Drug-Biopolymer Dispersions: Morphology- and Temperature- Dependent (Anti)Plasticizer Effect of the Drug and Component-Specific Johari–Goldstein Relaxations

Abstract

Amorphous molecule-macromolecule mixtures are ubiquitous in polymer technology and are one of the most studied routes for the development of amorphous drug formulations. For these applications it is crucial to understand how the preparation method affects the properties of the mixtures. Here, we employ differential scanning calorimetry and broadband dielectric spectroscopy to investigate dispersions of a small-molecule drug (the Nordazepam anxiolytic) in biodegradable polylactide, both in the form of solvent-cast films and electrospun microfibres. We show that the dispersion of the same small-molecule compound can have opposite (plasticizing or antiplasticizing) effects on the segmental mobility of a biopolymer depending on preparation method, temperature, and polymer enantiomerism. We compare two different chiral forms of the polymer, namely, the enantiomeric pure, semicrystalline L-polymer (PLLA), and a random, fully amorphous copolymer containing both L and D monomers (PDLLA), both of which have lower glass transition temperature (Tg) than the drug. While the drug has a weak antiplasticizing effect on the films, consistent with its higher Tg, we find that it actually acts as a plasticizer for the PLLA microfibres, reducing their Tg by as much as 14 K at 30%-weight drug loading, namely, to a value that is lower than the Tg of fully amorphous films. The structural relaxation time of the samples similarly depends on chemical composition and morphology. Most mixtures displayed a single structural relaxation, as expected for homogeneous samples. In the PLLA microfibres, the presence of crystalline domains increases the structural relaxation time of the amorphous fraction, while the presence of the drug lowers the structural relaxation time of the (partially stretched) chains in the microfibres, increasing chain mobility well above that of the fully amorphous polymer matrix. Even fully amorphous homogeneous mixtures exhibit two distinct Johari–Goldstein relaxation processes, one for each chemical component. Our findings have important implications for the interpretation of the Johari–Goldstein process as well as for the physical stability and mechanical properties of microfibres with small-molecule additives.

Dielectric Spectroscopy Studies of Conformational Relaxation Dynamics in Molecular Glass-Forming Liquids

“…Interestingly, polyesters with a smaller monomer unit, such as polylactic acid or poly(glycolide), were not reported to display conformational relaxations in dielectric studies [75,76]. This suggests that the observation of a well-defined intramolecular relaxation is hindered if the polar group involved is not sufficiently diluted along the polymer chain.…”

Eutectic Mixture Formation and Relaxation Dynamics of Coamorphous Mixtures of Two Benzodiazepine Drugs

“…Binary or multicomponent amorphous systems of compounds that do not form cocrystals are, in some cases, less prone to recrystallize due to the kinetic barrier to diffusion preventing phase separation. This effect is exploited in amorphous polymer dispersions, for example, which have, however, the drawback that the drug content is relatively low and that, in the presence of macromolecules, the control of sample morphology and heterogeneity is less straightforward [ 1 , 2 , 3 , 4 ].…”

How the Presence of Crystalline Phase Affects Structural Relaxation in Molecular Liquids: The Case of Amorphous Indomethacin

“…Namely, the deviations between the relaxation kinetics of the deeply relaxed states and in the near-T g equilibrium belong among the current hot topics [26][27][28][29][30]. Another even more extensive field of research is focused on the plasticization-induced changes in the glass transition behavior [31][32][33][34][35]. It is thus quite surprising that similar attention has not been paid to the relaxation movements being (possibly) influenced by the presence of the adjacent crystalline phase.…”