The cultivation of single crystals from solution is usually a time-consuming trial-and-error game. Here, we report a general strategy for rapidly cultivating single crystals from melt microdroplets within tens of...
Overprediction is a major limitation of current crystal structure prediction (CSP) methods. It is difficult to determine whether computer-predicted polymorphic structures are artefacts of the calculation model or are polymorphs that have not yet been found. Here, we reported the well-known vitamin nicotinamide (NIC) to be a highly polymorphic compound with nine solved single-crystal structures determined by performing melt crystallization. A CSP calculation successfully identifies all six Z′ = 1 and 2 experimental structures, five of which defy 66 years of attempts at being explored using solution crystallization. Our study demonstrates that when combined with our strategy for cultivating single crystals from melt microdroplets, melt crystallization has turned out to be an efficient tool for exploring polymorphic landscapes to better understand polymorphic crystallization and to more effectively test the accuracy of theoretical predictions, especially in regions inaccessible by solution crystallization.
Griseofulvin
(GSF) is a clinically used antifungal drug that was
reported to have three true polymorphs (Forms I–III) over the
past eight decades. Here, we present the discovery of two new polymorphs
(denoted Forms IV and V) that are accessible only in the presence
of polyethylene glycol (PEG). The crystal structures of Forms IV and
V were determined by X-ray crystallography using single crystals cultivated
by melt crystallization. The identification and crystallization behavior
of Forms IV and V were fully investigated. A solid-form landscape
of melt-crystallized GSF in the presence of PEG was established to
describe the complicated phase conversions among six solid forms,
including five true polymorphs and a previously known GSF-PEG inclusion
complex. The influence of the molecular weight and content of PEG
on the polymorphism of GSF was studied. This work suggests that PEG
addition is an alternative strategy that cannot be neglected in polymorphism
screening. The results also expand our understanding of the complicated
crystallization behavior of GSF in dispersions with PEG and highlight
the importance of polymorphism control during the manufacture and
storage of PEG-based solid dispersions to achieve reproducible and
consistent pharmaceutical performance.
Identification of a thermodynamically stable polymorph
is an important
step in the early stage of drug development. Ritonavir (RIT) is a
well-known case where the most stable polymorph II emerged after being
marketed, leading to a loss of $250 million. Herein, we report the
findings that routine melt crystallization can reveal the late-appearing
polymorph II of RIT at small supercooling, but the probability of
nucleation is very low. The addition of 30–50% polyethylene
glycol (PEG) promotes the crystallization of Form II as the only phase
at low supercooling, making it easier to detect in polymorphism screening.
During the course of our research, a new polymorph, denoted Form III,
was unexpectedly discovered, crystallizing as the major phase from
neat RIT melts. Single crystals of Form III were grown from melt microdroplets.
Benefiting from the ability of synchrotron radiation to detect weak
diffraction signals that cannot be accessible by a laboratory diffractometer,
a reasonable structure of Form III was solved with slight disorder
relative to thiazole groups (P1 space group and Z′ = 4). The thermodynamic stability ranking of the
three true polymorphs is Form II > Form I > Form III, as opposed
to
the order of solubility. The capacity to efficiently reveal rich polymorphs,
especially the kinetically hindered polymorph, and rapidly grow single
crystals of a new phase for structure determination together highlights
the necessity of incorporating melt crystallization into routine methods
for pharmaceutical polymorphism screening.
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