Nucleation and Growth of Pharmaceutical Crystals

Investigating nucleation, crystal growth and solid-state transformations at the nanoscale are of significant interest, as more complex routes have roused questions about the classical view of these processes. This thesis reports the characterisation of prenucleation clusters in olanzapine (OZPN) aqueous solutions, their role in non-classical heteronucleation of OZPN hydrates and during crystal growth mechanism. Atomic force microscopy studies of the (100)OZPNI face of OZPN I crystals in contact with water show the formation, growth, and order of dense nanodroplets leading to crystallization of OZPN dihydrate on the surface of OZPN I. Dihydrate polymorphic form is driven by a templating effect of the underlying OZPN I lattice. The size and volume fraction of nanodroplets in purely aqueous and mixed ethanol and water OZPN solutions show that their radius is steady in time at ca. 35 nm and it is independent of the OZPN concentration and the solvent composition. The OZPN fraction captured in the clusters is dictated by the solution thermodynamics. Both behaviours are consistent with the predictions of a model that assumes the formation of OZPN dimers and their decay upon exiting the clusters. Although the presence of prenucleation clusters is critical during OZPN phase transformation, it was observed that clusters do not take part in a growth mechanism and OZPN layers are generated by a spiral growth. Step velocity shows a nonlinear dependence on OZPN concentration. The proposed growth model suggests that OZPN layers propagate by incorporation of OZPN dimers present as a minor species in OZPN solution. The growth by dimers is faster not owing to spatial or entropic factors or weakly bound solvent, but to the accumulation of dimers on crystal surfaces due to stronger binding. These findings provide guidance towards enhanced control over nucleation, molecular transitions, and the solid forms in molecular systems.