Many important properties of the active pharmaceutical ingredient (API) in drugs are reliant on the crystal structure. A drug’s efficacy, for example, is largely dependent on the dissolution rate of the API in the intestinal tract. To improve physiochemical properties of APIs, scientists are discovering unique crystalline forms. Often crystals created by these novel techniques cannot be analyzed by single-crystal diffraction. Nuclear Magnetic Resonance crystallography (NMR), the combination of computational modeling and NMR data, may solve the crystal structure of these novel API crystals. This work will focus on solid-state NMR and Density Functional Theory (DFT) calculations of aniline derivatives and novel crystalline forms of erlotinib, a tyrosine kinase inhibiting drug used in the treatment of pancreatic and non-small cell lung cancers. New polymorphic forms of erlotinib have been prepared by heteronucleation using self-assembled monolayers of metal oxide tiles in organic acid. High resolution solid-state 15N NMR of the various forms of erlotinib display significant chemical shift changes. In order to understand the nature of 15N chemical shift variations of erlotinib’s quinazoline moiety, the chemical shift anisotropy of aniline derivatives is explored experimentally and by DFT calculations. Preliminary 15N chemical shift anisotropy measurements using 1D magic-angle-turning will be presented. The NMR parameters, calculated by the GIPAW method, are modeled with the RBPE functional and a planewave basis set after performing geometry optimizations of the crystal structures using the D2* dispersion correction method. Polynomic trends will be presented to show the relationship between principal values and the amine planarity. In addition, the anisotropy correlates with the pka of the aniline derivative. The chemical shift correlations of the aniline derivatives help provide a better understanding of the various crystal structures of erlotinib.

Investigating pharmaceutical drug crystals through solid-state NMR and density functional theory

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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