Controlling the crystal polymorph by exploiting the time dependence of nucleation rates

TL;DR

This study investigates the competing nucleation of glycine polymorphs, revealing distinct kinetics, and demonstrates how exploiting these differences can significantly improve polymorph purity, while also highlighting the limitations of conventional nucleation data.

Contribution

It provides a quantitative analysis of competing polymorph nucleation, showing how kinetic differences can be exploited to control polymorph outcomes and revealing limitations of traditional nucleation data.

Findings

Nucleation kinetics differ significantly between alpha and gamma glycine.

Exploiting kinetic differences increased gamma polymorph purity by a factor of ten.

Nucleation and growth processes are interconnected, with growth dependent on nucleation timing.

Abstract

Most substances can crystallise into two or more different crystal lattices, called polymorphs. Despite this, there are no systems in which we can quantitatively predict the probability of one competing polymorph forming, instead of the other. We address this problem using large scale (hundreds of events) studies of the competing nucleation of the alpha and gamma polymorphs of glycine. In situ Raman spectroscopy is used to identify the polymorph of each crystal. We find that the nucleation kinetics of the two polymorphs is very different. Nucleation of the alpha polymorph starts off slowly but accelerates, while nucleation of the gamma polymorph starts off fast but then slows. We exploit this difference to increase the purity with which we obtain the gamma polymorph by a factor of ten. The statistics of the nucleation of crystals is analogous to that of human mortality, and using a result from medical statistics we show that conventional nucleation data can say nothing about what, if any, are the correlations between competing nucleation processes. Thus we can show that, with data of our form, it is impossible to disentangle the competing nucleation processes. We also find that the growth rate and the shape of a crystal depends on when it nucleated. This is new evidence that nucleation and growth are linked.