Many pharmaceutical drugs in the marketplace and discovery pipeline suffer from poor aqueous solubility, thereby limiting their effectiveness for oral delivery. The use of an amorphous solid dispersion (ASD), a mixture of an active pharmaceutical ingredient and a polymer excipient, greatly enhances the aqueous dissolution performance of a drug without the need for chemical modification. Although this method is versatile and scalable, deficient understanding of the interactions between drugs and polymers inhibits ASD rational design. This current Review details recent progress in understanding the mechanisms that control ASD performance. In the solid-state, the use of high-resolution theoretical, computational, and experimental tools resolved the influence of drug/polymer phase behavior and dynamics on stability during storage. During dissolution in aqueous media, novel characterization methods revealed that ASDs can form complex nanostructures, which maintain and improve supersaturation of the drug. The studies discussed here illustrate that nanoscale phenomena, which have been directly observed and quantified, strongly affect the stability and bioavailability of ASD systems, and provide a promising direction for optimizing drug/polymer formulations.

The effects of cross-link density and composition on the loading and in vitro dissolution of the drug phenytoin as amorphous solid dispersions in emulsion polymerized poly(N-isopropylacrylamide) (PNIPAm) and poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) nanogels were investigated near the lower critical solution temperature (LCST). Nanogel size and particle density in phosphate buffered saline were quantified by dynamic light scattering (DLS) and viscometry experiments, while drug−nanogel interactions were revealed by cross peaks in aqueous-state nuclear Overhauser effect spectroscopy measurements. Spray-dried dispersions (SDDs) of drugloaded PNIPAm nanogel particles (R ≈ 43 nm) were directly visualized by cryogenic transmission electron microscopy and further quantified by small-angle X-ray scattering during in vitro dissolution. SDD dissolution profiles were highly dependent on the nanogel cross-link density and directly correlated with the state of dispersion of the drug-loaded nanogel particles. A balance between net particle hydrophobicity and hydrophilicity along with the distance in temperature from the LCST are shown to dictate the in vitro dissolution of the amorphous solid dispersions. Solubility enhancement mechanisms disclosed in this study provide essential guidance for the design of effective nanogels for oral drug delivery applications.

Amorphous solid dispersions (ASDs) of crystallizable drugs and polymer excipients are attractive for enhancing the solubility and bioavailability of hydrophobic drug molecules. In this study, the solution behavior of poly­(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PND) and poly­(vinylpyrrolidone-co-vinylacetate) (PVPVA), as polymer excipients, and nilutamide (NLT), phenytoin (PHY), and itraconazole (ITN) as model drugs, were monitored by an in vitro dissolution assay, small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and polarized optical microscopy (POM). High degrees of drug supersaturation were coincident with the formation of amorphous nanoparticles in each system. The difference in particle size and kinetic stability between PND and PVPVA systems suggest a difference in how the polymers interact with the drug-rich phase. A series of scenarios are proposed based on whether the polymer interacts more strongly with the drug-rich nanoparticles or with water. Understanding the contribution of drug-rich nanoparticles to achievable supersaturation and the effect of polymer excipients on these particles will inform the design of future solid dispersion systems through a better understanding of the polymer/drug solution relationship.

Bottlebrush polymers are characterized by an expansive parameter space, including graft length and spacing along the backbone, and these features impact various structural and physical properties such as molecular diffusion and bulk viscosity. In this work, we report a synthetic strategy for making grafted block polymers with poly­(propylene oxide) and poly­(ethylene oxide) side chains, bottlebrush analogues of poloxamers. Combined anionic and sequential ring-opening metathesis polymerization yielded low dispersity polymers, at full conversion of the macromonomers, with control over graft length, graft end-groups, and overall molecular weight. A set of bottlebrush poloxamers (BBPs), with identical graft lengths and composition, was synthesized over a range of molecular weights. Dynamic light scattering and transmission electron microscopy were used to characterize micelle formation in aqueous buffer. The critical micelle concentration scales exponentially with overall molecular weight for both linear and bottlebrush poloxamers; however, the bottlebrush architecture shifts micelle formation to a much higher concentration at a comparable molecular weight. Consequently, BBPs can exist in solution as unimers at significantly higher molecular weights and concentrations than the linear analogues.

Poloxamers consisting of poly­(ethylene oxide) (PEO) and poly­(propylene oxide) segments can protect cell membranes against various forms of stress. We investigated the role of the hydrophobic block chemistry on polymer/membrane binding and cell membrane protection by comparing a series of poly­(butylene oxide)-b-PEO (PBO-b-PEO) copolymers to poloxamer analogues, using a combination of pulsed-field-gradient (PFG) NMR experiments and a lactate dehydrogenase (LDH) cell assay. We found that the more hydrophobic PBO-b-PEO copolymers bound more significantly to model liposomes composed of 1-palmitol-2-oleoyl-glycero-3-phosphocholine (POPC) compared to poly­(propylene oxide) (PPO)/PEO copolymers. However, both classes of polymers performed similarly when compared by an LDH assay. These results present an important comparison between polymers with similar structures but with different binding affinities. They also provide mechanistic insight as enhanced polymer/lipid membrane binding did not directly translate to increased cell protection in the LDH assay, and therefore, additional factors need to be considered when trying to achieve greater membrane protection efficacy.