Insight into Amorphous Solid Dispersion Performance by Coupled Dissolution and Membrane Mass Transfer Measurements

Abstract

The tendency of highly supersaturated solutions of poorly water-soluble drugs to undergo liquid–liquid phase separation (LLPS) into drug-rich and water-rich phases when the concentration exceeds the amorphous solubility, for example, during dissolution of some amorphous solid dispersions, is thought to be advantageous from a bioavailability enhancement perspective. Recently, we have developed a high surface area, flow-through absorptive dissolution testing apparatus that enables fast mass transfer providing more in vivo relevant conditions and time frames for formulation testing. Using this apparatus, the absorption behaviors of solutions with different extents of supersaturation below and above the amorphous solubility were evaluated. In addition, simultaneous dissolution–absorption testing of amorphous solid dispersions (ASDs) with varying drug loadings and polymer types was carried out to study and distinguish the absorption behavior of ASDs that do or do not undergo LLPS. When compared with closed-compartment dissolution testing, a significant influence of the absorptive compartment on the dissolution rate of ASDs, particularly at high drug loadings, was observed. The formation of drug-rich nanodroplets, generated by both solvent-addition and ASD dissolution, resulted in a higher amount of drug transferred across the membrane. Moreover, the mass transfer was further enhanced with increasing concentration above the amorphous solubility, thereby showing correlation with an increase in the number of drug-rich particles. The importance of including an absorptive compartment in dissolution testing is highlighted in this study, enabling coupling of dissolution to membrane transport, and providing a more meaningful comparison between different formulations.

Impact of HPMCAS on the Dissolution Performance of Polyvinyl Alcohol Celecoxib Amorphous Solid Dispersions

“…This phenomenon describes a phase transition of a supersaturated solution into a drug-rich and solvent-rich phase [33]. The occurrence of nanoscale colloids or liquid-liquid phase separation can act as a reservoir for the supersaturation level as a result of rapid re-dissolution kinetics and it is also related to an enhanced absorption [33][34][35]. Consequently, the occurrence of that phenomenon can be considered as beneficial for an ASD upon dissolution.…”

Interplay of Supersaturation and Solubilization: Lack of Correlation between Concentration-Based Supersaturation Measurements and Membrane Transport Rates in Simulated and Aspirated Human Fluids

“…10 Nevertheless, the formation of these colloidal species has been hypothesized to be beneficial for oral drug delivery, by serving as a reservoir and continuously replenishing the absorbed drug. 10,14 Diffusion through the unstirred water layer is often considered the ratelimiting step for intestinal uptake of highly permeable lipophilic compounds. [15][16][17] Therefore, particle drifting into the unstirred water layer, has also been suggested as a mechanism by which absorption is enhanced by colloidal drug aggregates.…”

Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

“…The maximum permeability then reaches a new plateau at a high apparent drug concentration. Experimentally, Siddhi et al demonstrated the dissolution performance and membrane mass transportation for atazanavir (ATZ) ASD using a high surface area apparatus [111]. Figure 5A illustrated the maximum drug concentration (C max ) and the area under the curve (AUC) values in the acceptor compartment in relation to the drug's apparent concentration in the donor compartment.…”

“…In contrast, polymers stabilizing the supersaturated drug solution without significantly affecting the thermodynamic activity may result in a better permeability enhancement. [111], American Chemical Society, 2018. (B) A comparison of the itraconazole in vivo data and permeability models with or without modified with the effect of nanoparticles in aqueous solution "drifting" into the ABL.…”