Generation of a Weakly Acidic Amorphous Solid Dispersion of the Weak Base Ritonavir with Equivalent In Vitro and In Vivo Performance to Norvir Tablet

Abstract

Ritonavir is an anti-viral compound that has also been employed extensively as a CYP3A4 and P-glycoprotein (Pgp) inhibitor to boost the pharmacokinetic performance of compounds that undergo first pass metabolism. For use in combination products, there is a desire to minimize the mass contribution of the ritonavir system to reduce patient pill burden in these combination products. In this study, KinetiSol® processing was utilized to produce an amorphous solid dispersion of ritonavir at two times the drug load of the commercially available form of ritonavir, and the composition was subsequently developed into a tablet dosage form. The amorphous intermediate was demonstrated to be amorphous by X-ray powder diffraction and 13C solid-state nuclear magnetic resonance and an intimately mixed single-phase system by modulated differential scanning calorimetry and 1H T1/1H T solid-state nuclear magnetic resonance relaxation. In vitro transmembrane flux analysis showed similar permeation rates for the KinetiSol-made tablet and the reference tablet dosage form, Norvir®. In vivo pharmacokinetic comparison between the two dosage forms resulted in equivalent exposure with approximately 20% Cmax reduction for the KinetiSol tablet. These performance gains were realized with a concurrent reduction in dosage form mass of 45%.

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Correspondence to Daniel J. Ellenberger.

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Ellenberger, D.J., Miller, D.A., Kucera, S.U. et al. Generation of a Weakly Acidic Amorphous Solid Dispersion of the Weak Base Ritonavir with Equivalent In Vitro and In Vivo Performance to Norvir Tablet. AAPS PharmSciTech 19, 1985–1997 (2018). https://doi.org/10.1208/s12249-018-1060-x

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Key words

  • KinetiSol
  • amorphous solid dispersions (ASD)
  • ritonavir
  • bioavailability
  • transmembrane flux