Enhancing the Solubility of Metronidazole Using Deep Eutectic Solvents: A Computational Insight Into a Green Formulation Strategy

Enhancing the Solubility of Metronidazole Using Deep Eutectic Solvents: A Computational Insight Into a Green Formulation Strategy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Enhancing the Solubility of Metronidazole Using Deep Eutectic Solvents: A Computational Insight Into a Green Formulation Strategy Umar Mogaji Muhammed, Toyese Oyegoke This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8106095/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract This study investigates the potential of choline chloride–propylene glycol (CHL-PG) deep eutectic solvents (DES) to enhance the solubility of metronidazole (MNZ), a widely used but poorly water-soluble antimicrobial drug via computational modeling approach. Density functional theory (DFT) with the ωB97X-D functional and 6-31G(D) [3-21G(*)] dual basis set in Spartan software was used, various interactions and configurations of CHL and PG were modeled to identify the most stable DES formation pathways. HOMO–LUMO energy gaps were evaluated to determine component stability, while solubility strength was obtained using binding energy calculations of MNZ in the DES and water. Finding from our study indicates that the CHL–PG system feasibly formed a stable DES through a dual hydrogen-bonding pathway involving H₂CO–HOCH₂ and NCl–HOCH, which exhibited a formation energy of − 1.50 to − 1.51 eV, making it the most favorable route among all pathways evaluated. MNZ demonstrated significantly higher solubility in the formed DES, with a solubility strength of − 0.93 eV, compared to − 0.50 eV in water, indicating solubility enhancement potential. The narrow HOMO–LUMO gap in the DES further supports its molecular reactivity and suitability for pharmaceutical applications. These findings highlight the feasibility of CHL-PG as a green and effective solubilizing medium for MNZ providing insight to guide the design of DES-based drug formulations as alternative to conventional solvent in pharmaceutical development. Deep eutectic solvents Choline chloride Propylene glycol Metronidazole Modeling Density Functional Theory Solubility Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 1 INTRODUCTION The limited aqueous solubility of many Active Pharmaceutical Ingredients (APIs) poses a significant challenge to the development of effective drug formulations, frequently resulting in poor bioavailability, diminished therapeutic outcomes, and increased dosage requirements [ 1 ]. Approximately 40% of APIs suffer limited therapeutic efficacy due to poor solubility [ 2 ] and almost 90% of the medicines under development are poorly soluble in aqueous media causing difficulties in formulation of classes II and IV, Biopharmaceutical Classification System (BCS) drugs [ 3 ]. Metronidazole (MNZ) [1-(2-Hydroxyethyl)-2-methyl-5-nitroimidazole] [ 4 ] discovered in 1959, is a synthetic antibiotic derived from azomycin, a nitroimidazole characterized by the presence of a nitro group attached to an imidazole ring produced by the genera Actinobacteria and Proteobacteria [ 5 ]. It is physically available in white to pale yellow crystals or crystalline powder with 159-163 0 C melting point. It is sparingly soluble in water and in alcohol; slightly soluble in ether and chloroform [ 6 ]. Also known with the brand name Flagyl [ 7 ], it is used to treat infections caused by parasites (amoeba) and anaerobe bacteria. It is also approved by the Food and Drug Administration (FDA) for the treatment of protozoal infections such as diarrhea caused by Entamoeba histolytica , Giardia lamblia , Trichomoniasis vaginalis , Clostridium difficile and Balantidium coli as well as anaerobic bacterial infections caused by Bacteroides , Clostridium, Fusobacterium, Peptococcus, Peptostreptococcus, Eubacterium , Helicobacter , Campylobacter , Espiroquetas, Gardnerella vaginalis and Helicobacter pylori [ 8 ]. It is widely accepted and approved for the treatment of intestinal amebiases, liver amebiasis, bacterial septicemia, bone and joint infections, endocarditis, endometritis, bacterial vaginosis, intra-abdominal infections, lower respiratory tract infections, central nervous system (CNS) infections (meningitis and brain abscess), gynecologic infections (endometritis, tubo-ovarian abscess, bacterial vaginosis), skin structure infections, and surgical prophylaxis (colorectal surgeries) [ 9 ]. Metronidazole, despite its large therapeutic application is slightly soluble in water (approx. 10 mg/mL at 298.15 K), according to United States Pharmacopeia (USP) [ 10 ]. Its poor aqueous solubility significantly limits its bioavailability and poses challenges for effective drug formulation, leading to incomplete and inconsistent absorption after oral or topical administration. This causes suboptimal therapeutic outcomes and the need for higher or more frequent dosing [ 4 ]. Accordingly, the investigation and implementation of advanced solubility enhancement methods are not only vital for converting prospective drug candidates into practical therapeutic solutions but also for assuring reliable drug absorption kinetics and improving the ultimate clinical outcomes for patients [ 11 ]. Several strategies have been employed to enhance the solubility of MNZ. Some of which include solid dispersion. This technique involves dispersing metronidazole in hydrophilic polymers such as polyethylene glycols (PEGs) and polyvinylpyrrolidone (PVP) significantly increasing its dissolution rate and bioavailability [ 12 ]. The solvent evaporation and fusion methods are commonly employed, with higher drug-to-polymer ratios yielding greater solubility improvements. The loss of crystallinity and formation of amorphous or colloidal solutions are key mechanisms underlying these enhancements. Ref [ 13 ] demonstrated that MNZ solid dispersions with polyethylene glycol (PEG-4000) and polyvinylpyrrolidone (PVP) markedly improved solubility; up to 100% drug release within one hour for MNZ:PEG-4000 at 1:5 ratios. Ref [ 14 ] reported solubility of metronidazole from solid dispersions increases by 14–17% in comparison with the original substance with PEG-2000 at a 1:5 ratio, however physical and chemical stability as well as recrystallization over time remains a major concern [ 15 ]. In addition, hydrotropic solubilization which involves introducing a second solute; an hydrotrope (urea and sodium benzoate) has been used to increase the aqueous solubility of MNZ by more than 14-fold compared to its solubility in water alone [ 6 ]. Similarly, nicotinamide as an hydrotrope was used to solubilize MNZ in aqueous media causing several-fold increase in its aqueous solubility [ 16 ]. Kadam in 2012, increased the solubility of MNZ more than 14 times in mixed hydrotropic solution as compared to its solubility in distilled water [ 17 ]. The high concentrations of these hydrotropic agents cause toxicity and compatibility issues [ 18 ]. Another pharmaceutical technology for enhancing the solubility of metronidazole is co-crystallization process which involves preparing a cocrystal of MNZ and ethyl gallate. The formation of the cocrystal alters the solid-state structure of the drug, creating new intermolecular interactions with ethyl gallate thereby enhancing water interaction, leading to faster dissolution rates and higher solubility [ 4 ]. Another established solubility enhancement technique is cyclodextrin complexation in which cyclodextrin inclusion complexes, especially with β-cyclodextrin and its methylated derivatives, have been shown to dramatically enhance the solubility and dissolution of MNZ [ 19 ]. The formation of stable 1:1 complex increases apparent solubility by up to 100-fold, with the added benefit of preserving the drug's antimicrobial activity [ 20 ]. In addition, cyclodextrin-based nanofibrous webs and oral delivery systems have also demonstrated rapid dissolution and improved bioavailability [ 21 ]. The drawback of this process is a limited complexation capacity, high cost, potential for toxicity or altered drug release [ 22 ]. Another technique is prodrug formation which involves the synthesis of MNZ phosphate and amino acid esters to yield water-soluble derivatives that are rapidly hydrolyzed to release active MNZ and result to increase in solubility up to 140-fold [ 23 ]. However, the approach requires chemical modification and possible changes in pharmacokinetics [ 24 ]. Other established solubility enhancement techniques are; particle size reduction via micronization and milling to enhance dissolution by increasing surface area and reducing crystallinity [ 25 ] but concerns of broad particle size distribution and risk of thermal/chemical degradation occurs [ 26 ], and co-solvency which involves utilizing water-miscible solvents like ethanol and propylene glycol to increase the solubility of poorly soluble drugs like MNZ [ 27 , 28 ]. However, these conventional solubility enhancement approaches often pose threats of toxicity, cost, environmental implications, unsustainability and energy-intensive [ 29 ]. Recent technological advancements have introduced deep eutectic solvents (DES) as green, biodegradable, and low-cost alternatives to conventional organic solvents. These novel solvents are formed by mixing a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA) to form eutectic mixtures with melting points lower than that of the individual species. They exhibit low volatility, simple preparation and tunable physicochemical properties such as hydrogen-bonding capacity and polarity [ 30 , 31 ]. This unique structure enables DESs to interact effectively with polar and non-polar drugs, modifying their solvation dynamics. DESs especially those combining choline chloride with hydrogen bond donors are increasingly recognized as eco‑friendly alternatives for solubilizing poorly soluble drugs [ 3 , 32 ]. Szewczyk et al. [ 10 ] demonstrated the effectiveness of choline chloride and citric acid natural deep eutectic solvent (NADES) in improving MNZ solubility at differing conditions of temperature and concentrations [ 10 ]. These studies emphasize the flexibility of DESs as both solubilizing and stabilizing agents in drug formulation. Nevertheless, the underlying mechanisms driving these enhancements remain poorly understood, these studies do not provide detailed insights into the intermolecular interactions governing the solubility enhancement. Furthermore, while the use of DESs to improve drug solubility is well-documented, the rational design of DESs for MNZ molecules is still challenging due to the limited understanding of the factors that govern DES-MNZ interactions [ 33 ]. To address the existing research limitations stated earlier in the literature review, the mechanism involved in forming an energetically stable DES from the use of choline chloride (CHL) and propylene glycol (PG) was investigated. Furthermore, the potential of choline chloride–propylene glycol DES as a solubility enhancement medium for metronidazole was explored in relation to its solubility in conventional solvent (water) using hybridthrough density functional theory (DFT) computational level. 2 METHODOLOGY 2.1 Computational Details In the study of the metronidazole solubility in a DES, we employed the use of Spartan molecular modeling package for the modeling and simulation of the solvent and its behavior with a computing device of 8GB RAM, core i7 processor, processor speed of 2.60GHz, and 256GB SSD storage capacity. Following the strength of our computing resource, we deployed a hybrid approach of combining the use of semi-empirical with density functional theory (DFT) calculation method. In which, PM3 equilibrium conformer calculations were first carried out at an SCF tolerance of 10 9 to obtained most stable geometry for the model structures in the study. After which ωB97X-D hybrid DFT calculations method with dual basis set (6-31G(D) [3-21G(*)]) was employed to improve on the accuracy of the energies obtained from the geometry optimization calculations, with the inclusion of dispersion [ 34 , 35 ] and basis set superposition error [ 36 – 38 ] correction for obtaining quality results useful for computing the drug solubility (evaluated as a function of the drug binding energy with the solvent) in the solvent in line with literature [ 39 ] which suggests the use of dual basis set as one of measure for correcting the BSSE in the package. 2.2 Study strategy In Fig. 1 , we diagrammatically presented the strategy employed in the study beginning with the building of the molecular models for CHL, PG, MNZ, and water. Each model was then subjected to geometry optimization to obtain most relax form of structures suitable for subsequent analysis using MMFF method. Next was the conformation of PG that was carried out through equilibrium conformer calculations performed at the semi-empirical PM3 level, considering 200 conformers. The optimized conformer was then used to evaluate the possible pathways for DES (CHL-PG) formation from which the most stable structure was identified. The solubility evaluation of MNZ was then carried out by analyzing its interaction with the most stable DES (CHL-PG) and with water. This step enabled identification of the most favorable DES–MNZ and H₂O–MNZ interaction routes. Finally, all results were assessed to determine the extent of solubility of MNZ in the DES compared to water. Noting that all the geometries and energies were obtained using the computational details presented earlier in Section 2.1. 2.3 Modelling of HBA, HBD, Water and MNZ used in the study The approaches of modeling the ionic interaction of CHL as the HBA of the DES was employed using single bond to maintain consistency in the study. This is in accordance to the literature [ 39 ] in which the use of no bond, generic, or single bond shows no significant difference irrespective of the level of calculation employed. Further analysis of the conformer structures of PG as the HBD for the potential DES was evaluated using Parameterized Method (PM3) of the semi-empirical computational method [ 40 ] to employ the use of the most stable structure for this application. Similarly, water and metronidazole structural models were built, geometrically optimized to represent the actual structures of these components for the study. 2.3.1 Evaluation of the des models’ components used in the study An infrared spectroscopy plot was computationally generated for the HBA and HBD employed and was compared with experimental value obtained from a wet laboratory. The similarities and differences visible on their respective plots were analyzed to determine the accuracy of the modelled structures. 2.3.2 Evaluation of the DES formation mechanism The study evaluated several CHL-PG DES formation mechanisms by analyzing different interaction points on CHL (C, N, O, and Cl) and PG (H) with their corresponding formation energy (F.E). The energies are computed as F.E = Edes - EHBA – EHBD, where the Edes is the electronic energies of the DES, EHBA is the electronic energies of the hydrogen bond acceptor, EHBD is the electronic energies of the hydrogen donor, Edes (Bonded) is the electronic energies of the DES and Edes (Unbonded) is the electronic energies of the DES while in unbonded state. All the electronic energies are collected in eV. The energy that is the most negative predict or confirms the most feasible interaction formation pathway that would lead to the formation of the DES. In Fig. 2, we demonstrated different interaction pathways explored in our study. 2.3.3 Stability Analysis of the Components The stability analysis of all component structures was evaluated using the energy band gap, which is the difference between the energy of the highest occupied molecular orbital E(HOMO) and energy of the lowest unoccupied molecular orbital E(LUMO) as expressed in the literature reports. 2.3.4 Evaluation of the solubility of MNZ in different solvents (DES and Water) To evaluate the solubility strength of MNZ in the solvent, we measure the drug solubility as a function of binding energy [ 38 , 41 , 42 ] with the solvent, which was computed as SS MNZ = E (solvent/MNZ) – E(solvent) – E (MNZ), where SS MNZ is Solubility Strength, E (solvent/MNZ) is Combined energy of MNZ interactions with the solvent, E(solvent) is total energy of the solvents, and E (MNZ) is total energy of MNZ. 3 RESULTS AND DISCUSSIONS 3.1 DES model components’ molecular properties prediction and model validation Analysis of the results presented in Table 1 shows that the energies of the HOMO, LUMO, and their corresponding energy gaps indicate that choline chloride (CHL) exhibits a smaller energy gap compared to propylene glycol (PG). This suggests that CHL is more chemically reactive than PG. Table 1 HOMO-LUMO properties of the DES model components Specie E (HOMO) (eV) E (LUMO) (eV) E Gap Choline chloride (CHL) -7.85 3.06 10.91 Propylene Glycol (PG) -9.70 3.75 13.45 Furthermore, the analysis of possible interactions between CHL and PG suggests that CHL predominantly interacts through its HOMO (highest occupied molecular orbital), while PG interacts through its LUMO (lowest unoccupied molecular orbital) during DES formation. The resulting interaction energy gap (11.60 eV) indicates favorable electronic compatibility between the two species. In agreement with literature reports, CHL acts as the electron donor, whereas PG serves as the electron acceptor in the hydrogen-bonding interactions responsible for DES formation. To assess the reliability and validity of our molecular model, infrared (IR) spectral analysis was performed. The computed IR spectra were compared with corresponding experimental spectra available in the literature. Previous validation of the CHL model in our earlier studies showed strong agreement between computed and experimental spectra. However, since no prior computational IR spectrum was available for PG, its IR spectrum was calculated in this study (Fig. 3), and the results were compared with experimental data reported in the literature (Table 2 ). The main peaks identified from the analysis are summarized in Table 2 . The broad O–H stretching vibration, experimentally observed between 3550–3200 cm⁻¹, is attributed to hydrogen bonding and is absent as a distinct band in the DFT spectrum. The C–H stretching vibrations were calculated at 2916 and 2933 cm⁻¹, aligning well with the experimental absorptions at 2975, 2935, and 2870 cm⁻¹. Additional C–H stretching modes appeared between 3019 and 3108 cm⁻¹, consistent with the experimental band near 3000 cm⁻¹. The C–H bending vibrations were found between 1304 and 1475 cm⁻¹, corresponding to the experimental peaks at 1375 and 1460 cm⁻¹. Similarly, C–O stretching vibrations of the alcohol group were calculated at 1041–1211 cm⁻¹, which agree closely with the experimental absorptions at 1040, 1070, and 1120 cm⁻¹. In the lower frequency region, C–H wagging vibrations were observed at 814–960 cm⁻¹, matching experimental bands at 820, 890, and 750 cm⁻¹, while a skeletal vibration mode was calculated at 521 cm⁻¹ and corresponds to the experimental feature around 600 cm⁻¹. Table 2 Comparison of theoretical and experimental IR peaks for propylene glycol Peaks DFT (cm⁻¹) Expt. (cm⁻¹) [ 43 ] O–H stretching, broad (3200–3600) - 3550–3200 C–H stretching (2850–3000) 2916, 2933 2975, 2935, 2870 C–H stretching (3000–3100) 3019, 3035, 3096, 3108 3000 C–H bending (1350–1470) 1304, 1349, 1394, 1439, 1460, 1475 1460, 1375 C–O stretching of alcohol (1000–1260) 1041, 1101, 1133, 1174, 1211 1120, 1070, 1040 C–H wagging (720–900) 814, 922, 960 890, 820, 750 Not available 521 600 Overall, the DFT-calculated spectra for both CHL and PG showed strong consistency with experimental data, validating the reliability of the developed molecular models. This confirms that the computationally derived CHL–PG DES model is suitable for use in solubility enhancement simulations. 3.2 Investigation of DES Formation Pathway and Stability An in-depth investigation of the formation pathway and stability of the Deep Eutectic Solvent (DES) composed of choline chloride (CHL) as the hydrogen bond acceptor (HBA) and propylene glycol (PG) as the hydrogen bond donor (HBD) was carried out. The evaluation considered six possible interaction sites on the HBA (H₃C–, H₂C–, H₂CO–, NCl–, ClN–, and OHC– atoms), interacting with different hydrogen atoms of the HBD (–HOCH, –HCOH, –HCH₂, –HCH, and –HOCH₂). In Table 3 , the electronic energies of CHL, PG, and their combined unbonded DES geometry are presented. At this stage, no defined bonding model or hydrogen-bonding pathway was imposed; the data serve as a reference prior to exploring the potential hydrogen-bond formation routes discussed later in Sections 3.2.1 to 3.2.8. Table 3 Electronic energies of DES model components Label Mol. Wt. (amu) Energy (eV) Formation Energy (eV) Choline Chloride (CHL) 139.63 -21467.85 - Propylene Glycol (PG) 76.10 -7332.78 - CHL: PG (Unbonded) 215.72 -28801.59 −0.96 The electronic energies of CHL and PG were calculated to be − 21467.85 eV and − 7332.78 eV, respectively. The total energy of the unbonded CHL–PG system was found to be − 28801.59 eV, corresponding to a formation energy of − 0.96 eV. The negative formation energy indicates that the CHL–PG combination is thermodynamically feasible, suggesting a favorable tendency for DES formation even before specific hydrogen-bonding interactions are established. 3.2.1 Evaluation of DES formation via H 3 C–X interaction routes An assessment of the DES formation via the methyl group (H 3 C) of CHL through various interaction routes, H 3 C–X (X = HOCH, HCOH, HCH 2 , HCH, HOCH 2 ), was conducted and the energy results are presented in Table 4 . Table 4 Stability of the CHL-PG DES via H3C- as a point of interaction Label Energy (eV) Relative Energy (eV) Formation Energy (eV) HBA Sites HBD Sites H 3 C HOCH -28801.66 -0.08 -1.04 HCOH -28801.59 -0.00 -0.96 HCH 2 -28801.59 -0.00 -0.96 HCH -28800.88 0.71 -0.25 HOCH 2 -28800.95 0.64 -0.33 The interaction labeled H 3 C–HOCH yielded the most stable formation pathway as displayed in Table 4 , with a formation energy of − 1.04 eV, suggesting favorable hydrogen bonding at that site. Meanwhile, other routes such as H 3 C–HCOH and H 3 C–HCH 2 maintained the same energy as the unbonded system (− 0.96 eV), indicating negligible interaction. Comparatively weaker interactions were observed for H 3 C–HCH (− 0.25 eV) and H 3 C–HOCH 2 (− 0.33 eV), implying limited stability. The geometry of the most feasible formation pathway is presented in Fig. 4. 3.2.2 Evaluation of DES formation via ClN–X interaction routes A comparative analysis was carried out for the interactions formed through the ClN- site of CHL, represented as ClN–X (X = HOCH, HCOH, HCH 2 , HCH, HOCH 2 ). The energy results are presented in Table 5 and the geometry of the most feasible formation pathway is presented in Fig. 5. Table 5 Stability of the CHL-PG DES via ClN- as a point of interaction Label Energy (eV) Relative Energy (eV) Formation Energy (eV) HBA Sites HBD Sites ClN HOCH -28801.04 0.55 -0.41 HCOH -28801.45 0.13 -0.83 HCH 2 -28801.23 0.36 -0.60 HCH -28801.49 0.10 -0.86 HOCH 2 -28801.34 0.25 -0.71 Among these, the interactions ClN–HCH with formation energy of − 0.86 eV and ClN–HCOH with formation energy of − 0.83 eV showed moderate stability, as presented in Table 5 while other interactions like ClN–HOCH 2 and ClN–HCH 2 had slightly lower energies of − 0.71 eV and − 0.60 eV, respectively. The ClN–HOCH interaction resulted in the weakest interaction − 0.41 eV. This suggests that the ClN site is more selective and tends to interact better with hydroxyl- and aldehyde-like groups than with primary alcohols. Figure 5 shows that most stable optimized ClN–HCH interaction. 3.2.3 Evaluation of DES formation via H 2 C–X interaction routes A further evaluation was performed on the H 2 C site through interactions denoted as H 2 C–X (X = HOCH, HCOH, HCH 2 , HCH, HOCH 2 ), as presented in Table 6 . Table 6 Stability of the CHL-PG DES via H2C- as a point of interaction Label Energy (eV) Relative Energy (eV) Formation Energy (eV) HBA Sites HBD Sites H 2 C HOCH -28801.62 -0.03 -1.00 HCOH -28801.71 -0.12 -1.08 HCH 2 -28801.69 -0.10 -1.06 HCH -28801.56 0.03 -0.93 HOCH 2 -28801.62 -0.03 -0.99 The strongest interaction for this was recorded for H 2 C–HCOH having a formation energy of − 1.08 eV, followed closely by H 2 C–HCH 2 (− 1.06 eV), confirming that this sites actively participates in DES formation. The HOCH and HOCH 2 routes also displayed notable formation energies (− 0.99 eV each), signifying meaningful hydrogen bonding potential. The weakest interaction in this group was found in H 2 C–HCH (− 0.93 eV), which still exhibited better binding than most interactions from other sites. Figure 6 shows the most stable optimized H 2 C–HCOH interaction. 3.2.4 Evaluation of DES formation via OHC–X interaction routes The interaction behavior of the OHC site with various HBD donor sites designated as OHC–X (X = HOCH, HCOH, HCH 2 , HCH, HOCH 2 ) was also explored presented in Table 7 . Table 7 Stability of the CHL-PG DES via OHC- as a point of interaction Label Energy (eV) Relative Energy (eV) Formation Energy (eV) HBA Sites HBD Sites OHC HOCH -28801.51 0.08 -0.89 HCOH -28801.20 0.38 -0.58 HCH 2 -28801.71 -0.12 -1.08 HCH -28802.03 -0.44 -1.40 HOCH 2 -28801.49 0.10 -0.86 Among these, the most stable configuration was obtained from OHC–HCH with formation energy of − 1.40 eV, The optimized structure of the geometry is shown in Fig. 7. This is followed closely by OHC–HCH 2 having formation energy of − 1.08 eV. These results suggest significant hydrogen bond formation involving these pathways. On the other hand, interactions like OHC–HCOH (− 0.58 eV) and OHC–HOCH (− 0.89 eV) were found to be less stabilizing, possibly due to less favorable alignment or steric hindrance. The HOCH 2 route also showed moderate formation energy (− 0.86 eV), supporting its partial involvement in DES stabilization at the OHC site. 3.2.5 Evaluation of DES formation via NCl–X interaction routes The evaluation of NCl interaction routes, represented as NCl–X (X = HOCH, HCOH, HCH 2 , HCH, HOCH 2 ), showed generally weaker stabilization compared to other interaction centers as shown in Table 8 . Table 8 Stability of the CHL-PG DES via NCl - as a point of interaction Label Energy (eV) Relative Energy (eV) Formation Energy (eV) HBA Sites HBD Sites NCl HOCH -28801.24 0.35 -0.61 HCOH -28801.26 0.33 -0.64 HCH 2 -28801.37 0.22 -0.74 HCH -28801.01 0.58 -0.38 HOCH 2 -28801.49 0.10 -0.86 The best interaction shown in Fig. 8 was NCl–HOCH 2 (− 0.86 eV), followed by NCl–HCH 2 (− 0.74 eV), NCl–HCOH (− 0.64 eV) and NCl–HOCH (− 0.61 eV). The lowest binding energy occurred with NCl–HCH (− 0.38 eV), indicating this site do not favor the DES formation. Despite these moderate values, the involvement of the NCl site cannot be entirely neglected, as it supports structural geometry indirectly. 3.2.6 Evaluation of DES formation via H 2 CO–X interaction routes An investigation into the interaction routes involving the H 2 CO site of HBA with HBD sites denoted as H 2 CO–X (X = HOCH, HCOH, HCH 2 , HCH, HOCH 2 ) whose results was presented in Table 9 revealed H 2 CO–HOCH 2 as the most favorable formation route shown in Fig. 9 with a formation energy of − 1.51 eV. Table 9 Stability of the CHL-PG DES via H 2 CO - as a point of interaction Label Energy (eV) Relative Energy (eV) Formation Energy (eV) HBA Sites HBD Sites H 2 CO HOCH -28802.04 -0.45 -1.41 HCOH -28801.20 0.39 -0.57 HCH 2 -28801.32 0.27 -0.69 HCH -28801.65 -0.07 -1.03 HOCH 2 -28802.14 -0.55 -1.51 Other interactions including H 2 CO–HOCH with formation energy of − 1.41 eV and H 2 CO–HCH interaction with formation energy of − 1.03 eV also demonstrated considerable stability. Meanwhile, H 2 CO–HCH 2 formation pathways with − 0.69 eV and H 2 CO–HCOH interaction routes with energy of − 0.57eV were comparatively weaker. These results indicate that the H 2 CO site preferentially interacts with hydroxyl groups environments to form strong hydrogen bonds. 3.2.7 Most Stable Interaction Pathways for DES Formation Table 10 presents a summary of the most stable interaction routes analyzed for the formation of the CHL–PG Deep Eutectic Solvent (DES). The results compare the unbonded formation mechanism with six possible single-site hydrogen bonding pathways between the hydrogen bond acceptor (CHL) and donor (PG). Table 10 Most stable interactions across the different single site DES formation pathways Label Energy (eV) Formation Energy (eV) CHL-PG (Unbonded) -28801.59 -0.96 HBA Sites HBD Sites H 3 C HOCH -28801.66 -1.04 H 2 C HCOH -28801.71 -1.08 H 2 CO HOCH 2 -28802.14 -1.51 NCl HOCH 2 -28801.49 -0.86 ClN HCH -28801.49 -0.86 OHC HCH -28802.03 -1.40 Among all the interaction pathways examined, the H₂CO–HOCH₂ configuration (Fig. 10) was identified as the most stable and energetically favorable, exhibiting the lowest formation energy of − 1.51 eV. This strong stability implies that this pathway provides the most favorable conditions for effective complexation between CHL and PG. The negative formation energy further confirms spontaneous DES formation at this site, suggesting that the oxygen atom of the H₂CO group in CHL forms a strong hydrogen bond with the hydrogen atom of the HOCH₂ group in PG. This finding highlights the importance of the hydroxyl and ether functionalities in stabilizing the CHL–PG DES structure through strong electrostatic interactions. 3.2.8 Investigation into double-sites DES formation pathway The formation pathways of the CHL–PG Deep Eutectic Solvent (DES) were further investigated by evaluating possible hydrogen-bonding interactions between the hydrogen bond acceptor (HBA), choline chloride (CHL), and the hydrogen bond donor (HBD), propylene glycol (PG). In the initial single-site interaction analysis, each interaction site on the HBA (H₃C, H₂C, H₂CO, NCl, ClN, and OHC) formed a single hydrogen bond with one of the hydrogen atoms from the HBD (HOCH, HCOH, HCH₂, HCH, HOCH₂). To explore whether a more stable DES formation mechanism could be achieved, a double-site interaction pathway was examined. In this formation mechanism, the oxygen atom of CHL interacted with a hydrogen atom of PG’s hydroxyl group (H₂CO–HOCH₂), while the chlorine atom of CHL simultaneously interacted with another hydrogen atom of PG (NCl–HOCH), in accordance with the form of geometry obtained for the most stable single site hydrogen bonding interaction pathway shown in Fig. 10. Table 11 presents the analysis results (formation energies, bond lengths etc) of the double site configuration in comparison with the single site configuration. Table 11 Analysis of single and double sites DES showing bond lengths Most stable Energy (eV) Formation Energy (eV) Shortest bond length (Å) O-H (H 2 CO-HOCH 2 ) Shortest bond length (Å) Cl-H (NCl-HOCH) Single site -28802.14 -1.51 1.826 2.426 Double site -28802.13 -1.50 1.826 2.437 Analysis of the results presented in Table 11 shows that the dual hydrogen-bonding interaction formation mechanism, which was evaluated through the H₂CO–HOCH₂ and NCl–HOCH interaction sites was found to have exhibited a geometry formation energy (− 1.50 to − 1.51 eV), and hydrogen-bond distances (O–H = 1.826 Å; Cl–H = 2.437 Å) that are closely comparable to those obtained for the most stable single-site interaction pathway. The most stable double site configuration geometry is shown in Fig. 11. Overall, the DES (CHL:PG) formed from choline chloride and propylene glycol was predicted to feasibly develop through this dual-site hydrogen-bonding arrangement, whereas other pathways were less favorable due to their comparatively weaker formation energies. This indicates that cooperative hydrogen bonding may play a significant role in enhancing DES structural stability and modulating its physicochemical properties. Consequently, all subsequent analyses in this study will employ the CHL–PG (H₂CO–HOCH₂ : NCl–HOCH) pathway and refer to it as the formed DES derived from CHL and PG. 3.3 Stability analysis of components The molecular properties of the DES (CHL-PG) and its model components with water and metronidazole (MNZ) are presented in Table 12 . These properties provide insight into the electronic structure, reactivity, and potential interaction mechanisms relevant to MNZ solubility enhancement. Table 12 Molecular Properties of all Components Specie E HOMO (eV) E LUMO (eV) E Gap (eV) IEG-mnzHOMO (eV) IEG-mnzLUMO (eV) MNZ -9.89 -1.61 8.28 8.28 8.28 DES -8.67 2.37 11.05 12.27 7.06 H 2 O -10.35 4.21 14.56 14.09 8.74 The energy band gap (E-Gap) serves as a vital descriptor of molecular stability and reactivity. A larger band gap indicates higher stability and lower chemical reactivity, whereas a smaller band gap reflects increased reactivity, which can favor solubility enhancement [ 44 ]. Among the studied species, DES exhibited an energy band gap of 11.05 eV, which is lower than that of water (14.56 eV) but higher than that of MNZ (8.28 eV). This intermediate band gap suggests that the DES is sufficiently reactive to interact effectively with MNZ while maintaining moderate stability. Consequently, CHL–PG is predicted to promote MNZ solubility more efficiently than water. Figure 12 presents the optimized geometry of water and MNZ. The interaction energy gap (IEG) provides additional insight into the feasibility and directionality of solvent–solute interactions. A lower IEG corresponds to a more favorable interaction, signifying easier electron transfer between the interacting species. As shown in Table 12 , the lowest IEG value (7.06 eV) was obtained when the DES (CHL–PG) interacted through its HOMO orbital with the LUMO of MNZ. This indicates a strong interaction pathway favorable for MNZ solubility enhancement. In contrast, water exhibited a higher IEG (8.74 eV), suggesting a less feasible interaction with MNZ. Overall, these findings highlight that the DES (CHL–PG) system, particularly in its double-site configuration, exhibits a more suitable electronic structure for MNZ solubility enhancement compared to conventional solvents like water. 3.4 Evaluation of the Solubility of Metronidazole in Water Metronidazole (MNZ) solubility in water (H₂O) was evaluated using DFT calculation at a dual basis correction set to ensure improved convergence and accuracy. Several potential interaction pathways between MNZ and H₂O were modeled to identify the most energetically favorable mode of molecular interaction. The computed electronic energies and corresponding solubility strengths are presented in Table 13 . Table 13 Solubility Strength Calculation as a function of Binding Energy via MNZ in water interaction Species Molecular Weight (amu) E (eV) Solubility Strength (eV) H 2 O 18.015 -2078.59 - MNZ 171.156 -16970.62 - MNZ–H 2 O Interactions H 3 CC-OH 2 189.171 -19049.54 -0.33 HCH-OH 2 189.171 -19049.48 -0.26 HO-HOH 189.171 -19049.71 -0.50 O 2 N-OH 2 189.171 -19049.50 -0.28 O 2 N-HOH 189.171 -19049.31 -0.09 The results presented in Table 13 and Fig. 13 reveal that the solubility strength of MNZ in water varies across different interaction pathways, with the HO–HOH configuration exhibiting the most negative binding energy (− 0.50 eV). This pathway therefore represents the most stable and favorable interaction route between MNZ and H₂O molecules. In line with existing literature, the more negative binding energy values correspond to stronger intermolecular interactions and higher solubility strength, as they reflect a more exothermic and energetically favorable process. The observed low solubility strength of − 0.50 eV indicates weak interaction between MNZ and water, implying limited solubility. This aligns with the findings of the literature [ 10 ], who reported a solubility of MNZ in water of approximately 1.00 × 10⁻³ molar fraction. These results collectively confirm that while MNZ forms stable hydrogen-bonding interactions with water, their relatively low binding strength restricts the compound’s overall solubility in aqueous media. 3.5 Evaluation of the Solubility of MNZ in the DES Here, our findings obtained for the analysis of different molecular interaction pathways that could possibly predicts the solubility of MNZ in the DES are presented in Table 14 . Table 14 MNZ solubility strength in DES [CHL:PG (H 2 CO–HOCH 2 :NCl–HOCH)] Species Molecular Weight (amu) E (eV) Solubility Strength (eV) CHL:PG 215.721 -28802.13 - MNZ 171.156 -16970.62 - MNZ–DES Interactions OH-ClN 386.877 -45773.68 -0.93 HO-HCOH 386.877 -45773.35 -0.60 HCH-OCH 2 386.877 -45773.54 -0.79 O 2 N-HCH 2 386.877 -45773.17 -0.42 NO-HCH 2 386.877 -45772.94 -0.19 Determination of the solubility strength of MNZ through CHL:PG DES is presented in Table 14 by employing several routes on the MNZ shows that the highest solubility strength of -0.93 eV was investigated via the OH-ClN bonded pathway as presented in Fig. 14. This is evident from the strong electrostatic attraction between the hydroxyl group in MNZ and chlorine in the DES. This result aligns with the solubility of MNZ in 1:4 CHL-PG determined by [ 10 ] with solubility of 5.01 × 10⁻³ molar fraction. The results in Tables 13 and 14 shows that both solvents influence the solubility of MNZ. However, CHL:PG DES best improves the solubility performance of MNZ evident from its higher affinity with the drug unlike water with low solubility characteristics. Figure 14 presents the geometrical structure of most stable MNZ interactions with the DES. 3.6 Summary of metronidazole solubility in the different solvents In Table 15 , we summarize the most stable solubility strength of MNZ in both water and choline chloride–propylene glycol (CHL:PG) deep eutectic solvent (DES) systems. The solubility strength values were computed based on the most energetically favorable interaction identified in previous sections. Table 15 MNZ solubility in water and DES. S/N Solvent Medium Interactions Site Mol. Wt (amu) Energy (eV) Solubility Strength (eV) 1 MNZ–H 2 O HO-HOH 189.171 -19049.71 -0.50 2 MNZ–DES OH-ClN 386.877 -45773.68 -0.93 The results in Table 15 clearly show that metronidazole exhibits stronger interaction and higher solubility in DES than in water. Among the different configurations, the DES interaction (OH–ClN) displays the most negative solubility strength (− 0.93 eV), indicating a more exothermic and stable solvation process. In contrast, the solubility of MNZ in water (− 0.50 eV) is comparatively weaker, signifying limited hydrogen-bonding interactions within the aqueous medium. The stronger interactions observed in the DES systems can be attributed to the synergistic hydrogen-bond network and the electron-donating capability of CHL and PG functional groups, which promote enhanced stabilization of the MNZ molecule within the solvent matrix. These findings affirm that DES provides a superior solvation environment for MNZ compared to conventional water solvent, highlighting its potential as an efficient green solvent for pharmaceutical solubilization applications. 4 CONCLUSIONS This study explored the potential of a choline chloride–propylene glycol (CHL–PG) deep eutectic solvent (DES) as an effective and eco-friendly medium for enhancing the solubility of metronidazole (MNZ) relative to water, using a hybrid quantum method of PM3 semi-empirical for geometry optimization and ωB97X-D with dual basis set (6-31G(D) [3-21G(*)]) for the improvement of its energy calculation. The DES model components (CHL as HBA and PG as HBD), water, and MNZ were individually developed and optimized to assess their stability and reactivity characteristics. The CHL–PG system feasibly formed a stable DES through a dual hydrogen-bonding pathway involving H₂CO–HOCH₂ and NCl–HOCH, which exhibited a formation energy of − 1.50 to − 1.51 eV, making it the most favorable route among all pathways evaluated. MNZ demonstrated significantly higher solubility in the formed DES, with a solubility strength of − 0.93 eV, compared to − 0.50 eV in water. This enhanced interaction is supported by the lower interaction energy gap of 7.06 eV, indicating a stronger affinity and improved feasibility for MNZ–DES interaction. Additionally, the DES (CHL–PG) exhibited a narrower HOMO–LUMO band gap (11.04 eV) compared to water (14.56 eV), suggesting increased molecular reactivity and superior solvation potential for MNZ. Overall, the findings align with existing experimental reports and reinforce that the CHL–PG DES is a promising and sustainable solvent system capable of significantly enhancing MNZ solubility. 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1","display":"","copyAsset":false,"role":"figure","size":245599,"visible":true,"origin":"","legend":"\u003cp\u003eBlock flow diagram of the overall process employed in the study\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/695545b9027f2da4bb0d0172.jpg"},{"id":96710729,"identity":"832ea13f-3169-44de-b2d4-1918f58b54d6","added_by":"auto","created_at":"2025-11-25 10:11:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":413749,"visible":true,"origin":"","legend":"\u003cp\u003eThe different molecular interaction pathways investigated in our study.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/0abf60a9db4c0dc4a0b32294.png"},{"id":96680904,"identity":"b739da48-1b20-4781-b789-e7fc7813acbd","added_by":"auto","created_at":"2025-11-25 03:26:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":23694,"visible":true,"origin":"","legend":"\u003cp\u003eIR analysis of Propylene glycol using DFT\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/07e02fb2b9ea6ed3a72112a3.png"},{"id":96680902,"identity":"85a43082-2038-4279-8b9b-8dcee1ecdd64","added_by":"auto","created_at":"2025-11-25 03:26:27","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":120113,"visible":true,"origin":"","legend":"\u003cp\u003eThe most stable geometric structure of the DES for the H\u003csub\u003e3\u003c/sub\u003eC-X interaction (a) one view (b) another view.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/3f9d9ac4664e297942141273.png"},{"id":96680856,"identity":"aa215e6d-38e7-43c7-80f5-fd677fdbc9f6","added_by":"auto","created_at":"2025-11-25 03:26:22","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":132746,"visible":true,"origin":"","legend":"\u003cp\u003eThe most stable geometric structure of the DES for the ClN-X interaction (a) one view (b) another view.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/2d507fc8971268d4e4387f88.png"},{"id":96680858,"identity":"ff84822f-ae82-4ba3-a37b-ac6770426295","added_by":"auto","created_at":"2025-11-25 03:26:22","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":142737,"visible":true,"origin":"","legend":"\u003cp\u003eThe most stable geometric structure of the DES for the H\u003csub\u003e2\u003c/sub\u003eC-X interaction (a) one view (b) another view.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/25532849712dd9faca8030a2.png"},{"id":96680864,"identity":"d673167f-35ca-479c-b31d-e3f3b1202193","added_by":"auto","created_at":"2025-11-25 03:26:22","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":141107,"visible":true,"origin":"","legend":"\u003cp\u003eThe most stable geometric structure of the DES for the OHC-X interaction (a) one view (b) another view.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/4f0ab5a057a2a500b1a6d2ff.png"},{"id":96710576,"identity":"4034d5cd-0b01-466f-b15e-822d11164ef1","added_by":"auto","created_at":"2025-11-25 10:10:56","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":146529,"visible":true,"origin":"","legend":"\u003cp\u003eThe most stable geometric structure of the DES for the NCl-X interaction (a) one view (b) another view\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/ba5d05e8e89d91dcbfed2fa9.png"},{"id":96680863,"identity":"410005dc-a7c1-4807-bca1-eac96a1fa72d","added_by":"auto","created_at":"2025-11-25 03:26:22","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":142195,"visible":true,"origin":"","legend":"\u003cp\u003eThe most stable geometric structure of the DES for the H\u003csub\u003e2\u003c/sub\u003eCO-X interaction (a) one view (b) another view\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/afab011d8fb16ce56cf4a09f.png"},{"id":96710701,"identity":"ec72d434-5c7d-434d-a440-589f7d12626b","added_by":"auto","created_at":"2025-11-25 10:11:06","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":48141,"visible":true,"origin":"","legend":"\u003cp\u003eThe most stable geometric structure of the single site formed DES via H\u003csub\u003e2\u003c/sub\u003eCO-HOCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e","description":"","filename":"10.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/32209bcef56c9cd37dcf6262.png"},{"id":96680865,"identity":"cd50fd3b-c758-4d0b-9f5c-cd105f49b86a","added_by":"auto","created_at":"2025-11-25 03:26:22","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":57221,"visible":true,"origin":"","legend":"\u003cp\u003eThe most stable geometric structure of the double site formed DES via H\u003csub\u003e2\u003c/sub\u003eCO-HOCH\u003csub\u003e2 \u003c/sub\u003eand NCl-HOCH.\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/7c89d5ad9f8f6fbd69655ac0.png"},{"id":96680874,"identity":"59274d56-f633-4a57-8d19-d5c8713cb627","added_by":"auto","created_at":"2025-11-25 03:26:22","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":74501,"visible":true,"origin":"","legend":"\u003cp\u003eOptimized geometry of water and metronidazole (MNZ)\u003c/p\u003e","description":"","filename":"12.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/64b1dff479525c786c1afb0b.png"},{"id":96680867,"identity":"101d6b38-2a29-41ff-ba99-5de892d43afd","added_by":"auto","created_at":"2025-11-25 03:26:22","extension":"png","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":60214,"visible":true,"origin":"","legend":"\u003cp\u003eOptimized geometry structure of most negative MNZ-H\u003csub\u003e2\u003c/sub\u003eO interaction.\u003c/p\u003e","description":"","filename":"13.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/51986899c66c59b7ec0d27f9.png"},{"id":96710891,"identity":"ec7b0a86-3946-4ab6-86d2-a3ab5e20dfae","added_by":"auto","created_at":"2025-11-25 10:11:22","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":80447,"visible":true,"origin":"","legend":"\u003cp\u003eOptimized geometry structures of most negative MNZ-DES interaction.\u003c/p\u003e","description":"","filename":"14.png","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/cfb1db0e242b578e1c7b9de6.png"},{"id":104402652,"identity":"3f339e0d-87fd-4a24-980d-3ca02931c772","added_by":"auto","created_at":"2026-03-11 12:16:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3562680,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8106095/v1/a0f5e32b-badf-4b66-915d-41b4785c6b20.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eEnhancing the Solubility of Metronidazole Using Deep Eutectic Solvents: A Computational Insight Into a Green Formulation Strategy\u003c/p\u003e","fulltext":[{"header":"1 INTRODUCTION","content":"\u003cp\u003eThe limited aqueous solubility of many Active Pharmaceutical Ingredients (APIs) poses a significant challenge to the development of effective drug formulations, frequently resulting in poor bioavailability, diminished therapeutic outcomes, and increased dosage requirements [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Approximately 40% of APIs suffer limited therapeutic efficacy due to poor solubility [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and almost 90% of the medicines under development are poorly soluble in aqueous media causing difficulties in formulation of classes II and IV, Biopharmaceutical Classification System (BCS) drugs [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMetronidazole (MNZ) [1-(2-Hydroxyethyl)-2-methyl-5-nitroimidazole] [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] discovered in 1959, is a synthetic antibiotic derived from azomycin, a nitroimidazole characterized by the presence of a nitro group attached to an imidazole ring produced by the genera Actinobacteria and Proteobacteria [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. It is physically available in white to pale yellow crystals or crystalline powder with 159-163\u003csup\u003e0\u003c/sup\u003eC melting point. It is sparingly soluble in water and in alcohol; slightly soluble in ether and chloroform [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Also known with the brand name Flagyl [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], it is used to treat infections caused by parasites (amoeba) and anaerobe bacteria. It is also approved by the Food and Drug Administration (FDA) for the treatment of protozoal infections such as diarrhea caused by \u003cem\u003eEntamoeba histolytica\u003c/em\u003e, \u003cem\u003eGiardia lamblia\u003c/em\u003e, \u003cem\u003eTrichomoniasis vaginalis\u003c/em\u003e, \u003cem\u003eClostridium difficile\u003c/em\u003e and \u003cem\u003eBalantidium coli\u003c/em\u003e as well as anaerobic bacterial infections caused by \u003cem\u003eBacteroides\u003c/em\u003e, \u003cem\u003eClostridium, Fusobacterium, Peptococcus, Peptostreptococcus, Eubacterium\u003c/em\u003e, \u003cem\u003eHelicobacter\u003c/em\u003e, \u003cem\u003eCampylobacter\u003c/em\u003e, \u003cem\u003eEspiroquetas, Gardnerella vaginalis\u003c/em\u003e and \u003cem\u003eHelicobacter pylori\u003c/em\u003e [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It is widely accepted and approved for the treatment of intestinal amebiases, liver amebiasis, bacterial septicemia, bone and joint infections, endocarditis, endometritis, bacterial vaginosis, intra-abdominal infections, lower respiratory tract infections, central nervous system (CNS) infections (meningitis and brain abscess), gynecologic infections (endometritis, tubo-ovarian abscess, bacterial vaginosis), skin structure infections, and surgical prophylaxis (colorectal surgeries) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMetronidazole, despite its large therapeutic application is slightly soluble in water (approx. 10 mg/mL at 298.15 K), according to United States Pharmacopeia (USP) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Its poor aqueous solubility significantly limits its bioavailability and poses challenges for effective drug formulation, leading to incomplete and inconsistent absorption after oral or topical administration. This causes suboptimal therapeutic outcomes and the need for higher or more frequent dosing [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Accordingly, the investigation and implementation of advanced solubility enhancement methods are not only vital for converting prospective drug candidates into practical therapeutic solutions but also for assuring reliable drug absorption kinetics and improving the ultimate clinical outcomes for patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSeveral strategies have been employed to enhance the solubility of MNZ. Some of which include solid dispersion. This technique involves dispersing metronidazole in hydrophilic polymers such as polyethylene glycols (PEGs) and polyvinylpyrrolidone (PVP) significantly increasing its dissolution rate and bioavailability [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The solvent evaporation and fusion methods are commonly employed, with higher drug-to-polymer ratios yielding greater solubility improvements. The loss of crystallinity and formation of amorphous or colloidal solutions are key mechanisms underlying these enhancements. Ref [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] demonstrated that MNZ solid dispersions with polyethylene glycol (PEG-4000) and polyvinylpyrrolidone (PVP) markedly improved solubility; up to 100% drug release within one hour for MNZ:PEG-4000 at 1:5 ratios. Ref [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] reported solubility of metronidazole from solid dispersions increases by 14\u0026ndash;17% in comparison with the original substance with PEG-2000 at a 1:5 ratio, however physical and chemical stability as well as recrystallization over time remains a major concern [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In addition, hydrotropic solubilization which involves introducing a second solute; an hydrotrope (urea and sodium benzoate) has been used to increase the aqueous solubility of MNZ by more than 14-fold compared to its solubility in water alone [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Similarly, nicotinamide as an hydrotrope was used to solubilize MNZ in aqueous media causing several-fold increase in its aqueous solubility [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Kadam in 2012, increased the solubility of MNZ more than 14 times in mixed hydrotropic solution as compared to its solubility in distilled water [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The high concentrations of these hydrotropic agents cause toxicity and compatibility issues [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Another pharmaceutical technology for enhancing the solubility of metronidazole is co-crystallization process which involves preparing a cocrystal of MNZ and ethyl gallate. The formation of the cocrystal alters the solid-state structure of the drug, creating new intermolecular interactions with ethyl gallate thereby enhancing water interaction, leading to faster dissolution rates and higher solubility [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Another established solubility enhancement technique is cyclodextrin complexation in which cyclodextrin inclusion complexes, especially with β-cyclodextrin and its methylated derivatives, have been shown to dramatically enhance the solubility and dissolution of MNZ [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The formation of stable 1:1 complex increases apparent solubility by up to 100-fold, with the added benefit of preserving the drug's antimicrobial activity [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In addition, cyclodextrin-based nanofibrous webs and oral delivery systems have also demonstrated rapid dissolution and improved bioavailability [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The drawback of this process is a limited complexation capacity, high cost, potential for toxicity or altered drug release [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Another technique is prodrug formation which involves the synthesis of MNZ phosphate and amino acid esters to yield water-soluble derivatives that are rapidly hydrolyzed to release active MNZ and result to increase in solubility up to 140-fold [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, the approach requires chemical modification and possible changes in pharmacokinetics [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Other established solubility enhancement techniques are; particle size reduction via micronization and milling to enhance dissolution by increasing surface area and reducing crystallinity [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] but concerns of broad particle size distribution and risk of thermal/chemical degradation occurs [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], and co-solvency which involves utilizing water-miscible solvents like ethanol and propylene glycol to increase the solubility of poorly soluble drugs like MNZ [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, these conventional solubility enhancement approaches often pose threats of toxicity, cost, environmental implications, unsustainability and energy-intensive [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecent technological advancements have introduced deep eutectic solvents (DES) as green, biodegradable, and low-cost alternatives to conventional organic solvents. These novel solvents are formed by mixing a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA) to form eutectic mixtures with melting points lower than that of the individual species. They exhibit low volatility, simple preparation and tunable physicochemical properties such as hydrogen-bonding capacity and polarity [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. This unique structure enables DESs to interact effectively with polar and non-polar drugs, modifying their solvation dynamics. DESs especially those combining choline chloride with hydrogen bond donors are increasingly recognized as eco‑friendly alternatives for solubilizing poorly soluble drugs [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Szewczyk et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] demonstrated the effectiveness of choline chloride and citric acid natural deep eutectic solvent (NADES) in improving MNZ solubility at differing conditions of temperature and concentrations [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These studies emphasize the flexibility of DESs as both solubilizing and stabilizing agents in drug formulation. Nevertheless, the underlying mechanisms driving these enhancements remain poorly understood, these studies do not provide detailed insights into the intermolecular interactions governing the solubility enhancement. Furthermore, while the use of DESs to improve drug solubility is well-documented, the rational design of DESs for MNZ molecules is still challenging due to the limited understanding of the factors that govern DES-MNZ interactions [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo address the existing research limitations stated earlier in the literature review, the mechanism involved in forming an energetically stable DES from the use of choline chloride (CHL) and propylene glycol (PG) was investigated. Furthermore, the potential of choline chloride\u0026ndash;propylene glycol DES as a solubility enhancement medium for metronidazole was explored in relation to its solubility in conventional solvent (water) using hybridthrough density functional theory (DFT) computational level.\u003c/p\u003e"},{"header":"2 METHODOLOGY","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Computational Details\u003c/h2\u003e\u003cp\u003eIn the study of the metronidazole solubility in a DES, we employed the use of Spartan molecular modeling package for the modeling and simulation of the solvent and its behavior with a computing device of 8GB RAM, core i7 processor, processor speed of 2.60GHz, and 256GB SSD storage capacity. Following the strength of our computing resource, we deployed a hybrid approach of combining the use of semi-empirical with density functional theory (DFT) calculation method. In which, PM3 equilibrium conformer calculations were first carried out at an SCF tolerance of 10\u003csup\u003e9\u003c/sup\u003e to obtained most stable geometry for the model structures in the study. After which ωB97X-D hybrid DFT calculations method with dual basis set (6-31G(D) [3-21G(*)]) was employed to improve on the accuracy of the energies obtained from the geometry optimization calculations, with the inclusion of dispersion [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] and basis set superposition error [\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] correction for obtaining quality results useful for computing the drug solubility (evaluated as a function of the drug binding energy with the solvent) in the solvent in line with literature [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] which suggests the use of dual basis set as one of measure for correcting the BSSE in the package.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Study strategy\u003c/h2\u003e\u003cp\u003eIn Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, we diagrammatically presented the strategy employed in the study beginning with the building of the molecular models for CHL, PG, MNZ, and water. Each model was then subjected to geometry optimization to obtain most relax form of structures suitable for subsequent analysis using MMFF method.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNext was the conformation of PG that was carried out through equilibrium conformer calculations performed at the semi-empirical PM3 level, considering 200 conformers. The optimized conformer was then used to evaluate the possible pathways for DES (CHL-PG) formation from which the most stable structure was identified. The solubility evaluation of MNZ was then carried out by analyzing its interaction with the most stable DES (CHL-PG) and with water. This step enabled identification of the most favorable DES\u0026ndash;MNZ and H₂O\u0026ndash;MNZ interaction routes. Finally, all results were assessed to determine the extent of solubility of MNZ in the DES compared to water. Noting that all the geometries and energies were obtained using the computational details presented earlier in Section 2.1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Modelling of HBA, HBD, Water and MNZ used in the study\u003c/h2\u003e\u003cp\u003eThe approaches of modeling the ionic interaction of CHL as the HBA of the DES was employed using single bond to maintain consistency in the study. This is in accordance to the literature [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] in which the use of no bond, generic, or single bond shows no significant difference irrespective of the level of calculation employed. Further analysis of the conformer structures of PG as the HBD for the potential DES was evaluated using Parameterized Method (PM3) of the semi-empirical computational method [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] to employ the use of the most stable structure for this application. Similarly, water and metronidazole structural models were built, geometrically optimized to represent the actual structures of these components for the study.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e2.3.1 Evaluation of the des models\u0026rsquo; components used in the study\u003c/h2\u003e\u003cp\u003eAn infrared spectroscopy plot was computationally generated for the HBA and HBD employed and was compared with experimental value obtained from a wet laboratory. The similarities and differences visible on their respective plots were analyzed to determine the accuracy of the modelled structures.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.3.2 Evaluation of the DES formation mechanism\u003c/h2\u003e\u003cp\u003eThe study evaluated several CHL-PG DES formation mechanisms by analyzing different interaction points on CHL (C, N, O, and Cl) and PG (H) with their corresponding formation energy (F.E). The energies are computed as F.E\u0026thinsp;=\u0026thinsp;Edes - EHBA \u0026ndash; EHBD, where the Edes is the electronic energies of the DES, EHBA is the electronic energies of the hydrogen bond acceptor, EHBD is the electronic energies of the hydrogen donor, Edes (Bonded) is the electronic energies of the DES and Edes (Unbonded) is the electronic energies of the DES while in unbonded state. All the electronic energies are collected in eV.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe energy that is the most negative predict or confirms the most feasible interaction formation pathway that would lead to the formation of the DES. In Fig.\u0026nbsp;2, we demonstrated different interaction pathways explored in our study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\u003ch2\u003e2.3.3 Stability Analysis of the Components\u003c/h2\u003e\u003cp\u003eThe stability analysis of all component structures was evaluated using the energy band gap, which is the difference between the energy of the highest occupied molecular orbital E(HOMO) and energy of the lowest unoccupied molecular orbital E(LUMO) as expressed in the literature reports.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003e2.3.4 Evaluation of the solubility of MNZ in different solvents (DES and Water)\u003c/h2\u003e\u003cp\u003eTo evaluate the solubility strength of MNZ in the solvent, we measure the drug solubility as a function of binding energy [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] with the solvent, which was computed as SS\u003csub\u003eMNZ\u003c/sub\u003e = E (solvent/MNZ) \u0026ndash; E(solvent) \u0026ndash; E (MNZ), where SS\u003csub\u003eMNZ\u003c/sub\u003e is Solubility Strength, E (solvent/MNZ) is Combined energy of MNZ interactions with the solvent, E(solvent) is total energy of the solvents, and E (MNZ) is total energy of MNZ.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"3 RESULTS AND DISCUSSIONS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.1 DES model components\u0026rsquo; molecular properties prediction and model validation\u003c/h2\u003e\u003cp\u003eAnalysis of the results presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows that the energies of the HOMO, LUMO, and their corresponding energy gaps indicate that choline chloride (CHL) exhibits a smaller energy gap compared to propylene glycol (PG). This suggests that CHL is more chemically reactive than PG.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eHOMO-LUMO properties of the DES model components\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpecie\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eE (HOMO) (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eE (LUMO) (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eE Gap\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCholine chloride (CHL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-7.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10.91\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePropylene Glycol (PG)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-9.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e13.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFurthermore, the analysis of possible interactions between CHL and PG suggests that CHL predominantly interacts through its HOMO (highest occupied molecular orbital), while PG interacts through its LUMO (lowest unoccupied molecular orbital) during DES formation. The resulting interaction energy gap (11.60 eV) indicates favorable electronic compatibility between the two species. In agreement with literature reports, CHL acts as the electron donor, whereas PG serves as the electron acceptor in the hydrogen-bonding interactions responsible for DES formation.\u003c/p\u003e\u003cp\u003eTo assess the reliability and validity of our molecular model, infrared (IR) spectral analysis was performed. The computed IR spectra were compared with corresponding experimental spectra available in the literature. Previous validation of the CHL model in our earlier studies showed strong agreement between computed and experimental spectra. However, since no prior computational IR spectrum was available for PG, its IR spectrum was calculated in this study (Fig.\u0026nbsp;3), and the results were compared with experimental data reported in the literature (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe main peaks identified from the analysis are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The broad O\u0026ndash;H stretching vibration, experimentally observed between 3550\u0026ndash;3200 cm⁻\u0026sup1;, is attributed to hydrogen bonding and is absent as a distinct band in the DFT spectrum. The C\u0026ndash;H stretching vibrations were calculated at 2916 and 2933 cm⁻\u0026sup1;, aligning well with the experimental absorptions at 2975, 2935, and 2870 cm⁻\u0026sup1;. Additional C\u0026ndash;H stretching modes appeared between 3019 and 3108 cm⁻\u0026sup1;, consistent with the experimental band near 3000 cm⁻\u0026sup1;. The C\u0026ndash;H bending vibrations were found between 1304 and 1475 cm⁻\u0026sup1;, corresponding to the experimental peaks at 1375 and 1460 cm⁻\u0026sup1;. Similarly, C\u0026ndash;O stretching vibrations of the alcohol group were calculated at 1041\u0026ndash;1211 cm⁻\u0026sup1;, which agree closely with the experimental absorptions at 1040, 1070, and 1120 cm⁻\u0026sup1;. In the lower frequency region, C\u0026ndash;H wagging vibrations were observed at 814\u0026ndash;960 cm⁻\u0026sup1;, matching experimental bands at 820, 890, and 750 cm⁻\u0026sup1;, while a skeletal vibration mode was calculated at 521 cm⁻\u0026sup1; and corresponds to the experimental feature around 600 cm⁻\u0026sup1;.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of theoretical and experimental IR peaks for propylene glycol\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeaks\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDFT (cm⁻\u0026sup1;)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExpt. (cm⁻\u0026sup1;) [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eO\u0026ndash;H stretching, broad (3200\u0026ndash;3600)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3550\u0026ndash;3200\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC\u0026ndash;H stretching (2850\u0026ndash;3000)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2916, 2933\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2975, 2935, 2870\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC\u0026ndash;H stretching (3000\u0026ndash;3100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3019, 3035, 3096, 3108\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC\u0026ndash;H bending (1350\u0026ndash;1470)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1304, 1349, 1394, 1439, 1460, 1475\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1460, 1375\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC\u0026ndash;O stretching of alcohol\u003c/p\u003e\u003cp\u003e(1000\u0026ndash;1260)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1041, 1101, 1133, 1174, 1211\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1120, 1070, 1040\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC\u0026ndash;H wagging (720\u0026ndash;900)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e814, 922, 960\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e890, 820, 750\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot available\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e521\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e600\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOverall, the DFT-calculated spectra for both CHL and PG showed strong consistency with experimental data, validating the reliability of the developed molecular models. This confirms that the computationally derived CHL\u0026ndash;PG DES model is suitable for use in solubility enhancement simulations.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Investigation of DES Formation Pathway and Stability\u003c/h2\u003e\u003cp\u003eAn in-depth investigation of the formation pathway and stability of the Deep Eutectic Solvent (DES) composed of choline chloride (CHL) as the hydrogen bond acceptor (HBA) and propylene glycol (PG) as the hydrogen bond donor (HBD) was carried out. The evaluation considered six possible interaction sites on the HBA (H₃C\u0026ndash;, H₂C\u0026ndash;, H₂CO\u0026ndash;, NCl\u0026ndash;, ClN\u0026ndash;, and OHC\u0026ndash; atoms), interacting with different hydrogen atoms of the HBD (\u0026ndash;HOCH, \u0026ndash;HCOH, \u0026ndash;HCH₂, \u0026ndash;HCH, and \u0026ndash;HOCH₂).\u003c/p\u003e\u003cp\u003eIn Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the electronic energies of CHL, PG, and their combined unbonded DES geometry are presented. At this stage, no defined bonding model or hydrogen-bonding pathway was imposed; the data serve as a reference prior to exploring the potential hydrogen-bond formation routes discussed later in Sections 3.2.1 to 3.2.8.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eElectronic energies of DES model components\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLabel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMol. Wt. (amu)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFormation Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCholine Chloride (CHL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e139.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-21467.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePropylene Glycol (PG)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e76.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-7332.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCHL: PG (Unbonded)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e215.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026minus;0.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe electronic energies of CHL and PG were calculated to be \u0026minus;\u0026thinsp;21467.85 eV and \u0026minus;\u0026thinsp;7332.78 eV, respectively. The total energy of the unbonded CHL\u0026ndash;PG system was found to be \u0026minus;\u0026thinsp;28801.59 eV, corresponding to a formation energy of \u0026minus;\u0026thinsp;0.96 eV. The negative formation energy indicates that the CHL\u0026ndash;PG combination is thermodynamically feasible, suggesting a favorable tendency for DES formation even before specific hydrogen-bonding interactions are established.\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\u003ch2\u003e3.2.1 Evaluation of DES formation via H\u003csub\u003e3\u003c/sub\u003eC\u0026ndash;X interaction routes\u003c/h2\u003e\u003cp\u003eAn assessment of the DES formation via the methyl group (H\u003csub\u003e3\u003c/sub\u003eC) of CHL through various interaction routes, H\u003csub\u003e3\u003c/sub\u003eC\u0026ndash;X (X\u0026thinsp;=\u0026thinsp;HOCH, HCOH, HCH\u003csub\u003e2\u003c/sub\u003e, HCH, HOCH\u003csub\u003e2\u003c/sub\u003e), was conducted and the energy results are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStability of the CHL-PG DES via H3C- as a point of interaction\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eLabel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRelative Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFormation Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBA Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHBD Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eH\u003csub\u003e3\u003c/sub\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28800.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28800.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe interaction labeled H\u003csub\u003e3\u003c/sub\u003eC\u0026ndash;HOCH yielded the most stable formation pathway as displayed in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, with a formation energy of \u0026minus;\u0026thinsp;1.04 eV, suggesting favorable hydrogen bonding at that site. Meanwhile, other routes such as H\u003csub\u003e3\u003c/sub\u003eC\u0026ndash;HCOH and H\u003csub\u003e3\u003c/sub\u003eC\u0026ndash;HCH\u003csub\u003e2\u003c/sub\u003e maintained the same energy as the unbonded system (\u0026minus;\u0026thinsp;0.96 eV), indicating negligible interaction. Comparatively weaker interactions were observed for H\u003csub\u003e3\u003c/sub\u003eC\u0026ndash;HCH (\u0026minus;\u0026thinsp;0.25 eV) and H\u003csub\u003e3\u003c/sub\u003eC\u0026ndash;HOCH\u003csub\u003e2\u003c/sub\u003e (\u0026minus;\u0026thinsp;0.33 eV), implying limited stability. The geometry of the most feasible formation pathway is presented in Fig.\u0026nbsp;4.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003e3.2.2 Evaluation of DES formation via ClN\u0026ndash;X interaction routes\u003c/h2\u003e\u003cp\u003eA comparative analysis was carried out for the interactions formed through the ClN- site of CHL, represented as ClN\u0026ndash;X (X\u0026thinsp;=\u0026thinsp;HOCH, HCOH, HCH\u003csub\u003e2\u003c/sub\u003e, HCH, HOCH\u003csub\u003e2\u003c/sub\u003e). The energy results are presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and the geometry of the most feasible formation pathway is presented in Fig.\u0026nbsp;5.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStability of the CHL-PG DES via ClN- as a point of interaction\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eLabel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRelative Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFormation Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBA Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHBD Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eClN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.83\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.71\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAmong these, the interactions ClN\u0026ndash;HCH with formation energy of \u0026minus;\u0026thinsp;0.86 eV and ClN\u0026ndash;HCOH with formation energy of \u0026minus;\u0026thinsp;0.83 eV showed moderate stability, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e while other interactions like ClN\u0026ndash;HOCH\u003csub\u003e2\u003c/sub\u003e and ClN\u0026ndash;HCH\u003csub\u003e2\u003c/sub\u003e had slightly lower energies of \u0026minus;\u0026thinsp;0.71 eV and \u0026minus;\u0026thinsp;0.60 eV, respectively. The ClN\u0026ndash;HOCH interaction resulted in the weakest interaction \u0026minus;\u0026thinsp;0.41 eV. This suggests that the ClN site is more selective and tends to interact better with hydroxyl- and aldehyde-like groups than with primary alcohols. Figure\u0026nbsp;5 shows that most stable optimized ClN\u0026ndash;HCH interaction.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003e3.2.3 Evaluation of DES formation via H\u003csub\u003e2\u003c/sub\u003eC\u0026ndash;X interaction routes\u003c/h2\u003e\u003cp\u003eA further evaluation was performed on the H\u003csub\u003e2\u003c/sub\u003eC site through interactions denoted as H\u003csub\u003e2\u003c/sub\u003eC\u0026ndash;X (X\u0026thinsp;=\u0026thinsp;HOCH, HCOH, HCH\u003csub\u003e2\u003c/sub\u003e, HCH, HOCH\u003csub\u003e2\u003c/sub\u003e), as presented in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStability of the CHL-PG DES via H2C- as a point of interaction\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eLabel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRelative Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFormation Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBA Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHBD Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.93\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.99\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe strongest interaction for this was recorded for H\u003csub\u003e2\u003c/sub\u003eC\u0026ndash;HCOH having a formation energy of \u0026minus;\u0026thinsp;1.08 eV, followed closely by H\u003csub\u003e2\u003c/sub\u003eC\u0026ndash;HCH\u003csub\u003e2\u003c/sub\u003e (\u0026minus;\u0026thinsp;1.06 eV), confirming that this sites actively participates in DES formation. The HOCH and HOCH\u003csub\u003e2\u003c/sub\u003e routes also displayed notable formation energies (\u0026minus;\u0026thinsp;0.99 eV each), signifying meaningful hydrogen bonding potential. The weakest interaction in this group was found in H\u003csub\u003e2\u003c/sub\u003eC\u0026ndash;HCH (\u0026minus;\u0026thinsp;0.93 eV), which still exhibited better binding than most interactions from other sites. Figure\u0026nbsp;6 shows the most stable optimized H\u003csub\u003e2\u003c/sub\u003eC\u0026ndash;HCOH interaction.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\u003ch2\u003e3.2.4 Evaluation of DES formation via OHC\u0026ndash;X interaction routes\u003c/h2\u003e\u003cp\u003eThe interaction behavior of the OHC site with various HBD donor sites designated as OHC\u0026ndash;X (X\u0026thinsp;=\u0026thinsp;HOCH, HCOH, HCH\u003csub\u003e2\u003c/sub\u003e, HCH, HOCH\u003csub\u003e2\u003c/sub\u003e) was also explored presented in Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStability of the CHL-PG DES via OHC- as a point of interaction\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eLabel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRelative Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFormation Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBA Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHBD Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eOHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28802.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAmong these, the most stable configuration was obtained from OHC\u0026ndash;HCH with formation energy of \u0026minus;\u0026thinsp;1.40 eV, The optimized structure of the geometry is shown in Fig.\u0026nbsp;7. This is followed closely by OHC\u0026ndash;HCH\u003csub\u003e2\u003c/sub\u003e having formation energy of \u0026minus;\u0026thinsp;1.08 eV. These results suggest significant hydrogen bond formation involving these pathways. On the other hand, interactions like OHC\u0026ndash;HCOH (\u0026minus;\u0026thinsp;0.58 eV) and OHC\u0026ndash;HOCH (\u0026minus;\u0026thinsp;0.89 eV) were found to be less stabilizing, possibly due to less favorable alignment or steric hindrance. The HOCH\u003csub\u003e2\u003c/sub\u003e route also showed moderate formation energy (\u0026minus;\u0026thinsp;0.86 eV), supporting its partial involvement in DES stabilization at the OHC site.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section3\"\u003e\u003ch2\u003e3.2.5 Evaluation of DES formation via NCl\u0026ndash;X interaction routes\u003c/h2\u003e\u003cp\u003eThe evaluation of NCl interaction routes, represented as NCl\u0026ndash;X (X\u0026thinsp;=\u0026thinsp;HOCH, HCOH, HCH\u003csub\u003e2\u003c/sub\u003e, HCH, HOCH\u003csub\u003e2\u003c/sub\u003e), showed generally weaker stabilization compared to other interaction centers as shown in Table\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab8\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStability of the CHL-PG DES via NCl - as a point of interaction\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eLabel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRelative Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFormation Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBA Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHBD Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eNCl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.74\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe best interaction shown in Fig.\u0026nbsp;8 was NCl\u0026ndash;HOCH\u003csub\u003e2\u003c/sub\u003e (\u0026minus;\u0026thinsp;0.86 eV), followed by NCl\u0026ndash;HCH\u003csub\u003e2\u003c/sub\u003e (\u0026minus;\u0026thinsp;0.74 eV), NCl\u0026ndash;HCOH (\u0026minus;\u0026thinsp;0.64 eV) and NCl\u0026ndash;HOCH (\u0026minus;\u0026thinsp;0.61 eV). The lowest binding energy occurred with NCl\u0026ndash;HCH (\u0026minus;\u0026thinsp;0.38 eV), indicating this site do not favor the DES formation. Despite these moderate values, the involvement of the NCl site cannot be entirely neglected, as it supports structural geometry indirectly.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section3\"\u003e\u003ch2\u003e3.2.6 Evaluation of DES formation via H\u003csub\u003e2\u003c/sub\u003eCO\u0026ndash;X interaction routes\u003c/h2\u003e\u003cp\u003eAn investigation into the interaction routes involving the H\u003csub\u003e2\u003c/sub\u003eCO site of HBA with HBD sites denoted as H\u003csub\u003e2\u003c/sub\u003eCO\u0026ndash;X (X\u0026thinsp;=\u0026thinsp;HOCH, HCOH, HCH\u003csub\u003e2\u003c/sub\u003e, HCH, HOCH\u003csub\u003e2\u003c/sub\u003e) whose results was presented in Table\u0026nbsp;\u003cspan refid=\"Tab9\" class=\"InternalRef\"\u003e9\u003c/span\u003e revealed H\u003csub\u003e2\u003c/sub\u003eCO\u0026ndash;HOCH\u003csub\u003e2\u003c/sub\u003e as the most favorable formation route shown in Fig.\u0026nbsp;9 with a formation energy of \u0026minus;\u0026thinsp;1.51 eV.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab9\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 9\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStability of the CHL-PG DES via H\u003csub\u003e2\u003c/sub\u003eCO - as a point of interaction\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eLabel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRelative Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFormation Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBA Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHBD Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eCO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28802.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.03\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28802.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOther interactions including H\u003csub\u003e2\u003c/sub\u003eCO\u0026ndash;HOCH with formation energy of \u0026minus;\u0026thinsp;1.41 eV and H\u003csub\u003e2\u003c/sub\u003eCO\u0026ndash;HCH interaction with formation energy of \u0026minus;\u0026thinsp;1.03 eV also demonstrated considerable stability. Meanwhile, H\u003csub\u003e2\u003c/sub\u003eCO\u0026ndash;HCH\u003csub\u003e2\u003c/sub\u003e formation pathways with \u0026minus;\u0026thinsp;0.69 eV and H\u003csub\u003e2\u003c/sub\u003eCO\u0026ndash;HCOH interaction routes with energy of \u0026minus;\u0026thinsp;0.57eV were comparatively weaker. These results indicate that the H\u003csub\u003e2\u003c/sub\u003eCO site preferentially interacts with hydroxyl groups environments to form strong hydrogen bonds.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section3\"\u003e\u003ch2\u003e3.2.7 Most Stable Interaction Pathways for DES Formation\u003c/h2\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab10\" class=\"InternalRef\"\u003e10\u003c/span\u003e presents a summary of the most stable interaction routes analyzed for the formation of the CHL\u0026ndash;PG Deep Eutectic Solvent (DES). The results compare the unbonded formation mechanism with six possible single-site hydrogen bonding pathways between the hydrogen bond acceptor (CHL) and donor (PG).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab10\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 10\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMost stable interactions across the different single site DES formation pathways\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eLabel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFormation Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCHL-PG (Unbonded)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-28801.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBA Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHBD Sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eH\u003csub\u003e3\u003c/sub\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-1.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-1.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eCO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28802.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-1.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNCl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHOCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28801.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-28802.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-1.40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAmong all the interaction pathways examined, the H₂CO\u0026ndash;HOCH₂ configuration (Fig.\u0026nbsp;10) was identified as the most stable and energetically favorable, exhibiting the lowest formation energy of \u0026minus;\u0026thinsp;1.51 eV. This strong stability implies that this pathway provides the most favorable conditions for effective complexation between CHL and PG. The negative formation energy further confirms spontaneous DES formation at this site, suggesting that the oxygen atom of the H₂CO group in CHL forms a strong hydrogen bond with the hydrogen atom of the HOCH₂ group in PG. This finding highlights the importance of the hydroxyl and ether functionalities in stabilizing the CHL\u0026ndash;PG DES structure through strong electrostatic interactions.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section3\"\u003e\u003ch2\u003e3.2.8 Investigation into double-sites DES formation pathway\u003c/h2\u003e\u003cp\u003eThe formation pathways of the CHL\u0026ndash;PG Deep Eutectic Solvent (DES) were further investigated by evaluating possible hydrogen-bonding interactions between the hydrogen bond acceptor (HBA), choline chloride (CHL), and the hydrogen bond donor (HBD), propylene glycol (PG). In the initial single-site interaction analysis, each interaction site on the HBA (H₃C, H₂C, H₂CO, NCl, ClN, and OHC) formed a single hydrogen bond with one of the hydrogen atoms from the HBD (HOCH, HCOH, HCH₂, HCH, HOCH₂). To explore whether a more stable DES formation mechanism could be achieved, a double-site interaction pathway was examined. In this formation mechanism, the oxygen atom of CHL interacted with a hydrogen atom of PG\u0026rsquo;s hydroxyl group (H₂CO\u0026ndash;HOCH₂), while the chlorine atom of CHL simultaneously interacted with another hydrogen atom of PG (NCl\u0026ndash;HOCH), in accordance with the form of geometry obtained for the most stable single site hydrogen bonding interaction pathway shown in Fig.\u0026nbsp;10.\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab11\" class=\"InternalRef\"\u003e11\u003c/span\u003e presents the analysis results (formation energies, bond lengths etc) of the double site configuration in comparison with the single site configuration.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab11\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 11\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAnalysis of single and double sites DES showing bond lengths\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMost stable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFormation Energy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eShortest bond length (\u0026Aring;)\u003c/p\u003e\u003cp\u003eO-H (H\u003csub\u003e2\u003c/sub\u003eCO-HOCH\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eShortest bond length (\u0026Aring;)\u003c/p\u003e\u003cp\u003eCl-H (NCl-HOCH)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSingle site\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-28802.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-1.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.826\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.426\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDouble site\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-28802.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-1.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.826\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.437\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAnalysis of the results presented in Table\u0026nbsp;\u003cspan refid=\"Tab11\" class=\"InternalRef\"\u003e11\u003c/span\u003e shows that the dual hydrogen-bonding interaction formation mechanism, which was evaluated through the H₂CO\u0026ndash;HOCH₂ and NCl\u0026ndash;HOCH interaction sites was found to have exhibited a geometry formation energy (\u0026minus;\u0026thinsp;1.50 to \u0026minus;\u0026thinsp;1.51 eV), and hydrogen-bond distances (O\u0026ndash;H\u0026thinsp;=\u0026thinsp;1.826 \u0026Aring;; Cl\u0026ndash;H\u0026thinsp;=\u0026thinsp;2.437 \u0026Aring;) that are closely comparable to those obtained for the most stable single-site interaction pathway. The most stable double site configuration geometry is shown in Fig.\u0026nbsp;11. Overall, the DES (CHL:PG) formed from choline chloride and propylene glycol was predicted to feasibly develop through this dual-site hydrogen-bonding arrangement, whereas other pathways were less favorable due to their comparatively weaker formation energies. This indicates that cooperative hydrogen bonding may play a significant role in enhancing DES structural stability and modulating its physicochemical properties. Consequently, all subsequent analyses in this study will employ the CHL\u0026ndash;PG (H₂CO\u0026ndash;HOCH₂ : NCl\u0026ndash;HOCH) pathway and refer to it as the formed DES derived from CHL and PG.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Stability analysis of components\u003c/h2\u003e\u003cp\u003eThe molecular properties of the DES (CHL-PG) and its model components with water and metronidazole (MNZ) are presented in Table\u0026nbsp;\u003cspan refid=\"Tab12\" class=\"InternalRef\"\u003e12\u003c/span\u003e. These properties provide insight into the electronic structure, reactivity, and potential interaction mechanisms relevant to MNZ solubility enhancement.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab12\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 12\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMolecular Properties of all Components\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpecie\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eE HOMO (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eE LUMO (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eE Gap (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIEG-mnzHOMO (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIEG-mnzLUMO (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMNZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-9.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-1.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e8.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-8.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e12.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-10.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e8.74\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe energy band gap (E-Gap) serves as a vital descriptor of molecular stability and reactivity. A larger band gap indicates higher stability and lower chemical reactivity, whereas a smaller band gap reflects increased reactivity, which can favor solubility enhancement [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Among the studied species, DES exhibited an energy band gap of 11.05 eV, which is lower than that of water (14.56 eV) but higher than that of MNZ (8.28 eV). This intermediate band gap suggests that the DES is sufficiently reactive to interact effectively with MNZ while maintaining moderate stability. Consequently, CHL\u0026ndash;PG is predicted to promote MNZ solubility more efficiently than water. Figure\u0026nbsp;12 presents the optimized geometry of water and MNZ.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe interaction energy gap (IEG) provides additional insight into the feasibility and directionality of solvent\u0026ndash;solute interactions. A lower IEG corresponds to a more favorable interaction, signifying easier electron transfer between the interacting species. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab12\" class=\"InternalRef\"\u003e12\u003c/span\u003e, the lowest IEG value (7.06 eV) was obtained when the DES (CHL\u0026ndash;PG) interacted through its HOMO orbital with the LUMO of MNZ. This indicates a strong interaction pathway favorable for MNZ solubility enhancement. In contrast, water exhibited a higher IEG (8.74 eV), suggesting a less feasible interaction with MNZ. Overall, these findings highlight that the DES (CHL\u0026ndash;PG) system, particularly in its double-site configuration, exhibits a more suitable electronic structure for MNZ solubility enhancement compared to conventional solvents like water.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Evaluation of the Solubility of Metronidazole in Water\u003c/h2\u003e\u003cp\u003eMetronidazole (MNZ) solubility in water (H₂O) was evaluated using DFT calculation at a dual basis correction set to ensure improved convergence and accuracy. Several potential interaction pathways between MNZ and H₂O were modeled to identify the most energetically favorable mode of molecular interaction. The computed electronic energies and corresponding solubility strengths are presented in Table\u0026nbsp;\u003cspan refid=\"Tab13\" class=\"InternalRef\"\u003e13\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab13\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 13\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSolubility Strength Calculation as a function of Binding Energy via MNZ in water interaction\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eSpecies\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMolecular Weight (amu)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eE (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSolubility Strength (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2078.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eMNZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e171.156\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-16970.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eMNZ\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO Interactions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eH\u003csub\u003e3\u003c/sub\u003eCC-OH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e189.171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-19049.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH-OH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e189.171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-19049.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHO-HOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e189.171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-19049.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.50\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eO\u003csub\u003e2\u003c/sub\u003eN-OH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e189.171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-19049.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eO\u003csub\u003e2\u003c/sub\u003eN-HOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e189.171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-19049.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe results presented in Table\u0026nbsp;\u003cspan refid=\"Tab13\" class=\"InternalRef\"\u003e13\u003c/span\u003e and Fig.\u0026nbsp;13 reveal that the solubility strength of MNZ in water varies across different interaction pathways, with the HO\u0026ndash;HOH configuration exhibiting the most negative binding energy (\u0026minus;\u0026thinsp;0.50 eV). This pathway therefore represents the most stable and favorable interaction route between MNZ and H₂O molecules. In line with existing literature, the more negative binding energy values correspond to stronger intermolecular interactions and higher solubility strength, as they reflect a more exothermic and energetically favorable process. The observed low solubility strength of \u0026minus;\u0026thinsp;0.50 eV indicates weak interaction between MNZ and water, implying limited solubility. This aligns with the findings of the literature [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], who reported a solubility of MNZ in water of approximately 1.00 \u0026times; 10⁻\u0026sup3; molar fraction. These results collectively confirm that while MNZ forms stable hydrogen-bonding interactions with water, their relatively low binding strength restricts the compound\u0026rsquo;s overall solubility in aqueous media.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Evaluation of the Solubility of MNZ in the DES\u003c/h2\u003e\u003cp\u003eHere, our findings obtained for the analysis of different molecular interaction pathways that could possibly predicts the solubility of MNZ in the DES are presented in Table\u0026nbsp;\u003cspan refid=\"Tab14\" class=\"InternalRef\"\u003e14\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab14\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 14\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMNZ solubility strength in DES [CHL:PG (H\u003csub\u003e2\u003c/sub\u003eCO\u0026ndash;HOCH\u003csub\u003e2\u003c/sub\u003e:NCl\u0026ndash;HOCH)]\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eSpecies\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMolecular Weight (amu)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eE (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSolubility Strength (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCHL:PG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e215.721\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-28802.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eMNZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e171.156\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-16970.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eMNZ\u0026ndash;DES Interactions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOH-ClN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e386.877\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-45773.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.93\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHO-HCOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e386.877\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-45773.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHCH-OCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e386.877\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-45773.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eO\u003csub\u003e2\u003c/sub\u003eN-HCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e386.877\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-45773.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.42\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNO-HCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e386.877\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-45772.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.19\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eDetermination of the solubility strength of MNZ through CHL:PG DES is presented in Table\u0026nbsp;\u003cspan refid=\"Tab14\" class=\"InternalRef\"\u003e14\u003c/span\u003e by employing several routes on the MNZ shows that the highest solubility strength of -0.93 eV was investigated via the OH-ClN bonded pathway as presented in Fig.\u0026nbsp;14. This is evident from the strong electrostatic attraction between the hydroxyl group in MNZ and chlorine in the DES. This result aligns with the solubility of MNZ in 1:4 CHL-PG determined by [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] with solubility of 5.01 \u0026times; 10⁻\u0026sup3; molar fraction.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe results in Tables\u0026nbsp;\u003cspan refid=\"Tab13\" class=\"InternalRef\"\u003e13\u003c/span\u003e and \u003cspan refid=\"Tab14\" class=\"InternalRef\"\u003e14\u003c/span\u003e shows that both solvents influence the solubility of MNZ. However, CHL:PG DES best improves the solubility performance of MNZ evident from its higher affinity with the drug unlike water with low solubility characteristics. Figure\u0026nbsp;14 presents the geometrical structure of most stable MNZ interactions with the DES.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003e3.6 Summary of metronidazole solubility in the different solvents\u003c/h2\u003e\u003cp\u003eIn Table\u0026nbsp;\u003cspan refid=\"Tab15\" class=\"InternalRef\"\u003e15\u003c/span\u003e, we summarize the most stable solubility strength of MNZ in both water and choline chloride\u0026ndash;propylene glycol (CHL:PG) deep eutectic solvent (DES) systems. The solubility strength values were computed based on the most energetically favorable interaction identified in previous sections.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab15\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 15\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMNZ solubility in water and DES.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eS/N\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSolvent Medium\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eInteractions Site\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMol. Wt (amu)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEnergy (eV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSolubility Strength (eV)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMNZ\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHO-HOH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e189.171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-19049.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.50\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMNZ\u0026ndash;DES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOH-ClN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e386.877\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-45773.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.93\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe results in Table\u0026nbsp;\u003cspan refid=\"Tab15\" class=\"InternalRef\"\u003e15\u003c/span\u003e clearly show that metronidazole exhibits stronger interaction and higher solubility in DES than in water. Among the different configurations, the DES interaction (OH\u0026ndash;ClN) displays the most negative solubility strength (\u0026minus;\u0026thinsp;0.93 eV), indicating a more exothermic and stable solvation process. In contrast, the solubility of MNZ in water (\u0026minus;\u0026thinsp;0.50 eV) is comparatively weaker, signifying limited hydrogen-bonding interactions within the aqueous medium. The stronger interactions observed in the DES systems can be attributed to the synergistic hydrogen-bond network and the electron-donating capability of CHL and PG functional groups, which promote enhanced stabilization of the MNZ molecule within the solvent matrix. These findings affirm that DES provides a superior solvation environment for MNZ compared to conventional water solvent, highlighting its potential as an efficient green solvent for pharmaceutical solubilization applications.\u003c/p\u003e\u003c/div\u003e"},{"header":"4 CONCLUSIONS","content":"\u003cp\u003eThis study explored the potential of a choline chloride\u0026ndash;propylene glycol (CHL\u0026ndash;PG) deep eutectic solvent (DES) as an effective and eco-friendly medium for enhancing the solubility of metronidazole (MNZ) relative to water, using a hybrid quantum method of PM3 semi-empirical for geometry optimization and ωB97X-D with dual basis set (6-31G(D) [3-21G(*)]) for the improvement of its energy calculation. The DES model components (CHL as HBA and PG as HBD), water, and MNZ were individually developed and optimized to assess their stability and reactivity characteristics. The CHL\u0026ndash;PG system feasibly formed a stable DES through a dual hydrogen-bonding pathway involving H₂CO\u0026ndash;HOCH₂ and NCl\u0026ndash;HOCH, which exhibited a formation energy of \u0026minus;\u0026thinsp;1.50 to \u0026minus;\u0026thinsp;1.51 eV, making it the most favorable route among all pathways evaluated. MNZ demonstrated significantly higher solubility in the formed DES, with a solubility strength of \u0026minus;\u0026thinsp;0.93 eV, compared to \u0026minus;\u0026thinsp;0.50 eV in water. This enhanced interaction is supported by the lower interaction energy gap of 7.06 eV, indicating a stronger affinity and improved feasibility for MNZ\u0026ndash;DES interaction. Additionally, the DES (CHL\u0026ndash;PG) exhibited a narrower HOMO\u0026ndash;LUMO band gap (11.04 eV) compared to water (14.56 eV), suggesting increased molecular reactivity and superior solvation potential for MNZ.\u003c/p\u003e\u003cp\u003eOverall, the findings align with existing experimental reports and reinforce that the CHL\u0026ndash;PG DES is a promising and sustainable solvent system capable of significantly enhancing MNZ solubility. This positions the CHL\u0026ndash;PG DES as a viable candidate for improving drug formulation and delivery in pharmaceutical applications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eU.M.M. and T.O. wrote the main manuscript text and prepared figures 1-3 with T.O. supervision. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors wish to acknowledge the support of Wavefunction Inc. 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Accessed 22 Nov 2025\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSantos CBR dos, Lobato CC, de Sousa MAC, Mac\u0026ecirc;do WJ da C, Carvalho JCT (2014) Molecular Modeling: Origin, Fundamental Concepts and Applications Using Structure-Activity Relationship and Quantitative Structure-Activity Relationship. Reviews in Theoretical Science 2:1\u0026ndash;25. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1166/rits.2014.1016\u003c/span\u003e\u003cspan address=\"10.1166/rits.2014.1016\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Deep eutectic solvents, Choline chloride, Propylene glycol, Metronidazole, Modeling, Density Functional Theory, Solubility","lastPublishedDoi":"10.21203/rs.3.rs-8106095/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8106095/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study investigates the potential of choline chloride\u0026ndash;propylene glycol (CHL-PG) deep eutectic solvents (DES) to enhance the solubility of metronidazole (MNZ), a widely used but poorly water-soluble antimicrobial drug via computational modeling approach. Density functional theory (DFT) with the ωB97X-D functional and 6-31G(D) [3-21G(*)] dual basis set in Spartan software was used, various interactions and configurations of CHL and PG were modeled to identify the most stable DES formation pathways. HOMO\u0026ndash;LUMO energy gaps were evaluated to determine component stability, while solubility strength was obtained using binding energy calculations of MNZ in the DES and water. Finding from our study indicates that the CHL\u0026ndash;PG system feasibly formed a stable DES through a dual hydrogen-bonding pathway involving H₂CO\u0026ndash;HOCH₂ and NCl\u0026ndash;HOCH, which exhibited a formation energy of \u0026minus;\u0026thinsp;1.50 to \u0026minus;\u0026thinsp;1.51 eV, making it the most favorable route among all pathways evaluated. MNZ demonstrated significantly higher solubility in the formed DES, with a solubility strength of \u0026minus;\u0026thinsp;0.93 eV, compared to \u0026minus;\u0026thinsp;0.50 eV in water, indicating solubility enhancement potential. The narrow HOMO\u0026ndash;LUMO gap in the DES further supports its molecular reactivity and suitability for pharmaceutical applications. These findings highlight the feasibility of CHL-PG as a green and effective solubilizing medium for MNZ providing insight to guide the design of DES-based drug formulations as alternative to conventional solvent in pharmaceutical development.\u003c/p\u003e","manuscriptTitle":"Enhancing the Solubility of Metronidazole Using Deep Eutectic Solvents: A Computational Insight Into a Green Formulation Strategy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-25 03:26:17","doi":"10.21203/rs.3.rs-8106095/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ad416c38-1b93-4599-944c-b1bfa1e47c53","owner":[],"postedDate":"November 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-05T16:10:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-25 03:26:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8106095","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8106095","identity":"rs-8106095","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}