On the Mesoscale Solubility in Liquid Solutions and Mixtures - The

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B: Fluid Interfaces, Colloids, Polymers, Soft Matter, Surfactants, and Glassy Materials

On the Mesoscale Solubility in Liquid Solutions and Mixtures Dmytro Rak, and Marian Sedlak J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b10638 • Publication Date (Web): 11 Dec 2018 Downloaded from http://pubs.acs.org on January 8, 2019

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The Journal of Physical Chemistry

On the Mesoscale Solubility in Liquid Solutions and Mixtures Dmytro Rak & Marián Sedlák* Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, 040 01 Košice, Slovakia. * corresponding author. Email: [email protected], tel.: +421 55 7922245

ABSTRACT We report on a mesoscale solubility reflecting the fact that solubility is achieved not only by the wellknown “like likes like” or “like dissolves like” based on molecular solvation but also on mesoscale solubilization of dislike compounds characterized in that the solubility (homogeneous distribution over the whole volume of the system) is achieved on a mesoscale level ranging from tens to hundreds of nanometers. It is shown that mesoscale solubility is a spontaneously occurring, literally everywhere present phenomenon which was hidden and overlooked for a long time. This paper reveals the physical mechanism of mesoscale solubilization comprising nucleation and aggregation accompanied by the development of significant surface zeta potentials on nanoprecipitates giving them a long-term stability. We show that mesoscale solubilization is common for aqueous as well as nonaqueous systems. Experiments with organic solvents not capable of self-ionization (self-dissociation) instead of water sheds also light on the mechanism of the generation of surface zeta potentials at hydrophobic interfaces. We identified the key parameters enabling the mesoscale solubilization and mapped its occurrence as their function. Mesoscale structures including their formation kinetics, long-term stability, and different types of solubilization procedures were characterized by scattering and ultramicroscopic visualization comprising sizing and counting.

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1. INTRODUCTION Since a vast majority of phenomena and processes in nature, industry, and research practice take place in the form of solutions and mixtures instead of pure compounds, understanding of solubilization/mixing mechanisms is crucially important. Some experimental indications about existence of mesoscale structures of unknown origin in liquid solutions and mixtures of common chemical compounds (i.e. the presence of structures on length scales between molecular and macroscopic, respectively) appeared earlier in literature. For instance anomalously high light scattering of unknown origin was reported in connection with aqueous solutions of tert-Butyl alcohol1 4 exhibiting also unusual thermodynamic properties. However, no unambiguous explanation was reached. Some two decades later, independently of the forgotten TBA story, a series of three extensive experimental papers from our lab5-7 showed that mesoscale structures appreciably exceeding dimensions of individual molecules are not a privilege of one or a few special systems like TBA, but are present rather in whole classes of systems. It was concluded5 that mesoscale structures are real objects with macroscopic lifetimes (not fluctuations) and that these are discrete objects (not bicontinuous phases with large correlation lengths) possessing near-spherical shapes with radii in the range 30nm – 300nm and variable polydispersities. Kinetics of their formation and their long-term stability were documented by light scattering as well6. The presence of mesoscale structures in solutions and liquid mixtures was correlated with various characteristics of the solutes/solvent pairs like electrostatic charges, dipole moments, protic vs. aprotic character, etc.7 In spite of a detailed mapping of the occurrence of mesoscale structures as a function of these parameters via a very large number of systems investigated7, no solid explanation was found regarding the origin of these phenomena.7 Experimental observations of mesoscale structures were reported also by other groups8,9, but their nature was remaining still unclear. It was hypothesized that these may be nanobubbles,8 but this hypothesis was later declined.10,11 While bringing evidence against the nanobubble interpretation, it was noted11 that the scattering signal is sensitive to the purity of the 2 ACS Paragon Plus Environment

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solute and so, in principle, may originate from some kind of mesophase separation of minority components contained in the solute prior to its dissolution in a solvent. Similar conclusion was drawn from LS and SANS data on THF/water mixtures where THF contained hydrophobic Butylhydroxytoluene antioxidant as a preservative12. Anisimov et al. then reopened the debate on aqueous solutions of TBA13 with a conclusion that the source of mesoscale structures is segregation of propylene oxide expected to be commonly present in TBA as an unwanted admixture13. While the concept was roughly correct, we have shown later14 that propylene oxide is in fact truly molecularly miscible with water and TBA while mesoscale structures in TBA aqueous solutions are formed by more hydrophobic compounds that were exactly analytically identified by GC-MS chromatography14. This paper presents a detailed and extensive experimental study focusing on the origin, nature, and occurrence of mesoscale structures in liquid solutions and mixtures. The outcomes of this paper show that these structures enable effective solubilization (homogeneous distribution over the whole volume of the system) of compounds in dislike solvents which do not provide classical molecular solubilization (molecular mixing). This type of solubility is referred to as a mesoscale solubility. It is shown that mesoscale solubilization is a spontaneously occurring, literally everywhere present phenomenon which was quite hidden and overlooked for a long time. Particularly we focus in this paper on: (1) investigation of the occurrence of mesoscale solubilization in a very wide variety of mixtures with differing compositions, (2) working mainly with well-defined ternary mixtures with controlled composition and a high purity of components, (3) identification of the key physicochemical parameters enabling mesoscale solubilization and mapping its occurrence as their function, (4) revealing the physical mechanism of mesoscale solubilization where we show that the key role is played by the surface zeta potential developing on nanoprecipitates, (5) complex characterization of mesoscale structures in terms of their size, number concentration, zeta potential, and composition, (6) investigation of the kinetics of formation of mesoscale structures and their long-time stability, (7 ) describing different routes to the formation of mesoscale structures, (8) investigation of ternary nonaqueous mixtures 3 ACS Paragon Plus Environment


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showing that this phenomenon is universal, not restricted to aqueous systems, and (9) discussion covering important and unimportant factors enabling mesoscale solubility, processes acting against mesoscale solubilization, differences with respect to other known submicron and nano structures in soft matter, etc.

2. EXPERIMENT Materials. TBA (tert-Butyl alcohol) used in experiment shown in Fig.1C was from Sigma-Aldrich (99.7%) and used as delivered. All organic liquids used in ternary mixtures as major components were purified with emphasis on removing mainly hydrophobic impurities using the following procedure. 20% water solution of a p.a. grade organic liquid was filtered via nanoporous filters to remove practically completely hydrophobic impurities segregated into nanodroplets. The organic liquid was then distilled off and water residuals were subsequently removed via drying over a molecular sieve. Water was purified by reversed osmosis and activated carbon TOC reduction, freshly double-distilled in a quartz apparatus, and subsequently deionized by analytical grade mixed-bed ion exchange resins (Bio-Rad, Richmond, CA). We have used also water from commercial apparatus ELGA Purelab Ultra Analytic (Elga, United Kingdom). No dependence of results on water source was observed. The resistivity of water was always above 18 M cm. The ternary mixture where water as a solvent was replaced by ethyleneglycol (Figs. 4A,B) was prepared in dry argon atmosphere to avoid air humidity. New (unopened) anhydrous reagents were used for its preparation: ethanol (Merck, 99.9%, ≤0.01% H2O) and ethylene glycol (Sigma Aldrich, 99.8%, ≤0.003% H2O). n-Octadecane (Alfa Aesar, 99.5+%) was used as delivered. All other compounds used as minor components in ternary mixtures were also of p.a. grade and used as delivered.


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Static light scattering (SLS) measurements were made using a 40 mW HeNe laser, model 25LHP928 (CVI Melles Griot, Albuquerque, NM) with 632.8 nm vertically polarized beam and a laboratory made goniometer with angular range from 30º to 135º. Scattering intensities were measured by photon counting and normalized using doubly distilled and filtered benzene as a standard and expressed as ratios I/IB, where I and IB are scattering intensities from sample and benzene, respectively.

Dynamic light scattering (DLS). An ALV7004 correlator (ALV, Langen, Germany) was used for photon correlation measurements. Correlation curves were fitted by CONTIN program enabling multimodal fitting and in combination with measurement of scattering intensity in absolute units subsequently evaluation of scattering from mesoscale structures separately from so called molecular scattering5-7,11. Particle masses were calculated from their sizes obtained by either static or dynamic light scattering and compound densities.

GC-MS (gas chromatography coupled with mass spectrometry). Samples were analyzed on Agilent 7890A GC system with Agilent 5975 C Mass Selective Detector (Agilent, Palo Alto, CA) and nonpolar HP-5ms column (30 m × 0.25 mm × 0.25 μm). Two methods were used: direct injection and the HSSPME method (HeadSpace Solid-Phase Microextraction), respectively. Helium was used as a carrier gas (99.998 %; flow rate: 0.9 mL/min; SIAD, Bergamo, Italy). In the case of HS-SPME method, 3 ml aliquots of solutions in 20 ml glass vials with silicone septum were sampled using DVB/CAR/PDMS (Divinylbenzene/Carboxen/ Polydimethylsiloxane) extraction fiber (SUPELCO, Bellefonte, USA) for 1 hour at ambient temperature. Desorption occurred in the injection port at 280 °C for 5 min, the flow rate was 2 mL/min. for 12 sec. and then 0.9 mL/min. for the rest of analysis. Separated compounds were identified based on their mass spectra in the range 29 – 520 m/z (m being the mass and z the charge) , comparison with the NIST08 spectra library, and taking into account other facts and factors such as expected elution order and literature data on boiling points. 5 ACS Paragon Plus Environment


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Nanoparticle Tracking Analysis (NTA) was carried out with an LM10B Nanoparticle characterization system from Nano Sight (Amesbury, United Kingdom) with trinocular microscope and LM12 viewing unit with a 60mW laser working at λ = 405 nm. Videosequences were recorded via a CCD camera operating at 30 frames per second (fps) and evaluated via NANOSIGHT NTA 3.1 Analytical Software Suite.

Zeta potential measurements were made using Malvern Zetasizer Nano Z, model ZEN2600 (Malvern Instruments, UK) based on a mixed mode measurement consisting of P.A.L.S. (Phase Analysis Light Scattering) procedure and of laser Doppler velocimetry. This combination enables to measure distribution of electrophoretic mobilities with an accurate electroosmotic correction. Malvern folded capillary cells were used for all measurements. Zeta potentials were calculated from measured electrophoretic mobilities via Hückel approximation. According to Oshima33, the Hückel approximation can be used in salt-free systems upon assumption of negligible volume fraction of particles irrespective of actual values of electrophoretic mobility. This assumption is satisfactorily fulfilled in all our systems where electrophoretic mobility was measured. Nevertheless we have also calculated zeta potentials using Oshima analytic expression34 upon approximation of ionic strength in our systems by 10-6M KCl. With respect to main conclusions drawn from zeta potential data in this paper, the obtained difference was insignificant. Measurements of zeta potential at macroscopic interfaces were performed via streaming potential and streaming current methods using Anton Paar SurPASS electrokinetic analyzer for solid surface analysis. Cylindrical measurement cell were filled with crushed octadecane and then a corresponding electrolyte were pumped through it. Mobile phase were prepared by mixing of dried ethanol (Merck, 99.9%, ≤0.01% H2O) with dried DMSO (Honeywell, 99.9%, ≤0.02% H2O) or water in a ratio 1:4. Conductivity was adjusted using KCl. Zeta potentials were calculated from obtained streaming potential and streaming current values using Helmholtz-Smoluchowski equation. 6 ACS Paragon Plus Environment

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Coagulation rates calculation. Coagulation rates were calculated according to the theory of Wang and Davis18 according to which these are dependent on the composite Hamaker constant, relative viscosity ηrel of particles/droplets with respect to the surrounding liquid influencing hydrodynamic interactions, and on the number concentration of particles/droplets.

3. RESULTS AND DISCUSSION A typical picture from optical microscopy in a laser beam showing mesoscale structures with sizes well below Abbé limit as individual bright spots (point scatterers) can be found in Fig. 1A. Video sequence capturing their Brownian motion can be found in SI. It is possible to analyze tracks of individual particles via NTA (Nanoparticle Tracking Analysis) method15 yielding particle size distributions that agree well with our results5 from ORT analysis16 of light scattering. NTA also enables direct counting of nanoparticles. Revealing of the chemical composition of mesoscale structures is possible by comparison of GC-MS data prior to and after filtration by nanoporous filters which are capable of complete and irreversible removal of mesoscale structures from solution while molecularly dissolved compounds freely pass through filters. Fig. 1C shows data from aqueous solution of a commercial p.a. grade TBA containing some twenty minority compounds as impurities. Decrease of the detector signal after filtration corresponding to the decrease in concentration of particular compound is plotted here as a function of the logarithm of the octanol/water partition coefficient P reflecting hydrophobicity/hydrophilicity. While weakly hydrophobic compounds with log P < 3 dissolve molecularly, compounds with 3 < log P < 6 dissolve partly molecularly and partly mesoscopically, and compounds with log P > 6 dissolve practically exclusively mesoscopically. A similar scenario is found



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Figure 1. Basic characteristics of mesoscale solubility. (A) Typical microscopic image from a nanoparticle tracking analysis experiment capturing the presence and dynamics of mesoscale structures (video is available in SI). Aqueous solution of ethanol (c = 200 g/kg). Ethanol was first purified, subsequently doped with octadecane (0.1%), and finally mixed with water. The captured area is 80 × 100 μm while the focal depth is approximately 20 μm. (B) Water/ethanol/octadecane ternary mixtures. The concentration of octadecane in ethanol cOCT was fixed at 0.015%. I(0°) is zero angle scattering from mesoscale structures having radius R, and cEtOH is concentration of ethanol in the ternary mixture. No octadecane was macroscopically separated. The dashed line shows schematically a situation when a more hydrophobic major component (better solvating octadecane) is used instead of ethanol. (C) Aqueous solution of a p.a. grade tert-Butyl alcohol (cTBA= 150 g/kg) was analyzed by HS-SPME GC-MS method (headspace solid-phase microextraction gas chromatography coupled with mass spectrometry) before and after filtration, respectively. Data show abundance decrease of some twenty compounds identified in TBA due to removal of mesoscopically soluble compounds. A list of particular compounds can be found in Table S1 in SI. (D) Dependence of critical concentrations on the octanol/water partition coefficient P of the third component in a ternary mixture with water and ethanol: onset of mesoscale solubility (□) and onset of coexistence of mesoscale solubility with macrophase separation (□). Concentration of ethanol in water was fixed at 20%. Concentrations plotted on the ordinate refer to concentrations of the third component in ethanol prior to mixing with water. (E, F) Samples prepared as in Fig. 1A while octadecane concentration cOCT was varied. Benzenenormalized zero-angle scattering intensity from mesoscale structures (○), radius of mesoscale structures obtained by static (○) and dynamic (○) light scattering, and number concentration obtained by NTA (○). The dashed line corresponds to the uncorrected intensity decreased due to multiple light scattering. 8 ACS Paragon Plus Environment

n, particles/ml

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for other compounds than TBA. Several parameters were identified as the key ones that control mesoscale solubility: (i) nature of the major compound which is being dissolved in water in terms of its hydrophobicity/hydrophilicity, preferably expressed via log P; (ii) log P of minority components contained in the major component; (iii) concentration of the major compound; and (iv) concentrations of minority components. In order to explore rigorously the role of these parameters, we proceeded by using well defined ternary mixtures composed of water, one major component with moderate concentrations of several percent or tens of percent, and one minor component with low concentrations typically well below one percent. The major component was thoroughly purified, then mixed truly molecularly with the minor component, and finally this binary mixture was mixed with water. Fig. 1B shows the influence of concentration of the major component in a ternary mixture. Water/ethanol/octadecane was chosen as a model system (solvent/major component/minor component). Scattering intensity from mesoscale structures was normalized such that it reflects the fraction of octadecane dissolved mesoscopically while the rest is dissolved molecularly. It can be seen that all octadecane is mesoscopically solubilized from 0% to 50% of ethanol in the mixture, then from 50% to 80% of ethanol the fraction of mesoscopically segregated octadecane decreases at the expense of increase of octadecane molecular solubility, and for concentration of ethanol > 80% all octadecane is molecularly dissolved. The next fundamental parameter as outlined above is the concentration of the minor compound. Fig. 1E shows results on the same ternary mixture water/ethanol/octadecane. Concentration of ethanol was fixed at 20%. At concentrations of octadecane cOCT below ~ 2 10-4 % all octadecane is dissolved molecularly and its scattering is not measurable against the scattering from the water/ethanol mixture. Above cOCT ~ 2 10-4% octadecane is not soluble molecularly anymore but becomes mesoscopically soluble in the form of nanoparticles/nanodroplets distributed homogeneously over the whole volume of the system. Number concentration and size of nanoparticles/nanodroplets are shown in Fig. 1F. Above cOCT ~ 0.3 % the situation is such that a macrophase separation of octadecane begins and macroscopically separated 9 ACS Paragon Plus Environment


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octadecane coexists with octadecane mesoscopically soluble in the form of nanodroplets. While the former undergoes flotation, the latter keeps homogeneously filling the whole volume of the water phase. Two critical concentrations can be defined, one as an onset of mesoscale solubility and the other one as an onset of coexistence of mesoscale solubility with macrophase separation (Fig. 1D). Both are dependent on log P of the minor component of the ternary mixture. In the next paragraph we restrict to small concentrations of the hydrophobe, i.e. the hydrophobe remains a “minor component” of the mixture and no macroscopic phase separation occurs. Figure 2 shows results of mapping the occurrence of mesoscale solubility. Since we deal here with aqueous mixtures, the parameter of interest is the hydrophobicity/hydrophilicity of the components expressed via log P. The quantity plotted on the z-axis reflects the concentration of mesoscopically solubilized minor component (zero-angle scattering intensity from mesoscale particles normalized by their mass). It can be seen from the plot A that minor components with log P > ~3 become mesoscopically soluble while the concentration of mesoscopically solubilized material is strongly increasing with log P and a full mesoscale solubilization is reached at log P > ~ 6. There is practically no dependence on the log P of the major component unless its concentration is raised from 20% (plot A) to 30% (plot B). It is evident from the plot B that the higher the log P of the major component the less pronounced becomes the mesoscale solubilization at the expense of molecular solubilization increase (mixture of water with major component becomes better and better solvent for the molecular solubilization of the minor component). It should be also noted that, especially for smaller content of the major component (plot A), the effect of mesoscale solubilization is not dependent on the character of the major component such as its state (liquid/solid), molecular size, symmetry, etc. It will be also shown further in this paper that contrary to some earlier hypothesis17 the major component does not play a significant role in the stabilization of mesoscale structures. In the absence of hydrophobic minor


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Figure 2. 3D representations of influence of partition coefficients of components of aqueous ternary mixtures on mesoscale solubility. Ternary mixtures water/major component/minor component where the major component is truly molecularly miscible with water and the minor component is truly molecularly miscible with the major component. Concentration of the major component in ternary mixtures is 20% (A, C) and 30% (B). Concentration of the minor component in the major component before mixing with water is 0.05%. P is octanol/water partition coefficient expressing hydrophobicity/hydrophilicity of the components. Plots A and B show degree of mesoscale solubility of the minor component in a.u., expressed as a ratio of zero angle scattering intensity and mesoscale particles mass. Intensities are corrected for different scattering contrasts for different compounds. Plot C shows zeta potential of mesoscale particles. List of particular compounds used in Fig. 2 can be found in Table S2 of the SI together with their log P values. Tabulated values of all parameters can be found in Tables S3 and S4 of the SI.



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component, no structuring on length scales equal or larger than few nanometers were observed for all major components investigated. The key factor for the stabilization of mesoscale structures is their negative surface zeta potential (Fig. 2C). Zeta potentials (~ -40mV to – 60mV) are independent of the character of the minor component and just weakly (and not systematically) dependent on the character of the major component. The negligible influence of the major component on zeta potential can be also supported by experiments where the major component was removed by evaporation without any changes in the zeta potential (Fig. 3). Measured zeta potentials provide a very good colloidal stability of mesoscale particles. Fig. 3A shows results of monitoring this stability for over one year. A slight increase of particles size in the beginning is interpreted as a result of ultraslow Ostwald ripening leading to increase of the size average as obtained from DLS. When ethanol is removed from the mixture by evaporation (Fig. 3B), Ostwald ripening is suppressed since the diffusion of octadecane through pure water is much more difficult than through a 20% aqueous solution of ethanol. The key role of the surface zeta potential was tested by elimination of zeta potential upon lowering pH by HCl. Particles with zero zeta potential (within the accuracy of measurements via electrophoretic light scattering) coagulate on a time scale predicted by theory18 (Fig. 3C). A more detailed quantitative analysis would require to know exactly the accuracy of the determination of number concentrations by NTA analysis, but accurate calibration standards for NTA are not available. Our interest was also focused on the kinetics of the formation of mesoscale structures. In a majority of experimental conditions covered by this paper, the kinetics is fast (below one second) and its monitoring would require a special stopped-flow light scattering instrumentation. While we do plan such experiments in future, we were already able to monitor kinetics under conditions where formation of mesoscale particles is slowed-down due to a higher concentration of the major component in the mixture (Fig. 3D, Fig. 1B). It can be seen that a homogeneous ternary mixture without any large scale inhomogeneities (very low scattering intensity) is reached in the beginning and only afterwards the 12 ACS Paragon Plus Environment

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nuclei of segregated octadecane start to grow. Ethanol well miscible with water serves as a carrier which distributes octadecane molecules evenly over the whole volume of system and only afterwards octadecane starts to nucleate and aggregate. In this paragraph we would like to show how universal is the phenomenon of mesoscale solubility. First of all, it is not limited to aqueous systems. Fig. 4A shows a summary of results of experiments where water as a solvent was replaced by various organic liquids. Much care was devoted to using anhydrous liquids as well as to verifying that small traces of water do not alter the data. In order to make a quantitative comparison with detailed data on aqueous systems, the previously used ethanol and octadecane were chosen as the major and minor components of a ternary mixture, respectively. Similarly to aqueous systems, two critical concentrations can be defined, one as an onset of mesoscale solubility and the other one as an appearance of macrophase separation (onset of coexistence of mesoscale solubility with macrophase separation). The onset of formation of mesoscale structures (its critical octadecane concentration) is proportional to the solubilization power of the corresponding organic liquid with respect to octadecane. The other critical concentration is less dependent on the nature of the organic liquid substituting water. The long-term stability of mesoscale particles and surface zeta potential as its source is similar to aqueous systems (Fig. 4B). A detailed analysis of data in Fig. 4B shows in addition to the main conclusion about the long-term stability of mesoscale particles a very small increase in radius (and consequently also in scattering intensity) at short times followed by a slow decrease at long times. The former is caused most probably by Ostwald ripening, the latter by flotation. Preferential flotation of the largest particles decreases the average value of their radius. Compared to the analogous aqueous mixture, the nanoparticles are bigger as well as ethyleneglycol is more dense than water which leads to a stronger flotation. In case of organic liquids with relatively higher solubilization power for octadecane (DMSO, NMF, DMF), no mesoscale solubility is found and the ternary system goes directly from a full molecular solubility of octadecane to its macrophase separation. The reason for 14 ACS Paragon Plus Environment

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Figure 4. Universality of the effect of mesoscale

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of decane was gently poured on top of 20% aqueous

500

D

102

solution of ethanol. Spontaneous formation of decane mesoscale particles detected in the lower aqueous layer. Meaning of symbols as in plot B. Zeta potential ζ = −82.1 mV.

400

101

300

100

200

10-1

100

10-2

0

50

100

t, days


150

0 200

R, nm

formation of mesoscale particles. An excess amount

I / IB (0o)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



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the absence of a mesoscale solubility regime in these systems is evidently not the missing zeta potential at the interface. For instance, zeta potential at the interface octadecane/(20% ethanol in DMSO) was found via streaming current method to be ~ -10mV, which is enough to give some stability to eventual mesoscale structures. The reason is that the upper limit of true molecular solubility (octadecane saturation concentration cOCT,sat) in these systems is relatively high. Therefore when cOCT/cOCT,sat is raising above 1.0 the number of nuclei is low (low supersaturation, low nucleation rate) but the total amount of octadecane available for segregation (cOCT - cOCT,sat) is large. It means that a large amount of octadecane segregates into a small number of particles which must be therefore very large and flotate immediately to form a macrophase. This is exactly observed experimentally. Fig. 4C deals with the issue of mesoscale solubility in the whole range of concentrations of the component being mesoscopically solubilized, i.e. including the regime of coexistence with macrophase separation. It shows the concentration of mesoscopically dissolved decane in a.u. derived from light scattering data as a function of concentration cDEC of decane in TBA prior to mixing with water. While the maximum is found around cDEC = 5% - 10%, the effect of mesoscale solubility is found up to cDEC ~ 80%. For cDEC > 10%, the absolute value of mesoscopically dissolved decane is decreasing which can be rationalized as a consequence of the fact that at extremely large supersaturations spinodal decomposition gradually overrides the nucelation mechanism. Fig. 4D introduces an alternative way of formation of mesoscale particles. An excess amount of decane was gently poured on top of 20% aqueous solution of ethanol. Spontaneous formation and growth of decane mesoscale particles was subsequently detected in the lower layer comprised of the ethanol/water mixture. Importantly, scattering intensity as well as particles size steadily increases from small values. It means that mesoscale particles form due to diffusion of decane into the ethanol/water layer and subsequent nucleation and growth rather than by some kind of mechanical detachment of decane particles from the interface via its break-up due to interfacial turbulence as suggested for binary water/oil interfaces19. It should be noted that the nucleation and 16 ACS Paragon Plus Environment

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growth was suggested also as an alternative explanation for particles formation at above mentioned binary water/oil interfaces20,21.

In conclusion, mesoscale solubility is an ever-present effect

occurring in coexistence with true molecular solubility and occasionally also with macrophase separation. Mesoscale nanoparticles/ nanodroplets are not true equilibrium structures but kinetically trapped structures with often virtually infinite lifetimes. The non-equilibrium nature of mesoscale structures is supported by the dependence on the preparation route. Consider for instance the mixture water/ethanol/octadecane which was studied in most detail (Fig. 1). If the mixture is prepared such that first water is mixed with ethanol and subsequently octadecane is added, no mesoscale structures appear in the whole range of octadecane concentration investigated. If the mixture is prepared as described in this paper, mesoscale structures form via nucleation and growth mechanism, which is most probably accompanied in early stages by aggregation since in case of a pure nucleation and growth mechanism the number of particles should increase as a function of supersaturation while their size should decrease, which is apparently not the case here. The kinetics of the formation of mesoscale particles is typically fast (subsecond) followed by stabilization via a negative surface potential. Processes which may act against colloidal stability are Ostwald ripening and flotation/sedimentation, commonly referred to as creaming. The former is occurring when the difference in log P between the minor component and solvent, respectively, is relatively low. Creaming is controlled by the size of mesoscale particles and their density. Experiments on water/ethanol/octadecane mixtures show that the overall volume of mesoscale particles (as revealed by NTA) does not exceed the total volume of octadecane in the sample and hence no swelling by the major component (ethanol) is present. In case of solutes with lower log P, swelling cannot be excluded. A special case of mesoscale solubility represents the so called “Ouzo effect”, named after the Greek alcoholic beverage ouzo that forms a milky oil-in-water emulsion when diluted with water. There trans-anethole, highly soluble in ethanol, segregates when quality of the solvent is decreased by addition 17 ACS Paragon Plus Environment


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of water. Behavior of water/ethanol/ trans-anethole mixtures was studied22 as well as behavior of mixtures where trans-anethole was substituted by similar compounds23 in terms of their hydrophobicity/hydrophilicity (log P). We recall that log P of trans-anethole is 3.4. As can be seen from Fig. 2 and Fig. 1D, this compound is rather on the edge of the occurrence of the effect of mesoscale solubility with a relatively short gap between the critical concentrations shown in Fig. 1D. Mesoscale particles in these systems are stable typically from several hours to several days only. The crucial role of the surface zeta potential was not revealed in the seminal papers on the Ouzo effect22,23. Later on, the term “Ouzo effect” was being progressively used for systems where particles are stabilized by surfactants, referring just to the way of preparation consisting of mixing solute dissolved molecularly in solvent with another liquid which is miscible with the solvent but serves as a non-solvent for the solute. Another term used for this situation is solvent shifting24. Somewhat similar, but physically principally different effect was investigated recently and named as a “pre-Ouzo effect” or “surfactant-free microemulsions”25,26. It was detected in ternary mixtures of water, lower alcohol (mostly ethanol), and a weak hydrophobe, with compositions approximately 1:1:1. In most cases 1-octanol (log P = 3.07) was used as a weak hydrophobe. Such a mixture is still a one phase optically fully transparent system, but it was claimed that it consisted of thermodynamically stable hydrophobe-rich and water-rich domains sized typically 1-2 nm. Since the resemblance to microemulsions (in terms of the thermodynamic stability, size, and composition), but absence of surfactants, these structures were named “surfactant-free microemulsions (SFMEs)”25,26. It was claimed27 that the structuring of ethanol (or other hydrotropes) in water plays an active role in solubilizing of weak hydrophobes in SFMEs. The mechanism of mesoscale solubilization described here does not depend on the character of the major component (that could be considered in most cases as a hydrotrope) and its role is only passive. Namely it just co-determines the solubilization power of the mixture formed with water or other solvent for molecular solubilization of the solute. The key factor for the long-term stability of mesoscale structures is their negative surface zeta 18 ACS Paragon Plus Environment

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potential. An active role of the surface zeta potential is expected also in the fast kinetics of their formation which proceeds via nucleation and aggregation rather than via pure nucleation and growth. The existence of negative surface zeta potentials at hydrophobic surfaces in water is known for a long time28 although the nature of this potential is still a subject of intense scientific discussions. There are alternative explanations of the origin of this potential29-32. The most common explanation of the oilwater interface charging is due to the accumulation of hydroxyl ions29. Surface charge was also attributed to trace amounts of fatty acids present as impurities in the oil32 while this interpretation was opposed30. Another explanation31 is based on the fact that the symmetry between donating and accepting hydrogen bonds pertained in bulk liquid water is broken in the proximity of the oil-water interface. A shift of electron density between adjacent water molecules then leads to the redistribution of the electron density near the interface31. While we plan to perform in future in a separate paper a critical analysis of our intensive data sets on zeta potentials in various systems in relation to these alternative explanations, it can be already now concluded that our data do oppose the explanation based on fatty acids residuals since zeta potentials do not correlate with variable purities of oils (hydrophobic minor components in our language). Results from nonaqueous systems where water was exchanged for organic solvents not capable of generation of hydroxyl ions by self-ionization (self-dissociation), but capable of hydrogen bonding, are in favor of the explanation based on the breaking of the symmetry between donating and accepting hydrogen bonds pertained in bulk liquid31. In every case, the accumulation of hydroxyl ions at interfaces cannot be the only one source of surface zeta potentials.

4. CONCLUSIONS Mesoscale solubility (homogeneous distribution of a chemical compound over the whole volume of the system achieved via mesoscale structures/particles with sizes typically ranging from tens to hundreds of 19 ACS Paragon Plus Environment


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nanometers) is an everywhere present phenomenon usually met in daily life and research practice which has been, however, bizarrely hidden and overlooked for a long time. As a result of mesoscale solubility, practically all aqueous (and many nonaqueous) solutions and mixtures comprise typically 1011-1012 nanoparticles/nanodroplets per milliliter which are formed by solutes not able to molecularly mix with solvent that mesoscopically segregate instead of being macroscopically phase separated. The everpresence of mesoscale solubilization in daily life and research practice is coming from the fact that really pure chemical compounds are produced and used rather exceptionally. Even compounds considered commonly as pure, like for instance p.a. grade chemicals, are in fact multicomponent mixtures of the main compound plus several minority compounds with rather substantial concentrations 2-5 g/L (99.5% – 99.8% typical purity of the main compound). Dissolution of the main compound in a proper solvent (preparation of an ordinary binary solution) is then practically always accompanied by molecular solubilization and/or mesoscale solubilization of minority compounds based on their particular affinities to solvent used. Mesoscale solubility in its full strength and variety was bizarrely hidden for a long time due to the fact that solutions with ever-present mesoscale structures are usually optically perfectly clean and these structures are not visible to the naked eye or to the optical microscope due to their small size. Scattering techniques are perfectly capable of their detection, however, these methods are routinely used with intensive sample filtrations prior to measurement aimed at removing mainly the dust. Nevertheless such filtrations also perfectly destroy/remove the mesoscale structures. Regarding the physical mechanism of mesoscale solubilization, our results show that once the solute is solvophobic enough to trigger nucleation and growth of nuclei, it is at the same time capable to generate a sufficiently high surface zeta potential giving a long-time colloidal stability to mesoscale particles. This mechanism lies behind the everpresence of mesoscale structures in aqueous as well as nonaqueous solutions and mixtures. It is not the low zeta potential, but other mechanisms that in certain cases lead to their lower colloidal stability. These are namely the growth of particles via Ostwald 20 ACS Paragon Plus Environment

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ripening followed by creaming (flotation or sedimentation). It is also not the low zeta potential but other reasons that in certain cases lead to macrophase separation, in coexistence with mesoscale solubilization or instead of it. These are extremely large supersaturations leading to spinodal decomposition as a competing process to nucelation in the former case and extremely large saturation concentrations in the latter case. In case of aqueous solutions and mixtures, solvophobicity means hydrophobicity and mesoscale solubilization concerns hydrophobic compounds in ternary mixtures comprising hydrophobe, water, and a water-miscible compound which is at the same time miscible with the hydrophobe (referred commonly to as a hydrotrope). Our results show that the role of hydrotropes in mesoscale solubilization is only passive. They just co-determine the solubilization power of the mixture formed with water for molecular solubilization of the solute. Hydrotropes do not take active part in the stabilization of mesoscale particles and can be removed from solution without affecting their stability. The occurrence of mesoscale solubilization was mapped as a function of key parameters, which are octanol/water partition coefficients and concentrations of the hydrophobe and hydrotrope, respectively. Mesoscale nanoparticles/nanodroplets are kinetically trapped nonequilibrium structures with long-time (often virtually infinite) stability. They differ in their very nature from equilibrium structures such as microemulsions or surfactant-free microemulsions, as well as from nonequilibrium classical emulsions since they do not comprise surfactants reducing the surface tension, they do not need an energy input from outside (form spontaneously) and the process of their formation is a bottom-up (not top-down) process. Lessons can be learnt from understanding spontaneously occurring mesoscale solubilization in nature and utilized in various application areas where intentional targeted mesoscale solubilization can be advantageous compared to classical molecular solubilization. This can be for instance engineering of nanoparticles comprising important compounds such as drugs or biologically active compounds without any need for the stabilization by surfactants or stabilizing polymeric moieties (green formulations). 21 ACS Paragon Plus Environment


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ASSOCIATED CONTENT Supporting Information Video sequence capturing the Brownian motion of mesoscale particles in solution. Tables with lists of chemical compounds used in experiments with corresponding values of logarithm of their water/octanol partition coefficient P and basic characteristics of mesoscale structures. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected], Tel.: +421 55 7922245 ORCID identifier 0000-0003-2951-2846 Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS Authors acknowledge support from the Scientific Grant Agency VEGA (grant no. 2/0177/17) and the Slovak Research and Development Agency (project NANOSEG No. 16-0550). This work was realized within the frame of the project “Buildup of the infrastructure of the Centre of excellence for progressive materials with nano- and submicron structure”, project No. 26220120035 financed through the European Regional Development Fund. We thank P. Bartak from Palacky University Olomouc, Czech Republic, for acquiring and interpreting GCMS elugrams and I. Shepa for technical assistance with some experiments.


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On the Mesoscale Solubility in Liquid Solutions and Mixtures - The

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