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Nucleation of One Polymorph by Another

Lian Yu, University of Wisconsin (Madison)

We continued to study the cross-nucleation between crystal polymorphs, a newly discovered mechanism of crystal nucleation in polymorphic systems.  Polymorphism is the ability of the same substance to crystallize in different structures.  Polymorphism is important in developing drugs, pigments, explosives, and other materials because polymorphs have different properties. Controlling polymorphism remains an unsolved problem; for example, polymorphs may crystallize concomitantly and even suddenly disappear. Cross-nucleation is the nucleation of a new, faster-growing polymorph on the growing crystals of the initial polymorph. This phenomenon is important because seeding is the principal method for controlling polymorphs.  It invalidates the common assumption that the polymorph of the initial nucleation is the polymorph of the final crystallization product. The phenomenon is also important to the theory of nucleation, a foundation of science and technology.  It differs from other nucleation processes in that the new phase nucleates on an initial phase of the same substance that continues to grow.
Major accomplishments during this period:
(1) We reported the first systematic study of the cross-nucleation between D-mannitol polymorphs in seeded crystallization.  Seeding the liquid of D-mannitol with its three polymorphs revealed several cases of cross-nucleation.  Only seeds of the alpha polymorph (the structure of the intermediate thermodynamic stability and the fastest growth rate) yielded the same polymorph in new growth.  Seeds of the delta polymorph yielded the alpha polymorph in new growth.  Seeds of the beta polymorph yielded the beta polymorph in new growth at small undercoolings; at lower temperatures, the alpha polymorph nucleated on beta seeds and its amount in the product increased with decreasing temperature.  Seeding with single crystals of the beta polymorph showed that the orientation of the seed crystal affected how much the seed polymorph could grow before cross-nucleation occurred.  Cross-nucleation makes seeding ineffective for achieving polymorphic selectivity, but is sometimes avoidable by choosing suitable crystallization conditions. 

(2) CrystEngComm invited this lab to submit a Highlight to describe our research on cross-nucleation.  Whereas controlling the crystallization of a liquid able to yield multiple polymorphs is often assumed to be a matter of controlling the initial nucleation, the article argues that this view is flawed. An early nucleating polymorph can nucleate another, faster-growing polymorph. This review examines how cross-nucleation is controlled by thermodynamic and kinetic factors and how it can aid the discovery of new polymorphs.  The selective crystallization of a polymorph depends not only on the initial nucleation but also on the cross-nucleation between polymorphs and the relative growth rates of polymorphs.
(3) We discovered new polymorphic systems that exhibit the cross-nucleation phenomenon: Phenobarbital and Carbamazepine/Nicotinamide co-crystal.  Together with our previously studied systems D-mannitol and, these new systems help assess the generality of the phenomenon.  The Carbamazepine/Nicotinamide system provides the first example of cross-nucleation between polymorphs observed in a multi-component system.

(4) We made progress toward developing a new and more rigorous way to determine the rate of cross-nucleation.  The previous method relies on counting all cross-nucleation events on a single spherulite of the initial polymorph.  It suffers from an inherent error that later events occur on a surface that is partially diminished by earlier events.  The new method uses only the very first cross-nucleation event of each free-growing spherulite for calculation and is therefore free from such bias. This is the first time nucleation kinetics can be quantitatively studied on identical virgin surfaces.
(5) We used cross-nucleation to initiate the growth of polymorphs that do not spontaneously nucleate near the glass transition temperature, which was instrumental for our study to elucidate the crystal structure dependence of the fast crystal growth from organic glasses. A remarkable property of certain glass-forming liquids is that a fast mode of crystal growth is activated near the glass transition temperature Tg and continues in the glassy state.  This growth mode, termed GC (glass-crystal), is so fast that it is not limited by molecular diffusion in the bulk liquid.  We have studied the GC mode by growing seven polymorphs from the liquid of, currently the top system for the number of coexisting polymorphs of known structures.  Some polymorphs did not show GC growth, while others did, with the latter having higher density and more isotropic molecular packing.  These observations enabled us to evaluate various explanations for GC growth and conclude that it is solid-state transformation enabled by local molecular motions native to glasses and disrupted by the liquid’s structural relaxation.

In this year, four papers from this lab acknowledge PRF support, as well as 12 presentations (all invited) at leading scientific societies, universities, and companies.

Ongoing studies aim to understand why cross-nucleation has different kinetics from other types of nucleation in the same liquid, to complete the development of the new method to determine rates of cross-nucleation, and to determine how the new systems showing cross-nucleation differ from those already characterized.

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