Investigation and mathematical description of the real driving force of passive transport of drug molecules from supersaturated solutions

The aim of this study was to investigate the impact of formulation excipients and solubilizing additives on dissolution, supersaturation, and membrane transport of an active pharmaceutical ingredient (API). When a poorly water-soluble API is formulated to enhance its dissolution, additives, such as surfactants, polymers, and cyclodextrins, have an effect not only on dissolution profile but also on the measured physicochemical properties (solubility, pKa, permeability) of the drug while the excipient is present, therefore also affecting the driving force of membrane transport. Meloxicam, a nonsteroidal anti-inflammatory drug, was chosen as a poorly water-soluble model drug and formulated in order to enhance its dissolution using solvent-based electrospinning. Three polyvinylpyrrolidone (PVP) derivatives (K30, K90, and VA 64), Soluplus, and (2-hydroxypropyl)-β-cyclodextrin were used to create five different amorphous solid dispersions of meloxicam. Through experimental design, the various formulation additives that could influence the characteristics of dissolution and permeation through artificial membrane were observed by carrying out a simultaneous dissolution-permeation study with a side-by-side diffusion cell, μFLUX. Although the dissolution profiles of the formulations were found to be very similar, in the case of Soluplus containing formulation the flux was superior, showing that the driving force of membrane transport cannot be simplified to the concentration gradient. Supersaturation gradient, the difference in degree of supersaturation (defined as the ratio of dissolved amount of the drug to its thermodynamic solubility) between the donor and acceptor side, was found to be the driving force of membrane transport. It was mathematically derived from Fick's first law, and experimentally proved to be universal on several meloxicam containing ASDs and DMSO stock solution. © 2016 American Chemical Society

In vitro dissolution–permeation evaluation of an electrospun cyclodextrin-based formulation of aripiprazole using μFlux™

Since it is a well-known fact that among the newly discovered active pharmaceutical ingredients the number of poorly water soluble candidates is continually increasing, dissolution enhancement of poorly water soluble drugs has become one of the central challenges of pharmaceutical studies. So far the preclinical studies have been mainly focused on formulation methods to enhance the dissolution of active compounds, in many cases disregarding the fact that the formulation matrix not only affects dissolution but also has an effect on the transport through biological membranes, changing permeation of the drug molecules. The aim of this study was to test an electrospun cyclodextrin-based formulation of aripiprazole with the novel μFlux apparatus, which monitors permeation together with dissolution, and by this means better in vitro–in vivo correlation is achieved. It was evinced that a cyclodextrin-based electrospun formulation of aripiprazole has the potential to ensure fast drug delivery through the oral mucosa owing to the ultrafast dissolution of the drug from the formulation and the enhanced flux across membranes as shown by the result of the novel in vitro dissolution and permeation test

Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions

The aim of this study was to investigate the impact of formulation excipients and solubilizing additives on dissolution, supersaturation, and membrane transport of an active pharmaceutical ingredient (API). When a poorly water-soluble API is formulated to enhance its dissolution, additives, such as surfactants, polymers, and cyclodextrins, have an effect not only on dissolution profile but also on the measured physicochemical properties (solubility, p<i>K</i>_a, permeability) of the drug while the excipient is present, therefore also affecting the driving force of membrane transport. Meloxicam, a nonsteroidal anti-inflammatory drug, was chosen as a poorly water-soluble model drug and formulated in order to enhance its dissolution using solvent-based electrospinning. Three polyvinylpyrrolidone (PVP) derivatives (K30, K90, and VA 64), Soluplus, and (2-hydroxypropyl)-β-cyclodextrin were used to create five different amorphous solid dispersions of meloxicam. Through experimental design, the various formulation additives that could influence the characteristics of dissolution and permeation through artificial membrane were observed by carrying out a simultaneous dissolution–permeation study with a side-by-side diffusion cell, μFLUX. Although the dissolution profiles of the formulations were found to be very similar, in the case of Soluplus containing formulation the flux was superior, showing that the driving force of membrane transport cannot be simplified to the concentration gradient. Supersaturation gradient, the difference in degree of supersaturation (defined as the ratio of dissolved amount of the drug to its thermodynamic solubility) between the donor and acceptor side, was found to be the driving force of membrane transport. It was mathematically derived from Fick’s first law, and experimentally proved to be universal on several meloxicam containing ASDs and DMSO stock solution