We studied 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 (as the ability of carbon to crystallize as diamond, graphite, and C₆₀).� Polymorphism is important in the development of drugs, pigments, explosives, and other materials because polymorphs have different physical properties. �Controlling polymorphism remains an unsolved problem in industrial crystallization; for example, polymorphs may crystallize concomitantly and even suddenly disappear.� Cross-nucleation between polymorphs 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.� Cross-nucleation 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 kinetic measurement of cross-nucleation between polymorphs, a newly discovered phenomenon important to the theory and control of crystallization (J. Phys. Chem. B 2006, 110, 7098).� D-mannitol crystallized from its melt first as the d polymorph and then as the a polymorph, with a nucleating on d.� The kinetics of cross-nucleation was determined from the frequencies of a nuclei appearing on d spherulites, the distances between a and d nuclei, and the growth rate of the d spherulite.� The presence of poly(vinylpyrrolidone), a melt-miscible additive, accelerated cross-nucleation.

(2) We discovered a solid solution of the enantiomers of the chiral drug tazofelone (TZF) by seeding its racemic liquid with enantiomerically pure crystals (J. Am. Chem. Soc. 2006, 128, 11985).� This is the rarest of three outcomes of crystallizing a racemic liquid of enantiomers.� Without seeding, the racemic liquid crystallized as a racemic compound.� The solid solution has similar structure as the enantiomorph, but has static disorder arising from the random substitution of enantiomers.� It is a kinetic product of crystallization made possible by its faster growth rate compared to that of the competing racemate.� Its free energy continuously varies with the enantiomeric composition between those of the conglomerate and the racemates.� The ability of TZF to simultaneously form racemate and solid solution originates from its conformational flexibility.� Similar solid solutions of enantiomers may exist in other systems and may be discovered in similar ways.� The study demonstrates the use of cross-nucleation for discovering and engineering crystalline materials to optimize physical properties.

(3) We studied the cross-nucleation between D-mannitol polymorphs (a, b, and d) in seeded crystallization (Cryst. Growth & Design 2007, in press). �Only seeds of �polymorph a (phase of intermediate thermodynamic stability and fastest growth rate) yielded the same polymorph in new growth.� d seeds yielded a new growth. �b seeds yielded b new growth only at undercoolings of a few degrees; at lower temperatures, polymorph a nucleated on b seeds and its amount increased with decreasing temperature. �Seeding with b single crystals (rods elongated along c) showed that seed orientation affected how much the seed polymorph could grow before cross-nucleation occurred.� Cross-nucleation makes seeding ineffective for achieving polymorphic selectivity, but can be avoided under suitable crystallization conditions.

(4) In an invited Highlight, we reviewed how cross-nucleation is controlled by thermodynamic and kinetic factors and how it can aid the discovery of new polymorphs (CrystEngComm 2007, Advance Article, DOI: 10.1039/b709260c).� It is common to assume that controlling polymorphism in crystallization is a matter of controlling the initial nucleation.� This view is flawed because an early nucleating polymorph can nucleate another, faster-growing polymorph. �The selective crystallization of polymorphs depends not only on initial nucleation but also on cross-nucleation between polymorphs and relative growth rates of polymorphs.

We gave 11 presentations on this research (nine invited) at ACS, AAPS, Frontiers of X-Ray Analysis, TAP Pharmaceuticals, Vertex Pharmaceuticals, Association for Crystallization Technologies, University of Kentucky, University of Washington, and University of Wisconsin.

Ongoing studies aim to understand how cross-nucleation is related to primary nucleation.� We are measuring the kinetics of the two nucleation processes in the same liquid and from their different kinetics, will elucidate their different activation barriers.� Special attention is directed to how interfacial velocity affects cross-nucleation.� We are studying how nucleation sites differ for the two types of nucleation; in particular, whether they recur in space or are random.� We are using the dependence of nucleation rate on liquid thickness to probe whether cross-nucleation occurs at crystal/liquid interfaces or is aided by container walls.� To understand how to inhibit cross-nucleation, we are studying the effect of polymeric additives on the phenomenon.� We will use cross-nucleation to nucleate novel crystal forms as in the discovery of the solid solution of tazofelone enantiomers.