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.