(355e) Controlled Crystallization through Microfluidization As an Alternative Particle Engineering Technology for Inhalation Products

Anti-solvent controlled crystallization using microfluidization is a promising particle engineering technology that can be used to control the size, shape, and surface characteristics of particles. This technique involves the use of a microfluidic device to create a turbulent flow of the drug solution and anti-solvent, which leads to rapid mixing and nucleation of the drug particles. The resulting particles are typically micron-sized, with a narrow size distribution and high surface area, making them ideal for inhalation delivery.

Process development is a critical aspect of anti-solvent crystallization using microfluidization, as it can affect the quality and properties of the resulting particles. The process variables that need to be optimized include the composition of the solution, the type and concentration of anti-solvent, the flow rates of the solution and anti-solvent, the temperature and pressure conditions. The present work discusses a methodology for process development of controlled crystallization through microfluidization and impact of process variables on product quality and performance as inhalation product in carried based formulation.

The work was divided in three stages: i) solvent and anti-solvent selection, ii) process parameters influence as DoE and iii) benchmark with the conventional process.

Firstly, a study was performed using a model drug soluble in acetone and where three antisolvents were assessed. Prototypes with different pairs of solvent and anti-solvent were produced at same conditions and their quality assessed. The anti-solvent showed to impact on the particle morphology and on fine particle fraction. On the other hand, limited impact on crystalline content was observed in which the material had approximately all content in crystalline form.

After selecting the most suitable solvent/anti-solvent pair based on processability, a Design of Experiments was performed to optimizes the process parameters. The composition of the solution can be optimized to adjust the solubility of the drug and the rate of precipitation, which affects the size and morphology of the particles. The type and concentration of the anti-solvent can also be adjusted to control the rate of precipitation and the degree of supersaturation, which can affect the size and shape of the particles. Smaller and smoother particles were obtained when using a high Solvent:Antisolvent ratio and low solid concentrations. All powders had similar crystalline content and it was observed that the formulations composed by smaller particles had a better performance as inhalation product.

The proposed technology was benchmarked with the JM and WP, showing that the top-down approaches led to formulations with lower fine particle fractions, proving the efficiency of the bottom-up approach studied as an promising technology for inhalation products.

In conclusion, anti-solvent controlled crystallization using microfluidization is a promising particle engineering technology that can be used to produce particles with specific properties and characteristics. The development of this process requires careful optimization of the process variables, nonetheless, it was shown during this work that controlled crystallization through microfluidization is a promising technique in Particle Engineering field.