Publications

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.

JTD Keywords: amorphous pharmaceuticals, beta-relaxation, constant loss, crystallization, dielectric spectroscopy, dynamics, formulation morphology, glass transition, molecular mobility, nanofibers, polylactide, polymer enantiomerism, secondary relaxations, valium metabolite, viscous-liquids, Amorphous pharmaceuticals, Glass-transition, Secondary relaxations

We characterize amorphous solid dispersions (ASDs) of the Chloramphenicol antibiotic in two biodegradable polylactic acid polymers, namely a commercial sample of enantiomeric pure PLLA and a home-synthesized PDLLA copolymer, investigating in particular the effect of polylactic acid in stabilizing the amorphous form of the drug and controlling its release (e.g. for antitumoral purposes). Broadband dielectric spectroscopy and differential scanning calorimetry are employed to study the homogeneity, glass transition temperature and relaxation dynamics of solvent-casted ASD membranes with different drug concentrations. We observe improved physical stability of the ASDs with respect to the pure drug, as well as a plasticizing effect of the antibiotic on the polymer, well described by the Gordon-Taylor equation. The release of the active pharmaceutical ingredient from the films in a simulated body fluid is studied by UV/vis spectroscopy at two different drug concentrations (5 and 20% in weight). The amount of released drug is found to be proportional to the square root of time, with proportionality constant that is almost the same in both dispersions, despite the fact that the relaxation time and thus the viscosity of the two samples differ by four orders of magnitude at body temperature. Since the drug release kinetics does not display a significant dependence on the drug content in the carrier, it may be expected to remain roughly constant during longer release times.

JTD Keywords: Amorphous drug, Controlled liberation, Dielectric spectroscopy, Molecular mobility, Plasticizer, Polymer enantiomerism