Dataset Information

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.

SUBMITTER: Gui Y

PROVIDER: S-EPMC7927142 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Gui Yue Y McCann Erin C EC Yao Xin X Li Yuhui Y Jones Karen J KJ Yu Lian L

Molecular pharmaceutics 20210201 3

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 ...[more]

PMID: 33522821

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Project description:Weak polyelectrolytes (WPEs) are responsive materials used as active charge regulators in a variety of applications, including controlled release and drug delivery in crowded bio-related and synthetic environments. In these environments, high concentrations of solvated molecules, nanostructures, and molecular assemblies are ubiquitous. Here, we investigated the effect of high concentrations of non-adsorbing, short chains of poly(vinyl alcohol), PVA, and colloids dispersed by the very same polymers on charge regulation (CR) of poly(acrylic acid), PAA. PVA does not interact with PAA (throughout the full pH range) and thus can be used to examine the role of non-specific (entropic) interactions in polymer-rich environments. Titration experiments of PAA (mainly 100 kDa in dilute solutions, no added salt) were carried out in high concentrations of PVA (13-23 kDa, 5-15 wt%) and dispersions of carbon black (CB) decorated by the same PVA (CB-PVA, 0.2-1 wt%). The calculated equilibrium constant (and pKa) was up-shifted in PVA solutions by up to ~0.9 units and down-shifted in CB-PVA dispersions by ~0.4 units. Thus, while solvated PVA chains increase the charging of the PAA chains, as compared to PAA in water, CB-PVA particles reduce PAA charging. To investigate the origins of the effect, we analyzed the mixtures using small-angle X-ray scattering (SAXS) and cryo-TEM imaging. The scattering experiments revealed re-organization of the PAA chains in the presence of the solvated PVA but not in the CB-PVA dispersions. These observations clearly indicate that the acid-base equilibrium and the degree of ionization of PAA in crowded liquid environments is affected by the concentration, size, and geometry of seemingly non-interacting additives, probably due to depletion and excluded volume interactions. Thus, entropic effects that do not depend on specific interactions should be taken into consideration when designing functional materials in complex fluid environments.

Dataset Information

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

Publications

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

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