Salt Selection and Simultaneous Polymorphism Assessment via High-Throughput Crystallization: The Case of Sertraline

High-throughput (HT) crystallization experiments were conducted with sertraline free base in the presence of mono-, di-
and triacidic salt formers. Over 3600 crystallization trials were
conducted, leading to the identification and characterization
of 18 crystalline salt forms. Due to the large number of
crystallization conditions for a given salt type, it was possible
to gauge the propensity of a given salt form to exhibit
polymorphism. Four salt forms were found to exist (in this
limited screen) as monomorphic materials. Unlike the HCl salt
in the marketed drug product, the HBr salt appears resistant
to polymorphism, crystallizing as a single form from over 140
discrete trials. This observation underscores the lack of predictability of polymorphic behavior of pharmaceuticals even when
seemingly minor changes to the composition are made. The
experiments highlight the importance of coupling salt selection
studies with simultaneous polymorph screening to gain a more
comprehensive understanding of solid form diversity as part
of the form selection process for pharmaceutical development.