Abstract
Early formulation screening can alleviate development of advanced oral drug formulations, such as amorphous solid dispersions (ASDs). Traditionally, dissolution is used to predict ASD performance. Here, a high-throughput approach is described that simultaneously screens drug dissolution and permeation employing a two-compartment 96-well plate. Freeze-drying from hydro-alcoholic solutions was used to prepare amorphous formulations. The screening approach was tested on amorphous and crystalline tadalafil formulations with and without Soluplus®. The workflow consisted of: (1) dispersion of the formulations; (2) incubation within the two-compartment plate, where a dialysis membrane separated donor (dispersed formulation) and acceptor; (3) sampling (donor and acceptor), where donor samples were centrifuged to remove non-dissolved material; and (4) quantification by UHPLC-UV. To identify optimal screening conditions, the following parameters were varied: dispersion medium (buffer/biomimetic media), acceptor medium (buffer/surfactant solutions), and incubation time (1, 3, and 6 h). Surfactants (acceptor) increased tadalafil permeation. Biomimetic medium (donor) enhanced dissolution, but not permeation, except for freeze-dried tadalafil, for which the permeated amount increased. The predictiveness was evaluated by comparing dissolution-/permeation-results with in vivo bioavailability. In general, both dissolution and permeation reflected bioavailability, whereof the latter was a better predictor. High-throughput dissolution/permeation is regarded promising for formulation screening.
Highlights
Drug candidates selected by drug discovery approaches are advanced to preclinical and clinical development by formulation efforts
Due to the increasing fraction of new chemical entities (NCEs) with challenging physico-chemical properties, the demand for simple, rapid, yet effective formulation screening tools has increased in recent years
Poor aqueous solubility is a frequently experienced challenge that has resulted in the widespread use of candidate-enabling formulation strategies with the aim to increase the oral bioavailability of poorly soluble drug compounds
Summary
Drug candidates selected by drug discovery approaches are advanced to preclinical and clinical development by formulation efforts. High-throughput screening (HTS) of formulation additives, such as polymer(s), polymer/surfactant combinations and drug loading, of amorphous solid dispersions (ASDs) has been suggested [4]. The HTS methods described above and further high-throughput formulation screenings described in literature so far have in common that they use the ‘dissolved’ amount of drug compound as primary parameter to predict the performance of the formulation. In these pharmaceutical assessments, different ‘dissolved’ states of the drug compound are typically not distinguished. All dispersion- and acceptor media were stored at 4 to 8 ◦C for up to three months
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