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dc.contributor.authorStephenson, G.A.*
dc.contributor.authorKendrick, John*
dc.contributor.authorWolfangel, C.*
dc.contributor.authorLeusen, Frank J.J.*
dc.date.accessioned2014-04-28T11:21:23Z
dc.date.available2014-04-28T11:21:23Z
dc.date.issued2012
dc.identifier.citationStephenson, G. A., Kendrick, John, Wolfangel, Craig, Leusen, Frank J. J. (2012) Symmetry breaking: polymorphic form selection by enantiomers of the melatonin agonist and its missing polymorph. Crystal Growth & Design, 12 (8), 3964-3976.
dc.identifier.urihttp://hdl.handle.net/10454/6203
dc.description.abstractSynthesis of a melatonin agonist for treatment of sleep disorders produced a pair of enantiomers, of which one is biologically active. Two polymorphs were discovered using the inactive enantiomer, conserving the active enantiomer for toxicological testing. Later studies with the active enantiomer yielded only the metastable form, despite more than 1000 attempts to isolate the stable form. The difficulty is surprising, since the stable form is favored by 0.7 kcal mol–1, which is toward the extreme for stability differences between organic polymorphs. Study of individual enantiomers allowed the phase behavior of polymorphs of greatly different energy to be examined without interconversion. A number of unusual features are noted. After the stable polymorph of the inactive enantiomer was nucleated, the metastable form became very difficult to isolate. The metastable form converts into a less soluble monohydrate structure in water, whereas the stable polymorph does not due to its reduced activity. Both chiral polymorphs are denser than the racemic crystalline form at low temperature, the stable form being at the extreme for chiral-racemic pairs. Free energy-temperature relations predict “spontaneous resolution” of the racemic crystalline form into a conglomerate mixture of stable polymorph at low temperature. The unusual characteristics of the system are explained by hydrogen bonding and conformational flexibility of the molecule. Ab initio calculations aid in understanding the relative contributions of these interactions to the lattice energies and the role that conformational energy differences play in the polymorphic stability. This system highlights the importance of the creation of the very first nuclei of a crystalline form. The reluctance of the stable form to nucleate is attributed to a large energy difference between polymorphic forms. The large interfacial tension for primary nucleation reduces the probability of forming clusters of size sufficient for favorable growth in the absence of heterogeneous nucleation. This study highlights how nucleation of a new form can revise the readily “accessible” region of a compound’s crystal form landscape.en
dc.relation.isreferencedbyhttp://dx.doi.org/10.1021/cg300398a
dc.subjectREF 2014; Melatonin agonist; Enantiomers; Polymorphs;
dc.titleSymmetry breaking: polymorphic form selection by enantiomers of the melatonin agonist and its missing polymorph
dc.typeArticle


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