Applications and Mechanistic Studies of Polymorph Selection by PolymerHeteronuclei.

[摘要] Polymer-induced heteronucleation (PIHn) is a powerful technique to control the selective formation of solid-state forms across a broad range of materials; in the studies presented here PIHn was able to access multiple crystalline phases of commercially available pharmaceutical compounds of the fenamic acid class and synthesized analogues thereof. Heptamorphism, pentamorphism, and trimorphism of non-steroidal anti-inflammatory drugs flufenamic, tolfenamic, and niflumic acid have been established through structural elucidation of their solid forms grown using polymers as heteronuclei. Furthermore, a systematic investigation of the structure-polymorphism relationship in other commercial as well as synthesized analogues of tolfenamic acid supports the notion that certain structural motifs within this molecular class, the polymorphophore, promotes the adoption of multiple solid forms.The phase-selection mechanism of PIHn was investigated on the model system acetaminophen through a combined experimental and computational approach. Examination of the polymer-crystal interfaces using powder X-ray diffraction and sum frequency generation vibrational spectroscopy indicates that phase-selection depends on the difference in the accessibility of the functional groups on the surface of the heteronucleant, which in turn may affect interfacial interactions and ultimately direct nucleation along a specific crystal face, the preferred orientation plane. These results were further interpreted with the aid of computed polymer-crystal binding energies using docking simulations. Moreover, this investigation emphasizes the dependence of the polymorph selection process on both the polymer surface and the solvent media as it was possible to change solid form based on the ability of the solvent to mediate hydrogen bonding.The application studies of polymorph selection by polymer heteronuclei presented here aid in the understanding of the structural factors responsible for the appearance of multiple crystalline forms, polymorphs, based on the notion that a collective ensemble of steric and electronic features in these structures, the polymorphophore, is responsible for the adoption of multiple packing modes. Furthermore, the mechanistic studies described here enhance the understanding of a polymorph discovery technique centered on polymer heteronucleants by providing a rationale for the interactions governing phase-selection occurring at the polymer-crystal interface.

[发布机构] University of Michigan

[效力级别] Chemistry

[关键词] Polymorph Selection by Polymer Heteronuclei;Chemistry;Science;Chemistry