Abstract

In a previous contribution, entitled “First Steps for the Direct Purification of L-Leu-L-Leu Dipeptide
through Cocrystallisation”, we reported and evidenced cocrystallisation as a route to purify freshly synthesised
TFA-contaminated Leu-Leu peptides. In this contribution ternary and quaternary crystal forms, isolated as
transient phases to the previously reported pure cocrystals, are presented. This contribution and the one
previously reported present the outcomes of large cocrystallisation screening undertaken on the L-Leu-L-Leu
Dipeptide; where a competing range of multiple crystal forms from target co-crystal to TFA salt are accessible.
As a key point for this contribution we report the isolation of transient phases that consist of Leu-Leu peptide
(both with amidic and carboxylic C-terminals) either with pyridazine, 1H-pyrazole, pyridine N-oxide or pyrazine
plus TFA, or solvent alcohol or water with TFA. Such a diversity of multicomponent phases add further to the
understanding of the differential crystallisation process established when cocrystallisation is used to purify the
crude synthesised peptide product contaminated with TFA. A description of the overall packing landscape was
undertaken from a crystal engineering point of view to illustrate how the presence of trifluoroacetate anions,
strong hydrogen bond acceptors, affect the crystal packing. Typically, the Leu-Leu peptide forms a multi-layered
structure with guest in cavities between the layers; however, alternative novel arrangements were also seen. The
structures are part of a wide-landscape of possible complexes that are difficult to isolate as they often represent
transient phases that are hard to reproduce. Nevertheless, the reported phases give further insight into the
purification through cocrystallisation pathway and, critically, help to understand the interplay between crystal
growth and the packing landscape.