Polymorph Identification for Flexible Molecules: Linear Regression Analysis of Experimental and Calculated Solution- and Solid-State NMR Data

The analysis of solid forms is an important but technically challenging part of drug development. Pharmaceutical molecules can often crystallise in different solid forms (polymorphs) with distinct molecular arrangements and properties – one may behave as desired while another dissolves so slowly as to prevent absorption from an oral dose. Failure to identify and control polymorphism can lead to manufacturing issues or even cause a drug to be withdrawn from the market post approval.

Studying the differences between NMR measurements of furosemide in solution and in a solid form, and comparing these to simulated values, we demonstrate that we can easily identify which of the three known solid forms was present. We show that our methodology performs more robustly than established methods and suggest how it may be modified to be more accessible by other groups studying this phenomenon.