Amorphous Drug–Polymer Salt with High Stability under Tropical Conditions and Fast Dissolution: The Case of Clofazimine and Poly(acrylic acid)

Abstract

We report that the stability of amorphous clofazimine (CFZ) against crystallization is vastly improved by salt formation with a polymer without sacrificing dissolution rate. A simple slurry method was used to produce the amorphous salt of CFZ with poly(acrylic acid) (PAA) at 75 wt % drug loading. The synthesis was performed under a mild condition suitable for thermally unstable drugs and polymers. Salt formation was confirmed by visible spectroscopy and glass temperature elevation. The amorphous salt at 75 wt % drug loading is remarkably stable against crystallization at 40 °C and 75% RH for at least 180 days. In contrast, the amorphous solid dispersion containing the un-ionized CFZ dispersed in poly(vinylpyrrolidone) crystallized in 1 week under the same condition. The high stability of the amorphous drug–polymer salt is a result of the absence of a drug–polymer crystalline structure, reduced driving force for crystallizing the free base, and reduced molecular mobility. Despite the elevated stability, the amorphous drug–polymer salt showed fast dissolution and high solution concentration in two biorelevant media (SGF and FaSSIF). Additionally, the amorphous CFZ–PAA salt has improved tabletability and powder flow relative to crystalline CFZ. The CFZ–PAA example suggests a general method to prepare amorphous drugs with high physical stability under tropical conditions and fast dissolution.

Amorphous Drug-Polymer Salts

“…We illustrate the formation of amorphous drug-polymer salts and their pharmaceutical benefits using the reaction of the acidic polymer poly(acrylic acid) (PAA) with two basic drugs, clofazimine (CFZ) [64] and lumefantrine (LMF) [65]. For both systems, a simple slurry method was used to produce the amorphous salt at a high drug loading (75% for CFZ-PAA and 50% for LMF-PAA).…”

“…By extrapolation, the saturation drug loading is determined at 70% [64]. Reproduced with permission from [64], American Chemical Society, 2021. [64].…”

“…Reproduced with permission from [64], American Chemical Society, 2021. [64]. No crystallization was observed in 6 months, while the neutral CFZ−PVP and CFZ−PVP/VA dispersions at the same drug loading both crystallized.…”

“…No crystallization was observed in 6 months, while the neutral CFZ−PVP and CFZ−PVP/VA dispersions at the same drug loading both crystallized. Reproduced with permission from [64], American Chemical Society, 2021. (B) LMF-PAA salt (50% drug loading) [65].…”

“…The solvent evaporation method requires a common solvent for the drug and the polymer, which could be difficult to find when the polymer is hydrophilic (an electrolyte) and the drug is hydrophobic and poorly water soluble. The mixing of two solutions, one of the drug and the other of the polymer, has been used to prepare drug–polymer salts (“complexes”) and nanoparticles [ 64 ]. In our work, slurry conversion was used as a low-cost method to prepare amorphous drug–polymer salts [ 64 ].…”