(606f) Problematic Crystal Shapes - Causality and Solvent Selection Guidance Based On Periodic Bond Chain Diagrams

Crystals with needle like or flat plate like shapes, as typified by aspect ratios ~ 1 : 1 : >100 and 1 : >100 : >100, are often the steady-state growth shapes in the crystallization of pharmaceutical compounds from solution.  Crystals with such high aspect ratios may be problematic during subsequent processing steps; e.g., filtration, drying.  Furthermore, the crystallization of active pharmaceutical ingredients (APIs) that result in such shapes present additional concerns during the additional drug product processing.  Although mechanical techniques such as milling and non-mechanical techniques such as thermal cycling may be able to avoid the isolation of crystals with high aspect ratio shapes, it is often more desirable (especially during early development) to determine appropriate solvents that avoid such shapes altogether.  In this presentation, a causality for the formation of needles will be discussed.  This causality stems from the three dimensional network of anisotropic intermolecular interactions within a crystal; which are understood using periodic bond chain diagrams.  This causality will be applied to different case studies that demonstrate the importance of the dispersive and associative interactions within the crystal and the set of corresponding solvents that are likely abate the formation of needle shaped crystals.  From these case studies, a classification system for different types of needles will be provided.  The foundations of a similar causality for flat plates and the role of solubility will also be described.