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Microencapsulation: Methods and Pharmaceutical
Applications
Ying Lu
Purdue University, College of Pharmacy, West Lafayette, Indiana, U.S.A.
Kinam Park
Purdue University, Departments of Biomedical Engineering and Pharmaceutics, West Lafayette, Indiana, U.S.A.
INTRODUCTION extended period of time. This has important implica-
Microencapsulation is the process of preparing micron- tions in the improvement of patient compliance, which Methods and Pharmaceutical Applications
sized particles consisting of one or more core materials generally benefi ts from reduced number of necessary
within single or multiple shell materials. The concept of administrations.
microencapsulation dates back at least to the 1930s, when ● Signal-Responsive Release: Drug release from mic-
carbonless copy paper became the fi rst commercial product roparticles in response to internal or external stimuli is
to emerge as a result of microencapsulation technology (1). a sophisticated way to modify the release profi les of
Since then this technology has developed rapidly, leading conventional formulations. In this case, microparticles oencapsulation:
to a variety of products in pharmaceutical, medical, agri- release little or no drug until a signal is detected that Micr
cultural, food, manufacturing, and cosmetics industries. modifi es the release rate. Signifi cant diffi culties have
Microencapsulation techniques are particularly prevalent been encountered in attempts to couple drug release to
in the development and production of drug delivery sys- internal stimuli such as local chemical signals or bio-
tems within the pharmaceutical fi eld. Representative and logical needs. However, release triggered by external
potential applications and benefi ts of microencapsulation stimuli such as magnetic fi eld has been studied exten-
in pharmaceutical industry include: sively with promising results. In addition, magnetic
fi eld can direct the local accumulation of microparti-
● Reduction of adverse effect and increase of therapeutic cles. Signal-responsive release can potentially reduce
effi cacy by targeting the intended site toxic side effects associated with systemic administra-
● Control of drug release from encapsulated microparti- tion of parenteral formulations.
cles ● Pulsatile Release: Pulsed systems involve the release
● Enhancement of stability of drugs by forming a barrier of drugs in one or more pulses over a controlled period
between drug and surrounding environment of time. Usually, these systems are produced by engi-
● Enhancement of solubility of poorly soluble drugs by neering a single or multiple cycles of time delay in the
particle size reduction microparticle degradation mechanism. The concept of
● Masking of taste and odor of certain drugs (2). pulsatile delivery is still in its infancy but promises
Microencapsulated particles have become indispensable great potential, especially for the delivery of multiple-
in controlled drug release systems. Biocompatible mic- challenge antigens and peptide hormones. Delivery of
roparticles with modifi ed drug release profi les are particu- antibiotics in divided pulses prevents the formation of
larly useful for the development of parenteral formulations. antibiotic-resistant microbacterial strains. Patient com-
Examples of useful types of modifi ed release profi les pliance can be enhanced by eliminating the need for
include: subsequent boost injections following an initial injec-
tion, since pulsatile systems can be made to mimic the
● Sustained release: Encapsulation of drugs within one or drug delivering effect of the process (3).
more shell materials controls the rate at which drugs
diffuse out of the microparticle into the surrounding As new materials continue to be discovered and technol-
environment. In addition, some microparticles release ogy advances, the science of microencapsulation and its
drugs by an erosion mechanism, whereby the rate and applications will grow and expand to encompass a wider
extent of drug release is directly related to the rate and range of processes and products. However, to date no sin-
extent of shell material degradation. Consequently, gle encapsulation process has been developed that is capa-
drugs are released from the microparticles continuously ble of producing the full range of encapsulation products. It
over a period of time. The duration of drug release can may be simply impossible to develop one microencapsula-
generally be controlled by defi ning a set of microencap- tion method that can be used for widely different applica-
sulation process parameters. The major advantage of tions, since the nature of the drug and microparticles will
this approach is the ability to maintain drug concentra- vary signifi cantly depending on the applications. This
tions in the blood within the therapeutic window for an chapter is designed to provide an up-to-date overview of
Encyclopedia of Pharmaceutical Science and Technology DOI: 10.3109/9781841848204.000: Microencapsulation: Methods and Pharmaceutical Applications
Copyright © 2012 by Informa Healthcare USA, Inc. All rights reserved. 1
2 Encyclopedia of Pharmaceutical Science and Technology, Fourth Edition, Volume 1
Micr the existing microencapsulation methods with emphasis on coacervation involves inducing polymer–polymer interac-
oencapsulation:processes that have achieved signifi cant pharmaceutical tion between two oppositely charged polymers, such that
use and to discuss the various current applications of electrostatic interaction between two oppositely charged
microencapsulation, including potential applications that polymers produces phase separation. In general, for both
are yet to be commercialized. simple and complex coacervation, formation of immiscible
phases is followed by polymer deposition on the core
material(s). The deposited polymer can be stabilized by
Methods and Pharmaceutical ApplicationsTERMINOLOGY cross-linking, desolvation or temperature change (9).
A vast number of articles and reviews have been devoted to The successful encapsulation of drugs by coacervation
the subject of microparticulate systems. In these texts the is dependent upon several process parameters. The ability
terms ‘microparticle’, ‘microsphere’, ‘microcapsule’ and of a coacervating agent to spread and engulf dispersed
sometimes even ‘nanoparticle’ are used interchangeably. drugs is highly affected by the types of coacervate used
There is no universally accepted defi nition of ‘microparti- and its viscosity (10). Complex coacervation involves
cle’ or ‘nanoparticle’ because it is diffi cult to use any one electrostatic interactions, and thus, the pH of the medium
parameter, such as diameter, for such a defi nition. For sim- must be carefully controlled to maintain the charges on
plicity, a ‘microparticle’ is defi ned in this chapter, as a par- the polymeric species. For example, in a gelatin–gum ara-
ticle with an equivalent diameter of around 1 µm and bic system, the pH should be adjusted to below the iso-
higher. The concept of equivalent diameter was developed electric point of gelatin such that the positively charged
for the size determination of non-spherical objects and is gelatin is attracted to the negatively charged gum Arabic
well-defi ned by the IUPAC (4). The term ‘microcapsule’ (11). In the same study, it was shown that the acidifying
originally refers to microparticles that consist of one or rate of the medium affects the microparticle size distribu-
more core materials surrounded by a distinct shell or wall, tion (11). Another factor is the concentration of surfac-
but it has evolved to include microparticles in which the tants used in the process. Several studies have
core materials are embedded randomly or homogeneously demonstrated the effect of various concentrations of sur-
dispersed within a matrix (shell). In some texts, spherical factant on particle size distribution (12), coacervation
microparticles in which the core material is dispersed yield (13) and drug-loading (14).
evenly throughout the shell material are also known as
‘microspheres.’ A variety of materials have been used in
microencapsulation, ranging from drugs, agrochemicals, Interfacial and In Situ Polymerization
enzymes and fragrances for the core and polymers, fats and Interfacial polymerization is a microencapsulation technol-
waxes for the shell. In consideration of the scope of this ogy routinely used to produce pesticides and herbicides. In
chapter, the discussion will be limited primarily to encap- this process, a capsule or shell is formed at the interface
sulation using synthetic or natural polymers. between the core material and shell material through
polymerization of reactive monomers. This technique can
METHODS OF MICROENCAPSULATION be used to encapsulate both water-miscible and water-
Currently, there are many methods of microencapsulation. immiscible core materials. A water-miscible core material
We will examine the representative techniques with empha- is dissolved in an aqueous solution to which a polymeriz-
sis on processes that have produced commercially signifi - ing reactant is added. When the aqueous mixture is dis-
cant products and identify important parameters that affect persed in an organic phase containing a coreactant, rapid
the quality of the microparticulate systems produced. polymerizing occurs at the interface to produce a capsule
shell surrounding the core material. For water-immiscible
Coacervation core materials, the reaction sequence is reversed. The
organic phase now contains the core material along with a
The process of coacervation is the fi rst reported microen- multifunctional monomer. The organic phase is dispersed
capsulation method to be adapted for the industrial produc- into an aqueous phase and a coreactant is added, resulting
tion of microparticles (1). The fi rst signifi cant commercial in polymerization at the interface. Microparticles formed
product that utilizes coacervation was carbonless copy by interfacial polymerization often have a continuous
paper. Coacervation involves the partial desolvation of a core–shell structure with a spherical shape.
homogeneous polymer solution into a polymer-rich phase In situ polymerization is closely related to interfacial
(coacervate) and a polymer-poor dilute liquid phase (coac- polymerization in that shell formation occurs via polymer-
ervation medium) (5). Two types of coacervation have ization reactions within the encapsulation mixture. How-
been identifi ed, namely simple and complex coacervation. ever, a major difference between these two methods is that
The mechanisms of microparticle formation for these two no reactive agents are added to the phase containing core
processes are similar with the exception of the method in materials in the in situ polymerization. At the interface
which phase separation is carried out. Simple coacervation between dispersed core materials and the continuous phase,
requires a change in the temperature of the polymer solu- polymerization occurs exclusively on the side facing the
tion (6) or the addition of a desolvation agent, usually a continuous phase. As the polymer grows, it deposits onto
water-miscible non-solvent such as ethanol, acetone, diox- the surface of the core material, where cross-linking reac-
ane, isopropanol or propanol (7), or an inorganic salt such tions may occur alongside polymer chain growth, eventu-
as sodium sulfate (8). On the other hand, complex ally forming a solid capsule shell. In situ polymerization
Encyclopedia of Pharmaceutical Science and Technology, Fourth Edition, Volume 1 3
Liquid crystal, percolated structure
or biocontinuous phase
OIL
Oil-in-water emulsion
C
A Inverted micelle
D SURF
A
CT Methods and Pharmaceutical Applications
ANT
B
Micelle
WATER
Figure 1 Hypothetical phase diagram of emulsion system composed of water, oil and surfactant. The different regions of the phase oencapsulation:
diagram (A, B, C, and D) are presented as well as the characteristic structures formed from these regions. Micr
has been used extensively in the production of microcap- of oil-in-water (O/W) emulsion is widely used for encapsu-
sules loaded with carbonless paper inks or perfume for lation of lipophilic active moieties like steroidal hormones
scented strips (15). In the cosmetics industry, this technique (19) and neuroleptics (20). The procedure can be adapted
is used to produce microcapsules containing mineral oils. for encapsulation of hydrophilic drugs, where the drug is
In the discussion of processing and formulation parame- incorporated into an aqueous dispersed phase and poured
ters that affect interfacial and in situ polymerization, two into an organic continuous phase containing wall-forming
common processes can be isolated and discussed separately. polymer (water-in-oil, W/O). This primary emulsion is
First is an emulsifi cation step which determines the mic- then further emulsifi ed in an external aqueous phase, lead-
roparticle size and size distribution, and the second is a cap- ing to a type of double emulsion known as water-in-oil-in-
sule formation step. Parameters that affect emulsifi cation water (W/O/W) emulsion. Yet another class of emulsions
will be discussed in more detail in the section devoted to consists of oil-in-oil (O/O) emulsion and multiple emul-
emulsions. Several important processing variables govern sions involving O/O procedures (W/O/O and W/O/O/O).
the formation of capsules. The thickness of the capsule wall W/O/O and W/O/O/O processes are carried out with the
is dependent upon the wall growing time (i.e., reaction primary purpose of protecting highly water-soluble active
time) (16), as well as the chemical nature and concentration agents from partitioning into the oil-water interface, caus-
of the monomers (17). The thickness of the capsule wall in ing drug loss and low encapsulation effi ciencies. For all
turn affects the rupture resistance of the capsule wall. The types of emulsions, the emulsifi cation procedure is fol-
ratio of monomer to cross-linking agent infl uences the lowed by solvent elimination step in complement with
integrity and morphology of the capsule shell (18). Other solidifi cation step. Depending on the method of solidifi ca-
parameters such as pH, stirring rate and temperature, also tion, emulsion can be further classifi ed as solvent evapora-
play a role in determining the success of interfacial and tion, solvent extraction and cross-linking method.
in situ polymerization. In the solvent-evaporation method, solvent is eliminated
Emulsion in two stages: fi rst the solvent diffuses through the dis-
persed phase into the continuous phase, and second the sol-
A common method to prepare microparticles is the emul- vent is eliminated at the continuous phase–air interface. To
sion technique. An emulsion is a mixture of two or more facilitate the evaporation of solvent from the continuous
immiscible liquids. Pharmaceutically relevant liquids usu- phase–air interface, an appropriate amount of heat may be
ally include some type of volatile organic solvent as the applied to the system. Theoretically, if the solvent can be
dispersed phase and water containing appropriate tensioac- extracted completely from the microparticle into the con-
tive substance as the continuous phase (Fig. 1). For exam- tinuous phase, then the solvent evaporation step is no lon-
ple, hydrophobic drugs can be dissolved along with the ger necessary. In practice, this is the concept behind the
wall-forming polymer in a common organic solvent, such solvent extraction method. Using a suffi ciently large vol-
as methylene chloride or dichloromethane, and the entire ume ratio of continuous phase to dispersed phase or by
mixture emulsifi ed in an aqueous solution containing a choosing a cosolvent in the dispersed phase that has a great
polymeric surfactant such as poly(vinyl alcohol). This type affi nity to the continuous phase, the solvent can be extracted
4 Encyclopedia of Pharmaceutical Science and Technology, Fourth Edition, Volume 1
Micr from the microparticle to completion. The third type of Spray Drying
oencapsulation:emulsion method is the cross-linking method, which takes Spray drying is a relatively low cost, commercially viable
advantage of the ability of certain naturally available method of microencapsulation. Current industrial applica-
hydrophilic polymers such as gelatin, albumin, starch, dex- tions of spray drying range from the encapsulation of fl a-
tran, and chitosan to cross-link and solidify. The cross- vors and fragrances by the food industry to paint pigments
linking reactions may take place upon heating (21) or the in manufacturing. During this process, the core material is
addition of counter polyions (22) and cross-linking fi rst emulsifi ed or dispersed into a concentrated solution of
Methods and Pharmaceutical Applicationsagents (23). It is crucial to take into consideration of the the shell material. The mixture is then atomized into a
toxicity of added reagents when formulating pharmaceuti- heated chamber containing carrier gas where the solvent is
cally relevant microparticles using this method. rapidly removed to produce dry microparticles (Fig. 2).
A vast number of studies have been conducted on the A major advantage of spray drying is the ability to mass
parameters that infl uence emulsion. Here, we will briefl y produce microparticles with relative ease and low cost.
examine some of the most important ones. The character- However, one major limitation is the restricted use of many
istics of microparticles produced by emulsion may be solvents other than water due to fl ammability issues. This
affected by physical parameters(such as the confi guration severely limits the types of shell materials to those soluble
of the apparatus, stirring rate, volume ratio of the dis- or at least dispersible in water. Currently, other solvent
persed to continuous phase, and weight ratio of encapsu- options such an ethanol–water cosolvent system (32) and
lated core material to shell material),physicochemical methylene chloride (33) are being explored. Another disad-
parameters (such as interfacial tension, viscosities and vantage of spray drying is the limited control over the
densities of the dispersed and continuous phases), and geometries of the produced microparticles and the ten-
chemical parameters (such as the types of polymer, drug, dency for the microparticles to form aggregates.
surfactant and solvent used in the emulsion reactor). The The viscosity and particle size distribution of the pri-
optimization of these parameters is material-specifi c, i.e., mary emulsion have signifi cant impact on the morphology
for different drug–polymer systems, the values of the and size distribution of subsequent spray drying process.
parameters differ. Furthermore, the set of parameters pro- For example, if the viscosity is too high, elongated and
ducing the most signifi cant impact on microparticle char- large droplets may form (34). The concentration of wall-
acteristics varies with the system of drug–polymer under forming materials in the solution has a direct impact on the
investigation. For the well-characterized poly(lactide-co- microencapsulation effi ciency of core materials (35). Dur-
glycolide) (PLGA) system it is generally accepted that ing spray drying, a number of processing parameters must
mean particle size increases with increasing polymer con- be optimized in order to produce high quality microparti-
centration (24,25) and is independent of the ratio of lac- cles. These parameters include feed temperature, air inlet
tide to glycolide units. The ideal weight percentage of and outlet temperatures (36), as well as the rate of emul-
drug in polymer is in the range of 20–40%. Higher theo- sion mixture being delivered to the atomizer and rate of air
retical drug loading generally leads to lower encapsula- fl ow (37). Optimization of these and many other factors
tion effi ciency of drugs in PLGA microparticle (26). that affect spray drying microencapsulation are mainly car-
Increasing the volume of continuous phase relative to the ried out by trial and error experimentation.
dispersed phase is expected to reduce the PLGA matrix
density in the microparticle, resulting in increased Spray Coating
burst release (27). However, if the volume ratio is
increased suffi ciently high, a decrease in burst release is Spray coating is used extensively in encapsulating solid or
observed (28). porous particles. In spray coating processes, particles are
rotated and moved around in a designed pattern so that a
Supercritical Fluid liquid coating formulation can be sprayed evenly onto the
surfaces of the individual particles. The coating formula-
Supercritical fl uids offer a wider scope of choices as tion is allowed to dry by solvent evaporation or cooling.
solubilizing agents for core and/or shell materials. The Usually, the coating cycle may be repeated until a desired
ability of supercritical fl uids to solvate core and shell capsule thickness is achieved. Depending upon the method
materials can be altered by varying temperature and by which the particles are rotated and mixed, spray coating
pressure conditions, the two key parameters in this par- can be broadly classifi ed as fl uidized bed coating and pan
ticular microencapsulation technique. In addition to sol- coating. The former is widely used in microencapsulation,
vating the active principles, the use of supercritical whereas the latter is more often used to coat the surface of
fl uids as extractants are also well documented (29). tablets. Our discussion here will be limited to fl uidized bed
Therefore, if the starting solution is appropriately pre- coating only.
pared, the fi nal microencapsulated product can be Fluidized bed coaters function by suspending the solid
obtained in one step that consists of two main processes: microparticles in a moving gas stream. Three types of fl uid-
solvation of active principles by supercritical fl uid in the ized bed coaters are available, each differ in the position of
rapid expansion of supercritical solutions (RESS) pro- the nozzles that apply the liquid coating formulation: top
cess (30) and precipitation of compounds by the spray, tangential spray and bottom spray (Fig. 3). In a top
supercritical fl uid in the supercritical anti-solvent spray coater, the coating solution is sprayed from the top part
crystallization (SAS) process (31). of the unit onto the fl uidized bed. Microparticles are moved
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