Journal Of Controlled Release Volume 128 Issue 3 2008 [doi 10.1016_j.jconrel.2008.02.007] Nicolas Anton; Jean-pierre Benoit; Patrick Saulnier -- Design And Production Of Nanoparticles Formulated Fro.pdf

Journal of Controlled Release 128 (2008) 185–199

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Journal of Controlled Release j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l

Review

Design and production of nanoparticles formulated from nano-emulsion templates—A review Nicolas Anton a,b, Jean-Pierre Benoit a,c,⁎, Patrick Saulnier a a

Inserm U646, Ingénierie de la vectorisation particulaire, 10 rue A. Boquel, F-49100 Angers, France; University of Angers, F-49100 Angers, France ESPCI, Laboratoire Colloïdes et Matériaux Divisés, ParisTech, 10 rue Vauquelin, Paris, F-75005 France; CNRS, UMR 7612, Paris, F-75005 France; Université Pierre et Marie Curie-Paris 6, Paris, F-75005 France c École pratique des hautes études (EPHE), 12 rue Cuvier, F-75005 Paris, France b

A R T I C L E

I N F O

Article history: Received 3 December 2007 Accepted 11 February 2008 Available online 23 February 2008 Keywords: Nano-emulsion Nanoparticle Nanocapsule Colloidal carrier High-energy method Low-energy method Drug delivery Solvent displacement Phase inversion temperature PIT method

A B S T R A C T A considerable number of nanoparticle formulation methods are based on nano-emulsion templates, which in turn are generated in various ways. It must therefore be taken into account that active principles and drugs encapsulated in nanoparticles can potentially be affected by these nano-emulsion formulation processes. Such potential differences may include drug sensitivity to temperature, high-shear devices, or even contact with organic solvents. Likewise, nano-emulsion formulation processes must be chosen in function of the selected therapeutic goals of the nano-carrier suspension and its administration route. This requires the nanoparticle formulation processes (and thus the nano-emulsion formation methods) to be more adapted to the nature of the encapsulated drugs, as well as to the chosen route of administration. Offering a comprehensive review, this paper proposes a link between nano-emulsion formulation methods and nanoparticle generation, while at the same time bearing in mind the above-mentioned parameters for active molecule encapsulation. The first part will deal with the nano-emulsion template through the different formulation methods, i.e. high energy methods on the one hand, and low-energy ones (essentially spontaneous emulsification and the phase inversion temperature (PIT) method) on the other. This will be followed by a review of the different families of nanoparticles (i.e. polymeric or lipid nanospheres and nanocapsules) highlighting the links (or potential links) between these nanoparticles and the different nanoemulsion formulation methods upon which they are based. © 2008 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The great stability of nano-emulsions . . . . . . . . . . . . . . . . . . . . . . High-energy emulsification methods . . . . . . . . . . . . . . . . . . . . . . 3.1. Devices and processes . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. The choice of surfactants, monomers, aqueous and oily phases . . . . . . . 3.3. On the potentialities, advantages and disadvantages of high-energy methods Low-energy emulsification methods . . . . . . . . . . . . . . . . . . . . . . . 4.1. Spontaneous nano-emulsification . . . . . . . . . . . . . . . . . . . . . 4.1.1. The diffusion mechanism and diffusion path theory . . . . . . . . 4.1.2. The emulsion inversion point (EIP) method . . . . . . . . . . . . 4.2. Phase inversion temperature (PIT) method . . . . . . . . . . . . . . . . The generation of nanoparticles from the nano-emulsion template . . . . . . . . 5.1. On nanoparticle definition . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Polymeric nanospheres . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. ‘in situ’ polymerization . . . . . . . . . . . . . . . . . . . . . 5.2.2. Formulations with preformed polymers . . . . . . . . . . . . . 5.3. Solid lipid nanoparticles (SLNs) . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author. Inserm U646, Ingénierie de la vectorisation particulaire, 10 rue A. Boquel, F-49100 Angers, France; University of Angers, F-49100 Angers, France. E-mail addresses: [email protected] (N. Anton), [email protected] (J.-P. Benoit), [email protected] (P. Saulnier). 0168-3659/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2008.02.007

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5.4.

Nanocapsules (NC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.1. Polymeric nanocapsules: ‘in situ’ interfacial polymer synthesis . . . 5.4.2. Polymeric nanocapsules: nanoprecipitation of preformed polymers . 5.4.3. Lipid nanocapsules (LNC) . . . . . . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Over the past few decades, extensive research has been done on the study of nanoparticle generating processes. Owing to the variety of the application fields of such colloidal objects (from nanomedicine, drug delivery and cosmetics, to printing ink or petroleum sciences...), and as existing nanoparticles are now innumerable, a thorough knowledge of the formulating processes (and their potentialities) is essential in order to achieve the given purposes and needs for research. Likewise, in that most nanoparticle formulations are effectively based on nanometric-scaled emulsions, so-called nano-emulsions, the study of nanoparticle formulation has to include knowledge of nanoemulsion formation governing phenomena. Nano-emulsions are nanometric-sized emulsions, typically exhibiting diameters of up to 500 nm. Nano-emulsions are also frequently known as miniemulsions, fine-dispersed emulsions, submicron emulsions and so forth, but are all characterized by a great stability in suspension due to their very small size, essentially the consequence of significant steric stabilization between droplets, which goes to explain why the Ostwald ripening is the only adapted droplet destabilization process (detailed below). It follows therefore that nano-emulsion systems can be regarded as a template for nanoparticle generation, even if these two steps can often be combined into one. Therefore, the innumerable variants of nanoparticle formulation are mainly based on three different groups of methods for the generation of nanoemulsions, i.e. high-energy methods, the low-energy spontaneous emulsification method, and the low-energy phase inversion temperature (PIT) method. The different kinds, or morphologies, of the nanoparticles generated, can be broken down into polymeric nanospheres, solid lipid nanoparticles (SLNs), or polymeric or lipid nanocapsules. The links between nano-emulsion formulation processes and nanoparticle morphology are neither obvious nor systematic and should be tackled with particular detachment: Such is the purpose of the current review. Indeed, by establishing a link between the formulation of nanoemulsions and nanoparticle generation, our intention has been to highlight the extent to which experimental processes can be adapted to given specifications. In the first part, the nano-emulsion template is presented by a thorough description of the mechanisms and phenomena governing its formation, including a comprehensive review of the different existing methods. Special attention has been given to the ‘low-energy’ processes, since they constitute a privileged way to prevent the potential degradation of encapsulated molecules during processing and are also important for, (among others) energy yields in the case of industrial scale-up. In the second part, nanoparticle formulation processes are reviewed with regard to the place of the nano-emulsion generation methods (amongst others) that they are based on. Furthermore, their potential adaptation to other nano-emulsion forming methods is discussed and their potential significance highlighted. Accordingly, the choice of the energy-type method, the use of organic solvent in the formulation, the choice of the polymer according to its biocompatibility or biodegradability, even the choice of an in situ synthesis during nanoparticle generation, as well as the use of preformed polymers and finally the choice of nanoparticle morphology, all of these parameters must be thoroughly considered and closely adapted to the therapeutic objectives.

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In the case of polymers in situ synthesized with polymeric nanospheres of nanocapsule creation, the potential interactions between drugs (or active molecules to be encapsulated) and the polymers being formed must be systematically considered. Indeed, covalent bonds may be established between drugs and polymers, and thus their potential mutual reactivity must be taken into account in the choice of monomers and nanoparticle-generating systems. The last remark concerns nano-emulsion and nanoparticle characterization. Given the numerous papers and reviews (e.g. [1–3]) where this aspect has been covered in great detail, we have not dealt with it in the present review. The droplet size distribution is essentially disclosed by dynamic light scattering (DLS), but also by transmission electronic microscopy (TEM) coupled with negative staining, or cryoTEM, freeze-fracturing followed by replication plus TEM, or capillary hydrodynamic fractionation (CHDF), etc. More detailed information on surface particle characterization may be obtained by surface potential characterization (such as [1–3] potential) and an indication of the nanoparticle surface morphology may be highlighted by specific approximations of electrophoretic models (e.g. soft particle model [4]). Finally, small-angle neutron scattering (SANS) or small-angle X-ray scattering (SAXS) may be useful for investigating the internal morphology of such colloidal objects. 2. The great stability of nano-emulsions The main particularity of nano-emulsions, making them prime candidates for nanoparticle engineering, is their great stability of droplet suspension. A kinetic stability that lasts for months, stability against dilution or even against temperature changes, totally unlike the (thermodynamically stable) microemulsions. Emulsions are thermodynamically unstable systems, due to the free energy of emulsion formation (ΔGf) greater than zero. The large positive interfacial energy term (λΔA) outweighs the entropy of droplet formation (TΔSf), also positive. The terms λ and ΔA respectively represent the surface tension and the surface area gained with emulsification. Emulsion instability is therefore induced by the positive sign of ΔGf (Eq. (1)). DGf ¼ gDA  TDSf

ð1Þ

Accordingly, the physical destabilization of emulsions is related to the spontaneous trend towards a minimal interfacial area between the two immiscible phases. Therefore, a minimization of interfacial area is attained by two mechanisms: (i) Flocculation followed mostly by coalescence, and (ii) Ostwald ripening. In nano-emulsion systems, flocculation is naturally prevented by steric stabilization, essentially due to the sub-micrometric droplet size. In short [5–7], when interfacial droplet layers overlap, steric repulsion occurs,from two main origins. The first one is the unfavorable mixing of the stabilizing chain of the adsorbed layer, depending on the interfacial density, interfacial layer thickness δ, and Flory–Huggins parameter χ1,2 (which reflects the interactions between the interfacial layer and solvent). The second one is the reduction of the configurational entropy, due to the bending stress of the chains, which occurs when inter-droplet distance h becomes lower than δ. Generally, the sum of the energies of interaction UT adopts a typical shape of systems wherein molecules repel and particles attract each other, showing a weak minimum, around h= 2δ, and a very rapid increase below this value (see Fig. 1 for illustration). The depth of the

N. Anton et al. / Journal of Controlled Release 128 (2008) 185–199

Fig. 1. Diagram of the influence of emulsion droplet radius on steric stabilization.

minimum |U0| will induce predispositions for coagulate in the colloidal suspension, that is to say, it is intimately linked to the stability of the suspension. |U0| is shown to be dependent on the particle radius r, the Hamaker constant A, and the adsorbed layer thickness δ, with the result that the higher the δ/r ratio, the lower the value of |U0|. Now, in the case of nano-emulsion droplets, δ/r becomes very high in comparison with macro-emulsions, which in the end totally inhibits its ability to coagulate. On the other hand, it is worth noting that the small droplet sizes also induce stabilization against sedimentation or creaming, in so far as the droplets are solely under the influence of the Brownian motion. Taking all this into account, the destabilization of nano-emulsions is due only to a mass transfer phenomenon between the droplets through the bulk phase, well described in the literature [8] as Ostwald ripening in emulsions. At theorigin of this destabilization process, the differences, however slight, of the droplet radius induce differences in chemical potential of the material within the drops. The reduction of free energy in the emulsion will result in the decrease of the interfacial area, and therefore in the growth of the bigger emulsion droplets at the expense of the smaller ones. The dispersed phase migrates through the bulk from the smaller droplets to the bigger ones, owing to the higher solubility in the bulk of the smaller droplets. Ostwald ripening is initiated and will increase throughout the process. As an illustration and under the assumption that only one component composes the dispersed phase, the solubility, C(r), of the dispersed material throughout the dispersion medium is expressed as a function of the droplet radius r, from the Kelvin equation [9], Eq. (2),   2gM C ðrÞ ¼ Cl exp qRTr

ð2Þ

where C∞ is the bulk solubility of the dispersed phase, M its molar mass, and ρ its density. In most studies, the follow-up of Ostwald ripening as the temporal evolution of the droplet diameter still remains well fitted, even under the approximations involved in Eq. (2). In addition, the literature provides a number of theories dealing with calculations of the rate of ripening, such as the most famous (and complete) given by Lifshitz and Slezov [10,11] and Wagner [12], the socalled LSW theory. Besides the consideration of Eq. (2), the diffusion of dispersed materials through the continuous medium is assumed to be diffusion-controlled, i.e. crossing the interface with ease. Details on LSW theories are fully developed and discussed in the literature [13,14,8] leading to the commonly used expression of the ageing rate, ω, in Eq. (3), x¼

drc3 8DCl gM ¼ dt 9q2 RT

ð3Þ

where rc is the critical radius of the system at any given time, at the frontier between the growth and decrease of the droplets. Conse-

187

quently, Ostwald ripening is reflected by a linear relationship between the cube radius and time. In processes involved in nanoparticle engineering, i.e. for multicomponent emulsion droplets, by adding monomer, polymer, or simply surfactant or co-surfactant, the above approximation is surpassed. The rate of ripening can be reduced by several orders of magnitude when the additive has a substantially lower solubility in the bulk phase than the main component of the droplet. This phenomenon has been widely studied [15–22], since it appears to be an efficient method to reduce the Ostwald ripening rate, even when using small amounts of additives. In short, it is explained by the difference of solubility in the continuous phase between the dispersed phase noted (1) and the additive (2), less soluble in this example. The first step remains similar to the ripening without additives, since only the component (1) diffuses from the smaller to the larger droplets, due to the higher chemical potential of the materials within the smaller drops. Gradually, the chemical potential in the larger droplets increases due to the presence of the component (2), until the diffusion process of (1) is stopped. Equilibrium is reached between the two opposing effects and the limiting process becomes the diffusion of the less soluble additive (2), significantly reducing the ripening rate and the nano-emulsion destabilization. A final remark, which may be of importance here, concerns the influence on the nano-emulsion destabilization of layer density and structure in the interfacial zone. Indeed, up to now it has been considered that Ostwald ripening is a diffusion-controlled process, but this assumption does not take into account the fact that surfactants, polymeric emulsifiers or stabilizers can create a thick steric barrier at the droplet interface [23,24]. As a consequence, the diffusion of the inner material of the droplets may be slowed down, reducing the ripening rate.. The substantial difference in stability between nanoemulsions and nanocapsules for instance, appears essentially from such details. 3. High-energy emulsification methods In this section, we will consider emulsification methods involving high (mechanical) energy used in the formation of nano-emulsion, that is to say, the use of devices to force the creation of huge interfacial areas. Nano-emulsion generation is very commonly performed with such high-energy emulsification methods, particularly exploited in nano-emulsion polymerization [1,2]. The formation of such nanometric-scaled droplets is governed by directly controllable formulation parameters such as the quantity of energy, amount of surfactant and nature of the components, unlike the low-energy methods (presented in the following sections), governed by the intrinsic physicochemical properties and behavior of the systems. It follows therefore that high-energy methods present natural predispositions to preserve the formation processes of nano-emulsions droplets, against even the slightest potential modifications of the formulation like the addition of monomer, initiator, surfactant, etc. 3.1. Devices and processes The mechanical processes generating nanometric emulsions include, as a first step of the drop creation, the deformation and disruption of macrometric initial droplets, followed by the surfactant adsorption at their interface to insure the steric stabilization discussed above. The challenge of these mechanical nano-emulsification methods is to combine these two steps, in order to allow and optimize nano-emulsion generation. Three main groups of devices are used in the literature: The rotor/stator devices, which appear in the first articles on nano-emulsions, and then high-efficiency devices, including ultrasound generators and high-pressure homogenizers. Rotor/stator type apparatuses, such as Omni-mixerpsy® or Ultraturraxpsy®, do not provide a good dispersion in terms of droplet size and monodispersity [25] in comparison with the nano-emulsions

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generated by thetwo others kinds of devices (and also with the lowenergy methods). Indeed, the energy provided is mostly dissipated, generating heat and being wasted in viscous friction [26,27]. Therefore, the additional free energy ΔGf necessary to create the huge interfacial area of nano-emulsions is not obtained. Nano-emulsions generated by sonifiers are generally attributed to a mechanism of cavitation [28,29], but are not as yet understood well enough. The ultrasound waves in liquid macroscopic dispersion, result in a succession of mechanical depressions and compressions, generating cavitation bubbles, which tend irremediably to implode. Subsequently, this shock provides sufficient energy locally to increase ΔA corresponding to nanometric-scaled droplets. Efficiency of nanoemulsification by sonication (considered as the final size of the nanoemulsion droplets as well as the time needed to attain this asymptotic size), depends both on the composition of the emulsion and the power device. Indeed, the addition of surfactants and/or monomers has been shown an important parameter to efficiently reduce droplet sizes [30]. Sonication is thus the most popular way to produce nano-emulsions and nanoparticles for research purposes. It does not, however, appear practical for use on an industrial scale, for which high-pressure [31] devices (and low-energy methods) are often preferred. High-pressure homogenizers, generally Microfluidizer or Manton– Gaulin devices, are designed in order to force macro-emulsions to pass through narrow gaps, by imposing high pressures. The fluid accelerates dramatically,reaching, in the microchannels of Microfluidizers [2] for instance, a velocity of around 300 m·s− 1. As a result, shear, impact and cavitation forces are applied on very small volumes and generate nano-scaled nano-emulsion droplets (closely related to the phenomena involved in the use of sonifiers). 3.2. The choice of surfactants, monomers, aqueous and oily phases The nature and amount of the surfactant, monomer or hydrophobe used in the formulation completely determine the size distribution, structure and stability of the resulting nano-emulsions and nanoparticles. Thus, the different components are chosen in function of the formulation strategies undertaken. For instance, Landfester [32–36] presented from nano-emulsions (by sonication), (i) the formulation of inorganic particles by playing on thephysicochemical properties of molten salt droplets, (ii) the formulation of polymeric nanospheres by in situ polymer synthesis within nano-emulsion droplets, (iii) the combination of both these types of technology to provide hybrid nanoparticles, and finally (iv) the use of oil as a hydrophobe to generate core-shell nanocapsules, by polymer-specific synthesis and segregation to the oil/water region [35], or by interfacial nanoprecipitation [36]. As regards high-energy methods for generating nanoparticles, the literature extensively reports comparisons between the different devices, hydrophobes, surfactants and monomers, for instance in Ref. [1]. In the current paper, by describing the various reported strategies for generating nanoparticles and nanocapsules, we draw a parallel between high-energy technologies and those involving only low-energy methods. Our purpose here is thus to propose further insights into the possible transpositions from high-energy to lowenergy nanoparticle-generating methods. 3.3. On the potentialities, advantages and disadvantages of high-energy methods In general, high-energy nano-emulsification methods present a good potential for polymeric nanoparticle generation, since the formulation parameters are directly controllable. Thus the addition of monomers, initiators, or encapsulating molecules appears not to influence the emulsification process, governed by the high shear processes. If anything, it may be and additional molecules to be encapsulated, monomers, initiators, or stabilizing agents that interfere with the emulsification process, unlike for the low-energy methods in

which nano-emulsification is totally governed by the physicochemical behaviors of the surfactants. However, when the purpose of the experiment is the encapsulation of fragile molecules such as peptides, proteins, ornucleic acid, often encountered in pharmaceutical or medical research, high-energy methods may give rise to drug degradation, denaturation or activity loss during processing. Moreover, in the case of an industrial scale-up, it is of importance to consider the energetic yield, which is incomparable between high and low-energy methods [37,7]. This is especially true for sonication, since during the emulsification process, only the near-volume of the sonifier nip is affected by ultrasonic waves, and for high volumes, a weak additional mechanical stirring is needed to homogenize the sizes and generate nano-emulsions. In concrete terms, the emulsification time (i.e. energy) to provide homogeneous nano-emulsions increases in function of the volume to nano-emulsify, which is fundamentally not the case for all low-energy methods. 4. Low-energy emulsification methods Let us now move on to nano-emulsification methods, involving only a low quantity of applied energy to generate nano-emulsions. Nanometric-scaled emulsion droplets may be obtained by diverting the intrinsic physicochemical properties of the surfactants, co-surfactants and excipients composing the formulation Two groups of methods are proposed in the literature and developed below: (i) The first one describes emulsification as a spontaneous phenomenon [38–47], which uses the rapid diffusion of water-soluble solvent, solubilized first in the organic phase, moving towards the aqueous one when the two phases are mixed. Among the works on spontaneous emulsification, the literature emphasizes the solvent displacement method [4–51], also called the Ouzo effect [52], which consists in nano-emulsion formulation due to the specific and very rapid diffusion of an organic solvent (e.g. acetone, ethanol...) from the oily phase to the aqueous one. In theory, the spontaneous nano-emulsification process can provide as much oilin-water as water-in-oil nano-emulsions, but the majority of the reported studies concern o/w generation. (ii) Secondly, the so-called phase inversion temperature (PIT) method [53–64], which uses the specific properties of polyethoxylated surfactants to modify their partitioning coefficient as a function of the temperature, and leads to the creation of bicontinuous systems when the temperature is close to the PIT, broken-up to generate nano-emulsions. Practically, it leads to o/ w nano-emulsions. 4.1. Spontaneous nano-emulsification 4.1.1. The diffusion mechanism and diffusion path theory This section describes the main principles of spontaneous emulsification, underlining the governing phenomena and mechanisms and considering the suitability of this method for nanoparticle generation. It is interesting to note first that the spontaneous features of such phenomena are simply the results of the initial non-equilibrium states of the two bulk liquids when they are brought into contact without stirring. It is only under specific conditions that spontaneous emulsification occurs and in some cases, nanometric-scaled droplets are generated. The spontaneous emulsification process itself increases entropy and thus decreases the Gibbs free energy of the system [65]. The establishment of phase diagrams, as well as video-microscopy experiments is essential for evidencing the conditions related to spontaneous emulsification [45]. Evolution of the system is basically promoted by diffusion of a solute into the phase in which it has greater solubility. Thus, spontaneous emulsification behaviors can potentially be predicted by following the diffusion pathway within the phase diagram.. The different cases are described below, and of course, this theory has been widely supported by experiments reported in the literature. The video-microscopy technique was introduced to observe the behavior of the liquid at the interface of the two immiscible phases

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brought into contact without stirring. Thus, the regions of spontaneous emulsification may be disclosed, as well as their respective location towards the interface. The source of energy of spontaneous emulsification reportedly stemmed mainly from interfacial turbulences, closely related to the surface tension gradient induced by the diffusion of solutes between two phases. Likewise, the interfaces are subject to capillary waves from thermal origins, gradually amplified as the surface tension decreases [45]. The drops are created as a result of sufficiently large interfacial corrugations, similar to the dynamic behavior of the frontier between microemulsion and the bulk phase in multi-phase equilibrium systems, i.e. a continuous coalescence and break-off of emulsion droplets [66]. Such a phenomenon has been called dispersion, spontaneously increasing the entropy and decreasing the Gibbs free energy of the system. The other (complementary) spontaneous emulsification mechanism, known as condensation, is also assumed to be intimately linked to the fluctuation of the interfacial amphiphile concentration. Owing to theregion of local supersaturation (overconcentration of surfactant at interface) induced by the diffusion process, spontaneous interfacial expansion takes place, resulting in the nucleation and growth of drops. These conditions appear analogous to the system behavior in the two-phase microemulsion regions, for instance, where drops are continuously nucleated, grow, by similar spontaneous phenomena and disappear by coalescing (maintaining the two-phase equilibrium). The theoretical mechanism was proposed by Ruschak and Miller [67], and has since been broadly corroborated by experiments and by the literature. These authors have put forward their theory from the solution of the diffusion equations for thesemi-infinite phase, and under some assumptions detailed below. The variation of composition in each phase (aqueous and oily) is directly represented on the ternary phase diagram by straight lines, from the semi-infinite reservoirs, to the interfacial concentration. Such a schematic representation of the evolution of the concentration within each phase is called a ‘diffusion path’. This model, however, is based on the following assumptions, (i) that non-equilibrium phases are brought into contact, and eventually some species should diffuse into the opposite phase, (ii) that for ‘semi infinite’ phases, the theory is limited to time, for which some proportions of both contacted phases retain their initial composition, (iii) that the diffusion coefficients of all components are equal in a phase, which is precisely the condition for representing the diffusion paths as straight lines, and finally (iv) that the interface presents a local equilibrium. Thus, spontaneous emulsification only depends on the diffusion path with regards to the equilibrium phase diagram. On the other hand, stirring the two phases brought into contact has no influence on the own mechanism of spontaneous emulsification, even though it increases the rate of emulsification by increasing the interfacial area A. The first illustration is provided by the study of the water/alcohol/ oil ternary system, presented in Fig. 2 inspired from Ref. [45], where a pure water {w} phase (point 1) is brought into contact with an alcohol plusoil {a + o} phase (point 4). The local equilibrium at the interface is shown via the dotted segment (2–3) at the frontier of the two-phase equilibrium region (in the phase diagram). Depending on the initial composition and on the nature of the alcohol, the location of the interfacial equilibrium appears to condition spontaneous emulsification, as illustrated by the difference between the Fig. 2a and b. Actually, it allows the diffusion path to cross the two-phase microemulsion equilibrium region (i.e. spontaneous emulsification (SE) region). This may indicate that the maximum intensity of spontaneous emulsification is not necessarily near the interface, but at the maximum depth within the SE region. Hence, the deeper the diffusion path within the SE region, the higher the interfacial turbulences and dispersion, diffusion or condensation phenomena. It is therefore easy to imagine a bridge with the droplet size of the forming emulsion intimately linked to the intensity of the spontaneous phenomenon. Nano-emulsion

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Fig. 2. Diffusion path in a typical water/alcohol/oil system. Segment (1–2), diffusion path of the aqueous phase. Segment (3–4), diffusion path of the oily phase. Segment (2– 3), interfacial local equilibrium. (a) Case where no spontaneous emulsification occurs. (b) Spontaneous emulsification occurs when the diffusion path crosses the two-phase equilibrium region, segment (1'–2).

droplets appear to be formed in this way, with the use of a high quantity of diffusing solvent in the oily phase [48–51]. Bouchemal et al. [51], for instance, proposed a study on the optimization of the solvent displacement method formulating nano-emulsions for cosmetic and pharmaceutical applications, in which the overall solvent/oil ratio was around 0.01. Likewise, these authors disclosed the important influence on the nano-emulsification process, of oil viscosity, surfactant HLB, and the nature of the solvent (also as a function of its toxic potential) and miscibility with water. Of course, in all these optimized systems for nano-emulsion (and nanoparticle) formulation by such spontaneous emulsification methods, the systems are more complex than the three-component model described above. In fact, this model only accounts for the droplet formation, nonetheless unstable and highly subject to destabilization after formation (even the nanometric-scaled droplets). Therefore, after creation, the newly formed interfaces have to be stabilized by surfactant adsorption. Hence, the initial phase diagrams are modified accordingly, and a more complex diffusion path has to be considered between the different phases potentially formed in the interfacial region. It is to be noted that the presence of liquid crystalline (LC) phases are acknowledged as playing a decisive role in these spontaneous-forming formulations. Two examples presenting the spontaneous emulsification of such quaternary systems are proposed in Fig. 3, for both surfactants having a negative and positive Winsor R ratio. R is defined as the ratio between the inter-molecular interactions per unit interfacial area, surfactant–oil/surfactant–water [68]. In the case shown in Fig. 3a, of the rather hydrophilic surfactant (R b 1), the formation of the LC phase in the semi-infinite aqueous one (point 1) appears in equilibrium with a pure aqueous sub-phase,

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established microemulsion structures, the surfactant hydration is potentially changed, as well as their affinity for the aqueous phase, and thus instabilities are created in the microemulsion network, resulting in its break-up into nano-emulsions. The addition of water {w}, for instance, in oil plus surfactant {o + s} continuous medium [78–80] gives rise to weak oil/water interfacial curvature fluctuations, thereby inducing the system to fall into the thermodynamically favorable state of nano-emulsion at this time. Of course after formation, other destabilizing mechanisms affect the nano-emulsion, such as Ostwald ripening, mentioned in the previous sections. Once again, in order to determine suitable conditions for generating nano-emulsion, the equilibrium phase diagram needs to be carefully studied and the phases analyzed and characterized. This time, it is the dilution pathway which indicates the best conditions to form nanoemulsions, i.e. the conditions for which the emulsion droplets formed are the smallest. The main results appear to show that nanometric-sized emulsion droplets are formed when the whole phase to be dispersed appears solubilizedin the bicontinuous system in the phase diagram [59,60,80]. These phases are reported to be either bicontinuous microemulsion, or lamellar liquid crystals Lα. To finish, regarding the formulation of nanoparticles from nano-emulsions, this method is very similar to that of solvent diffusion, owing to the fact that the process may be very dependent and sensitive to phase behavior. Thus, adapting the process to some formulation specifications (addition of monomers, initiators, drugs to be encapsulated...) is likely to modify the phase diagram, and thus potentially disrupt the nano-emulsion formation process. 4.2. Phase inversion temperature (PIT) method

Fig. 3. Diffusion path in a typical water/alcohol+surfactant/oil system (see details in the text).

segment (2–3), before establishing the local interface equilibrium with the oil-rich phase, segment (4–5). The diffusion path is simpler and presents the spontaneous emulsification of hydrophilic droplets in the oil segment (5–5'). Symmetric phenomena are also conceivable in the case where the rather lipophilic surfactant (R N 1) is used, presented in Fig. 3b, where an isotropic phase is generally formed in the surfactant/ oil-rich region. Subsequently, spontaneous emulsification of oily droplets in water arises within the segment (1'–2). The study of nano-emulsion formation using this method implies a thorough establishment of the phase diagram to disclose the potential feasibility diagram and optimization. In this context, it follows that the potential influence of additional components (like monomers and polymers, whether or not they are neutral in the formulation), need to be investigated, both on the phase diagrams and on the diffusion pathway. This may, to some extent imply restrictions in terms of ease of handling, modifying and adapting the nanoparticle formulation to the given needs. However, the generation of nanocapsules and nanospheres by nanoprecipitation or in situ polymerization, from nano-emulsions using the solvent displacement method, has provided a great number of examples developed below, e.g. the works of Fessi et al. [69–73]. 4.1.2. The emulsion inversion point (EIP) method Another spontaneous emulsification method, known as the emulsion inversion point method, has been reported in numerous works. At a constant temperature, it consists in diverting the intrinsic features of thermodynamically stable microemulsions D or Liquid crystals LC to be nano-structured by a progressive dilution with water or oil, in order to create thermodynamically unstable but kinetically stable, respectively direct or inverse nano-emulsions [74–82]. In fact, these authors explain that by slightly changing the water or oil proportion within

The phase inversion temperature (PIT) method is particularly interesting since it is an organic, solvent-free and low-energy method. The latter two experimental conditions are potentially the most suitable for application in the fields of nano-medicine, pharmaceutical sciences and cosmetics, to prevent the drug to be encapsulated from degradation during processing. Likewise, since the process is relatively simple and low-energy consuming, it allows easy industrial scale-up. The PIT concept was introduced in the last decade by Shinoda and Saito [53,54], using the specific ability of surfactants, usually nonionic, (NS) such as polyethoxylated surfactants, to modify their affinities for water and oil in function of the temperature, andtherefore to undergo a phase inversion. Indeed, the so-called transitional emulsion phase inversion occurs when, at fixed composition, the relative affinity of the surfactant for the different phases is changed, resulting in a gradual modification of the temperature. For example, an oil-in-water (o/w) emulsion is subjected to a phase inversion, giving rise to a water-in-oil (w/o) one, when the temperature rises. Within the transitional region between macro-emulsions, i.e. for the temperatures at which the nonionic surfactants exhibit a similar affinity for the two immiscible phases, the ternary system shows an ultralow interfacial tension and curvature, typically creating microemulsions, bicontinuous and nanoscaled systems [56,83–89]. Therefore, the PIT method consists in suddenly breaking-up the chosen bicontinuous microemulsion maintained at the PIT, by a rapid cooling [59,62,64] or by a sudden dilution in water or oil [57,61,90,91]. Nano-emulsions are immediately generated. These bi-continuous systems have been thoroughly and widely characterized by establishing phase diagrams at equilibrium and formulation maps under dynamic conditions. The influence of the formulation (electrolyte concentration, temperature...) and composition parameters (surfactant amount or water/oil weight ratio, WOR = 100 × water / (water + oil)), has been largely reported on the potentialities to formulate nanometric-scaled emulsion droplets [57,59,60,62–64,83,92]. During the emulsion inversion phenomena, the respective affinity of the NS for both immiscible phases is given by the difference between the chemical potentials of the surfactants in each phase. According to the physicochemical definition of De Donder, Eq. (4), the

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surfactant affinity difference (SAD) is defined with Eq. (5), at the physicochemical equilibrium, considering the activity coefficients close to the unity. It follows that the SAD is closely linked to the NS partitioning coefficient. Ai ¼ ABi þ RTlnðai Ci Þ

ð4Þ

μi is the chemical potential of the NS in phase i, μi° are the standards, a the activity coefficients, and C the surfactant concentration.   Coil SAD ¼ ABwater  ABoil ¼ RTln Cwater

ð5Þ

In the case of ionic surfactants, the emulsion inversion corresponds to the SAD= 0, but this is not the case for nonionic surfactants and corresponds to a given reference noted SADref. Hence, this deviation with regards to the optimum formulation was defined with an adimensional variable [93–97], known as the ‘hydrophilic lipophilic deviation’ (HLD), given for ionic and nonionic surfactants, and for a hydrocarbon n-alcane oily phase by the following Eqs. (6) and (7), respectively. HLD ¼ SAD=RT ¼ r þ lnS  kACN þ tDT þ aA

ð6Þ


HLD ¼ SAD  SADref =RT ¼ a  EON þ bS  kACN þ tDT þ aA

ð7Þ

where EON is the number of ethylene oxide groups for NS, S is the weight percentage of electrolytes in the aqueous phase, ACN the amount of carbon numbers of the n-alcane composing the oily phase, ΔT the temperature difference from the reference temperature (25 °C), A the weight percentage of alcohol potentially added (not necessary for the PIT method), σ, α, k, t parameters in function of the used surfactant, a a constant given from the types of alcohol and surfactant, and finally b a constant function of the nature of the added electrolytes. Thus, the correlation between the HLD empirical expressions (6) and (7), and the SAD definition (5), gives the link between the temperature variation and the amphiphile partitioning coefficient [98], and thereby the surfactant behavior regarding the water/oil interface when using the PIT method. Hence, when NS is mainly used for generating nano-emulsions by the PIT method, formulationcomposition maps are typically built, as reported in Fig. 4a. Under constant stirring and for a fixed surfactant amount in the formulation, the emulsion gradually undergoes a phase inversion, as the HLD is changed by temperature variation. According to the HDL variation, at a constant WOR, the process is called transitional phase inversion. Moreover, for the lowest and highest WOR, emulsion inversion does not occur, due to the excessively rich water and oil regions. The emulsion morphology changes from the ‘normal’ to the ‘abnormal’ emulsion types, to form simple or multiple emulsions, respectively in

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accordance with Bancroft's rule and not. The illustration is provided in Fig. 4a with the transitions between (i) o/w and w/o/w, and (ii) w/o and o/w/o. In this case, even if the emulsion does not clearly exhibit a phase inversion, conditions are still suitable to perform the PIT method, where particular microemulsion structures can form at HLD = 0, thus also leading to the generation of nano-emulsions, see for instance Ref. [99]. The study of emulsion inversion involving only the variation of WOR at a constant HLD is known as catastrophic phase inversion, and has been extensively studied [100–105]. It regards the transitions (horizontal pathways in Fig. 4a) between (i) w/o and w/o/w for HLD N 0 and (ii) o/w and o/w/o for HLD b 0, therefore this phenomenon is basically not included in the PIT method. Fig. 4b and c show the corresponding equilibrium phase diagrams, exhibiting the different thermodynamic equilibriums Winsor I to IV in function of the temperature. Kahlweit-fish diagram [57,60,63,64,83] finally traces as well, such an evolution of the system morphology. For instance, in the case of WOR = 50, a rise in temperature crosses the fish body in Fig. 4b, and crosses the caudal fin in Fig. 4c. According to the comprehensive study proposed by Morales et al. [60], optimum conditions for nano-emulsion generation are closely linked to the ability of the microemulsion, precisely at the PIT, to solubilize all thephases to be dispersed. Indeed in most cases, this corresponds to the Winsor II and IV microemulsion formation, when the system is maintained at the PIT. In the basic cases of Fig. 4b and c, the nano-emulsions will be generated from the systems exhibiting W IV equilibrium microemulsions, or potentially W IV + LC, at the PIT, essentially for systems with higher surfactant amounts, Fig. 4c. Finally, the process implied in the PIT method of generating nano-emulsions, which suddenly breaks-up the microemulsions, can essentially be considered as irreversible since the nano-suspension formed is kinetically stable. It appears to go beyond the confines of the studied ternary system from the phase diagrams and formulation-composition maps, to create a kinetically stable nanoemulsion state. Of course, it should only be interpreted as a quasistable state, even if it is stable for months, and when achieved, the destabilization will provide the phase equilibrium considered above. Establishing the phase diagram is a requisite preliminary study in order to grasp and analyze the conditions suitable for nano-emulsion formulation. In this context, the link between EIP and PIT methods is clarified, highlighting the latter (PIT) as the one providing suitable experimental conditions to attain the nanometric structuring of the ternary system (in function of the formulation variables), similar to structures already established with mixing the components using the EIP method at room temperature (see above). Thus, the PIT method appears exclusively governed by the PEOsurfactant phase behavior with regards to the formulation variables, and particularly the temperature. In this context, it is totally conceivable to

Fig. 4. (a) Typical ‘formulation-composition map’ for water/nonionic surfactant/oil system, showing the emulsion inversion zones. Typical equilibrium phase diagrams for the same system, HLD as a function of the composition, (b) for low surfactant amounts, and (c) for high surfactant amounts. The frontier between both behaviors is roughly defined at 10 wt.%.

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add neutral components to the formulation, which influence neither the system phase behavior, nor the forming domain of nano-emulsions. For instance, some formulations based on the PIT method [99,106–109], include the addition of neutral amphiphiles for the formulation (such as phospholipids), in order to play on the final nanoparticle properties and structure: In these examples, the presence of phospholipids increases the lipid nanocapsule stability and acts as a framework on the final shell structure. To summarize, the phase inversion mechanisms of emulsions stabilized by PEO-surfactants, appear to establish close links between the NS partitioning coefficients and the temperature variation. Furthermore, many works elucidate this solubilizing behavior of NS moving towards the aqueous phase as the consequence of the hydration state of the surfactant ethylene oxide (EO) chains [110–117]. In concrete terms, the water solubility and self association of NS are totally governed by the structuring state of water molecules, associated by hydrogen bonds into flickering clusters, wrapping the surfactant polar head. This well documented, volumic surfactant behavior was transposed at the water/oil interface, showing the analogy between cloud point and PIT [118,119], and more recently [120] a comprehensive study presented this molecular behavior of structured water, within the inversion of emulsions. In these works, NS behavior appears related to a salting-out effect, itself induced by the formulation variables and by the temperature pathway imposed on the system. To conclude, the low-energy and solvent-free PIT method generally appears relatively adaptable, easy to handle. The incorporation of additional molecules (to a certain extent of course) in most cases has been shown to be neutral for the formulation, or only slightly influence the global trends (weak PIT shift, weak modification of the nanoemulsion droplet size...), but not the global phenomena governing the process. It follows then that the potentiality of the PIT method to generate nanoparticles at a low energetic cost, free from the toxicity of organic solvent, with a potentially low amount of surfactant (e.g. at 5 wt.% in [90]), makes such a process essentially one of the most appealing methods. However, as presented below, the literature mainly reports formulation of nanoparticles based on nano-emulsion templates formed by highenergy methods and by the solvent displacement method. Transposition and adaptation to the low-energy PIT method thus remains anecdotal. 5. The generation of nanoparticles from the nano-emulsion template 5.1. On nanoparticle definition Nanoparticles are frequently defined [121] as solid colloidal particles ranging in size from 10 nm to 1 μm. Nanoparticles are built from macromolecular and/or molecular assemblies, in which the active principle is dissolved, entrapped, encapsulated, or even adsorbed or attached to the external interface. Thus, one fundamental advantage of nanoparticles with regard to other colloidal drug delivery systems (liposomes, niosomes, microemulsions etc.) and a fortiori to nanoemulsions, is their great kinetic stability and rigid morphology. Therefore, nanoparticles can be divided into two main families: nanospheres, which have a homogeneous structure in the whole particle, and nanocapsules, which exhibit a typical core-shell structure. A main challenge of the formulation of nanoparticles isadapting the choice of their own structure to the final aims of drug delivery: Biocompatibility of the polymer, physicochemical properties of the drug, and therapeutic goals. Hence, the following sections will focus on polymeric or lipid nanospheres and nanocapsules, thus presenting (i) a general overview on the different formulation methods, the strategies undertaken and the process-governing phenomena, (ii) a few illustrations by way of a non-exhaustive list of examples, and (iii) the extent to which the high- and low-energy methods are used or could be used for similar results. Finally, the partitioning coefficient will govern the choice of the formulation, and even the choice of particle morphology.

5.2. Polymeric nanospheres 5.2.1. ‘in situ’ polymerization The generation of polymeric nanospheres formed by in situ polymerization is exclusively provided by the literature from nanoemulsions formed using high-energy methods. The chemical reactions are principally described as the radical polymerization of droplets, monomers are generally used as hydrophobe and specific surfactants are chosen for generating nano-emulsions.Thus, the nano-emulsions are composed of pure monomer droplets surrounded by the adsorbed, stabilizing surfactants. Subsequently, polymerization starts in the droplets themselves by the addition, in most cases, of the initiator in the continuous phase, chosen for the hydrophobic phase in function of its partial solubility. The initiation of droplet polymerization can also be UV-induced [122], or ultrasonically induced [123], or even enzymeinduced [124]. As regards the prevalent way for initiating the polymerization process by adding initiator molecules, the widely accepted mechanism [1,2] for successful nano-emulsion polymerization is described as the droplet nucleation mechanism. It suggests that the radicals enter each one of the monomer droplets taken as individual reaction sites, and in that way, the particle number and size do not change during polymerization. This is consistent with the trend, which correlates the use of an oil-soluble initiator to the improvement in the number of nucleated droplets. Initiator molecules can also be included from the start within the nano-emulsion droplets. Polymerization is then started up by raising the temperature, e.g. in Ref. [125]. Azobisisobutyronitrile (AIBN) is added in the oil prior to ultrasonication, whereas potassium persulfate (KPS) is subsequently added in the external phase for the same system. Inverse nano-emulsion polymerization is also conceivable [126–128], and hydrophilic components may thus be entrapped in the droplets. This type of radical polymerization of nano-emulsions is frequently chosen in the literature, and it is a non-negligible detail to consider, since it could also be aggressive for the potentially encapsulated fragile molecules. Antonietti and Landlester [1] briefly reviewed their works dealing with non-radical polymerization in nano-emulsions, which include polyaddition [34,129], anionic polymerization [130], or metal catalysed polymerization reactions [131]. For instance in [34,129], they made polyurethane latex nanospheres by direct nanoemulsification (sonication) of a mixture of the two lipophilic species: diisocyanate and activated diol, which react to eachother within the nano-emulsion droplets. The successful reaction is due to the fact that (i) the reactants have to exhibit low water solubility, (ii) polymerization kinetics is lower than emulsification time, (iii) the diisocyanate has to show a higher reactivity with the other hydrophobe reactant (diol) than with the water that forms the continuous phase. Finally, a number of examples of nano-emulsion polymerizations using such polymerization technology (radical or not) and high-energy methods, are reported, for instance in the literature reviewed in great detail by Antonietti and Landlester [1], or by Asua [2]. Such a listing is not our purpose in the current paper. Does this nanosphere technology seem adaptable to low-energy methods? The literature provides few examples of nanosphere formulation by in situ polymerization with low-energy methods. The reason is simple: The hydrophobic phase in high-energy processes is only composed of the monomer itself, whereas in low-energy methods, it includes the oil. Theoretically speaking, adapting the former to the latter requires similar behavior and interaction of surfactants/oil and surfactants/hydrophobic monomer, which appears relatively unlikely. Nevertheless, as proposed by Magdassi and Spernath [132], it is only when such conditions are met that it may be conceivable to perform the PIT nano-emulsification method easily, even then only after thorough characterization of the systems. As a result, monomer nano-emulsion droplets are formed and the initiation process can be carried out until the formation of polymeric nanospheres.

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Finally, as reported in the works of Gallardo et al. [133], during the formulation process of nanocapsules using a reactive alkylcyanoacrylate monomer and a solvent diffusion method, nanospheres can be generated and favored by the use of a protic solvent [134]. These objects should in fact have a mixed oil/polymer morphology, a porous matrix and should potentially be surrounded by a polymer capsule. 5.2.2. Formulations with preformed polymers This section presents formulations in which the macromolecules are dissolved in the phase to be dispersed (mainly organic solvent). The process irremediably involves the removal of the organic (and volatile) solvent from the formulation and therefore polymer precipitation within the organic phase template. Removing the solvent can be performed by evaporation or diffusion shock. The main difference from the previous process appears to be the fact that not only are synthetic polymers used, but also natural macromolecules, such as chitosan, polysaccharides, alginate, gelatin etc, hence increasing their biocompatibility with the potential therapeutic objectives. The second point differing from the previous section is the number of examples in the literature proposing the formulation of nanoparticles by low-energy method, especially the solvent displacement method. Let us first consider a few examples of nanosphere formulation using classical sonication methods. Polymeric nano-dispersion is created simply by dissolving the polymer in the organic phase, and by nanoemulsification using an appropriate method of sonication. Then, the polymer-containing nano-droplets formed are gradually evaporated to generate nanoparticles, as described in Ref. [135]. Kietzke et al. [136] proposed novel approaches working with semiconducting polymer blends. Likewise, Yang et al. [137] used chloroform to dissolve a mainchain liquid crystalline polymer (MCLCP), and after a 5 min-sonication phase to establish the nano-emulsion, the solvent was removed by evaporation and a very stable suspension of nanoparticles was generated.Today, numerous examples are provided in the field of drug delivery and in the controlled release of lipophilic and hydrophilic components [138] such as protein in PLGA nanospheres [139]. Perez et al. [140] proposed an original method for encapsulating plasmid DNA under PLA-PEG nanoparticles with a double emulsion-like structure (w/ o/w), by a two-step sonication, followed by solvent (ethyl acetate/ methylene chloride) evaporation in order to induce polymer precipitation. An alternative of their second sonication consists in a solvent diffusion which creates the final nanoparticles (i.e. spontaneous emulsification by solvent displacement), inducing polymer precipitation: This could constitute a bridge to the low-energy, nanoparticlegenerating methods. We can also cite some works studying the phenomena of crystallization and undercooling of poly(ethylene oxide) [141,142] within the nano-emulsion droplets. Finally, working on the intrinsic solubility and melting point (Tm) of a particular polymer without the use of an organic solvent, Quaglia et al. [143] reported a method known as ‘melting/sonication’ (MS) which consists in the nanoemulsifation by sonication in water, of a fluid, non water-miscible copolymer at T N Tm. Cooling to room temperature then hardens the copolymer. As a result, spherical and non-aggregated particles are formed, and depending on the macromolecule properties, particular structures (i.e. core-shell...) can be adopted by the nanospheres. Most nanosphere engineering using preformed polymers described in the literature, is shown to be performed by low-energy spontaneous nano-emulsification, the so-called solvent displacement method described above. The general idea is to consider the macromolecules dissolved in organic solvent (plus possibly hydrophobes, like oil), as neutral for the spontaneous nano-emulsification process. Thus, the solvent diffusion towards the aqueous phase, generating nano-emulsions causes the polymer to precipitate uniformly within the nano-emulsion template. Classical examples are the works of Fessi et al. [144–147] or Leroux et al. [49,71,148]. Many different polymers and organic solvents are commonly used. We can find for instance the couples {poly(D,L-lactic acid)/ethyl acetate} in

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[145], {Eudragitpsy® L/acetone, dimethyl sulfoxide, isopropyl alcohol, ethanol or ethyl lactate} in [146], {poly(D,L-lactic acid), Eudragitpsy® E, cellulose acetate phthalate, cellulose acetate trimelitate/ethyl acetate, 2-butanone} in [49], or {PLGA, PLGA:poloxamer, PLGA:poloxamine/ dichloromethane, methylene chloride} in [149–152]. As regards such formulation through the phase inversion temperature methods, it is the process itself that seems ill adapted to the concept of desolubilizing the polymer from the nano-emulsion droplets to create nanoparticles. In fact, a non-volatile dispersed phase is generally used, and avoiding it does not appear physically possible. However, by substituting oil with a volatile solvent, into which the polymer has been introduced beforehand, cf Ref. [132], the authors established nanoemulsion followed by solvent evaporation below the PIT to generate nanoparticles. To date, the literature does not provide other formulations of polymeric nanospheres using the PIT method. Likewise, in that using dissolved polymers involves the use of harmfulorganic solvents, the main advantage of PIT methods, that of being organic solvent-free, is lost: There appears to be no further interest to change the phase inversion temperature method in such a way. 5.3. Solid lipid nanoparticles (SLNs) Solid lipid nanoparticles [153–155] are commonly defined as nanoscaled lipid matrices, solid at physiological temperatures and stabilized by surfactants. Owing to the choice of lipids (generally biocompatible and biodegradable) and given that the particles are stable for years, this type of nanoparticle appears to be a privileged, promising drug delivery system, especially for the parenteral method. However, the limits lie in the fact that the drug molecules to be encapsulated generally have a poor solubility in lipids, and are thus rapidly expelled after polymorphic transition [156]. Ongoing research is looking to increase encapsulation rates and lower these problems, using nanostructured lipid matrices [157] or lipid-drug conjugates [158]. Here, the formulation of SLNs is provided by both high- and low-energy methods. High-energy production methods of SLNs [159,160] for nanoemulsion generation may be similar to those described above for copolymers, such as the melting/sonication method: It consists in (i) maintaining the lipid phase (plus potentially solubilized drug) 5–10 °C above its melting point, (ii) premixing it in aqueous surfactant solution at the same temperature, (iii) nano-emulsifying the preemulsion using a high-energy method (high pressure homogenizer [153–155,159–161] or sonication [162–166]), and finally (iv) cooling it down to room temperature to crystallize the lipids. Special care has to be taken to avoid the lipid memory effect, making new crystallization possible [167]. These processes are reviewed in detail by Müller et al. [154]. These authors illustrate the advantages of such a protocol even for encapsulating thermo-sensitive drugs, since exposure to an increased temperature is relatively short. For highly thermo-sensitive or hydrophilic molecules, they propose an alternative method known as the ‘cold homogenization technique’ [154]. Low-energy methods are also used for generating solid-matrix lipid nanospheres. These methods are mainly based on the formulation of microemulsions (still above the melting point), followed by water dilution which induces a cooling of the system and lipidnanoparticle precipitation [168–171]. This process can be compared to the EIP method (presented above) for nano-emulsion generation, by substituting oil for melt lipid. Additional cooling gives rise to lipid crystallization and the generation of SLNs. Other processes found in the literature are based on the solvent diffusion spontaneous emulsification method [172–178]. Like nanoemulsions, SLNSs are generated by the solvent displacement method, but again substituting oil for melt lipids, for instance, glyceryl monostearate,used in Ref. [172]. Of course, it means controling the temperature of the organic phase solubilizing the lipid, typically 5– 10 °C above the lipid melting point. The suspension of SLNs is then quickly formed and the lipids crystallized after pouring this hot

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organic solution into an aqueous one at room temperature. In Ref. [172], the authors solubilized glyceryl monostearate in a mixture of ethanol and acetone at 50 °C, before generating SLNs by dilution into an acidic aqueous solution. The nanoparticles formed exhibited diameters from 50 to 500 nm, depending on the experimental conditions (pH, drug encapsulated, etc.). Thus, it is conceivable that when oil is added with the lipids in the formulation process at temperatures above the lipid melting point, a certain structuring may be induced in the particle, as it is the case in the formulation of nanocapsules by solventdiffusion (see below). Therefore, the addition of oil will create a porous lipid matrix as with the nanoparticle structure, in which the porosity will be controlled by the amount of oil [178]. Such a particle appears to be a relatively good candidate for drug delivery, since it offers a fine arrangement of the release profiles from the specifications. As a last remark, high-energy methods may be used to incorporate this oil, in view of controlling the particle morphology. The PIT method also appears easily adaptable to the process of generating SLNs and to our knowledge, no work of this nature has yet been reported. Excipients should be chosen in function of their physicochemical properties: (i) to allow the system to undergo a transitional phase inversion, and (ii) to exhibit a sufficiently high PIT, compared to the lipid melting point. Hence, strong system characterization and optimization has to be done for the finely dispersed SLN generation. Finally, it may also be possible to produce the abovementioned porous lipid matrix using the solvent diffusion method by the further incorporation of oil in the oily phase. 5.4. Nanocapsules (NC) Let us now move on to the last category of nanoparticles formulated from the nano-emulsion template covered in the present review: Nanocapsules (NC). It consists of colloidal objects exhibiting a core-shell structure. The core acts as a liquid reservoir for drugs, mainly lipophilic solvent (and usually oil) but also aqueous core NC, Both are described below. The shell is generally made of polymers, preferentially biodegradable, i.e. dense and rigid, even if on the nanometric scale, such a concept is still being discussed. For the past 20 years, as reviewed in Ref. [3], Couvreur's team have been doing extensive research on nanocapsules as drug carriers and on their therapeutic applications. The advantages of such a structure are: Firstly, the high drug encapsulation efficiency due to the optimized drug solubility in the nanoparticle core and low polymer content compared to polymeric nanospheres. Secondly, since the drug is ‘protected’ within the NC core, tissue irritation at the administration site as well as the burst effect are lowered, and the drug itself remains protected against degradation. Experimentally speaking, several methods are usually used to establish such a core-shell structure on a nanometric scale. As for nanospheres, these include: In situ polymerization at the nano-emulsion droplet interface, nanocapsule generation using preformed polymer and the generation of lipid nanocapsules. The NC morphology and the formulation strategy totally depend on the therapeutic objectives and on the drug to encapsulate. Mainly, lipophilic and hydrophilic cores of the NC are distinguished, requiring the NC to be dispersed respectively in water and in oil.Thus, for the parenteral administration route, it is evidently the aqueous dispersion medium which will be adopted, the aqueous-core NC dispersed in oil being an unsuitable system. Therefore over the past few years, much effort has been made to formulate aqueous-core NC as a hydrophilic drug carrier, eventually with a polymerosome or vesicule-like structure, as presented below. 5.4.1. Polymeric nanocapsules: ‘in situ’ interfacial polymer synthesis The first remark about this strategy of nanocapsule formulation is the universality of the method with regard to the formulation of the nano-emulsion template. Since polymer synthesis is performed at a specific location (the droplet interface), and after the formation of

nano-emulsion, this process may be considered independent from the method chosen to generate nano-emulsions. Hence, regarding the choice of monomers and the chemical reactions during polymerization, the nano-emulsion template can constitute the starting point of the process. Thus, all the methods used to formulate nano-emulsions, both low and high-energy, can be considered. It is possible to introduce the monomers (i) in the continuous phase, reacting with the material constituting the droplets, (ii) vice versa in the droplets, reacting with the continuous phase, or polymerization initiated by adding initiator in the continuous phase, and finally the combination (iii) in both phases, reacting together to induce an interfacial polycondensation. These three points are developed below. In cases (ii) and (iii), the monomers have to be included in the formulation process. However, the weak amounts generally added do not influence nano-emulsion formulation. (i) In the first case, monomers can be added in the external phase after completing the nano-emulsion formulation. Thus, the monomer is freely soluble in the continuous medium and a reagent towards the dispersed phase itself. The interfactial polymerization reaction is initiated at contact with the droplet and the morphology of the polymer shell is in function of the initial quantity of the monomer. For instance the polymerization of oil-soluble alkylcyanoacrylate on aqueous droplets of inverted nano-emulsion, are part of a process initiated by Lambert et al. [179–182] for the formulation of aqueouscore nanocapsules. Nanometric-scaled emulsion droplets are generated using a mechanical method and monomer isobutyl-cyanoacrylate is then added, a very reactive species towards the aqueous droplets. The reaction is catalyzed (and initiated) by the presence of nucleophiles such as hydroxyl ions. Interfacial polymerization is completed within seconds and w/o nanocapsules are generated. The authors then extract colloidal objects from the organic phase and perform a resuspension in water. Various hydrophilic drugs have been encapsulated in this way, such as oligonucleotides [179–181,183] including antisenses [182], or siRNA [184]. Overall a relatively high encapsulation efficacy has been observed. More recently, this process has even been optimized by Hillaireau et al. [185,186] by polymerizing onto a w/o microemulsion template (surely similarly to water-loaded inverted micelle suspension), instead of mechanically established nanometric aqueous dispersion. Prime candidate monomers for performing such nanocapsule formulation strategies appear to have both a good solubility in the external phase and a sufficient reactivity with the phase constituting the dispersed nano-emulsion droplets. The morphology of theresulting nanocapsules will be in function of the amount of monomer added as well as the polymerization time. Thus, molecules other than alkylcyanoacrylates could be considered as candidates for nano-emulsion in situ interfacial polymer synthesis. Take for example diisocyanate lipophilic molecules, in which the isocyanate functions are possibly hydrolizable by an electrophile site-rich solvent such as water, leading to amine formation. The amine, then reacts rapidly with another monomer molecule, since it is more reactive than water: The polycondensation reaction occurs exactly at the interface. Our recent works [187] report the formation of aqueouscore nanocapsules, which work on the same principle, but through different formulation strategies, i.e. by low-energy (PIT method), and interfacial nano-emulsion diisocyanate polycondensation. However, such interfacial polycondensation is nothing other than the adaptation to nanometric dispersion of the interfacial polycondensation reported for microcapsule generation, for instance by Pensé et al. [188,189]. To summarize: When the monomer is added in the continuous phase (case (i)), interfacial polymerization does not appear dependent on the method chosen to generate the nano-emulsion templates, high- and low-energy, PIT method, spontaneous emulsification, etc. (ii) In the second case, a great number of publications present the formulation of nanocapsules by interfacial polymerization, where the monomer is included in the dispersed nano-emulsion droplets. Let us

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begin by the high-energy formulations of Tiarks et al. [35,32] (see also [190]), with the formulation of polymeric nanospheres: The hydrophobe is now composed of a monomer, an initiator and oil, dispersed in water by sonication, generating nano-emulsions. Polymerization is initiated via the temperature, the monomer precipitates in oil and there is gradually segregation towards the water/oil interface, thus generating nanocapsules. In fact, this phenomenon has given rise to the theory of droplets composed of binary mixture [191], and the polymer/oil system can adopt several configurations (i.e. the polymer can engulf the oil totally, partially or not at all). Nanocapsule generation requires the polymer to totally engulf the oil core after its segregation. Such segregating behavior is governed by the respective interfacial tensions between the three immiscible species. As regards the solvent displacement method, (still) concerning alkylcyanoacrylate, a large number of papers have been reported, initiated by Al Khouri Fallouh et al. [192,193] and thereafter widely studied and optimized [134,194–199]. These authors include alkylcyanoacrylate monomers within the (water miscible) organic solvent plus oil phase, and polymerization is initiated along with the instantaneous diffusion of the solvent to the aqueous bulk phase. Since both the generation of nano-emulsions and the interfacial polymerization reaction are extremely fast, it is assumed that they are produced simultaneously. (iii) Finally, in the third case, the nano-emulsion is first prepared including a monomer within the oil droplets (for instance diisocyanate) and the polycondensation reaction proceeds at the water/oil interface. Thus again, it is possible to generatenano-emulsions using both high- and low-energy methods, as long as the inner monomer is included and without further reaction of the latter with the aqueous phase. The main challenge of these studies is to adapt the interfacial polycondensation processes, well known for micrometric droplets [200–202], to a nanometric dispersion exhibiting a huge water/oil interface, as well as to the characterization methods used, in order to ensure that the polymer coating is successfully achieved. For example, Takasu and Kawaguchi [203] propose the synthesis of a polyurea shell, by coating nano-emulsion made of styrene in the hydrophobe phase (before generating latex core-shell nanoparticles via a second styrene polymerization). Nano-emulsions containing diisocyanates (such as isophorone diisocyanate or tolylene-2,4diisocyanate) are established by sonication and the polycondensation reaction begins subsequently, when the aqueous solution of diamine (isophorone diamine or hexamethylene diamine) is added to the o/w nano-emulsion. The reaction mixture is then slowly stirred for no more than 2 h to complete the water-insoluble polyurea coating. Montasser et al. [204–206] and Bouchemal et al. [72] have provided some examples regarding such an in situ interfacial polycondensation, for which the nano-emulsion template is generated by a low-energy method: Solvent displacement. The reaction is performed by a stepwise reaction between for instance, diisocyanate molecules within oil droplets and activated diols, poly(ethylene oxide), or even diamine, solubilized in the aqueous phase, in order to generate, respectively, polyurethane or poly(ether urethane) shells, or polyurea. It is to be noted that the diols have to be ‘activated’ with the help, for instance, of diazobicyclo, 2-2-2,octane molecules. Finally about the PIT method, it appears conceivable to incorporate diisocyanate into the droplets in order to induce similar interfacial chemical reactions (as in the case (i)), but only when the selected diisocyanate exhibits low reactivity with the aqueous phase during processing until completion of nano-emulsion generation. 5.4.2. Polymeric nanocapsules: nanoprecipitation of preformed polymers The general protocol to specifically induce the precipitation of preformed polymers at the droplet interface appears principally based on the solvent displacement nano-emulsifying method. It is the only experimental procedure which combines (i) the use of solvents efficient enough to solubilize the macromolecules, and (ii) its specific

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displacement towards the bulk phase, during which the precipitating polymers will be deposed according to the profile of the nanometric oil droplets being formed. Earlier works on such a process were proposed by Fessi et al. [69,70] using poly(D,L-lactic acid) (PLA) or poly (alkylcyanoacrylate) polymers and acetone as the displacing solvent. Of course, these pioneer works were followed by a large number of variants, applications and patents (e.g. [73]), using different polymers such as for instance poly(isobutyl-cyanoacrylate) [207], PLA, Eudragitpsy® E, poly(ε-caprolactone) (PCL) [208–210], poly(lactic-coglycolic acid) (PLGA) [211] and so forth. The first advantage thus appears to be the apparent lack of potential and aggressive drug-monomer interaction owing to the absence of chemical reaction, in comparison with other methods in which the polymerization (interfacial or not) is in direct contact with the drug. Secondly, as various types of polymers are used (see also [3]), this method appears relatively adaptable to given specific and therapeutic purposes, etc. However, this low-energy process inexorably implies the use of organic solvents and their specific drawbacks for pharmaceutical applications. Another method (somewhat anecdotal in comparison with the one described above), presents the generation of polymeric nanocapsules with preformed polymers in two steps: (i) Firstly, by preparing the nano-emulsion template, whatever the (high- or low-energy) method used and (ii) secondly, by coating it with the polymer deposition on the water/oil nano-emulsion surface. The polymers are added in the continuous phase (even after nano-emulsion is complete) and their precipitation onto the nano-emulsion droplets is induced by solvent evaporation. For instance, Paiphansiri et al. [36] propose the encapsulation of an antiseptic agent, a chorhexidine digluconate solution, within a w/o nano-emulsion generated by sonication. The polymers they use, poly(methyl methacrylate) (PMMA), poly(methacrylate) (PMA) or PCL, are solubilzed in dichloromethane (DCM) gradually added in the continuous organic phase of the nano-emulsion. Next, the temperature is maintained, with slow stirring, above boiling point until the DCM has completely evaporated. The polymers precipitate onto the nano-emulsion water droplets, thus forming nanocapsules. The authors present such a mechanism of specific segregation on the droplet interface, similar to their other works presented above (Section 5.4.1) dealing with polymer synthesis and specific segregation and therefore totally engulfing the nanocapsule core, depending solely on the respective interfacial tension between the three species [35]. Finally, another strategy was developed by Prego et al. [212–214], reporting specific chitosan or PEG-chitosan nano-emulsion coating. Nano-emulsions are obtained by the low-energy solvent displacement method, and stabilized by lecithin. After eliminating the solvent, the nanocapsules are created by simple incubation with the polymer. These nanocapsules have been used as carriers for hydrophilic molecules such as peptides (e.g. salmon calcitonin in Refs. [213,214]), simply by including the peptide within the organic solvent before it is poured into the aqueous phase to diffuse and generate nanoemulsions. The peptides are entrapped within the o/w nano-emulsion, and the surrounding chitosan wall acts as a barrier, preventing extensive release. To summarize, the formulation of nanocapsules using preformed polymers are mainly performed (in the first case) by combining the solvent displacement method and the specific nanoprecipitation of polymers onto the water/oil interface of the forming oil droplets. These objects are exclusively o/w nanocapsules. A second strategy consists in establishing first the nano-emulsion template, and then forcing the polymer (solubilized in the continuous phase) to specifically precipitate to the nano-emulsion interface. Oily-core as well as aqueous-core nanocapsules can be formulated. Furthermore, since the two formulation steps can be dissociated, nano-emulsion formulation can be performed whatever the method chosen. Thus, if the specifications are respected, it is conceivable to include the solvent-free and low-energy PIT method for nano-emulsion generation.

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5.4.3. Lipid nanocapsules (LNC) Lipid nanocapsules were introduced by Heurtault et al. [106– 108,215], and are commonly defined as exhibiting a core-shell structure composed of a liquid oily core and an amorphous surfactant shell. The formulation process is in fact based on the PIT method plus the temperature cycling treatment. Biocompatible excipients are chosen for the formulation and for nanocapsule administration via a parenteral route, mainly medium-chain triglycerides (caprilic triglycerides) as the oil phase, a polyoxyethylene-660-12-hydroxy stearate as the PEO nonionic surfactant and MilliQpsy® water plus NaCl as the aqueous phase. An additional, somewhat neutral component, lecithin, was introduced in the formulation, and has been shown [216–218] to increase the nanocapsule stability significantly, creating a ‘framework’ in the shell. Therefore, the own formulation process was actually established as a function of the physicochemical properties of such adequate components. Since the temperature cycling process has been shown [90] to increase the quality of the nano-emulsions (in terms of size and PDI) by increasing the surfactant amount at the water/oil interface, the generation of nano-emulsions by the PIT method plus temperature cycling leads, in fact, to droplets exhibiting an important quantity of surfactants in the interfacial region. In addition to the present case, the fact that the final formulation is reached by a sudden dilution with water at temperature below the nonionic surfactant melting point (~30 °C), indicate that shell crystallization could occur. Finally, as discussed above concerning droplets stabilized with macromolecular assemblies or thick polymeric species [23,24], Ostwald ripening is significantly reduced even more than for the simple nano-emulsions, and it is precisely the case for LNC. In view of all these results, these particular nano-emulsions, formulated by temperature cycling, are denominated as lipid nanocapsules. Nevertheless, the structure of these LNC being specific and typical of the formulating method and of the properties of the used nonionic surfactants, it is hard to imagine the formulation of similar objects using methods other than the PIT method. 6. Conclusions The formulation of nanoparticulate drug carriers, based on nanoemulsion formulation, appears at first to require adaptation to the therapeutic aims and specificity of the drug to encapsulate. That is to say, both high- and low-energy nano-emulsion formulation methods, whether or not they include the use of organic solvents, have to be adapted according to the active molecule properties, i.e. sensitivity to temperature, high-shear devices, contact with organic solvents, etc. This review has presented the extent to which these nanoparticulate drug carriers are generated using various nano-emulsion formulation processes. High- and low-energy methods used to establish nanoemulsions are presented in the first part. The second part proposes a link towards the generation of nanoparticles. The formulation of the main groups of nanoparticles, i.e. polymeric nanospheres, solid lipid nanoparticles and nanocapsules, are reviewed in the light of the nanoemulsion formation method as well as conceivable alternatives (not necessarily reported in the literature). The global aim of this review is to provide the formulator with a broad basis on the adaptation, or even the carrying out of a process, according to specific needs. References [1] M. Antonietti, K. Landfester, Polyreactions in miniemulsions, Prog. Polym. Sci. 27 (2002) 689–757. [2] J.M. Asua, Miniemulsion polymerization, Prog. Polym. Sci. 27 (2002) 1283–1346. [3] P. Couvreur, G. Barratt, E. Fattal, P. Legrand, C. Vauthier, Nanocapsule technology: a review, Crit. Rev. Ther. Drug Carr. Syst. 19 (2) (2002) 99–134. [4] H. Ohshima, Electrophoresis of soft particles: analytic approximations, Electrophoresis 27 (2006) 526–533. [5] D.H. Napper, Polymeric Stabilisation of Colloidal Dispersions, Academic Press, London, 1983. [6] T.F. Tadros, The Effect of Polymer on Dispersion Properties, Polymer adsorption and colloid stability, 1982.

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