Accepted Manuscript

Title: Polymer Nanoparticles: Preparation Techniques and

Size-Control Parameters

Authors: J. Prasad Rao, Kurt E. Geckeler

PII: S0079-6700(11)00023-2
DOI: doi:10.1016/j.progpolymsci.2011.01.001
Reference: JPPS 674

To appear in: Progress in Polymer Science

Received date: 24-6-2010

Revised date: 11-1-2011
Accepted date: 12-1-2011

Please cite this article as: Rao JP, Geckeler KE, Polymer Nanoparticles: Preparation
Techniques and Size-Control Parameters, Progress in Polymer Science (2008),
doi:10.1016/j.progpolymsci.2011.01.001

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 Polymer Nanoparticles: Preparation Techniques and Size-Control

Parameters

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J. Prasad Raoa) and Kurt E. Geckeler a,b)*

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a) Department of Materials Science and Engineering, b) Department of Nanobio Materials and Electronics,

World-Class University (WCU), Gwangju Institute of Science and Technology (GIST), 1 Oryong-dong), Buk-gu,

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Gwangju 500-712, South Korea

Tel.: +82-62-970-2316; Fax: +82-62-970-2338;

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E-mail: keg@gist.ac.kr
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Abstract

Polymer nanoparticles have attracted the interest of many research groups and have been
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utilized in an increasing number of fields during the last decades. Generally, two main strategies
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are employed for their preparation: the dispersion of preformed polymers and the polymerization
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of monomers. Various techniques can be used to produce polymer nanoparticles, such as solvent
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evaporation, salting-out, dialysis, supercritical fluid technology, micro-emulsion, mini-emulsion,

surfactant-free emulsion, and interfacial polymerization. The choice of method depends on a

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number of factors, such as, particle size, particle size distribution, area of application, etc. This

review covers the general description of the preparation of polymer nanoparticles and the

detailed description of the crucial parameters involved in techniques designed to obtain the

desired properties.

Key Words: Polymer nanoparticles, solvent evaporation, salting-out, dialysis, supercritical fluid,

emulsion, micro-emulsion, mini-emulsion.

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Page 1 of 61
Contents
1. Introduction
2. Definition and classification of polymer nanoparticles
3. Overview of polymer nanoparticles preparation techniques
4. Dispersion of preformed polymers

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4.1. Solvent evaporation
4.2. Salting-out

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4.3. Nanoprecipitation
4.4. Dialysis

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4.5. Supercritical fluid technology
4.5.1. Rapid expansion of supercritical solution

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4.5.2. Rapid expansion of supercritical solution into liquid solvent
5. Polymerization of monomers
5.1. Emulsion polymerization
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5.1.1. Conventional emulsion polymerization
5.1.2. Surfactant-free emulsion polymerization
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5.2. Mini-emulsion polymerization

5.3. Micro-emulsion polymerization
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5.4. Interfacial polymerization

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5.5. Controlled/living radical polymerization

6. Conclusions and outlook
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Acknowledgement
References
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1. Introduction

The field of polymer nanoparticles (PNP) is quickly expanding and playing a pivotal role in a

wide spectrum of areas ranging from electronics to photonics, conducting materials to sensors,

medicine to biotechnology, pollution control to environmental technology, and so forth during

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the past decades [1-9]. This fact can be realized from the ever increasing number of publications

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as depicted in Fig. 1. This trend is based on their unique properties, which meet a wide range of

applications and market needs.

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The properties of PNPs have to be optimized depending on the particular application. In

order to achieve the properties of interest, the mode of preparation plays a vital role. Thus, it is

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highly advantageous to have preparation techniques at hand to obtain PNPs with the desired
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properties for a particular application. Although some information regarding preparation

techniques of PNPs is available, it is scattered in the literature and restricted to a few areas. For
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example, there are a few individual reviews on techniques such emulsion polymerization and
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nanoencapsulation [10-19 ], but none for other techniques and none integrating all these

techniques and considering the size control parameters. Therefore, the objective in this review to
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collect and compile this missing information, to update the few previous reviews made on this
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subject, and also to highlight recent developments.

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The aim of this review article is primarily not to provide comprehensive information

about a particular method of PNP preparation, but to provide and explain vital criteria and factors

involved in the different methods of PNP preparation. We cover not only the different

preparation techniques for PNP, but also highlight a series of properties and parameters such as

the particle size, particle size distribution, surface area, etc. The particle size and the particle size

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Page 3 of 61
distribution of PNPs are of great importance because they determine their key properties such as

viscosity, surface area, and packing density.

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2. Definition and classification of polymer nanoparticles

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Nanoparticles are frequently defined as solid, colloidal particles in the range 10-1,000 nm

[20,21]. The term PNP is a collective term given for any type of polymer nanoparticle, but

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specifically for nanospheres and nanocapsules. Nanospheres are matrix particles, i.e., particles

whose entire mass is solid and molecules may be adsorbed at the sphere surface or encapsulated

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within the particle. In general, they are spherical, but "nanospheres" with a nonspherical shape
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are also described in the literature [22]. Nanocapsules are vesicular systems, acting as a kind of

reservoir, in which the entrapped substances are confined to a cavity consisting of a liquid core
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(either oil or water) surrounded by a solid material shell [23]. A schematic representation of
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PNPs is shown in Fig. 2.

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3. Overview of the preparation techniques for polymer nanoparticles

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PNPs can be conveniently prepared either from preformed polymers or by direct

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polymerization of monomers using classical polymerization or polyreactions [24]. Methods like

solvent evaporation, salting-out, dialysis and supercritical fluid technology, involving the rapid

expansion of a supercritical solution or rapid expansion of a supercritical solution into liquid

solvent, can be utilized for the preparation of PNP from preformed polymers. On the other hand,

PNPs can be directly synthesized by the polymerization of monomers using various

polymerization techniques such as micro-emulsion-, mini-emulsion-, surfactant-free emulsion-

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Page 4 of 61
and interfacial polymerization. An illustration of different preparation techniques for PNP is

given in Fig. 3. The choice of preparation method is made on the basis of a number of factors

such as the type of polymeric system, area of application, size requirement, etc. For instance, a

polymeric system that is developed for an application in the biomedical or environmental fields

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should be completely free from additives or reactants such as surfactants or traces of organic

solvents. In this case, techniques like full RESS (rapid expansion of a supercritical solution) or

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RESOLV (rapid expansion of a supercritical solution into a liquid solvent) can be selected, as

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they do not utilize any surfactant or organic solvent during the PNP preparation. These are just a

few of many factors that have to be considered before choosing a particular technique for the

PNP preparation.

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4. Dispersion of preformed polymers
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Several methods developed and successfully utilized to prepare PNPs by dispersing

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preformed polymers are discussed in detail in the following sections.

4.1. Solvent evaporation

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Solvent evaporation was the first method developed to prepare PNPs from a preformed
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polymer [25]. Although originally proposed by polymer chemists, its main developments are
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found in pharmaceutical technology where biodegradable polymers have been applied in the

production of drugs [26]. In this method, polymer solutions are prepared in volatile solvents and

emulsions are formulated. In the past, dichloromethane and chloroform were widely used, but are

now replaced with ethyl acetate which has a better toxicological profile. The emulsion is

converted into a nanoparticle suspension on evaporation of the solvent for the polymer, which is

allowed to diffuse through the continuous phase of the emulsion [27,28].

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 Solvent evaporation is the most widely employed technique to prepare nanoparticles of

polymers in the current literature on techniques using a dispersion of preformed polymers. In the

conventional methods, two main strategies are being used for the formation of emulsions: the

preparation of single-emulsions, e.g., oil-in-water (o/w) or double-emulsions, e.g., (water-in-oil)-

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in-water, (w/o)/w. These methods utilize high-speed homogenization or ultrasonication, followed

by evaporation of the solvent, either by continuous magnetic stirring at room temperature or

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under reduced pressure. Afterwards, the solidified nanoparticles can be collected by

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ultracentrifugation and washed with distilled water to remove additives such as surfactants.

Finally, the product is lyophilized. Generally, a polymer dissolved in an organic solvent forms

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the oil-phase, whereas the aqueous phase containing the stabilizer forms the water phase. Fig. 4

summarizes the preparation method by the double-emulsion-solvent evaporation method.

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Nanoparticles have been prepared from polymers and copolymers using different solvents
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and stabilizers (shown in Table 1). For example, PLGA nanoparticles with a diameter of 130 ±
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27 nm were prepared by Venier-Julienne et al. [29]. Poly(organophosphazene) derivative-based

nanoparticles with a particle size of around 200 nm were prepared by Vandorpe et al. [30] using
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acetone and poloxamine 908 as the solvent and stabilizing agent, respectively. Song et al. [31]
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prepared nanoparticles of PLGA with a typical particle size of 60-200 nm by employing

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dichloromethane and acetone (8:2, v/v) as the solvent system and PVA as the stabilizing agent.

PLGA nanoparticles of about 200 nm were produced by Lemoine et al. [32] by utilizing

dichloromethane 1.0% (w/v) as the solvent and PVA or Span 40 as the stabilizing agent. They

adopted both the single-emulsion and double-emulsion method to prepare the nanoparticles and

studied the effect of the emulsion method and the experimental parameters on the particle size.

They observed that in the case of the single-emulsion method, an increase of the PVA (stabilizer)

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Page 6 of 61
concentration resulted in a marked decrease of the nanoparticle size, while the homogenizer

speed, the evaporation rate or the freeze-drying only slightly influenced the nanoparticle size. In

contrast, with the double-emulsion method, it has been noted that PVA in the internal aqueous

phase decreased the nanoparticle size compared to that with Span 40. The PVA concentration in

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the external aqueous phase, the homogenizer speed, or freeze drying only slightly influenced the

nanoparticle size.

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In an another report [33], an extensive study was made on the influence of experimental

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parameters such as the preparation temperature, solvent evaporation method, internal aqueous

phase volume, surfactant concentration, and the influence of the molecular mass of the polymer

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on the particle size, the zeta potential, the residual surfactant percentage, and the polydispersity

index of the PLA nanoparticles prepared by the double-emulsion method. They concluded from
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their study that a high surfactant concentration (3%, w/v, or higher) ensures a good
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emulsification process and, therefore, leads to smaller particles, with a satisfactory polydispersity
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index. When the nanoparticle characteristics and the residual amount of PVA are taken into

account, a 3 to 5% PVA solution is required. On the other hand, the molecular mass of PLA does
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not appear to be a critical parameter for the particle characteristics. PEG-coated nanospheres
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with a mean diameter of about 200 nm have been also prepared [34]. They used sodium cholate
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as the stabilizing agent instead of PVA for the double-emulsion solvent evaporation method. A

preparation of monomethoxy-poly(ethylene oxide)-poly(lactic acid) (mPEO-PLA) nanoparticles

was reported using the double-emulsion method [35]. Sucrose was added to overcome the

aggregation of the nanoparticles during freeze-drying, and their concentration was found to

depend on the proportion of monomethoxy-poly(ethylene oxide) in the nanoparticle suspension.

PNPs based on PLLA, PCL and PLGA were reported, with the smallest particles, with a mean

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Page 7 of 61
diameter of 76 nm obtained for PLGA, with SDS as the surfactant, while the PCL particles were

the largest reported [36].

The mixing technique is important in the preparation of PNPs by the solvent evaporation

method. Bilati et al. [37] studied the influence of the sonication process on the characteristics of

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PLGA nanoparticles prepared by the water-in-oil/water solvent evaporation method. The

duration and intensity of sonication were investigated with respect to the ability to modify the

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size and distribution of the nanoparticle population. It was demonstrated that the duration of the

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second mixing step, which leads to the w/o/w emulsion, has a greater influence on the final mean

particle size than the first step for the water-in-oil emulsion. When the second emulsification

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time period was increased, the mean particle size decreased to a certain level. This study

suggested that a threshold exists for the sonication intensity leading to a controlled particle size
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with a narrow distribution.
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There has been a continuous search for developing PNPs with optimum properties, and in
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this respect various types of stabilizing agents and solvent systems have been studied.

Poly(ethylene oxide)-modified poly(β-amino ester) nanoparticles with an average size of 100-

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150 nm (Fig. 5) were prepared using the single-emulsion method [38]. Ethanol was the solvent
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and Pluronic F-108, a non-ionic surfactant composed of a poly(ethylene oxide)-poly(propylene

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oxide)-poly(ethylene oxide) triblock copolymer, was the stabilizer.

The concentrations of polymer and solvent used in the preparation of the emulsion also

affect the final properties of the PNPs prepared by the solvent evaporation method. This effect

was examine in a work in which either of two organic solvents (methylene chloride and ethyl

acetate) were utilized as the dispersed phase to prepare nanoparticles of PLGA [39]. They

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Page 8 of 61
concluded that the size of the particles prepared with methylene chloride was larger those

prepared with ethyl acetate.

The preparation of polystyrene copolymer nanoparticles by a very simple method has

been reported [40]. To this end, a small amount of a poor solvent (water) of the polymer was

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slowly added to the solution of the polymer in a "good" solvent. The solution, initially optically

transparent immediately after mixing, gradually became turbid on standing at room temperature

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as the good solvent due evaporated, leaving the precipitated polymer in the form of fine particles.

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The size of the PNPs was affected by the preparation conditions, such as the concentration of the

solution and the procedure for mixing of the poor solvent with the solution. In this method: 1) in

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order to preferentially evaporate the good solvent, the boiling point of the good solvent should be

lower than that of the poor solvent, and, 2) the good solvent should be miscible with the poor
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solvent. Higuchi et al. [41] prepared hemispherical polystyrene nanoparticles by employing a
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similar method, concluding that the hemispherical particles of polystyrene were formed by
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adding water to dilute the tetrahydrofuran solution at a concentration of less than 0.2 g/L.

Although the solvent evaporation method can be a simple method for the preparation of
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PNP, it is time consuming and possible coalescence of the nanodroplets during the evaporation
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process may affect the final particle size and morphology.

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4.2. Salting-out

The methods discussed in the previous section require the use of organic solvents, which

are hazardous to the environment as well as to physiological systems. To overcome this hurdle,

Bindschaedler et al. [42] first disclosed a modified version of emulsion process that involves a

salting-out process, which avoids surfactants and chlorinated solvents. The emulsion is

formulated with a polymer solvent which is normally totally miscible with water, i.e., acetone,

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Page 9 of 61
and emulsification of the polymer solution in the aqueous phase is achieved, more like an

Ouzo-effect, without employing any high-shear forces [43], by dissolving high concentration of

salt or sucrose chosen for a strong salting-out effect in the aqueous phase. Magnesium chloride,

calcium chloride and magnesium acetate are commonly used suitable electrolytes [44-56]. The

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miscibility properties of water with other solvents are modified as these components dissolve in

the water. A reverse salting-out effect, obtained by dilution of the emulsion with a large excess

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of water, leads to the precipitation of the polymer dissolved in the droplets of the emulsion. In

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fact, upon dilution, migration of the solvent for the polymer from the emulsion droplets is

induced due to the reduction of the salt or sucrose concentration in the continuous phase of the

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emulsion. A compilation of the polymer nanoparticles prepared by employing the salting-out

method is given in Table 2.

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In a typical process carried out by Allemann et al. [43], an electrolyte-saturated, or a
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nonelectrolyte-saturated aqueous solution containing PVA as a viscosity-increasing agent and

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stabilizer, was added to an acetone solution of the polymer under continuous stirring. The

saturated aqueous solution prevented the acetone from mixing with the water by a salting-out
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process. After the preparation of an oil-in-water emulsion, water was added in a sufficient
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amount to allow the complete diffusion of acetone into the aqueous phase, resulting in the
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formation of nanospheres.

PLA nanoparticles were prepared by Leroux and co-workers [57] by adding an aqueous

gel containing magnesium acetate tetrahydrate and PVA to an acetone solution of the polymer,

forming a water-in-oil emulsion. Despite the miscibility of water with acetone, a liquid-liquid

two-phase system was formed due to the presence of the salting-out agent. An oil-in-water

emulsion was obtained on further addition of the aqueous gel, finally, sufficient enough pure

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Page 10 of 61
water was added to allow diffusion of acetone into the aqueous phase, which resulted in the

formation of nanoparticles with an average size of 295 nm.

In a recent work carried out by the Zhang group [58], PTMC nanoparticles were prepared

by both the single-emulsion method and the salting-out method. In addition, a comparative study

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has been conducted on the effect of the stirring speed and polymer concentration on the

nanoparticle size. It has been noticed that, when applying the salting-out method, PTMC with a

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size between 183 and 251 nm were formed. The effect of stirring speed and polymer

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concentration on the nanoparticle size were less pronounced than in the single-emulsion method

and much smaller particles were always obtained under comparable conditions. These

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differences are probably due to the fact that the organic solvent used in the salting-out method

(THF) is water-miscible, while this is not the case for CH2Cl2, which is used in the single-
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emulsion method. The required energy for forming the droplet surface is therefore expected to be
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less in the salting-out method. In a work carried out by Song et al. [59] PLGA nanoparticles were
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prepared by employing NaCl as the salting out agent instead of MgCl2 or CaCl2.

4.3. Nanoprecipitation
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The nanoprecipitation method was developed by Fessi et al. [60] for the preparation of
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PNP. It is also called as solvent displacement method. The basic principle of this technique is
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based on the interfacial deposition of a polymer after displacement of a semipolar solvent,

miscible with water, from a lipophilic solution. Rapid diffusion of the solvent into non-solvent

phase results in the decrease of interfacial tension between the two phases, which increases the

surface area and leads to the formation of small droplets of organic solvent [60, 61 ].

Nanoprecipitation system consists of three basic components: the polymer (synthetic, semi

synthetic or natural), the polymer solvent and the non-solvent of the polymer. Organic solvent

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(i.e., ethanol, acetone, hexane, methylene chloride or dioxane) which is miscible in water and

easy to remove by evaporation is choosen as polymer solvent. Due to this reason, acetone is the

most frequently employed polymer solvent in this method. [60,62,63] Sometimes, it consists of

binary solvent blends, acetone with small amount of water [64], blends of acetone with ethanol

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[65,66,67] and methanol [68]. On the other hand, the non-solvent phase consisting of a non-

solvent or a mixture of non-solvents is supplemented with one or more naturally occurring or

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synthetic surfactants. Table 3 shows different examples of polymers, solvents, non-solvents and

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stabilizing agents used in the nanoprecipitation formulations and particle size acheived. As it can

be seen, although an extensive range of polymers [69] can be used theoretically, in practice

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research has been performed with only a limited number of them.

The polymers commonly used are biodegradable polyesters, especially poly(ε-capro-

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lactone) (PCL) [70-74], polylactide (PLA) [75,76] and poly(lactide-co-glycolide) (PLGA).
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[77,78] Eudragit [66] can also be used as many other polymers such as polyalkylcyanoacrylate
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(PACA) [79-81]. Natural polymers such as allylic starch [82], dextran ester [83] were also used

though synthetic polymers have higher purity and better reproducibility than natural polymers
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[ 84 ]. On the other hand, some polymers are PEG copolymerized in order to decrease
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nanoparticle recognition by the reticular endothelial system [68].

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PNPs are produced by slow addition of the organic phase to the aqueous phase under

moderate stirring. Even, reversing this order by adding the aqueous phase to the organic phase

also leads to the formation of PNP. The nanoparticles with a well-defined size are characterized

by a narrow distribution formed instantaneously during the rapid diffusion of the polymer

solution in the non-solvent phase.

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Page 12 of 61
 The key variables determining the success of the method and affecting the

physicochemical properties of PNP are those associated with the conditions of adding the

organic phase to the aqueous phase, such as organic phase injection rate, aqueous phase agitation

rate, the method of organic phase addition and the organic phase to aqueous phase ratio.

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Likewise, PNP characteristics are influenced by the nature and concentration of their

components [70,74]. Although, a surfactant is not required to ensure the formation of PNP by

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nanoprecipitation, the particle size is influenced by the surfactant nature and concentration. [73,

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70] Moreover, the addition of surfactants helps to preserve the nanoparticle suspensions from

agglomeration over long storage periods [60].

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Lince et al. [85] indicated that the process of particle formation in the nanoprecipitation

method comprises three stages: nucleation, growth and aggregation. The rate of each step
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determines the particle size and the driving force of these phenomena is the ratio of polymer
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concentration over the solubility of the polymer in the solvent mixture. The separation between
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the nucleation and the growth stages, is the key factor for uniform particle formation. Ideally,

operating conditions should allow a high nucleation rate strongly dependent on supersaturation
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and low growth rate.

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Nanoprecipitation is a simple, fast and reproducible method which is widely used for the
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preparation of both nanospheres and nanocapsules. Eventhough low polymer surfactant

concentrations are employed, challenges pertaining to low polymer concentration in the organic

phase have to be addressed.

4.4. Dialysis

Dialysis offers a simple and effective method for the preparation of small, narrow-

distributed PNP [60,86-88]. Polymer is dissolved in an organic solvent and placed inside a

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Page 13 of 61
dialysis tube with proper molecular weight cutoff. Dialysis is performed against a non-solvent

miscible with the former miscible. The displacement of the solvent inside the membrane is

followed by the progressive aggregation of polymer due to a loss of solubility and the formation

of homogeneous suspensions of nanoparticles. The mechanism of PNP formation by dialysis

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method is not fully understood at present. It is thought that it may be based on a mechanism

similar to that of nanoprecipitation (see Section 4.3) proposed by the Fessi et al. [60] A number

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of polymer and copolymer nanoparticles [89-98] were obtained by this method and table 4

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provides a compendium of various parameters employed in dialysis systems.

Oh et al. [99] reported the formation of poly(γ-benzyl-L-glutamate)-b-poly(ethylene

an
oxide) nanoparticles by using DMF. Poly(lactide)-b-poly(ethylene oxide) nanoparticles were

prepared by the Lee group [100] using DMF as the solvent. The solvent used in the preparation
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of the polymer solution affects the morphology and particle size distribution of the nanoparticles.
d

Akagi et al. [101], prepared poly(γ-glutamic acid) nanoparticles using solvents such as DMSO,
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DMF, DMAc, NMPy and they observed that in the case of DMSO, the morphologies of the

nanoparticles were spherical, with diameters that ranged from about 100 to 200 nm. In contrast,
p

various-sized nanoparticles were formed when NMPy was used as the initial solvent. Moreover,
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the solvent NMPy induced a broader size distribution (Fig. 6). ‘Intelligent’ nanoparticles with
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multi-functional sensitivity have been reported by Lo et al. [102], through PLA-g-P(NIPAm-co-

MAA) graft copolymers by the dialysis method using DMSO as the solvent. In another work

carried out by the Na group [103], poly(L-lactic acid)-b-poly(ethylene glycol) nanoparticles of

spherical shape with a size range of 90–330 nm were produced by employing DMSO as the

solvent.

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Page 14 of 61
 Poly(ethylenimine)-b-poly(ethyleneglycol)-bis-(p-nitrophenyl carbonate) nanoparticles

were prepared with a size range of 18-75 nm by Nimesh et al. [104]. The p-nitrophenoxide ions

generated during the reaction were easily removed by dialysis against a 5% sodium bicarbonate

solution for 3 days prior to dialyzing against distilled water. Hornig et al. [105] recently reported

t
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the preparation of cellulose acetate and mixed cellulose esters ie., cellulose acetate propionate, -

butyrate and –pthalate, nanoparticles. The samples were dissolved in DMAc at low

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concentrations (4mg/ml), dialyzed against distilled water by employing a dialysis membrane

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with MMCO 3500 g/mol and obtained PNP ranging from 166 to 399 nm. Chronopoulou et al.

[106] reported a novel osmosis based method (Fig. 7) for the preparation of various natural- and

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synthetic PNP. It is based on the use of a physical barrier, specifically dialysis membrane or

common semipermeable membranes that allow the passive transport of solvents to slow down
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the mixing of the polymer solution with a nonsolvent; the dialysis membrane contains the
d

solution of the polymer. Fig. 8 shows the SEM micrographs of polystyrene nanoparticles
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obtained under varying preparation conditions.

4.5. Supercritical fluid technology

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As may be noted, the methods in the preceding subsections involve organic solvents, and
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the need to develop environmentally safer methods for the production of PNP has motivated
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research on the utility of supercritical fluids as more environmental friendly solvents, with the

potential to produce PNPs with high purity and without any trace of organic solvent [107,108].

Supercritical fluid and dense gas technology are expected to offer an interesting and effective

technique of particle production, avoiding most of the drawbacks of the traditional methods.

Indeed, examples have been published on pharmaceutical particle formation, formulation, and

control with a supercritical fluid and dense gas [109-113].

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Page 15 of 61
 Two principal processes have been developed for the production of nanoparticles using

supercritical fluids:

1. Rapid expansion of supercritical solution (RESS); and

2. Rapid expansion of supercritical solution into liquid solvent (RESOLV).

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These are considered in turn in the following two subsections.

4.5.1. Rapid expansion of supercritical solution

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In traditional RESS, the solute is dissolved in a supercritical fluid to form a solution,

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followed by the rapid expansion of the solution across an orifice or a capillary nozzle into

ambient air. The high degree of supersaturation, accompanied by the rapid pressure reduction in

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the expansion, results in homogenous nucleation and, thereby, the formation of well-dispersed

particles. Results from mechanistic studies of different model solutes for the RESS process
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indicate that both nanometer- and micrometer-sized particles are present in the expansion jet
d

[114].
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A few studies have been carried out on the production of PNPs using RESS. Chernyak et

al. [115] produced droplets of poly(perfluoropolyether diamide) from the rapid expansion of CO2
p

solutions. The RESS experimental apparatus is shown schematically in Fig. 9. It consists of three
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major units: a high-pressure stainless steel mixing cell, a syringe pump, and a pre-expansion unit.
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A solution of polymer in CO2 is prepared at ambient temperature. Before the solution leaves the

nozzle, using syringe pump, it is pumped to the pre-expansion unit and is heated isobarically to

the pre-expansion temperature. The supercritical solution is now allowed to expand through the

nozzle, at ambient pressure.

The concentration and degree of saturation of the polymer have a considerable effect on

the particle size and morphology of the particles for RESS. Blasig et al. performed a RESS

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Page 16 of 61
process with poly(heptadecafluorodecyl acrylate) using concentrations of 0.5-5 wt.-% in CO2

[116].

The RESS process was used by the Lim group [117] to produce spherical particles of

PSFTE, 50–500 nm in size, from solutions (0.1–0.5 wt.-% PSFTE) in CO2 at pre-expansion

t
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temperatures of 40 oC and at pre-expansion pressures of 27.6 E6 Pascal. In a typical experiment,

CO2 was introduced into PSFTE using the syringe pump and after displacing the CO2 from pre-

cr
heater, PSFTE sample was collected by directly spraying particles, through the nozzle, onto a

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slide glass. In addition to concentration and degree of saturation other factors such as material

properties, processing conditions, molecular mass of the polymer, etc., also play a vital role in

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determining the particle size. Sane et al. [118] performed rapid-expansion experiments with CO2

+ THF solutions of PLLA and have demonstrated that the solid-state diffusion coefficient of the
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solute (D) is a key variable for controlling the particle size during the RESS processing. PLLA
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polymers with melting points (Tm) of 121 and 162 OC, pre-expansion temperatures (Tpre) of 70
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and 100 OC, and THF co-solvent concentrations of 10 and 20 wt. % were investigated for their

effect on the solid-state diffusion coefficient. The mass average molecular masses of the
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investigated PLLAs were 1340 and 6050 g/mol, well below the critical molecular mass for the
ce

entanglement Mc, which is approximately 9 kg/mol. An increase in Tm, a decrease in Tpre, and a
Ac

decrease in THF concentration, resulted each in a consistent decrease in both particle size and

interparticle fusion. In general, RESS products from PLLA consisted predominantly of

nanoparticles 30–100 nm in diameter, dispersed with either micron-sized particles or

agglomerates of nano- and submicron-sized particles, with the type of dispersion depending on

the value of D. These results suggest that the initially formed precipitates during RESS are nano-

17
Page 17 of 61
sized and that the larger particles are subsequently obtained, because of coalescence in the free

jet, a process that is favored by higher values of solid-state diffusion coefficient of the solute (D).

Even though this technique utilizes no organic solvent for the formation of PNPs, the

prime products obtained using this technique are microscaled rather than nanoscaled, which is

t
ip
the main drawback of RESS. In order to overcome this drawback a new supercritical fluid

technology known as RESOLV has been developed.

cr
4.5.2. Rapid expansion of supercritical solution into liquid solvent

us
A simple, but significant modification to RESS involves expansion of the supercritical

solution into a liquid solvent instead of ambient air, termed as RESOLV [119]. The liquid

an
solvent apparently suppresses the particle growth in the expansion jet, thus making it possible to

obtain primarily nanosized particles. A schematic representation of RESOLV process is

M
presented in Fig. 10.
d

Meziani et al. [120] reported the preparation of PHDFDA nanoparticles having an

te

average size of less than 50 nm. The polymer was soluble in supercritical CO2, but insoluble in

water. In a typical experiment, a CO2 solution of the polymer PHDFDA (0.3 wt %) was
p

pressurized in a syringe pump and pushed through the heating unit to reach the desired
ce

supercritical temperature before reaching the expansion nozzle. The expanding solution passed
Ac

through the nozzle into a chamber containing water at ambient temperature. Since the polymer

was insoluble in water, it precipitated to form nanoparticles. The expansion of the supercritical

CO2 solution of 60 mL took about 30 min. In the first 5 min of the rapid expansion, the aqueous

nanoparticle suspension appeared clear and stable. However, SEM micrographs (Fig. 11)

revealed that as the rapid expansion progressed, larger particles were formed in the aqueous

suspension due to aggregation of the initially formed nanoparticles. The use of an aqueous NaCl

18
Page 18 of 61
solution in place of water at the receiving end of the expansion process stabilized the initially

formed nanoparticles to some extent due to the increased ionic strength in the suspension.

The polymer concentration in the pre-expansion supercritical solution plays a vital role in

determining the product morphology. This effect has been observed by the Meziani group [121],

t
ip
while working on the RESOLV processing of PMMA and the biodegradable polymer PLLA in

supercritical CO2-cosolvent. Accordingly, the co-solvent increases the polymer solubility and

cr
the rapid expansion of the polymer solutions in supercritical CO2 with low and high

us
concentrations into an ambient aqueous sodium chloride solution produces exclusively

nanoparticles and nanofibers, respectively.

an
In spite of the availability of a number of supercritical fluids, e.g., carbon monoxide, n-

pentane, water, ammonia, etc. [122], the main hurdle in utilizing the RESS and RESOLV green
M
technologies for the production of PNPs, is the poor solubility or even non-solubility of polymers
d

in these supercritical fluids.

te

5. Polymerization of monomers
p
ce

The techniques discussed previously involve the production of PNPs from preformed

polymers and did not involve any polymerization processes. To attain the desired properties for a
Ac

particular application, suitable polymer nanoparticles must be designed, which can be done

during the polymerization of monomers. Processes for the production of PNPs through the

polymerization of monomers are discussed, focusing principally on mini-, micro-, and emulsion

polymerization techniques as the three major techniques currently in use. Other hetero-phase

polymerizations, such as interfacial and living/controlled radical polymerization, are also

employed in the preparation of PNPs.

19
Page 19 of 61
5.1. Emulsion polymerization

Emulsion polymerization is the most common method used for the production of a wide

range of specialty polymers. The use of water as the dispersion medium is environmentally

friendly and also allows excellent heat dissipation during the course of the polymerization. Based

t
ip
on the utilization of surfactant, it can be classified as conventional and surfactant-free emulsion

polymerization [123,124].

cr
5.1.1. Conventional emulsion polymerization

us
Conventional emulsion polymerization accounts for the majority of the world’s

production by emulsion polymerization. In the conventional system, the ingredients are

an
comprised of water, a monomer of low water solubility, water-soluble initiator and a surfactant.

At the end of the reaction, PNPs are typically ~102 nm in size, each containing many polymer
M
chains. Examples of conventional emulsion polymerization are listed in Table 5. Colloidal
d

stabilizers may be electrostatic, steric or electrosteric, displaying both stabilizing mechanisms.

te

Initiation occurs when a monomer molecule dissolved in the continuous phase collides with an

initiator molecule that may be an ion or a free radical. Alternatively, the monomer molecule can
p

be transformed into an initiating radical by high-energy radiation, including γ-radiation,

ce

ultraviolet or strong visible light. Phase separation and formation of solid particles can take place
Ac

before or after the termination of the polymerization reaction [125]. Polystyrene (PS) [126-133],

poly(methylmethacrylate) (PMMA) [134,135 ], poly(vinylcarbazole) [136], poly(ethylcyano-

acrylate) (PECA) and poly(butylcyanoacrylate) [137] nanoparticles were produced by dispersion

via surfactants into solvents, such as cyclohexane, n-pentane, and toluene. Methods of

polymerization developed to prepare polyalkylcyanoacrylate nanoparticles are well understood,

leading to nanoparticles with well-defined properties. The majority of poly(alkylcyanoacrylate)

20
Page 20 of 61
nanoparticles are obtained through anionic polymerization [138-142] of the corresponding

monomer. This reaction is spontaneously initiated by the hydroxyl groups of water or by other

nucleophilic groups present on the molecules dissolved in the polymerization system. The

diameter of the PNPs depends on the type of surfactant added to the polymerization medium.

t
ip
The smallest aqueous PNPs with a diameter of 50 nm were obtained with polyethyleneoxide

lauryl ester (Brij 35), whereas the addition of an anionic surfactant led to the formation of PNPs

cr
with diameters of approximately 300 nm [143].

us
5.1.2. Surfactant-free emulsion polymerization

Conventional emulsion polymerization systems utilize varying quantities of surfactants

an
that need to be eliminated from the final product but are hard to completely remove. Removal of

surfactants is a time-consuming process that increases the cost of production. Moreover,

M
increasing environmental and energy concerns cannot be effectively addressed because of these
d

drawbacks. As an alternative, emulsion polymerization has been performed in the absence of

te

added emulsifier, often referred to in literature as surfactant-free, emulsifier-free, or soap-less

emulsion polymerization. This technique has received considerable attention [144-150] for use as
p

a simple, green process for PNP production without the addition and subsequent removal of the
ce

stabilizing surfactants. Examples of surfactant-free emulsion polymerization formulations are

Ac

presented in Table 6. The reagents used in an emulsifier-free system include deionized water, a

water-soluble initiator (i.e., KPS, potassium per sulphate) and monomers, more commonly vinyl

or acryl monomers. In such polymerization systems, stabilization of PNPs occurs through the use

of ionizable initiators or ionic co-monomers. Several mechanisms of nucleation and particle

growth have been proposed for emulsion polymerization without an emulsifier, for example,

micellar-like nucleation [151,152] and homogeneous nucleation [145,153-158]. The distinction

21
Page 21 of 61
between the two is based on the aqueous solubility of the monomer. Homogenous nucleation is

important in surfactant-free emulsion polymerization [145].

PMMA nanoparticles were prepared by promoting polymerization with microwave

irradiation [159,160]. It was reported that the average particle size was primarily controlled by

t
ip
the monomer concentration. The particle size increased from 103 nm to 215 nm when the

concentration was increased from 0 to 0.3 mol/L. Chiu et al. [161] directly initiated the MMA

cr
polymerization using a Cu2+/HSO3- redox initiation system and obtained PMMA nanoparticles

us
with a negative charge because of anionic sulfite ion-bonding. Fang et al. [162] prepared PMMA

nanospheres with a particle size of 200 to 600 nm via SFEP. Hydrophilic laponite clay was used

an
to stabilize the emulsions of MMA dispersed in distilled water. Synthesis of PMMA

nanoparticles was additionally reported by Camili and group [163], where KPS and acetone were
M
employed as the initiator and co-solvent, respectively. According to the authors, the particle
d

diameter is determined by the following: i) solution dielectric constant, and ii) solubility of the
te

MMA monomer.

Polyacrylate nanoparticles [164] with a particle size of 172.5 nm were prepared by

p

employing NaSS as the stabilizing agent; the particle size was reduced from 263.4 nm to 172.5
ce

nm by altering the NaSS concentration. Using ultrasonic irradiation, an anionic ionizable water-
Ac

soluble initiator, KPS, and cetyl alcohol as the co-stabilizer, polystyrene nanoparticles [165]

were prepared with a higher polymerization rate and a particle size of 200 to 250 nm. The

particles had a narrow molecular mass distribution, and the sonication time played a vital role in

controlling the particle size and distribution. Lee et al. [166] reported the preparation of

poly(styrene/thiophene) nanoparticles by Fe3+ oxidative polymerization. The particle size ranged

from 300 to 800 nm with a core-shell morphology that resulted from the difference in

22
Page 22 of 61
polymerization rates of the monomers and the electrostatic attraction between sulfonate and Fe3+

ions. PHEMA nanoparticles with an average size of 150 nm in diameter, a polydispersity index

of 1.171, and a specific surface area of 17,779 m2/g were produced by Ozturka and group [167].

Frank et al. [168] employed an imidazolium-based ionic liquid as a continuous phase to prepare

t
ip
polyimide nanoparticles (ca. 69 nm) through the hetero-phase polycondensation of aromatic

tetracarboxylic acids and diamines. The polyimides, which were insoluble in the ionic liquid,

cr
could be easily separated by precipitation with an immiscible solvent and centrifugation.

us
Monomer and costabilizers act as stabilizing agents for one another. Polypyrrole nanospheres

were fabricated by Kim et al. [169] by employing various continuous phases, such as octanol,

an
benzene, and ethyl acetate. Smaller spheres, with an average particle size of 60 nm, were

obtained by altering the water and octanol volume ratios (Fig. 12).
M
Surfactant-free emulsion polymerization has emerged as a simple, green process for PNP
d

production without the addition and subsequent removal of stabilizing surfactants. Even with this
te

success, several challenges still exist that greatly hinder the expanded utility of traditional

surfactant-free emulsion polymerization, including the preparation of monodisperse and

p

precisely controlled particle size [170].

ce

5.2. Mini-emulsion polymerization

Ac

Publications on the mini-emulsion polymerization and the development of a wide range

of useful polymer materials have recently increased substantially. A typical formulation used in

mini-emulsion polymerization consists of water, monomer mixture, co-stabilizer, surfactant, and

initiator (Fig. 13). The key difference between emulsion polymerization and mini-emulsion

polymerization is the utilization of a low molecular mass compound as the co-stabilizer and also

23
Page 23 of 61
the use of a high-shear device (ultrasound, etc). Mini-emulsions are critically stabilized, require a

high-shear to reach a steady state and have an interfacial tension much greater than zero.

Versatile PNPs have been developed with various co-stabilizers and initiator

combinations [171-179]. These combinations have a predominant influence on the formation and

t
ip
nature of the nanoparticles. A brief inference can be obtained from the compilation of different

mini-emulsion polymerization formulations, summarized in Table 7.

cr
PMMA [ 180 ] and poly(n-butylacrylate) [ 181 ] nanoparticles were produced by

us
employing SLS/DDM and SLS/hexadecane as surfactant/co-stabilizer systems, respectively.

Polyacrylicacid nanoparticles were synthesized by Kriwet et al. [182] using a co-emulsifier

an
system consisting of a mixture of Span 80 and Tween 80. The polymerization was initiated by

free radicals, and the particle size was dependent on the type of radical initiator used. Using
M
water-soluble initiators, such as APS, microparticles were obtained; however, nanoparticles were
d

generated almost exclusively with a diameter between 80 and 150 nm when lipophilic radical
te

initiators, such as AIBN, were used.

Landfester et al. [183] studied the preparation of PHEMA nanoparticles using Span 80 or
p

KLE3729 as the surfactant, and CH or HD as co-stabilizer. It was reported that non-ionic,

ce

amphiphilic block copolymers with poly(ethylene-co-butylene) tails were the most efficient
Ac

stabilizers that produced small and narrowly distributed latexes in a size range between 50 and

200 nm. The same group [184] produced stable dispersions of polyacrylonitrile nanoparticles in

the size range of 100 to 180 nm (Fig. 14) by polymerization in a mini-emulsion system using

SDS and HD as the surfactant and co-stabilizer, respectively.

Although mini-emulsion-based polymerization utilizes only a small amount of surfactant,

a quantity of surfactant remains in the polymer latex, thus, changing the properties of the PNPs.

24
Page 24 of 61
To overcome this drawback, extremely hydrophobic SMA and DMA were utilized [185] to

stabilize the mini-emulsion during the polymerization of styrene. The primary feature of this

approach was that the SMA or DMA acted as a co-surfactant in the preparation of the mini-

emulsion and it became chemically incorporated into the emulsion polymer during

t
ip
polymerization. The presence of undesired volatile organic compounds in the latex product was

minimized.

cr
Core-shell polymer nanoparticles, consisting of a magnetic core, magnetite, and a

us
biodegradable polymeric shell (poly(ethyl-2-cyanoacrylate)), were successfully prepared using

mini-emulsion polymerization [186]. Along with morphological characterization of the particles

an
produced, the efficiency of the coating was demonstrated by a thorough surface analysis carried

out by electrophoresis and contact angle measurements. The mobility of the composite particles
M
changed with pH and the ionic strength of the medium in a way similar to the pure polymer.
d

Therefore, the electrical surface properties of magnetite were almost completely masked by the
te

polymeric coating. Polystyrene single-walled carbon nanotube composites were prepared using

mini-emulsion polymerization [187], where SDS and 1-pentanol were employed as the surfactant
p

and co-surfactant, respectively. Zieglar et al. [188] reported the synthesis of polystyrene and
ce

PMMA nanoparticles using Lutensol AT 50 (Fig. 15).

Ac

5.3. Micro-emulsion polymerization

Micro-emulsion polymerization is a new and effective approach for preparing nanosized

polymer particles and has attracted significant attention. Although emulsion and micro-emulsion

polymerization appear similar because both methods can produce colloidal polymer particles of

high molar mass, they are entirely different when compared kinetically. Emulsion

polymerization exhibits three reaction rate intervals, whereas only two are detected in micro-

25
Page 25 of 61
emulsion polymerization. Both particle size and the average number of chains per particle are

considerably smaller in micro-emulsion polymerization [189]. In micro-emulsion polymerization,

an initiator, typically water-soluble, is added to the aqueous phase of a thermodynamically stable

micro-emulsion containing swollen micelles. The polymerization starts from this

t
ip
thermodynamically stable, spontaneously formed state and relies on high quantities of surfactant

systems, which possess an interfacial tension at the oil/water interface close to zero. Furthermore,

cr
the particles are completely covered with surfactant because of the utilization of a high amount

us
of surfactant. Initially, polymer chains are formed only in some droplets, as the initiation cannot

be attained simultaneously in all microdroplets. Later, the osmotic and elastic influence of the

an
chains destabilize the fragile micro-emulsions and typically lead to an increase in the particle

size, the formation of empty micelles, and secondary nucleation. Very small latexes, 5 to 50 nm
M
in size, coexist with a majority of empty micelles in the final product. Readers can refer to the
d

review literature for a more detailed description [14]. Differences among various emulsions
te

[14,190-193] are schematically represented in Fig. 16 and compiled in Table 8.

The types of initiator and concentration, surfactant, monomer and reaction temperature
p

are some of the critical factors affecting the micro-emulsion polymerization kinetics and the
ce

properties of PNP. A number of studies have been performed to investigate the effect of these
Ac

important factors, and a summary of monomers, which were polymerized using micro-emulsion

polymerization, is presented in Table 9.

Macias et al. [194] synthesized particles of a copolymer of MMA and NMA in a micro-

emulsion using AOT as surfactant, studying the effects of the type of initiator and amount of

functional monomer on the reaction kinetics. Sosa et al. [195] prepared vinyl acetate micro-

emulsions stabilized with AOT. They achieved nanosized particles smaller than 40 nm in

26
Page 26 of 61
diameter based on micro-emulsion systems containing 1% AOT and 3 % VA. This group also

examined the micro-emulsions as a function of concentration, type of initiator (V-50 and KPS)

and temperature. In other work performed by the same group [196], a comparative study was

presented on the characteristics of polyvinylacetate prepared by emulsion and micro-emulsion

t
ip
polymerization.

Various types of surfactants and their combinations [197-204] have been tested in the

cr
micro-emulsion polymerization of different monomers. In research described by the Xu and

us
group [205], a new surfactant with a Y-structure, SHOA, was synthesized and used to stabilize

the styrene micro-emulsion. At low initiator and high monomer content, a plateau of the

an
polymerization rate was observed when the micro-emulsion polymerization was initiated with

AIBN or BPO. The length of the plateau decreased with an increase in initiator concentration and
M
a decrease in monomer concentration, and disappeared at very low monomer quantities and at
d

very high initiator concentrations.

te

Poly(dimethylsiloxane) nanoparticles [206] in the range of 12 to 80 nm were produced

using a cationic surfactant; the CTAB and nonionic surfactants with the general formula
p

CxH2x+1[OCH2CH2]yOH were typically noted as CxEy. Polyhexylmethacrylate nanoparticles

ce

[207] with a range of 38 to 53 nm were prepared using a mixture of DTAB and DDAB as
Ac

stabilizer and VA-044 as the initiator. A surfactant mixture of SDS and AOT was employed in

micro-emulsion polymerization of butylacrylate, and latexes with a particle size smaller than 40

nm were obtained [208].

Surfactants can have adverse effects on latex properties. The non-polymerizable

surfactants adsorbed onto the surfaces of the latexes may desorb, resulting in a latex

destabilization. To overcome this drawback, Xu et al. [209] successfully utilized two poly-

27
Page 27 of 61
merizable anionic surfactants the SABSn, (n = 8 or 10) for the copolymerization with BMA using

the redox initiator APS/TMEDA at room temperature. They also reported the formation of

monodisperse particles ranging from 18 to 33 nm in diameter. Jang et al. [210] reported the

synthesis of polypyrrole nanoparticles with an average diameter of 02 nm (Fig. 17), using

t
ip
cationic the surfactant DeTAB.

Despite the many potential applications of polymer latexes obtained by micro-emulsion

cr
polymerization, the commercial use of this process has been limited because typical polymer

us
formulations are dilute and require a large ratio of surfactant to monomer. The surfactant

concentrations usually exceed the amount required for polymer stability.

5.4. Interfacial polymerization

an
Interfacial polymerization is one of the well-established methods used for the preparation
M
of polymer nanoparticles [211-215]. It involves step polymerization of two reactive monomers or
d

agents, which are dissolved respectively in two phases (i.e., continuous- and dispersed-phase),
te

and the reaction takes place at the interface of the two liquids [216]. The relative ease of

obtaining IP has made it a preferred technique in many fields, ranging from encapsulation of
p

pharmaceutical products [217] to preparation of conducting polymers [218].

ce

Nanometer-sized hollow polymer particles were synthesized by employing interfacial

Ac

cross-linking reactions as polyaddition and polycondensation [ 219 - 221 ] or radical poly-

merization [222,223]. Oil-containing nanocapsules were obtained by the polymerization of

monomers at the oil/water interface of a very fine oil-in-water micro-emulsion [224]. The

organic solvent, which was completely miscible with water, served as a monomer vehicle and the

IP of the monomer was believed to occur at the surface of the oil droplets that formed during

emulsification [225-227]. To promote nanocapsule formation, the use of aprotic solvents, such as

28
Page 28 of 61
acetone and acetonitrile, was recommended. Protic solvents, such as ethanol, n-butanol, and

isopropanol, were found to induce the formation of nanospheres in addition to nanocapsules

[228]. Alternatively, water-containing nanocapsules can be obtained by the IP of monomers in

water-in-oil micro-emulsions. In these systems, the polymer formed locally at the water-oil

t
ip
interface and precipitated to produce the nanocapsule shell [229,230]. Formulations for the

interfacial polymerization of different monomers are provided in Table 10.

cr
IP combined with spontaneous emulsification is a new technique used for nanoparticle

us
formation. Polyurethane nanocapsules with a particle size of approximately 258±29 nm were

prepared by Bouchemal and group [231]. The molecular masses of diols and polyols exhibited a

an
considerable influence on the nanocapsule characteristics, and an increase in molecular mass of

the polyols increased the mean size of the nanocapsules from 232±3 nm using EG to 615±39 nm
M
using PEG 600. Sub-micrometric particles containing an oil core and a polymer shell were
d

synthesized by combining the emulsification process and an IP reaction in a single stage [232]. A
te

fast dispersion of oil droplets (ca. 100 to 400 nm) was produced by spontaneous emulsification,

and a subsequent polycondensation reaction took place at the oil droplet surface. Polystyrene
p

60
nanocapsules [233] with liquid cores were prepared by Co γ-ray radiation, where NVP was
ce

used as the polar monomer. Poly(alkylcyanoacrylate) nanoparticles [234] with a particle size of
Ac

approximately 250 nm were prepared by Krauel and co-workers, using selected w/o droplet,

bicontinuous- or solution-type micro-emulsions with ethyl-2-cyanoacrylate. Polyaniline

nanoparticles [235] in the range of 30 to 80 nm were fabricated by carrying out IP at water/ionic

liquid ([C4mim]PF6) interface, where the water and ionic liquid formed a continuous and

dispersed phase, respectively. Kuo and co-workers [236] reported the synthesis of water-

dispersible polyaniline nanoparticles through the IP route by employing chemical oxidative

29
Page 29 of 61
polymerization of aniline with ammonium peroxidisulfate in aqueous PSS. The particle size of

the PANI-PSS nanoparticles was controlled by modulating the molar ratio of aniline/PSS and 5-

15 nm sized nanoparticles with uniform size distribution were obtained for aniline/PSS ratios

less than 1/1. Zhang and Lui [237] reported the fabrication of 100 to 200 nm sized polyaniline

t
ip
nanocapsules in the static condition, or with stirring, and investigated the amounts of the

surfactant, solvent, monomer and water on the formation of intact polyaniline capsules.

cr
Polyindole nanoparticles were synthesized by micro-emulsion polymerization and IP using

us
(NH4)2S2O8 as an oxidant, while CTAB was utilized as a surfactant in the micro-emulsion

system [238]. The different synthetic methods had a significant influence on the morphology and

an
electrochemical activity of polyindole. According to the authors, micro-emulsion polymerization

was superior to the IP and was potentially due to the introduction of surfactant in the former
M
method.
d

Although numerous methods are available for the production of PNPs using IP, problems
te

related to the precise size control remain. As an alternate option that has gained interest in recent

years, the use of membrane reactors that exhibit different functions, such as separation of
p

products from reaction mixtures and immobilization of catalysts, have been considered [239,240].
ce

The controlled addition of one reactant (the organic phase) to another reactant (the aqueous
Ac

phase) can be achieved by membrane reactors. This process may be compared to the membrane

emulsification process, where the dispersed phase permeates through the membrane pores to

form droplets in the continuous phase for the preparation of emulsions [241,242]. Other

advantages of this membrane reactor include the versatility of the preparation of either

nanocapsules or nanospheres by methods involving a polymerization of dispersed monomers.

Moreover, precise control of the average nanoparticle size can be attained by an appropriate

30
Page 30 of 61
choice of the membrane and membrane parameters. A schematic representation of the membrane

reactor for the preparation of PNPs is shown in Fig.18, and the degree of importance of various

parameters [243-248] of membrane emulsification process is provided in Table 11.

Charcosset and Fessi [249] performed IP using a membrane reactor and synthesized

t
ip
nanoparticles. They also investigated the influence of the following process parameters:

membrane pore radius, cross-flow rate, and transmembrane pressure. Yanagishita et al. [250]

cr
reported the photopolymerization of an undisclosed photocurable monomer, PAK-02, using the

us
membrane emulsification process by anodic porous alumina membrane. PNPs were fabricated by

employing different membranes with a varying pore radius. Fig. 19 shows the SEM images of

an
monodisperse nanoparticles prepared using anodic porous alumina with pore sizes of (a) 130, (b)

220, and (c) 320 nm.

M
Although the membrane reactor process offers useful advantages, key limitations, such as
d

level of complication, environmental burden and expensive processes, exist. To control the size
te

of the products, various membranes with different sizes of inner pores are required. These

drawbacks need to be addressed effectively and efficiently to promote the widespread utilization
p

of such techniques.
ce

5.5. Controlled/living radical polymerization (C/LRP)

Ac

The primary limitations of radical polymerization include the lack of control over the

molar mass, the molar mass distribution, the end-functionalities and the macromolecular

architecture. The limitations are caused by the unavoidable fast radical-radical termination

reactions. The recent emergence of many so-called controlled or ‘living’ radical polymerization

(C/LRP) processes has opened a new area using an old polymerization technique [251-253].The

most important factors contributing to this trend of the C/LRP process are increased

31
Page 31 of 61
environmental concern and a sharp growth of pharmaceutical and medical applications for

hydrophilic polymers. These factors have given rise to “green chemistry” and created a demand

for environmentally and chemically benign solvents such as water and supercritical carbon

dioxide. Industrial radical polymerization is widely performed in aqueous dispersed systems and

t
ip
specifically in emulsion polymerization. The primary goal was to control the characteristics of

the polymer in terms of molar mass, molar mass distribution, architecture and function.

cr
Implementation of C/LRP in the industrially important aqueous dispersed systems, resulting in

us
the formation of polymeric nanoparticles with precise particle size and size distribution control,

is crucial for future commercial success of C/LRP [254].

an
Among the available controlled/living radical polymerization methods [255,256], three

approaches (shown in Table 12) are presently successful and extensively studied and are listed
M
here: nitroxide-mediated polymerization (NMP) [257-261], atom transfer radical polymerization
d

(ATRP) [262-268] and reversible addition and fragmentation transfer chain polymerization
te

(RAFT) [269,270,271]. The nature and concentration of the control agent, monomer, initiator

and emulsion type (apart from temperature) are vital in determining the size of PNPs. Of these,
p

the nature of the control agent is critical in determining the particle size of the final product. For
ce

instance, the effect of nitroxides on the particle size was examined in detail by Cao et al. [272]
Ac

and Lansalot et al. [273] for C/LRP of styrene. They reported the formation of stable latexes with

small particle size (below 100 nm and 120 nm, respectively) and good consistency when acetoxy

derivatives (N6) and SG1 (N8) were employed. Matyjaszewski et al. [274] reported the

preparation of polyn-butylacrylate nanoparticles approximately 300 nm in size, which varied

with the concentrations of the initiator, the mediating (control) agent, the surfactant and the

temperature.

32
Page 32 of 61
 C/LRP has created a spectrum of opportunities for synthesizing PNPs with potential

applications in functional materials. Rapid growth in interest has occurred during recent years to

understand the heterogeneous C/LRP in NMP, ATRP, and RAFT. Despite the advances made in

understanding the fundamental aspects of the chemistry of C/LRP systems, a number of

t
ip
challenges must still be addressed. Some of these issues are common to the different forms of

C/LRP, whereas others are unique to each particular system. Problems common to NMP, ATRP,

cr
and RAFT include the presence of a residual control agent in the product, added process

us
complexity and cost, as compared to conventional radical polymerizations. The presence of

residual control agents raises concerns about color, odor, stability, and environmental legislative

an
compliance. Removal of the mediating agents from aqueous dispersions is likely to be more

difficult than from homogeneous solutions. These issues must be addressed to successfully
M
commercialize a product using C/LRP.
d
te

6. Conclusions and outlook

The main goal of this review is to provide information about the methods that are
p

available for preparing these fascinating polymer nanoparticles. It was observed that preparing
ce

PNP is a state-of-art that requires choosing a suitable technique among the various possible
Ac

methods, thorough utility of homogenization process, appropriate surfactants, worthy co-

surfactant, and suitable initiating system to obtain desired polymer with optimum property

enhancement. Methods like RESS, RESOLV and surfactant-free emulsion polymerization can be

successfully utilized for producing surfactant free PNP and moreover they are environment

friendly.

33
Page 33 of 61
 On the other hand, the fundamental knowledge about the processes in the preparation of

PNP is still limited. The effect of the homogenization conditions and the control of droplet size

distribution, which determines the particle size and morphology are not fully understood.

The field of PNP is now transforming from a budding stage to a blossoming stage and

t
ip
requires lot of attention on fundamental research to develop new functional materials, using these

beguiling particles, so that mankind can derive fruits out of them. Future research work should

cr
be focused on the development of techniques that provide precise control over the particle size

us
and morphology, which are the key determinants of the properties and applications of these

wondrous particles. These efforts will speed up the commercial utilization of PNP.

Acknowledgement an
M
This work was supported by the World-Class University (WCU) program at the Gwangju
d

Institute of Science and Technology (GIST) through a grant provided by the Ministry of
te

Education, Science and Technology (MEST) of Korea (Project No. R31-2008-000-10026-0).

p
ce
Ac

34
Page 34 of 61
Abbreviations

AA, acrylic acid; AAm, acrylamide; ACPA, 4,4’-azobis(4-cyanopentanoic acid); AIBN, 2,2’-

azobisisobutyronitrile; AOT, sodium bis(2-ethylhexyl) sulfosuccinate; AMA-80, sodium dihexyl

t
sulfosuccinate; Amphi-Dex, amphiphilic derivative of dextran; AN, acrylonitrile; Ani, aniline;

ip
APS, ammonium persulfate; ASPS, alkali soluble polymeric surfactant; ATRP, atom transfer

cr
radical polymerization; BA, butyl acrylate; BCA, n-butyl cyanoacrylate; BMA, butyl

us
methacrylate; BPO, benzoyl peroxide; BPMODA, bis(2-pyridylmethyl)-octadecylamine; Brij 30,

polyoxyethylene-4-lauryl ether; [C4mim]PF6, 1-butyl-3-methylimidazolium hexafluorophosphate;

an
CA897, poly(oxyethylene) octyl phenyl ether; CaCl2, calcium chloride; CAN, cerium

ammonium nitrate; CH, cyclohexane; CH2Cl2 ,methylene chloride; C4H6O2, methacrylic acid;
M
C/LRP, controlled/living radical polymerization; CMC-A9, polymeric surfactant based on

carboxymethyl cellulose and alkyl poly(etheroxy)acrylate; CMPEG, carboxymethylated

d

poly(ethylene glycol); CMS, chloromethyl styrene; CO2, carbon dioxide; CPDB, 2-cyanoprop-2-
te

yl dithiobenzoate; CTAB, cetyltrimethylammonium bromide; CTMA-Cl, cetyltrimethyl-

p

ammonium chloride; CuSO4.5H2O, cupric sulfate; DDAB, didodecyldimethylammonium

ce

bromide; DDA-HEEE, dodecanoic acid 2-(2-hydroxyethoxy)ethyl ester (neutral surfactant);

DeTAB, decyltrimethylammonioumbromide; DDM, dodecyl mercaptane; DexEst, dextran ester;

Ac

DIAMA-Na, SG1-based difunctional alkoxyamine; DMAc, dimethyl acetamide; DMA, dodecyl

methacrylate; DMAEMA, (dimethylamino)ethyl methacrylate; DMF, dimethylformamide;

DMMA-PS, 3-(N,N-dimethylmyristylammonio) Propanosulfonate (zwitterionic salt); DMSO,

dimethyl sulfoxide; C12H26S, dodecyl mercaptane; Dowfax 8390, a mixture of mono- and

dihexadecyl disulfonated diphenyloxide disodium salts; DTAB, dodecyltrimethylammonioum-

bromide; C4H8O2, ethyl acetate; EBiB, ethyl 2-bromoisobutyrate; ECNA, ethyl cyanoacrylate;

35
Page 35 of 61
EG, ethylene glycol; EUDRAGIT L100-55, methacrylic acid copolymer Type C USP/NF;

FeCl3.6H2O, ferric chloride; GMA, glycidyl methacrylate; HO-EBiB, 2-hydroxyethyl 2-

bromoisobutyrate; H2O2, hydrogen peroxide; HCl, hydrochloric acid; HD, hexadecane; HEMA,

hydroxylethyl methacrylate; HMA, hexyl methacrylate; IP, interfacial polymerization; IPDI,

t
ip
isophorone diisocyanate; K2CO3, potassium carbonate; KLE3729, poly(ethylene-co-butylene)-b-

poly(ethylene oxide); KPS, potassium persulfate; LMA, lauryl methacrylate; MAMA, SG1-

cr
based water-soluble alkoxyamine derived from methacrylic acid (also called BlocBuilder);

us
Mg(CH3COO)2.4H2O, magnesium acetate tetrahydrate; MgCl2, magnesium chloride; MgCl2. 6

H2O, magnesium chloride hexahydrate; Miglyol 812, mixture of triglycerides; MIM,

an
macroinimer; MONAMS, SG1-based alkoxyamine derived from methyl acrylate; mPEG,

monomethoxy-poly(ethylene glycol); mPEO-PLA, monomethoxy-poly(ethylene oxide)-poly-

M
(lactic acid); MMA, methyl methacrylate; MMCO, molar mass cut-off; NaCl, sodium chloride;
d

NaHCO3, sodium bicarbonate; Na2S2O3,Sodium Thiosulphate; NaSS, 4-styrenesulfonic acid

te

sodium salt hydrate; (NH4)2S2O8, ammonium persulfate; NMA, N-methylolacrylamide; NMPy,

N-methyl-2-pyrrolidone; NMP, nitroxide-mediated polymerization; NPA, N-propargylamide;

p

NVP, N-vinyl pyrrolidone; OEOMA, oligo(ethylene oxide) monomethyl ether methacrylate;

ce

OTAB, octyl trimethyl ammonium bromide; (o/w), oil-in-water; PA, pullulan acetate; PAK-02,
Ac

photocurable monomer; PANI-PSS, polyaniline-poly(styrenesulfonic acid); P(B/E-b-EO),

poly(butylenes-co-ethylene)-b-poly(ethylene oxide); PBG-PEO, poly(γ-benzyl-L-glutamate)-b-

poly(ethylene oxide); PCL, poly(ε-caprolactum); PDMAAm-TTC, poly(N,N-dimethylacryl-

amide)s (PDMAAm) with a reactive trithiocarbonate; PE/F68, poly(oxyethylene)-

poly(oxypropylene) copolymer; PEO, poly(ethylene oxide); PEG, poly(ethyleneglycol); PHB,

poly(hydroxyl butyrate); PHDFDA, poly(heptadecafluorodecylacrylate); PHEMA, poly-

36
Page 36 of 61
(hydroxyethyl methacrylate); PLAF, poly(lactide-fumarate); PLGA, poly(D,L-lactic acid-co-

glycolic acid); PLGF, poly(lactide-co-glycolide fumarate); PLLA, poly(L-lactic acid); Pluronic

F-108, non-ionic surfactant; PMA, poly(α,β-L-malic acid); PMMA, poly(methyl methacrylate);

P(MAA-co-S)-SG1 Macroinitiator, SG1 nitroxide-capped poly(methacrylic acid-co-styrene)

t
ip
macroalkoxyamines, P(NIPAM-MAA), poly(N-isopropylacrylamide-co-methacrylic acid);

Poloxamine 908, poly(ethylene oxide)-poly(propylene oxide) ethylene diamine co-polymer; PNP,

cr
polymer nanoparticles; POP, Poly(organophosphazene); PSFTE, poly[2-(3-thienyl) acetyl-

us
3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanoate]; PSS, poly(styrenesulfonic acid); PTMC,

poly(trimethylene carbonate); PVA, poly(vinyl alcohol); Py, pyrrole; RAFT, reversible addition

an
and fragmentation transfer; RESOLV, rapid expansion of supercritical solution into liquid

solvent; RESS, rapid expansion of supercritical solution; Rh-Catyl, rhodium based catalyst;
M
SABS, sodium 4-(v-acryloyloxyalkyl) oxy benzene sulfonate; SDS, sodium dodecyl sulfate;
d

SEM, scanning electron microscopy; SG1 (trade name of the Arkema group), N-tert-butyl-N-(1-
te

diethyl-phosphono-2,2-dimethylpropyl) nitroxide; SHOA, sodium 12-hexinoyloxy-9-

octadecenate; SLS, sodium lauryl sulfate; SOBS, sodiumoctylbenzene sulfonate; SMA, stearyl
p

methacrylate; SMTAPE, 5-sulfoisophthalic acid dimethyl ester sodium salt modified

ce

tetracarboxylic acid-terminated polyester; Span 40, sorbitan monopalmitate; Span 80, sorbitan
Ac

monooleate; Span 85, sorbitane trioleate; SPS, sodium persulfate; St, styrene; SWNT, single-

walled carbon nanotube; TEM, transmission electron microscopy; Th, thiophene; THF,

tetrahydrofuran; TMEDA, tetramethylethylenediamine; TosDex, tosyl dextran; TPGS, D-α-

tocopheryl poly(ethylene glycol); TPMA, tris[(2-pyridyl)methyl]amine; Tween 80, non-ionic

surfactant; VA, vinyl acetate; VA-044, 2,2’-azobis[2-(2-imidazolin-2-yl)propane]dihydro-

chloride; V-50, 2,2’-azobis(2-amidinopropane) dichloride; (w/o)/w, (water-in-oil)-in-water.

37
Page 37 of 61
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