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

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.

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Conclusions
The amorphous salt of the basic drug CFZ and the acidic polymer PAA can be synthesized using a simple slurry method under mild conditions. This method is easy to implement and suitable for thermally unstable drugs and polymers. Salt formation is indicated by visible spectroscopy and Tg elevation. The amorphous drug–polymer salt is remarkably stable against crystallization under the highly stressful conditions of 40 °C and 75% RH. The high drug loading achieved exceeds the levels reported previously.(20−22) Despite elevated stability, the amorphous salt shows fast dissolution in biorelevant media. Furthermore, the amorphous CFZ–PAA salt shows improved tabletability and powder flow relative to crystalline CFZ.
We attribute the high stability of the amorphous CFZ–PAA salt under harshly stressful conditions to reduced thermodynamic driving force and increased kinetic stability. The strong ionic interaction in a drug–polymer salt makes the free energy of mixing more negative relative to a neutral drug–polymer dispersion. This in turn reduces the driving force for crystallization. From a kinetic standpoint, salt formation elevates the glass transition temperature to a greater extent than dispersing a neutral drug in a polymer matrix. This reduces molecular mobility and enhances kinetic stability. Given the generality of these effects, we expect salt formation to provide a general approach to stabilizing amorphous drugs against crystallization, especially under the highly stressful tropical conditions for global health applications.

Materials
Clofazimine [N,5-bis(4-chlorophenyl)-3-(1-methylethylimino)-5H-phenazin-2-amine, CFZ, ≥98% pure], poly(acrylic acid) (PAA, average Mv of 450 kg/mol), polyvinylpyrrolidone (PVP K15, average Mw of 8000 g/mol), sodium dodecyl sulfate (SDS, ≥98% pure), sodium chloride, and sodium phosphate monobasic monohydrate were purchased from Sigma-Aldrich (St. Louis, MO) and used as received. Kollidon VA 64 (PVP/VA 64, average Mv of 45–70 kg/mol) was purchased from BASF.