Investigation of Mexiletine Hydrochloride Binding on Transition Metal Oxide Nanoparticles by Capillary Electrophoresis

Investigation of Mexiletine Hydrochloride Binding on Transition Metal Oxide Nanoparticles by Capillary Electrophoresis | 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 Investigation of Mexiletine Hydrochloride Binding on Transition Metal Oxide Nanoparticles by Capillary Electrophoresis Eman T. Elmorsi, Edward P.C. Lai This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2344386/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 The binding affinity of pharmaceutical salts to metal oxide nanoparticles is a fundamental environmental process that determines their transport and bioavailability. Mexiletine hydrochloride (MEX.HCl) interactions with different transition metal oxide nanoparticles (TMONPs) in aqueous dispersion were evaluated by capillary electrophoresis to determine their binding affinities. The results indicated that MEX.HCl bound onto TiO 2 , Co 3 O 4 and ZnO nanoparticles in alkaline, neutral and acidic pH levels. Interestingly, TiO 2 manifested the highest binding affinity of 81 ± 1% at pH 9.4. It was shown that higher initial concentrations of MEX.HCl in an aqueous solution, increasing from 15 to 75 µg/mL, yielded higher binding affinities for TiO 2 than Co 3 O 4 and ZnO nanoparticles. The binding rate followed pseudo-second-order kinetics and the binding data were better modeled by the Freundlich isotherm than the Langmuir isotherm. These findings revealed that MEX.HCl binding occurred on the heterogeneous binding sites on TMONPs mainly by the physisorption mechanism via electrostatic attraction and hydrogen bonding. binding affinity isotherm kinetics transition metal oxide nanoparticles mexiletine hydrochloride capillary electrophoresis active pharmaceutical ingredients Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 1. Introduction Active pharmaceutical ingredients (APIs) can be used as diagnostic agents, therapeutic treatments, and disease mitigators (Kumar et al. 2022 ). Approximately 60% of APIs were reported to have low oral bioavailability because of their suboptimal water solubility, which may explain the reason for their unpredictable clinical response. Salt formation of APIs is a method of choice for improving their physical properties (Elder et al. 2013 ;Tran and Tran 2019 ) aqueous solubility (Fahr and Liu 2007 ; Douroumis and Fahr 2013 ; Bharate 2021), chemical stability, and gastrointestinal absorption. An effective concentration of the API, higher than those of nonionized free acid or base, can thus achieve (Elder et al. 2013 ; Wiedmann and Naqwi 2016 ; Gupta et al. 2018 ). It has been revealed that pharmaceutical salts account for about 43% of the total APIs (Wiedmann and Naqwi 2016 ). Most of the APIs, either weakly acidic or weakly basic, contain the proper functional groups that allow for salt formation. Basic APIs often require a strong inorganic acid (HCl) that provides a counterion (Cl − ) to form salts for enhanced stability in the drug formulation (Bharate 2021b ). Hydrochloride salt formulation is dictated by such factors as biochemistry, pharmacokinetics, and pharmacodynamics that would enhance the overall therapeutic effects(Wiedmann and Naqwi 2016 ; Gupta et al. 2018 ). The stability of formed salts is mainly determined by the negative logarithm of acid dissociation constant (pK a ). A basic API forms a stable salt when the difference between the ionizable group pKa and the counterion pKa is greater than two or three units (Lee 2014 ). There are as many as 61 counterions used in all approved pharmaceutical salts (Bharate 2021b ). In the past twenty years, anionic counterions such as chloride, mesylate, bromide, acetate, and fumarate are used to form salts from basic APIs. HCl, in particular, is a safe acid and the chloride ion is abundant throughout the human body. Thus, HCl salts account for about 60% of all basic drugs. These salts are characterized by high water solubility and thermodynamic stability (Bharate 2021a ). Mexiletine (MEX) is an aromatic ether and primary amine compound (pK a 9.5) known as the 2,6-dimethyl phenyl ether of aminopropyl. Mexiletine is present in a racemic mixture (S-and R-enantiomers), but the desirable action of mexiletine is only associated with the (R)-enantiomer(Andrews et al. 2021 ). The HCl salt of mexiletine is used as an anti-arrhythmia drug (Class IB) by inhibiting the sodium influx in cardiac cells which reduces the rising rate of the heart action potential. Consequently, the heartbeat is stabilized, and nerve impulses slow down (Nakagawa et al. 2019 ; Modoni et al. 2020 ). Toxicity is common with mexiletine and can manifest in several organ systems. Cardiovascular, central nervous system and gastrointestinal-related symptoms most commonly occur. Due to its extensive cardiac side effect profile, patients generally consider mexiletine a risky drug. This led to the suspension of mexiletine treatment in a number of countries for a long period of time(Modoni et al. 2020 ). However, a recent study showed that mexiletine does not cause any hazardous cardiac arrhythmias; it is a highly effective and inexpensive drug (Statland 2012 ; Modoni et al. 2020 ). Mexiletine is rapidly absorbed following oral administration with a systemic bioavailability of about 90% (Labbé and Turgeon 1999 ). The molecular structure of protonated mexiletine (MEX.H + ) showed three-center binding sites the protonated or unprotonated nitrogen of the amine group, the lone electron pairs of oxygen, and the phenyl ring. These binding centers would allow MEX.H + to interact with different organic and inorganic compounds. For example, MEX.H + interacts with transmembrane protein receptors through anionic and cationic sites due to intermolecular hydrogen bonds formed between neutral MEX.HCl and the polar sites of protein receptors. In addition, the nitrogen of the amino group in MEX.H + may coordinate with different cations such as Na + and K + ions of protein receptors (Remko et al. 1999 ). MEX.HCl is extensively metabolized in men, with less than 10% of the dose being excreted unchanged in urine which ends in different aquatic environments leading to the spreading of contamination and pollution (Akıncı et al. 2011 ). Hence, the presence of MEX.HCl in the environment may undergo organic and inorganic interactions such as interactions with transition metal oxide nanoparticles (TMONPs) which would affect its bioavailability in ecotoxicology(CHMP 2018 ) and control its environmental transportation. TMONPs have gained significant attention due to their extraordinary physical, chemical, optical and electronic properties when compared to bulk materials (Agnihotri et al. 2021). In addition, because of their size, shape, stability and larger surface area, they are included in various applications. TMONPs of different shapes and structures have been synthesized using different techniques. Biocompatible TMONPs are generally used to immobilize biomolecules to produce immunosensors, sensors of DNA and enzymes but semiconducting metal oxide nanoparticles are usually used as tracers and markers in electrochemical analysis (Kango et al. 2013 ; Agnihotri et al. 2021; Tajik et al. 2022 ). Although nanoparticles have evolved to play a prominent role in our economy, their increased use poses potential human health risks (Huang et al. 2010 ). Nanoparticles may enter the environment directly or indirectly(Kaegi et al. 2011 ; Al-Kattan et al. 2015 ; Meier et al. 2016 ) through different sources(Bundschuh et al. 2018 ) such as release during the production of raw material, during use, and after disposal of consumer products (Gottschalk et al. 2013 ; Tolaymat et al. 2017 ). It has been reported that TMONPS such as TiO 2 and ZnO are released into landfills, sediments, and soil because they are mostly used in cosmetics, electronics, and medicine. Therefore, TiO 2 and ZnO nanoparticles are accumulated in sewage sludge during wastewater treatments (Mueller and Nowack 2008 ; Keller et al. 2013 ; Sun et al. 2016 ). Also, the unique properties of Co 3 O 4 nanoparticles, are attracting enormous interest in different applications such as electrochemistry, storage of energy, sensors and catalytic processes leading to its discharge into aquatic systems and affecting its sustainability (Ates et al. 2016 ). Several simple, rapid, sensitive, and selective analytical methods were reported for the determination of MEX.HCl and its synthetic impurity 2,6-dimethylphenol (DMP) (Belal et al. 2008 ). A reverse-phase HPLC method was developed for the quality control analysis of MEX.HCl in various dosage forms (Kaushik and Alexander 2003 ). The applicability of capillary electrophoresis, capillary electro-chromatography, and micro/capillary/nano-liquid chromatography for the analysis of pharmaceutical formulations, active pharmaceutical ingredients, drug impurity testing, chiral drug separation, determination of drugs and metabolites in biological fluids was thoroughly reviewed (Aturki et al. 2014 ). In the present work, the separation of TMONPs from the MEX.HCl solution would be necessary. Capillary electrophoresis (CE) has become one of the most widely used analytical techniques for separating nanoparticles and detecting pharmaceutical compounds in the last two decades (Adelantado et al. 2022 ). According to their sizes, shapes, surface modifications, and compositions (Chetwynd et al. 2018 ), TMONPs can be hypothetically analyzed by studying their interaction with organic molecules followed by the analysis of the molecules by capillary electrophoresis. Hence, the strength and bond type between the adsorbed compounds as MEX.H + and TMONPs depends on the respective functional group and corresponding affinity of MEX.HCl, TMNOPs surface charge, and pH of the medium (McNamara et al. 2010 ; Gulley-Stahl et al. 2010 ; Brennan et al. 2013 ). The objective of this study is to evaluate the binding of MEX.H + as a model of pharmaceutical hydrochloride salt onto the surface of TMONPs such as TiO 2 , ZnO, and Co 3 O 4 at different pH levels to investigate its potential bioavailability in the aquatic environment. The points of zero charge were found at pH 3.5 for TiO 2 (anatase), pH 6.5 for TiO 2 (rutile), pH ~ 8 for Co 3 O 4 and pH 8.0-9.7 for ZnO nanoparticles (Kosmulski 2011 ; Skocaj et al. 2011 ). In a background electrolyte solution at pH 9.4 for CE analysis, TiO 2 (anatase) has a negative charge, TiO 2 (rutile) has a partial negative charge, Co 3 O 4 has a partial positive charge, and ZnO has a positive charge. 2. Materials And Methods 2.1. Materials Mexiletine hydrochloride, or 1-(2,6-dimethylphenoxy)-2-propylamine hydrochloride with a molecular formula of C 11 H 17 NO·HCl and MW = 215.72 g/mol (Fig. 1 ), Co 3 O 4 (240.8 g/mol) nanopowder with particle size < 50 nm, TiO 2 (79.865 g/mol) nanopowder with particle size < 100 nm and ZnO (81.406 g/mol) nanopowder with particle size < 50 nm were obtained from Sigma-Aldrich (St. Louis, MO). Sodium phosphate dibasic (Na₂HPO₄) and sodium phosphate monobasic (NaH 2 PO 4 ) were obtained from Fisher Scientific. HPLC-grade methanol was purchased from Caledon (Georgetown, ON, Canada). 2.2. Analytical method and procedures The binding of MEX.HCl to TMONPs was investigated using an Agilent capillary electrophoresis (CE) instrument equipped with a capillary of 28 cm length from the inlet to the detection window. The diode array detector was set up to record at two UV wavelengths of 200 and 254 nm. The stock solution of 100 µg/mL MEX.HCl was diluted to five concentrations of 15, 30, 45, 60 and 75 µg/mL for constructing the binding isotherms and to determine the kinetics study. Different doses of TMONPs (0.5, 1, 2, 5, and 10 g/L) were then added to study their effects on the % binding. All the solutions were prepared in 10 mM of Na 2 HPO 4 which was used as the background electrolyte (BGE). All samples were ultrasonically homogenized for 5 minutes and allowed to undergo static adsorption for 24 hours before being injected for CE analysis. Adsorption is defined as the transfer of organic substances from a liquid phase onto the surface of a solid phase. 2.3. Capillary electrophoresis-ultraviolet (CE-UV) analysis The samples were analyzed with capillary electrophoresis (G1600AX CE system, Agilent Technologies, Santa Clara, USA). To display the migration time of analytes, the diode array detector (DAD) equipped with an Agilent CE system was set up at a wavelength of 200 nm. The fused silica capillary was filled with 10 mM Na 2 HPO 4 BGE to attain pH 9.4. It was run under an applied voltage of 18 kV to attain a stable current between 18–25 µA. The capillary was equilibrated at a temperature of 20°C. About 1 nL of the solution was uploaded for CE analysis with an injection time of 2 seconds. The concentrations of mexiletine before and after binding with TMONPs were determined using a standard calibration curve. Each binding test was repeated at least three trials, and the average result was calculated. 2.4. Determining mexiletine concentration using capillary electrophoresis CE was used to analyze standard MEX.HCl solutions (100, 50, 25, 12.5,6.25,3.125 and 1.5 µg/ml) were prepared by serial dilution from the stock solution (100 µg/ml). A calibration curve was constructed for determining the unknown concentrations of MEX.HCl after adsorption on TMONPs. The % bindings of MEX.H + to TiO 2 , ZnO and Co 3 O 4 nanoparticles were investigated by adding 1 mg/mL of TMONPs into the aqueous solution of 15 µg/mL MEX.HCl at room temperature to start a static adsorption process. The experiments were performed at pH 5.1, pH 7.2 and pH 9.4 as the pH level could cause surface charge variations on the TMONPs in addition to the degree of MEX.HCl ionization (Mohammed and Kareem 2019 ). The binding affinity (% binding) and the amount adsorbed ( q e ) were calculated according to Eqs. (1) and (2) respectively: $$\% Binding=\left( \frac{{C}_{o}-{C}_{f}}{{C}_{0}}\right)x 100 \left(1\right)$$ $${q}_{e}=\left( \frac{{C}_{o}-{C}_{f}}{M}\right)x V \left(2\right)$$ where \({C}_{0}\) and \({C}_{f}\) are the initial and final concentrations of the adsorption process, respectively. \(M\) and \(V\) represent the mass of nanoparticles and the volume of MEX.HCl standard solution respectively. Triplicate runs were carried out to determine the reproducibility of the analysis result and the standard deviation (SD) was calculated to verify the precision of the analysis. 2.5. Determining the point of zero charge for TMONPs To characterize the surface charges of TiO 2 , ZnO and Co 3 O 4 nanoparticles, a titration method was used to determine their individual points of zero charge (PZC) (Balderas-Hernandez et al. 2006 ; Taoufik et al. 2019 ). The solution ionic strength was set at 1 mM KCl, followed by pH adjustment to several values between 3 and 10 using NaOH or HCl solution (0.1 M). Each solution (10 ml) at a different pH containing 10 mg of nanoparticles was homogenized using ultrasound and then left in a static process for 24 hours at room temperature. The final pH was then measured of each solution. The point of zero charge (PZC) value could then be determined by the point of intersection on the x-axis when ∆pH was plotted versus pH. 2.6. Binding Kinetics The rate of binding of MEX.HCl to the surface of TMONPs at given experimental conditions was investigated by linear kinetic forms of Lagergren’s pseudo-first order (PFO) and pseudo-second order (PSO) models along with intraparticle diffusion model (IPD). 2.7. Binding Isotherm The relationship of adsorption isotherms at equilibrium is critical to investigate the proposed binding interaction between MEX.HCl and the surface of TMONPs. There are several equilibrium models that have been developed to describe this relationship. In this study, we used linear forms of Freundlich and Langmuir models. OriginPro software was used for fitting the experimental data and calculating linear kinetic and isotherm parameters. 2.8. Error analysis Error analysis functions such as the sum of the squares of the errors (SSE) was used in order to evaluate the linear isotherm and kinetic models. The objective was to minimize the SSE between the experimental and calculated values of the dependent variable in the binding experiments. The value of SSE was calculated using this $$SSE= \sum _{i=1}^{n}({q}_{e, exp }- {q}_{e, cal}{)}^{2} \left(4\right)$$ where \({q}_{e, exp }\) and \({q}_{e, calc }\) are the experimental and the calculated values of binding at equilibrium ( \({ \text{C}}_{e}\) ) of MEX.HCl, \(n\) represented the number of data points during the experiments. It should be emphasized that the smaller the error values, the better the predictive models performance, indicating that there is an agreement between the experimental and calculated data, and the more the model becomes favourable. 3. Results And Discussion 3.1. Binding of MEX.HCl to TMONPs MEX.HCl contains an amino group, a hydrocarbon chain, a phenoxy moiety, and two methyl groups. The basic amino group (-NH 2 ) is able to accept protons under low pH conditions (Bizi and el Bachra 2021 ). At pH 7.2, the amino group in the MEX.HCl salt exists as its conjugate acid (a protonated ammonium ion, -NH 3 + ) as shown in Fig. 2 . The phenoxy moiety, of crucial importance for biological activity, can mimic amino acid residues forming hydrogen bonds (Kozyra and Pitucha 2022 ). It was hypothesized that Ti(IV), Co(II)/Co(III), and Zn(II) atoms present on the surface of TMONPs were capable of binding with MEX.HCl and its conjugate acid (MEX.H + ) through hydrogen bonding, coordinate bonding, and electrostatic interaction. The first two interactions occur in both MEX.HCl and MEX.H + through the nitrogen atom of amino and the oxygen atom of phenoxy electron-donating groups. On the other hand, electrostatic interaction exist between the positive charge of MEX.H + and the negative charge of TMONPs. It was reported that the pK a of MEX.H + is 9.5 (Zhu et al. 2019 ). Notably, the surface charge on TMONPs is governed by the solution pH relative to their PZC value. The PZC of TiO 2 was determined to be 6.7 (Tabish et al. 2018 ). Hence TiO 2 carries a positive charge at a pH lower than the PZC and becomes negative at a pH higher than the PZC as shown in the chemical equilibrium expressions below. If pH PZC: TMONP + OH − ↔ TMONP − + H 2 O However, the amount of positive or negative charges on the surface of TMONPs varies according to the deviation of solution pH from the PZC. The % bindings of MEX.HCl to TiO 2 , Co 3 O 4 and ZnO determined by our own experiments are presented in Fig. 3 . The results indicated that MEX.HCl can bind to TiO 2 , Co 3 O 4 and ZnO nanoparticles in alkaline, neutral and acidic solutions. TiO 2 attained the highest % binding compared to Co 3 O 4 and ZnO at all three solution pH levels. At pH 5.1, mainly MEX.H + (15 mg/L) bound to TiO 2 up to 46 ± 1.5%, which is higher than 34 ± 1.2% for Co 3 O 4 and 23 ± 1% for ZnO. According to the pK a and PZC values, MEX.H + bind to TiO 2 nanoparticles mainly due to hydrogen bonding and coordinate bonding. Importantly, the binding of MEX.H + to TiO 2 increased to 57 ± 1.2% at pH 7.2 and reached 81 ± 1% at pH 9.4. At pH 7.2 the surface charge of TiO 2 becomes slightly negative which may enhance the electrostatic interaction with the positively charged MEX.H + in addition to hydrogen bonding and coordinate bonding. At pH 9.4, the surface of TiO 2 becomes more negatively charged, thus enhancing the electrostatic attraction to MEX.H + and resulting in the highest binding %. Also, Co 3 O 4 binds to MEX.H + with 34 ± 1.2% at pH 5.1 and increases in an alkaline medium to reach 64 ± 2.1% at pH 9.4. The empirical PZC value of Co 3 O 4 is 7.3, which is higher than the PZC value of TiO 2 , leading to an increase in the amount of positive charge on the Co 3 O 4 surface at pH5. Thus, the electrostatic repulsion between the positively charged conjugate acid ions and the positive H + ions on the surface of Co 3 O 4 in an acidic medium lead to a decrease in the binding %. This may be attributed to the synergistic effect of the redox cycle of Co 2+ /Co + 3 on the surface of Co 3 O 4 which contributes to an increase in the positive charge and lead to a decrease in the binding % of MEX.H + (Fu et al. 2021 ). Similar results were shown for the adsorption of pharmaceuticals such as tetracycline.HCl (TEC) (Mohammed and Kareem 2019 ). It was noted that the adsorption process at different pH levels was related to the molecular structure of TEC and the surface charges on the adsorbent surface. Furthermore, the opposite trend was reported for the adsorption of different negatively charged ions of emerging contaminants (atenolol, carbamazepine, ciprofloxacin, diclofenac, gemfibrozil, and ibuprofen) on porous graphene (PG) (Khalil et al. 2020 ). The adsorption was drastically reduced above pH 9.4 due to an increase in the electrostatic repulsion between those negatively charged ions and the PG nano-sheet covered with negative hydroxide ions, as confirmed by both the pK a value of TEC and the PZC value for PG (Tabish et al. 2018 ). Last, it was noted that the binding of MEX.H + to ZnO was lower in acidic and neutral mediums with 23 ± 1% and 27 ± 1.6% respectively. However, the % binding increased to reach 58 ± 1.7% at pH 9 due to increasing the surface negative charge. Similarly, it was reported that the adsorption of asphaltene was lower on the surface of ZnO compared to Co 3 O 4 (Hosseini et al. 2019 ). 3.2. Growing the binding of MEX.HCl onto TMONPs surfaces The relationship between the \({q}_{e}\) (equilibrium adsorption capacity) values of TMONPs and \({C}_{e}\) (the equilibrium concentration of MEX.HCl in an aqueous solution (monitored over 24 hr in a static adsorption process) is presented in Fig. 4 . Increasing the initial concentrations of MEX.HCl in the solution from 15 to 75 mg/L increased the driving force which may enhance the growth of its binding to TMONPs surfaces. The binding of MEX.H + onto the surface of TiO 2 starts to grow from 21 ± 1 mg/g at pH 5.1 and increases to 28 ± 1 mg/g at pH 9.4. Also, the binding of MEX.H + grows on the surface of Co 3 O 4 from 14 ± 1 mg/g at pH 5.1 to 21 ± 2 mg/g at pH 9.4, while ZnO exhibited low growth of binding from 11 ± 1 mg/g at pH 5 to 22 ± 1 mg/g at pH 9.4 after 24 hr. 3.3. Binding Kinetics To explain the binding mechanism, it is useful to investigate the binding rate and the rate-limiting step (mass transfer) in addition to the adsorption capacity of TMONPs. The linear forms of PFO Eq. (5) and PSO Eq. (6) were used to study the kinetics and to determine the rate constant of MEX.HCl binding onto TMONPs. $$\text{l}\text{n} \left({\text{q}}_{\text{e}}-{\text{q}}_{\text{t}}\right)=\text{l}\text{n} {\text{q}}_{\text{e}}-{\text{k}}_{1} \text{t} \left(5\right)$$ $$\frac{\text{t}}{{\text{q}}_{\text{t}}}=\frac{1}{{\text{k}}_{2} {q}_{e}^{2}}+\frac{1}{{\text{q}}_{\text{e}} }\text{t} \left(6\right)$$ where \({q}_{e}\) and \({q}_{t}\) (mg/g) are the amount of MEX.HCl adsorbed at equilibrium and at any time prior (t) respectively; \({k}_{1}\) (min − 1 ) and \({k}_{2}\) (g/mg.min) are the PFO and the PSO rate constants respectively. Furthermore, the intra-particle diffusion (IPD) model (Weber-Morris) was used to determine the rate-limiting step and the diffusion mechanism as shown in Eq. ( 7 ): $${ \text{q}}_{\text{t}}={\text{k}}_{\text{i}\text{d}} \sqrt{\text{t}} +\text{C}$$ 7 where \({k}_{id}\) is the rate constant of intraparticle diffusion (mg/g.min 1/2 ) and \(C\) provides information that is directly proportional to the boundary layer thickness (mg/g) on the diffusion (Uma Maheswari et al. 2022 ). An increase in the value of C indicates an increase in the boundary layer thickness and a decrease in external mass transfer, which in turn led to an increase in internal mass transfer. The values of \({k}_{id} and C\) can be obtained from the slope and intercept, respectively. The kinetics of binding of MEX.HCl to the surface of TMONPs (TiO 2 , ZnO and Co 3 O 4 ) and the IPD model plot are worth investigating. Figure 5 (a) shows an initial period of 25 min for rapid binding, followed by a subsequent period exceeding 300 min for slow binding. These results suggest different interactions between MEX.HCl molecules and the surface of TMONPs. In the rapid stage, a quantity (q t ) of MEX.HCl interacted strongly with the TMONPs to form a monolayer of adsorbate molecules on each nanoparticle surface. The values of the kinetic parameters, \({R}^{2}\) , \({k}_{1}\) and \({k}_{2}\) are presented in Table 1 . After that, adsorption of more MEX.HCl molecules to form a second layer slowed down tremendously due to weak interactions. It took additional molecules a long time to gradually build up a second layer, reaching the quantities (q e,exp ) of 5.45 ± 0.5, 10.54 ± 0.5 and 11.37 ± 0.5 mg/g at 324 min, for ZnO, Co 3 O 4 and TiO 2 respectively. In the rapid stage, the surface of TMONPs provided a large number of strong binding sites for MEX.HCl, resulting in rapid increases of q t . After formation of a monolayer, binding of more molecules slowed down due to a lack of available binding sites and a larger distance from the nanoparticle surface. Figures 5 (b) and 5(c) fit the binding data to both PFO and PSO models. Table 1 indicates that the correlation coefficient (R 2 ) values from the PSO model are higher than those for the PFO model, and that the calculated values of adsorbed quantity at equilibrium \({(q}_{e, cal})\) are very similar to the experimental values of adsorbed quantity at equilibrium \({(q}_{e, exp})\) in the PSO model. Hence, PSO is better model to represent the binding of MEX.HCl to TiO 2 , Co 3 O 4 and ZnO nanoparticles. Furthermore Fig. 5 (d) presents a Weber-Morris plot, which shows the linear relationship between q t and square root of time, for the IPD model. If the straight line passes through the origin, the rate limiting step of the binding process can be attributed only to the intraparticle diffusion process (Campos et al. 2018 ). Table 2 indicates that the IPD model is suitable for the depiction of experimental data because the R 2 values range from 0.980 to 0.988. However, none of the straight lines pass through the origin. Significant intercept (C) values of 6.26 ± 0.17, 5.78 ± 0.16 and 3.10 ± 0.098 (mg/g) were obtained in the order of TiO 2 > Co 3 O 4 > ZnO, which is in agreement with their corresponding intraparticle diffusion rate ( \({k}_{id}\) ) values of 0.29 ± 0.01 > 0.25 ± 0.01 > 0.13 ± 0.01. These trends suggest that MEX.H + bound to the internal surfaces of TMONPs and the rate limitting step consisted of intra-particle diffusion (Pholosi et al. 2020 ). The IPD model assumes that mass transfer is due to diffusion of MEX.HCl molecules within the pores of TMONPs (Campos et al. 2018 ). Table 1 Determined parameters and error analysis for kinetic and intra-particle diffussion models for binding of 20 mg/L MEX.HCl to TiO 2 , Co 3 O 4 and ZnO nanoparticles at room temperature at pH 9.4. Standard deviations of slope and y-intercept were used to determine uncertainties. SSE was used to show the fitness of the model. Model q e,exp (mg/g) q e,calc (mg/g) k 1 (min − 1 ), k 2 (g/mg.min) R 2 SSE (mg 2 /g 2 ) TiO 2 PFO 11.37 ± 0.53 8.87 ± 0.39 0.014 ± 0.002 0.882 1.540 PSO 12.15 ± 0.01 0.003 ± 8.0 x 10 − 6 0.998 1.330 Co 3 O 4 PFO 10.54 ± 0.52 5.75 ± 0.18 0.008 ± 0.001 0.898 0.591 PSO 10.54 ± 0.01 0.005 ± 1.4 x 10 − 5 0.991 1.160 ZnO PFO 5.45 ± 0.47 2.97 ± 0.19 0.009 ± 0.001 0.912 0.598 PSO 5.69 ± 0.01 0.007 ± 2.2 x 10 − 5 0.996 0.350 Table 2 Intra-particle diffusion kinetic parameters for binding of 20 mg/L MEX.HCl to TiO 2 , Co 3 O 4 and ZnO nanoparticles at room temperature at pH 9.4. TMONPs Intra-particle diffusion \({k}_{id}\) (mg/g.min 1/2 ) C (mg/g) R 2 SSE (mg 2 /g 2 ) TiO 2 0.29 ± 0.01 6.26 ± 0.17 0.988 0.146 Co 3 O 4 0.25 ± 0.01 5.78 ± 0.16 0.985 0.109 ZnO 0.13 ± 0.01 3.10 ± 0.01 0.980 0.048 3.4. Affinity of Surface TMONPs to MEX.HCl Binding affinity measures the strength, and hence extent, of binding between the adsorbent and the adsorbate. Binding affinity values at equilibrium readily imparts a better understanding of the adsorption process for potential improvement of the adsorption pathway (Ayawei et al. 2017 ). The Freundlich and Langmuir isotherms were used to evaluate the binding affinity between TMONPs and MEX.HCl. The Freundlich adsorption isotherm (Eq. 8 ) is an empirical model that assumes the involvement of binding sites on a heterogeneous surface with different adsorption energies. $$Log {q}_{e}=log {K}_{f}+ \frac{1}{n} log {C}_{e}$$ 8 where \({K}_{f}\) measures the binding capacity of adsorbent (TMONPs) and \(\frac{1}{n}\) measures the binding affinity for adsorbate (MEX.HCl) that varies with changes in adsorption density. Higher \(n\) values indicate stronger adsorbate/adsorbent affinities and larger distributions of adsorbate over the adsorbent surface (Liu 2015 ). On the other hand, the Langmuir adsorption isotherm (Eq. 9) assumes a monolayer of adsorbate binding to an adsorbent surface that possesses identical or energetically equivalent sites. $$\frac{1}{{q}_{e}}=\frac{1}{{q}_{max}}+ \frac{1}{{K}_{L} {q}_{max}} \frac{1}{{C}_{e}} \left(9\right)$$ where \({K}_{L}\) (l/mg) is the Langmuir isotherm constant, \({q}_{e}\) (mg/g) is the amount adsorbed per gram of adsorbent, \({C}_{e}\) (mg/l) is the adsorbate concentration at equilibrium, and \({q}_{max}\) (mg/g) is the maximum amount of MEX.HCl that can be adsorbed per gram of adsorbent. The Freundlich isotherms for TiO 2 , Co 3 O 4 and ZnO nanoparticles at pH 5.1, pH 7.2 and pH 9.4 are presented in Fig. 6 . The data of \({log C}_{e}\) versus \({log q}_{e}\) fitted well with the Freundlich equation based on both the good R 2 values (in the range of 0.981–0.993) and the low SSE values (in the range of 2x10 − 5 -5x10 − 5 ) in Table 3 . The \({K}_{f}\) results, which represent the adsorption capacities for MEX.HCl, increased with higher pH levels in the order of pH 5.1 < pH 7.2 5.38 mg/g for Co 3 O 4 > 3.47 mg/g for ZnO. The \(n\) results, which represent the affinity of TMONPs for MEX.HCl, also increased with higher pH levels in the order of pH 5.1 < pH 7.2 2.7 for Co 3 O 4 > 2.1 for ZnO. All these results indicate binding of MEX.HCl molecules with a distribution of heterogenous sites on the surface of each TMONP as controlled by a physisorption mechanism. The Langmuir isotherm model was next tested by plotting \(1/{q}_{e}\) versus \(1/{C}_{e}\) in Fig. 7 . Data fitting in Table 4 for TiO 2 nanoparticles produced reasonable R 2 values (in the range of 0.958 to 0.991) but high SSE values (in the range of 9x10 − 4 to 3x10 − 3 ). Their maximum capacity ( \({q}_{max}\) ) results increased from 24.3 mg/g at pH5 to 27.9 mg/g at pH9. By comparison, the \({q}_{max}\) results for Co 3 O 4 and ZnO nanoparticles increased from 19.8 to 26.4 mg/g and from 19.5 to 25.2 mg/g respectively. The best binding capacity for MEX.HCl is again provided by TiO 2 nanoparticles. Taking both isotherm models together, our interpretation of all results is that MEX.HCl binding forms a monolayer of adsorbate molecules on the TMONP surface that possesses identical or energetically equivalent site, followed by accumulation of additional molecules on the heterogeneous surface with different adsorption energies. This proposed mechanism is similar to the adsorption of Cu(II) onto the surface of Biochar composites (Hussain et al. 2022 ). Table 3 Freundlich parameters for adsorption of MEX.HCl onto TiO 2 , Co 3 O 4 and ZnO nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4. [MEX.HCl] 0 = 15, 30, 45, 60 and 75 mg/L. TiO 2 Co 3 O 4 ZnO pH K f (mg/g) 1/n R 2 SSE (mg 2 /g 2 ) K f (mg/g) 1/n R 2 SSE (mg 2 /g 2 ) K f (mg/g) 1/n R 2 SSE (mg 2 /g 2 ) 5.1 1.87 0.590 0.983 3x10 − 4 1.29 0.590 0.999 8x10 − 5 0.78 0.640 0.992 2x10 − 4 7.2 3.54 0.460 0.993 5x10 − 5 1.76 0.550 0.991 2x10 − 4 1.01 0.600 0.995 1x10 − 4 9.4 8.91 0.300 0.981 2x10 − 5 5.38 0.370 0.997 1x10 − 5 3.47 0.480 0.993 1x10 − 3 Table 4 Langmuir parameters for adsorption of MEX.HCl onto TiO 2 , ZnO and Co 3 O 4 nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4. [MEX.HCl] 0 = 15, 30, 45, 60 and 75 mg/L. TiO 2 Co 3 O 4 ZnO pH K L (L/mg) q max (mg/g) R 2 SSE (mg 2 /g 2 ) K L (L/mg) q max (mg/g) R 2 SSE (mg 2 /g 2 ) K L (L/mg) q max (mg/g) R 2 SSE (mg 2 /g 2 ) 5.1 0.046 24.280 0.958 3x10 − 3 0.033 19.775 0.994 1x10 − 4 0.015 19.479 0.911 1x10 − 2 7.2 0.076 25.105 0.987 9x10 − 4 0.044 21.103 0.979 1x10 − 3 0.023 22.843 0.956 6x10 − 3 9.4 0.264 27.846 0.991 2x10 − 3 0.105 26.349 0.925 8x10 − 3 0.080 25.214 0.971 6x10 − 4 3.5. Favorability of the Binding Process Thus far, the binding isotherm fitted well with the Freundlich model, and the binding kinetics obeyed the PSO model involving IPD. Both findings suggest physicochemical adsorption of MEX molecules on heterogeneous TMONP surfaces (Jiang et al. 2022 ). Favourable binding of MEX.HCl to TMONPs is indicated by both the Freundlich \(\frac{1}{n}\) value and the Langmuir separation factor ( \({R}_{L}\) ) value (Hussain et al. 2022 ). The binding process is favorable when 0 < \({R}_{L}\) 1\) . \({R}_{L}\) is a dimensionless parameter that can be calculated: $${R}_{L}=\frac{1}{{(1+\text{K}}_{\text{L}} {C}_{0})} \left(9\right)$$ where \({\text{K}}_{\text{L}}\) is the Langmuir constant (mg/g) and \({C}_{0}\) is the initial concentration of MEX.HCl (mg/L). Figure 8 presents three plots of R L versus the initial concentrations of MEX.HCl at different pH levels. Obviously all the R L values for TiO 2 , Co 3 O 4 and ZnO nanoparticles fall between 0 and 1, indicating the favourable binding of MEX.HCl onto the TMONPs. Separation factor calculated from Langmuir isotherms versus [MEX.HCl] 0 for binding onto (a) TiO 2 , (b) Co 3 O 4 and (c) ZnO nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4. [MEX.HCl] 0 = 15, 30, 45, 60 and 75 mg/L. 3.6. Binding mechanism of MEX.HCl As suggested above, the mechanism of MEX.HCl binding to the TMONPs was based on the pK a value and the molecular structure of MEX.HCl versus the surface charge of TMONPs at the three pH levels studied. MEX.HCl (with pK a 9.5) and the TMONPs (TiO 2 , Co 3 O 4 , and ZnO with PZC of 6.7, 7.2 and 7.6 respectively) would carry different charges in the solution due to protonation-deprotonation processes (Fig. 9 ). Optimal binding occurred at pH 9.4 where MEX.H + acts as the conjugate acid with a slight positive charge and the surface of each TMNOP bears a negative charge. This strongly suggests that the adsorption mechanism may involve electrostatic interaction between the negative OH − groups on the TMONP surface and the positive charge of MEX.H + . Furthermore, hydrogen bonding between the amino/phenoxy group of MEX.HCl and the oxide/hydroxide group of TMONP may also contribute to the overall binding mechanism. Also, the binding may occur by electrostatic interaction between the negative surface of TMONPs -O − and the protonated ammonium ion of MEX.HCl at different pHs as shown by the following equations: $$TMON{P}_{s}-{O}^{-}+ {H}^{+}-MEX \underrightarrow{Electrostatic attraction} TMONPs-{O}^{-} {H}^{+}-MEX \left(10\right)$$ $$TMON{P}_{s}-OH+{NH}_{2}-MEX \underrightarrow{Hydrogen bonding} TMONPs-OH\dots . {NH}_{2}-MEX \left(11\right)$$ $$TMON{P}_{s}-OH+OR-MEX \underrightarrow{Hydrogen bonding} TMONPs-OH\dots .OR-MEX \left(12\right)$$ 3.7. Conclusion Capillary electrophoresis was used to investigate at room temperature the binding of MEX.HCl onto TiO 2 , Co 3 O 4 and ZnO nanoparticles at different pH levels. Alkaline water at pH 9.4 led to efficient binding of MEX molecules, at 81 ± 1%, 64 ± 2% and 58 ± 2% for TiO 2 , Co 3 O 4 and ZnO respectively. The time-based binding data was best fitted with a pseudo second-order kinetic model with \({\text{q}}_{\text{e}, \text{c}\text{a}\text{l}}\) values similar to \({\text{q}}_{\text{e}, \text{e}\text{x}\text{p}}\) results, which suggests MEX.HCl binding through a physicochemical adsorption. Investigation of rate-limiting steps by the IPD model revealed that MEX.H + binding occurred also within the internal surface of porous TMONPs, in the order of TiO 2 > Co 3 O 4 > ZnO. Although both the Freundlich and Langmuir models contribute to the binding affinity of MEX.HCl on TMONP surfaces, the former model showed better fitting with higher R 2 values and lower SSE uncertainties. It can be concluded that MEX.HCl molecules bind to heterogenous sites on TMONPs mainly under the control of physisorption. The binding capacity (q max ) was maximal at pH 9.4, following the order of 27.0 > 26.4 > 25.2 mg/g for TiO 2, Co 3 O 4 and ZnO respectively. The small R L values, at different pH levels, confirmed favorable binding of MEX.HCl onto the studied TMONPs, mainly accomplished via electrostatic interaction and hydrogen bonding. Declarations Ethical Approval Not applicable. Consent to Participate Not applicable. Consent to Publish All the authors agreed to be published. Author Contributions Edward Lai: conceptualisation, resources, review & editing, supervision, project administration, funding acquisition. Eman Elmorsi: investigation, visualisation, methodology, formal analysis, writing original draft, review & editing. Funding The authors acknowledge support from the Natural Sciences and Engineering Research Council of Canada (NSERC) RGPIN-2018-05320 for the financial support of this research. Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Availability of data and materials Not applicable. References Adelantado C, Zougagh M, Ríos Á (2022) Contributions of capillary electrophoresis in analytical nanometrology: a critical view. Crit Rev Anal Chem 52:1094–1111. https://doi.org/10.1080/10408347.2020.1859983 Agnihotri AS, Varghese A, M N (2021) Transition metal oxides in electrochemical and bio sensing: a state-of-art review. Appl Surf Sci Adv 4:100072. https://doi.org/10.1016/j.apsadv.2021.100072 Akıncı E, Yüzbaşıoglu Y, Coşkun F (2011) Hemodialysis as an alternative treatment of mexiletine intoxication. 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Circ Res 124:539–552. https://doi.org/10.1161/CIRCRESAHA.118.314050 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2344386","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":166577385,"identity":"7cee590e-715a-4157-907b-1e5958a08063","order_by":0,"name":"Eman T. Elmorsi","email":"","orcid":"","institution":"Carleton University","correspondingAuthor":false,"prefix":"","firstName":"Eman","middleName":"T.","lastName":"Elmorsi","suffix":""},{"id":166577386,"identity":"a2a452d0-1d29-43b0-be2b-7a3a9a66a57d","order_by":1,"name":"Edward P.C. Lai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYFCCBCBmY5BhYGY+AGRZEK+Fh4GZDcSSALKI1sLAY0CcFn72HMPPFWUMPPztPB8//NwjIWfP3nuA4UcNbi2SPW+MJc+cY+CROMy7WbLnmYQxD8+5BMaeY7i1GNzI3SDZ2AZ0zmHebQw8ByQSeyRyDJiBTsUJ7G/kbv4J0iJ/mOcZ458DEvUQLf/w2CKRuw1si8FhHjZmoC0JPCAtjG24tUicef/NsuGcBI/hYTZjaZkDEoY9Z84YHOztw62Fvz0t+WZDmY2c3PnDDz++OWAjz97eY/jgxzfcWmCWoXIPENQwCkbBKBgFowAvAAAVmEhF0usIggAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-6046-1138","institution":"Carleton University","correspondingAuthor":true,"prefix":"","firstName":"Edward","middleName":"P.C.","lastName":"Lai","suffix":""}],"badges":[],"createdAt":"2022-12-05 05:01:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2344386/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2344386/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":31503631,"identity":"ac479b1e-0111-478f-88ce-8814feeee9f6","added_by":"auto","created_at":"2023-01-12 21:22:19","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":8559,"visible":true,"origin":"","legend":"\u003cp\u003eChemical structure of mexiletine hydrochloride (pK\u003csub\u003ea\u003c/sub\u003e =9.5)\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/339a56974db2ef40ee11ac13.jpeg"},{"id":31505019,"identity":"ff0cfb00-502a-404b-a5f5-9cf84c4eb05d","added_by":"auto","created_at":"2023-01-12 21:38:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":11835,"visible":true,"origin":"","legend":"\u003cp\u003eMexiletine and conjugate acid\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/9e9f91ffd6c464a222175e53.png"},{"id":31504635,"identity":"05fc47cb-943a-4d0e-8777-78b1d2248f49","added_by":"auto","created_at":"2023-01-12 21:30:19","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":49531,"visible":true,"origin":"","legend":"\u003cp\u003eBinding % of MEX.HCl to TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4, [MEX.HCl]\u003csub\u003e0\u003c/sub\u003e = 15 mg/L, TMONPs dose = 1 g/L.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/3fc5a08205ee7fec0c4a6466.jpg"},{"id":31504638,"identity":"54eacce7-b5c7-457d-ac34-ead52c73fdaa","added_by":"auto","created_at":"2023-01-12 21:30:19","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44935,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of initial MEX.HCl concentration (c\u003csub\u003ee\u003c/sub\u003e) on equilibrium adsorption capacity (q\u003csub\u003ee\u003c/sub\u003e) onto the surface of (a) TiO\u003csub\u003e2\u003c/sub\u003e, (b) Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e, and (c) ZnO for different pH levels at room temperature. Error bar shows the standard deviation of four replicate trials.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/44ad2993ab070b2a53cda612.jpg"},{"id":31505313,"identity":"f63038e9-841e-4d3b-be76-a39fe0739511","added_by":"auto","created_at":"2023-01-12 21:46:19","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":67750,"visible":true,"origin":"","legend":"\u003cp\u003eTime-dependent binding of MEX.HCl with TMONPs:\u0026nbsp; (a) effect of contact time on q\u003csub\u003et\u003c/sub\u003e, (b) first-order model, (c) second-order model, and (d) intra-particle diffusion model. [MEX.HCl]\u003csub\u003e0\u003c/sub\u003e = 20 mg/L; TMONPs dose = 1.0 g/L. Error bar shows standard deviation of four replicate trials.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/d19ffb82a38a4d966e765ec2.png"},{"id":31505414,"identity":"06caa06f-d5fb-4683-90e4-06ecf0b7f3cf","added_by":"auto","created_at":"2023-01-12 21:54:19","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":22584,"visible":true,"origin":"","legend":"\u003cp\u003eFreundlich isotherm model for binding MEX.HCl onto (a) TiO\u003csub\u003e2\u003c/sub\u003e, (b) Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and (c) ZnO nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4. [MEX.HCl]\u003csub\u003e0\u003c/sub\u003e = 15, 30, 45, 60 and 75 mg/L.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/c3d778fe4b2b587f17004cbc.png"},{"id":31505018,"identity":"7f2e7274-384f-4e30-8377-586826929cca","added_by":"auto","created_at":"2023-01-12 21:38:19","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":24326,"visible":true,"origin":"","legend":"\u003cp\u003eLangmuir isotherm model for binding MEX.HCl onto (a) TiO\u003csub\u003e2\u003c/sub\u003e, (b) Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and (c) ZnO nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4. \u0026nbsp;[MEX.HCl]\u003csub\u003e0\u003c/sub\u003e = 15, 30, 45, 60 and 75 mg/L.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/ad5bd501b536766a1d0fb120.png"},{"id":31504641,"identity":"6e8074f9-2a77-4ed4-81e1-6d34d38e2775","added_by":"auto","created_at":"2023-01-12 21:30:19","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":14764,"visible":true,"origin":"","legend":"\u003cp\u003eSeparation factor calculated from Langmuir isotherms versus [MEX.HCl]\u003csub\u003e0\u003c/sub\u003e for binding onto (a) TiO\u003csub\u003e2\u003c/sub\u003e, (b) Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and (c) ZnO nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4. [MEX.HCl]\u003csub\u003e0\u003c/sub\u003e = 15, 30, 45, 60 and 75 mg/L.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/a893edf4af095fe8dcb66715.png"},{"id":31503640,"identity":"adb5d4d4-d7eb-4233-a488-cf818e119da1","added_by":"auto","created_at":"2023-01-12 21:22:19","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":40536,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003ea) Speciation of MEX.HCl as a function of pH in aqueous solution, and (b) point of zero charge for TiO\u003csub\u003e2\u003c/sub\u003e, ZnO and Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e nanoparticles as a function of pH in aqueous dispersion.\u003c/p\u003e","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/76fe506d7b51a8677b2af5ee.png"},{"id":31503635,"identity":"e0731a51-e924-4f8c-9ec2-29ffbd24e6e4","added_by":"auto","created_at":"2023-01-12 21:22:19","extension":"jpg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":40449,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic diagram of mexiletine binding with TMONPs.\u003c/p\u003e","description":"","filename":"10.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/f5a6fae304c23e77f9dc0664.jpg"},{"id":33291777,"identity":"76979e30-173a-4ab7-8feb-fa0f08df2d51","added_by":"auto","created_at":"2023-02-22 15:05:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":836926,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2344386/v1/440194d6-5134-4671-b6a9-1246fd7a639a.pdf"}],"financialInterests":"","formattedTitle":"Investigation of Mexiletine Hydrochloride Binding on Transition Metal Oxide Nanoparticles by Capillary Electrophoresis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eActive pharmaceutical ingredients (APIs) can be used as diagnostic agents, therapeutic treatments, and disease mitigators (Kumar et al. \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Approximately 60% of APIs were reported to have low oral bioavailability because of their suboptimal water solubility, which may explain the reason for their unpredictable clinical response. Salt formation of APIs is a method of choice for improving their physical properties (Elder et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2013\u003c/span\u003e;Tran and Tran \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) aqueous solubility (Fahr and Liu \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Douroumis and Fahr \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Bharate 2021), chemical stability, and gastrointestinal absorption. An effective concentration of the API, higher than those of nonionized free acid or base, can thus achieve (Elder et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Wiedmann and Naqwi \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Gupta et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). It has been revealed that pharmaceutical salts account for about 43% of the total APIs (Wiedmann and Naqwi \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Most of the APIs, either weakly acidic or weakly basic, contain the proper functional groups that allow for salt formation. Basic APIs often require a strong inorganic acid (HCl) that provides a counterion (Cl\u003csup\u003e\u003cb\u003e\u0026minus;\u003c/b\u003e\u003c/sup\u003e) to form salts for enhanced stability in the drug formulation (Bharate \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2021b\u003c/span\u003e). Hydrochloride salt formulation is dictated by such factors as biochemistry, pharmacokinetics, and pharmacodynamics that would enhance the overall therapeutic effects(Wiedmann and Naqwi \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Gupta et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). The stability of formed salts is mainly determined by the negative logarithm of acid dissociation constant (pK\u003csub\u003ea\u003c/sub\u003e). A basic API forms a stable salt when the difference between the ionizable group pKa and the counterion pKa is greater than two or three units (Lee \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). There are as many as 61 counterions used in all approved pharmaceutical salts (Bharate \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2021b\u003c/span\u003e). In the past twenty years, anionic counterions such as chloride, mesylate, bromide, acetate, and fumarate are used to form salts from basic APIs. HCl, in particular, is a safe acid and the chloride ion is abundant throughout the human body. Thus, HCl salts account for about 60% of all basic drugs. These salts are characterized by high water solubility and thermodynamic stability (Bharate \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021a\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMexiletine (MEX) is an aromatic ether and primary amine compound (pK\u003csub\u003ea\u003c/sub\u003e 9.5) known as the 2,6-dimethyl phenyl ether of aminopropyl. Mexiletine is present in a racemic mixture (S-and R-enantiomers), but the desirable action of mexiletine is only associated with the (R)-enantiomer(Andrews et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The HCl salt of mexiletine is used as an anti-arrhythmia drug (Class IB) by inhibiting the sodium influx in cardiac cells which reduces the rising rate of the heart action potential. Consequently, the heartbeat is stabilized, and nerve impulses slow down (Nakagawa et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Modoni et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Toxicity is common with mexiletine and can manifest in several organ systems. Cardiovascular, central nervous system and gastrointestinal-related symptoms most commonly occur. Due to its extensive cardiac side effect profile, patients generally consider mexiletine a risky drug. This led to the suspension of mexiletine treatment in a number of countries for a long period of time(Modoni et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). However, a recent study showed that mexiletine does not cause any hazardous cardiac arrhythmias; it is a highly effective and inexpensive drug (Statland \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Modoni et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Mexiletine is rapidly absorbed following oral administration with a systemic bioavailability of about 90% (Labb\u0026eacute; and Turgeon \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e1999\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe molecular structure of protonated mexiletine (MEX.H\u003csup\u003e+\u003c/sup\u003e) showed three-center binding sites the protonated or unprotonated nitrogen of the amine group, the lone electron pairs of oxygen, and the phenyl ring. These binding centers would allow MEX.H\u003csup\u003e+\u003c/sup\u003e to interact with different organic and inorganic compounds. For example, MEX.H\u003csup\u003e+\u003c/sup\u003e interacts with transmembrane protein receptors through anionic and cationic sites due to intermolecular hydrogen bonds formed between neutral MEX.HCl and the polar sites of protein receptors. In addition, the nitrogen of the amino group in MEX.H\u003csup\u003e+\u003c/sup\u003e may coordinate with different cations such as Na\u003csup\u003e+\u003c/sup\u003e and K\u003csup\u003e+\u003c/sup\u003e ions of protein receptors (Remko et al. \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). MEX.HCl is extensively metabolized in men, with less than 10% of the dose being excreted unchanged in urine which ends in different aquatic environments leading to the spreading of contamination and pollution (Akıncı et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Hence, the presence of MEX.HCl in the environment may undergo organic and inorganic interactions such as interactions with transition metal oxide nanoparticles (TMONPs) which would affect its bioavailability in ecotoxicology(CHMP \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) and control its environmental transportation. TMONPs have gained significant attention due to their extraordinary physical, chemical, optical and electronic properties when compared to bulk materials (Agnihotri et al. 2021). In addition, because of their size, shape, stability and larger surface area, they are included in various applications. TMONPs of different shapes and structures have been synthesized using different techniques. Biocompatible TMONPs are generally used to immobilize biomolecules to produce immunosensors, sensors of DNA and enzymes but semiconducting metal oxide nanoparticles are usually used as tracers and markers in electrochemical analysis (Kango et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Agnihotri et al. 2021; Tajik et al. \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Although nanoparticles have evolved to play a prominent role in our economy, their increased use poses potential human health risks (Huang et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Nanoparticles may enter the environment directly or indirectly(Kaegi et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Al-Kattan et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Meier et al. \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) through different sources(Bundschuh et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) such as release during the production of raw material, during use, and after disposal of consumer products (Gottschalk et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Tolaymat et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). It has been reported that TMONPS such as TiO\u003csub\u003e2\u003c/sub\u003e and ZnO are released into landfills, sediments, and soil because they are mostly used in cosmetics, electronics, and medicine. Therefore, TiO\u003csub\u003e2\u003c/sub\u003e and ZnO nanoparticles are accumulated in sewage sludge during wastewater treatments (Mueller and Nowack \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Keller et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Sun et al. \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Also, the unique properties of Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e nanoparticles, are attracting enormous interest in different applications such as electrochemistry, storage of energy, sensors and catalytic processes leading to its discharge into aquatic systems and affecting its sustainability (Ates et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSeveral simple, rapid, sensitive, and selective analytical methods were reported for the determination of MEX.HCl and its synthetic impurity 2,6-dimethylphenol (DMP) (Belal et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). A reverse-phase HPLC method was developed for the quality control analysis of MEX.HCl in various dosage forms (Kaushik and Alexander \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). The applicability of capillary electrophoresis, capillary electro-chromatography, and micro/capillary/nano-liquid chromatography for the analysis of pharmaceutical formulations, active pharmaceutical ingredients, drug impurity testing, chiral drug separation, determination of drugs and metabolites in biological fluids was thoroughly reviewed (Aturki et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). In the present work, the separation of TMONPs from the MEX.HCl solution would be necessary. Capillary electrophoresis (CE) has become one of the most widely used analytical techniques for separating nanoparticles and detecting pharmaceutical compounds in the last two decades (Adelantado et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). According to their sizes, shapes, surface modifications, and compositions (Chetwynd et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), TMONPs can be hypothetically analyzed by studying their interaction with organic molecules followed by the analysis of the molecules by capillary electrophoresis. Hence, the strength and bond type between the adsorbed compounds as MEX.H\u003csup\u003e+\u003c/sup\u003e and TMONPs depends on the respective functional group and corresponding affinity of MEX.HCl, TMNOPs surface charge, and pH of the medium (McNamara et al. \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Gulley-Stahl et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Brennan et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). The objective of this study is to evaluate the binding of MEX.H\u003csup\u003e+\u003c/sup\u003e as a model of pharmaceutical hydrochloride salt onto the surface of TMONPs such as TiO\u003csub\u003e2\u003c/sub\u003e, ZnO, and Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e at different pH levels to investigate its potential bioavailability in the aquatic environment. The points of zero charge were found at pH 3.5 for TiO\u003csub\u003e2\u003c/sub\u003e (anatase), pH 6.5 for TiO\u003csub\u003e2\u003c/sub\u003e (rutile), pH\u0026thinsp;~\u0026thinsp;8 for Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and pH 8.0-9.7 for ZnO nanoparticles (Kosmulski \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Skocaj et al. \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). In a background electrolyte solution at pH 9.4 for CE analysis, TiO\u003csub\u003e2\u003c/sub\u003e (anatase) has a negative charge, TiO\u003csub\u003e2\u003c/sub\u003e (rutile) has a partial negative charge, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e has a partial positive charge, and ZnO has a positive charge.\u003c/p\u003e"},{"header":"2. Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Materials\u003c/h2\u003e \u003cp\u003eMexiletine hydrochloride, or 1-(2,6-dimethylphenoxy)-2-propylamine hydrochloride with a molecular formula of C\u003csub\u003e11\u003c/sub\u003eH\u003csub\u003e17\u003c/sub\u003eNO\u0026middot;HCl and MW\u0026thinsp;=\u0026thinsp;215.72 g/mol (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e (240.8 g/mol) nanopowder with particle size\u0026thinsp;\u0026lt;\u0026thinsp;50 nm, TiO\u003csub\u003e2\u003c/sub\u003e (79.865 g/mol) nanopowder with particle size\u0026thinsp;\u0026lt;\u0026thinsp;100 nm and ZnO (81.406 g/mol) nanopowder with particle size\u0026thinsp;\u0026lt;\u0026thinsp;50 nm were obtained from Sigma-Aldrich (St. Louis, MO). Sodium phosphate dibasic (Na₂HPO₄) and sodium phosphate monobasic (NaH\u003csub\u003e2\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e) were obtained from Fisher Scientific. HPLC-grade methanol was purchased from Caledon (Georgetown, ON, Canada).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Analytical method and procedures\u003c/h2\u003e \u003cp\u003eThe binding of MEX.HCl to TMONPs was investigated using an Agilent capillary electrophoresis (CE) instrument equipped with a capillary of 28 cm length from the inlet to the detection window. The diode array detector was set up to record at two UV wavelengths of 200 and 254 nm. The stock solution of 100 \u0026micro;g/mL MEX.HCl was diluted to five concentrations of 15, 30, 45, 60 and 75 \u0026micro;g/mL for constructing the binding isotherms and to determine the kinetics study. Different doses of TMONPs (0.5, 1, 2, 5, and 10 g/L) were then added to study their effects on the % binding. All the solutions were prepared in 10 mM of Na\u003csub\u003e2\u003c/sub\u003eHPO\u003csub\u003e4\u003c/sub\u003e which was used as the background electrolyte (BGE). All samples were ultrasonically homogenized for 5 minutes and allowed to undergo static adsorption for 24 hours before being injected for CE analysis. Adsorption is defined as the transfer of organic substances from a liquid phase onto the surface of a solid phase.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Capillary electrophoresis-ultraviolet (CE-UV) analysis\u003c/h2\u003e \u003cp\u003eThe samples were analyzed with capillary electrophoresis (G1600AX CE system, Agilent Technologies, Santa Clara, USA). To display the migration time of analytes, the diode array detector (DAD) equipped with an Agilent CE system was set up at a wavelength of 200 nm. The fused silica capillary was filled with 10 mM Na\u003csub\u003e2\u003c/sub\u003eHPO\u003csub\u003e4\u003c/sub\u003e BGE to attain pH 9.4. It was run under an applied voltage of 18 kV to attain a stable current between 18\u0026ndash;25 \u0026micro;A. The capillary was equilibrated at a temperature of 20\u0026deg;C. About 1 nL of the solution was uploaded for CE analysis with an injection time of 2 seconds. The concentrations of mexiletine before and after binding with TMONPs were determined using a standard calibration curve. Each binding test was repeated at least three trials, and the average result was calculated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Determining mexiletine concentration using capillary electrophoresis\u003c/h2\u003e \u003cp\u003eCE was used to analyze standard MEX.HCl solutions (100, 50, 25, 12.5,6.25,3.125 and 1.5 \u0026micro;g/ml) were prepared by serial dilution from the stock solution (100 \u0026micro;g/ml). A calibration curve was constructed for determining the unknown concentrations of MEX.HCl after adsorption on TMONPs. The % bindings of MEX.H\u003csup\u003e+\u003c/sup\u003e to TiO\u003csub\u003e2\u003c/sub\u003e, ZnO and Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e nanoparticles were investigated by adding 1 mg/mL of TMONPs into the aqueous solution of 15 \u0026micro;g/mL MEX.HCl at room temperature to start a static adsorption process. The experiments were performed at pH 5.1, pH 7.2 and pH 9.4 as the pH level could cause surface charge variations on the TMONPs in addition to the degree of MEX.HCl ionization (Mohammed and Kareem \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The binding affinity (% binding) and the amount adsorbed (\u003cem\u003eq\u003c/em\u003e\u003csub\u003e\u003cem\u003ee\u003c/em\u003e\u003c/sub\u003e) were calculated according to Eqs.\u0026nbsp;(1) and (2) respectively:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\% Binding=\\left( \\frac{{C}_{o}-{C}_{f}}{{C}_{0}}\\right)x 100 \\left(1\\right)$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n$${q}_{e}=\\left( \\frac{{C}_{o}-{C}_{f}}{M}\\right)x V \\left(2\\right)$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003ewhere \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({C}_{0}\\)\u003c/span\u003e\u003c/span\u003e and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({C}_{f}\\)\u003c/span\u003e\u003c/span\u003e are the initial and final concentrations of the adsorption process, respectively. \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(M\\)\u003c/span\u003e\u003c/span\u003e and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(V\\)\u003c/span\u003e\u003c/span\u003e represent the mass of nanoparticles and the volume of MEX.HCl standard solution respectively. Triplicate runs were carried out to determine the reproducibility of the analysis result and the standard deviation (SD) was calculated to verify the precision of the analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. \u003cb\u003eDetermining the point of zero charge for TMONPs\u003c/b\u003e\u003c/h2\u003e \u003cp\u003eTo characterize the surface charges of TiO\u003csub\u003e2\u003c/sub\u003e, ZnO and Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e nanoparticles, a titration method was used to determine their individual points of zero charge (PZC) (Balderas-Hernandez et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Taoufik et al. \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The solution ionic strength was set at 1 mM KCl, followed by pH adjustment to several values between 3 and 10 using NaOH or HCl solution (0.1 M). Each solution (10 ml) at a different pH containing 10 mg of nanoparticles was homogenized using ultrasound and then left in a static process for 24 hours at room temperature. The final pH was then measured of each solution. The point of zero charge (PZC) value could then be determined by the point of intersection on the x-axis when ∆pH was plotted versus pH.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6. Binding Kinetics\u003c/h2\u003e \u003cp\u003eThe rate of binding of MEX.HCl to the surface of TMONPs at given experimental conditions was investigated by linear kinetic forms of Lagergren\u0026rsquo;s pseudo-first order (PFO) and pseudo-second order (PSO) models along with intraparticle diffusion model (IPD).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7. Binding Isotherm\u003c/h2\u003e \u003cp\u003eThe relationship of adsorption isotherms at equilibrium is critical to investigate the proposed binding interaction between MEX.HCl and the surface of TMONPs. There are several equilibrium models that have been developed to describe this relationship. In this study, we used linear forms of Freundlich and Langmuir models. OriginPro software was used for fitting the experimental data and calculating linear kinetic and isotherm parameters.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.8. Error analysis\u003c/h2\u003e \u003cp\u003eError analysis functions such as the sum of the squares of the errors (SSE) was used in order to evaluate the linear isotherm and kinetic models. The objective was to minimize the SSE between the experimental and calculated values of the dependent variable in the binding experiments. The value of SSE was calculated using this\u003cdiv id=\"Equc\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equc\" name=\"EquationSource\"\u003e\n$$SSE= \\sum _{i=1}^{n}({q}_{e, exp }- {q}_{e, cal}{)}^{2} \\left(4\\right)$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003ewhere \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({q}_{e, exp }\\)\u003c/span\u003e\u003c/span\u003e and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({q}_{e, calc }\\)\u003c/span\u003e\u003c/span\u003e are the experimental and the calculated values of binding at equilibrium (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({ \\text{C}}_{e}\\)\u003c/span\u003e\u003c/span\u003e) of MEX.HCl, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(n\\)\u003c/span\u003e\u003c/span\u003e represented the number of data points during the experiments.\u003c/p\u003e \u003cp\u003eIt should be emphasized that the smaller the error values, the better the predictive models performance, indicating that there is an agreement between the experimental and calculated data, and the more the model becomes favourable.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results And Discussion","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Binding of MEX.HCl to TMONPs\u003c/h2\u003e \u003cp\u003eMEX.HCl contains an amino group, a hydrocarbon chain, a phenoxy moiety, and two methyl groups. The basic amino group (-NH\u003csub\u003e2\u003c/sub\u003e) is able to accept protons under low pH conditions (Bizi and el Bachra \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). At pH 7.2, the amino group in the MEX.HCl salt exists as its conjugate acid (a protonated ammonium ion, -NH\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e+\u003c/sup\u003e) as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The phenoxy moiety, of crucial importance for biological activity, can mimic amino acid residues forming hydrogen bonds (Kozyra and Pitucha \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIt was hypothesized that Ti(IV), Co(II)/Co(III), and Zn(II) atoms present on the surface of TMONPs were capable of binding with MEX.HCl and its conjugate acid (MEX.H\u003csup\u003e+\u003c/sup\u003e) through hydrogen bonding, coordinate bonding, and electrostatic interaction. The first two interactions occur in both MEX.HCl and MEX.H\u003csup\u003e+\u003c/sup\u003e through the nitrogen atom of amino and the oxygen atom of phenoxy electron-donating groups. On the other hand, electrostatic interaction exist between the positive charge of MEX.H\u003csup\u003e+\u003c/sup\u003e and the negative charge of TMONPs. It was reported that the pK\u003csub\u003ea\u003c/sub\u003e of MEX.H\u003csup\u003e+\u003c/sup\u003e is 9.5 (Zhu et al. \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Notably, the surface charge on TMONPs is governed by the solution pH relative to their PZC value. The PZC of TiO\u003csub\u003e2\u003c/sub\u003e was determined to be 6.7 (Tabish et al. \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Hence TiO\u003csub\u003e2\u003c/sub\u003e carries a positive charge at a pH lower than the PZC and becomes negative at a pH higher than the PZC as shown in the chemical equilibrium expressions below.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIf pH\u0026thinsp;\u0026lt;\u0026thinsp;PZC: TMONP\u0026thinsp;+\u0026thinsp;H\u003csup\u003e+\u003c/sup\u003e \u0026harr; TMONPH\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIf pH\u0026thinsp;\u0026gt;\u0026thinsp;PZC: TMONP\u0026thinsp;+\u0026thinsp;OH\u003csup\u003e\u0026minus;\u003c/sup\u003e \u0026harr; TMONP \u003csup\u003e\u0026minus;\u003c/sup\u003e + H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eHowever, the amount of positive or negative charges on the surface of TMONPs varies according to the deviation of solution pH from the PZC. The % bindings of MEX.HCl to TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO determined by our own experiments are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe results indicated that MEX.HCl can bind to TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles in alkaline, neutral and acidic solutions. TiO\u003csub\u003e2\u003c/sub\u003e attained the highest % binding compared to Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO at all three solution pH levels. At pH 5.1, mainly MEX.H\u003csup\u003e+\u003c/sup\u003e (15 mg/L) bound to TiO\u003csub\u003e2\u003c/sub\u003e up to 46\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5%, which is higher than 34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2% for Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and 23\u0026thinsp;\u0026plusmn;\u0026thinsp;1% for ZnO. According to the pK\u003csub\u003ea\u003c/sub\u003e and PZC values, MEX.H\u003csup\u003e+\u003c/sup\u003e bind to TiO\u003csub\u003e2\u003c/sub\u003e nanoparticles mainly due to hydrogen bonding and coordinate bonding. Importantly, the binding of MEX.H\u003csup\u003e+\u003c/sup\u003e to TiO\u003csub\u003e2\u003c/sub\u003e increased to 57\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2% at pH 7.2 and reached 81\u0026thinsp;\u0026plusmn;\u0026thinsp;1% at pH 9.4. At pH 7.2 the surface charge of TiO\u003csub\u003e2\u003c/sub\u003e becomes slightly negative which may enhance the electrostatic interaction with the positively charged MEX.H\u003csup\u003e+\u003c/sup\u003e in addition to hydrogen bonding and coordinate bonding. At pH 9.4, the surface of TiO\u003csub\u003e2\u003c/sub\u003e becomes more negatively charged, thus enhancing the electrostatic attraction to MEX.H\u003csup\u003e+\u003c/sup\u003e and resulting in the highest binding %.\u003c/p\u003e \u003cp\u003eAlso, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e binds to MEX.H\u003csup\u003e+\u003c/sup\u003e with 34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2% at pH 5.1 and increases in an alkaline medium to reach 64\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1% at pH 9.4. The empirical PZC value of Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e is 7.3, which is higher than the PZC value of TiO\u003csub\u003e2\u003c/sub\u003e, leading to an increase in the amount of positive charge on the Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e surface at pH5. Thus, the electrostatic repulsion between the positively charged conjugate acid ions and the positive H\u003csup\u003e+\u003c/sup\u003e ions on the surface of Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e in an acidic medium lead to a decrease in the binding %. This may be attributed to the synergistic effect of the redox cycle of Co\u003csup\u003e2+\u003c/sup\u003e/Co\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e on the surface of Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e which contributes to an increase in the positive charge and lead to a decrease in the binding % of MEX.H\u003csup\u003e+\u003c/sup\u003e (Fu et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Similar results were shown for the adsorption of pharmaceuticals such as tetracycline.HCl (TEC) (Mohammed and Kareem \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). It was noted that the adsorption process at different pH levels was related to the molecular structure of TEC and the surface charges on the adsorbent surface. Furthermore, the opposite trend was reported for the adsorption of different negatively charged ions of emerging contaminants (atenolol, carbamazepine, ciprofloxacin, diclofenac, gemfibrozil, and ibuprofen) on porous graphene (PG) (Khalil et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). The adsorption was drastically reduced above pH 9.4 due to an increase in the electrostatic repulsion between those negatively charged ions and the PG nano-sheet covered with negative hydroxide ions, as confirmed by both the pK\u003csub\u003ea\u003c/sub\u003e value of TEC and the PZC value for PG (Tabish et al. \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2018\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLast, it was noted that the binding of MEX.H\u003csup\u003e+\u003c/sup\u003e to ZnO was lower in acidic and neutral mediums with 23\u0026thinsp;\u0026plusmn;\u0026thinsp;1% and 27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6% respectively. However, the % binding increased to reach 58\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7% at pH 9 due to increasing the surface negative charge. Similarly, it was reported that the adsorption of asphaltene was lower on the surface of ZnO compared to Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e (Hosseini et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Growing the binding of MEX.HCl onto TMONPs surfaces\u003c/h2\u003e \u003cp\u003eThe relationship between the \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({q}_{e}\\)\u003c/span\u003e\u003c/span\u003e (equilibrium adsorption capacity) values of TMONPs and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({C}_{e}\\)\u003c/span\u003e\u003c/span\u003e (the equilibrium concentration of MEX.HCl in an aqueous solution (monitored over 24 hr in a static adsorption process) is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Increasing the initial concentrations of MEX.HCl in the solution from 15 to 75 mg/L increased the driving force which may enhance the growth of its binding to TMONPs surfaces. The binding of MEX.H\u003csup\u003e+\u003c/sup\u003e onto the surface of TiO\u003csub\u003e2\u003c/sub\u003e starts to grow from 21\u0026thinsp;\u0026plusmn;\u0026thinsp;1 mg/g at pH 5.1 and increases to 28\u0026thinsp;\u0026plusmn;\u0026thinsp;1 mg/g at pH 9.4. Also, the binding of MEX.H\u003csup\u003e+\u003c/sup\u003e grows on the surface of Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e from 14\u0026thinsp;\u0026plusmn;\u0026thinsp;1 mg/g at pH 5.1 to 21\u0026thinsp;\u0026plusmn;\u0026thinsp;2 mg/g at pH 9.4, while ZnO exhibited low growth of binding from 11\u0026thinsp;\u0026plusmn;\u0026thinsp;1 mg/g at pH 5 to 22\u0026thinsp;\u0026plusmn;\u0026thinsp;1 mg/g at pH 9.4 after 24 hr.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Binding Kinetics\u003c/h2\u003e \u003cp\u003eTo explain the binding mechanism, it is useful to investigate the binding rate and the rate-limiting step (mass transfer) in addition to the adsorption capacity of TMONPs. The linear forms of PFO Eq.\u0026nbsp;(5) and PSO Eq.\u0026nbsp;(6) were used to study the kinetics and to determine the rate constant of MEX.HCl binding onto TMONPs.\u003cdiv id=\"Equd\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equd\" name=\"EquationSource\"\u003e\n$$\\text{l}\\text{n} \\left({\\text{q}}_{\\text{e}}-{\\text{q}}_{\\text{t}}\\right)=\\text{l}\\text{n} {\\text{q}}_{\\text{e}}-{\\text{k}}_{1} \\text{t} \\left(5\\right)$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Eque\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Eque\" name=\"EquationSource\"\u003e\n$$\\frac{\\text{t}}{{\\text{q}}_{\\text{t}}}=\\frac{1}{{\\text{k}}_{2} {q}_{e}^{2}}+\\frac{1}{{\\text{q}}_{\\text{e}} }\\text{t} \\left(6\\right)$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003ewhere \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({q}_{e}\\)\u003c/span\u003e\u003c/span\u003e and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({q}_{t}\\)\u003c/span\u003e\u003c/span\u003e (mg/g) are the amount of MEX.HCl adsorbed at equilibrium and at any time prior (t) respectively; \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({k}_{1}\\)\u003c/span\u003e\u003c/span\u003e (min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({k}_{2}\\)\u003c/span\u003e\u003c/span\u003e (g/mg.min) are the PFO and the PSO rate constants respectively. Furthermore, the intra-particle diffusion (IPD) model (Weber-Morris) was used to determine the rate-limiting step and the diffusion mechanism as shown in Eq.\u0026nbsp;(\u003cspan refid=\"Equ1\" class=\"InternalRef\"\u003e7\u003c/span\u003e):\u003cdiv id=\"Equ1\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equ1\" name=\"EquationSource\"\u003e\n$${ \\text{q}}_{\\text{t}}={\\text{k}}_{\\text{i}\\text{d}} \\sqrt{\\text{t}} +\\text{C}$$\u003c/div\u003e\u003cdiv class=\"EquationNumber\"\u003e7\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003ewhere \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({k}_{id}\\)\u003c/span\u003e\u003c/span\u003e is the rate constant of intraparticle diffusion (mg/g.min\u003csup\u003e1/2\u003c/sup\u003e) and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(C\\)\u003c/span\u003e\u003c/span\u003e provides information that is directly proportional to the boundary layer thickness (mg/g) on the diffusion (Uma Maheswari et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). An increase in the value of C indicates an increase in the boundary layer thickness and a decrease in external mass transfer, which in turn led to an increase in internal mass transfer. The values of \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({k}_{id} and C\\)\u003c/span\u003e\u003c/span\u003e can be obtained from the slope and intercept, respectively.\u003c/p\u003e \u003cp\u003eThe kinetics of binding of MEX.HCl to the surface of TMONPs (TiO\u003csub\u003e2\u003c/sub\u003e, ZnO and Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e) and the IPD model plot are worth investigating. Figure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e(a) shows an initial period of 25 min for rapid binding, followed by a subsequent period exceeding 300 min for slow binding. These results suggest different interactions between MEX.HCl molecules and the surface of TMONPs. In the rapid stage, a quantity (q\u003csub\u003et\u003c/sub\u003e) of MEX.HCl interacted strongly with the TMONPs to form a monolayer of adsorbate molecules on each nanoparticle surface. The values of the kinetic parameters, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({R}^{2}\\)\u003c/span\u003e\u003c/span\u003e, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({k}_{1}\\)\u003c/span\u003e\u003c/span\u003e and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({k}_{2}\\)\u003c/span\u003e\u003c/span\u003e are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. After that, adsorption of more MEX.HCl molecules to form a second layer slowed down tremendously due to weak interactions. It took additional molecules a long time to gradually build up a second layer, reaching the quantities (q\u003csub\u003ee,exp\u003c/sub\u003e) of 5.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5, 10.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 and 11.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 mg/g at 324 min, for ZnO, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and TiO\u003csub\u003e2\u003c/sub\u003e respectively. In the rapid stage, the surface of TMONPs provided a large number of strong binding sites for MEX.HCl, resulting in rapid increases of q\u003csub\u003et\u003c/sub\u003e. After formation of a monolayer, binding of more molecules slowed down due to a lack of available binding sites and a larger distance from the nanoparticle surface.\u003c/p\u003e \u003cp\u003eFigures \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e(b) and 5(c) fit the binding data to both PFO and PSO models. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e indicates that the correlation coefficient (R\u003csup\u003e2\u003c/sup\u003e) values from the PSO model are higher than those for the PFO model, and that the calculated values of adsorbed quantity at equilibrium \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({(q}_{e, cal})\\)\u003c/span\u003e\u003c/span\u003e are very similar to the experimental values of adsorbed quantity at equilibrium \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({(q}_{e, exp})\\)\u003c/span\u003e\u003c/span\u003e in the PSO model. Hence, PSO is better model to represent the binding of MEX.HCl to TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles. Furthermore Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e (d) presents a Weber-Morris plot, which shows the linear relationship between q\u003csub\u003et\u003c/sub\u003e and square root of time, for the IPD model. If the straight line passes through the origin, the rate limiting step of the binding process can be attributed only to the intraparticle diffusion process (Campos et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e indicates that the IPD model is suitable for the depiction of experimental data because the R\u003csup\u003e2\u003c/sup\u003e values range from 0.980 to 0.988. However, none of the straight lines pass through the origin. Significant intercept (C) values of 6.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17, 5.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16 and 3.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.098 (mg/g) were obtained in the order of TiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;ZnO, which is in agreement with their corresponding intraparticle diffusion rate (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({k}_{id}\\)\u003c/span\u003e\u003c/span\u003e) values of 0.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u0026thinsp;\u0026gt;\u0026thinsp;0.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u0026thinsp;\u0026gt;\u0026thinsp;0.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01. These trends suggest that MEX.H\u003csup\u003e+\u003c/sup\u003e bound to the internal surfaces of TMONPs and the rate limitting step consisted of intra-particle diffusion (Pholosi et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). The IPD model assumes that mass transfer is due to diffusion of MEX.HCl molecules within the pores of TMONPs (Campos et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2018\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \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\u003eDetermined parameters and error analysis for kinetic and intra-particle diffussion models for binding of 20 mg/L MEX.HCl to TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles at room temperature at pH 9.4. Standard deviations of slope and y-intercept were used to determine uncertainties. SSE was used to show the fitness of the model.\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModel\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eq\u003csub\u003ee,exp\u003c/sub\u003e (mg/g)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eq\u003csub\u003ee,calc\u003c/sub\u003e (mg/g)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ek\u003csub\u003e1\u003c/sub\u003e(min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e),\u003c/p\u003e \u003cp\u003ek\u003csub\u003e2\u003c/sub\u003e (g/mg.min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSSE\u003c/p\u003e \u003cp\u003e(mg\u003csup\u003e2\u003c/sup\u003e/g\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eTiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePFO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e11.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.014\u0026thinsp;\u0026plusmn;\u0026thinsp;0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.882\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.540\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0 x 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.330\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eCo\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePFO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e10.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u0026thinsp;\u0026plusmn;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.898\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.591\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.005\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 x 10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.991\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.160\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eZnO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePFO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e5.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.009\u0026thinsp;\u0026plusmn;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.912\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.598\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.007\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2 x 10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.996\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.350\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 \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\u003eIntra-particle diffusion kinetic parameters for binding of 20 mg/L MEX.HCl to TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles at room temperature at pH 9.4.\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMONPs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eIntra-particle diffusion\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({k}_{id}\\)\u003c/span\u003e\u003c/span\u003e (mg/g.min\u003csup\u003e1/2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC (mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSSE (mg\u003csup\u003e2\u003c/sup\u003e/g\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.988\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCo\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.985\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZnO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.980\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Affinity of Surface TMONPs to MEX.HCl\u003c/h2\u003e \u003cp\u003eBinding affinity measures the strength, and hence extent, of binding between the adsorbent and the adsorbate. Binding affinity values at equilibrium readily imparts a better understanding of the adsorption process for potential improvement of the adsorption pathway (Ayawei et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). The Freundlich and Langmuir isotherms were used to evaluate the binding affinity between TMONPs and MEX.HCl. The Freundlich adsorption isotherm (Eq.\u0026nbsp;\u003cspan refid=\"Equ2\" class=\"InternalRef\"\u003e8\u003c/span\u003e) is an empirical model that assumes the involvement of binding sites on a heterogeneous surface with different adsorption energies.\u003cdiv id=\"Equ2\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equ2\" name=\"EquationSource\"\u003e\n$$Log {q}_{e}=log {K}_{f}+ \\frac{1}{n} log {C}_{e}$$\u003c/div\u003e\u003cdiv class=\"EquationNumber\"\u003e8\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003ewhere \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({K}_{f}\\)\u003c/span\u003e\u003c/span\u003e measures the binding capacity of adsorbent (TMONPs) and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\frac{1}{n}\\)\u003c/span\u003e\u003c/span\u003e measures the binding affinity for adsorbate (MEX.HCl) that varies with changes in adsorption density. Higher \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(n\\)\u003c/span\u003e\u003c/span\u003e values indicate stronger adsorbate/adsorbent affinities and larger distributions of adsorbate over the adsorbent surface (Liu \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). On the other hand, the Langmuir adsorption isotherm (Eq.\u0026nbsp;9) assumes a monolayer of adsorbate binding to an adsorbent surface that possesses identical or energetically equivalent sites.\u003cdiv id=\"Equf\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equf\" name=\"EquationSource\"\u003e\n$$\\frac{1}{{q}_{e}}=\\frac{1}{{q}_{max}}+ \\frac{1}{{K}_{L} {q}_{max}} \\frac{1}{{C}_{e}} \\left(9\\right)$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003ewhere \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({K}_{L}\\)\u003c/span\u003e\u003c/span\u003e (l/mg) is the Langmuir isotherm constant, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({q}_{e}\\)\u003c/span\u003e\u003c/span\u003e (mg/g) is the amount adsorbed per gram of adsorbent, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({C}_{e}\\)\u003c/span\u003e\u003c/span\u003e(mg/l) is the adsorbate concentration at equilibrium, and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({q}_{max}\\)\u003c/span\u003e\u003c/span\u003e (mg/g) is the maximum amount of MEX.HCl that can be adsorbed per gram of adsorbent.\u003c/p\u003e \u003cp\u003eThe Freundlich isotherms for TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles at pH 5.1, pH 7.2 and pH 9.4 are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. The data of \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({log C}_{e}\\)\u003c/span\u003e\u003c/span\u003e versus \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({log q}_{e}\\)\u003c/span\u003e\u003c/span\u003e fitted well with the Freundlich equation based on both the good R\u003csup\u003e2\u003c/sup\u003e values (in the range of 0.981\u0026ndash;0.993) and the low SSE values (in the range of 2x10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e-5x10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e) in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({K}_{f}\\)\u003c/span\u003e\u003c/span\u003e results, which represent the adsorption capacities for MEX.HCl, increased with higher pH levels in the order of pH 5.1\u0026thinsp;\u0026lt;\u0026thinsp;pH 7.2\u0026thinsp;\u0026lt;\u0026thinsp;pH 9.4 for TMONPs. At pH 9.4, the \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({K}_{f}\\)\u003c/span\u003e\u003c/span\u003e value reached 8.9 mg/g for TiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;5.38 mg/g for Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;3.47 mg/g for ZnO. The \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(n\\)\u003c/span\u003e\u003c/span\u003e results, which represent the affinity of TMONPs for MEX.HCl, also increased with higher pH levels in the order of pH 5.1\u0026thinsp;\u0026lt;\u0026thinsp;pH 7.2\u0026thinsp;\u0026lt;\u0026thinsp;pH 9.4. At pH 9.4, the n value reached 3.3 for TiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;2.7 for Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;2.1 for ZnO. All these results indicate binding of MEX.HCl molecules with a distribution of heterogenous sites on the surface of each TMONP as controlled by a physisorption mechanism.\u003c/p\u003e \u003cp\u003eThe Langmuir isotherm model was next tested by plotting \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(1/{q}_{e}\\)\u003c/span\u003e\u003c/span\u003e versus \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(1/{C}_{e}\\)\u003c/span\u003e\u003c/span\u003e in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e. Data fitting in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e for TiO\u003csub\u003e2\u003c/sub\u003e nanoparticles produced reasonable R\u003csup\u003e2\u003c/sup\u003e values (in the range of 0.958 to 0.991) but high SSE values (in the range of 9x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e to 3x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e). Their maximum capacity (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({q}_{max}\\)\u003c/span\u003e\u003c/span\u003e) results increased from 24.3 mg/g at pH5 to 27.9 mg/g at pH9. By comparison, the \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({q}_{max}\\)\u003c/span\u003e\u003c/span\u003e results for Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles increased from 19.8 to 26.4 mg/g and from 19.5 to 25.2 mg/g respectively. The best binding capacity for MEX.HCl is again provided by TiO\u003csub\u003e2\u003c/sub\u003e nanoparticles. Taking both isotherm models together, our interpretation of all results is that MEX.HCl binding forms a monolayer of adsorbate molecules on the TMONP surface that possesses identical or energetically equivalent site, followed by accumulation of additional molecules on the heterogeneous surface with different adsorption energies. This proposed mechanism is similar to the adsorption of Cu(II) onto the surface of Biochar composites (Hussain et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \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\u003eFreundlich parameters for adsorption of MEX.HCl onto TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4. [MEX.HCl]\u003csub\u003e0\u003c/sub\u003e = 15, 30, 45, 60 and 75 mg/L.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eTiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eCo\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c13\" namest=\"c10\"\u003e \u003cp\u003eZnO\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eK\u003csub\u003ef\u003c/sub\u003e (mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSSE\u003c/p\u003e \u003cp\u003e(mg\u003csup\u003e2\u003c/sup\u003e/g\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eK\u003csub\u003ef\u003c/sub\u003e (mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1/n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSSE\u003c/p\u003e \u003cp\u003e(mg\u003csup\u003e2\u003c/sup\u003e/g\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eK\u003csub\u003ef\u003c/sub\u003e (mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1/n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eSSE\u003c/p\u003e \u003cp\u003e(mg\u003csup\u003e2\u003c/sup\u003e/g\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.590\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.590\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8x10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.640\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.992\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.460\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5x10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.550\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.991\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.995\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.981\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2x10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.370\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.997\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1x10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.480\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e\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 \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\u003eLangmuir parameters for adsorption of MEX.HCl onto TiO\u003csub\u003e2\u003c/sub\u003e, ZnO and Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4. [MEX.HCl]\u003csub\u003e0\u003c/sub\u003e = 15, 30, 45, 60 and 75 mg/L.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eTiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eCo\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c13\" namest=\"c10\"\u003e \u003cp\u003eZnO\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eK\u003csub\u003eL\u003c/sub\u003e (L/mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eq\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSSE\u003c/p\u003e \u003cp\u003e(mg\u003csup\u003e2\u003c/sup\u003e/g\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eK\u003csub\u003eL\u003c/sub\u003e (L/mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eq\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSSE\u003c/p\u003e \u003cp\u003e(mg\u003csup\u003e2\u003c/sup\u003e/g\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eK\u003csub\u003eL\u003c/sub\u003e (L/mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eq\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eSSE\u003c/p\u003e \u003cp\u003e(mg\u003csup\u003e2\u003c/sup\u003e/g\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.958\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e19.775\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.994\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e19.479\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.911\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1x10\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.987\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.979\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e22.843\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.956\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e6x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.991\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26.349\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.925\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e25.214\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.971\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e6x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Favorability of the Binding Process\u003c/h2\u003e \u003cp\u003eThus far, the binding isotherm fitted well with the Freundlich model, and the binding kinetics obeyed the PSO model involving IPD. Both findings suggest physicochemical adsorption of MEX molecules on heterogeneous TMONP surfaces (Jiang et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Favourable binding of MEX.HCl to TMONPs is indicated by both the Freundlich \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\frac{1}{n}\\)\u003c/span\u003e\u003c/span\u003e value and the Langmuir separation factor (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({R}_{L}\\)\u003c/span\u003e\u003c/span\u003e) value (Hussain et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). The binding process is favorable when 0 \u0026lt; \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({R}_{L}\\)\u003c/span\u003e\u003c/span\u003e \u0026lt; 1, or unfavorable when \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({R}_{L}\u0026gt;1\\)\u003c/span\u003e\u003c/span\u003e. \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({R}_{L}\\)\u003c/span\u003e\u003c/span\u003e is a dimensionless parameter that can be calculated:\u003cdiv id=\"Equg\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equg\" name=\"EquationSource\"\u003e\n$${R}_{L}=\\frac{1}{{(1+\\text{K}}_{\\text{L}} {C}_{0})} \\left(9\\right)$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003ewhere \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({\\text{K}}_{\\text{L}}\\)\u003c/span\u003e\u003c/span\u003e is the Langmuir constant (mg/g) and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({C}_{0}\\)\u003c/span\u003e\u003c/span\u003e is the initial concentration of MEX.HCl (mg/L).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure 8 presents three plots of R\u003csub\u003eL\u003c/sub\u003e versus the initial concentrations of MEX.HCl at different pH levels. Obviously all the R\u003csub\u003eL\u003c/sub\u003e values for TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles fall between 0 and 1, indicating the favourable binding of MEX.HCl onto the TMONPs.\u003c/p\u003e \u003cp\u003eSeparation factor calculated from Langmuir isotherms versus [MEX.HCl]\u003csub\u003e0\u003c/sub\u003e for binding onto (a) TiO\u003csub\u003e2\u003c/sub\u003e, (b) Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and (c) ZnO nanoparticles at room temperature at pH 5.1, pH 7.2 and pH 9.4. [MEX.HCl]\u003csub\u003e0\u003c/sub\u003e = 15, 30, 45, 60 and 75 mg/L.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.6. Binding mechanism of MEX.HCl\u003c/h2\u003e \u003cp\u003eAs suggested above, the mechanism of MEX.HCl binding to the TMONPs was based on the pK\u003csub\u003ea\u003c/sub\u003e value and the molecular structure of MEX.HCl versus the surface charge of TMONPs at the three pH levels studied. MEX.HCl (with pK\u003csub\u003ea\u003c/sub\u003e 9.5) and the TMONPs (TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e, and ZnO with PZC of 6.7, 7.2 and 7.6 respectively) would carry different charges in the solution due to protonation-deprotonation processes (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e9\u003c/span\u003e). Optimal binding occurred at pH 9.4 where MEX.H\u003csup\u003e+\u003c/sup\u003e acts as the conjugate acid with a slight positive charge and the surface of each TMNOP bears a negative charge. This strongly suggests that the adsorption mechanism may involve electrostatic interaction between the negative OH\u003csup\u003e\u0026minus;\u003c/sup\u003e groups on the TMONP surface and the positive charge of MEX.H\u003csup\u003e+\u003c/sup\u003e. Furthermore, hydrogen bonding between the amino/phenoxy group of MEX.HCl and the oxide/hydroxide group of TMONP may also contribute to the overall binding mechanism. Also, the binding may occur by electrostatic interaction between the negative surface of TMONPs -O\u003csup\u003e\u0026minus;\u003c/sup\u003e and the protonated ammonium ion of MEX.HCl at different pHs as shown by the following equations:\u003cdiv id=\"Equh\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equh\" name=\"EquationSource\"\u003e\n$$TMON{P}_{s}-{O}^{-}+ {H}^{+}-MEX \\underrightarrow{Electrostatic attraction} TMONPs-{O}^{-} {H}^{+}-MEX \\left(10\\right)$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equi\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equi\" name=\"EquationSource\"\u003e\n$$TMON{P}_{s}-OH+{NH}_{2}-MEX \\underrightarrow{Hydrogen bonding} TMONPs-OH\\dots . {NH}_{2}-MEX \\left(11\\right)$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equj\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equj\" name=\"EquationSource\"\u003e\n$$TMON{P}_{s}-OH+OR-MEX \\underrightarrow{Hydrogen bonding} TMONPs-OH\\dots .OR-MEX \\left(12\\right)$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.7. Conclusion\u003c/h2\u003e \u003cp\u003eCapillary electrophoresis was used to investigate at room temperature the binding of MEX.HCl onto TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles at different pH levels. Alkaline water at pH 9.4 led to efficient binding of MEX molecules, at 81\u0026thinsp;\u0026plusmn;\u0026thinsp;1%, 64\u0026thinsp;\u0026plusmn;\u0026thinsp;2% and 58\u0026thinsp;\u0026plusmn;\u0026thinsp;2% for TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO respectively. The time-based binding data was best fitted with a pseudo second-order kinetic model with \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({\\text{q}}_{\\text{e}, \\text{c}\\text{a}\\text{l}}\\)\u003c/span\u003e\u003c/span\u003e values similar to \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({\\text{q}}_{\\text{e}, \\text{e}\\text{x}\\text{p}}\\)\u003c/span\u003e\u003c/span\u003e results, which suggests MEX.HCl binding through a physicochemical adsorption. Investigation of rate-limiting steps by the IPD model revealed that MEX.H\u003csup\u003e+\u003c/sup\u003e binding occurred also within the internal surface of porous TMONPs, in the order of TiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;ZnO. Although both the Freundlich and Langmuir models contribute to the binding affinity of MEX.HCl on TMONP surfaces, the former model showed better fitting with higher R\u003csup\u003e2\u003c/sup\u003e values and lower SSE uncertainties. It can be concluded that MEX.HCl molecules bind to heterogenous sites on TMONPs mainly under the control of physisorption. The binding capacity (q\u003csub\u003emax\u003c/sub\u003e) was maximal at pH 9.4, following the order of 27.0\u0026thinsp;\u0026gt;\u0026thinsp;26.4\u0026thinsp;\u0026gt;\u0026thinsp;25.2 mg/g for TiO\u003csub\u003e2,\u003c/sub\u003e Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO respectively. The small R\u003csub\u003eL\u003c/sub\u003e values, at different pH levels, confirmed favorable binding of MEX.HCl onto the studied TMONPs, mainly accomplished via electrostatic interaction and hydrogen bonding.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish\u003c/strong\u003e All the authors agreed to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEdward Lai: conceptualisation, resources, review \u0026amp; editing, supervision, project administration, funding acquisition.\u003c/p\u003e\n\u003cp\u003eEman Elmorsi: investigation, visualisation, methodology, formal analysis, writing original draft, review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge support from the Natural Sciences and Engineering Research Council of Canada (NSERC) RGPIN-2018-05320 for the financial support of this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eInterests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAdelantado C, Zougagh M, R\u0026iacute;os \u0026Aacute; (2022) Contributions of capillary electrophoresis in analytical nanometrology: a critical view. 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J Clean Prod 143:401\u0026ndash;412. https://doi.org/10.1016/j.jclepro.2016.12.094\u003c/li\u003e\n \u003cli\u003eTran, Tran (2019) Nanoconjugation and encapsulation strategies for improving drug delivery and therapeutic efficacy of poorly water-soluble drugs. Pharmaceutics 11:325. https://doi.org/10.3390/pharmaceutics11070325\u003c/li\u003e\n \u003cli\u003eUma Maheswari B, Sivakumar VM, Thirumarimurugan M (2022) Synthesis of novel nanobioadsorbent for the effective removal of Pb\u003csup\u003e2+\u003c/sup\u003e and Zn\u003csup\u003e2+\u003c/sup\u003e ions\u0026mdash;adsorption, equilibrium, modeling, and optimization studies. In: Nano-Biosorbents for Decontamination of Water, Air, and Soil Pollution. Elsevier, pp 503\u0026ndash;528\u003c/li\u003e\n \u003cli\u003eWiedmann TS, Naqwi A (2016) Pharmaceutical salts: theory, use in solid dosage forms and in situ preparation in an aerosol. Asian J Pharm Sci 11:722\u0026ndash;734. https://doi.org/10.1016/j.ajps.2016.07.002\u003c/li\u003e\n \u003cli\u003eZhu W, Mazzanti A, Voelker TL, et al (2019) Predicting patient response to the antiarrhythmic mexiletine based on genetic variation. Circ Res 124:539\u0026ndash;552. https://doi.org/10.1161/CIRCRESAHA.118.314050 \u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"binding affinity, isotherm, kinetics, transition metal oxide nanoparticles, mexiletine hydrochloride, capillary electrophoresis, active pharmaceutical ingredients","lastPublishedDoi":"10.21203/rs.3.rs-2344386/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2344386/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe binding affinity of pharmaceutical salts to metal oxide nanoparticles is a fundamental environmental process that determines their transport and bioavailability. Mexiletine hydrochloride (MEX.HCl) interactions with different transition metal oxide nanoparticles (TMONPs) in aqueous dispersion were evaluated by capillary electrophoresis to determine their binding affinities. The results indicated that MEX.HCl bound onto TiO\u003csub\u003e2\u003c/sub\u003e, Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles in alkaline, neutral and acidic pH levels. Interestingly, TiO\u003csub\u003e2\u003c/sub\u003e manifested the highest binding affinity of 81\u0026thinsp;\u0026plusmn;\u0026thinsp;1% at pH 9.4. It was shown that higher initial concentrations of MEX.HCl in an aqueous solution, increasing from 15 to 75 \u0026micro;g/mL, yielded higher binding affinities for TiO\u003csub\u003e2\u003c/sub\u003e than Co\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e and ZnO nanoparticles. The binding rate followed pseudo-second-order kinetics and the binding data were better modeled by the Freundlich isotherm than the Langmuir isotherm. These findings revealed that MEX.HCl binding occurred on the heterogeneous binding sites on TMONPs mainly by the physisorption mechanism via electrostatic attraction and hydrogen bonding.\u003c/p\u003e","manuscriptTitle":"Investigation of Mexiletine Hydrochloride Binding on Transition Metal Oxide Nanoparticles by Capillary Electrophoresis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-12 21:22:14","doi":"10.21203/rs.3.rs-2344386/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":"b82bf6e0-a37a-4e9f-8e5e-31149b82a11a","owner":[],"postedDate":"January 12th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-02-22T15:05:41+00:00","versionOfRecord":[],"versionCreatedAt":"2023-01-12 21:22:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2344386","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2344386","identity":"rs-2344386","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}