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This project focused on lyophilization of PLGA nanoparticles, more specifically on finding an optimal formulation and optimal lyophilization conditions. Preliminary tests were performed to investigate the influence of several cryo/lyoprotectans on nanoparticle characteristics such as particle size and polydispersity index. Determinations of the glass transition temperature of freeze-concentrated solutions and a design of experiments were performed and mannitol-sucrose 5% (m/V) (1:1) was selected as an optimal formulation. Several freezing methods were evaluated and both batch freezing and continuous freezing resulted in satisfactory results regarding cake appearance, reconstitution time, particle size and polydispersity index. Optimization of the primary drying step could not be performed due to the early termination of the project. Since mannitol is a crystalline component that can be present in an anhydrous (α, β, and δ) or hemi-hydrate state, experiments were conducted to investigate the solid state of mannitol in the selected formulation (mannitol-sucrose 5% (m/V) (1:1)). Storage of a product containing mannitol hemi-hydrate could result in a transformation to anhydrous mannitol accompanied by release of lattice water, which will result in loss of stability (1). Off-line raman spectra revealed that in the selected formulation, mannitol was present in its hemi-hydrate state. Possible strategies to eliminate this mannitol hemi-hydrate, are addition of an annealing step or secondary drying at a temperature of approximately 40°C (1). However, the glass transition temperature of the formulation was determined to be 43,8°C indicating that secondary drying at a temperature of 40°C might risk cake collapse. Therefore, in-line raman spectroscopy was performed to determine the minimum annealing temperature needed to promote transition of mannitol hemi-hydrate to a more stable, anhydrous state. Analysis of these spectra was performed using principal component analysis. Results showed that a transition to β-mannitol occurred at a temperature of -12,5°C. Therefore, it can be concluded that an annealing step at a minimum temperature of -12,5°C should be included in the lyophilization cycle to promote the formation of β-mannitol.