Crystallization via Ultrasonic Anti-Solvent Mixing
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Solution Overview
Problem
Current methods for producing small crystals, such as those used in pharmaceutical and agro-chemical industries, often result in particles that are unsuitable due to morphological alterations and high charging, affecting their properties and usability, particularly in aerosols, and do not effectively control crystal and precipitate particle size.
Innovation Solution
A process involving the contact of a saturated solvent solution with a non-solvent stream in a high flow rate ratio, typically greater than 20:1, under ultrasonic irradiation to form emulsions or dispersions, which allows for the controlled crystallization of active principles into desired sizes ranging from 100 nm to 10 μm, using non-miscible liquids and optional additives like surfactants and buffering agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Length of moving object
If milling processes are used to make small particles, then particle size is reduced, but particle morphology deteriorates and surface polymorphological transformation occurs
Solution Approach 1:
The invention employs phase transition of the solvent system by introducing an anti-solvent to reduce solubility of the active principle, inducing crystallisation from solution rather than mechanical size reduction. This phase change approach allows particles to form their natural crystal structure without the morphological damage caused by milling
Solution Approach 2:
The invention replaces the mechanical milling system with a chemical/crystallisation system. Instead of using mechanical force to reduce particle size, the process uses controlled crystallisation from supersaturated solution, substituting mechanical action with a chemical phase transition mechanism that preserves particle morphology
2Length of moving object
If milling processes are used to make small particles, then particle size is reduced, but flow rate deteriorates due to high charging
Solution Approach 1:
By using phase transition (crystallisation from supersaturated solution) instead of mechanical size reduction, the invention produces particles with appropriate surface charge characteristics that maintain good flow rates, unlike milled particles which become highly charged and exhibit poor flow properties
3Quantity of substance
If conventional crystallisation with flow rate ratio of anti-solvent:solvent up to 10:1 is used, then crystals are produced, but precise control of small crystal size (100 nm to 10 μm) is difficult to achieve
Solution Approach 1:
The invention achieves precise control of crystal size by changing the parameter of flow rate ratio to greater than 20:1 (anti-solvent:solvent), which creates a more rapid and pronounced supersaturation condition. This parameter change enables better control over nucleation and crystal growth, producing consistent small crystal sizes in the range of 100 nm to 10 μm that are difficult to achieve with conventional lower ratios
Solution Approach 2:
The continuous flow system with ultrasonic irradiation creates periodic conditions for nucleation and growth control, allowing precise size distribution of crystals to be achieved through controlled periodic supersaturation and crystallisation cycles
4Productivity
If ultrasonic irradiation is used during mixing, then crystallisation is enhanced, but energy consumption increases
Solution Approach 1:
The invention applies ultrasonic irradiation in a controlled manner during the mixing phase to enhance nucleation, but does not require continuous ultrasonic treatment throughout the entire process. This partial application of ultrasonic energy achieves the crystallisation enhancement benefit while limiting energy consumption to only the critical mixing period
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 enables the production of crystals with precise size control, minimizing morphological issues and charging, thereby producing stable and suitable particles for various applications, including inhalation and oral administration, by manipulating the flow rate ratio and using ultrasonic irradiation for nucleation.
Implementation Method 1
subjecting the emulsion or dispersion to ultrasonic irradiation
Implementation Method 2
subjecting the emulsion or dispersion to ultrasonic irradiation
Implementation Method 3
forming an emulsion or a dispersion wherein the said solute is present in a super-saturated solution within the droplets
Implementation Method 4
forming an emulsion or a dispersion wherein the said solute is present in a super-saturated solution within the droplets
Data Source
AI summary
A process for preparing an emulsion or a dispersion comprising crystalline particles of at least one active principal that comprises contacting a solution of at least one solute in a solvent or mixture of solvents in a first flowing stream with a non-solvent in a second flowing stream wherein the non-solvent and solvent are not miscible with each other, so as to form an emulsion or a dispersion. Super saturation is brought about by suitable means, and the emulsion or dispersion is subjected to ultrasonic irradiation to mediate crystal nucleation.