The Assessment of pH-Induced Supersaturation and Impact of an Additional Drug on the Solution Phase Behavior of Saquinavir
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The goal of this study was to investigate the ability of saquinavir to generate the in vivo supersaturation and the impact of the presence of another solute, i.e., ritonavir, on the phase behavior of the former.
The phase behavior of saquinavir alone and in the presence of ritonavir was studied by pH shift supersaturation assay. The generation of drug-rich phase was confirmed by dynamic light scattering (DLS) and UV extinction method. The nature of precipitate generated after pH shift was investigated by employing DSC and XRPD. Further, the flux studies were performed by employing dialysis membrane using Franz diffusion cell.
Saquinavir precipitated in the amorphous form exhibiting type-II precipitation behavior generating the drug-rich phase and undergoing glass-liquid phase separation (GLPS) after the shift in pH towards higher side. The supersaturation advantage of saquinavir was marginally lowered in the presence of amorphous ritonavir. However, the free drug concentration of ritonavir was significantly reduced below the saturation solubility generating a subsaturated state. Both the drugs exhibited lowering in the chemical potential in the presence of each other, thereby reducing their flux/diffusion. The decrease in the free drug concentration and chemical potential were found dependent on the mole fraction of the solute present in the binary supersaturated solution.
The findings of the phase behavior of weak bases in the presence of other solutes are of great value not only in fixed-dose combination and concomitantly administered drugs but also in formulating supersaturated systems like amorphous solid dispersions and co-amorphous systems.
KeywordsSaquinavir Glass-liquid phase separation pH shift supersaturation Amorphous
- 7.Miller JM, Beig A, Carr RA, Spence JK, Dahan A. A win-win solution in oral delivery of lipophilic drugs: supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability. Mol Pharm. ACS Publications. 2012;9:2009–16.CrossRefGoogle Scholar
- 25.Dengale SJ, Ranjan OP, Hussen SS, Krishna BSM, Musmade PB, Gautham Shenoy G, et al. Preparation and characterization of co-amorphous ritonavir-indomethacin systems by solvent evaporation technique: improved dissolution behavior and physical stability without evidence of intermolecular interactions. Eur J Pharm Sci. 2014;62:57–64.CrossRefGoogle Scholar
- 26.Hsieh Y-L, Ilevbare GA, Van Eerdenbrugh B, Box KJ, Sanchez-Felix MV, Taylor LS. pH-induced precipitation behavior of weakly basic compounds: determination of extent and duration of supersaturation using potentiometric titration and correlation to solid state properties. Pharm Res . Springer. 2012;29:2738–53.CrossRefGoogle Scholar