Atomic force microscopy studies on two-step nucleation and epitaxial growth

Continues advancement and rapid development of techniques operating at the nanoscale open new opportunities to revise and question commonly accepted nucleation and crystal growth theories. Atomic Force Microscopy (AFM) has been successfully involved in various aspects of active pharmaceutical ingredient (API) characterisation including crystal growth, stability of solid dispersions, surface morphology, phase changes and dissolution [1]. Recent studies conducted on proteins crystallisation at nanoscale show new evidence disproving generally accepted Classical Nuclea/on Theory (CNT)[2]. Currently, ‘dense liquid droplets’ seen in protein crystallisation and ‘pre-nucleation clusters’ [3] seen mostly in inorganic salt crystallisation, are two main concepts of non-classical nucleation theory, although no significant progress has been made towards better understanding of mechanisms controlling heterogeneous nucleation in small organic molecules systems, what is in particular interest, as an epitaxial ordering phenomenon is frequently used to enhance nucleation rates and control properties of materials. Our studies present a new light on heteronucleation and the epitaxial growth mechanisms based epitaxial growth of olanzapine dihydrate D on the surface of olanzapine form I (OZPN I) both in high humidity conditions and water solu*on. Results obtained from Peak Force Quan/ta/ve Nanomechanical Mapping Atomic Force Microscopy (PF- QNM-AFM) [4] indicate the presence of intermediate dense liquid-like phase in process of dihydrate D nucleation.