Towards Exhaustive and Automated High-Throughput Screening for Crystalline Polymorphs

Methods
capable of exhaustively screening for crystal polymorphism
remain an elusive goal in solid-state chemistry. Particularly promising
among the new generation of approaches is polymer-induced heteronucleation
(PIHn), a tool utilizing hundreds of unique polymers for granting
kinetic access to polymorphs. Here PIHn is redeployed in a high density
format in which 288 distinct polymers, each acting as a heteronucleant,
are arrayed on one substrate. This format allows determining the outcome
of thousands of crystallizations in an automated fashion with only
a few milligrams of sample. This technology enables the study of a
broader range of targets, including preclinical candidates, facilitating
determination of polymorphism propensity much earlier in the drug
development process. Here the efficacy of this approach is demonstrated
using four pharmaceutically relevant compounds: acetaminophen, tolfenamic
acid, ROY, and curcumin.