Effect of Formulation Additives on Drug Transport through Size-Exclusion Membranes

Abstract

The aim of this research was to investigate the driving force of membrane transport through size-exclusion membranes and to provide a concentration-based mathematical description of it to evaluate whether it can be an alternative for lipophilic membranes in the formulation development of amorphous solid dispersions. Carvedilol, an antihypertensive drug, was chosen and formulated using solvent-based electrospinning to overcome the poor water solubility of the drug. Vinylpyrrolidone-vinyl acetate copolymer (PVPVA64) and Soluplus were used to create two different amorphous solid dispersions of the API. The load-dependent effect of the additives on dissolution and permeation through regenerated cellulose membrane was observed by a side-by-side diffusion cell, μFLUX. The solubilizing effect of the polymers was studied by carrying out thermodynamic solubility assays. The supersaturation ratio (SSR, defined as the ratio of dissolved amount of the drug to its thermodynamic solubility measured in exactly the same medium) was found to be the driving force of membrane transport in the case of size-exclusion membranes. Although the transport through lipophilic and size-exclusion membranes is mechanistically different, in both cases, the driving force of membrane transport in the presence of polymer additives was found to be the same. This finding may enable the use of size-exclusion membranes as an alternative to lipid membranes in formulation development of amorphous solid dispersions.

Leveraging bile solubilization of poorly water-soluble drugs by rational polymer selection

“…Polymer excipients used for drug formulation were traditionally referred to as "inert" [18][19][20] in spite of a role in e.g. drug transporter inhibition [21], allergic reactions [22], or physicochemical interactions [23]. Other reports highlighted the impact of these excipients on the natural solubilization systems [24,25] and the current manuscript is within this context.…”

Towards more accurate solubility measurements with real time monitoring: a carvedilol case study

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