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In vitro and in silico Dissolution and Permeation Assessment
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Orientador(es)
Resumo(s)
New chemical entities (NCEs) under development tend to be progressively more poorly
water soluble. As conventional dissolution tests are not representative of in vivo conditions and
thus not predictive of its in vivo behavior, formulation of these orally administered drug products
is often compromised. The design of a biorelevant dissolution method reflects the physiological
conditions in the gastrointestinal (GI) tract, possessing a biological discriminative power given
e.g. by the increased solubilization of drug molecules by bile salts and lecithin, which is of significant
importance when evaluating the dissolution behavior of poorly soluble drugs. Moreover,
there has been an increasing trend in the pharmaceutical industry to use mechanistic models to
complement in vitro data that are an inexpensive and fast way of assisting the formulation process.
The present work aims at using a biorelevant dissolution methodology to support drug
product development, employing USP Apparatus 2 and different formulations (enteric and nonenteric
polymers, different binders and granule sizes) of tablets of spray dried dispersions (SDDs)
of Itraconazole (ITZ), a poorly water-soluble drug. SDDs, tablets and the reference commercial
product dissolution were assessed in biorelevant media and a biorelevant pH shift was performed.
Also, an attempt was made to simultaneously evaluate dissolution and in vitro permeation of ITZ,
using the reverse dialysis membrane methodology. Finally, an in silico model describing dissolution
phenomena of amorphous active pharmaceutical compounds (APIs) was developed.
Crystalline ITZ solubility in biorelevant media could not be assessed, since it was below
the limit of quantification of the employed method. SDDs could not be properly tested in USP
Apparatus 2 due to the characteristic poor wettability of these powders, that led to powder floating.
The potential for higher bioavailability of solid oral ITZ through intestinal targeting was demonstrated
via pH shift. It was not possible to quantify the molecularly dissolved ITZ through reverse
dialysis method, which lacks further development and optimization. The obtained results show
that the compendial dissolution methodology is not enough to evaluate poorly-soluble dosage
forms performance because they can often lead to a sub or over estimation of its solubility.
Descrição
Palavras-chave
in vitro in silico dissolution biorelevant poorly-soluble-drugs free-drug