Review Article

[Singh et al., 2(9): Sep., 2011]

ISSN: 0976-7126

INTERNATIONAL JOURNAL OF PHARMACY & LIFE SCIENCES

A review on solid dispersion
Sameer Singh1*, Raviraj Singh Baghel2 and Lalit Yadav3
1, Institute of Pharmacy Vikram University Ujjain, (M.P) - India
2, School of Pharmacy, Bhopal, (M.P) - India
3, Rajeev Gandhi College of Pharmacy, Bhopal, (M.P) - India
Abstract
Solid dispersions have attracted considerable interest as an efficient means of improving the dissolution rate and
hence the bioavailability of a range of poorly water-soluble drugs. Solid dispersions of poorly water-soluble drugs
with water-soluble carriers have been reduced the incidence of these problems and enhanced dissolution. The focus
of this review article on advantages, disadvantages and the method of preparation, and characterization of the solid
dispersion.
Key-Words: Solubility, Solid Dispersions, Carrier, Bioavailability

Introduction
The enhancements of oral bioavailability of such
poorly water-soluble drugs often show poor
bioavailability because of low and erratic levels of
absorption. Drugs that undergo dissolution rate limited
gastrointestinal absorption generally show improved
dissolution and bio availability as a result of reduction
in particle size. However, micronizing of drugs often
leads to aggregation and agglomeration of particles,
which results in poor wettability. Solid dispersions of
poorly water-soluble drugs with water-soluble carriers
have been reduced the incidence of these problems and
enhanced dissolution. The development of solid
dispersions as a practically viable method to enhance
bioavailability of poorly water-soluble drugs overcame
the limitations of previous approaches such as salt
formation, solubalization by cosolvents, and particle
size reduction. Studies revealed that drugs in solid
dispersion need not necessarily exist in the micronized
state. A fraction of the drug might molecularly disperse
in the matrix, thereby forming a solid dispersion. When
the solid dispersion is exposed to aqueous media, the
carrier dissolves and the drug releases as fine colloidal
particles.
* Corresponding Author:
E-mail: [email protected]
Mob: 0945657194, 07879555116

The resulting enhanced surface area produces higher

dissolution rate and bioavailability of poorly watersoluble drugs. In addition, in solid dispersions, a
portion of drug dissolves immediately to saturate the
gastrointestinal tract fluid, and excess drug precipitates
as fine colloidal particles or oily globules of submicron
size. solid dispersion technique was firstly
demonstrated by Sekiguchi and Obi. They proposed the
faster absorption of poorly water-soluble drugs such as
sulfathiazole by the formation of eutectic mixture with
a water-soluble and physiologically inert carries like
urea. Upon exposure to aqueous fluids the active drug
released into fluids is fine, dispersed particles because
of fine dispersion of the drug in the solid eutectic
mixture and the faster dissolution of the soluble matrix.
The eutectic mixture contained 52 per cent w/w of
sulfathiazole and 48 per cent w/w of urea. The
possibility of using solid solution approach in which a
drug is molecularly dispersed in soluble carrier was
subsequently introduced.
A solid dispersion technique has been used by various
researchers who have reported encouraging results with
different drugs The first drug whose rate and extent of
absorption was significantly enhanced using the solid
dispersion technique was sulfathiazole by Sekiguchi
and Obi (Sekiguchi, 1961). Technique for the
preparation of solid dispersions, Lyophilization has
also been thought of as a molecular mixing technique
where the drug and carrier were co-dissolved in
cyclohexanol, frozen and then sublimed under vacuum
to obtain a lyophilized molecular dispersion (Lin,
1980).1

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Numerous solid dispersion systems have been
demonstrated in the pharmaceutical literature to
improve the dissolution properties of poorly watersoluble drugs. Other methods, such as salt formation,
complexation with cyclodextrins, solubilization of
drugs in solvent(s), and particle size reduction have
also been utilized to improve the dissolution properties

of poorly water-soluble drugs; however, there are

substantial limitations with each of these techniques.
On the other hand, formulation of drugs as solid
dispersions offers a variety of processing and excipient
options that allow for flexibility when formulating oral
delivery systems for poorly water soluble drugs.

POORLY WATER
SOLUBLE DRUG

Tablet/ capsule

Dosage form

Solid dispersion/
Solution

Disintegration

Large solid particle

Disintegration

Drug in GI tract

Colloidal Particles/

(Usually 5-

Fine Oily Globules

100 micron)

(usually <1 micron)

Lower dissolution

Higher Dissolution

Rate

Rate
ABSORPTION IN TO
BODY SYSTEM

Fig.. 1: A schematic representation of the bioavailability enhancement of a poorly water- soluble drug by solid
dispersion compared with conventional tablet or capsule.

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Oral bioavailability of a drug depends on its solubility
and/or dissolution rate, and dissolution may be the rate
determining step for the onset of therapeutic activity.
Therefore efforts to increase drug dissolution of drug
are often needed. Methods available to improve
dissolution include salt formation, micronization and
addition of solvent or surface active agents. Solid
dispersion (SD) is one of such methods and it involves
a dispersion of one or more active ingredients in an
inner carrier or matrix in solid state prepared by
melting, dissolution in solvent or melting-solvent
method4. The technique has been used for a wide
variety of poorly aqueous soluble drug.
Poorly soluble drugs represent a problem for their
scarce availability related to their low dissolution rate.
The major drawback of low aqueous solubility is
delays its absorption from the gastrointestinal tract.
Solubility behavior of a drug is one of the key
determinants of its oral bioavailability. NoyeshWhitney equation provides some hints as to how the
dissolution rate of even very poorly soluble compounds
might be improved to minimize the limitations to oral
availability. [1, 2]

Where, dC/dt - is the rate of dissolution, A -is the

surface area available for dissolution, D - is the
diffusion coefficient of the compound, Cs- is the
solubility of the compound in the dissolution medium,
C -is the concentration of drug in the medium at time t
and h - is the thickness of the diffusion boundary layer
adjacent to the surface of the dissolving compound.
To increase the dissolution rate from equation the
following approaches are available.

To increases the surface area available for
dissolution Decreasing the particle size of drug.

Optimizing the wetting characteristics of
compound surface.

To decrease the boundary layer thickness.

Ensure sink condition for dissolution.

Improve apparent solubility of drug under
physiologically relevant conditions.

Drug administered in fed state is a way to
improve the dissolution rate.
Of these possibilities, changes in the hydrodynamics
are difficult to invoke in-vivo and the maintenance of
sink conditions will depend on how permeable the
gastrointestinal mucosa is to the compound as well as
on the composition and volume of the luminal Fluids.
Although some research effort has been directed
towards permeability enhancement using appropriate

excipients, results to date have not been particularly

encouraging. Administration of the drug in the fed state
may be an option to improve the dissolution rate and
also to increase the time available for dissolution; the
likely magnitude of the food effect can be forecasted
from dissolution tests in biorelevant media. [3]
The approaches that have commonly been used to
overcome drawbacks associated with poorly watersoluble drugs, in general includes micronization, salt
formation, use of surfactant and use of pro- drug [5],
however all these techniques have certain limitations.
Techniques that have commonly been used to improve
dissolution and bioavailability of poorly water-soluble
drugs, in general, include micronization, the use of
surfactant, and the formation of solid dispersions.
Chiou and Riegelman outlined 6 types of drug carrier
interactions in solid-state dispersions: simple eutectic
mixtures, solid solutions, glass solutions and glass
suspensions, amorphous precipitates, and compound or
complex formation. Other factors such as increased
wettability, solubilization of the drug by the carrier at
the diffusion layer, and the reduction or absence of
aggregation and agglomeration may also contribute to
increased dissolution. Micronization has several
disadvantages, the main one being the limited
opportunity to control important characters of the final
particle such as size, shape, morphology, surface
properties and electrostatic charges. In addition
micronization is a high-energy process, which causes
disruptions in the drug s crystal lattice, resulting in the
presence of disordered or amorphous regions in the
final product. The amorphous regions are
thermodynamically unstable and are therefore
susceptible to recrystallization upon storage,
particularly in hot and humid conditions [6-8]. All poorly
water-soluble drugs are not suitable for improving their
solubility by salt formation. The dissolution rate of a
particular salt is usually different form that of parent
compound. However sodium and potassium salts of
weak acids dissolve more rapidly than the free salts.
Potential disadvantages of salt forms include high
reactivity with atmospheric carbon dioxide and water
resulting in precipitation of poorly water-soluble drug,
epigastric distress due to high alkalinity.
Use of co-solvents or surfactants to improve
dissolution rate pose problems, such as patient
compliance and commercialization. Even though
particle size reduction increases the dissolution rate,
the formed fine powders showing poor wettability and
flow properties. Solid dispersion technique has come
into existence to eliminate all these problems.
However, the most attractive option for increasing the

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release rate is improvement of the solubility

formulation approaches.

through

[9, 10]

Fig. 2: Summarizes the various formulation and

chemical approaches that can be taken to improve
the solubility or to increase the available surface
area for dissolution.
Solid dispersion
Chiou and Riegelman defined the term solid dispersion
as a dispersion involving the formation of eutectic
mixtures of drugs with water soluble carriers by
melting of their physical mixtures [11].
The term solid dispersion refers to the dispersion of
one or more active ingredient in an inert carrier or
matrix at solid state prepared by melting (fusion),
solvent, or the melting solvent method. Sekiguchi et.al.
Suggested that the drug was present in a eutectic
mixture in a microcrystalline state [8], after few years
Goldberg et.al. reported that all drug in solid dispersion
might not necessarily be presents in a microcrystalline
state, a certain fraction of the drug might be molecular
dispersion in the matrix, thereby forming a solid
solution.[5] Once the solid dispersion was exposed to
aqueous media & the carrier dissolved, the drug was
released as very fine, colloidal particles. Because of
greatly enhanced surface area obtained in this way, the
dissolution rate and the bioavailability of poorly water-

soluble drugs were expected to be high. The

commercial use of such systems has been limited
primarily because of manufacturing problems with
solid dispersion systems may be
overcome by using surface active and
self-emulsifying carriers. The carriers are
melted at elevated temperatures and the
drugs are dissolved in molten carriers.
The term solid dispersion refers to a
group of solid products consisting of at
least two different components, generally
a hydrophilic matrix and a hydrophobic
drug. The matrix can be either crystalline
or amorphous. The drug can be dispersed
molecularly, in amorphous particles
(clusters) or in crystalline particles. Solid
dispersion refers to the dispersion of one
or more active ingredients in an inert
carrier or matrix at solid state prepared
by the melting (fusion), solvent or
melting solvent method. The dispersion
of a drug or drugs in a solid diluent or
diluents by traditional mechanical mixing
is not included in this category. The solid
dispersion, a first stated by Mayersohn
and Gibaldi.
Classification of solid dispersion
Based on their molecular arrangement,
six different types of solid dispersions
can be distinguished. (In Table 1.1) Moreover, in
various studies the designation of solid dispersions is
based on the method of preparation. However, since
different preparation methods can result in the same
subtypes or similar preparation methods can result in
different subtypes, it can be argued that solid
dispersions should preferably be designated according
to their molecular arrangement. Moreover, not the
preparation method but the molecular arrangement
governs the properties of solid dispersions. Therefore,
it is essential to use terms that indicate the molecular
arrangement in the solid dispersion. Knowledge about
the molecular arrangement will enlarge comprehension
of the properties and behavior of solid dispersions.
Furthermore, it will facilitate optimization of their
properties required for a specific application [12].
For example, the mechanism underpinning the
dissolution of solid dispersions is poorly understood.
Many case studies showed accelerated dissolution of
hydrophobic compounds using solid dispersions but
mechanisms are rarely discussed. The most important
reason for that is the lacking knowledge about the
mode of incorporation of the hydrophobic drug in the
matrix, despite numerous efforts to clarify this. A

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question like, is the drug present as a crystalline phase
drug depends on the mode of incorporation. If drug
or as amorphous nano-particles or molecularly
molecules, for example, are present in amorphous
dispersed throughout the matrix is rarely discussed [13].
nano-particles, crystallization requires only rotational
All three situations result in different drug
rearrangement. On the other hand, for a molecularly
concentrations at the dissolving interface. Still it has
dispersed drug, translational diffusion is necessary
not been fully elucidated how this affects dissolution
before crystallization can occur by rotational
behaviour of solid dispersions. Secondly, the physical
rearrangements.
and chemical stability of the matrix or the incorporated
Table 1.1: Classification of solid dispersions in six subtypes

*A: matrix in the amorphous state, C: matrix in the

crystalline state, **A: drug dispersed as amorphous
clusters in the matrix, C: drug dispersed as crystalline
particles in the matrix, M: drug molecularly dispersed
throughout the matrix
The physical state of the matrix is also important for
the chemical stability of the drug. The crystallinity of
the matrix influences the translational and rotational

rearrangements of the drug necessary for degradation

reactions. Finally, then influence of drug load and
method of preparation on dissolution behavior and
stability of solid dispersions can only be understood
and predicted when the relation between these
characteristics and the mode of incorporation is
known.[14]

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Current trends in solid dispersions techniques
New manufacturing processes to obtain solid
dispersions have also been developed to reduce the
drawbacks of the initial process. It is intended to
discuss the recent advances related on the area of solid
dispersions. The classification of solid dispersions
according to implementation and recent advancement
[15]

Fig. 3: The classification of solid dispersions.

First generation solid dispersions
The first description of solid dispersions was from
Sekiguchi and Obi in 1961. They noted that the
formulation of eutectic mixtures improves the rate of
drug release and consequently, the bioavailability of
poorly water soluble drugs. In the same decade, several
solid dispersions were described using poorly water
soluble drugs, such as sulfathiazole [17] and
chloramphenicol [16] using urea as high water soluble
carrier. These solid dispersions produced faster release
and higher bioavailability than conventional
formulations of the same drugs. The small particle size
and the better wettability of the drug were the main
reasons for the observed improvements in
bioavailability.
Later, Levy [18] and Kaning [19] developed solid
dispersion systems, containing mannitol as carrier, by
preparing solid solutions through molecular dispersions
instead of using eutectic mixtures. The observed
improvements were attributed to a faster carrier
dissolution, releasing microcrystals or particles of drug
[21]
.These solid dispersions, which could be designed
as first generation solid dispersions, were prepared
using crystalline carriers. Crystalline carriers include
urea [16, 17] and sugars [19], which were the first carriers
to be employed in solid dispersions. They have the
disadvantage of forming crystalline solid dispersions,

which were more thermodynamically stable and did not

release the drug as quickly as amorphous ones.
Second generation solid dispersions
In the late sixties it was observed that solid dispersions,
where the drug was maintained in the crystalline state,
might not be as effective as the amorphous, because the
former were more thermodynamically stable [21-23].
Therefore, a second generation of solid dispersions
appeared, containing amorphous carriers instead of
crystalline. Indeed, the most common solid dispersions
do not use crystalline carriers but amorphous. In the
latter, the drugs are molecularly dispersed in an
irregular form within an amorphous carrier, which are
usually polymers [24]. Polymeric carriers have been the
most successful for solid dispersions, because they are
able to originate amorphous solid dispersions. They are
divided into fully synthetic polymers and natural
product-based polymers. Fully synthetic polymers
include povidone (PVP) [2530], polyethyleneglycols
(PEG) [23,3133] and polymethacrylates [34,35]. Natural
product based polymers are mainly composed by
cellulose
derivatives,
such
as
hydroxypropylmethylcellulose (HPMC), ethylcellulose
or hydroxypropylcellulose [39] or starch derivates, like
cyclodextrins [36-41]. Amorphous solid dispersions can
be classified according to the molecular interaction of
drug and carriers in solid solutions, solid suspensions
or a mixture of both [26]. In amorphous solid solutions,
drug and carrier are totally miscible and soluble,
originating a homogeneous molecular interaction
between them [2]. In these systems, the drug and carrier
interaction energy is extremely high, resulting in a
really true solution. The use of polymers in the
preparation of a true solid solution creates an
amorphous product in which the crystalline drug is
dissolved [42]. This type of amorphous solid dispersion
is homogeneous on a molecular level. Therefore, only
one phase is present [2]. Amorphous solid suspensions
occur when the drug has limited carrier solubility or an
extremely high melting point [43]. Molecularly, the
obtained dispersion does not have a homogeneous
structure, but is composed of two phases. Small drug
particles, when dispersed in polymeric carriers, are able
to provide an amorphous final product. When a drug is
both dissolved and suspended in the carrier, a
heterogeneous structure is obtained with mixed
properties of amorphous solid solutions and amorphous
solid suspensions [2, 20]. In second generation solid
dispersions, the drug is in its supersaturated state
because of forced solubilization in the carrier [40].
These systems are able to reduce the drug particle size
to nearly a molecular level, to solubilize or co-dissolve
the drug by the water soluble carrier, to provide better

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wettability and dispersibility of the drug by the carrier
material, and to produce amorphous forms of the drug
and carriers [44, 45]. In these solid dispersions, the carrier
dissolution (or mixtures of carriers) dictates the drug
release profile.
Third generation solid dispersions
Recently, it has been shown that the dissolution profile
can be improved if the carrier has surface activity or
self-emulsifying properties, therefore third generation
solid dispersions appeared. These contain a surfactant
carrier, or a mixture of amorphous polymers and
surfactants as carriers. These third generation solid
dispersions are intended to achieve the highest degree
of bioavailability for poorly soluble drugs and to
stabilize the solid dispersion, avoiding drug
recrystallization. The use of surfactants such as inulin
[2],
inutec SP1 [42], compritol 888 ATO [46], gelucire
44/14 [48] and poloxamer-407[47] as carriers was shown
to be effective in originating high polymorphic purity
and enhanced in vivo bioavailability. The association
of amorphous polymers and surfactants has also been
reported. For instance, the dissolution rate and
bioavailability of LAB68, a poor water soluble drug,
were improved after being dispersed in a mixture of
PEG and polysorbate 80. The bioavailability of this
solid dispersion was 10-fold higher compared to the
dry blend of micronized drug. In addition, the solid
dispersion system was physically and chemically stable
for at least 16 months [49]. HPMC was also associated
with poloxamer and polyoxyethylene hydrogenated
castor oil to prepare an amorphous felodipine solid
dispersion [36]. The inclusion of surfactants in the
formulation containing a polymeric carrier may help to
prevent precipitation and/or protect a fine crystalline
precipitate from agglomeration into much larger
hydrophobic particles [6]
The advantageous properties of solid dispersions
Management of the drug release profile using solid
dispersions is achieved by manipulation of the carrier
and solid dispersion particles properties. Parameters,
such as carrier molecular weight and composition, drug

crystallinity and particle porosity and wettability, when

successfully controlled, can produce improvements in
bioavailability [59].
Particles with reduced particle size and increased
dissolution rate
Molecular dispersions, as solid dispersions, represent
the last state on particle size reduction, and after carrier
dissolution the drug is molecularly dispersed in the

dissolution medium. Solid dispersions apply this

principle to drug release by creating a mixture of a
poorly water soluble drug and highly soluble carriers.
A high surface area is formed, resulting in an increased
dissolution rate and, consequently, improved
bioavailability [60].
The fact that more than 40% of newly discovered drugs
have little or negligible water solubility presents a
serious challenge to the successful development and
commercialization of new drugs in the pharmaceutical
industry (Connors & Elder, 2004). Solubility and
permeability are the main factors that control oral
bioavailability of a drug substance. Generally, when
the drug solubility in water is less than 10 mg/ml,
dissolution is the rate-limiting step in the process of
drug absorption (Habib, 2000). Factors influencing
drug dissolution rate in aqueous solution are described
in Noyes-Whitney equation:
where dC/dT is the rate of dissolution, A is the surface
area available for dissolution, D is the diffusion
coefficient of the drug, Cs is the solubility of the drug
in the dissolution medium, C is the concentration of
drug in the medium at time t and h is the thickness of
the diffusion boundary layer adjacent to the surface of
the dissolving drug (Leuner & Dressman, 2000).
According to this equation, dissolution rate can be
increased through increasing the surface area, and this
can be achieved through reducing the particle size.
Different methods have been used to reduce the
particle size, such as micronization, recrystallization,
freeze drying and spray drying. Micronization of
poorly soluble drugs by milling has been used for many
years in the pharmaceutical industry in order to
enhance the dissolution rate of those drugs. For
example the dissolution rate of micronized
spironolactone was higher than that of the standard
form (McInnes et al., 1982). However, fine particles
may not always produce the expected faster
dissolution. This primarily results from the aggregation
and agglomeration of fine particles. In addition, poor
wettability of fine powders may reduce the dissolution
rate (Bloch & Speiser, 1987; Rippie, 1986). Solid
dispersion techniques have been used to enhance the
dissolution rate of many poorly water soluble drugs.
Particle size reduction and reduced agglomeration
would both increase the exposed surface area of the
drug. When solid solutions or amorphous precipitations
are formed, particle size of the active ingredient is
reduced to the minimum level. In addition, the carrier
material may contribute to increasing the dissolution
rate through its solubilizing and wettability-enhancing
properties. It was reported that urea increased the
dissolution rate of chlorpropamide incorporated into

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urea, through its solubilizing properties (Ford &
Rubenstein, 1977). The enhancement in dissolution
rate as a result of solid dispersion formation, relative to
pure drug, varies from as high as 400-fold to less than
two-fold (Vadnere, 2002).
Particles with improved wettability
A strong contribution to the enhancement of drug
solubility is related to the drug wettability
improvement verified in solid dispersions [52]. It was
observed that even carriers without any surface
activity, such as urea [18] improved drug wettability.
Carriers with surface activity, such as cholic acid and
bile salts, when used, can significantly increase the
wettability properties of drugs. Moreover, carriers can
influence the drug dissolution profile by direct
dissolution or co-solvent effects [61]. Recently, the
inclusion of surfactants [42, 62] in the third generation
solid dispersions reinforced the importance of this
property.
Particles with higher porosity
Particles in solid dispersions have been found to have a
higher degree of porosity. The increase in porosity also
depends on the carrier properties, for instance, solid
dispersions containing linear polymers produce larger
and more porous particles than those containing
reticular polymers and, therefore, result in a higher
dissolution rate. The increased porosity of solid
dispersion particles also hastens the drug release profile
[59, 63]
.
Drugs in amorphous state
Poorly water soluble crystalline drugs, when in the
amorphous state tend to have higher solubility [29, 29].
The enhancement of drug release can usually be
achieved using the drug in its amorphous state, because
no energy is required to break up the crystal lattice
during the dissolution process [64]. In solid dispersions,
drugs are presented as supersaturated solutions after
system dissolution, and it is speculated that, if drugs
precipitate, it is as a metastable polymorphic form with
higher solubility than the most stable crystal form [53].
For drugs with low crystal energy (low melting
temperature or heat of fusion), the amorphous
composition is primarily dictated by the difference in
melting temperature between drug and carrier. For
drugs with high crystal energy, higher amorphous
compositions can be obtained by choosing carriers,
which exhibit specific interactions with them [62].
Strategies to avoid drug recrystallization
Recrystallization is the major disadvantage of solid
dispersions. As amorphous systems, they are
thermodynamically unstable and have the tendency to
change to a more stable state under recrystallization.
Molecular mobility is a key factor governing the

stability of amorphous phases, because even at very

high viscosity, below the glass transition temperature
(Tg), there is enough mobility for an amorphous
system to crystallize over pharmaceutically relevant
time scales. Furthermore, it was postulated that
crystallization above Tg would be governed by the
configurational entropy, because this was a measure of
the probability of molecules being in the appropriate
conformation, and by the mobility, because this was
related to the number of collisions per unit time [67, 68].
Several experiments have been conducted to
understand the stabilization of solid dispersions. Recent
studies observed very small reorientation motions in
solid dispersions showing a detailed heterogeneity of
solid dispersions and detecting the sub-glass transition
beta-relaxation as well as alpha-relaxation [69], which
may lead to nucleation and crystal growth [66].
Molecular mobility of the amorphous system depends,
not only on its composition, but also on the
manufacturing process as stated by Bhugra et al. [70].
Solid
dispersions exhibiting high conformational entropy and
lower molecular mobility are more physically stable
[67]
. Polymers improve the physical stability of
amorphous drugs in solid dispersions by increasing the
Tg of the miscible mixture, thereby reducing the
molecular mobility at regular storage temperatures, or
by interacting specifically with functional groups of the
drugs. For a polymer to be effective in preventing
crystallization, it has to be molecularly miscible with
the drug [56, 71]. For complete miscibility, interactions
between the two components are required. It is
recognized that the majority of drugs contain
hydrogen-bonding sites, consequently, several studies
have shown the formation of iondipole interactions
and intermolecular hydrogen bonding between drugs
and polymers, and the disruption of the hydrogen
bonding pattern characteristic to the drug crystalline
structure. These lead to a higher miscibility and
physical stability of the solid dispersions Specific drug
polymer interactions were observed by Teberekidis et
al., showing that interaction energies, electron density,
and vibrational data revealed a stronger hydrogen bond
of felodipine with PVP than with PEG, which was in
agreement with the dissolution rates of the
corresponding solid dispersions.[71-74]
Advantages of solid dispersions over other
strategies to improve bioavailability of poorly water
soluble drugs
Improving drug bioavailability by changing their water
solubility has been possible by chemical or formulation
approaches. Chemical approaches to improving
bioavailability without changing the active target can

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be achieved by salt formation or by incorporating polar
or ionizable groups in the main drug structure, resulting
in the formation of a pro-drug. Solid dispersions appear
to be a better approach to improve drug solubility than
these techniques, because they are easier to produce
and more applicable. For instance, salt formation can
only be used for weakly acidic or basic drugs and not
for neutral. Furthermore, it is common that salt
formation does not achieve better bioavailability
because of its in-vivo conversion into acidic or basic
forms [51, 52]. Moreover, these types of approaches have
the major disadvantage that the sponsoring company is
obliged to perform clinical trials on these forms, since
the product represents a NCE [2]. Formulation
approaches include solubilization and particle size
reduction techniques, and solid dispersions, among
others. Solid dispersions are more acceptable to
patients than solubilization products, since they give
rise to solid oral dosage forms instead of liquid as
solubilization products usually do. Milling or
micronization for particle size reduction is commonly
performed as approaches to improve solubility, on the
basis of the increase in surface area. Solid dispersions
are more efficient than these particle size reduction
techniques, since the latter have a particle size
reduction limit around 25 mm which frequently is not
enough to improve considerably the drug solubility or
drug release in the small intestine and, consequently,
to improve the bioavailability. Moreover, solid
powders with such a low particle size have poor
mechanical properties, such as low flow and high
adhesion, and are extremely difficult to handle. [51-55]
Solid dispersions disadvantages
Despite extensive expertise with solid dispersions, they
are not broadly used in commercial products, mainly
because there is the possibility that during processing
(mechanical stress) or storage (temperature and
humidity stress) the amorphous state may undergo
crystallization [47, 56]. The effect of moisture on the
storage stability of amorphous pharmaceuticals is also
a significant concern, because it may increase drug
mobility and promote drug crystallization [57].
Moreover, most of the polymers used in solid
dispersions can absorb moisture, which may result in
phase separation, crystal growth or conversion from the
amorphous to the crystalline state or from a metastable
crystalline form to a more stable structure during
storage. This may result in decreased solubility and
dissolution rate [58]. Therefore, exploitation of the full
potential of amorphous solids requires their
stabilization in solid state, as well as during in-vivo
performance [27].

The limitations of this technology have been a

drawback for the commercialization of solid

dispersions. The limitations include

Laborious and expensive methods of preparation,

Reproducibility
of
physicochemical
characteristics,

Difficulty in incorporating into formulation of
dosage forms,

Scale-up of manufacturing process, and

Stability of the drug and vehicle.
Detection of crystallinity in solid dispersions [75]
Several different molecular structures of the drug in the
matrix can be encountered in solid dispersions
(Figure.3). Many attempts have been made to
investigate the molecular arrangement in solid
dispersions. However, most effort has been put in
discrimination between amorphous and crystalline
material. Consequently, for that purpose many
techniques are available which detect the amount of
crystalline material in the dispersion. The amount of
amorphous material is never measured directly but is
mostly derived from the amount of crystalline material
in the sample. It should be noted that through the
assessment of crystallinity as method to determine the
amount of amorphous drug it will not be revealed
whether the drug is present as amorphous drug
particles or as molecularly dispersed molecules, e.g.
solid dispersions of type II or III and V or VI (see
previous section).
Fig. 4: Schematic representation of three modes of
incorporation of the drug in a solid dispersion
Currently, the following techniques are available to
detect (the degree of) crystallinity:

Powder X-ray diffraction can be used to
qualitatively detect material with long range
order. Sharper diffraction peaks indicate more
crystalline material. Recently developed X-ray
equipment is semi-quantitative.

Infrared spectroscopy (IR) can be used to detect
the variation in the energydistribution of
interactions between drug and matrix. Sharp

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vibrational bands indicate crystallinity [52].

Fourier Transformed Infrared Spectroscopy
(FTIR) was used to accurately detect
crystallinities ranging from 1 to 99% in pure
material. However in solid dispersions only
qualitative detection was possible.
Water vapour sorption can be used to
discriminate between amorphous and crystalline
material when the hygroscopicity is different.
This method requires accurate data on the
hygroscopicity of both completely crystalline
and completely amorphous samples. In some
studies, amorphous materials were plasticized by
water sorption and crystallized during the
experiment. However, crystallization can be
accompanied by expel of water depending on the
degree of hydration of crystalline material. In
this case, the loss of water is used to calculate the
amount of amorphous material. However, water
vapour sorption in a binary mixture, e.g. solid
dispersions, can be much more complicated than
in pure materials, firstly because water vapour
sorption is not always proportional to the
composition of a binary intimately mixed
system. The second complication is that matrix
or drug crystallization during water vapour
sorption is often not complete within the
experimental time scale due to sterical hindrance
and proceeds to an unknown extent.
Isothermal Microcalorimetry measures the
crystallization energy of amorphous material that
is heated above its Tg. However, this technique
has some limitations. Firstly, this technique can
only be applied if the physical stability is such
that only during the measurement crystallization
takes place. Secondly, it has to be assumed that
all amorphous material crystallizes. Thirdly, in a
binary mixture of two amorphous compounds a
distinction between crystallization energies of
drug and matrix is difficult.
Dissolution Calorimetry measures the energy of
dissolution, which is dependent on the
crystallinity of the sample. Usually, dissolution
of crystalline material is endothermic, whereas
dissolution of amorphous material is exothermic.
The dissolution energies of the two components
in both crystalline and amorphous state should
be determined in separate experiments in order to
use this technique quantitatively. However, also
drug-matrix interactions will contribute to the
dissolution energy of the solid dispersion.
Macroscopic
techniques
that
measure
mechanical properties that are different for

amorphous and crystalline material can be

indicative for the degree of crystallinity. Density
measurements and Dynamic Mechanical
Analysis (DMA) determine the modulus of

elasticity and viscosity and thus affected by the

degree of crystallinity. However, also these
techniques require knowledge about the
additivity of these properties in intimately mixed
binary solids.

The extent of supersaturation during dissolution
experiments of solid dispersions are sometimes
correlated to the mode of incorporation of the
drug. It is unmistakable that the mode of
incorporation largely determines the dissolution
behaviour, but knowledge about dissolution
behaviour is too poor to draw any conclusions
from dissolution experiments, because it cannot
be
excluded
that
during
dissolution
crystallization of the drug occurs.
Methods of preparation of solid dispersions
Various methods used for preparation of solid
dispersion system. These methods are given bellow.
1 Melting method
2 Solvent method
3 Melting solvent method (melt evaporation)
4 Melt extrusion methods
5 Lyophilization techniques
6 Melt agglomeration Process
7 The use of surfactant
8 Electrospinning
9 Super Critical Fluid (Scf) technology
Fig. 5: Methods of preparation of solid dispersion
1. Melting method

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The melting or fusion method is the preparation of
physical mixture of a drug and a water-soluble carrier
and heating it directly until it melted. The melted
mixture is then solidified rapidly in an ice-bath under
vigorous stirring. The final solid mass is crushed,
pulverized and sieved. Appropriately this has
undergone many modifications in pouring the
homogenous melt in the form of a thin layer onto a
ferrite plate or a stainless steel plate and cooled by
flowing air or water on the opposite side of the plate. In
addition, a super-saturation of a solute or drug in a
system can often be obtained by quenching the melt
rapidly from a high temperature. Under such
conditions, the solute molecule is arrested in the
solvent matrix by the instantaneous solidification
process. The quenching technique gives a much finer
dispersion of crystallites when used for simple eutectic
mixtures [76].
However many substances, either drugs or carriers,
may decompose during the fusion process which
employs high temperature. It may also cause
evaporation of volatile drug or volatile carrier during
the fusion process at high temperature. Some of the
means to overcome these problems could be heating
the physical mixture in a sealed container or melting it
under vacuum or in presence of inert gas like nitrogen
to prevent oxidative degradation of drug or carrier.
2. Solvent method
In this method, the physical mixture of the drug and
carrier is dissolved in a common solvent, which is
evaporated until a clear, solvent free film is left. The
film is further dried to constant weight. The main
advantage of the solvent method is thermal
decomposition of drugs or carriers can be prevented
because of the relatively low temperatures required for
the evaporation of organic solvents [77].
However, some disadvantages are associated with this
method such as
1) The higher cost of preparation.
2) The difficulty in completely removing liquid
solvent.
3) The possible adverse effect of traces of the solvent
on the chemical stability
4) The selection of a common volatile solvent.
5) The difficulty of reproducing crystal form.
6) In addition, a super saturation of the solute in the
solid system cannot be attained except in a
System showing highly viscous properties.
3. Melting solvent method (melt evaporation)
It involves preparation of solid dispersions by
dissolving the drug in a suitable liquid solvent and then
incorporating the solution directly into the melt of

polyethylene glycol, which is then evaporated until a

clear, solvent free film is left. The film is further dried
to constant weight. The 5 10% (w/w) of liquid
compounds can be incorporated into polyethylene
glycol 6000 without significant loss of its solid
property. It is possible that the selected solvent or
dissolved drug may not be miscible with the melt of the
polyethylene glycol. Also the liquid solvent used may
affect the polymorphic form of the drug, which
precipitates as the solid dispersion. This technique
possesses unique advantages of both the fusion and
solvent evaporation methods. From a practical
standpoint, it is only limited to drugs with a low
therapeutic dose e.g. below 50 mg [76].
4. Melt extrusion method
The drug/carrier mix is typically processed with a twinscrew extruder. The drug/carrier mix is simultaneously
melted, homogenized and then extruded and shaped as
tablets, granules, pellets, sheets, sticks or powder. The
intermediates can then be further processed into
conventional tablets. An important advantage of the hot
melt extrusion method is that the drug/carrier mix is
only subjected to an elevated temperature for about 1
min, which enables drugs that are somewhat thermo
labile to be processed [78].
Solid dispersion by this method is composed of active
ingredient and carrier, and prepare by hot-stage
extrusion using a co-rotating twin-screw extruder. The
concentration of drug in the dispersions is always 40%
(w/w) [79]. The screw-configuration consist of two
mixing zones and three transport zones distribute over
the entire barrel length, the feeding rate is fix at 1 kg/h
and the screw rate is set at 300 rpm. The five
temperature zones are set at 100, 130, 170, 180, and
185C from feeder to die. The extrudates are collect
after cooling at ambient temperature on a conveyer
belt. Samples are milled for 1 min with a laboratorycutting mill and sieve to exclude particles >355m
[80]
.
5. Lyophilization Technique
Lyophilization involves transfer of heat and mass to
and from the product under preparation. This technique
was proposed as an alternative technique to solvent
evaporation. Lyophilization has been thought of a
molecular mixing technique where the drug and carrier
are co dissolved in a common solvent, frozen and
sublimed to obtain a lyophilized molecular dispersion
[81]
.
6. Melt Agglomeration Process
This technique has been used to prepare solid
dispersion wherein the binder acts as a carrier. In
addition, solid dispersion are prepared either by heating
binder, drug and excipient to a temperature above the

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melting point of the binder (melt- in procedure) or by
spraying a dispersion of drug in molten binder on the
heated excipient (spray-on procedure) by using a high
shear mixer [83]. The rotary processor might be
preferable to the high melt agglomeration because it is
easier to control the temperature and because a higher
binder content can be incorporated in the agglomerates.
The effect of binder type, method of manufacturing and
particle size are critical parameters in preparation of
solid dispersion by melt agglomeration. It has been
found that the melt in procedure gives a higher
dissolution rates than the spray-on procedure with PEG
3000, poloxamer 188 and gelucire 50/13 attributed to
immersion mechanism of agglomerate formation and
growth. In addition the melt in procedure also results in
homogenous distribution of drug in agglomerate.
Larger particles results in densification of agglomerates
while fine particle cause complete adhesion to the mass
to bowl shortly after melting attributed to distribution
and coalescence of the fine particles [84].
7. Melt Agglomeration Process
The utility of the surfactant systems in solubilization is
very important. Adsorption of surfactant on solid
surface can modify their hydrophobicity, surface
charge, and other key properties that govern interfacial
processes such as flocculation/dispersion, floatation,
wetting, solubilization, detergency, and enhanced oil
recovery and corrosion inhibition. Surfactants have
also been reported to cause solvation/plasticization,
manifesting in reduction of melting the active
pharmaceutical
ingredients,
glass
transition
temperature and the combined glass transition
temperature of solid dispersions. Because of these
unique properties, surfactants have attracted the
attention of investigators for preparation of solid
dispersions [85-86].
8. Electrospinning
Electrospinning is a process in which solid fibers are
produced from a polymeric fluid stream solution or
melt delivered through a millimeter-scale nozzle [87].
This process involves the application of a strong
electrostatic field over a conductive capillary attaching
to a reservoir containing a polymer solution or melt and
a conductive collection screen. Upon increasing the
electrostatic field strength up to but not exceeding a
critical value, charge species accumulated on the
surface of a pendant drop destabilize the hemispherical
shape into a conical shape (commonly known as Taylor
s cone). Beyond the critical value, a charged polymer
jet is ejected from the apex of the cone (as a way of
relieving the charge built-up on the surface of the
pendant drop). The ejected charged jet is then carried
to the collection screen via the electrostatic force. The

Coulombic repulsion force is responsible for the

thinning of the charged jet during its trajectory to the
collection screen. The thinning down of the charged jet
is limited
If the viscosity increases, the charged jet is dried [88].
This technique has tremendous potential for the
preparation of nanofibres and controlling the release of
biomedicine, as it is simplest, the cheapest this
technique can be utilized for the preparation of solid
dispersions in future [89].
9. Super Critical Fluid (Scf) Technology
The supercritical fluid antisolvent techniques, carbon
dioxide are used as an antisolvent for the solute but as a
solvent with respect to the organic solvent. Different
acronyms were used by various authors to denote
micronization processes: aerosol solvent extraction
system, precipitation with a compressed fluid
antisolvent, gas anti-solvent, solution enhanced
dispersion by supercritical fluids, and supercritical antisolvent. The SAS process involves the spraying of the
solution composed of the solute and of the organic
solvent into a continuous supercritical phase flowing
concurrently [90]. Use of supercritical carbon dioxide is
advantageous as it is much easier to remove from the
polymeric materials when the process is complete,
even though a small amount of carbon dioxide remains
trapped inside the polymer; it poses no danger to the
patient. In addition the ability of carbon dioxide to
plasticize and swell polymers can also be exploited and
the process can be carried out near room temperature.
Moreover, supercritical fluids are used to lower the
temperature of melt dispersion process by reducing the
melting temperature of dispersed active agent. The
reason for this depression is the solubility of the lighter
component (dense gas) in the forming phase (heavier
component) [91].
Characterization of solid dispersion
Several different molecular structures of the drug in the
matrix can be encountered in solid dispersions. Several
techniques have been available to investigate the
molecular arrangement in solid dispersions. However,
most effort has been put into differentiate between
amorphous and crystalline material. Many techniques
are available which detect the amount of crystalline
material in the dispersion [92].
Drug -carrier miscibility
Hot stage microscopy
Differential scanning calorimetry
Powder X-ray diffraction
NMR 1H Spin lattice relaxation time
Drug carrier interactions
FT-IR spectroscopy
Raman spectroscopy

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Solid state NMR
Physical Structure
Scanning electron microscopy
Surface area analysis
Surface properties
Dynamic vapor sorption
Inverse gas chromatography
Atomic force microscopy
Raman microscopy
Amorphous content
Polarised light optical microscopy
Hot stage microscopy
Humidity stage microscopy
DSC (MTDSC)
ITC
Powder X-ray diffraction
Stability
Humidity studies
Isothermal Calorimetry
DSC (Tg, Temperature recrystallization)
Dynamic vapor sorption
Saturated solubility studies
Dissolution enhancement
Dissolution
Intrinsic dissolution
Dynamic solubility
Dissolution in bio-relevant media
Powder X-ray diffraction
Powder X-ray diffraction can be used to qualitatively
detect material with long range order.
Sharper
diffraction peaks indicate more crystalline material.
Infrared spectroscopy (IR)
Infrared spectroscopy (IR) can be used to detect the
variation in the energy distribution of interactions
between drug and matrix. Sharp vibrational bands
indicate crystallinity. Fourier Transformed Infrared
Spectroscopy (FTIR) was used to accurately detect
crystallinity ranging from 1 to 99% in pure material [93].
Water vapour sorption
Water vapour sorption can be used to discriminate
between amorphous and crystalline material when the
hygroscopicity is different [94]. This method requires
accurate data on the hygroscopicity of both completely
crystalline and completely amorphous samples.
Isothermal Microcalorimetry
Isothermal microcalorimetry
measures
the crystallization energy of amorphous
material that is heated above its glass transition
temperature (Tg) [95]. This technique has some
limitations. Firstly, this technique can only be applied
if the physical stability is such that only during the
measurement crystallization takes place. Secondly, it

has to be assumed that all amorphous material

crystallizes. Thirdly, in a binary mixture of two
amorphous compounds a distinction between
crystallization energies of drug and matrix is
difficult.
Dissolution calorimetry
Dissolution calorimetry measures the energy of
dissolution, which is dependent on the crystallinity of
the sample [96]. Usually, dissolution of crystalline
material is endothermic, whereas dissolution of
amorphous material is exothermic.
Macroscopic techniques
Macroscopic techniques that measure mechanical
properties that are different amorphous and crystalline
material can be indicative for the degree of
crystallinity. Density measurements and Dynamic
Mechanical Analysis (DMA) determine the modulus of
elasticity for and viscosity and thus affected by the
degree of crystallinity. However, also these
techniques require knowledge about the additivity of
these properties in intimately mixed binary solids.
Differential Scanning Calorimetry (DSC)
Frequently used technique to detect the amount of
crystalline material is Differential Scanning
Calorimetry (DSC) [97]. In DSC, samples are heated
with a constant heating rate and the amount of energy
necessary for that is detected. With DSC the
temperatures at which thermal events occur can be
detected. Thermal events can be a glass to rubber
transition, (re)crystallization, melting or degradation.
Furthermore, the melting- and (re)crystallization
energy can be quantified. The melting energy can be
used to detect the amount of crystalline material.
Confocal Raman Spectroscopy
Confocal Raman Spectroscopy is used to measure the
homogeneity of the solid mixture. It is described that a
standard deviation in drug content smaller than10%
was indicative of homogeneous distribution.
Because of the pixel size of 2 m3, uncertainty remains
about the presence of nano-sized amorphous drug
particles.
Temperature Modulated Differential Scanning
Calorimetry (TMDSC)
Temperature
Modulated
Differential
Scanning
Calorimetry (TMDSC) can be used to assess the degree
of mixing of an incorporated drug. Due to the
modulation, reversible and irreversible events can be
separated. For example, glass transitions (reversible)
are separated from crystallization or relaxation
(irreversible) in amorphous materials. Furthermore, the
value of the Tg is a function of the composition of the
homogeneously mixed solid dispersion. It has been
shown that the sensitivity of TMDSC is higher than

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conventional DSC [98]. Therefore this technique can be
used to assess the amount of molecularly dispersed
drug [99]. And from that the fraction of drug that is
dispersed as separate molecules is calculated [100].
In Vitro Dissolution Studies
In vitro dissolution studies are done for the find out
dissolution behavior. The in-vitro dissolution study can
be used to demonstrate the bioavailability or
bioequivalence of the drug product through in vitro - in
vivo correlation (IVIVC). On the other hand if
absorption of the drug is dissolution rate limited that
means the drug in the gastrointestinal fluid passes
freely through the bio-membranes at a rate higher than
it dissolves or is released from the dosage form. The
specifically designed in-vivo dissolution study will be
required in solid dispersion system to access the
absorption rate, and hence its bioavailability and to
demonstrate the bioequivalence ultimately. There are
some apparatus used in United States pharmacopoeia
for dissolution testing these are following.
Solubility Studies
Solubility studies are done for the finding out the
solubility behavior shown by the solid dispersion
system in different types of solvent system and body
fluids.

7.

8.

9.

10.

11.

12.

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