| Introduction: In recent years, cocrystallization and nanoprecipitation have gained increasing popularity as viable strategies for improving the pharmaceutical properties and in vivo performance of drugs. The present thesis was aimed at assessing these two approaches for potential applications in pharmaceutical formulation and manufacture with five model drugs, viz. curcumin (CUR), flurbiprofen (FLU), ibuprofen (IBU), ketoprofen (KET) and loxoprofen (LOX). Selection of these drugs for the study was guided mainly by their poor water solubility, poor compactibility, typical drug's lipophilicity (log P =3-5), and potential for treatment of Alzheimer's disease. Cocrystallization was induced by the attainment of a sufficient supersaturation level through rapid solvent removal from a solution containing the drug and the coformer, nicotinamide (NCT), while flash nanoprecipitation (FNP) was achieved by rapid and homogenous mixing of drug solution (with stabilizer and co-stabilizer if required) with antisolvent in the mixing chamber of a specially designed confined impinging jet mixer (CIJM) or multi-inlet vortex mixer (MIVM).;Methods: Cocrystals were prepared by rotary solvent evaporation or slow evaporation of a solution of drug and NCT in ethanol, and characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetry, moisture sorption analysis, Fourier transform infrared spectroscopy, intrinsic dissolution rate (IDR) measurement and compaction analysis. Polymer-stabilized drug nanoparticles were prepared by FNP using a two-stream CIJM or four-stream MIVM under defined conditions of varying flowrate, solvent type, molecular weight of amphiphilic diblock (PEG-PLA) copolymer XIII (stabilizer), or drug-to-copolymer ratio. The resulting nanoparticles were characterized for particle size by dynamic light scattering; zeta potential by electrophoretic light scattering; particle morphology and surface properties by scanning electron microscopy and atomic force microscopy; surface composition by X-ray photoelectron spectroscopy (XPS); and drug loading and encapsulation efficiency (EE) by high performance liquid chromatography.;Results: Phase-pure 1:1 cocrystals of IBU and FLU with NCT were obtainable by rotary solvent evaporation, but not slow evaporation. Similar solvent removal failed to cause any cocrystal formation for KET and LOX while inducing partial cocrystal conversion for CUR. Both IBU-NCT and FLU-NCT cocrystals displayed enhanced IDR, reduced moisture sorption and improved tabletability compared with the individual profen crystals. FNP studies using the MIVM confirmed the flowrate, solvent type, molecular weight of PEG-PLA copolymer, and drug-to-copolymer mass ratio being important process variables for controlling particle size and particle stability. Particle stability could be enhanced with a hydrophilic co-stabilizer (e.g., PVA). Such costabilizers possibly act by binding to the PEG corona at the particle surface to reinforce the protective steric barrier, as substantiated by XPS data. Comparative studies on nanoparticle production by FNP for the four profens indicated that three structurerelated intrinsic solution properties of the profens, namely, water solubility, log P and pKa, were important determinants of the particle size and EE of nanoparticles, as determined by multiple linear regression analysis.;Conclusion: Cocrystallization with NCT can simultaneously improve the tableting behavior, hygroscopicity, and dissolution performance of IBU and FLU. Proper XIV optimization of the process variables in FNP is critical to the controlled production of polymer-stabilized drug nanoparticles with consistent properties and storage stability. |
