Using a laser monitoring observation technique, we determined the solubilities of paroxetine hydrochloride
hemihydrate in N,N-dimethylformamide, methyl isobutyl ketone, tetrahydrofuran, ethyl acetate, methanol,
ethanol, 1-propanol, 1-butanol, and 2-butanol by the synthetic method from 286 K to 363 K. Results of
these measurements were correlated by an empirical equation.
Three intrinsic properties of solvent
were used to evaluate the effects of solvent on polymorph formation
of prasugrel hydrochloride. In situ Raman spectroscopy, FTIR, and
powder X-ray diffraction were used to characterize two solvent-free
polymorphs and five solvates of prasugrel hydrochloride, the two of
which were reported for the first time. Reactive crystallization in
24 different pure solvents was studied at 313.15 K. It was found that
polymorph formation of prasugrel hydrochloride directly depends on
the solvents used in the experiments. Form I was obtained in solvents
with low values of hydrogen bond donor ability (HBD), while form II
was obtained in solvents with high values of HBD. The thermodynamic
and kinetic reasons for the solvent effects were explained by using
the solubility data and the nucleation experiments. The solubilities
of forms I and II were experimentally determined by a gravimetric
method, and an equation based on the linear free energy approach for
predicting solubility was applied to correlate the solubility of form
II. It was found that the values of HBD of the solvents also affect
the solubility of prasugrel hydrochloride. From desolvation experiments
of the five solvates in seven pure solvents at 293.15 and 313.15 K,
it was found that the polymorphs of prasugrel hydrochloride obtained
after desolvation are closely related to the solvents. The heterogeneous
nucleation of form I during the solvent-mediated polymorphic transformation
was also studied at 313.15 K, and it was found that the solute–solvent
interactions will also affect the nucleation rate of form I. A hypothesis
was then proposed that prasugrel hydrochloride form I is prone to
crystallize when van der Waals force dominates the interaction between
the solute and the solvent molecules, while prasugrel hydrochloride
form II is prone to nucleate and grow when hydrogen bonding dominates
the interaction between the solute and the solvent molecules.
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