Compared
to free base forms, salt forms are more frequently obtained
as hydrates during solid form screening, although physically unstable
hydrates are difficult to select for drug development. In this study,
loxoprofen sodium dihydrate (LOXNa-2H2O), a widely used
anti-inflammatory drug, was selected as a model drug to investigate
the potential use of sugar as a coformer for cocrystallization with
Na salts and the effect of salt cocrystallization with sugars on hydrate
formation. In a screening study by liquid-assisted grinding with ethanol,
two sugars, ribose (RIB) and fructose (FRU), formed new salt cocrystals
with LOXNa. Differential scanning calorimetry, thermogravimetry, temperature-programmed
powder X-ray diffraction, and water vapor sorption/desorption isotherm
measurements revealed that the LOXNa·RIB and LOXNa·FRU salt
cocrystals were a monohydrate and anhydrate, respectively. Single-crystal
X-ray structural analysis of both salt cocrystals showed that direct
ionic interaction did not occur between the Na cation and the carboxylate
anion of LOX. Instead, sugars were coordinated around a Na cation,
and a consecutive alternating structure of Na cations and sugars with
a one-dimensional chain was formed along the b-axis.
These characteristic chain structures prevented water molecules from
approaching the Na cation and reduced the propensity for hydrate formation.
FRU possesses one more hydroxyl group than the RIB molecule. The resulting
strong hydrogen bonding network stabilized the LOXNa-FRU as an anhydrate
without water molecules. Since sugars are safe and inexpensive excipients
with various species, they can be useful coformers for salt cocrystals
with various drug Na salts.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.