Amorphous drug-polymer salt with high stability under tropical conditions and fast dissolution: The challenging case of lumefantrine-PAA.

Abstract

Lumefantrine (LMF), a high-mobility and easy-to-crystallize WHO drug for treating malaria, can form an amorphous salt with poly(acrylic acid) (PAA) that is remarkably stable against crystallization at high humidity and temperature and has fast dissolution rate. The amorphous salt up to 75 % drug loading was synthesized under a mild slurry condition easily implemented in basic facilities for global health. Salt formation was confirmed by IR spectroscopy and the much elevated glass transition temperature. At 50 % drug loading, the amorphous salt resists crystallization for at least 18 months under the highly stressful condition of 40°C and 75 % RH. In contrast, the dispersion containing neutral LMF in PVP fully crystallized in 4 d and the dispersion in HPMCAS, a weak polyelectrolyte of lower charge density than PAA, crystallized by 50 % in 7 d. The amorphous salt at 50 % drug loading showed much faster dissolution than crystalline LMF: In SGF, the area under the curve (AUC) was 30 times larger within the gastric emptying time (4 h); in FaSSIF, the enhancement was even larger - by 200 times. Nanodroplets were detected during the dissolution in SGF, possibly accounting for the apparent enhancement of dissolution rate. The LMF-PAA example as a challenging case, along with the previously reported clofazimine-PAA, demonstrates the general utility of amorphous drug-polymer salts to achieve high stability under tropical conditions and enhanced dissolution and bioavailability.