Precipitation with a compressed-fluid antisolvent: Injector development and applications to the design of particulate pharmaceuticals

This thesis provides a method and the understanding required to produce particles with a controlled size and crystal habit using Precipitation with a Compressed-fluid Antisolvent (PCA). A new injector was designed and developed which optimized mixing miscible fluid streams within a confined mixing chamber at high pressure. The injector was capable of delivering mixing times less than the characteristic time for particle nucleation and growth, and process performance was duplicated at the pilot-plant scale. The injector design, grounded in mixing theory, is inherently different from conventional PCA spray injector designs and allows production of poly (L-lactic acid) (PLLA) nanoparticles.; Developmental work with this injector was extended to measure nucleation and growth rates of PLLA microparticles produced during PCA, where limited experimental data exist for precipitation kinetics. The new injector satisfies the constraints and assumptions incorporated in the development of the mixed-suspension, mixed-product-removal (MSMPR) population balance theory, and results from product particle size distributions allowed nucleation and growth rates to be determined through the use of population balances. First-order dependence of the nucleation rate on suspension density and supersaturation suggests secondary nucleation mechanism(s) are operative within this PCA flow system, and explains the relative insensitivity of particle size distributions to changes in PCA operating conditions.; The effect of crystallizing griseofulvin by PCA in the presence of poly (sebacic anhydride) (PSA) was investigated. Griseofulvin crystal habit was modified from acicular to bipyramidal and the habit modification was attributed to a preferential adsorption mechanism of PSA to the fastest growing crystal face of the acicular crystal form. X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis indicated no changes in the griseofulvin crystalline form after the habit modification. Despite the change in crystal habit, griseofulvin crystals achieved 100% dissolution within 60 minutes in a simulated gastric fluid.; Four scaling criteria were used to scale-up the PCA process from the laboratory to the pilot-plant scale using the new injector. Scaling the injector with a constant residence time and suspension density, or a constant energy dissipation rate resulted in similar PLLA particle size distributions at each scale of operation, and was attributed to maintaining comparable mixing quality and similar precipitation kinetics with a change in process scale.