1 research outputs found
Exploring Polymorphism: Hydrochloride Salts of Pitolisant and Analogues
Pitolisant hydrochloride is used
to treat excessive daytime sleepiness
in adults with narcolepsy. The drug is formulated as a crystalline
solid, and a monoclinic P21 form has been
claimed in patents, but little additional information about the structure
and polymorphism of the compound has been published. No new forms
were obtained when we grew crystals from solution under various conditions.
Re-examination of the crystals revealed a disordered and partially
hydrated structure that resembles the one reported earlier but is
not identical. Further insight was obtained by synthesizing analogues
of pitolisant with its Cl substituent replaced by Me, F, and Br, followed
by structural analysis of the hydrochloride salts by X-ray diffraction.
Pitolisant hydrochloride and its three analogues showed very similar
solid-state behavior, and each compound yielded new metastable forms
when crystallized from melts. The lifetime of metastable form III
of pitolisant hydrochloride could be extended significantly by adding
small amounts of the fluoro analogue, but none of the metastable forms
could be obtained as single crystals suitable for structural analysis.
Computational predictions of the polymorphic landscapes of pitolisant
hydrochloride and its analogues identified possible structures of
the metastable forms. Dual experimental and computational approaches
are already widely used in polymorphic screening, but our work shows
the value of broadening these searches to include sets of structural
analogues