Effect of Organic Additives on the Phase Separation Phenomenon of Amphiphilic Drug Solutions

The effect of various organic additives, viz. sugars, ureas, alcohols, hydrotropes and bile salts on the clouding (phase separation) phenomenon of the amphiphilic antidepressant drug amitriptyline hydrochloride was investigated in the present study. All sugars lowered the cloud point (CP) due to their water structure-making property. Urea and alkylureas were found to lower the CP. In contrast, thioureas increased the CP slightly, but the presence of methyl group(s) had a similar effect in alkylureas. Short chain alcohols affected the CP insignificantly while higher ones decreased it, and medium chain alcohols showed peak behavior. Addition of hydrotropes and bile salts increased the CP at lower concentrations, while a decrease was observed at higher concentrations (like the medium chain alcohols). In addition, thermodynamic parameters were also evaluated but only for those additives which formed mixed micelles with the drug.     

Organic Additives and Electrolytes as Cloud Point Modifiers in Octylphenol Ethoxylate Solutions

Cloud point measurements of nonionic surfactant Triton X-100, an octylphenol ethoxylate, were carried out in the absence and presence of various organic additives such as n-alkanols (methanol, ethanol, propanol and butanol), glycols (ethylene glycol, diethylene glycol and triethylene glycol), glycol ethers (ethylene glycol monomethyl ether, ethylene glycol monoethyl ether and ethylene glycol monobutyl ether (EGMBE)) and electrolytes (LiCl, KCl, NaF, NaCl, NaBr, NaI, MgCl₂ and AlCl₃). The combined effect of these organic additives and electrolytes on cloud point (CP) measurement was also investigated. The effect of nature of cation, anion and valency of cation on CP is also reported. Among the n-alkanols and glycol ethers as additives, n-butanol and EGMBE were found to decrease the CP while all other additives increase the cloud point. The addition of electrolytes (LiCl, NaCl and KCl) to the solution of Triton X-100 (TX-100) decreases the CP but the rate of decrease in CP with concentration does not follow the lyotropic series of effect. Sodium halides (except NaI) also decrease the CP and the rate of decrease follows the lyotropic series of effect even in the presence of organic additives. NaI is a water structure breaker, hence it increases the cloud point. Further, cations of increasing valency lessen the depression in CP of TX-100 with the rate of decrease in CP following the order Na⁺ > Mg²⁺ > Al³⁺ even in the presence of organic additives.

Effect of different additives on the cloud point of a polyethylene oxide-polypropylene oxide-polyethylene oxide block copolymer in aqueous solution

Cloud point studies on aqueous solutions of a polyethylene oxide (PEO)-polypropylene oxide-PEO triblock copolymer (Pluronic^® L64: EO₁₃PO₃₀EO₁₃, total m.w.=2900, PEO=40%; EO=ethylene oxide; PO=propylene oxide) in the presence of different additives show some interesting features. The effect of various inorganic salts was an increase or decrease in cloud point based on their salting in and salting out action and followed the Hofmeister lyotropic series. Nonelectrolytes and hydrotropes increased the cloud point by influencing water structure. Hydrotropes altered the cloud point of the copolymer at much lower concentrations than inorganic salts. Ionic surfactants produced a marked increase in the cloud point of copolymer solutions. The effect was greater for surfactants with greater hydrophobicity. Alcohols and other organic liquid additives that are infinitely miscible with water increase the cloud point of the copolymer, whereas additives that are partially miscible in water decrease the cloud point.     

Quaternary salts as solubilization site modifiers of organic compounds in anionic micellar solutions

The effects of the addition of different salts (quaternary bromides or NaBr) on the viscosity (measured under Newtonian flow conditions) of sodium dodecylbenzenesulfonate (SDBS) micellar solutions were studied at 30°C. Tetra-n-butylammonium bromide (Bu₄NBr) was found most effective in increasing the viscosity (due to possible change in micellar shape) at fairly low SDBS concentration (50 mM). The effectiveness of Bu₄NBr may be due to the presence of four butyl chains and to the positive charge on its counterion (Bu₄N⁺) which can subsequently interact with anionic SDBS micelles electrostatically as well as hydrophobically; owing to solubility/steric problems, other salts were ineffective. Organic additives such as cyclohexylamine and cyclohexanol had marginal effects on viscosity when added to 50 mM SDBS solutions having no Bu₄NBr. However, in the presence of Bu₄NBr, the effect was dependent on salt concentration and the nature of the additive. The overall effect is discussed on the basis of change in the solubilization site of the additive in the presence of Bu₄NBr.     

Thermodynamic parameters of amitriptyline hydrochloride–additives at cloud point: effects of the ethanol–water mixed media

Abstract

Addition of organic solvents is known to change the properties of amphiphiles through modification of bulk phase. Amitriptyline hydrochloride (AMT) is a tricyclic amphiphilic drug which is usually used as an antidepressant. In drug delivery, the cloud point (CP) of the drug is an important parameter. This article discusses the effects of ethanol–water (EtOH–WR) compositions on the energetic parameters, such as changes in Gibbs energy of clouding (Δ_sG⁰), enthalpy of clouding (Δ_sH⁰), and entropy of clouding (TΔ_sS⁰) of AMT-additive systems. Monovalent alkali halide salts, cationic conventional surfactants, and gemini surfactants were used as additives in the EtOH–WR mixed media whose compositions were varied between 0 and 15% (w/w). The Δ_sG⁰ values are positive for all the additives and the values decrease with the rise in mole fractions of the additives. The Δ_sH⁰ and TΔ_sS⁰ were noted to be positive except for KF in 15% EtOH–WR mixed media.     

Role of quaternary bromides in changing the solubilization site of <Emphasis Type="Italic">n</Emphasis>-heptylamine in cationic micellar solutions

Newtonian flow conditions were adopted to take viscosity measurements at 30°C of solutions of cationic surfactants (cetyltrimethylammonium bromide, C₁₆TAB, and tetradecyltrimethylammonium bromide, C₁₄TAB) with the addition of n-heptylamine (C₇NH₂) and quaternary salts (tetra-n-propylammonium bromide, Pr₄NBr; tetra-n-butylammonium bromide, Bu₄NBr; tetraamylammonium bromide, Am₄NBr; tetra-n-octylammonium bromide, Oc₄NBr; tetra-n-butylphosphonium bromide, Bu₄PBr; tetraphenylphosphonium bromide, Φ₄PBr; n-propyltriphenylphosphonium bromide, PrΦ₃PBr₃) by having either a fixed C₇NH₂ or salt concentration and varying the other. Systems containing a comparatively higher Bu₄NBr content showed a dramatic decrease in viscosity at higher C₇NH₂ concentration. Further, the viscosity-salt concentration profiles of 0.1 M C₁₆TAB solutions containing fixed C₇NH₂ concentrations showed a peaked behavior. The peak positions and salt contents at the peaks were dependent on the length of the alkyl part of the particular salt and the connecting atom (N or P) but independent of the nature of the surfactant and C₇NH₂ concentration. The behavior is discussed in the light of a change in the solubilization site of C₇NH₂ caused by the presence of quaternary salts. Cavities in the quaternary salts present in the bulk solvent are proposed to be the new sites of solubilization.     

Co-nonsolvency effects in the thermoprecipitation of oligomeric polyacrylamides from hydro-organic solutions

Co-solutes and co-solvents influence the thermoprecipitation of stimulus-responsive polymers from aqueous solution. Taking the behavior of oligomeric poly-(N-isopropylacrylamide) prepared by chain transfer polymerization as reference, the influence of organic solvents (concentration <2 M) on the thermoprecipitation of polyacrylamides with critical solution temperatures (CST) in pure water between 30 and 75 °C is investigated using turbidity and differential scanning calorimetry. Depending on the system, both increase and decrease but also the disappearance of the CST is observed. The strength of the observed effect is related not only to the size but also the structure of the hydrophobic domain of the solvent molecule. Contrary to the effects observed upon the addition of simple salts as additives, the chemistry of the investigated polyacrylamide is of direct consequence for the effect of a given solvent. Certain parallels can hence be drawn to the behavior previously observed for additives such as anionic surfactants and alkylamines.     

Micellar association in simultaneous presence of organic salts/additives

Viscosity measurements under Newtonian flow conditions had been performed on cetyltrimethylammonium bromide (CTAB) aqueous solutions in the combined presence of sodium salts of aromatic acids (sodium salicylate, NaSal; sodium benzoate, NaBen; sodium anthranilate, NaAn) and organic additives (1-hexanol, C₆OH; n-hexylamine, C₆NH₂) at 30°C. On addition of C₆OH or C₆NH₂, the viscosity of 25 mM CTAB solution remained nearly constant without salt as well as with a lower salt concentration. This is due to low CTAB concentration which is not sufficient to produce structural changes in this concentration range of salts. However, as the salt concentration was increased further, the effect of C₆OH/C₆NH₂ addition was different with different salts: The viscosity first increased; then a decrease was observed with the former while with C₆NH₂ a decrease followed by constancy appeared in plots of relative viscosities (η _r ) vs. organic additive concentrations. At further higher salt concentration, the magnitude of η _r was much higher. The viscosity increase is explained in terms of micellar growth and the decrease in terms of swollen micelle formation (due to interior solubilization of organic additive) or micellar disintegration (due to formation of water + additive pseudophase).     

Effect of water‐miscible solvents on the organic solvent‐resistant tyrosinase from Streptomyces sp. REN‐21

The effect of various water‐miscible organic solvents (ethanol, methanol, acetone, acetonitrile, N,N‐dimethylformamide (DMF) and dimethylsulfoxide (DMSO)) on the kinetics of 4‐tert‐butylcatechol (tBC) oxidation in the presence of different samples of organic solvent‐resistant tyrosinase (OSRT) has been studied. In contrast to mushroom tyrosinase the enzyme shows a high relative stability in solutions of organic solvents and increased activity toward the bulky and hydrophobic substrate, tBC, in respect to catechol. Rates of the studied OSRT‐catalyzed reactions are however reduced by the presence of organic solvents and for all studied samples of OSRT decrease exponentially with the content of an organic solvent. The effect has been satisfactorily described by the effect of organic solvents on the thermodynamic activity of tBC. The correlation of the inhibition parameters with the hydrophobicity of a particular solvent (log P), its intrinsic molar volume, V_i, and the Dimroth–Reichardt parameter, E_T(30), are shown. The results allow also the prediction of OSRT activity in aqueous solutions of water‐miscible organic solvents. Copyright © 2003 Society of Chemical Industry     

Tuning of the Cloud Point of Promethazine Hydrochloride with Surfactants and Polymers

The effect of additives (surfactants and polymers) and pH on the clouding behavior of promethazine hydrochloride (PMT, a phenothiazine drug) was investigated. Cloud point (CP) decreases with increase in pH due to deprotonation of drug molecules. The same trend occurs in the presence of surfactants. However, at constant pH, and depending on their structure and nature, these additives behave differently. Anionic surfactants show peaked behavior, whereas cationic (conventional as well as geminis) and non-ionic surfactants increase the CP, although the mechanisms differ. Cationic surfactants hinder drug association (due to interaggregate repulsion) resulting in an increase in CP, while non-ionic surfactants form mixed micelles with the drug, increasing micelle hydration and CP. Polymers can cause both a decrease as well as an increase in CP, depending on their molecular weight. A large CP increase (with the increase in surfactant concentration) for gemini surfactants suggests they are excellent candidates for drug delivery.

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Effect of Polar Organic Solvents on Self‐Aggregation of Some Cationic Monomeric and Dimeric Surfactants

Surface and micellization behavior of some cationic monomeric surfactants, viz., cetyldiethylethanolammonium bromide (CDEEAB), cetyldimethylethanolammonium bromide (CDMEAB), tetradecyldiethylethanolammonium bromide (TDEEAB) and dimeric surfactants, i.e., alkanediyl‐α, ω‐bis(dimethylhexadecylammonium bromide) (C₁₆‐s‐C₁₆, 2Br^? where s = 4, 12), butanediyl‐1,4‐bis(dimethyldodecylammonium bromide (C₁₂‐4‐C₁₂, 2Br^?) and 2‐butanol‐1,4‐bis(dimethyldodecylammonium bromide) (C₁₂‐4(OH)‐C₁₂, 2Br^?), was studied in water‐organic solvents [10 and 20 % v/v ethylene glycol (EG) and diethylene glycol (DEG)] by conductivity, surface tension and steady‐state fluorescence methods at 300 K. The main focus of the present work is on the study of the effect of organic solvents on the critical micelle concentration (CMC), Gibbs free energy of micellization (ΔG°_m), Gibbs free energy of transfer (ΔG°_trans), Gibbs adsorption energy (ΔG°_ads) and some interfacial parameters such as the surface excess concentration (Γ_max), minimum area per surfactant molecule (A_min) and surface pressure (π_CMC). The aggregation number (N_agg) and Stern‐Volmer quenching constant (K_SV) were also determined by the steady‐state fluorescence method. It was observed that N_agg decreased with increasing volume percent of organic solvent. The results exhibited an increase in CMC in water‐organic solvents as compared to the respective surfactants in pure water. The negative values of ΔG°_m and ΔG°_ads indicate a spontaneous micellization process. The thermodynamics of micellization revealed that the micellization‐reducing efficiency of glycols increases with the concentration and the number of ethereal oxygens in the glycol.     

Partition Coefficients of Alkyl Parabens and Ibuprofen in Micellar Systems

The partitioning of alkyl parabens and ibuprofen in aqueous solutions of nonionic and ionic surfactants is studied experimentally and via a priori predictions using the COSMO‐RS model. The effects of organic (Bu₄NBr) and inorganic (NaCl) electrolytes are examined. Addition of NaCl results in a slight increase in the partition coefficients of parabens in solutions of octylphenolpoly(ethyleneglycolether) and a more pronounced increase in the sodium dodecyl sulfate (SDS) system. The partition coefficients of ibuprofen increase on addition of NaCl to aqueous solutions of SDS and decrease if Bu₄NBr is added to dodecyl trimethyl ammonium bromide (DTAB) solutions. Good agreement between experimental and calculated data shows a high potential of COSMO‐RS in the prediction of micelle/water partition coefficients in the presence of electrolytes and makes it a valuable tool in drug and drug‐carrier design as well as in optimizing micellar reactions or micelle‐enhanced separation processes.     

Effect of Quaternary Ammonium Salts on Carrier-Mediated Transport of Lanthanide Ions through Cellulose Triacetate Membranes

Abstract

Fluxes of all lanthanides, except promethium, across cellulose triacetate membranes were determined by using mixtures of o-nitrophenyl n-octyl ether and quaternary ammonium salts as plasticizers, and 4-benzoyl-3-methyl-1-phenyl-5-pyrazolone (BMPP) and 4-trifluoroacetyl-3-methyl-1-phenyl-5-pyrazolone (TMPP) as carriers. The quaternary ammonium salts used were didodecyldimethyl-, distearyldimethyl-, tetrahexyl-, tetraoctyl-, and tetradecylammonium bromides [referred to as (C₁₂)₂NBr, (C₁₈)₂NBr, (C₆)₄NBr, (C₈)₄NBr, and (C₁₀)₄NBr, respectively]. The effect of these ammonium bromides on the flux was demonstrated. For membranes containing 0.1 M (C₁₂)₂NBr and (C₁₈)₂NBr, BMPP exhibited considerably high fluxes. The fluxes of lanthanum and cerium using BMPP for (C₁₂)₂NBr were higher than those of the other lanthanides. For the membranes containing 0.5 M (C₁₂)₂NBr and 0.1 M (C₁₈)₂NBr, however, no difference in flux among the lanthanides was observed. The fluxes using TMPP for (C₁₂)₂NBr and (C₁₈)₂NBr were very small, with the exception of some lanthanides. Appreciably high fluxes were observed for membranes containing 0.1 M (C₆)₄NBr using BMPP. For (C₈)₄NBr and (C₁₀)₄NBr, BMPP exhibited low fluxes. For these membranes using TMPP, the lanthanides were scarcely transported.     

Stabilization of CO2‐in‐water emulsions with high internal phase volume using PVAc‐b‐PVP and PVP‐b‐PVAc‐b‐PVP as emulsifying agents

Two newly‐designed hydrocarbon surfactants, that is, poly(vinyl acetate)‐block‐poly(1‐vinyl‐2‐pyrrolidone) (PVAc‐b‐PVP) and PVP‐b‐PVAc‐b‐PVP, were synthesized using reversible addition–fragmentation chain transfer polymerization and used to form CO₂/water (C/W) emulsions with high internal phase volume and good stability against flocculation and coalescence up to 60 h. Their structures were precisely determined by nuclear magnetic resonance, gel permeation chromatography, thermal gravimetric analysis, and differential scanning calorimetry. Besides low temperature and high CO₂ pressure, the surfactant structures were the key factors affecting the formation and stability of high internal phase C/W emulsions, including the polymerization degrees of CO₂‐philic block (PVAc) and hydrophilic block (PVP), as well as the number of hydrophilic tail. The surface tension of the surfactant aqueous solution and the apparent viscosity of the C/W emulsions were also measured to characterize the surfactants efficiency and effectiveness. The surfactants with double hydrophilic tails showed stronger emulsifying ability than those with single hydrophilic tail. The great enhancement of the emulsions stability was due to decrease of the interface tension as well as increase of the steric hindrance in the water lamellae, preventing a frequent collision of CO₂ droplets and their fast coalescence. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46351.     

Small-angle neutron scattering studies on sodium dodecylbenzenesulfonate-tetra-n-butylammonium bromide systems

A phase study was completed on aqueous sodium dodecylbenzenesulfonate (SDBS) and tetra-n-butyl-ammonium bromide (Bu₄NBr) systems, and consolute boundaries were drawn through cloud points. Samples were selected from both miscibility regions [under the lower consolute boundary (LCB) and above the upper consolute boundary (UCB)] for small-angle neutron scattering (SANS) studies. In the first set of experiments, the effect of varying Bu₄NBr concentration on micellular parameters of 100 mM SDBS was studied at 30°C. The pure SDBS micelle has an aggregation number (n _s ) of 51, and the effective charge on the monomer (α) is 0.17. With the addition of Bu₄NBr, the n _s of SDBS micelles increases while α decreases. The system with [Bu₄NBr]=39.5 mM (an above-UCB sample) showed clouding near room temperature (≈29°C) and had a high n _s value (300) and a low α (=0.09). The data indicated that the micelles lose ionic character in the presence of Bu₄NBr. The temperature effect on this sample shows that α remains almost constant, while n _s decreases on heating. A similar effect was observed with samples of lower Bu₄NBr concentration (32 or 25 mM) in the presence of 100 mM SDBS. The same type of temperature effect was seen on a sample of under-LCB region (50 mM SDBS+32 mM Bu₄NBr); the n _s values increased significantly as the LCB was approached. The overall SANS observations suggest that the micelles have low ionic character together with high n _s values (a case of micellar growth) near LCB/UCB.     

Partitioning behaviour of cephalexin and 7‐aminodeacetoxicephalosporanic acid in PEG/ammonium sulfate aqueous two‐phase systems

In order to develop an aqueous two‐phase system (ATPS) for cephalexin synthesis with extractive bioconversion, the partitioning behaviour of cephalexin and 7‐aminodeacetoxicephalosporanic acid (7‐ADCA) in poly(ethylene glycol) (PEG)/salt ATPS were examined. Parameters such as PEG size, salt type and tie line length were investigated to find a primary extraction system. In PEG400/ammonium sulfate and PEG400/magnesium sulfate systems, the partition coefficient of cephalexin (K_C) was larger than 1 while that of 7‐ADCA (K_A) deviated about 1.5. Addition of neutral salts, surfactants and water‐miscible solvents were also investigated in the primary ATPS in order to improve the separation efficiency. K_C greatly increased when neutral salts and surfactants were added to the PEG400/ammonium sulfate primary systems whereas K_A was only slightly higher than that of the additive‐free ATPS. In an improved ATPS for extractive bioconversion, consisting of PEG400 (20% w/w), ammonium sulfate (17.5% w/w), methanol (5% w/w) and NaCl (3% w/w), a K_C value of up to 15.2 was achieved; K_A was 1.8; K_P (partition coefficient of phenylglycine methyl ester) was 1.2 and the recovery yield of cephalexin was 94.2%. The results obtained from the extractive bioconversion of cephalexin in the improved ATPS showed that it is feasible to perform such an enzymatic process in an ATPS and the system offers the potential as a model for enzymatic synthesis of some water soluble products. © 2001 Society of Chemical Industry     

Micellization Studies of Dicationic Gemini Surfactants (m-2-m Type) in the Presence of Various Counter- and Co-Ions

Salts have the ability to influence the water activity and self-association of ionic micelles. In the present case, gemini surfactants; ethanediyl-α,ω-bis(dimethyl alkyl ammonium bromide) (referred to as m-2-m, m = 10, 12, 14) are synthesized and their micellization study in aqueous medium in presence of monovalent inorganic (NaBr, NaNO₃, NaCl, KCl, LiCl) and organic salts (NaTos, NaBenz, NaSal) at 303 K is systematically investigated by conductometric and tensiometric methods. All the salts have the tendency to lower the critical micelle concentration of the surfactants. The effect of inorganic salts on the micellization properties has been found to obey the Hofmeister series. Organic salts reduce the CMC more effectively as compared to inorganic salts. The theoretical models of Rubingh and Rosen have been used to compare the results and obtain the interaction parameters, minimum area per molecule, surface excess, mixed micelle composition, activity coefficients and free energies of micellization/adsorption.     

The Clouding Phenomenon for Anionic Sodium Dodecyl Sulfate + Quaternary Bromides in Polar Nonaqueous-Water-Mixed Solvents

Aqueous sodium dodecyl sulfate (SDS) solutions show clouding in the presence of tetra-n-butylammonium bromide (TBAB) and tetra-n-butylphosphonium bromide (TBPB). In this study, we report the effect of various volume percents of different polar nonaqueous solvents (acetonitrile, AN; dimethylsulfoxide, DMSO; methyl ethylene glycol ether, MC; formamide, FA; ethylene glycol, EG) on the clouding behavior of SDS + quaternary bromide (TBAB or TBPB) systems. The cloud point (CP) was found to decrease with initial increase in the volume percent of the above solvents in mixtures (with water). After a minimum in CP vs. volume percent plots, further increase in the volume percent caused an increase in the CP, followed by a near constant region. The data have been discussed on the basis of the effect of the above solvents on the two types of water present in the system: hydrated water and bulk water. As AN had shown a gradual decrease in the CP to a larger volume percent, it was chosen for detailed studies. Compared to TBAB, TBPB has diminished the effect of AN on CP increase due to its bigger size. The limited CMC data also run parallel to CP results.

The study of free radical polymerization of acrylonitrile by oxidation–reduction system using potassium persulfate–thiourea in aqueous medium

The polymerization kinetics of acrylonitrile (AN) with the potassium persulfate (K₂S₂O₈)/thiourea redox system has been investigated volumetrically in an aqueous medium in the temperature range of 40–80°C. The rate of polymerization (R_p) and rate of K₂S₂O₈ disappearance have been measured. The effects of some water‐miscible organic solvents, cationic, anionic, nonionic surfactants, and complexing agents on the R_p were investigated. The temperature dependence of the rate was studied, and the activation parameters were computed using the Arrhenius and Eyring plots. The effects of organic solvents on polymerization were also investigated. All of them depressed both the initial rate and limiting conversion. A mechanism consistent with the experimental data involving K₂S₂O₈–thiourea complex formation, which generates free radicals, is suggested. Molecular weight of the polymer was determined by viscometry. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Kinetic study of S-alkylation of 2-mercaptobenzimidazole by allyl bromide in the presence of potassium hydroxide

The S-alkylation (substitution on sulfur atom) of 2-mercaptobenzimidazole (MBI or ArSH) by allyl bromide (RBr) was successfully carried out in an aqueous solution of KOH/organic solvent two-phase medium. The reaction, which may take place either in the organic phase or on the interface, is greatly enhanced in the presence of KOH without the aid of quaternary salts as the catalyst to promote the reaction. No product was obtained from N-alkylation (substitution on nitrogen atom) during or after the reaction period by using a limited amount of allyl bromide (RBr) relative to that of MBI. Based on the experimental evidence, the kinetic behaviors and the characteristics of the reaction are sufficiently described by the pseudo-first-order rate law. The effects of the reaction conditions, including the agitation speed, the amount of KOH, volume of water, volume of dichloromethane, amount of allyl bromide, amount of 2-mercaptobenzimidazole, organic solvents and temperature on the conversion of allyl bromide and the apparent rate constants (k_app) were investigated in detail. Peculiar result is obtained in studying the effect of the volume of water on the conversion (or the reaction rate) in this work. Rational explanations are provided for the observed phenomena from experimental results.