Crystallization and Solid-State Characterization of the Hemihydrate of Albuterol Hemisulfate

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 aw > 0.63 at 5 °C, aw > 0.65 at 20 °C, and aw > 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.