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Mass transfer induced multi-step phase separation in emulsion droplets: toward self-assembly multilayered emulsions and onion-like microspheres Shuaishuai Liang, Jiang Li, Jia Man, and Haosheng Chen Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.6b01665 • Publication Date (Web): 18 Jul 2016 Downloaded from http://pubs.acs.org on July 23, 2016

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Mass transfer induced multi-step phase separation in emulsion droplets: toward self-assembly multilayered emulsions and onion-like microspheres Shuaishuai Liang1, 2, Jiang Li2, Jia Man1, Haosheng Chen1* 1, State Key Laboratory of Tribology, Tsinghua University, Beijing 100084, China 2, School of Mechanical Engineering, University of Science and Technology Beijing, Beijing 100083, China

Abstract Mass transfer induced multi-step phase separation was found in emulsion droplets. The agent system consists of a monomer, Ethoxylated trimethylolpropane triacrylate (ETPTA), an oligomer, polyethyleneglycol diacrylate (PEGDA) 700, and water. The PEGDA in the separated layers offered partial miscibility of all the components throughout the multi-step phase separation procedure, which was terminated by the depletion of PEGDA in the outermost layer. The number of the separated portions was determined by the initial PEGDA content, while the initial droplet size influenced the mass transfer process and consequently determined the sizes of the separated layers. The resultant multilayered emulsions were demonstrated to offer an orderly

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temperature-responsive release of the inner cores. Moreover, the emulsion droplets can be readily solidified into onion-like microspheres by ultraviolet light curing, providing a new strategy in designing particle structures.

Introduction Liquid-liquid phase separation is a useful technique in preparing membranes, emulsions, particles with specific structures.1-4 Basically, there are two kinds of phase separation： Thermally induced phase separation (TIPS) and mass transfer induced phase separation (MTIPS).1 TIPS is based on the principle that the solubility of the polymer varies as the temperature changes.5 Hence, phase separation occurs as the solution reaches the upper or lower critical temperature. As for MTIPS, it is conducted by extraction, evaporation of solvent in a polymer solution or its mutual exchange with the nonsolvent in the surroundings, which leads to a gradual change of the composition of the solution.3 Recently, MTIPS has attained rising interest as a novel route for producing multiple emulsions by microfluidics.6-10 These multiple emulsions used to be fabricated by emulsification method to have complex internal structures, such as multi-core,11 Janus-like,12,13 multilayered structures,8,14 are proved to have significant potentials in a wide array of applications, including pharmaceutics,15,16 cosmetics,17,18 foods,19 microcapsules,20 and chemical separations.21,22 Due to the self-assembly nature of MTIPS, it can achieve facile regioselective encapsulation of active agents into the desired compartments, and simultaneously avoid the hydrodynamic heterogeneities,6,7 which remains a significant challenge in mechanically producing multiple


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emulsions with precise control over their size and structure.11,23-25 However, the utilization of this new method is restricted due to the limited selection of appropriate agent systems for MTIPS, which is of great importance in applying this method.6 Especially, for mass transfer induced multi-step phase separation, the reported suitable agent systems consists of either a ternary mixture of an oil, a polar solvent, and water;6,8 or a monomer, a separation agent and their respective solvents.7 Therefore, the exploration of more multi-step phase separation agent systems is urgently needed in order to extend the application fields of this technique. Besides, in the finite reported agent systems, the mechanism of multi-step phase separation slightly differs. For example, Haase et al.8 considers the multi-step phase separation process as a series of selfsimilar cycles of mass transfer, while Choi et al.7 assigned it to the prolonged diffusion time resulted from the increasing viscosity of the droplets. Hence, it is important to investigate more agent systems, in order to gain a more comprehensive understanding of its mechanism. Herein, we report a new multi-step phase separation agent system, consisting of a monomer, Ethoxylated trimethylolpropane triacrylate (ETPTA), an oligomer, polyethyleneglycol diacrylate (PEGDA) 700, and water containing a surfactant, polyvinyl alcohol (PVA). By adjusting the initial content of PEGDA in the monodisperse droplets formed in a coaxial microfluidic device, multi-step phase separation in the emulsion droplets can be achieved, resulting in multilayered emulsions. It is found that the multi-step phase separation process is governed by the partial miscibility for all components offered by the PEGDA in the separated layers. The number of separated layers is dependent on the initial PEGDA concentration, while the size of each layer is affected by the initial droplet size. Typically, the variation of the size ratio of consecutive layers with the whole droplet size does not obey the previously reported conclusions, indicating the different separation mechanism. The multilayered emulsions prepared with the current agent


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system are able to give an orderly temperature-responsible release of the inner cores. Besides, both ETPTA and PEGDA of this system are ultraviolet (UV) light curable, thus facilitates the process of solidifying the multilayered emulsions into onion-like particles, down to several microns, providing an alternative template method in designing particles.

Experimental Section Materials and reagents The formation of initial single emulsion droplets was carried out in a coaxial capillary microfluidic device. An aqueous solution of 10 wt% PVA (Mw 13000 ~ 23000, 87%-89% hydrolyzed, Sigma-Aldrich, USA) was used as the outer fluid (continuous phase). The mixture of PEGDA 700 (Mn 700, Sigma-Aldrich, USA) and ETPTA (Mn ~428, Sigma-Aldrich, USA) was used as the inner fluid (disperse phase). The content of PEGDA in the mixture was ranged from 10% to 70% v/v at a variance interval of 10% v/v. 1% v/v 2-Hydroxy-2-methylpropiophenone was used as the photo initiator for UV light curing.

Fabrication of the glass capillary microfluidic device The configuration of the capillary microfluidic device used to generate single emulsions is shown in Figure 1a. Specifically, cylindrical glass capillaries with inner and outer diameters of 0.58 mm and 1.0 mm, respectively, were tapered at one tip by a pipet puller (P-97, Sutter Instrument Inc., USA) and used as the injection tube. The tapered tips of the capillaries were then polished until its inner diameter reached about 8 µm and 80 µm, in order to generate


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droplets of different sizes. Subsequently, the polished tip of the capillary was inserted into another cylindrical glass capillary (the collection tube), and both of the two cylindrical capillaries were coaxially positioned inside a square glass capillary with an inner dimension of 1.05 mm.

Droplet formation and multi-step phase separation When preparing the single emulsion droplets, the inner and outer fluids were separately injected into the injection tube and the interspace between the injection tube and the square capillary, respectively, by syringe pumps. The inner fluid formed a dripping flow under the shear effect of the outer fluid, producing monodisperse single emulsion droplets of the mixture of ETPTA and PEGDA. The size of the prepared droplets was controlled by adjusting the flow rate ratio of the outer to the inner fluid. As the droplets were flowing downstream, MTIPS occurs and new cores emerged in the droplets, gradually forming the second, third and fourth layers. Different periods of the multi-step phase separation process were captured using a high speed camera (Phantom Miro M110) (see Video S1). The pristine mixtures of PEGDA and ETPTA were dyed by Sudan III (Technical grade, Sigma-Aldrich, USA), Toluidine Blue O (Technical grade, Sigma-Aldrich, USA), and carminic acid (CA, Analytical standard, Sigma-Aldrich, USA) in order to provide distinct images for the investigation of the mass transfer process during multistep phase separation.

UV curing of emulsion droplets The photo initiator was added at 1% v/v into the pristine mixture of ETPTA and PEGDA followed by vigorous stirring. After the formation of the phase separated droplets, they were


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allowed to stand under UV light for 20 s to solidify the separated layers, afterward, onion-like microparticles can be obtained.

Results and Discussion Monodisperse single emulsion droplets of PEGDA and ETPTA mixture were formed at the orifice of the injection tube. As the droplets flowed downstream, mass transfer between the droplets and the continuous phase started, inducing the multi-step phase separation process to form double, triple, and quadruple emulsions sequentially in the microfluidic channel, as shown in Figure 1a. Hereinafter for the resultant multilayered emulsions, we name the separated layers orderly from outside to inside as first layer, second layer, and so on. During the phase separation process, PEGDA rich and ETPTA rich phases emerged alternately, as verified by the experimental results in Figure 1b. For initial droplets of the same size (~400 µm), double, triple and quadruple emulsions were formed for the initial PEGDA concentration at 10%, 40%, and 60% v/v, respectively. Meanwhile, the first step phase separation finished at about 230 s, 126 s, and 5 s since the single emulsions left the orifice for initial PEGDA concentration at 10%, 40%, and 60% v/v, respectively, suggesting that the phase separation occurs faster for higher initial PEGDA content. A hydrophilic fluorescence indicator, CA, was premixed into the ETPTA and PEGDA mixture, and was automatically assembled into the PEGDA rich layers during the multistep phase separation. The PEGDA rich layers were then labeled by red fluorescence areas, as shown by the images in the right column of Figure 1b. This result proves the ability of the current multi-step phase separation system to encapsulate active agents by self-assembly, and the MTIPS process can be controlled by adjusting the initial PEGDA content.


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Figure 1. (a) Schematics of the capillary microfluidic device used for preparing single emulsion droplets. (b) Formation of double, triple and quadruple droplets over time with initial PEGDA concentration (CP) at 10%, 40% and 60% v/v, respectively. The droplets shown in the microscopy images were dyed by Sudan III. The right column shows fluorescent images referring to the PEGDA rich (red, dyed by CA) and ETPTA rich (dark) regions. Scale bars are 200 µm. It is essential to analyze the mass transfer process during multi-step phase separation. Herein, we take the two-step phase separation (CP = 40% v/v) for example, as illustrated by the schematic in Figure 2a. In addition, the ternary phase diagram shown in Figure 2b was employed


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to assist the analysis, where the binodal curve (solid line) was obtained experimentally (see Figure S1), while the spinodal curve (dashed line) was drawn hypothetically. The composition of the initial single emulsion droplets located at point A on the ETPTA-PEGDA boundary, representing a PEGDA concentration of 40% v/v. Downstream the droplets were saturated in the aqueous solution of PVA, then the infiltration of water and PVA (see Video S2 and Figure S2) and the leakage of PEGDA (see Video S3) took place simultaneously (Figure 2(a1)), causing the composition of the droplet to move to point B across the binodal curve. Consequently, the PEGDA rich small droplets nucleated, grew and coalesced into a new second layer, forming a double emulsion as shown in Figure 2(a2). According to the lever rule,1 the compositions of the separated first and second layer should locate at point D (ETPTA rich phase) and C (PEGDA rich phase) along the tie line (see Figure S3 and S4) in Figure 2b, respectively. At this stage, there was still much PEGDA remained in the first layer, which can offer a high level of partial miscibility of the components on both sides of the first layer, allowing further infiltration of continuous phase and leakage of the remaining PEGDA in the droplet. As a result, the compositions of the first and second layer continuously changed from D to H and C to E, respectively, as shown in Figure 2b. As for the second layer, composition E separated into F (ETPTA rich phase) and G (PEGDA rich phase), with F forming a new third layer and G forming the second layer (Figure 2(a3)). Concurrently for the first layer, composition H separated into I (PEGDA rich phase) and J (ETPTA rich phase), with J forming a thinner first layer with less PEGDA remained, and I merging into the second layer (Figure 2 (a3)). Finally, the PEGDA remained in the first layer was insufficient to offer the partial miscibility, therefore the mass transfer process stopped and the multi-step phase separation procedure came to an end. Figure 2c shows the gradual decrease of the first layer volume as the multi-step phase separation


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process occurs step by step, indicating the depletion of PEGDA. The in-situ observation of the phase separation in a pendant droplet (see Figure S5) also showed that the sizes of all the separated layers were continuously changing throughout the phase separation process, suggesting the shrinkage of the outermost layer.

Figure 2. (a) Schematic of the mass transfer process in two-step phase separation. (b) Ternary phase diagram illustrating the composition path of the droplet in two-step phase separation. (c) Evolution of the volume of the separated first layer during multi-step phase separation process for initial PEGDA concentration at 10%, 40% and 60% v/v. The dependence of initial PEGDA concentration on the multi-step phase separation process and geometry of the phase separated droplets was also investigated. By fixing the flow rate ratio


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of the outer to the inner fluid (Qout/Qin = 10), and varying the initial PEGDA concentration, single emulsion droplets with the same pristine size but various PEGDA content were obtained. After phase separation in the microfluidic channel, the diameter of each separated layer was measured using microscopy, as shown in Figure 3a. As the initial PEGDA concentration increased, more separated layers were generated (Figure 3a) and the multi-step phase separation process finished within shorter time (Figure 1b). This observation can be understood based on the partial miscibility explanation discussed above. Figure 3b shows the comparison of the first step phase separation for high (K, 60% v/v) and low (A, 40% v/v) initial PEGDA concentration. Similar with the separation process discussed above, K and A moved to L and B, then separated into M (ETPTA rich), N (PEGDA rich) and D (ETPTA rich), C (PEGDA rich), respectively. Obviously, composition M contained more PEGDA than D, and N more than C. Therefore, M and N allowed more mass transfer than D and C before the depletion of PEGDA, resulting in more subsequent phase separation steps to generate more separated layers. Meanwhile, the larger amount of remaining PEGDA in the separated layers offers higher partial miscibility, which facilitates mass transfer with higher velocity. Hence, the multi-step phase separation speeds up with higher initial PEGDA concentration. Additionally, it should be noted that in the present study, the starting mixture is a binary mixture of ETPTA and PEGDA, while in previously reported works, ternary starting mixtures are usually used.6-8 The comparison of multilayered emulsion droplets separated from binary and ternary starting mixtures (see Figure S6) suggested that the phase separation processes started from near the binodal curve can encapsulate more water phase in the separated droplets, in contrast with those started from the boundary.


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Figure 3. (a) Diameter of each layer and layer number of the phase separated droplets prepared with diverse initial PEGDA concentrations. (b) Comparison of the composition path on the phase diagram for high (K, 60% v/v) and low (A, 40% v/v) initial PEGDA concentration. The sizes of the separated layers were then investigated and it was found that the initial droplet size played an important role. Figure 4a shows the measured d1, d2, d3 plotted versus d1, where dj refers to the diameter of jth layer of the droplet. According to the self-similar cycles of


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mass transfer, the diameters of consecutive separated layers follow dj＋1=adj－b, , a and b are constants fitted with experimental data.8 Consequently, d2=ad1－b, d3=ad2－b, then ௗమ ௗభ

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In our experiment, the evolution of consecutive layer diameter ratios in the current agent system, d2/d1 and d3/d2, does not obey the equations. As shown in Figure 4b, d3/d2 increases and d2/d1 decreases with the increase of d1, whereas according to the above equations, d3/d2 and d2/d1 should both increase as d1 increases. This tendency can be understood as following. For a given initial PEGDA concentration, the mass transfer velocity of an emulsion droplet is determined by its surface area, which is proportionate to d02, where d0 is the diameter of the pristine single emulsion droplet. Meanwhile, the volume of a droplet is proportionate to d03. Hence, the mass transfer velocity (v0) per unit volume of the droplet should be proportionate to 1/ d0. The phase diagram in Figure 4c shows the comparison of the first step phase separation for large (①) and small (②) droplets. For small droplets, v0 is faster, and the corresponding composition path is from A to O, while the composition of large droplets transfer from A to B. Subsequently, O and B separates into P (PEGDA rich), Q (ETPTA rich) and C (PEGDA rich), D (ETPTA rich). Specifically, P and C form the new second layers, while Q and D form the first layers for small and large droplets, respectively. It is revealed in the phase diagram that the formation of phase P consumes more PEGDA percentage of the pristine single droplet than C, and leaves less PEGDA in the first layer (phase Q), making d2/d1 larger for smaller droplets. On the other hand, because phase P contains a smaller percentage of ETPTA than C, it will produce a relatively smaller third layer after second step phase separation, causing smaller d3/d2 for smaller droplets.


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Figure 4. (a) Diameters of each layer plot versus diameter of the first layer d1. Initial PEGDA concentration is 40% v/v. (b) The variation of d2/d1 and d3/d2 with d1. (c) Comparison of the composition path for large (①) and small (②) droplets. Inset, phase separated droplets of 380

µm and 16 µm prepared with the same initial PEGDA concentration (40% v/v). In the previous work done by Haase and Brujic,8 the phase separated droplets were stable for weeks. However, the multilayered emulsions prepared with the present agent system can be stabilized for only several minutes, this may because that the molecular weight of the surfactant PVA is relatively lower for the present ternary agent system (see Figure S7). Interestingly, the as-produced multilayered emulsions can offer a gradual release of the separated cores in an order


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from inner to outer layers. Taking the 45 µm triple emulsion at T=25℃ for example, as shown in Figure 5a, its third layer core broke and coalesced with the outermost layer at 4 min, and subsequently the second layer core broke and coalesced with the continuous phase at 10 min. In addition, when raised the temperature to 60℃, the third layer and second layer cores broke faster at 1 min and 2.5 min, respectively, as shown in Figure 5a. This orderly temperature-responsive release of the inner separated cores is expected to be a desired feature for delivering active chemical agents by using the MTIPS method. In the current multi-step phase separation system, both ETPTA and PEGDA are UV light curable. Therefore, the as-produced multilayered emulsions can be readily solidified into single, double, triple and quadruple layered microspheres by UV light curing. By tuning the initial PEGDA concentration and size of the pristine droplet, the layer number of the phase separated emulsions can be adjusted, resulting in onion-like microspheres, as shown in Figure 5b. Figure 5c is the SEM image of a double layered microsphere cut open, clearly shows the core-shell structure. In addition, monodisperse double emulsions with diameters under 10 µm, which are difficult to prepare by common multi-emulsification method, were prepared through multi-step phase separation, and followed by UV light curing to form core-shell structured microspheres, as shown in Figure 5d. In general, the present multi-step phase separation template provides a simple, alternative, and efficient method in designing microparticles.


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Figure 5 (a) Orderly temperature-responsive release of the inner separated cores. (b) Schematic of the preparation of multilayered microspheres through UV light curing. (c) SEM image of a core-shell structured microsphere obtained by solidifying phase separated double emulsions. (d) Core-shell structured microspheres under 10 µm prepared by multi-step phase separation and UV curing.


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Conclusions In summary, the multi-step phase separation in an emulsion droplet of a new agent system consisting of ethoxylated trimethylolpropane triacrylate, polyethyleneglycol diacrylate 700 and water was demonstrated. Analysis of the phase separated droplets suggested that the multi-step phase separation process was governed by the partial miscibility of all components offered by the remaining polyethyleneglycol diacrylate 700 in the separated layers. The initial concentration of polyethyleneglycol diacrylate 700 determines the number of the separated layers, and the sizes of the separated layers can be controlled by varying the initial droplet size. The as-produced multilayered emulsions were demonstrated to offer an orderly temperature-responsive release of the inner separated cores. This multiple emulsion template can also be used for preparing solid multilayered microspheres, simply by ultraviolet light curing. Generally, the present multi-step phase separation system provides new opportunities in extending the application of the mass transfer induced phase separation method in related research fields.

Acknowledgement The authors acknowledge the financial support by the National Natural Science Foundation of China (No. 51322501, No 51420105006) and the Project funded by China Postdoctoral Science Foundation (No. 2015M581082).

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(20) Koo, H. Y.; Chang, S. T.; Choi, W. S.; Park, J. H.; Kim, D. Y.; Velev, O. D. EmulsionBased Synthesis of Reversibly Swellable, Magnetic Nanoparticle-Embedded Polymer Microcapsules. Chem. Mater. 2006, 18, 3308-3313. (21) Chakraborty, M.; Petya, I. M.; Bart, H. J. Selective Separation of Toluene from n‐Heptane via Emulsion Liquid Membranes Containing Substituted Cyclodextrins as Carrier. Sep. Sci. Technol. 2006, 41, 3539-3552. (22) Chakraborty, M.; Bart, H. J. Separation of Toluene and n-Heptane through Emulsion Liquid Membranes Containing Ag + as Carrier. Chem. Eng. Technol. 2005, 28, 1518-1524. (23) Utada, A. S.; Lorenceau, E.; Link, D. R.; Kaplan, P. D.; Stone, H. A.; Weitz, D. A. Monodisperse Double Emulsions Generated from a Microcapillary Device. Science 2005, 308, 537-541. (24) Seo, M.; Paquet, C.; Nie, Z.; Xu, S.; Kumacheva, E. Microfluidic consecutive flow-focusing droplet generators. Soft Matter 2007, 3, 986-992. (25) Okushima, S.; Nisisako, T.; Torii, T.; Higuchi, T. Controlled Production of Monodisperse Double Emulsions by Two-Step Droplet Breakup in Microfluidic Devices. Langmuir 2004, 20, 9905-9908.


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Figure 1. (a) Schematics of the capillary microfluidic device used for preparing single emulsion droplets. (b) Formation of double, triple and quadruple droplets over time with initial PEGDA concentration (CP) at 10%, 40% and 60% v/v, respectively. The droplets shown in the microscopy images were dyed by Sudan III. The right column shows fluorescent images referring to the PEGDA rich (red, dyed by CA) and ETPTA rich (dark) regions. Scale bars are 200 µm. 83x67mm (300 x 300 DPI)


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Figure 2. (a) Schematic of the mass transfer process in two-step phase separation. (b) Ternary phase diagram illustrating the composition path of the droplet in two-step phase separation. (c) Evolution of the volume of the separated first layer during multi-step phase separation process for initial PEGDA concentration at 10%, 40% and 60% v/v. 168x120mm (300 x 300 DPI)


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Figure 3. (a) Diameter of each layer and layer number of the phase separated droplets prepared with diverse initial PEGDA concentrations. (b) Comparison of the composition path on the phase diagram for high (K, 60% v/v) and low (A, 40% v/v) initial PEGDA concentration. 83x118mm (300 x 300 DPI)


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Figure 4. (a) Diameters of each layer plot versus diameter of the first layer d1. Initial PEGDA concentration is 40% v/v. (b) The variation of d2/d1 and d3/d2 with d1. (c) Comparison of the composition path for large (①) and small (②) droplets. Inset, phase separated droplets of 380 µm and 16 µm prepared with the same initial PEGDA concentration (40% v/v). 83x78mm (300 x 300 DPI)


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Figure 5 (a) Orderly temperature-responsive release of the inner separated cores. (b) Schematic of the preparation of multilayered microspheres through UV light curing. (c) SEM image of a core-shell structured microsphere obtained by solidifying phase separated double emulsions. (d) Core-shell structured microspheres under 10 µm prepared by multi-step phase separation and UV curing. 83x113mm (300 x 300 DPI)


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Mass-Transfer-Induced Multistep Phase ... - ACS Publications

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