The Assessment of pH-Induced Supersaturation and Impact of an Additional Drug on the Solution Phase Behavior of Saquinavir

Sujata D. Sakhare, V. Sai Krishna Anand, Aishwarya Karan, K. Navya Sree, S. G. Vasantharaju, Girish Pai, Swapnil J. Dengale

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Method: 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. Results: 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. Conclusion: 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.

Original languageEnglish
JournalJournal of Pharmaceutical Innovation
DOIs
Publication statusAccepted/In press - 01-01-2018

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Saquinavir
Ritonavir
Pharmaceutical Preparations
Solubility
Glass
Dialysis
Membranes

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science
  • Drug Discovery

Cite this

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title = "The Assessment of pH-Induced Supersaturation and Impact of an Additional Drug on the Solution Phase Behavior of Saquinavir",
abstract = "Purpose: 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. Method: 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. Results: 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. Conclusion: 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.",
author = "Sakhare, {Sujata D.} and Anand, {V. Sai Krishna} and Aishwarya Karan and Sree, {K. Navya} and Vasantharaju, {S. G.} and Girish Pai and Dengale, {Swapnil J.}",
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The Assessment of pH-Induced Supersaturation and Impact of an Additional Drug on the Solution Phase Behavior of Saquinavir. / Sakhare, Sujata D.; Anand, V. Sai Krishna; Karan, Aishwarya; Sree, K. Navya; Vasantharaju, S. G.; Pai, Girish; Dengale, Swapnil J.

In: Journal of Pharmaceutical Innovation, 01.01.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The Assessment of pH-Induced Supersaturation and Impact of an Additional Drug on the Solution Phase Behavior of Saquinavir

AU - Sakhare, Sujata D.

AU - Anand, V. Sai Krishna

AU - Karan, Aishwarya

AU - Sree, K. Navya

AU - Vasantharaju, S. G.

AU - Pai, Girish

AU - Dengale, Swapnil J.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose: 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. Method: 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. Results: 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. Conclusion: 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.

AB - Purpose: 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. Method: 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. Results: 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. Conclusion: 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.

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