The mechanical properties of an amorphous copolymer are directly related to the dynamic processes occurring at the molecular level. Poly lactic-co-glycolic acid (PLGA) is a biodegradable copolymer, and in this work we investigate the dynamics of PLGA and its glass transition behaviour by performing variable temperature terahertz time-domain spectroscopy (THz-TDS) experiments. We correlate PLGA dynamics, as measured at terahertz frequencies, their temperature dependence, molecular weight (MW), lactide toglycolide ratio, and free volume. The THz-TDS data can be used to detect two distinct transition processes, T_β and T_g,α. To complement our analysis, we use dynamic mechanical analysis (DMA) to probe the β- and α-relaxation processes in PLGA, and compare the results obtained from the DMA experiments with those obtained using THz-TDS. The values of T_g,α, as determined from the THz-TDS experiments, are in good agreement with T_g,DSC, determined by calorimetric measurements, and with T_g,DMA, determined by the DMA measurements. We attribute T_β to the change in dipole moments associated with the β-relaxation process, originating from the local rotation of C–O macromolecular chain segments, and T_g,α to the change in dipole moments due to large segmental motion of the copolymer backbone associated with the α-relaxation process. By showing experimental temperature-dependent results from THz-TDS and DMA for PLGA, we demonstrate that the behaviour of PLGA is in line with the potential energy surface interpretation by Goldstein as well as the free volume theory of Fox and Flory, and that both concepts together can be used to understand amorphous polymers.

Probing the energy landscape and thermodynamics of biomolecules for drug design.

The solvation shell is essential for the folding and function of proteins, but how it contributes to protein misfolding and aggregation has still to be elucidated. We show that the mobility of solvation shell H₂O molecules influences the aggregation rate of the amyloid protein α‐synuclein (αSyn), a protein associated with Parkinson's disease. When the mobility of H₂O within the solvation shell is reduced by the presence of NaCl, αSyn aggregation rate increases. Conversely, in the presence CsI the mobility of the solvation shell is increased and αSyn aggregation is reduced. Changing the solvent from H₂O to D₂O leads to increased aggregation rates, indicating a solvent driven effect. We show the increased aggregation rate is not directly due to a change in the structural conformations of αSyn, it is also influenced by a reduction in both the H₂O mobility and αSyn mobility. We propose that reduced mobility of αSyn contributes to increased aggregation by promoting intermolecular interactions.

The β-relaxation associated with the sub-glass transition temperature (T_g,β) is attributed to fast, localised molecular motions which can occur below the primary glass transition temperature (T_g,α). Consistent with T_g,β being observed well-below storage temperatures, the β-relaxation associated motions have been hypothesised to influence protein stability in the solid state and could thus impact the quality of e.g. protein powders for inhalation or reconstitution and injection. Why then do distinct solid state protein formulations with similar aggregation profiles after drying and immediate reconstitution, display different profiles when reconstituted following prolonged storage? Is the value of T_g,β, associated with the β-relaxation process of the system, a reliable parameter for characterising the behaviour of proteins in the solid state? Bearing this in mind, in this work we further explore the different relaxation dynamics of glassy solid state monoclonal antibody formulations using terahertz time-domain spectroscopy and dynamical mechanical analysis. By conducting a 52 week stability study on a series of multi-component spray-dried formulations, an approach for characterising and analysing the solid state dynamics and how these relate to protein stability is outlined.

We present an approach for the rational development of stimuli-responsive ionogels which can be formulated for precise control of multiple unique ionogel features and fill niche pharmaceutical applications. Ionogels are captivating materials, exhibiting self-healing characteristics, tunable mechanical and structural properties, high thermal stability, and electroconductivity. However, the majority of ionogels developed require complex chemistry, exhibit high viscosity, poor biocompatibility, and low biodegradability. In our work, we overcome these limitations. We employ a facile production process and strategically integrate silk fibroin, the biocompatible ionic liquids (ILs) choline acetate ([Cho][OAc]), choline dihydrogen phosphate ([Cho][DHP]), and choline chloride ([Cho][Cl]), traditional pharmaceutical excipients, and the model antiepileptic drug phenobarbital. In the absence of ILs, we failed to observe gel formation; yet in the presence of ILs, thermoresponsive ionogels formed. Systems were assessed via visual tests, transmission electron microscopy, confocal reflection microscopy, dynamic light scattering, zeta potential and rheology measurements. We formed diverse ionogels of strengths ranging between 18 and 642 Pa. Under 25 °C storage, formulations containing polyvinylpyrrolidone (PVP) showed an ionogel formation period ranging over 14 days, increasing in the order of [Cho][DHP], [Cho][OAc], and [Cho][Cl]. Formulations lacking PVP showed an ionogel formation period ranging over 32 days, increasing in the order of [Cho][OAc], [Cho][DHP] and [Cho][Cl]. By heating from 25 to 60 °C, immediately following preparation, thermoresponsive ionogels formed below 41 °C in the absence of PVP. Based on our experimental results and density functional theory calculations, we attribute ionogel formation to macromolecular crowding and confinement effects, further enhanced upon PVP inclusion. Holistically, applying our rational development strategy enables the production of ionogels of tunable physicochemical and rheological properties, enhanced drug solubility, and structural and energetic stability. We believe our rational development approach will advance the design of biomaterials and smart platforms for diverse drug delivery applications.