posted on 2023-12-06, 17:33authored byPeerapon Rapeenun, Charline J. J. Gerard, Clément Pinètre, Yohann Cartigny, Paul Tinnemans, René de Gelder, Adrian E. Flood, Joop H. ter Horst
Chiral compounds that crystallize
as conglomerates from racemic
mixtures are desirable from the perspective of chiral resolution since
they are relatively easy to resolve using, for instance, preferential
crystallization. Here, a screening methodology to find conglomerate
cocrystals is demonstrated using racemic praziquantel (rac-PZQ). Cocrystallization of rac-PZQ was performed
using liquid-assisted grinding (LAG) with 20 potential achiral coformers.
LAG screening results show that N-phenyl urea (PU)
and 1,3-dimethylthiourea (DMTU) are the only two achiral coformers
that form new cocrystal compounds with rac-PZQ. Single-crystal
structure determination of cocrystals grown from solution shows that
the rac-PZQ:PU cocrystal is a racemic cocrystal with
space group P21/c, while
the rac-PZQ:DMTU cocrystal is a conglomerate cocrystal
with space group P21. Under gentle conditions, rac-PZQ:DMTU forms a true conglomerate cocrystal from solution.
However, when grown from solution under higher supersaturations, the
obtained single crystals of rac-PZQ:DMTU appear to
be disordered racemic twin cocrystals: these contain alternating domains
of (almost) pure enantiomers of PZQ that are related by inversion
symmetry. The disordered racemic twin cocrystals probably form due
to refreshment of the enantiomer at the crystal surface being diffusion-limited
from the bulk solution to the boundary layer. Discovery of a conglomerate
cocrystal form of PZQ opens up exciting possibilities for the optical
resolution of PZQ by preferential crystallization, allowing for easy
preparation of pure enantiomer formulations of this important API.