Role of the Strength of Drug–Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions

Abstract

The effects of specific drug-polymer interactions (ionic or hydrogen-bonding) on the molecular mobility of model amorphous solid dispersions (ASDs) were investigated. ASDs of ketoconazole (KTZ), a weakly basic drug, with each of poly(acrylic acid) (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP) were prepared. Drug-polymer interactions in the ASDs were evaluated by infrared and solid-state NMR, the molecular mobility quantified by dielectric spectroscopy, and crystallization onset monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (VTXRD). KTZ likely exhibited ionic interactions with PAA, hydrogen-bonding with PHEMA, and weaker dipole-dipole interactions with PVP. On the basis of dielectric spectroscopy, the α-relaxation times of the ASDs followed the order: PAA > PHEMA > PVP. In addition, the presence of ionic interactions also translated to a dramatic and disproportionate decrease in mobility as a function of polymer concentration. On the basis of both DSC and VTXRD, an increase in strength of interaction translated to higher crystallization onset temperature and a decrease in extent of crystallization. Stronger drug-polymer interactions, by reducing the molecular mobility, can potentially delay the crystallization onset temperature as well as crystallization extent.

Application of Vibrational Spectroscopy to Study Solid-state Transformations of Pharmaceuticals

“…Similar results were obtained in a study on felopidine ASDs in which an inverse correlation between the strength and extent of H bonding between API and polymer (as judged from the IR data) and crystal growth was established [214]. Drug-polymer interactions in ASDs of ketoconazole were also evaluated by IR and solid-state NMR spectroscopy and correlated to the molecular mobility and crystallization onset [215]. Démuth et al used Raman mapping to evaluate the longterm stability of itraconazole ASDs prepared by electrospinning [216].…”

In vitro/in vivo evaluation of an optimized fast dissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylic acids

“…For example, the C-H stretching and C ¼ N stretching were shortened and broadened and the shallow peak of N-H stretching also demonstrated shifting to 3394 cm À1 instead of 3217 cm À1 (Figure 3). These results strongly suggest that the interaction between OL and ascorbic acid may have taken place through H-bonding (Mistry et al, 2015).…”

Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs

“…Mistry et al have also shown that stronger drug-polymer interactions (ionic or H-bonding) reduce the molecular motion of amorphous ketoconazole which can potentially delay crystallization onset time and reduce crystallization extent. 126 In another interesting study conducted by Kothari et al 127 it has been found that the relaxation time of the drug increases with an increase in polymer concentration. The improved stability results were attributed to the restriction of molecular mobility of amorphous drug.…”