Crystallization and Solid-State Characterization of
the Hemihydrate of Albuterol Hemisulfate
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Abstract
Comprehensive
solid-state characterization and development of a
controlled crystallization process of the recently discovered hemihydrate
of albuterol hemisulfate (ASH) are presented. The ASH is physically
stable when stored at ambient conditions for at least 3 months and
at 0% relative humidity for at least 2 months. The thermal dehydration
of the hydrate occurs at ∼100 °C and proceeds without
a loss of crystallinity. The dehydrated crystal structure persists
up to decomposition temperature (∼160–185 °C).
An inspection of the single-crystal X-ray structure revealed an isolated-site
(class A) hydrate with a complex three-dimensional supramolecular
network sustained via multiple strong hydrogen bonds. Thermodynamic
stability studies established that the hydrate is more-stable relative
to the nonsolvated form at <i>a</i><sub>w</sub> > 0.63
at
5 °C, <i>a</i><sub>w</sub> > 0.65 at 20 °C,
and <i>a</i><sub>w</sub> > 0.80 at 40 °C. The constructed
phase
diagram for the anhydrate–hydrate system guided the development
of a controlled crystallization process at a 0.5 g scale with a yield
of ∼92 wt % using a combination of cooling and antisolvent
addition crystallizations