Accelerating Solid Form Discovery for Pharmaceuticals.

Abstract

Polymorphism is the ability of a molecule to exist in multiple crystalline phases, each with a different arrangement or conformation of molecules within the solid state. The focus of this thesis is the use of polymer-based approaches to crystallization control to explore the role of solid form diversity in pharmaceuticals and also developing methods based on these approaches to accelerate solid form discovery. Polymer-induced heteronucleation (PIHn), a powerful crystalline polymorph discovery method, has revealed two novel polymorphs of piperine exhibiting enhanced solubility relative to the known polymorph. As demonstrated by the discovery of these new piperine forms, it’s imperative to determine the potential polymorphism of a compound. However, methods capable of exhaustively screening for crystal polymorphism remain an elusive goal in solid-state chemistry due to large sample requirements and long analysis times. PIHn has now been redeployed in a high density format in which 288 distinct polymers are arrayed on one substrate. This format allows determining the outcome of thousands of crystallizations in an automated fashion with only a few milligrams of sample. This technology enables the study of a broader range of targets, including preclinical candidates, facilitating determination of polymorphism propensity much earlier in the drug development process. A further problem explored in this thesis relates to compounds which are very slow or even resistant to crystallization. This can hinder the development and formulation of a target pharmaceutical. To investigate the hypothesis that molecules acting as crystallization inhibitors in solution could be transformed into crystallization promoters, additives were synthesized that mimic the pharmaceuticals acetaminophen or mefenamic acid and also possess polymerizable functionality. It was found that, in solution, these additives face-selectively inhibit crystal growth and lead to overall slower crystal appearance. In contrast, when the tailor-made additives were incorporated into an insoluble polymer, the induction time for the onset of crystal formation for both pharmaceuticals was substantially decreased. This approach now allows for the synthesis of tailor-made polymers that decrease the induction time for crystal appearance and may find application in compounds that are resistant to crystallization or in improving the fidelity of heteronucleation approaches to solid form discovery.