Drug Property Optimization: Design, Synthesis, and Characterization of Novel Pharmaceutical Salts and Cocrystal-Salt of Lumefantrine

Lumefantrine (LMF) is a low-solubility antimalarial drug
that cures
acute, uncomplicated malaria. It exerts its pharmacological effects
against erythrocytic stages of Plasmodium spp. and
prevents malaria pathogens from producing nucleic acid and protein,
thereby eliminating the parasites. Modifying the structure of a drug
through the formation of a pharmaceutical cocrystal or salt presents
an avenue through which its physicochemical properties can be optimized.
In this work, we report the design/synthesis and solid-state characterization
of four new salts and cocrystal-salt forms of LMF; an LMF–ADP
salt, monoclinic space group P21/n; an LMF–FUM cocrystal-salt,
monoclinic space group P21/c; an LMF–TAR solvate
salt, monoclinic space group P21/n; and an LMF–SUC
salt, triclinic, space group P1̅ (ADP, dianion of adipic acid;
FUM, monoanion of fumaric acid; TAR, dianion of tartaric acid; SUC,
dianion of succinic acid). These salts can be obtained by solution
as well as by mechanochemical cocrystallization methods. The multicomponent
systems gain their stability from hydrogen and partial ionic bonding
interactions (N–H···O, O–H···O,
N+–H···O–, and
O–H+···O–) originating
from both the dibutyl ammonium (N+–H) site and the
alcohol hydroxyl (−OH) site of LMF toward the carboxylate (−C(O–)O) functional groups of the coformer anions.
SCXRD indicates for LMF–ADP, LMF–TAR, and LMF–SUC
complete transfer of all carboxylic acid protons (H+) toward
the LMF nitrogen, while for LMF–FUM, one of the protons is
transferred (leaving a hydrofumarate monoanion). Using salicylic and
acetylsalicylic acids as coformers yielded coamorphous solids. Solid-state
characterization using powder X-ray diffraction (XRD) and thermal
techniques (DSC and TGA) support and confirm the structures obtained
from single-crystal XRD. LMF–ADP and LMF–FUM present
superior stability under standard conditions (40 ± 2 °C,
75 ± 5% RH, and 3 months) compared to the amorphous samples and
the other two salts. LMF–SUC showed poor thermal stability
by DSC/TGA, and powder XRD patterns for LMF–TAR showed substantial
change after the 3-month stability test. Finally, the calculated equilibrium
solubilities for the cocrystal salts indicate an increase of more
than twofold compared to LMF’s solubility.