Directing Crystallization Outcomes of Conformationally Flexible Molecules: Polymorphs, Solvates, and Desolvation Pathways of Fluconazole

Control
over polymorphism and solvatomorphism in API assisted by
structural information, e.g., molecular conformation or associations
via hydrogen bonds, is crucial for the industrial development of new
drugs, as the crystallization products differ in solubility, dissolution
profile, compressibility, or melting temperature. The stability of
the final formulation and technological factors of the pharmaceutical
powders further emphasize the importance of precise crystallization
protocols. This is particularly important when working with highly
flexible molecules with considerable conformational freedom and a
large number of hydrogen bond donors or acceptors (e.g., fluconazole,
FLU). Here, cooling and suspension crystallization were applied to
access polymorphs and solvates of FLU, a widely used azole antifungal
agent with high molecular flexibility and several reported polymorphs.
Each of four polymorphic forms, FLU I, II, III, or IV, can be obtained
from the same set of alcohols (MeOH, EtOH, isPrOH) and DMF via careful
control of the crystallization conditions. For the first time, two
types of isostructural channel solvates of FLU were obtained (nine
new structures). Type I solvates were prepared by cooling crystallization
in Tol, ACN, DMSO, BuOH, and BuON. Type II solvates formed in DCM,
ACN, nPrOH, and BuOH during suspension experiments.
We propose desolvation pathways for both types of solvates based on
the structural analysis of the newly obtained solvates and their desolvation
products. Type I solvates desolvate to FLU form I by hydrogen-bonded
chain rearrangements. Type II solvates desolvation leads first to
an isomorphic desolvate, followed by a phase transition to FLU form
II through hydrogen-bonded dimer rearrangement. Combining solvent-mediated
phase transformations with structural analysis and solid-state NMR,
supported by periodic electronic structure calculations, allowed us
to elucidate the interrelations and transformation pathways of FLU.