(542b) Handling and Solid-State Method Development for Improved Isolation of Molecules with Complex API Structures

The pharmaceutical industry in general will continually encounter larger and more complex molecules due to the need for more novel disease targets. With these highly flexible and larger molecular structures come a higher propensity for solid forms of the API with more atypical behavior, e.g. variable hydrates/solvates and pseudo-stable amorphous forms that display a continuum of energetic states, rather than discrete solid form transitions. New approaches and methodologies must be explored and used to better characterize and understand these molecules to ensure robust and consistent isolation of the desired form, and to inform regulatory authorities upon submission.
Pharmaceutical case studies are presented describing how adapted methodologies are used to provide better understanding of complex solid forms with regard to solid-state properties and the isolation process. The utility of different advanced solid-state characterization tools such as VH/T-XRPD, TGA-MS, perfusion calorimetry, and Raman spectrometry are reviewed and discussed. In the first case study, the aforementioned characterization tools were used to guide development of a crystallization and isolation process for a variable hydrate/solvate that exhibited small subtle changes in crystallinity at different environments, which impacted the crystallization design and performance. The second case study describes an API that undergoes form change and partial amorphization during drying. The developed solid-state methods were able to quantify the extent of amorphous content and how it is directly related to desolvation behavior. The knowledge generated by these case studies not only supported advancement through development, but will also contribute to an effective presentation of the properties of these more complex forms to regulatory authorities.