A Novel Solid Form of Erlotinib: Synthesis by Heterogeneous Complexation and Characterization by NMR Crystallography

We describe the synthesis of a novel complex of the anticancer "active pharmaceutical ingredient erlotinib (<b>ERL</b>) via heterogeneous nucleation on polished zinc tiles. The resulting product, <b>ERL</b> _<b>2</b> <b>·ZnCl</b> _<b>2</b> , is characterized by single-crystal X-ray diffraction, multinuclear solid-state NMR (ssNMR) spectroscopy, and density functional theory (DFT) calculations. Also characterized are the hydrochloride salt (<b>ERL·HCl</b>) and monohydrate free base (<b>ERL·H</b> _<b>2</b> <b>O</b>) forms of erlotinib. ¹³C ssNMR spectroscopy is useful for site-by-site assignment and rapid fingerprinting, while also providing preliminary structural interpretations, such as the number of molecules in the asymmetric unit. ³⁵Cl ssNMR can readily differentiate between the chloride ions in <b>ERL·HCl</b> and the covalently bonded chlorine in <b>ERL</b> _<b>2</b> <b>·ZnCl</b> _<b>2</b> . ¹⁵N ssNMR proves to be critical here because of the large isotropic chemical shift differences between <b>ERL·H</b> _<b>2</b> <b>O</b>, <b>ERL·HCl</b>, and <b>ERL</b> _<b>2</b> <b>·ZnCl</b> _<b>2</b> . The ¹⁵N chemical shift tensors are linked directly to differences in structure and bonding with the aid of DFT calculations. Together, these results demonstrate the utility of multinuclear NMR crystallography for the characterization of solid forms of APIs, especially when other analytical techniques face significant challenges.