Dantrolene represents yet another
interesting example of abundant
molecular crystal polymorphism existing in at least six different
neat polymorphs, three of which can be obtained via crystallization
(I–III) and an additional three (IV– VI) via solid-state
dehydration from three different monohydrates (MH-I–MH-III).
The reasons for polymorph formation were rationalized by analyzing
the crystal structures of the polymorphs and hydrates used in their
preparation. The thermodynamic relations among the polymorphs were
established from calorimetric data, solubility measurements, and lattice
energy calculations.
Analysis of crystal
structures, molecular properties, interaction
strength in solution, and computationally generated nonsolvated form
crystal structure landscapes of five chloronitrobenzoic acid isomers
and two additional 2-substituted 4-nitrobenzoic acids were used to
rationalize the obtained solvate landscape of these compounds. Screening
of the solid forms was performed for each of the compounds, and crystal
structures of the obtained nonsolvated forms and selected solvates
were determined. Molecular conformation, intermolecular interactions,
and packing efficiency of nonsolvated forms and solvates were analyzed
to understand factors contributing to structure stabilization and
determining the formation of the observed crystal structures. Computationally
generated crystal structure landscapes of nonsolvated forms were tested
for the possibility to predict the propensity to form solvates and
identify polymorphic compounds. It was observed that most of the solvates
were obtained with solvents acting as strong hydrogen bond acceptors
and/or able to form aromatic interactions. Solute–solvent association
Gibbs energy representing interaction strength was found to be the
most apparent identifiable factor explaining the solvate formation
of the studied compounds, and using this tool, the existence of 3
new multicomponent phases was successfully predicted.
In
a study of the solid form landscape of R-encenicline hydrochloride
(Enc-HCl), it was found that this compound is dodecamorphic and presents
the first published example of polymorphism with a record-breaking
10 solved crystal structures. In addition to the four known polymorphs,
eighth new polymorphs and their precursor solvates as well as several
new hydrates have been characterized. The polymorph formation behavior
is investigated by analyzing crystal structures of polymorphs and
solvates used in their preparation. Molecular packing in crystal structures
of the polymorphs is highly similar to that in the precursor solvates,
whereas conformations in all structures are nearly identical and correspond
to the same energy minimum.
Encenicline hydrochloride
(Enc-HCl) crystallizes in four different
monohydrate phases, but at the same time crystallization in a nonsolvated
phase is not observed, indicating that water plays a crucial role
in guiding the crystallization process and ensuring structure stability.
All monohydrate phases show exceptionally high stability, and the
main structural motif stays intact even after dehydration, leading
to isostructural (for I and II) or isomorphic (for III) desolvates.
Three monohydrate phases with determined crystal structure information
consists of Enc-HCl-water hexamers that are stacked into similar slabs,
that are further packed identically in monohydrates I, II, and III.
The features of these hexamer slabs determine the properties of the
Enc-HCl monohydrates and dehydrates, the dehydration mechanism, and
stability of each phase. It was justified that in the Enc-HCl system
efficient intermolecular interactions provided by the incorporation
of water in the crystal structure play a crucial role in stabilization
of the structures.
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