Crystal Structures of Tetramorphic Forms of Donepezil
and Energy/Temperature Phase Diagram via Direct Heat Capacity Measurements
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Abstract
Donepezil
is used for the palliative treatment of mild to moderate
dementia of the Alzheimer’s disease. Donepezil crystallized
as four solvent-free polymorphs including forms I, II, C, and F which
differ in molecular conformations and packing. Conformational difference
comes from the torsion of the 2, 3-dihydroinden-1-one moiety and methyl-benzyl
ring with respect to piperidyl ring. Similar melting temperatures
and heats of fusion were observed for four solvent-free polymorphic
forms and made polymorph selection by solvent crystallization method
poor. The relative thermodynamic stability relationships of each polymorph
with respect to the amorphous form were determined using direct heat
capacity (<i>C</i><sub><i>p</i></sub>) measurement
and then used to evaluate the relative thermodynamic stability between
polymorphs. Form F was the stable form over the temperature ranges
we studied. Other than form F, form C was the stable form among three
polymorphic forms including I, II, and C, below 53 °C, and is
enantiotropically related to both forms I and II. Form II is the stable
form above 53 °C and monotropically related to form I. The thermodynamic
relationships between polymorphs were further confirmed by measuring
the solubility over temperatures ranging from 35 to 60 °C in
ethanol. Slurry conversion in ethanol, isopropyl alcohol, and cyclohexane
was conducted to provide a guideline to obtain pure and desired polymorphic
forms. The establishment of the thermodynamic relationships among
four polymorphic forms greatly facilitated polymorph selections of
donepezil