Abstract:
:Hydrophilic matrices are an effective option for oral controlled release but can face challenges in terms of bioavailability and efficacy when used in conjunction with poorly soluble, weakly basic drugs. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) imaging provides dynamic information relating to the location and chemical nature of both the sustained release matrix and the active pharmaceutical ingredient (API) during hydration/dissolution. In this study, we have identified a model system combining itraconazole (IT), a poorly soluble, weakly basic API that has pKa in the physiological range, and hydroxypropyl methylcellulose, which is a commonly used oral tablet matrix. This system was investigated to determine the swelling kinetics at different pH values at a fixed ionic strength and to facilitate the study of the influence of hydrating media pH on the drug particle movement (translocation). Using ATR-FTIR imaging, we were able to show that gel layer formation and swelling were independent of pH but highly dependent on the ionic strength of the hydrating medium in placebo tablets. When the ionic strength was fixed, gel layer formation and radial swelling were both shown to be pH-dependent when IT was incorporated into the matrix. This was verified using optical imaging. The chemical specificity of ATR-FTIR imaging permitted the observation of transformational changes of IT from the free base to the ionized form in the tablet core during hydration. This phenomenon was shown to be greater at pH 1.5 than at pH 7. ATR-FTIR imaging was able to follow drug particle translocation at both pH 1.5 and pH 7; however, the extent of migration away from the tablet core was shown to be greater at lower pH. The location of the translocated particles within the gel layer was different between the two studied pH values, with particles being located close to the swelling front at pH 7 and within the diffusion front at pH 1.5. In both pH environments, the translocated IT particles were shown to be predominantly in the free base form. No evidence of fully solubilized IT was observed in the surrounding medium because of the inherent aqueous solubility of IT being below the instrument detection limits. This work highlighted the value of utilizing a chemically specific spectroscopic tool to increase the understanding of the nature of the factors affecting the release of a pH-dependent, poorly soluble drug from a hydrophilic matrix at different pH values and permitted greater insights into what happens inside the polymer matrix during drug release.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Zahoor FD,Mader KT,Timmins P,Brown J,Sammon Cdoi
10.1021/acs.molpharmaceut.9b01063subject
Has Abstractpub_date
2020-04-06 00:00:00pages
1090-1099issue
4eissn
1543-8384issn
1543-8392journal_volume
17pub_type
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