Nanomaterials and Surface Engineering (Takadoum/Nanomaterials and Surface Engineering) ||...

Chapter 4

Microencapsulation1

4.1. Introduction

The microencapsulation process gathers all the procedures (chemical, physical, physico-chemical, etc.) based on the enclosure (embedding) of solid, liquid and sometimes gas substances in a material envelope. The size of the resulting products ranges from 0.5 to 2000 micrometers.

The corresponding technologies were created in the mid-twentieth century, during the manufacturing of non-carbon copy paper (or carbonless copy paper). This paper was made of two sheets:

– the first sheet was coated on one side with microencapsulated colorless ink;

– the opposite surface of the second sheet was coated with a reactive clay, with the two coated faces of the two sheets being in contact.

At the time of writing, the applied pressure was sufficient to break the wrapped microcapsules locally and to ensure the colored reaction.

FUJI films, currently on the market, are based on this principle, to ensure indications of pressure areas via an evolution towards products gathering both the microencapsulated ink and the reactive clay on the same sheet.

It is usual to differentiate the microcapsules strictly speaking from the microspheres. The microcapsules are shell-like systems protected by a polymer

Chapter written by Claude ROQUES-CARMES and Christine MILLOT.

90 Nanomaterials and Surface Engineering

membrane. The microspheres are matrix systems, i.e. products made up from phases dispersed in a polymer matrix. This differentiation is illustrated in Figure 4.1 obtained by scanning electron microscopy (SEM) after cryofracture.

(a) (b)

Figure 4.1. Comparative scanning electron microscopy after cryofracture of a microcapsule (a) and a microsphere (b)

Concerning the microcapsules, the properties of the encapsulating material (material that constitutes the microcapsule envelope, referred to as the shell, the coating or the membrane) with respect to the encapsulated material (material inside the microcapsule, referred to as the fill, the internal phase or the core) are crucial because this shell may play the role of a passive barrier between the encapsulated product and its environment. In this case, the encapsulated substance is protected against, for example, oxidation, moisture, evaporation, temperature, pH, external radiations, and more generally reactive contacts. The coating may also be used to improve the visual aspect of the encapsulated substance. The controlled release of the core of the microcapsules requires different mechanisms used on the shell such as dissolution, mechanical rupture or enzymatic action.

As an example, the shell, as a passive protection, is also used for masking an unpleasant taste, releasing perfumes or separating bicomposant resin bounds.

The shell can also play the role of an active barrier when the envelope is permeable or partially permeable to the core. The shell ensures in this case the controlled release of the core for various applications: controlled release of pharmaceutical or cosmetic products and long acting fertilizers effects. The release of the core is carried out (this time) by the diffusion equation modified by interfacial reactions of swelling or dissolution type characterizing the concept of membrane permeability.

Microencapsulation 91

Regarding the latest industrial developments, microencapsulation has numerous applications such as:

– controlled release of selective drugs;

– deodorant or “subodorant” microcapsules for socks and underwear;

– reversible or non-reversible thermochromic coatings for signaling applications;

– use of encapsulated products like weedkillers, pesticides and pheromones;

– modification in the aspect of fragmented products for decorative applications.

Whatever the considered applications, the microcapsules must fulfill the following conditions:

– stability of the properties under various environmental conditions (pH, temperature variations and hygroscopic rate);

– for some applications hypoallergenic properties, with cutaneous and even ocular tolerance.

For additional information, consult the following references: [AUB 06, BEN 96, BUR 85, DON 99, FAL 04, GHO 06, PRO 98, VAN 07, VAN 73].

4.2. The processes of microencapsulation [BUR 94, CHA 04, COU 96, GHO 06, GIU 95, ISR 94, PIE 04]

Microencapsulation processes in industrial applications must allow the manufacture of micro-particles whilst taking into account that the core properties can be hydrosoluble, liposoluble and even insoluble. Usually, these processes can be separated into two categories:

– those for which the micro-particles take form in a liquid medium which gathers chemical or physicochemical processes;

– those which require a physical mode of encapsulation or which are dedicated to powder form products.

The methods which are most frequently used in order to obtain micro-encapsuled products are based on different processes:

– physico-chemical processes, implying either the mechanism of the separation (evaporation/extraction techniques, coacervation) or evaporation/extraction of the solvent of an emulsion, and even gelation;

– chemical, associated with the classical interfacial polymerization or emulsion polymerization;


– physical, related to the techniques of fluidized air with pulverization, gelation or congelation of drops, hot or cold nebulization, supercritical fusion-extrusion/ coextrusion, supercritical fluids, as well as the electrostatic techniques.

Only the most traditional techniques will be described in this chapter.

4.2.1. Physico-chemical processes

4.2.1.1. Coacervation

The term coacervation (Latin: co = with, acervus = agglomerate) was first introduced in 1929 to describe a preparation methodology based on the principle of the phase separation of hydrocolloids. Nowadays, this term is generalized to the description of manufacturing processes based on crossing the solubility phases limits.

The coacervation phenomena, by lowering temperature on both sides of a demixtion curve separating a polymer mixture/solvent, is the easiest mechanism to illustrate. Indeed, it leads to a two-phase separation: one of the phases is a highly concentrated high-content solvent (and thus with a poor concentration in polymer), while the other one, called coacervate, is rich in polymer.

As a result, the phase diagram used in microencapsulation is based on three components: a polymer ensuring the coating, a solvent of this polymer, an immiscible product either with the polymer or with the solvent.

Gibbs phase rule applies:

v = c + 2 – ϕ. [4.1]

As the number of components is such as c = 3, and the number of external independent variables (temperature and pressure) is reduced to 1 if the experiments are done under atmospheric pressure, it results that:

v = 3 + 1 – ϕ = 4 – ϕ. [4.2]

If we consider that the limit of solubility concerns the separation between a single-phase and a two-phase domains, the number of phases φ is at most equal to 2 and therefore, v = 2. That means that the number of experimental variables reduced to 2 in a simple coacervation technique can be associated with:

– variations of the concentration of the two phases; or

– variations of the concentration of one phase and that of the temperature.


Figure 4.2. Various stages implied in the phenomena of coacervation

The diagram in Figure 4.2 illustrates the various stages of the simple process of coacervation which can be separated into:

– the manufacturing of an emulsion (O/W) in the form of microdrops of oil (O) dispersed in water (W) containing gelling polymer in a dissolved state (more generally, the word “oil” characterizing a product with hydrophobic property);

– the emulsified product is covered by the adsorption of the polymer after its precipitation by separation phases in the aqueous solution. The macromolecular element, precipitated and then adsorbed, forms the coacervate. Agglomeration of these coacervates is inhibited by the presence of surfactants;

– finally, the adsorbed products coalesce to form a continuous superficial film which will harden in the final step.

In the case of a complex coacervation, the addition of polyelectrolytes with gelling properties to the three components should be noted. It is thus usual, in order to obtain the surface layer via this technology, to select:

– gelatin maintained with a pH lower than that of the isoelectric point (pI = 8), where the first electrolyte is positively charged;

– polysaccharides with a pH higher than the isoelectric point (pI = 4.5), where the second electrolyte is, under this condition, negatively charged.

The complex coacervation imposing a pH ranging between 4.5 and 8.

We will thus retain that in case of a complex coacervation technique, it is the variation of pH which represents the major experimental variable at a well define temperature.

As a practical conclusion, it appears that simple coacervation involves only one polymer (e.g. gelatin) in order to ensure the coating of emulsified products, and that complex coacervation requires the presence of two polymers of opposite charges such as gelatin and polysaccharide.

H

E

Emulsion Formation of a film Deposit Coacervation


Figure 4.3. Procedure to obtain microcapsules by complex coacervation technique

For information, the diagram in Figure 4.3 specifies the procedure associated with the protocol supporting the manufacture of microcapsules via the complex coacervation mechanism.

4.2.1.2. Evaporation of solvant

The technology appealing to the solvent evaporation from an emulsion constitutes a simple principle as illustrated in Figure 4.4.

Firstly, the polymer used for coating and the product to be encapsulated are completely or partially dissolved in a volatile solvent which is immiscible in water.

Secondly, the element is emulsified in an aqueous solution containing a surfactant product. Via this emulsion, the solvent is subjected to the process of

Hydrophobic Liquid Product to Encapsulate

Emulsion O/W

Coacervation of Polymers by pH Adjustment

Polysaccharide in an Aqueous Solution

Gelatin

Gelation by Decreasing Temperature

Hardening of the Encapsulated Products Envelops

Washing, Drying


evaporation under reduced pressure and the microparticles are finally recovered by centrifugation.

Figure 4.4. A solvent evaporation process

4.2.2. Chemical processes

The most widespread process to obtain microencapsulated products in a chemical way is based on interfacial polymerization. It is carried out in two stages requiring the presence of two monomers, respectively, A and B, intrinsically reactive to form a polymer (A-B)n. Each monomer being dissolved, respectively, in each phase of the emulsion which can be of the type oil-in-water (O/W) or water-in-oil (W/O).

Initially, an emulsion with its monomer (A) of the product to be encapsulated is carried out and, in the second place, the product is introduced either into an organic phase containing the monomer (B) if the product is hydrophilic, or in an aqueous phase rich in monomer (B) if the product is lipophilic. Polymerization between the two monomers is then carried out and the reaction occurs in the organic phase as shown in Figure 4.5.

The membrane then consists of a polymer, such as polyamide or polyester, if we select monomers from the family of acid chlorides as the monomers of the organic phase and diamines or dialcools as the monomers of the aqueous phase. It is a matter of reactions of polycondensation which are carried out at the interface of two non-miscible liquids.

On a purely complementary informative basis, it can also be noticed that the polymerization of an emulsion requires the selection of a single monomer and is carried out by the adjustment of the pH. In the same way, the reticulation of an emulsion is carried out by chemical reaction starting with a polymer emulsion used for coating.

ΔT

Polymer +

Solvent

Water +

Surfactant


Figure 4.5. Interfacial polymerization (the liquid phase is of organic nature if the product to be encapsulated has hydrophilic properties; this phase is of aqueous nature if, on the

contrary, the product to be encapsulated presents lipophilic properties)

4.2.3. Other chemical and physico-chemical methodologies

Without being exhaustive, we must retain that the methods based on chemical or physico-chemical principles, require the preliminary realization of an emulsion and, then, of various processes gathered in interfacial polymerization, coacervation, polymerization in emulsion, solvent evaporation, etc. It is also possible to quote the realization of multiple emulsions, water-in oil-in water (W/O/W) in which the organic droplets contain small size droplets from the aqueous phase, with particles being made consistent by solvent evaporation (see Figure 4.6).

This technology allows us, on the one hand, to increase the encapsulation rate of absorbent compounds confined in phases having a hydrophobic structure and, on the other hand, to observe kinetics of a slow release of encapsulated products. This technology is favored, in particular, to separate different types of hydrocarbons, release bio-molecules or immobilize enzymes.

Figure 4.6. Water-in-oil-in-water multiple emulsion

Product to be Encapsulated +

Monomer A

Liquid +

Monomer B

A B

Liquid

A + B → AB

A

Liquid

nA + nB → (A⎯B)n

B

Phase with Hydrophobic Properties

External Aqueous Phase

Internal Aqueous Phase Including a Hydrophobic Product


Figure 4.7. Spray coaters: (a) top spray configuration; (b) bottom spray configuration

4.2.4. Fluidized bed equipment

The core technology using physical means is designated under the name “fluidized bed”.

The spray coating process uses a turbulent vertical air flow in which the solid particles to be encapsulated are in suspension. The encapsulating agent, a polymer diluted in a solvent, is applied after atomization from the top, from the bottom or tangentially to the fluidized bed.

Figure 4.7 illustrates both a top spray and a bottom spray coater. They incorporate a truncated conical (or a spherical) expansion chamber. The air flow must be selected so that the partially or none encapsulated particles are maintained in suspension, wherever those which are completely encapsulated fall back into the product container where they are collected.

For spherical particles of well-defined density, it is possible to optimize the maximum size of particles in such a way that they will be fluidized in the air flow (see Figure 4.8). It is noted as expected that the lower the density of the material, the larger the size of the particles.

Top Spray Bottom Spray

Air flow Air flow


0

1

2

3

4

5

6

7

8

0 200 400 600 800 1000 1200 1400 1600 1800

Particles radius (µm)

Den

sity

Figure 4.8. Correlation in spray coating process between the maximum radius of particles and their density

Figure 4.9. Covering steps applied to the solid particles

As far as the coating is concerned, we have to bear in mind that the small size of the ejected droplets from the pulverization nozzle must lead to a complete coverage of the surfaces by the dispersed particles (see Figure 4.9). In practice, these droplets having wettability properties spread out on the surface to finally ensure the film formation after evaporation of the coating solvent.

It is thus necessary to precise for each polymer coating the value of the minimum film-forming temperature (MFFT). From a practical point of view, it is to be noted

Coating Droplets Wettability Spreading Microcapsules

Evaporation of Solvent


that MFFT ranges between room temperature and glass transition temperature of the polymer (Tg).

The spreading out of the liquid (L) which ensures the covering of the solid (S) is described by means of an equilibrium spreading coefficient (E). This coefficient represents the difference between the adhesive energy (ωa) and the cohesive energy (ωc) of liquid.

,a L S SLω = γ + γ − γ [4.3]

2 ,c Lω = γ [4.4]

.a c S L SLE = ω −ω = γ − γ − γ [4.5]

If E > 0, the drops are spread on the surfaces and form a uniform film.

More generally, the drops submitted to the gravitational force form a cap of thickness h which characterizes the energy balance acting on the drop, that is to say the interfacial energies and the gravitational potential energy.

Various polymers can be selected in aqueous dispersion or in solvent dispersion. Among those dispersed, we can note, as non-restrictive examples:

– metacrylic/acrylates copolymers in aqueous dispersion with a solid content of 30% (EUDRAGIT 30D, TMFF = 30°C, pH = 6), or its equivalent the KOLLICOAT;

– aqueous dispersions of acrylic ester copolymers of 46% (MOWILITY, LDM 7966, TMFF = 35°C, pH = 8);

– epoxy polymers (BECKOPOX, TMFF = 36°C, pH = 4).

Finally, the general spray coating process variables are in particular:

– the fluidization air volume;

– liquid spray rate;

– fluidization air temperature and specific humidity.

4.2.5. Other physical processes

We must retain that the methods based on air suspension coating are generally selected. For additional information, the coextrusion whose process is illustrated in Figure 4.10 can be quoted. The microcapsules are given off by vibrational mode.


Figure 4.10. Coextrusion process

Figure 4.11. Difference in pressure process

We can also refer to the microencapsulation process via the difference in pressure through a calibrated gauge (see Figure 4.11).

4.3. Kinetics of release [CRA 75, HIG 60, HIG 61, MAR 93]

Special attention will be given to the models of controlled release of encapsulated material. This approach excludes the release obtained by various external actions (e.g. mechanical, chemical and biological). Various shapes of curves of release can be obtained (see Figure 4.12), descriptive of the involved mechanism and, in particular, those being carried out with a latent lag time, or those presenting a burst effect. This latter effect results in an important release of the encapsulated product during the first hours, followed by a deceleration of the

Vibrations

Material to be encapsulated

Encapsulating material

CO2

Polymer

Particles to be coated


kinetics of the release. This implies that, as a preliminary, the rate of encapsulation is optimized and, in fact, the content of the product to be encapsulated, i.e., the product mass to be encapsulated on the total mass of the microparticles, is also optimized.

For example, it will be noted that microencapsulation in an acrylic copolymer (EUDRAGIT L100) of a well-defined percentage of theophylline 89% is in fact experimentally estimated at 88 ± 2% by using UV spectrometry; the same percentage calculated out of albumin is only determined in experiments with the value of 54%.

Figure 4.12. Profiles of release of the microencapsulated products: (a) burst effect, (b) stationary mode, (c) release after a lag time noted by τ

Considering, as a first approach, that the release rate obeys a true diffusional mechanism, the FICK law applies to express either the flow of particles (or the mass) released (M) per unit of time (t) and surface (S) or the release speed (see Table 4.1). All of these values are proportional to the difference in concentration on both sides of the membrane (Table 4.1), as is illustrated in Figure 4.13(a). This may be written as:

1 2C.

CdM SDdt h

−⎛ ⎞= ⎜ ⎟⎝ ⎠

[4.6]

Flux Speed of release Diffusion coefficient concentration gradient

dM/S dt dM/dt D (C1 – C2) or D (C1 – C2)/h

Table 4.1. The flux is proportional to the concentration gradient

t

Cr (a)

(b)

(c)

τ


In practice, this mechanism, where the released flow describes the migration of the diffusing species, goes with a reaction to the interfaces of which a traditional example is the swelling type.

As a consequence, the concentration on both sides of the encapsulating membrane of thickness h must be corrected with the help of a variable K, designed as the partition coefficient or distribution coefficient (see equation [4.7] and Figure 4.13(b) where C1 and Cd on one side and C2 and Cr on the other side, respectively, indicate the concentrations in the donor compartment and the receiver compartment, with or without interfacial phenomena):

1 2 .d r

C CK

C C= = [4.7]

It results in the introduction of a permeability coefficient P which has units of linear velocity m/h:

.DKPh

= [4.8]

Thus, the velocity of the release through a homogenous polymeric film obeys relation [4.9] obtained from [4.6]:

( ) .dM PS C Crddt= − [4.9]

If we indicate by 0dC the initial concentration in the donor compartment, and Cr

the concentration in the receiver compartment, we can write:

0,r d dC C C= − [4.10]

that is to say:

02 .d r d rC C C C− = − [4.11]

By expressing the value of the concentration Cr, we obtain:

so .r rMC M C VV

= = [4.12]


(a) (b)

Figure 4.13. Concentration gradient across a membrane of thickness h (a) without interfacial phenomena, (b) with interfacial phenomena

We can deduce that:

2 .0

d C P Sr C Crddt hV⎛ ⎞= −⎜ ⎟⎝ ⎠

[4.13]

If the concentration in the receiver compartment is close to zero (sink conditions), expression [4.13] is simplified and leads to:

0

rd

d C P S Cdt hV

= so 0

.PSC C tr dhV= [4.14]

The slope of the curve Cr = f (t) allows the determination of P. If the preceding condition is no longer licit, it is necessary to integrate the equation which leads to:

02log 2 .

02

CdCr P S tC hVd

⎛ ⎞⎜ ⎟−⎜ ⎟ = −⎜ ⎟⎜ ⎟⎜ ⎟⎝ ⎠

[4.15]

The two preceding formulas are valid only when a stationary state is reached quasi-instantaneously. In the general case, we must write that:

2.

6P S C hdC tr hV D

⎛ ⎞= −⎜ ⎟⎜ ⎟

⎝ ⎠ [4.16]

Cd

Cr

C1

C2

C1

C2

h h


The intersection with the time axis defines the boundary between stationary states and the non-stationary states. This is shown in Figure 4.12 and it corresponds to a point τ as follows:

2.

6h

Dτ = [4.17]

It is thus usual to note the three types of curves in Figure 4.12 to illustrate the kinetics of the release of encapsulated materials.

On top of that, in order to increase the membrane permeability, various water-soluble products can sometimes be introduced into the membrane. Their globular or thread-like distribution may result, after the passage of an entering aqueous flow, in open porosities where the fluidic exchanges occur. The kinetics of the release is carried out, in this case, through these preferential ways. Figure 4.14 illustrates the fissured or porous structure being observed on the membrane thicknesses after dissolution of the incorporation of water-soluble products.

(a) (b)

Figure 4.14. Scanning electron microscopy of the porous structures associated with the addition of water-soluble materials in the polymer constituting the envelope:

(a) porous structure, (b) thread-like structure

In the case of a microporous structure, the expression of the speed of the release may be written as:

. '. . ,SCdM S Ddt T h

ε= [4.18]

where D' is the diffusion coefficient of the encapsulated material in the liquid phase impregnating the pores, ε represents porosity, i.e. the size which defines the volume of pores in relation to the total volume, T is tortuosity which represents the


relationship between the real path followed by the liquid and the shortest possible path, Cs representing the solubility of the encapsulated material in water.

For such structures, it can be noted that the release imposes a first flow through the membrane, then, after dissolution of the microencapsulated product, a second flow towards the outside. The release speed is linked to the relation resulting from the Higushi model, which leads to the following expression:

( )1/2

1/20

1 2 ,2 S S

dM DS C C C tdt T

−ε⎡ ⎤= −⎢ ⎥⎣ ⎦ [4.19]

where C0 is the initial concentration of the encapsulated material.

4.4. Conclusion [DUB 86, LEH 92, MUR 98, NEL 02, OKA 85, ROS 04]

The techniques of microencapsulation, consisting of enclosing condensed phases inside a polymeric membrane, apply as well to the realization of microcapsules as to microspheres. Morphologies of the obtained products in a powder form are easy to differentiate according to the chemical or physical nature of the processes retained for their manufacture, as illustrated in Figure 4.15.

(a) (b)

Figure 4.15. Scanning electron microscopy of the morphology of microencapsulated products either by a chemical path (a), or by using physical methods (b)

The technologies retained for the microencapsulation process are intermediate between those which allow film coating of tablets and, on the other side, those applying the manufacture of quantum-dots which are nanoparticles capable of emitting bright colors when they are illuminated by a source of light. For this reason, it can be noted that the described methodologies are far from being restrictive and if you take as an example food flavorings or perfumes, you can notice the


microencapsulation by beta-cyclodextrin which is an oligosaccharide whose origin is natural.

“Matrix” microcapsules are also retained for perfume which is absorbed in the porous structures of polymeric particles. For the cosmetic industry or pharmacy, we can also note the microencapsulation by stabilized liposomes. In addition, you will retain the modifications of encapsulating polymers in order to accelerate or delay the release of the encapsulated polymer.

The choice of materials ensuring the microencapsulation is far from being restrictive as it includes water-soluble polymers (poly(vinylacetate) (PVA), polyvinylpyrrolidones (PVP), the biocompatible polymers (PLAGA, ε-caprolactone), some modified natural polymers (cellulose ethers), polysaccharides (alginates, gum arabic), the copolymers (acrylic), the oleic substances (waxes of carnauba), etc.

The methods for the observation of encapsulated products mainly relies upon scanning electron microscopy coupled to a system of cryofracture. We can also note the micrographs, associated with confocal microscopy which is proved to be particularly interesting when the active compound and the polymer present fluorescent properties brought in by the markers.

The kinetics of the release of encapsulated products can be obtained by various spectrometries such as UV spectrometry if the active ingredient presents chromophoric groups, or mass spectrometry if the released quantity is weak. Membranes of the microcapsules are in fact permeable, semipermeable and impermeable.

Microencapsulation offers many opportunities for a considerable number of applications founded, for example, on the vectorization of the encapsulated products to their interactions with targets in a living organism. In this case, we speak about drug carriers which support a specific liberation. Originally, vehicles are of nanometric size, but the use of products of micrometric size appears possible with therapeutic applications. Other potential openings are gathered under the term of biencapsulation. The other potential openings relate in particular to metallic material coating or ceramic material in order to confer additional properties to them such as thermal or electric conductivity, even magnetic properties or, on the contrary, properties of insulation.

Friction of microcapsules bringing an olfactive sensation associated or not with a visual image can be used to promote a multisensorial analysis of a product. Microcapsules providing the olfactive function can be laid down by various processes of impression or included in a varnish. Phase shifts being able to occur


inside microcapsules with transparent coating, can in the same way, create progressive sensorial impressions.

In other words, the techniques of microencapsulation are based on the manufacture of microreactors, the voluminal and surface properties of which can be functionalized in order to implement the properties of use, and in particular those with progressive evolution.

4.5. Bibliography

[AUB 06] AUBRY J. M., DEROO S. and SEBAG H, Formulation cosmétique. Matières premières, concepts et procédés innovants, EDP Sciences, 2006.

[BEN 96] BENITA S., Microencapsulation: Methods and Industrial Applications, Marcel Dekker, 1996.

[BUR 85] BURI P., PUISEUX F, DOELKER E. and BENOIT J. P., Formes pharmaceutiques nouvelles, Lavoisier Tech/doc, 1985.

[BUR 94] Burgers J. D., “Complex coacervation: Microcapsule formation”, Macromolecular Complexes in Chemistry and Biology, Springer-Verlag, Heidelberg, Chapter 17, 1994.

[CHA 04] CHABON P., CLOUTET E. and CRAMAIL H., Macromolécules, vol. 37, pp. 5856–5859, 2004.

[COU 96] COUVREUR P., COUARRAZE G., DEVISSAGET J. P. and PUISEUX F., Microencapsulation: Methods and Industrial Applications, Jerusalem, Benitas, Chapter 8, pp. 183–211, 1996.

[CRA 75] CRANK J., The Mathematics of Diffusion, Clarendon Press, 2nd ed., 1975.

[DON 99] DONATH E., Microspheres, Microcapsules & Liposomes, Reza Arshady, Citrus Books, London, 1999.

[DUB 86] DUBERNET C. and BENOIT J. P., “La microencapsulation: ses techniques et ses applications en biologie”, Actualités Chimiques, vol.10, pp. 19–28, 1986.

[FAL 04] FALSON-RIEG F., FAIVRE V. and PIROT F., “Nouvelles formes médicamenteuses”, Lavoisier Tec/doc, 2004.

[GHO 06a] GHOSH S. K., Functional coatings by polymer microencapsulation, Lavoisier Tec/doc, 2006.

[GHO 06b] GHOSH S. K., Functional Coatings and Microencapsulation: A General Perspective, Functional Coating, pp. 1–27, Wiley-Verlag GmbH, 2006.

[GIU 95] GIUNCHEDI P. and CONTE U., “Spray-drying as a presentation method of microparticulate drug delivery systems, an overview”, STP Pharma Sciences, vol. 5, no. 4, pp. 276–290, 1995.

[HIG 60] HIGUCHI T., “Physical chemical analysis of percutaneous absorption process from creams and ointments”, J. Soc. Cosm. Chem., vol. 11, pp. 85–97, 1960.


[HIG 61] HIGUCHI T., “Rate of release of medicaments from ointment bases containing drugs in suspension”, J. Pharm. Soc., vol. 50, no. 10, pp. 874–875, 1961.

[ISR 94] ISRAELACHVILI J., “The science and application of emulsions: an overview”, Colloids and Surface A: Physicochemical an Engineering Aspects, vol. 91, pp. 1–8, 1994.

[LEH 92] LEHMANN K., Microcapsules and Nanoparticules in Medecine and Pharmacy, M. Donbrown, CRC Press, Boca Raton, pp. 73–97, 1992.

[MAR 93] MARTIN A., Physical Pharmacy, William and Wilkins, 4th Edition, Chapters 13 and 19, 1993.

[MUR 98] MURANO E., “Use of natural polysaccharides in the microencapsulation techniques”, Journal of Applied Ichtyology, vol. 14, no. 3-4, pp. 245–249, 1998.

[NEL 02] NELSON G., “Applications of microencapsulation in textiles”, International Journal of Pharmaceutics, vol. 242, no. 1-2, pp. 55–62, 2002.

[OKA 85] OKADA J., KUSAÏ A. and UEDA S., “Factors affecting microencapsulability in simple gelatin coacervation method”, J. Microencapsulation, vol. 2, no. 3, pp. 163–173, 1985.

[PIE 04] PIEGAY F., “Microencapsulation par polymérisation interfaciale”, Midi FABs, vol. 2, pp. 9–16, 2004.

[PRO 98] PROKOP A., Microencapsulation, microgels, interferes, Advances in Polymer Science, Lavoisier Tech/doc., vol. 136, 1998.

[ROS 04] ROSENBERG M. and LEE S. J., “Calcium alginate coated, whey protein-based microspheres: preparation, some properties and opportunities”, J. Microencapsulation, vol. 21, no. 3, pp. 263–281, 2004.

[SCH 56] SCHLEICHER L. and GREEN B. K., US Patent 2730456 no., 1956.

[VAN 73] VANDEGAER J. E., Microencapsulation Process and Applications, Plenum Press, New York, 1973.

[VAN 07] VANDAMME T. F., PONCELET D. and SUBRA-PATERNAULT P., Microencapsulation: des sciences aux technologies, Lavoisier Tec/doc, 2007.

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