Sulfonic Acid Salts of Donepezil and Stabilization of Amorphous Donepezil via Formation of Amorphous Salts

Three
crystal structures of donepezil salts formed with sulfonic
acids were obtained. Interestingly, donepezil-besylate and donepezil-tosylate
share similar crystal molecular conformations and crystal packing.
On the basis of PXRD patterns, donepezil-mesylate and donepezil-esylate
are likely to share similar crystal structures. The sulfonyl hydroxides
of all three sulfonic acids form an intermolecular hydrogen bond with
the piperidyl amine of donepezil. Solid state characterization showed
that the Tg’s of all four amorphous
donepezil salts are similar to each other and increase significantly
compared to Tg of donepezil. Stability
analysis found that the amorphous salts of donepezil formed with mesylate
and esylate led to significantly improved physical stability under
accelerated stability conditions, but the other donepezil-sulfonic
acid salts did not. Solubility data showed that mesylate/esylate salts
of donepezil significantly increase the solubility of donepezil that
is not shown by other salt forms. Solubility analysis indicated that
the solubility of donepezil-mesylate and donepezil-esylate is extremely
high compared to that of donepezil-besylate and donepezil-tosylate.
We concluded that the extremely high solubility is responsible for
delaying the rate of nucleation and thus improving the physical stability
of amorphous donepezil. This study highlights that the aqueous solubility
of amorphous material is an important factor when considering the
physical stability of amorphous material under high relative humidity.