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Solvent Magic for Organic Particles Bing Guo,† Eshu Middha,† and Bin Liu*
ACS Nano Downloaded from pubs.acs.org by EAST CAROLINA UNIV on 03/13/19. For personal use only.
Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585 ABSTRACT: Organic particles have attracted extensive attention due to their broad scientific and industrial applications. Solvents play important roles in producing organic particles with fine-tuned sizes, shapes, and surface morphologies, thus the advancement of microfluidic devices with a thorough understanding of solvent miscibility offers additional opportunities to fabricate organic particles in large quantities. In this issue of ACS Nano, Chen et al. report that solvents could play a seemingly magical role in switching both reaction directions and particle morphologies from the same starting materials. Through monitoring the particle formulation kinetics, both social self-sorting and narcissistic self-sorting mechanisms have been proposed, which offer powerful methods to yield organic particles with desirable shapes and compositions.
ORGANIC PARTICLE SYNTHESIS Organic particles integrate the merits of organic materials, such as tunable structures, tailorable properties, and facile processability, with flexible particle parameters, including size, shape, and surface morphology.1 As a result, organic particles have demonstrated widespread and appealing applications in photoelectrical devices, sensing, coating, catalysis, and biomedical theranostics.1−8 Because the performance of organic particles relies heavily on their morphological parameters, controllable formulation of organic particles has attracted increasing attention through one-pot or postsynthesis methods.1,5,6 To date, emulsion, nanoprecipitation, and self-assembly are the most widely used methods for organic particle production.6−8 During the particle formation process, inter- and intramolecular interactions, such as covalent bonding and noncovalent interactions (e.g., hydrogen bonding, π−π interactions, solvophobic interactions, van der Waals forces, electrostatic interactions, host−guest interactions, cation−π interactions, etc.), play important roles in controlling organic molecular aggregation.1,5,8 Therefore, organic solvents, which can easily modulate intermolecular interactions, impact formulation processes, affecting material solubility, reactions, and assembly, as well as the resultant particle compositions, morphologies, functionalities, and performances.9−15
EMULSION Among different organic particle fabrication methods, emulsion with surfactants is one of the simplest and most straightforward methods for the encapsulation of preformed molecules or in situ polymerization of monomers.6,16,17 In a typical oil-in-water emulsion, hydrophobic organic molecules are dissolved in hydrophobic solvent and the mixture is subsequently homogenized and dispersed in water with surfactant stabilizers. In the following step, the solvent is extracted by evaporation and organic molecules aggregate together in solid particles because of their intramolecular interactions and solvophobic effects.16 In the biomedical industry, many hydrophilic drug-containing particles are prepared using emulsion techniques with nonpolar solvents, forming heterogeneous drug aggregates located inside particles.16 These particles often exhibit burst release of drugs to yield suboptimal therapeutic outcomes. The poor distribution of hydrophilic drug in particles results from the solvophobic interactions between nonpolar solvents (e.g., chloroform) and hydrophilic drugs during the emulsion process. In contrast, adding a small amount of hydrophilic cosolvents such as acetone or acetonitrile could introduce effective solvent−drug interactions and overcome the solvophobic effects to yield homogeneous drug distribution inside emulsion particles.16 More importantly, this result would contribute to controlled drug release for optimal treatment.16 Therefore, the selection of particular solvents for emulsion is an important factor for controlling particle properties.
Organic solvents, which can easily modulate intermolecular interactions, impact formulation processes, affecting material solubility, reactions, and assembly, as well as the resultant particle compositions, morphologies, functionalities, and performances. © XXXX American Chemical Society
NANOPRECIPITATION Among different organic particle formulation methods, nanoprecipitation is the most straightforward and reproducible method to synthesize organic particles with sizes in the range of a few to hundreds of nanometers (Figure 1a).7,18,19,21,22 Nano-
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Figure 1. (a) Scheme of nanoparticle formulation process by the nanoprecipitation method. (b) Schematic of a microfluidic system for particle fabrication.20 (c) Changes of size and polydispersity index of particles in water/methanol (MeOH) mixture with different MeOH volume ratios.20 (d) Ternary phase diagram of solute/solvent/water system with ouzo zone, spinodal curve, and binodal curve. The binodal curve corresponds to the miscibility limit, and the spinodal curve indicates the thermodynamic stability limit.
dissolved in water-miscible solvents. Many organic small and macromolecules with excellent optical, electrical, and mechanical properties exhibit poor solubility in water-miscible solvents due to their strong π−π interactions, which can only be dissolved in water-immiscible solvents, such as dichlorobenzene or chloroform.20 Therefore, traditional nanoprecipitation cannot be universally applied to these compounds. To address this issue, we have developed an advanced microfluidic nanoprecipitation process with high throughput and excellent reproducibility for the synthesis of uniform NPs by strategically tuning the miscibility between antisolvents and solvents by premixing methanol in an antisolvent (Figure 1b). Taking the preparation of poly{2,2-[(2,5-bis(2-hexyldecyl)-3,6-dioxo2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)dithiophene]5,5-diyl-alt-thiophen-2,5-diyl} P0 NPs as an example, due to strong π−π stacking, the polymer cannot be dissolved well in pure THF.20 Therefore, both DPP3T and lipid−polymer DSPE−mPEG are dissolved into organic solvents composed of CHCl3 and THF (v/v = 1:9). When the solvent stream is mixed with an antisolvent (methanol, MeOH, and water mixture) in a microfluidic device, the presence of a low-volume percentage of MeOH in the antisolvent is not sufficient for complete miscibility with CHCl3 in the solvent stream. As a result, large droplets and micron-size aggregates form. As the amount of MeOH in the antisolvent increases, the miscibility
precipitation is a solvent displacement method in which precursors (e.g., polymers, dyes, drugs, etc.) are dissolved in a water-miscible organic solvent, such as acetone or tetrahydrofuran (THF). Swift injection of this organic solvent mix into the aqueous phase causes spontaneous formation of nanoparticles (NPs). The interplay of hydrophobic and hydrophilic forces between the core and shell and the level of supersaturation experienced by the encapsulated molecules aid the formation of stable micelles in aqueous media. For conventional bulk nanoprecipitation, NPs are fabricated in batch-type reactors (Figure 1a) and often exhibit broad size distributions, due to the effective variations in synthesis conditions.7,18 In contrast, continuous synthesis using microfluidic two-dimensional (2D) and three-dimensional (3D) devices with tunable physiochemical properties and efficient mixing can produce NPs at large scales with precise size control and narrow size distribution (Figure 1b).7,20 Several polymer-encapsulated NPs with high biocompatibility and biodegradability have been synthesized using microfluidics through the process of nanoprecipitation. The polymer matrices include poly(lactide-co-glycolic acid) (PLGA), poly(lactide-coglycolide)-b-poly(ethylene glycol) (PLGA-b-PEG), and 1,2distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-mPEG), among others.7,18,19,22 The process of nanoprecipitation is limited for organic molecules that can be B
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solvent, PS-b-P4VPMeI molecules aggregated into spheres by narcissistic self-sorting due to similar solubility parameters between THF and PS segments, as well as the strong electrostatic repulsion interactions among the polyelectrolyte chains. These molecules could also form rods composed of small spheres, vesicles, and large micelles at THF/dioxane weight ratios of 6:4, 5:5, and 0:10, respectively. These morphological changes are due to the difference in the dielectric constants between THF and dioxane, which affects intermolecular polyelectrolyte electrostatic interactions in different solvent mixtures.12 In another example, solvents were reported to influence solvophobic interactions, hydrogen bonding, and π−π interactions. This influence was illustrated using a butterflyshaped dioctaoxacycloporphyrin zinc complex (DOCP-Zn) molecule as an example (Figure 2).15 The DOCP-Zn molecule has a planar hydrophobic porphyrin ring and hydrophilic glycol side chains that can easily self-assemble, driven mainly by π−π interactions among porphyrin rings and hydrogen bonding among the side chains. On a silicon slide, in THF/MeOH (v/v = 1:1), DOCP-Zn molecules formed one-dimensional (1D) nanorods, whereas 2D nanoslices were observed in THF/ isopropyl alcohol (i-PrOH) (v/v = 1:1). Because alcohol is a poor solvent for porphyrin but a good solvent for glycol chains, both solvophobic and π−π interactions facilitated porphyrin assembly while hydrogen bonding between glycol chains and solvent minimized side-chain interactions. The two different morphologies are the result of differences in hydrogen bonding strengths between glycol chains and MeOH or i-PrOH and the solvent volatility. Once 4,4′-bipyridine was added to DOCP-Zn in the CHCl3/cyclohexane mixture, new coordination interactions formed between zinc atoms of porphyrins and nitrogen atoms of 4,4′-bipyridine (4,4′-bpy) to yield biporphyrin-zinc4,4′-bpy complex (BDOCP-Zn-bpy), which increased the distance between adjacent glycol side chains with reduced π−π interactions between porphyrins. As hydrogen bonding between the side chains and solvent does not exist in the CHCl3/ cyclohexane mixture, nanospheres were formed. Interestingly, the transition between nanospheres and nanoslices/nanorods was reversible by changing solvents. For example, adding iPrOH to nanospheres on the silicon slide led to nanoslice formation as the solvent impeded the coordination interactions. Further treatment in CHCl3/cyclohexane (v/v = 1:1) caused the nanoslices to return to nanospheres due to the recovery of coordination interactions in the presence of a nonpolar solvent mixture. The researchers noted that nanorods exhibited higher photoluminescence intensity than did nanospheres or nanoslices. These findings demonstrate that solvents play an important role in controlling the growth of organic assemblies with different optical functions.
increases, as well. A breakthrough point (25% MeOH) is identified when both streams are completely miscible, which results in the formation of monodispersed NPs (Figure 1c).20 When the amount of MeOH in the antisolvent is increased beyond the breakthrough point, the size of the NPs increases (Figure 1c). This size increase is due to the low supersaturation experienced by solute with an increase in solvent composition.21,22 With the presence of a high volume ratio of MeOH in antisolvent, the size and polydispersity of NPs increases with a polydispersity index above 0.3. According to Vitale and Katz, there is a metastable region between the binodal and spinodal curves in the ternary phase diagram of solute/solvent/ antisolvent, known as the “ouzo region”, where local supersaturation of solute results in the synthesis of small and stable NPs (Figure 1d).22 With increasing solvent-to-water ratios, the mixture goes beyond the ouzo zone and forms large aggregates (non-ouzo zone), due to the low level of supersaturation experienced by the solute molecules. At this point, only a few solute molecules experience supersaturation to form nuclei. Instead of encountering each other, these nuclei grow by accumulating all nearby isolated solute molecules to yield large aggregates. In this respect, the type and composition of solvent plays a major role in the preparation of organic nanoparticles.21,22 With the advanced microfluidic nanoprecipitation method, we can easily manipulate the properties of the solvent and antisolvent so that organic molecules, with both good and poor solubility in water-miscible solvents, can be synthesized into small and uniform NPs through nanoprecipitation.
SELF-ASSEMBLY In comparison to emulsion and nanoprecipitation methods in which external mechanical forces are commonly applied, selfassembly is an emerging, bottom-up approach to transform preformed molecules into particles noncovalently without applying external mechanical forces.1,5,8,13−15 The self-assembly process in a mixture can involve social self-sorting of different molecular species or narcissistic self-sorting of the same molecules in a kinetic and/or thermodynamic fashion.23,24 In addition, self-assembly processes are not only stimulated by a variety of intra/intermolecular driving forces but are also greatly affected by interactions between the solvent and the organic molecules.11−15
Self-assembly processes are not only stimulated by a variety of intra-/ intermolecular driving forces but are also greatly affected by interactions between the solvent and the organic molecules.
SOLVENT SWITCHED REACTION AND SELF-ASSEMBLY Despite extensive investigation in postsynthesis self-assembly of organic molecules, few researchers have demonstrated the ability to control both molecular synthesis and self-assembly of organic molecules in one step.26 The work by Chen and coauthors described in this issue of ACS Nano presents an interesting idea to produce organic particles with tunable chemical and morphology structures by simply adjusting reaction solvents from the same starting materials of compound 1 and compound 2 (Figure 3).26 In MeOH, the starting materials underwent a [2 + 2] cycloreaction to yield a Schiff base of macrocycle 3. Driven by the dynamic and reversible noncovalent interactions, such as CH···N and CH···O hydrogen
To date, much effort has been devoted to the design of organic molecules with specific structural features to introduce different driving forces for self-sorting. These molecules include amphiphilic block copolymers, polyelectrolytes, host−guest complexes, aromatic molecules, etc.1,5,8,12−15,25 Notably, solvent selection is the magic key to process molecules into selfassembly particles with designed morphologies.10,12−15 Taking ionic polystyrene-b-poly(4-vinylpyridinium methyl iodide) (PSb-P4VPMeI) block polyelectrolytes as an example, Yu et al. illustrated how solvent variation could affect electrostatic interactions during self-assembly. When THF was used as the C
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Figure 2. Illustration of the self-assembly process for porphyrin derivatives under different solvent systems. DOCP-Zn, as shown, complexed with 4,4′-bipyridine to form DOCP-Zn-bpy; tetrahydrofuran, THF; methanol, MeOH; cyclohexane, CH; isopropypl alcohol, i-PrOH. Reproduced from ref 15. Copyright 2012 American Chemical Society.
Figure 3. Synthetic route toward macrocycles 3 and 4 and the particle morphology changes under different solvent systems. Adapted from ref 26. Copyright 2019 American Chemical Society.
The work by Chen et al. presents an excellent example of preparing organic particles with tunable chemical compositions and morphologies in one pot by adjusting solvents. The success of this work relies on the careful selection of materials and their subtle responses to different solvents.9,26 It would be interesting to know if other reactions or assemblies could be realized using the same or a similar approach. The tunable self-assembly of organic particles with increased complexity may lead to unusual functionalities for different applications, which remains to be explored.
bonding and CH···π interactions, macrocycle 3 formed solid microspheres via intermediates including 1D quadrilateral columns, spherical cluster-like “burr lower balls”, and 3D aggregates. Interestingly, when more water was added to MeOH at MeOH/H2O (v/v ≤ 1:2), the reaction completely switched to a [1 + 1] cycloreaction to yield only macrocycle 4. Macrocycle 4 underwent several intermediate assemblies from a 1D quadrilateral column driven by CH···π interactions, to hollow 2D and 3D layers through CH···O bonding, to small vesicles before forming thermodynamically stable hollow vesicles. When the solvent system was changed to MeOH/H2O (v/v ≥ 1:2), the reaction between 1 and 2 yielded both macrocycles 3 and 4, forming core−shell-shaped spherical nanoparticles with 3 as the core and 4 as the shell via narcissistic self-sorting. Detailed characterization confirmed the reaction mechanisms and revealed the assembly processes for the particle formation.
CONCLUSION AND OUTLOOK The various applications of organic particles stimulate the development of advanced fabrication technologies to yield different particles with desirable compositions, sizes, and morphologies. Careful selection of solvent systems during D
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The work by Chen and co-authors described in this issue of ACS Nano presents an interesting idea to produce organic particles with tunable chemical and morphology structures by simply adjusting reaction solvents from the same starting materials.
particle formation processes, including emulsion, nanoprecipitation, and self-assembly, enables researchers to fine-tune both organic molecular interactions and the resultant particle morphologies. By adjusting the miscibility of solvent and antisolvent in microfluidics systems, it is possible to achieve continuous mass production of uniform NPs with high reproducibility. By adjusting reaction solvent systems from the same starting materials, Chen et al. report an elegant method to realize organic particles with tunable compositions and morphology parameters. These examples demonstrate the solvent magic in controlling the intermolecular interactions, reaction pathways, and particle formation, which should spark researchers to develop more organic particles with customized compositions and morphologies with optimal performance for targeted applications.
AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected]. ORCID
Bing Guo: 0000-0001-7981-0644 Eshu Middha: 0000-0002-9392-4805 Bin Liu: 0000-0002-0956-2777 Author Contributions †
B.G. and E.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS The authors are grateful to the Singapore NRF Competitive Research Program (R279-000-483-281), National University of Singapore (R279-000-482-133), and NRF Investigatorship (R279-000-444-281). REFERENCES (1) Yan, Y. L.; Zhao, Y. S. Organic Nanophotonics: From Controllable Assembly of Functional Molecules to Low-Dimensional Materials with Desired Photonic Properties. Chem. Soc. Rev. 2014, 43, 4325−4340. (2) Karimi, M.; Sahandi Zangabad, P.; Baghaee-Ravari, S.; Ghazadeh, M.; Mirshekari, H.; Hamblin, M. R. Smart Nanostructures for Cargo Delivery: Uncaging and Activating by Light. J. Am. Chem. Soc. 2017, 139, 4584−4610. (3) Guo, B.; Cai, X. L.; Xu, S. D.; Fateminia, S. M. A.; Liu, J.; Liang, J.; Feng, G. X.; Wu, W. B.; Liu, B. Decoration of Porphyrin with Tetraphenylethene: Converting a Fluorophore with AggregationCaused Quenching to Aggregation-Induced Emission Enhancement. J. Mater. Chem. B 2016, 4, 4690−4695. (4) Guo, B.; Sheng, Z. H.; Hu, D. H.; Liu, C. B.; Zheng, H. R.; Liu, B. Through Scalp and Skull NIR-II Photothermal Therapy of Deep Orthotopic Brain Tumors with Precise Photoacoustic Imaging Guidance. Adv. Mater. 2018, 30, 1802591−1802598. E
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(25) Feng, L. H.; Zhu, C. L.; Yuan, H. X.; Liu, L. B.; Lv, F. T.; Wang, S. Conjugated Polymer Nanoparticles: Preparation, Properties, Functionalization and Biological Applications. Chem. Soc. Rev. 2013, 42, 6620− 6633. (26) Chen, H. Y.; Huang, C.; Deng, Y. X.; Sun, Q.; Zhang, Q. L.; Zhu, B. X.; Ni, X. L. Solvent-Switched Schiff-Base Macrocycles: Self-Sorting and Self-Assembly-Dependent Unconventional Organic Particles. ACS Nano 2019, DOI: 10.1021/acsnano.8b09478.
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