Our previous work (Mol Pharm, 20 (2023) 3427) showed
that crystalline
excipients, specifically anhydrous dibasic calcium phosphate (DCPA),
facilitated the dehydration of carbamazepine dihydrate (CBZDH) and
the formation of an amorphous product phase during the mixing stage
of continuous tablet manufacturing. Understanding the mechanism of
this excipient-induced effect was the object of this study. Blending
with DCPA for 15 min caused pronounced lattice disorder in CBZDH.
This was evident from the 190% increase in the apparent lattice strain
determined by the Williamson–Hall plot. The rapid dehydration
was attributed to the increased reactivity of CBZDH caused by this
lattice disorder. Lattice disorder in CBZDH was induced by a second
method, cryomilling it with DCPA. The dehydration was accelerated
in the milled sample. Annealing the cryomilled sample reversed the
effect, thus confirming the effect of lattice disorder on the dehydration
kinetics. The hardness of DCPA appeared to be responsible for the
disordering effect. DCPA exhibited a similar effect in other hydrates,
thereby revealing that the effect was not unique to CBZDH. However,
its magnitude varied on a case-by-case basis. The high shear powder
mixing was necessary for rapid and efficient powder mixing during
continuous drug product manufacturing. The mechanical stress imposed
on the CBZDH, and exacerbated by DCPA, caused this unexpected destabilization.