Liquid–liquid equilibrium measurements and computational study of salt–polymer aqueous two phase system for extraction of analgesic drugs
At a Glance
Section titled “At a Glance”| Metadata | Details |
|---|---|
| Publication Date | 2022-08-16 |
| Journal | Scientific Reports |
| Authors | Fariba Ghaffari, Mohammad Khorsandi, Hemayat Shekaari, Mohammed Taghi Zafarani-Moattar |
| Institutions | University of Tabriz |
| Citations | 12 |
| Analysis | Full AI Review Included |
Executive Summary
Section titled “Executive Summary”This research details the development and characterization of a novel Aqueous Two-Phase System (ATPS) for the efficient extraction of analgesic drugs, combining experimental liquid-liquid equilibrium (LLE) measurements with advanced quantum computational analysis.
- Novel ATPS Developed: A system composed of Polyethylene Glycol 600 (PEG600) and Potassium Hydroxide (KOH) in water was fully characterized at 298.15 K.
- High Extraction Efficiency: The system achieved high extraction efficiencies (EE %) for both Ibuprofen (up to 93.42%) and Acetaminophen (up to 92.30%).
- Hydrophobic Partitioning: Both drugs preferentially partitioned into the PEG-rich (top) phase, confirming the ATPS’s utility for separating hydrophobic solutes.
- Hydrophobicity Correlation: The Partition Coefficient (K) trend, K(Ibuprofen) > K(Acetaminophen), directly correlates with the drugs’ respective log Kow values (3.97 vs. 2.34).
- Computational Validation: Density Functional Theory (DFT) and Natural Bond Orbital (NBO) analysis confirmed that Ibuprofen forms stronger intermolecular interactions (H-bonds) with PEG than Acetaminophen does, validating the observed partitioning trend.
- Engineering Models Applied: Experimental binodal and tie-line data were successfully correlated using established semi-empirical models (Merchuk, Zafarani-Moattar, Othmer-Tobias, Setschenow), ensuring data reliability and predictability.
Technical Specifications
Section titled “Technical Specifications”| Parameter | Value | Unit | Context |
|---|---|---|---|
| ATPS Components | PEG600 + KOH + H2O | - | Polymer-Salt System |
| Operating Temperature | 298.15 | K | LLE and Partitioning Experiments |
| Operating Pressure | ~85 | kPa | Atmospheric Pressure |
| PEG Molar Mass | 600 | g mol-1 | Polyethylene Glycol (PEG600) |
| Maximum Ibuprofen K | 14.20 | - | Partition Coefficient at highest TLL (66.1% w/w) |
| Maximum Acetaminophen K | 11.99 | - | Partition Coefficient at highest TLL (66.1% w/w) |
| Maximum Ibuprofen EE % | 93.42 | % | Extraction Efficiency (PEG-rich phase) |
| Maximum Acetaminophen EE % | 92.30 | % | Extraction Efficiency (PEG-rich phase) |
| Ibuprofen log Kow | 3.97 | - | Hydrophobicity Index |
| Acetaminophen log Kow | 2.34 | - | Hydrophobicity Index |
| Strongest Ibuprofen-PEG E2 | 16.12 | kcal/mol | NBO Second-Order Perturbation Energy (Donor-Acceptor) |
| Strongest Acetaminophen-PEG E2 | 12.37 | kcal/mol | NBO Second-Order Perturbation Energy (Donor-Acceptor) |
| Refractive Index Precision | ±0.0001 | - | Measurement of PEG concentration |
| Analytical Balance Precision | ±1 x 10-7 | kg | Gravimetric preparation of mixtures |
Key Methodologies
Section titled “Key Methodologies”The study utilized a combination of classical physical chemistry techniques for LLE determination and advanced quantum computing methods for molecular interaction analysis.
- Phase Diagram Determination (Cloud Point Titration):
- Aqueous solutions of PEG600 (60 wt%) and KOH (50 wt%) were used.
- Titration involved dropwise addition of KOH solution to PEG600 solution until the cloud point (biphasic region) was reached, followed by water addition until the solution became clear (monophasic region).
- Tie-Line Composition Analysis:
- Five overall mixture compositions were prepared gravimetrically (precision ±1 x 10-7 kg).
- Equilibrium was established by vigorous stirring (30 min) and subsequent placement in a water bath (298 K).
- KOH concentration in both phases was determined using a flame photometer.
- PEG concentration was determined via refractive index measurements (ATAGO DR-A1) using a linear calibration plot.
- Drug Partitioning and Efficiency Calculation:
- 0.002 mass fraction of Ibuprofen or Acetaminophen was added to the separated equilibrium phases.
- Samples were centrifuged (2,000 rpm for 10 min) and equilibrated for 24 hours.
- Acetaminophen concentration was measured using UV spectroscopy (284, 261, 303 nm).
- Ibuprofen concentration was measured using fluorescence spectrophotometry.
- Partition coefficient (K) and extraction efficiency (EE %) were calculated using standard mass fraction ratios.
- LLE Data Correlation:
- Binodal data were fitted using the three-parameter Merchuk and Zafarani-Moattar semi-empirical equations.
- Tie-line consistency was verified using the Othmer-Tobias, Bancraft, and Setschenow correlations.
- Computational Study (DFT):
- Geometry optimization of binary systems (Drug + PEG) was performed using Density Functional Theory (DFT) with the B3LYP-D3(BJ) functional.
- Interaction energies (Eint) were calculated to determine the relative stability of Ibuprofen-PEG versus Acetaminophen-PEG complexes.
- Quantum Interaction Analysis:
- Natural Bond Orbital (NBO) analysis was used to quantify donor-acceptor interactions (E2), confirming H-bond strength.
- Quantum Theory of Atoms in Molecules (QTAIM) and Non-Covalent Interaction (NCI) analyses were applied to characterize the nature (ionic-covalent mix) and strength of intermolecular interactions.
Commercial Applications
Section titled “Commercial Applications”The development of this highly efficient, non-toxic, salt-polymer ATPS offers significant advantages for separation processes in several high-value industries.
- Pharmaceutical Manufacturing:
- High-yield liquid-liquid extraction and purification of analgesic drugs (ibuprofen, acetaminophen) and other hydrophobic pharmaceutical compounds.
- Alternative to traditional organic solvent extraction, reducing environmental impact and improving biocompatibility.
- Biotechnology and Bioseparation:
- Extraction and recovery of sensitive biomolecules (proteins, peptides) where high water content and low interfacial tension are critical for maintaining structure and function.
- Chemical Engineering:
- Design and optimization of large-scale liquid-liquid extraction columns based on the established LLE and correlation models (Othmer-Tobias, Setschenow).
- Cosmetics and Food Industry:
- Separation processes utilizing PEG, a non-toxic, FDA-approved polymer, suitable for products requiring high purity and safety standards.
- Process Modeling and Simulation:
- The validated computational models (DFT, QTAIM) provide a predictive tool for screening new drug-polymer combinations, accelerating process development.