Abstract
Time-resolved carbamazepine crystallization from wet ethanol has been monitored using a combination of cryoTEM and 3D electron diffraction. Carbamazepine is shown to crystallize exclusively as a dihydrate after 180 s. When the timescale was reduced to 30 s, three further polymorphs could be identified. At 20 s, the development of early stage carbamazepine dihydrate was observed through phase separation. This work reveals two possible crystallization pathways present in this active pharmaceutical ingredient.
Highlights
Polymorphism occurs when a material crystallizes into more than one distinct solid form
In this paper we describe the use of cryo-transmission electron microscopy (Dubochet et al, 1988) to capture the earliest stages of crystallization of the polymorphic pharmaceutical carbamazepine
Alongside CBZDH, which was the dominant form, one crystal of CBZ-III with a somewhat indistinct morphology was identified from its monoclinic unit-cell dimensions a = 7.61, b = 11.30, c = 13.89 A, = 92.43 [Fig. 2(a)]. 3D ED data were collected to 52% completeness from this crystallite
Summary
Polymorphism occurs when a material crystallizes into more than one distinct solid form. Work on aragonite growth, which follows this pathway, has shown that partially aligned nanocrystalline domains spontaneously and simultaneously emerge within the amorphous framework, subsequently maturing to yield a crystal (Walker et al, 2017). These pathways have been extensively studied in inorganic minerals (De Yoreo et al, 2015), but information on organic systems is sparse. Subsequent crystal structure determinations on crystallites measuring only a few hundred nanometres lead to unambiguous polymorph identification (Broadhurst et al, 2020) This combination of imaging and diffraction reveals short-lived polymorphs, and the non-classical mechanism of crystal growth in this material (Walker et al, 2017). Form II contains cavities which can accommodate solvent (Fabbiani et al, 2007; Cabeza et al, 2007)
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