatures or extended processing times that would be needed if starting from larger particles.
2Length of moving object
If high temperatures or prolonged processes are used to achieve smaller particle sizes, then particle size is reduced, but thermosensitive compounds are damaged
Solution Approach 1:
The process segments particle formation into rapid nucleation followed by controlled growth, allowing size reduction without thermal damage. The rapid nucleation phase completes before significant heating can occur, protecting thermosensitive compounds while achieving small particle sizes.
Solution Approach 2:
The invention rushes through the critical nucleation phase extremely rapidly, completing particle formation before thermal effects can damage thermosensitive compounds. This time-compression approach achieves size reduction while avoiding the thermal damage associated with conventional prolonged high-temperature processes.
3Length of moving object
If rapid precipitation is used to form small particles, then particle size is reduced, but Ostwald ripening occurs causing larger particles to form
Solution Approach 1:
The process segments particle formation into rapid nucleation followed by immediate stabilization through controlled growth conditions. This segmentation prevents Ostwald ripening by establishing stable particle cores rapidly and then maintaining conditions that prevent further coarsening, preserving narrow size distribution.
Solution Approach 2:
The invention changes process parameters dynamically: using high supersaturation during nucleation to form small particles, then adjusting conditions to control growth and prevent Ostwald ripening. This parameter control maintains particle size distribution stability while achieving small final sizes.
4Length of moving object
If conventional methods are used to produce small particles, then nanoscale particles are achieved, but productivity is limited due to inefficient processes
Solution Approach 1:
The invention applies preliminary action by pre-forming stable nuclei rapidly, then proceeding with controlled growth. This preliminary nucleation step enables subsequent efficient production at scale without requiring repeated processing cycles, significantly improving productivity while maintaining small particle sizes.
Solution Approach 2:
The process maintains continuous useful action through uninterrupted controlled growth after nucleation, avoiding batch processing interruptions. This continuous operation improves productivity while the controlled conditions ensure consistent small particle size formation throughout the process.
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
This method achieves particle sizes well below previous art limits, with high drug loading efficiencies and flexibility in particle size control through varying polymer:drug ratios, temperatures, and pressures, while maintaining the integrity of thermosensitive compounds.
Implementation Method 1
The collision of the active substance - liquid jet with a water jet leads to a non-solvent precipitation and the formation of a fine mist
Implementation Method 2
the solvent is evaporated from the solvent-nonsolvent mixture practically at the same time as the precipitation
Implementation Method 3
in-situ spray evaporation of the solvent in the presence of a surface modifier
Implementation Method 4
Because of the high dynamic pressure of the liquids in front of the nozzles, the resulting high jet speeds of the colliding liquid jets and the resulting fineness of the mist droplets
Implementation Method 5
due to the increased temperature of at least one of the liquid jets and the additional flushing of the reactor with air, warm air, hot air or better yet, an optionally preheated inert gas such as nitrogen, the solvent evaporates very quickly
Data Source
Figure 1
AI summary
The invention relates to pharmaceutical active substance particles having small particle size, wherein said particles are produced by combining a solvent-non-solvent precipitate with an in-situ spray drying process. A pharmaceutical active substance is dispersed in a water-soluble solvent, in particular ethanol, and heated in an infeed line under pressure to above the boiling point of the solvent until solubilization. Said solution collides as a fine fluid jet with a fine water jet in a gas-permeated microreactor, and the fine mist so arising is thereby very rapidly vaporized. The organic solvent vaporizes first, then the water. The water can comprise surface modifiers.