European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813

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European Journal of Pharmaceutics and Biopharmaceutics

journal homepage: www.elsevier.com/locate/ejpb

Review article

Current trends and future perspectives of solid dispersions containing

poorly water-soluble drugs
Chau Le-Ngoc Vo, Chulhun Park, Beom-Jin Lee ⇑
Bioavailability Control Laboratory, College of Pharmacy, Ajou University, Suwon, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history:
Received 8 April 2013
Accepted in revised form 9 September 2013
Available online 18 September 2013
Keywords:
Classification of solid dispersions
Four generation-to-generation development
Poorly water-soluble drug
Problems and issues
Mechanism of drug release
Preparation and characterization
Future perspectives and strategies
Over 40% of active pharmaceutical ingredients (API) in development pipelines are poorly water-soluble
drugs which limit formulation approaches, clinical application and marketability because of their low
dissolution and bioavailability. Solid dispersion has been considered one of the major advancements in
overcoming these issues with several successfully marketed products. A number of key references that
describe state-of-the-art technologies have been collected in this review, which addresses various
pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs accord-
ing to the four generations of solid dispersions. This article reviews critical aspects and recent advances in
formulation, preparation and characterization of solid dispersions as well as in-depth pharmaceutical
solutions to overcome some problems and issues that limit the development and marketability of solid
dispersion products.
Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction development such as salt formation [7], prodrug formation [8],

The poor aqueous solubility and dissolution rate of API is one of
the biggest challenges in pharmaceutical development and is
becoming more common among new drug candidates over the
past two decades due to the use of high throughput and combina-
torial screening tools during the drug discovery and selection
phase [1–3]. According to the Biopharmaceutics Classification
System (BCS), a drug compound is poorly soluble if the highest
dose strength is not soluble in 250 ml aqueous media over the
pH ranges at 37 °C [4]. These compounds mostly belong to Class
II (IIa or IIb), which are poorly soluble and highly permeable
according to the pH of the gastrointestinal fluid and tend to present
solubility or dissolution rate-limited absorption [5]. Despite their
high permeability, these drugs often have low oral bioavailability
because of their slow and limited release of drug in gastrointestinal
fluid [6]. Therefore, one of the major challenges of the pharmaceu-
tical industry is to apply strategies that improve the dissolution
and/or apparent solubility of poorly soluble drugs to develop such
problematic compounds into orally bioavailable and therapeutic
effective drugs [3,5].
Various approaches to overcome the poor aqueous solubility of
drug candidates have been investigated in drug research and
⇑ Corresponding author. Bioavailability Control Laboratory, College of Pharmacy,
Ajou University, Suwon 443-749, Republic of Korea. Tel.: +82 31 219 3442; fax: +82
31 212 3653.
E-mail address: beomjinlee@gmail.com (B.-J. Lee).
particle size reduction [9], complexation [10], micelles [11], micro-
emulsions [12], nanoemulsions [13], nanosuspensions [14], solid–
lipid nanoparticle [15] and solid dispersion which is considered
one of the most successful strategies to improve the dissolution
profile of poorly soluble drugs. The term solid dispersions has been
defined as a dispersion of one or more API in an inert carrier or ma-
trix at the solid state prepared by solvent, melting or solvent–melt-
ing method [16]. The API in solid dispersions can be dispersed as
separate molecules, amorphous particles, or crystalline particles
while the carrier can be in the crystalline or amorphous state.
Numerous studies on solid dispersions have been published and
have showed many advantageous properties of solid dispersions
in improving the solubility and dissolution rate of poorly water-
soluble drugs. These advantages include reducing particle size,
possibly to molecular level, enhancing wettability and porosity,
as well as changing drug crystalline state, preferably into amor-
phous state [6].
Despite such high active research interests, the number of
marketed products arising from solid dispersion approaches is dis-
appointingly low. This low number is mainly due to scale-up prob-
lems and physicochemical instability in the manufacturing process
or during storage leading to phase separation and crystallization
[17–20]. Only a few commercial products have been marketed dur-
ing the past half-century (Table 1). Therefore, in-depth knowledge
that has been acquired on various aspects of solid dispersions such
as carrier properties, preparation methods, physicochemical char-
acterization techniques as well as the pharmaceutical mechanism

0939-6411/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ejpb.2013.09.007
800 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813

Table 1 solid dispersions, a crystalline drug is dispersed within a crystal-

Marketed products using solid dispersions [5,72,118]. line carrier forming a eutectic or monotectic mixture [16,21]. In
Product Model drug Carrier type Dosage form the eutectic mixture, the melting point of the mixture is lower than
Certican Ò
Everolimus HPMC Tablet the melting point of the drug and carrier whereas in the monotec-
CesametÒ Nabilone PVP Tablet tic mixture, the melting point of the carrier and drug are constant.
Gris-PEGÒ Griseofulvin PEG Tablet The eutectic mixture is always more preferable because both the
IsoptinÒ SR-E Verapamil HPC/HPMC Tablet drug and carrier will crystallize simultaneously in cooling process,
NivadilÒ Nivaldipine HPMC Tablet
RezulinÒ Troglitazone HPMC Tablet
resulting in a well-dispersed state of the drug in carrier, thus
KaletraÒ Lopinavir, Ritonavir PVPVA Tablet enhancing the dissolution rate. Moreover, the process temperature
IntelenceÒ Etravirine HPMC Tablet for melting eutectic mixture is lower than that of monotectic
ZelborafÒ Vemurafenib HPMCAS Tablet mixture. However, if the mixture of the drug and carrier is not ex-
IncivekÒ Telaprevir HPMCAS-M Tablet
actly at the eutectic composition, the solid dispersion will contain a
CrestorÒ Rosuvastatin HPMC Tablet
AfeditabÒ CR Nifedipin Poloxamer/PVP Tablet mixture of the microfine dispersion and another component as a
FenoglideÒ Fenofibrate PEG Tablet separate phase because one component will progressively crystal-
PrografÒ Tacrolimus HPMC Capsule line until the eutectic composition is reached. In fact the number of
SporanoxÒ Itraconazole HPMC Capsule studied solid dispersions having the exact eutectic composition is
very limited [22]. The API in crystalline solid dispersions may also
exist in amorphous particles or separate molecules (crystalline so-
of matrix formation and drug release are very important to ensure lid solutions). In crystalline solid solutions, the drug molecules can
the preparation of a productive and marketable solid dispersion. replace carrier molecule in the crystal lattice (substitutional crys-
The aim of this review is to provide new knowledge from recent talline solid solutions) or occupy the interstitial spaces between
advances on solid dispersion areas to overcome some problems the solvent molecules in the crystal lattice (interstitial crystalline
and issues that limit the marketability of solid dispersion products. solid solutions) [23].
As a continued work of previous reviews in this field, this article Crystalline carriers in the first generation solid dispersions com-
newly suggests the four classifications of solid dispersions prise of urea [21] and sugars such as sorbitol and mannitol [24].
according to the development by generation that has been investi- These carriers, especially sugars, have high melting point which
gated so far. Finally, the future perspectives and strategies of solid is not favorable for preparing solid dispersions by melting method.
dispersions are also discussed. Urea exhibits high solubility in water and many common organic
solvents while sugars have poor solubility in most of organic
2. The classification of solid dispersions solvents; therefore, sugars were less commonly used than other
carriers. The particle size reduction, wettability improvement and
Depending on the physical state of the carrier which is crystal- polymorphic change are the main reasons for enhancing drug
line or amorphous, the solid dispersions are divided into crystalline solubility and dissolution rate. Zajc et al. [25] prepared the solid
solid dispersions and amorphous solid dispersions respectively. dispersions of nifedipine and mannitol with different ratios by
The solid dispersions can also be classified into four generations melting method. The results showed markedly enhanced dissolu-
based on their composition (Fig. 1). tion rate of nifedipine in comparison with physical mixture
although the crystalline state of nifedipine did not change. The
2.1. First generation SEM results elucidated the mechanism of dissolution rate enhance-
ment which is improving the wettability of nifedipine crystals.
The first generation solid dispersions are crystalline solid Okonogi et al. [26] also tried to improve the dissolution rate of
dispersions. Sekiguchi and Obi [21] prepared the first solid disper- ofloxacin by solid dispersion systems with urea and mannitol.
sions for pharmaceutical application in which urea was used as a The dissolution rate of ofloxacin was significantly increased in urea
carrier to form eutectic mixture with sulphathiazole. In crystalline and mannitol based solid dispersions. Urea based solid dispersions

Poorly water soluble drug

+CC +AP +SFP + WIP or SP

+WIP

+SF +WIP
1stgeneration 2nd generation 3rd generation 4th generation

+SF

- Low dissolution - Dissolution rate - Highest dissolution - Dissolution rate

rate due to crystalline - Precipitation under rate - Controlled release
carrier supersaturation - Precipitation
- Low stability - Low stability under
supersaturation
- Stability

Fig. 1. Composition and properties of four generations of solid dispersions. CC: crystalline carrier, AP: amorphous polymer, SFP: surfactant polymer, WIP: water insoluble
polymer, SP: swellable polymer, SF: surfactant, ("): increase, (;): decrease.
 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813
Fig. 2. Modeling and comparison of dissolution profiles of four generations of solid
dispersions in supersaturated conditions, (0) pure API, (1) the first generation solid
dispersions which show improvement in dissolution rate compared to the pure API,
(2) the second generation solid dispersions which have improved dissolution profile
compared to the first generation thanks to their faster dissolution rate, (3) the third
generation solid dispersions which have improved dissolution profile compared to
second generation thanks to their faster dissolution rate and lower precipitation
rate and extend in supersaturated state, (4) the fourth generation solid dispersions
which have improved dissolution profile in a controlled or zero-order manner.
showed higher solubility and dissolution rate than mannitol based
solid dispersions because urea reduced the crystallinity of ofloxa-
cin more than mannitol which was proved by PXRD and DSC
results. The main disadvantage of crystalline solid dispersions is
the high thermodynamic stability of the carriers that lowers their
dissolution rate compared to amorphous solid dispersions (Fig. 2).
2.2. Second generation
The second generation solid dispersions contain amorphous
carriers which are mostly polymers. Amorphous solid dispersions
can be classified into amorphous solid solutions (glass solutions)
and amorphous solid suspensions according to the physical state
of the drug. In amorphous solid solution the drug and amorphous
carrier are completely miscible to form molecularly homogenous
mixture while amorphous solid suspension consists of two sepa-
rate phases. Amorphous solid suspensions are formed when the
drug has limited carrier solubility or an extremely high melting
point [27]. In these systems, the small drug particles mainly in
amorphous state are dispersed in amorphous carriers. It is impor-
tant to note that the API often exists more than one state in solid
dispersions, for instance, an API can both dissolve and suspend in
a carrier or exist in amorphous and crystalline state at the same
time. In amorphous solid dispersions, the API is dispersed in very
small size (molecular, amorphous particle or small crystals) and
exists in supersaturated state in amorphous carriers because of
forced solubilization [28–30]. The amorphous carriers can also
increase the wettability and dispersibility of drugs as well as
inhibit the precipitation process of drugs when amorphous solid
dispersions dissolved in water [31,32]. These properties along with
the fast dissolution rate of amorphous carriers due to the low ther-
modynamic stability of amorphous state carriers enhance the drug
solubility and release rate.
Amorphous carriers can be divided into full synthesis polymers
and natural products based polymers. The full synthesis polymer
801
includes povidone (PVP) [33], polyethylene glycol (PEG) [34],
crospovidone (PVP-CL) [35], polyvinypyrrolidone-co-vinylacetate
(PVPVA) [34], and polymethacrylates [36]. The natural product
based polymer consists of cellulose derivatives such as hydroxy-
propylmethyl cellulose (HPMC) [37], hydroxypropylcellulose
(HPC) [38], hydroxypropylmethylcellulose phthalate (HPMCP)
[39], hydroxylpropylmethylcellulose acetate succinate (HPMCAS)
[40], starch (corn starch, potato starch) [41] and sugar glass (treha-
lose, sucrose, inulin) [42]. Among them, HPMC, PEG and PVP are
most widely used [41]. Unlike other amorphous polymers listed
above, PEG has semi-crystalline structure but very low melting
point (below 65 °C) regardless of its molecular weight. Therefore,
PEG is very suitable for the preparation of solid dispersions by
the melting method especially when the drug is heat sensitive. In
contrast, PVP has relatively high glass transition temperature so
it is hardly utilized for the melting method [23]. All of these poly-
mers are soluble in some organic solvents or even wide variety of
solvents in the cases of PEG, PVP, HPC; therefore, these polymers
can be applied to prepare solid dispersions by the solvent method.
Except crospovidone, all of these polymers have high solublility in
water and thus can improve the drug’s wettability when the solid
dispersions are dispersed in water. Although crospovidone is not
soluble in water, this hydrophyllic polymer quickly swells when
contact to water and enhances the drug release rate [35]. The aque-
ous solubility of these polymers often decreases and the viscosity
becomes higher when their chain lengths or molecular weights in-
crease. The high viscosity polymers can prevent the recrystalliza-
tion of drugs in the preparation, storage and dissolution process.
However, they can hinder the dispersion of drugs in carriers in
the preparation process and delay the dissolution rate of drugs
when the solid dispersions are dispersed in water. Therefore, the
molecular weight of polymers is very important factor to select a
polymer as a carrier. In fact, PEG with molecular weights of
1500–20,000 and PVP with molecular weights of 2500–50,000
(K12 to K30) are commonly used in solid dispersions [23]. PEG
with a very low molecular weight can make the solid dispersions
too soft and sticky to manufacture tablets or capsules whereas
PVP with very high molecular weight will reduce the drug release
rate because of its low solubility and high viscosity [43]. The inter-
action between the drug and carrier is also important for carrier
selection. Some drugs have plasticizing effect on polymer or form
hydrogen bonds with carriers. These interactions can affect the
preparation process, the drug dissolution rate, the physical proper-
ties and the stability of the solid dispersions. Karavas et al. [44]
prepared felodipine solid dispersions by using different types of
PVP and PEG as carriers. FTIR data showed hydrogen bonding be-
tween felodipine and both polymers. In the felodipine–PVP disper-
sions, the drug existed as amorphous nanoparticles whereas in
felodipine–PEG dispersions, the drug was dispersed as crystalline
microparticles. This was explained by the higher hydrogen bonding
in the FELO–PVP complex compared to FELO–PEG complex. In that
research, the physical state (amorphous or crystalline) and the par-
ticle size of felodipine in the solid dispersions were determined by
the interaction between drug and polymer. Kohri et al. [160] inves-
tigated the oral bioavailability of albendazole solid dispersion
granule using HPMC, HPMCP and mixtures thereof as carriers.
The results showed that all formulations significantly improved
the dissolution profile of albendazole and the solid dispersions
containing both HPMC and HPMCP as carriers not only had excel-
lent solubility but also prevented albendazole crystallization in a
neutral medium for 8 h. The absorption study of orally adminis-
tered albendazole in rabbits with low gastric acidity showed more
than three times higher bioavailability of HPMC–HPMCP based so-
lid dispersions compared to physical mixtures. In fact, HPMC and
its derivatives have been successfully applied in many marketed
solid dispersion products (Table 1).
802 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813
Some enteric polymers such as HPMCP, HPMCAS, EudragitÒ L
can be used to avoid drug release in the stomach. Since the major-
ity of drug absorption occurs in the small intestine and the fast re-
lease of drugs in the stomach can cause precipitation due to drug
supersaturation, the gastric juice resistant polymers may be help-
ful to improve the in vivo bioavailability of drug. Zhang et al. [40]
prepared amorphous fenofibrate (FB) solid dispersions using solu-
plusÒ, HPMCE5 as carriers for immediate release and HPMCP55,
HPMCAS as carriers for enteric release. The in vitro dissolution test
showed more improvement in dissolution profile of FB-HPMCE5
and FB-HPMCAS solid dispersions. Although the maximum concen-
tration of the drug in the supersaturation dissolution profile of FB-
HPMCE5 and FB-HPMCAS solid dispersions were similar, the in vivo
pharmacokinetic study in rats showed significant improvement in
bioavailability of FB-HPMCAS granules in comparison with FB-
HPMCE5 granules. This was explained by the complete dissolution
of FB in the proximal small intestine and the stronger effect in
remaining drug supersaturation state of the FB-HPMCAS solid
dispersion.
Sugar glasses such as trehalose, sucrose and inulin are also used
to prepare solid dispersions thanks to their extremely fast dissolu-
tion rate. However, the rapid dissolution of carriers can result in a
very high concentration of drugs in the near vicinity of the dissolv-
ing solid dispersions which leads to precipitation and formation of
large drug crystals [42]. Inulin dissolves more slowly than sucrose
and trehalose because of its oligomeric nature; therefore, the pre-
cipitation and crystallization rate of inulin based solid dispersions
dispersed in water is lower than trehalose and sucrose based solid
dispersions [45].
2.3. Third generation
Although the amorphous solid dispersions can enhance drug
release rate, the subsequent supersaturation state of drugs may
cause drug precipitation and decrease the drug concentration
in vitro or in vivo, thus negatively affecting the bioavailability of
drugs. This phenomenon is very common, especially with sugar
glass based solid dispersions. The drug may also recrystallize from
amorphous state in the preparation process (cooling or solvent re-
moval) and during storage. In the third generation solid disper-
sions, the surface active agents or self-emulsifiers are introduced
as carriers or additives and showed significant improvement in
overcoming the above problems such as precipitation and recrys-
tallization. These surfactants are used as process aids and additives
which act to improve the biopharmaceutical performance of the
supersaturation systems. The introduction of surfactants or emul-
sifiers in solid dispersions improves not only the dissolution profile
(Fig. 2) but also the physical and chemical stability of drug. In fact,
surfactants with amphiphilic structure can enhance the miscibility
of drugs and carriers and thus reduce the recrystallization rate of
drugs. Moreover, surfactants or emulsifiers are able to improve
the wettability of drugs and prevent the drug precipitation due
to supersaturation by absorbing to the outer layer of drug particles
or forming micelles to encapsulate drugs.
The surfactants used as carriers include poloxamer [46], compr-
itol 888 ATO [47], gelucire 44/14 [48], inutec SP1 [20] and
soluplusÒ [49]. Poloxamer is a very common polymer which has
been used for such a long time in solid dispersions as a carrier or
additive while soluplusÒ has just been applied in recent years
and showed superior performance in hot melt extrusion processes
[50]. Ali et al. [51] prepared ibuprofen and ketoprofen solid disper-
sions at different mole ratios using poloxamer 407 and 188. FTIR
indicated the disruption of the ibuprofen, ketoprofen dimer con-
comitant with hydrogen bond formation between the drug and
carrier. Solid dispersions with mole ratio of drug–carrier 2:1 had
no drug crystal while at higher drug loading the drug co-existed
in amorphous and crystalline state. All solid dispersions signifi-
cantly improved the dissolution of ibuprofen and ketoprofen. Inu-
tec SP1 is a derivative of inulin prepared by the reaction between
isocyanates and the polyfructose backbone and can be used as an
emulsifier in pharmaceutical formulations [52,53]. It was intro-
duced into solid dispersions as a novel carrier in the research of
Van den Mooter et al. [20] and showed potential in improving drug
release.
Other surfactants and emulsifiers such as sodium lauryl sulfate
(SLS) [54], Tween 80 [55,56], d-alpha tocopheryl polyethylene
glycol 1000 succinate (TPGS 1000) [57], polyoxyethylene hydroge-
nated castor oil [58] and sucrose laurate [59] are used as additives
in solid dispersions. De Waard et al. [60] incorporated SLS in the
sugar glass based solid dispersions and prepared tablets. Physical
mixture of SLS and sugar glass based solid dispersions was also
compressed to make standard tablets. The dissolution of tablets
prepared from solid dispersions in which SLS was incorporated
was strongly improved compared to standard tablets. It was ex-
plained that SLS interacted with drug and carrier when it was
incorporated in solid dispersions; therefore, the dissolution of
SLS was prolonged and this helped to maintain the high concentra-
tion of the drug in the near vicinity of the dissolving tablet during
the whole dissolution process, thus preventing the drug precipita-
tion effectively.
2.4. Fourth generation
The fourth generation solid dispersion is a controlled release so-
lid dispersion (CRSD) containing poorly water-soluble drugs with a
short biological half-life. CRSD of poorly water-soluble drugs often
requires two targets: solubility enhancement and extended release
in a controlled manner. In CRSD, the molecular dispersion of poorly
water-soluble drugs in carriers will improve the drug solubility
while water insoluble polymers or swellable polymers can be used
to retard the drug release in the dissolution medium [61]. The
CRSD can deliver an adequate amount of drug for an extended per-
iod of time and thus offer many advantages such as improved pa-
tient compliance due to reduced dosing frequency, decreased side
effects, more constant or prolonged therapeutic effect for poorly
water-soluble drugs [62,63]. The conventional polymers used for
retarding the release of poorly water-soluble drugs in CRSD include
ethyl cellulose (EC) [62], HPC [28], EudragitÒ RS, RL [61,64],
poly(ethylene oxide) (PEO) and carboxyvinylpolymer (CarbopolÒ)
[65]. These polymers which are insoluble or dissolve very slowly
in water can sustain the release of poorly water-soluble drugs.
The CRSD uses these sustainable polymers or combines these poly-
mers in solid dispersion systems or can use other materials having
solubilizing capacity and sustaining action. The CRSD have two
main mechanisms by which the drug can be released: diffusion
and erosion. Cui et al. [64] prepared sustained-release nitrendipine
microspheres having solid dispersion structure. HPMCP-55 and
Aerosil were used as the solid dispersing agents to improve the dis-
solution of nitrendipine while EudragitÒ RS PO and EC were se-
lected as the retarding agent to control the drug release rate. The
bioavailability results in dogs showed the superior prolonged
absorption profile and bioavailability improvement of solid disper-
sion microspheres compared to the reference tablets (Baypress™)
and the conventional tablets. Ohara et al. [66] investigated the dis-
solution mechanism of indomethacin from extended release solid
dispersion system with EC and HPMC (1:1). It was concluded that
the hydrophobic interaction between indomethacin and EC oc-
curred under lower pH region and strongly delayed the dissolution
of indomethacin. Tran et al. [67] prepared polyethylene oxide
(PEO)-based CRSD containing aceclofenac, GelucireÒ 44/14, polox-
amer 407 and pH modifier (Na2CO3) for controlled release of poorly
water-soluble drug. The CRSD improved the dissolution profile of
 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813 803

aceclofenac with an aid of surfactant and pH modifier compared to egies. Solid dispersions can reduce the drug particle size into
pure drug and showed retard drug release in a zero-order manner molecular levels while other conventional particle size reduction
due to the water swellable property of PEO. techniques have particle size limit around 2–5 lm, which easily
agglomerate in the formulation, dissolution process or during stor-
age [69–71]. Novel nanosizing approaches can produce drug nano-
3. Mechanism of drug release from solid dispersions
crystals in a solid state but the preparation process is quite long,
complicated and requires stabilizers as well as special equipments
There are two main mechanisms of drug release from immedi-
[72]. In solid dispersions, the interaction between the drug and car-
ate release solid dispersions: drug-controlled release and carrier-
rier prevents the agglomeration of drug particles and the drug is
controlled release. When solid dispersions are dispersed in water,
released in supersaturation state which is advantageous for rapid
the carriers often dissolve or absorb water rapidly due to their
absorption. Even when the drug from solid dispersions precipitates
hydrophilic property and form concentrated carrier layer or gel
due to supersaturation in the dissolution media, the size of precip-
layer in some cases. If the drug dissolves in this layer and the vis-
itated particles are still in submicron (<1 lm) and the dissolution
cosity of this layer is high enough to prevent the diffusion of the
rate of these particles is still higher than microparticles prepared
drug through it, the rate limiting step will be the diffusion of the
by other techniques [23,73]. However, the precipitated drugs
carrier into the bulk phase and this mechanism is carrier-con-
may also exist in amorphous or different crystalline forms which
trolled release. If the drug is insoluble or sparingly soluble in the
have lower thermodynamic stability (higher energy state) than
concentrated layer, it can be released intact to contact with water
drug particles, leading to faster dissolution for in vivo situations.
and the dissolution profile will depend on the properties of drug
Moreover, solid dispersions can be formulated in solid oral dos-
particles (polymorphic state, particle size, drug solubility) [22]. In
age forms which are more acceptable for patients than liquid prod-
fact, these two mechanisms often occur simultaneously because
ucts produced by solubilization method [70,73]. The preparation
the drug may be partly soluble or entrapped in the concentrated
process of solid dispersions is also more simple and applicable than
carrier layer. However, these mechanisms help explain the differ-
some other techniques such as salt formation or nanosized prepa-
ent release behaviors of solid dispersions and figure out the way
ration (nanoparticle, nano-emulsions).
to improve the dissolution profile of solid dispersions. Numerous
Solid dispersions also have other advantages in improving the
researches showed the improvement of drug dissolution profile
drug bioavailabilty such as wettability, porosity enhancement
when the ratio of carriers in solid dispersions was increased be-
and polymorphic change. The fast dissolution or water absorption
cause the drug was dispersed better and the drug crystallinity de-
of carrier molecules surrounding drug particles can improve the
creased [26]. In these solid dispersions the main release
drug wettability, especially when surfactants or emulsifiers are
mechanism is drug-controlled release. In contrast, other researches
incorporated in solid dispersions. This reduces the risk of agglom-
demonstrated the decrease in drug dissolution rate when the ratio
eration of drug particles in the dissolution media and increase the
of carrier in solid dispersions was increased [68]. This can be ex-
dissolution rate of drug. Many polymers can act as solubilizers to
plained by the carrier-controlled mechanism in which the gel or
enhance drug solubility. Solid dispersions also have high porous
concentrated carrier layer is formed and acts as a diffusion barrier
structure, especially those prepared by solvent method. The fast
to delay drug release. The release mechanism may also be affected
solvent removal may leave some channels in the solid dispersion
by the ratio of drug–carrier in solid dispersions. Karavas et al. [44]
structure, thus increasing the porosity, surface specific area and
prepared felodipine solid dispersions by using different types of
the dissolution rate of drug. Linear polymer based solid dispersions
PVP, PEG as carriers and concluded that the proportion of the drug
often have higher porosity than reticular polymer based solid dis-
in solid dispersions determined the mechanism of drug release
persions [74]. Zhang et al. [40] when preparing amorphous FB solid
which was drug diffusion (through the polymer layer)-controlled
dispersions by thin film freezing techniques as mentioned above
at low drug contents and drug dissolution-controlled at high drug
also found that the thin film freezing process dramatically in-
contents. Therefore, in order to improve the dissolution profile of
creased the surface area of the aggregates of FB-polymer composi-
solid dispersions, it is important to identify the mechanism release
tions by at least 40-times compared to the bulk FB powder and the
of solid dispersions rather than only focus on the polymorphic
significant increase in surface area facilitated the enhancement of
state of drugs because in carrier-controlled release solid disper-
dissolution rate and bioavailability of FB. Numerous researches
sions, the carrier properties such as solubility, viscosity, gel form-
on solid dispersions demonstrated the change in polymorphic state
ing ability and the ratio of drug–carrier are the key factors
of drugs from crystalline to amorphous form. In general, the reduc-
affecting the drug dissolution profile.
tion of drug crystallinity will improve the dissolution rate because
In CRSD, depending on the characteristic of polymers and the
less energy is required to break up the crystal lattice during the
miscibility of the drug and carrier there are two main mechanisms
dissolution process, thus increasing the drug solubility [33]. The
by which the drug can be released from the system: diffusion and
polymorphic state of drugs in solid dispersions is mainly
erosion. If the drugs and polymers are well dispersed in internal
determined by the preparation process and the physicochemical
structure of solid dispersions, the diffusion of drugs through the
interactions between drug and carrier.
matrix will be the main mechanism. If the drugs and carriers exist
in separated particles, the solid dispersion erosion may become the
main mechanism for drug release. In some solid dispersions, both
5. Common problems of solid dispersions
of these mechanisms can control the drug release at the same time
[66].
Despite many advantages in improving dissolution profile of
poorly water soluble drugs, the number of commercial products
4. Advantages of solid dispersions using solid dispersions is limited because of some problems in
the preparation process and during storage. The most important
In comparison with other techniques used to improve bioavail- problem is the recrystallization of drugs from amorphous state
ability of poorly water soluble drugs such as salt formation, during storage which leads to decreased bioavailability of solid
particle size reduction (milling or micronization), and solubiliza- dispersions. The crystallization of drugs involves two steps: nucle-
tion (cosolvent, micelles, emulsions), solid dispersions show many ation followed by crystal growth that requires the diffusion or rear-
important advantages to become one of the most promising strat- rangement of drug molecules [1]. Therefore, molecular mobility of
804 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813
drugs is the key factor determining the drug physical stability. The
molecular mobility can be divided into global mobility (a-relax-
ations) which is the molecular rotation, translation for the glass
transition and local mobility (b-relaxations) which relates to the
movement of only a part of a molecule and occurs at a smaller time
scale than global mobility [3,75]. At 50 °C below the glass
transition temperature (Tg), the a-relaxations are negligible and
b-relaxations are thought to determine the rate of nucleation and
crystallization of amorphous materials [76–78]. The presence of
water often reduces the Tg of amorphous systems due to its plas-
ticizing effect and thus increases the molecular mobility [79,80].
The increased temperature also enhances the molecular mobility
and causes recrystallization in solid dispersions. Therefore, the
storage temperature and moisture are important factors affecting
the physical stability of drug. The poor scalability for the purposes
of manufacturing is also the main obstacle for solid dispersions to
be available in the market [6].
Furthermore, there are some common problems in the prepara-
tion, formulation and dissolution process that researchers have to
consider in research and development of solid dispersion products.
These problems include the thermal instability of drugs and
carriers in the melting method, the solvent residue in the solvent
method, the recrystallization of drugs in solidification and further
formulation process, the low in vivo–in vitro correlation, and the
precipitation of drugs after dissolving in water due to supersatura-
tion. Ayenew et al. [81] investigated the effect of compression in
the tableting process on miscibility of naproxen–PVP K25 solid dis-
persions. FTIR showed that the miscibility in the compositions with
30% and 40% (w/w) naproxen is markedly affected by the compres-
sion process. Compression pressures from beyond 565.05 MPa in-
duced apparent amorphous–amorphous phase separation. This
was explained by the weakening and/or disruption of intermolec-
ular hydrogen bonding between drug and polymer upon compres-
sion. It is important to mention the poor correlation between
in vitro dissolution data and in vivo absorption despite the use of
biorelevant in vitro dissolution media in case of poorly water-solu-
ble drugs [82]. Although SUPAC-based biowaiver is possible by FDA
in case of BCS Class I, in vivo testing or a clinical assessment would
be always needed for a BCS Class II (even III, IV) compound to prove
the efficiency of solid dispersions in improving bioavailability of
poorly water soluble drugs.
6. Strategies to overcome the common problems of solid
dispersions
Polymers often have higher glass transition temperature (Tg)
compared to the API so they can decrease the molecular mobility
of drug by increasing the Tg of the miscible mixture or by interact-
ing with drug molecules [33,76]. A polymer has to be miscible with
drug to prevent the drug recrystallization and the miscibility de-
pends on the molecular interaction between the drug and polymer
[17,83]. Hydrogen bonding between the drug and polymer is the
main force to increase the solid miscibility and thus hinder phase
separation and drug recrystallization. However, many polymers
are hygroscopic and the water absorbed by polymers may increase
molecular mobility. Therefore, selecting a suitable polymer which
has high Tg, strong interaction with drug and low hygroscopicity
is the way to stabilize the physical state of drugs in solid disper-
sions. Vasanthavada et al. [83] investigated factors influencing so-
lid solubility and phase separation kinetics of drugs in
griseofulvin–PVP and indoprofen–PVP solid dispersions. Griseoful-
vin did not exhibit any solid solubility in PVP, whereas a 13% w/w
indoprofen remained molecularly miscible with the polymer under
accelerated stability conditions of 40 °C/69% RH for 3 months. The
higher miscibility of indoprofen in PVP was explained by hydrogen
bonding between the drug and polymer proved by FTIR data. No
hydrogen bond between the griseofulvin and PVP was noticed;
therefore, the author concluded that phase separation rates ob-
tained were proportional to the drug–polymer interactions and
the drug content of the dispersion. In many researches, although
drugs existed in crystalline state in solid dispersions, the in vivo
bioavailability was increased significantly in comparison with
physical mixture. These solid dispersions will not face crystalliza-
tion problems and thus have good stability [51,84].
The appearance of surfactants and emulsifiers in third genera-
tion solid dispersions may increase the miscibility of drug–poly-
mer due to their amphiphilic structure and thus reduce the
recrystallization rate. The surface active agents can also reduce
the process temperature of melting method due to their plasticiz-
ing effect and increase the solubility of drugs and carriers in organ-
ic solvents in the solvent method. When solid dispersions are
dispersed in water, the surface active agents improve drug wetta-
bility and inhibit the precipitation process by absorbing on the sur-
face of drug particles or forming micelles encapsulating drugs.
Mura et al. [85] investigated the effect of anionic surfactants
including SLS, dioctylsulfosuccinate (DSS) and nonionic surfactant
(Tween 60) on the properties of ketoprofen ternary solid disper-
sions in polyethylene glycol 15,000. Although the binary system
(ketoprofen–PEG) showed the dissolution enhancement compared
to pure drug, the dissolution profile of solid dispersion was signif-
icantly improved when the surfactants were incorporated to make
ternary systems. It was explained by the presence of the surfac-
tants which improved wettability and decreased surface tension
of drug particles and dissolution medium, leading to the inhibition
of drug precipitation. The micellar solubilization effect of surfac-
tant was excluded because the surfactant concentration in the dis-
solution medium was generally below the critical micelle
concentration. The crystallinity degree of the ternary systems
was also lower than binary system which showed the efficiency
of surfactants in improving drug–polymer miscibility. The effec-
tiveness of the incorporated surfactants depended on the types of
surfactants (SDS > DSS > Tween 60) and the solubilizing efficiency
of anionic surfactants was higher than the nonionic one. The great-
est efficacy of SDS could be due to its high hydrophilic property
and strong solubilizing ability.
In order to prevent the recrystallization of drugs in the solidifi-
cation process (cooling, solvent removal) many techniques have
been developed to increase the solidification rate such as ultra ra-
pid freezing, spray drying and spray freezing which will be men-
tioned below.
7. Preparation method
There are three major preparation methods for solid dispersions
including melting method, solvent method and melting solvent
method (Fig. 3). In fact, the melting method and solvent method
are more common than the melting solvent method.
7.1. Melting method
7.1.1. Characteristic features, advantages and limitations of melting
method
The first solid dispersions for pharmaceutical application were
prepared by melting method or fusion method [21]. In the melting
method, the drug and carrier are melted together at a temperature
above the eutectic point, which is the lowest possible melting
point of the mixture, then the liquid is cooled or solidified by dif-
ferent techniques such as ice bath agitation [16], spreading on
stainless steel thin layer cooled by air or water [86], putting petri
dishes inside a dessicator [87] and immersion in liquid nitrogen
 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813
Preparation method
Melting Solvent evaporation Melting solvent
• Ice bath agitation • Oven drying
• Thin film cooling • Vacuum drying
• Liquid nitrogen • Rotary evaporation
• Heating on hot plate
• Spray congealing
• Spray drying
• Hot-melt extrusion
• Freeze drying
• MeltrexTM
• Supercritical anti-solvent
• Melt agglomeration • Co-precipitation
• Electrostatic spinning
• Spray freeze drying
• Ultra-rapid freezing
• Fluid-bed coating
Fig. 3. A branched tree used for the production of solid dispersions.
[88]. The resultant solid is then crushed, sieved, pulverized to re-
duce the particle size or injection molded into dosage forms with-
out undergoing milling. The advantage of this method is that it
does not require any solvent. An important prerequisite of this
method is the miscibility of the drug and carrier in the molten state
to obtain a homogenous mixture. Therefore, a suitable carrier
should shares similar physicochemical properties with the API.
PEG and poloxamer are two polymers that are commonly used to
prepare solid dispersions by the melting method. Kolašinac et al.
[68] prepared solid dispersions by melting method at a low tem-
perature (70 °C) using poloxamer P 188 and poloxamer P 407 to in-
crease the solubility and the dissolution rate of desloratadine. Solid
dispersions containing different weight ratio of poloxamers and
desloratadine were prepared and then were used for the prepara-
tion of immediate release tablet. The results showed that deslorat-
adine existed in the amorpohous state in solid dipersions and both
types of poloxamer significantly enhanced intrinsic solubility of
desloratadine (10–80 times) as well as the dissolution profile of
desloratadine tablets. Poloxamer P 407 was approximately 4-fold
less effective than poloxamer P 188 as a solubilizer because of its
higher molecular weight and higher proportion of hydrophobic
polyoxypropylene segment. The increase in poloxamer ratio over
1:1 in solid dispersions decreased intrinsic dissolution rate of desl-
oratadine because larger amount of poloxamer in solid dispersions
provide better conditions for gel layer formation when contacting
with water, which consequently acts as a diffusion barrier and de-
lays drug release. The high compression force reduced the dissolu-
tion rate of desloratadine by reducing the porosity of the tablet and
increasing bonding between poloxamer particles. Different types of
PEG such as PEG 4000 and PEG 6000 were also used as carriers to
increase the solubility of antiviral thiocarboxanilide UC-781 and
nimodipine in solid dispersions prepared by the melting method
[48,89].
Despite being frequently applied, the melting method has some
noticeable limitations that can severely impact attempts to en-
hance the bioavailability of poorly water-soluble drugs. A major
disadvantage is that the method can only be applied when the drug
and the carrier are compatible and miscible at the heating temper-
ature. An incompatibility causes phase separation and the high
viscosity of a polymeric carrier in the molten stage can prevent
the miscibility, thus resulting in an inhomogeneous solid disper-
805
sion. This phenomenon can be prevented in some cases by using
surfactants. The phase separation can also occur during cooling,
as the drug–carrier miscibility changes. Indeed, slow cooling the
mixture often produces drugs in crystalline state, while fast cooling
may yield drugs in amorphous state. This limitation can be con-
trolled by using spray congealing technique to quickly solidify
melted mixture in cool air. Spray congealing is a process in which
a hot molten mixture (solution or suspension of a drug in a molten
carrier) is atomized into an environment maintained at tempera-
tures below the carrier melting point [90,91]. The atomization
makes the melted droplets congeal rapidly to form solid particles.
This method was used in many researches to prepare solid disper-
sions [92,93].
Another limitation of the melting method is the thermostability
of the API and the carrier at high temperature. A modified tech-
nique to reduce the drug heating time and the process temperature
was performed by suspending the API in a previously molten car-
rier, instead of heating both drug and carrier at the same time to
obtain molten mixture. Mehanna et al. [94] applied this technique
to prepare tadalafil-PluronicsÒ solid dispersions. PluronicsÒ of var-
ious grades was melted at 70 ± 2 °C, followed by the addition of
drug powder to the molten carrier and stirring until a homogenous
dispersion was formed. The SEM, DSC, PXRD results showed micro-
crystalline uniform dispersion of tadalafil in the carrier matrix.
Although the drug was still in crystalline state, the dissolution rate
of tadalafil in Pluronic F-127 based solid dispersion significantly
increased compared to the physical mixture. Several important
modifications of melting method to overcome its limitations con-
sist of hot-melt extrusion, Meltrex™, and melt agglomeration.
7.1.2. Hot melt extrusion
In recent years, hot melt extrusion has become one of the most
common methods for solid dispersion preparation due to its high
scalability and applicability. In this method, the drug and carrier
are simultaneously mixed, heated, melted, homogenized and ex-
truded in a form of tablets, rods, pellets, or milled and blended
with other excipients for different purposes [95]. The intense mix-
ing and agitation forced by the rotating screw during the process
cause disaggregation of drug particles in the molten polymer,
resulting in a homogenous dispersion [32]. This process involves
the transformation of a solid mass of intertwined particles into a
viscous liquid or semisolid mass by heating and intense mixing.
The hot melt extruded systems are composed of drugs, one or more
meltable polymers and other additives such as plasticizers and pH
modifiers. The melting rate is mainly affected by the physical and
rheological properties of the polymer. The melting rate is much
faster when polymers are amorphous and low viscous. Hot melt
extrusion of miscible components may lead to a high trend of
amorphous solid dispersion formation, thus improving drug disso-
lution profile. In order to select a suitable polymer for hot melt
extrusion process, Hansen solubility parameter can be applied to
predict the drug–carrier miscibility [96,97]. Despite some prob-
lems such as the miscibility of drugs and carriers as well as high
local temperatures in the extruder due to high shear forces, hot
melt extrusion has considerable advantages for pharmaceutical
applications [98]. An important advantage of the hot melt extru-
sion method compared to other melting methods is the low resi-
dence time of the drug and carrier at elevated temperature in the
extruder which reduces the risk of degradation of thermolabile
drugs [23]. This method is also continuous, efficient, easy scale-
up and produce higher thermodynamic stability products than
other methods [99]. This technology has been successfully applied
to design many drug delivery systems such as immediate and con-
trolled release tablets, granules, pellets, implants, transdermal
drug delivery systems, ophthalmic ocular inserts [100]. Various
references have applied hot melt extrusion for solid dispersion
806 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813
preparation. For instance, fenofibrate solid dispersion with carrier
of Eudragit E100 or polyvinylpyrrolidone-vinyl acetate copolymer
S630 was prepared by hot melt extrusion technology, which re-
sulted in an increase in dissolution rate and oral bioavailability
[101]. Hot melt extrusion and its advanced technology, Meltrex™,
are the most successful ones to prepare solid dispersions with
many marketed products such as CesametÒ, RezulinÒ, KaletraÒ
(Meltrex™), NovirÒ (Meltrex™) and IsotipÒ (Meltrex™) [102,103].
7.1.3. Meltrex™ and melt agglomeration
Meltrex™ based on the hot melt extrusion principle is a
patented solid dispersions manufacturing process. In Meltrex™
technology, the use of a special twin screw extruder and the pres-
ence of two independent hoppers allow conveying the extruded
mass continuously throughout the extrusion channel and thus re-
duce the residence time of the drug (approximately 2 min) in the
extruder as well as avoid thermal stress to the drug and excipient
[6,104]. The temperatures of all the barrels are independent and
can be accurately controlled from low temperature (30 °C) to high
temperature (250 °C) [104]. This technique is suitable for drugs
which are sensitive to oxidation and hydrolysis because oxygen
and moisture may be eliminated during the process.
In general, the amorphous solid dispersion prepared by melting
method are soft, sticky and have poor flow properties and poor
compressibility which hinder their applications in a large pharma-
ceutical scale of tableting [105]. Melt agglomeration method, in
which the carrier acts as a meltable binder, is a feasible method
to solve these problems. Melt agglomeration is processed in high
shear mixers or rotary processor with the mixture prepared by
three ways: adding the molten carrier containing the drug to the
heated excipients [106,107], adding the molten carrier to a heated
mixture of the drug and excipients [46], or heating a mixture of the
drug, carrier and excipients to a temperature within or above the
melting range of the carrier [106]. The rotary processor may be
preferable to the high shear mixer in melt agglomeration tech-
nique because the temperature can be more easily controlled and
higher binder content can be incorporated in the agglomerates
[29]. Seo et al. [106] prepared the agglomerates containing solid
dispersions of diazepam by melt agglomeration in a high shear
mixer. This study showed significant increase in dissolution rate
of diazepam and a higher dissolution rate was obtained with a
lower drug concentration indicating a higher degree of molecular
dispersion at the lower concentration. It was concluded that the
dissolution rate was affected mainly by the type of meltable binder
since Gelucire 50/13 gave rise to faster dissolution rate compared
to PEG 3000.
7.2. Solvent evaporation method (solvent method)
In the solvent evaporation method, solid dispersion is obtained
after the evaporation of solvent from the solution containing a
drug and carrier [16]. The solvent method has solved main prob-
lems of the melting method relating to the decomposition of drugs
and carriers at high temperature because in the solvent method,
the solvent removal can be performed without heat such as freeze
drying technique. Some polymers hardly used as carriers in the
melting method due to their high melting point can be applied in
the solvent method. An important prerequisite of this method is
the sufficient solubility of the drug and carrier in a solvent or co-
solvent [23]. Finding a suitable non-toxic solvent is sometimes
difficult because carriers are hydrophilic whereas drugs are hydro-
phobic [108]. The solvents used in solvent method may include
methanol, ethanol, ethyl acetate, methylene chloride, acetone,
water. . .and mixtures thereof [109]. Some surfactants such as
Tween 80 and SLS can be utilized to increase the solubility of drugs
and carriers in solvents. However, their incorporation has to be
carefully considered, because a large excess may induce a signifi-
cant change in the matrix structure. The disadvantage of this meth-
od is that the residual solvent remaining after evaporation process
may cause toxicity and complete solvent removal is nearly impos-
sible. In addition, residual solvent can also, like water, lower the Tg
and act to plasticize the system, leading to phase separation due to
the increased mobility of components. The use of solvent mixtures
has been proposed as the way to minimize the problems relating to
organic solvents. For example, Kumar [110] used a dioxane–buta-
nol–water mixture to prepare an amorphous solid dispersion of
an opioid antagonist. Other disadvantages of the solvent method
are its large environmental issues, the high cost of production
due to the extra facilities required for solvent removal and protec-
tion against explosion as well as low scalability. For these reasons,
hot melt extrusion is more favorable than solvent method to pre-
pare solid dispersions if the stability and bioavailability enhance-
ment of solid dispersions prepared by hot melt extrusion are
ensured.
Similar to the melting method, the solidification rate in solvent
method can determine the physical state of drugs in solid disper-
sions. A fast solidification method is always preferred to guarantee
the amorphous state of drugs. Therefore, there are many methods
developed for fast solvent removal such as heating on a hot plate
[62], vacuum drying [111], rotary evaporation [112], spray drying
[113], freeze drying [38], spray freeze drying [37] and ultra rapid
freezing [114].
7.2.1. Vacuum drying and rotary evaporation
Phase separation is a challenge that can arise during the solvent
removal process. The heating process can increase the molecular
mobility resulting in phase separation. Therefore, vacuum drying
and rotary evaporation at a moderate temperature are used to
avoid that risk and prevent the degradation of drugs and carriers
at high temperature. After solvent evaporation process, the resul-
tant solid dispersions may be stored in a vacuum desiccator for
complete removal of residual solvent. Although these methods
are easy to perform, the processes are quite long. Therefore, the
phase separation and recrystallization of drugs can easily occur
during the drying process.
7.2.2. Spray drying
Spray drying is an efficient technology for solid dispersion man-
ufacturing because it permits extremely rapid solvent evaporation
resulting in fast transformation of an API-carrier solution to solid
API-carrier particles [115]. In this technique, the API-carrier solu-
tion or suspension is transported from the container to the nozzle
entrance via a pump system and atomized into fine droplets with
large specific surface area. These droplets result in rapid evapora-
tion of the solvent and the formation of solid dispersions within
seconds. The size of the solid dispersion particles prepared by
spray drying can be customized by modulating the droplet size
via nozzle to meet the requirements for further processing or
applications. The drugs in solid dispersions prepared by spray dry-
ing are often in amorphous state; therefore, the solubility and dis-
solution rate are significantly increased. Spray drying is one of the
most common techniques used to prepare solid dispersions due to
the possibility of continuous manufacturing, ease of scalability,
good uniformity of molecular dispersion and cost-effectiveness in
large scale production with high recoveries (more than 95%)
[116–118]. Solid dispersion products prepared by spray drying
are commercially available such as IncivekÒ and IntelenceÒ [118].
7.2.3. Freeze drying
Freeze drying is an alternative method for drying solid
dispersions. This method shows promise as a suitable technique
for the incorporation of drugs into stabilizing matrices because
 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813
the drug is subjected to minimal thermal stress during the solid
dispersion formation. This method includes two steps: freezing
and lyophilization. The freezing rate is very important to control
phase separation. The basic process consists of immersing the
API-carrier solution in liquid nitrogen until it is fully frozen and
the frozen solution is then lyophilized [27,119]. The advantage of
this method is the minimized risk of phase separation and the dis-
advantage is that most organic solvents have low freezing temper-
atures and do not stay frozen during sublimation. Furthermore,
sample temperature has to be maintained below the Tg of the
frozen concentrated fraction when glass formation is required.
Therefore, the process will take much longer time if low tempera-
ture is required for freeze-drying of a sample. In order to obtain an
acceptable duration for the lyophilization process, the solvent
should have a sufficiently high vapor pressure.
7.2.4. Cryogenic processing techniques
Solid dispersions can also be obtained by cryogenic processing
techniques including spray freeze drying (SFD) and ultra-rapid
freezing (URF). These methods increase the freezing rate compared
to freeze drying technique. SFD allows for a reduction in the pri-
mary particle size of drug particles without intense frictional or
mechanical forces which can cause degradation of the API through
thermal stress [120]. SFD is a very promising drying technique in
which the solution of the drug and polymer is sprayed into/on li-
quid nitrogen or cold dry air and the frozen droplets are subse-
quently lyophilized. The large surface area and direct contact
with the cooling agents result in rapid vitrification, thereby reduc-
ing the risk of phase separation to a minimum. It also offers the
potential to customize the particle size to make it suitable for fur-
ther processing or applications. SFD usually produces drugs in
amorphous state because the rapid freezing rate can prevent
molecular arrangement into crystalline domains [121–123]. More-
over, in another research, Van Drooge et al. [124] demonstrated
that the drug stability in SFD solid dispersions is significantly bet-
ter than that of comparable freeze dried solid dispersions due to
higher cooling rate of SFD resulting in more incorporation of the
drug into matrix, especially at high drug loads. Another cryogenic
process, URF, involves the use of a solid cryogenic substrate with
thermal conductivity between 10 and 20 W/(m K) [114]. In this
technique, a drug–polymer solution is applied to a cryogenic solid
substrate and the frozen particles are then collected and removed
the solvent by lyophilization [125]. As the supercooling is extre-
mely fast, the nucleation of API crystals is minimized or completely
prevented, resulting in amorphous morphology after lyophilization
[126]. As compared to traditional methods, cryogenic processing
techniques offer more advantages. Spray drying and melting meth-
od are not always appropriate for use with thermolabile drugs.
However, SFD and URF were performed under sub-ambient condi-
tions and hence they can avoid heat or air that induces degradation
of drugs during drying processing. In a recent research described
by Badens et al. [127], SFD and supercritical anti-solvent (SAS)
were compared in preparation of solid dispersions containing
oxeglitazar. SFD showed lower crystallinity and higher dissolution
rate than SAS. However, SAS is more favorable in terms of time
consumption.
7.2.5. Supercritical anti-solvent (SAS)
SAS method generally uses supercritical carbon dioxide (CO2) as
a solubilizing solvent or anti-solvent. When supercritical carbon
dioxide is utilized as a solvent, this method is considered an envi-
ronmentally friendly technique because no organic solvent is re-
quired. Supercritical fluids are fluids whose temperature and
pressure are above the critical point. The favorable properties of
gases such as high diffusivity, low surface tension and low viscosity
imparted to liquids through manipulation of the pressure of super-
807
critical fluids allow the precise control of the solubilization of
many drugs. When using CO2 as a solvent, the drug and carrier
are dissolved in supercritical CO2 and sprayed through a nozzle
into an expansion vessel with lower pressure. The rapid expansion
induces rapid nucleation of the dissolved drugs and carriers, lead-
ing to the formation of solid dispersion particles with a desirable
size distribution in a very short time. When supercritical CO2 are
used as anti-solvent, it is introduced into the nozzle simulta-
neously with drug–carrier solution in an organic solvent. When
the solution is sprayed, the solvent is quickly extracted by the
supercritical CO2 leading to the precipitation of solid dispersion
particles [58].
7.2.6. Co-precipitation method
Co-precipitation is a suitable technique to prepare solid disper-
sions of poorly water-soluble drugs which have low solubility in
commonly used organic solvents and high melting points that can-
not be processed by melting and other solvent methods [128]. In
this method, a drug and carrier are completely dissolved in an or-
ganic solvent before being added to an anti-solvent which causes
simultaneous precipitation of the drug and carrier. The resulting
suspension is then filtered and washed to remove residual sol-
vents. The co-precipitated material obtained after filtration and
drying is referred to microprecipitated bulk powder (MPD) which
is a solid dispersion of the drug and carrier [129]. The polymers
used in co-precipitation method often have pH dependent solubil-
ity such as polymethylacrylate, polymethylmethacrylate, HPMCP,
HPMCAS, polyvinyl phthalate and cellulose acetate phthalate while
some solvents such as dimethylacetamide, dimethylformamide
and N-methyl pyrrolidone are mainly used due to their excellent
solvency power, particularly for high molecular weight polymers
[129]. Thanks to the poor solubility of ionic polymers in a specific
range of pH, the drug and polymer can be simultaneously precipi-
tated in water (as anti-solvent) and washed by aqueous solution to
remove residual organic solvents. The advantage of this method
compared to other methods is that it does not need elevated tem-
peratures which can cause degradation of the drug or carrier. The
solvents can be less volatile and can be washed by aqueous solu-
tion to remove organic solvents from the product [130]. Moreover,
co-precipitation method is applicable in large scale and ZelborafÒ
is the marketed solid dispersion product prepared by this technol-
ogy [131]. It is important to mention that the solvent and anti-sol-
vent mixture used in the precipitation process may act as
plasticizers resulting in high molecular mobility and crystallization
[130]. Therefore, the control of precipitation process and the selec-
tion of suitable polymer, solvent and anti-solvent are critical to the
success of final products. Dong et al. [132] used HPMC-AS to pre-
pare solid dispersions of a BCS Class II compound by co-precipita-
tion method and hot melt extrusion for comparison. PXRD results
indicated the amorphous state of the drug in both products.
Although two products have similar true densities, the co-precipi-
tation product is more porous and has a larger specific surface area
than the HME product which may explain for the faster dissolution
profile of co-precipitation product.
7.2.7. Electrostatic spinning
Electrostatic spinning (electrospinning) can be considered a
combination of solid dispersion technology and nanotechnology.
In this method, a drug–polymer solution is placed into a spinneret
connected with a microsyringe pump and a high voltage between 5
and 30 kV is applied to the needle tip to induce a charge on the sur-
face of the solution [133]. A fixed electrical potential is also applied
across a fixed distance between the spinneret and the collector
[134]. When electrical forces overcome the surface tension of the
feeding solution at the air interface, polymer jets are ejected
[135]. After coming out, the charged jets go straight for some
808 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813
distance, and then travel a spiral path because of the whipping
instability [133]. As the jet accelerates through the electric field,
the solvent evaporates rapidly to make fibers at micron or submi-
cron diameter which are collected on the screen or a spinning
mandril. The collected fibers produce a non-woven fabric, which
can be used in oral dosage forms by direct incorporation of the
materials into a capsule or by further processing such as milling
or grinding [135]. In this process, the diameter and morphology
of the filaments are affected by solution surface tension, the poly-
mer solution dielectric constant, feeding rate, the electric field
strength, tip-to-collector distance as well as some environmental
parameters such as temperature, humidity and air velocity in the
spinning chamber [134]. The main advantage of this technique re-
lates to the extremely high surface area per unit mass of fibers
which facilitates the fast and efficient solvent evaporation leading
to the formation of amorphous dispersions [136]. Therefore, the
dissolution of the API incorporated in these fibers is improved sig-
nificantly by two mechanisms: nanosizing and amorphization
[137]. Yu et al. [138] prepared PVP based solid dispersions of acet-
aminophen using electrostatic spinning and compared with other
methods. The results showed that electrospun nanofiber-based so-
lid dispersions had significantly faster dissolution profile compared
to other casting-film solid dispersions prepared by vacuum drying,
freeze drying, and heat-drying.
7.2.8. Fluid-bed coating
In this method, the drug and carrier are firstly dissolved in a
solvent. This solution mixture is sprayed through a nozzle onto
the surface of nonpareil pellet in a fluid-bed coater [139,140].
The solvent is removed by drying airflow and the co-precipitate
simultaneously deposited on the surface of nonpareil pellets
[141]. The advantage of this method is that solid dispersion
granules or pellets can be ready for tableting or encapsulating into
capsules without further handling. As showed in the researches of
Sun et al. [142], solid dispersions prepared by fluid-bed coating
demonstrated the bioavailability improvement of fenofibrate and
silymarin in vivo.
7.3. Melting-solvent method
The melting solvent method is the combination of the melting
method and the solvent method. In this method, the drugs are
dissolved in a suitable solvent and mixed with the molten carrier
followed by solvent removal and solidification to form solid disper-
sions. The advantage of this method is that the temperature and
the mixing time are lower than melting method, thus protecting
the drug from thermal degradation. In addition, the carrier in the
molten state is more easily dispersed and dissolved in the solvent
in comparison with solvent method.
A branched tree listed the preparation techniques for solid dis-
persion is showed in Fig. 1. In fact, the optimal method and tech-
nique for solid dispersion preparation was chosen based on the
physicochemical properties of drugs and carriers. In general, spray
drying and hot melt extrusion are most commonly used due to
their high scalability and applicability.
8. Characterization of physicochemical properties
The dissolution enhancement of poorly water-soluble drugs in
solid dispersions can be proven by the standard dissolution meth-
ods. Other properties of solid dispersions such as the physical
states of drugs, the drug–carrier interaction and the physical and
chemical stability of drugs should also be evaluated. Consequently,
many instrumental and analytical techniques are applied to mea-
sure these properties. The crystalline state of drugs and the degree
of crystallinity are importantly characterized. The amount of drugs
existing in amorphous state can be calculated indirectly from the
extent of crystallinity in the sample. The crystalline state of drugs
is commonly characterized by the following techniques: thermo-
analytical techniques such as Differential Scanning Calorimetry
(DSC) and Modulated Differential Scanning Calorimetry (MDSC);
powder X-ray diffraction (PXRD); Confocal Raman Spectroscopy.
Other instrumental techniques such as Fourier Transformed Infra-
red spectroscopy (FTIR), solid state nuclear magnetic resonance,
Thermal Gravimetry Analysis (TGA) are used to investigate the
chemical stability and molecular interaction of the drug and car-
rier. Microscopy techniques such as optical microscopy, transmis-
sion electron microscopy (TEM), scanning electron microscopy
(SEM) and atomic force microscopy (AFM) are also used to qualita-
tively characterize the crystalline states of drug, the molecular
miscibility, phase separation and surface morphology of solid
dispersions.
8.1. Differential Scanning Calorimetry (DSC) and Modulated
Differential Scanning Calorimetry (MDSC)
The basic principle of thermal analytical approaches is the
dynamic changes in the solid-state properties of material initiated
by the heating or cooling process. DSC, the most commonly used
thermal technique for solid dispersion characterization, provides
accurate information about melting point, glass transition temper-
ature as well as the energy changes associated with the phase tran-
sitions including crystallization and fusion process. The lack of a
drug melting peak in the DSC thermogram of a solid dispersion
indicates that the drug exists in an amorphous form. In DSC, the
glass transition endotherm, crystallization exotherm and fusion
endotherm can also be quantified and used to calculate the degree
of crystallinity [143]. For instance, Urbanetz [30] used DSC to eval-
uate the remaining amorphous content of a drug in solid disper-
sions during storage conditions. However, the degree of
crystallinity which is under 2% may not be detected by DSC [23].
DSC parameters, such as endotherm (DHtr, J/g), was also used to
predict the bioavailability of solid dispersion products by Berndl
et al. [144]. It was concluded that the solid dispersions of itraco-
nazole improved bioavailability as DHtr < 0.35 J/g and the lower
endotherm of solid dispersions obtained when the higher energy
inputted during melt extrusion process led to bioavailability
improvement.
Modulated DSC is an advanced thermal technique that can de-
convolute the different thermal events obtained from DSC. In
MDSC, a sinusoidal wave modulation is superimposed on top of
the conventional linear temperature ramp allowing the separation
of total heat flow in DSC into reversing and non-reversing thermal
transition [1]. Thermal events such as enthalpic relaxation, evapo-
ration, crystallization, thermal decomposition and some other
melting events are distributed in the non-reversing heat flow while
the reversing heat flow includes other melting events and glass
transition [145]. The application of this MDSC technique in solid
dispersion characterization has become very popular due to its
advantages such as the improvement of both sensitivity and reso-
lution, analysis of complex overlapping transitions, direct mea-
surement of the heat capacity and detection of weak glass
transitions compared to standard DSC [146]. As described by Gui-
not and Leveiller [146], MDSC method was successfully used to de-
tect and quantify low levels of amorphous phase in crystalline drug
through measurements of the heat capacity jump associated with
the amorphous phase glass transition. Ghosh et al. [145] tried to
develop a stable amorphous solid dispersion of a poorly water-sol-
uble and highly thermal sensitive compound by hot melt
extrusion. Preliminary MDSC studies showed that propylene glycol
was the most suitable plasticizer which could provide single phase
 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813
solid dispersion of the API with various polymers and also facilitate
low processing temperatures. The molecular miscibility, recrystal-
lization and phase separation of solid dispersions after preparation
and under accelerated stability conditions were characterized by
MDSC. In this study, a single Tg of solid dispersions showed
molecular miscibility and a new Tg detected by MDSC indicated
phase separation. The solid dispersion system was physically sta-
ble if no re-crystallization peaks were observed.
8.2. Powder X-ray diffraction (PXRD)
PXRD is the most widely used method to identify and character-
ize the crystalline state of drugs in solid dispersions. This method
can detect material with long-range order as well as expose sharp
diffraction peaks that indicate crystalline compound with
characteristic fingerprint region. Thanks to the specificity of the
fingerprint, the drug crystallinity can be separately identified from
the carrier crystallinity and thus can differentiate the amorphous
state and crystalline state of drugs in solid dispersions. However,
the crystallinities under 5–10% fraction may not be detected by
PXRD [23].
8.3. Fourier Transformed Infrared spectroscopy (FTIR)
FTIR is a common technique used to investigate the intermolec-
ular interaction and drug–carrier compatibility because it can
detect the physical and chemical reaction between drug and car-
rier. Hydrogen bonding between drugs and carriers which is very
important to explain the physical state and the stability of drugs
in solid dispersions can also be identified by FTIR. Miyazaki et al.
[39] studied the crystallization rates of nitrendipine (NTR) enanti-
omers in the presence of HPMC, HPMCP and PVP. FTIR results indi-
cated that PVP interacted with NTR through hydrogen bonding at
the NH moiety of NTR, and almost the same degrees of shift in
wavenumber for NH stretching suggested a similar strength of
hydrogen bonding interaction for enantiomers: ()NTR and
(+)NTR. Therefore, similar degree of physical stability between
()NTR and (+)NTR was observed in PVP based solid dispersions
whereas the overall crystallization rate and the nucleation rate of
(+)-NTR were lower than those of ()NTR in HPMC or HPMCP
based solid dispersions because of stereoselective interaction
between enantiomers and these carriers. The hydrogen bonding
between PVP and NTR also explained for the lower growth rate
of NTR crystal in PVP based solid dispersions compared to HPMC
and HPMCP based solid dispersions.
8.4. Thermal Gravimetry Analysis (TGA)
TGA is a method of thermal analysis that measures the weight
change as a function of time and temperature, thereby providing
information about the stability of a material and the compatibility
of different materials in a solid dispersion mixture. This method
can provide useful information about the stability of drugs and
carriers as well as the chemical and physical processes in solid dis-
persions to decide the preparation method and the processing
parameters for solid dispersion preparation. Other common appli-
cations in the pharmaceutical sciences include the determination
of moisture and solvent content as well as decomposition, vapori-
zation or sublimation temperatures [147]. However, this technique
is not effective for materials that do not exhibit a weight change
during degradation and some processes which do not involve the
loss of mass. Similar to DSC method, TGA results are changeable
and depend on the conditions of sample and experimental process
which is difficult to compare the work of one researcher to another
[147]. Frizon et al. [148] used TGA method to check the thermal
stability of loratadine in the temperature range of the preparation
809
process and the biocompatibility of loratadine and PVP in solid dis-
persions. The results showed that loratadine was stable up to
203 °C at which it started losing mass. The thermoanalytical curves
of solid dispersions and their components were not significant dif-
ferent, which suggested that chemical interactions accelerating
drug or polymer degradation did not occur.
Physicochemical characterization of solid dispersions is
essential to evaluate the pharmaceutical applicability of solid dis-
persions and thoroughly understand the pharmaceutical mecha-
nisms of drug dissolution enhancement and physicochemical
stability. Therefore, an ongoing development of new and advanced
characterization techniques in solid dispersion area is very
necessary.
9. Future perspectives and strategies
Solid dispersions have generated much interest from pharma-
ceutical scientists because of the increasing number of drug candi-
dates which is poorly water soluble and the recent advances on
this area. Although solid dispersions have been investigated for
such a long time, some novel carriers, additives and new prepara-
tion, characterization techniques have just been applied in recent
years. This brings new hope to develop more solid dispersion prod-
ucts in the future. Recent advances on solid dispersion area can be
divided into four main issues: (i) applying new carriers, (ii) adding
new additives such as surfactants, superdisintegrants and pH mod-
ifiers, (iii) developing novel preparation and characterization
methods, (iv) elucidating the thermodynamic mechanism of many
processes in the preparation, formulation, dissolution and storage
stage. These issues are interrelated and will be continuously inves-
tigated in the coming time.
To broaden and optimize the various carriers used in solid dis-
persions, several studies have introduced new carriers while many
other studies utilize more than two polymers as carriers to com-
bine the advantages of each polymer. Some novel carriers used in
recent years are soluplusÒ, inutec SP1 or KollicoatÒ IR. Lin et al.
[149] synthesized nano-sized flake carboxymethyl cassava starch
(CMCS) to prepare solid dispersions loading acetylsalicylic acid.
The results suggested that nano-sized CMCS based solid disper-
sions had much better dispersion capability for the drug than the
normal CMCS and micro-sized CMCS based solid dispersions. The
dissolution rate of nano-sized CMCS based solid dispersions was
considerably higher than that of pure drug. Al-Obaidi et al. [150]
investigated the impact of the third polymer on the physical stabil-
ity of drugs in binary solid dispersions. Poly[N-(2-hydroxypro-
pyl)methacrylate] (PHPMA) was added to drug–PVP solid
dispersions because it can form hydrogen bonds with drugs (gris-
eofulvin, progesterone, phenindione) while PVP cannot. The stabil-
ity results showed that the ternary solid dispersions crystallized
more slowly than binary solid dispersions. It was concluded that
the incorporation of a bridging polymer which can form hydrogen
bonds with the API and the second polymer can improve signifi-
cantly the stability of amorphous drug in immiscible binary solid
dispersions.
Many novel additives are also added in solid dispersions to
increase the solubility and the stability of API. These additives in-
clude novel surfactants, superdisintegrants, and pH modifiers
[151–153]. Szu } ts et al. [59] incorporated sucrose laurate into gem-
fibrozil-PEG6000 solid dispersions. The results showed that the
presence of the novel surfactant did not influence the solid-state
characteristics of the API significantly. The dissolution of gemfibro-
zil from the ternary solid dispersion systems was markedly im-
proved compared to the binary solid dispersion systems. It is
important to notice that two-thirds of poorly water-soluble drugs
have pH-dependent solubility. Accordingly, pH modifiers can be
810 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics 85 (2013) 799–813
proposed as a promising and important approach to improve the
solubility of such drugs in solid dispersions. Tran et al. [154]
proved that the alkalizers in PEG 6000 based solid dispersions syn-
ergistically enhanced dissolution of telmisartan, a weak acid, not
only by modulating the micro-environmental pH (pHM), but also
by changing drug crystallinity to an amorphous form via molecular
interactions. Srinarong et al. [155] showed that the dissolution rate
was more increased when the superdisintegrant was incorporated
in solid dispersions than when it was physically mixed with the
solid dispersions to prepare tablets. The dissolution rate enhance-
ment which was explained by the prevention of drug recrystalliza-
tion during dissolution process was strongly dependent on the
type of superdisintegrants.
KinetiSolÒ Dispersing (KSD) is a novel method of solid disper-
sion preparation. It is a high energy mixing process for the produc-
tion of amorphous pharmaceutical solids which uses a series of
rapidly rotating blades to process the drug and polymeric carrier
through a combination of kinetic and thermal energy without the
aid of external heating sources [156]. Dinunzio et al. [156]
prepared solid dispersions of itraconazole and hypromellose by
KSD and compared to identical formulations produced by hot melt
extrusion. Results showed that amorphous API was formed within
15 s by KSD while hot melt extrusion required over 300 s. The dis-
solution rates of compositions manufactured by KSD were also im-
proved compared to hot melt extrusion processed material. KSD
was considered a promising manufacturing technique for solid dis-
persion preparation which provided benefits over conventional
techniques in enhancing mixing for improved homogeneity and
reducing processing times. Various novel characterization tech-
niques have also been introduced to the area of solid dispersions
and showed many advantages. High performance DSC (HDSC), Pro-
ject Rapid Heat/Cool (RHC) and chip calorimetry have been applied
in solid dispersion area to overcome some shortages of DSC relat-
ing to slow cooling/heating scan which can cause sample degrada-
tion and undesired transformation to a different solid state form
[1,157]. Some thermal techniques such as nanothermal analysis
(NTA), localized thermal analysis (LTA). . .can carry out local ther-
mal analysis at defined points on a surface of solid dispersion
and map thermal properties during imaging to show drug–poly-
mer miscibility [1,158]. High resolution atomic force microscopy
was also utilized for the investigation of the solid dispersion struc-
ture and properties, providing intuitively the spatial conformation,
the interactions between the API and carrier in solid dispersions at
the molecular level [159]. This technique can even confirm directly
intermolecular hydrogen bonding within solid dispersions and was
used by Yu et al. [159] to investigate the structure and dissolution
properties of a solid dispersion containing lansoprazole and PVP.
The development of characterization techniques will help to dis-
cover the thermodynamic property and mechanism of solid disper-
sions; therefore, more strategies will be applied to overcome the
remaining problems of solid dispersions in the future.
10. Conclusions
Solid dispersions are currently considered one of the most
effective methods to solve the low bioavailability problem of
poorly water-soluble drugs. Although some problems relating to
instability and scalability still remain; novel and optimized manu-
facturing techniques with high potential to overcome these prob-
lems are being introduced, thanks to academic and industrial
researches. This review documents current efforts to overcome
these problems and discusses critical aspects for better under-
standing of solid dispersions. The deeper investigation in physico-
chemical properties and interactions of drugs and carriers as well
as the improvement of characterization techniques may help to
completely elucidate the structure and dissolution mechanism of
solid dispersions in the near future. This can lead to an optimal
selection of carriers and preparation methods for each poorly
water-soluble drug and thus will overcome the bioavailability
problems of drugs as well as the stability and scalability problems
of solid dispersions.
Acknowledgements
This work was supported by the Korean Health Technology R&D
Project, Ministry for Health and Welfare (A092018).
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