Drug Release and Nanodroplet Formation from Amorphous Solid Dispersions: Insight into the Roles of Drug Physicochemical Properties and Polymer Selection

Abstract

Dissolution of amorphous solid dispersions (ASD) can lead to the formation of amorphous drug-rich nano species (nanodroplets) via liquid−liquid phase separation or glass−liquid phase separation when the drug concentration exceeds the amorphous solubility. These nanodroplets have been shown to be beneficial for ASD performance both in vitro and in vivo. Thus, understanding the generation and stability of nanodroplets from ASD formulations is important. In this study, the impacts of polymer selection and active pharmaceutical ingredient (API) physicochemical properties (wet glass transition temperature (T g ) and log P) on nanodroplet release were studied. Six APIs with different physicochemical properties were formulated as ASDs with two polymers, polyvinylpyrrolidone/vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Their release performance was evaluated using both powder and surface normalized dissolution of compacts. In general, HPMCAS-based dispersions resulted in higher drug release compared to PVPVA-based dispersions. The two polymers also exhibited different trends in nanodroplet formation as a function of drug loading (DL). PVPVA ASDs exhibited a "falling-off-the-cliff" effect, with a dramatic decline in release performance with a small increase in drug loading, while HPMCAS ASDs exhibited a negative "slope" in the release rate as a function of drug loading. For both polymers, low T g compounds achieved higher levels of nanodroplet formation compared to high T g compounds. The nanodroplets generated from ASD dissolution were also monitored with dynamic light scattering, and HPMCAS was found to be more effective at stabilizing nanodroplets against size increase. Insights from this study may be used to guide formulation design and selection of excipients based on API physicochemical properties.

Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid dispersion fabrication for more robust release profiles

“…Indeed, the high sensitivity of delamanid to the polymer used to form that ASD is highlighted in Fig. S10 , where the enteric polymers facilitate drug release to a much greater extent than the two neutral polymers evaluated [56] .…”

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

“…Beyond physical stability constraints, a decline in drug release rate with an increased drug loading requires a high polymer/drug ratio, which is a major contributor toward the increased pill burden of these enabled formulations. There is emerging evidence that the decline in release performance is concomitantly associated with a change in dissolution mechanism, from “polymer-controlled” or congruent release of ASD components at low drug loadings to “drug-controlled” or incongruent release at higher drug loadings [ 4 , 7 , 8 , 16 , 33 , 34 ]. It should be noted that most of these studies focus on PVPVA-based ASDs, and the generality of these observations to ASDs formulated with other polymers is not fully established.…”

“…The polymer choice for an ASD is in large part typically based on its nucleation inhibition properties for the drug in the solid and solution states, which in turn is dependent on polymer glass transition temperature, polymer hygroscopicity, and drug–polymer interactions. More recently, the impact of polymer choice on the formation and stabilization of amorphous nanoparticles upon ASD dissolution has also started to gain attention [ 34 , 43 ]. Nevertheless, the limit of congruency is a property of a given drug–polymer ASD system, and it can be identified but not altered without changing the polymer.…”

Processing Impact on In Vitro and In Vivo Performance of Solid Dispersions—A Comparison between Hot-Melt Extrusion and Spray Drying

“…Many studies were conducted to understand the mechanism of bioavailability improvement through solid dispersions. Several factors contribute to the increased bioavailability of ASDs [ 10 , 11 , 12 , 13 , 14 , 15 ]. First, the conversion of the crystalline drug into its amorphous form results in a higher apparent solubility, and subsequently better bioperformance, especially when absorption of the drug is fast [ 10 , 11 ].…”

“…First, the conversion of the crystalline drug into its amorphous form results in a higher apparent solubility, and subsequently better bioperformance, especially when absorption of the drug is fast [ 10 , 11 ]. Second, the dispersion of API in the polymer matrix impacts drug dissolution through the improvement of API wettability, particle size reduction, and stabilization of the dissolved drug [ 12 , 13 , 14 , 15 ]. The ability of an amorphous dispersion to accelerate the dissolution rate and maintain the concentration of the drug in solution is often referred to as the “spring” and “parachute” mechanism and is expected to result in favorable bioperformance [ 16 ].…”