Chemistry Graduate Seminar by Vilmali Lopez-Mejias, Massachusetts Institute of Technology

Title: Exploring the New Regions of Polymorph Space through Polymer Induced Heteronucleation

Abstract:
Polymorphism, the ability of molecules to exhibit multiple crystalline phases, is a phenomenon of considerable interest because it challenges the notion that molecules will exclusively adopt the most thermodynamically stable crystalline form. Moreover, the inability to control polymorphism has an enormous economic impact on the regulation and manufacture of crystalline materials, as their properties are intrinsic to their solid form. Therefore, it is not only important to understand the molecular structure of a compound, but also how this structure influences the packing behavior in the solid-state in order to control a product’s performance. Presented here is the design development of polymer-induced heteronucleation (PIHn), a powerful technique for the selective discovery and control of polymorphism that utilizes polymers as heteronucleants. The application of PIHn has allowed access to an unprecedented number of new polymorphs in commercially available pharmaceutical compounds of the fenamic acid class. Octamorphism and pentamorphism of flufenamic and tolfenamic acid, respectively, have been established through the structural elucidation of their solid forms grown using PIHn. In addition, a systematic investigation of the structure-polymorphism relationship in commercial, as well as synthesized analogues of tolfenamic acid supports the notion that a collective ensemble of steric and electronic features common to these structures, a “polymorphophore,” is responsible for the adoption of multiple packing modes within this molecular class. The studies of polymorph selection by polymer heteronuclei introduced here aid in the understanding of the structural factors responsible for the appearance of multiple crystalline forms in molecular compounds. Lastly, a new design strategy for PIHn that combines favorable surface-solute interactions and geometric nano-confinement is discussed. This strategy was able to influence the nucleation kinetics of mefenamic acid (MA), a non-steroidal anti-inflammatory drug that possesses two structurally characterized polymorphs. The use of this strategy provided accesses to the metastable form, MA form II, exclusively on square nanopores imprinted on a biocompatible polymer surface. This provides the first example of selective crystallization of a more soluble pharmaceutical solid form on a functional polymer matrix for potential applications in drug formulation. Ultimately, the design of advanced strategies based on PIHn will help to explore new regions of polymorph space in order to experimentally derive the propensity for polymorphic behavior of a given molecular motif and perhaps provide a pathway to engineer molecular compounds with controlled properties in the presence of a functional polymer heteronucleant.