Solid Dispersion Technology As A Strategy To Improve The Bioavailability of Poorly Soluble Drugs

Review
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Solid dispersion technology as a strategy to

improve the bioavailability of poorly soluble
drugs
Alicia Graciela Cid‡ ,1 , Analı́a Simonazzi‡ ,1 , Santiago Daniel Palma2 & José Marı́a Bermúdez*,1
1
Instituto de Investigaciones para la Industria Quı́mica, Universidad Nacional de Salta – Consejo Nacional de Investigaciones
Cientı́ficas y Técnicas, Av. Bolivia 5150, Salta 4400, Argentina
2
Unidad de Investigación y Desarrollo en Tecnologı́a Farmacéutica, Universidad Nacional de Córdoba – Consejo Nacional de
Investigaciones Cientı́ficas y Técnicas, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba 5000, Argentina
*Author for correspondence: Tel.: +54 387 425 5410; Fax: +54 387 425 1006; josemariabermudez@gmail.com
‡
Authors contributed equally
Over the last half-century, solid dispersions (SDs) have been intensively investigated as a strategy to im-
prove drugs solubility and dissolution rate, enhancing oral bioavailability. In this review, an overview of
the state of the art of SDs technology is presented, focusing on their classification, the main prepara-
tion methods, the limitations associated with their instability, and the marketed products. To fully take
advantage of SDs potential, an improvement in their physical stability and the ability to prolong the super-
saturation of the drug in gastrointestinal fluids is required, as well as a better scientific understanding of
scale-up for defining a robust manufacturing process. Taking these limitations into account will contribute
to increase the number of marketed pharmaceutical products based on SD technology.
Graphical abstract:
Poorly water-
soluble drug
Solid dispersion/solution
Disintegration
(Super)saturation/colloidal particles/
fine oily globules (minor 1 µm)
Dissolution rate of drug
First draft submitted: 7 March 2019; Accepted for publication: 30 April 2019; Published online:
16 May 2019
10.4155/tde-2019-0007
C 2019 Newlands Press Ther. Deliv. (2019) 10(6), 363–382 ISSN 2041-5990 363
Review Cid, Simonazzi, Palma & Bermúdez
Keywords: bioavailability • hydrophilic polymers • melting method • poor aqueous solubility • solid dispersions •
solvent method
Solubility limitations for current therapeutics

During the development of a drug in a solid dosage form intended for oral administration, it is essential that it
has an adequate aqueous solubility to achieve high dissolution rates, and therefore, an acceptable bioavailability.
Interestingly, in recent years research and development activities have provided numerous drugs with high thera-
peutic potential, but whose use is limited by their limited aqueous solubility. On the other hand, new candidate
compounds with acceptable therapeutic activity have been generated by the advent of high-throughput screening
(HTS) and combinatorial chemistry [1,2], but among which a great number also presents limited solubility in water.
The solubility of the drug is one of the most important physicochemical properties governing the pharmacological
and biopharmaceutical profiles of its absorption, distribution, metabolism and elimination. The most frequent
rate-limiting factors for the oral absorption of drugs are poor solubility and low dissolution rates, mainly affecting
drugs with high permeability [3]. This has been pointed out as an important cause of the high clinical failure due
to poor pharmacokinetics.
The International Union of Pure and Applied Chemistry defines solubility as the analytical composition of a
saturated solution expressed as a proportion of a designated solute in a designated solvent [4]. In other words, it is
the concentration of a compound in a solution which is in contact with an excess amount of the solid compound
when the concentration and the solid form do not change over time [5]. Solubility is closely related to dissolution,
which is a kinetic process that involves the diffusion of drug molecules after their detachment from the solid
surface. The importance of the dissolution rate and, therefore, the aqueous solubility as a determining factor in
oral absorption was formally recognized with the establishment of the Biopharmaceutics Classification System in
1995 [6], which classifies drug molecules according to their solubility and permeability in order to make easier the
drug development [6]. The solubility classification of a drug in the Biopharmaceutics Classification System is based
on the highest dose strength in an immediate release product. A drug is considered highly soluble when the highest
strength is soluble in at least 250 ml (this volume is derived from typical bioequivalence study protocols) of aqueous
solution over the pH range of 1.0–7.5; otherwise, the drug is considered poorly soluble [7]. On the other hand, US
Pharmacopeia classifies the solubility regardless of the solvent used, just only in terms of quantification, into seven
categories (Table 1) [4,8].
Strategies to improve drug solubility

Different strategies can be applied to improve the oral bioavailability of drugs. One of them is based on the
fact that the therapeutic effect of drugs, when administered orally, depends on the molecules dissolving in the
gastrointestinal (GI) fluids so that they then cross the GI membrane and reach the circulatory system to reach the
target in sufficient quantity. In this sense, the increase in the rate of dissolution, the solubility of the drug, or both,
can lead to an increase in the concentration of the drugs dissolved in the GI fluids. Therefore, the ability of a drug
to remain soluble or supersaturated in the GI tract will impact on drug bioavailability. When the drug is present in
a supersaturated state, its absorption increases due to a high thermodynamic activity and flux through the intestinal
tract. The bioavailability can be compromised if the solubility of the drug in the GI fluids is not enough, being the
‘solubility limited’, or if the dissolution rate is slow, being ‘dissolution limited’, which is quite common for poorly
soluble compounds [9,10].
In this regard, pharmaceutical scientists find a great challenge regarding drugs with poor aqueous solubility.
Actually, it is estimated that between 60 and 70% of the compounds under development in the pharmaceutical
industry have limited solubility in water, a percentage that can reach up to 90% for certain categories of drugs [11].
In fact, poorly soluble compounds represent 40% of the top 200 oral drugs marketed in the USA, and the poorly
water-soluble or water-insoluble categories listed in the US Pharmacopeia account for more than one-third of the
total drugs [12].
Emergence of solid dispersion technology

Currently, different formulation strategies can be used to improve poor drug solubility, including co-solvent/solvent
evaporation, crystal habit modification (salt formation, metastable polymorphism and co-crystal formation), in-
crease of specific area by particle size reduction (nanoparticle dispersions, micronization), emulsification, surfactant
364 Ther. Deliv. (2019) 10(6) future science group

An overview on solid dispersions technology Review
Table 1. US Pharmacopeia solubility criteria.

Solubility definition Part of solvent required per part of solute Solubility range (mg/ml)
Very soluble ⬎1 ⬍1000
Freely soluble 1–10 100–1000
Soluble 10–30 33–100
Sparingly soluble 30–100 10–33
Slightly soluble 100–1000 1–10
Very slightly soluble 1000–10,000 0.1–1
Practically insoluble ⬍10,000 ⬎0.1
solubilization, cyclodextrin complexation, pH modification and adjustment, solid–solid drug dispersion, self-
amorphization and recently, the use of ordered mesoporous silica [13–15]. All these techniques seek to increase the
extension or rate of drug dissolution in order to achieve a better bioavailability. However, their success has been
often limited due to inherent problems of their efficacy or a lack of stability of the final product.
Among the different strategies mentioned, solid dispersions (SDs) have gained more attention in the last 10 years
and been intensively investigated over the last half-century for two main reasons: they provide a more significant
improvement in solubility or dissolution rate compared with traditional modification strategies of crystal habit,
and they also retard recrystallization/agglomeration of drug molecules or clusters due to molecular interactions and
steric hindrance within the carrier matrices [16]. However, the formulation of SDs also presents challenges, such as
the definition of the miscibility behavior between drug(s) and carrier polymers, the maintenance of the immediate
state after the treatment of the formulation, and the lack of adequate models that allow researchers to predict the
miscibility and stability [17].
The SDs were described for the first time in 1962 by Sekiguchi and Obi [18], who found that the rate of drug
release could be improved by the formulation of eutectic mixtures, impacting on the bioavailability of poorly
water-soluble drugs. Later in 1971, Chiou and Riegelman defined SD as the dispersion of one or more drugs in
an inert carrier or matrix in the solid state [19]. Actually, SDs are considered as single-phase mixtures of a drug
and water-soluble polymers intended to produce enhanced aqueous dissolution and oral bioavailability [20]. The
polymer has two main functions, on the one hand it contributes to the long-term storage stability of the drug
since it inhibits crystallization in the solid-state and on the other hand, it helps to maintain a desirable level of
supersaturation in the dissolution medium because it prevents the crystallization mediated by solvent.
The SDs can be used in order to improve the bioavailability of poorly water-soluble drugs with different
physicochemical properties since they allow increasing GI concentrations by rising their apparent solubility and
dissolution rate. A reduction in particle size, reduced agglomeration and improved wetting are some of the factors
contributing to the improvement of the bioavailability [21].
The use of SDs as drug delivery systems has the advantage of allowing the conformation of a molecular dispersion
between the poorly water-soluble drug and the hydrophilic carrier (amorphous or crystalline), which often improves
the dissolution behavior and supersaturation of the drug when the system enters in contact with water. This is due
to different reasons, such as a minimum particle size of the drug, a better wettability of the drug by the polymer,
the separation of the individual particles of the drug by the polymer particles, and the subsequent prevention of
drug precipitation in contact with an aqueous medium [22]. A scheme of the differences that make advantageous
the use of SDs compared with a conventional formulation like capsules or tablets is presented in Figure 1.
Although a reduction in particle size usually leads to a better dissolution rate of poorly water-soluble drugs due to
an increase in the surface area, reducing the size under the 2–5 μm range is difficult and on the other hand, during
the development of the pharmaceutical product a larger particle size is generally preferred for its ease of handling,
formulation and manufacture. In contrast, SD technology allows particle sizes as low as 1 μm, and while a part
of the drug dissolves immediately in contact with the GI fluid, producing a saturated or supersaturated solution
for rapid absorption, the rest of the drug is able to precipitate in the GI fluid in a very finely divided state. For
this reason, SDs result in a better drug absorption compared with conventional formulations, in which the drug
is in the crystalline state with larger particle sizes. Leuner and Dressman have reviewed in detail the applications
of SDs related to the improvement of the dissolution rate and oral bioavailability of drugs with limited aqueous
solubility [23].
future science group www.future-science.com 365

Poorly water-
soluble drug
Tablet/capsule Solid dispersion/solution
Disintegration Disintegration
Large solid particles (Super)saturation/colloidal particles/

(usually 5–100 µm) fine oily globules (minor 1 µm)
Dru
Drug
ug in
ug nGGII tract
tra
rac
ract
cctt
Lower Higher
LOW
dissolution Systemic drug absorption dissolution
HIGH
rate rate
Main advantage
Increased dissolution rate
Figure 1. Advantages of a solid dispersion formulation compared with conventional capsule or tablet formulations.
Considerations in the use of SDs for drug development

Over the years, the number of polymers used as carriers in the SDs reported in the literature has grown remarkably.
In the development process of SDs, the selection of the polymer is fundamental since it impacts on bioavailability,
manufacturing and stability of the final formulation. A first stage in the selection of polymers should consider the
evaluation of basic physicochemical properties of polymers, such as hygroscopicity, glass transition temperature
(Tg ), and the capacity of solid solution and solubilization, among others. Polymers can modulate the hygroscopicity
of the amorphous drug and prevent it from nucleation and crystallization. On the other hand, they help to achieve
and maintain the supersaturation state and the interactions between drug and polymer can also contribute in SD
stability due to an increase in the Tg , providing mechanical rigidity. A rational strategy for an adequate formulation
requires a deep understanding of the molecular and thermodynamic properties that influence SDs solubility and
stability [24], which include Tg , fragility, molecular mobility, thermal stability, devitrification kinetics, dissolution
profiles in organic solvents, chemical interactions and an optimal solubilization of the drug in the SD. Undoubtedly,
the dissolution of the drug is strongly influenced by the characteristics of the carrier, and while a water soluble
polymer will produce a more rapid release of the drug, a less soluble or insoluble one will produce a slower release
of the drug from the SD matrix. On the other hand, a carrier must have other desirable characteristics, such as
being pharmacologically inert and nontoxic and chemically compatible with the drug, in addition to being soluble
in several solvents if the solvent method is used for the SD preparation, or being thermostable with a low melting
point if the fusion method is selected [25].
It is important to keep in mind that the SD itself requires further formulation and processing steps to produce
a stable and effective oral solid dosage form. Therefore, an important initial goal is to produce a SD with a
minimum amount of polymer so that the required ‘dose’ of the drug and polymer combination is not so large
and does not impact on the size of the unit, influencing the type and quantities of the other excipients required
to ensure adequate manufacturing and performance. This minimization of the amount of polymer should be
such that the main function of the polymer is not lost as an inhibitor of the solid-state and solvent-mediated
crystallization. The formation of a single-phase ‘miscible’ system is fundamental for a SD to adequately play its role.
The thermodynamic principles that govern the mixing of solid materials are the same as those of liquid mixtures.
Therefore, when choosing an appropriate drug–polymer combination, the concentration of the components, their
interaction capacity, their shape and molecular size, and their degree of polarity are critical parameters [26].

Table 2. Marketed products based on solid dispersions techniques.

Trade name Manufacturer Drug Processing Polymer Dosage form SD generation
technology classification
Isoptin SRR Abbot Verapamil Hot melt extrusion HPC/HPMC Tablet 4th

Cesamet R
Valeant Nabilone Solvent evaporation PVP Tablet capsules 2nd
Sporanox
R
Janssen Itraconazole Fluid-bed bead HPMC Capsule 2nd
layering
Nivadil
R
Fujisawa Nivaldipine HPMC Tablet 4th
RezulinR † Pfizer Troglitazone Hot melt extrusion PVP Tablet 2nd
Kaletra
R
Abbot Ritonavir/Lopinavir Hot melt extrusion PVP-VA 64 Tablet 2nd
Intelence
R
Janssen Etravirine Spray drying HPMC Tablet 2nd
Zortress
R
Novartis Everolimus Spray drying HPMC Tablet 2nd

Norvir R
Abbot Ritonavir Hot melt extrusion PVP-VA 64 Tablet 2nd
OnmelR Stiefel Itraconazole Hot melt extrusion HPMC Tablet 2nd
Zelboraf
R
Roche Vemurafenib Solvent-controlled HPMC-AS Tablet 2nd
precipitation
Incivek
R
Vertex Telaprevir Spray drying HMPC-AS Tablet 2nd
Kalydeco
R
Vertex Ivacaftor Spray drying HPMC-AS Tablet 2nd
Crestor
R
Astra Zeneca Rosuvastatin Spray drying HPMC Tablet 2nd
Gris-PEG
R
Novartis Griseofulvin Melt-extrusion PEG Tablet 2nd

Afeditab CR R
Nifedipine Spray drying Poloxamer-PVP 4th
Adalat-XL
R
Bayer Nifedipine PEG 3350, HPC, Tablet 4th
Cellulose acetate
Certican
R
Novartis Everolimus HPMC, crospovidone, Tablet 2nd
hypromellose
Pro-Graf
R
Jansse-Cilag Tacrolimus HPMC, croscarmellose Capsule and injection 2nd
sodium, hypromellose
† Withdrawn from the market by the US FDA.
HPC: Hydroxypropylcellulose; HPMC: Hydroxypropylmethylcellulose; HPMC-AS: Hydroxypropylmethylcellulose acetate succinate; PEG: Polyethylene glycol; PVP: Polyvinylpyrrolidone; PVP-
VA: Polyvinylpyrrolidone-vinyl acetate.
The first SDs approaches based on polymers involved the use of polyvinylpyrrolidone (PVP) and polyethylene
glycol (PEG). The main polymers used to prepare SDs are soluble in water under all pH conditions or enteric coating
polymers containing acid groups, which ionize at higher pH values to become water soluble. However, despite
the available variety of materials, preferred polymers are generally those that have historically proven to be safe in
other pharmaceutical areas, and which are also capable of stabilizing the solid state of the drug and maintaining
supersaturation in an aqueous environment. Consequently, the most commercially marketed SD products (Table 2)
use cellulosic polymers such as hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate
succinate (HPMC-AS) and hydroxypropylcellulose (HPC), or povidones like PVP and polyvinylpyrrolidone-vinyl
acetate (PVP-VA).
The SDs as drug administration systems constitute an active and intensively sought research and development
area. In this review, we have attempted to give an overview of the state of the art of SDs technology, focusing on the
classification of SDs based on the advancement of knowledge, the main methods to prepare them, the limitations
associated with their instability, and the marketed products based on this technology.
Classification of SDs
Although the SD technology has been studied for more than half a century, its use in drug development has become
more important since the early 1990s due to the widespread application of combinatorial chemistry and HTS in
drug discovery that has favored the appearance of poorly water-soluble new chemical entities [27].
The SDs can be classified on different basis. According to the molecular arrangement, SDs can be divided into
four classes: eutectic mixtures, solid solutions, amorphous solid solutions, and glass solutions and glass dispersions.
Another approach to the classification of SDs is based on the advancement of knowledge and the complexity of
these systems [28]. In this scheme of classification, SD is categorized in first-, second-, third- and fourth-generation
SDs. Figure 2 shows the different materials used as drug carriers for the manufacture of the four generations of

Feature first generation Feature second generation
Crystalline Polymeric
carriers carriers
First generation Second generation
SOLID
DISPERSIONS
Fourth generation Third generation
Feature fourth generation Feature third generation
Mixture of surfactants and

Water-insoluble polymers polymers
Swellable polymers Mixture of polymers
Surfactants
Figure 2. Classification of solid dispersions.
SDs.
First-generation SDs
The first SD for pharmaceutical applications was reported by Sekiguchi and Obi, who prepared an eutectic mixture
with sulfathiazole using urea as carrier [18]. A eutectic mixture is a mixture of two or more components that,
although they do not interact to form a new structure, they form at certain ratios a system that solidifies at a lower
temperature than that of any of its components. The most frequently used method for preparing a eutectic mixture
is the rapid cooling of a molten mixture of the components. In such prepared solid eutectic mixtures, drugs with
limited solubility in water are usually present as very fine crystalline particles suspended in hydrophilic carriers [18].
Therefore, two factors influence on the dissolution behavior of a drug formulated in this mixture, the reduction
of the particle size and its incorporation within a hydrophilic polymeric carrier. This was the basis for the use of
SDs to improve drug dissolution. Following this concept, different polymer matrices were investigated as potential
carriers.
In 1963, the use of mannitol was reported as a carrier in SDs where the drug was present as a molecular
mixture [29]. A total of 2 years later, Goldberg et al. published a series of articles, in which it was demonstrated that
molecular dispersions could improve drug solubility and dissolution rate [30–33]. These molecular dispersions were
classified as solid solutions, and together with the eutectic mixtures were later considered as first-generation SD [28].
The carriers used for preparing first-generation SDs were usually low molecular weight crystalline compounds such
as urea and sugars including sorbitol and manitol [28]. Sugars are used less frequently, since they are poorly soluble in
most organic solvents, while urea is highly soluble in water and in many common organic solvents [34]. These SDs
produce faster release and greater bioavailability than conventional formulations of the same drugs [28]. Mohammadi
et al. prepared SDs of clarithromycin using urea as carrier by solvent, electrospraying and freeze drying methods
in three different ratios. The results showed that the SDs led to a faster drug release and improved bioavailability
in comparison with pure clarithromycin, what could then be translated in a minor dose of the drug, bringing an
economic benefit [35].
However, although the rigidity of the crystalline structure of the carriers is beneficial because it allows to kinetically
retain the drug dispersed throughout the matrix, the dissolution process is limited by the high energy needed to

dissolve the carrier itself. In addition, in these systems, the drugs are also mainly present in the crystalline state [36].
Curiously, amorphous carriers began to show clear advantages [37].
Second-generation SDs
Second-generation SDs were developed using amorphous materials exhibiting irregular short-range order as carriers.
Specifically, the polymeric carriers employed had an irregular distribution of their polymeric chains and were able
to disperse drug molecules at the molecular level. This type of formulation, where a glassy compound acts as a solid
solvent, is known as a glass solution. The presence of an amorphous polymer with a high Tg is advantageous in
terms of solubility and dissolution since it gives the glass solution the molecular conformation of a ‘frozen’ solution
at high temperature with high viscosity [38]. From a kinetic perspective, the high viscosity of glass solutions hinders
molecular movement due to the slow relaxation of polymer chains. In addition, homogeneity on a molecular
level offers maximum size reduction, which increases surface area [39]. The introduction of amorphous carriers
in SDs allowed improving the dissolution rate, compared with crystalline SDs, where the carriers present high
thermodynamic stability, lowering the dissolution process. On the other hand, carriers employed in first-generation
SDs, especially sugars, have usually a high melting point which is not adequate for preparing SDs by melting
method.
The second-generation SDs can be classified into amorphous solid solutions (glass solutions) and amorphous solid
suspensions, or a mixture of both taking into account the physical state of the drug [34]. In the case of the amorphous
solid solutions, the carrier and the drug are completely miscible and form a molecularly homogeneous mixture.
On the other hand, amorphous solid suspensions consist of dispersions in which two phases are present, one of the
amorphous drug and another of the amorphous carrier, either because they have limited miscibility, or because of
drug supersaturation inside the matrix [14]. Both in glass solutions and in amorphous suspensions, the solubilization
of the drug in the matrix polymers is forced at a high concentration (e.g., by HME [40] or lyophilisation [41]),
resulting in an oversaturation state which has as a disadvantage a high tendency to recrystallization when cooled
after processing or during storage. For this reason, it is desirable that the polymeric carrier be highly miscible with
the drug in order to inhibit recrystallization during drug release or storage [42]. Thermal analysis is the technique
most frequently used to evaluate the miscibility of drugs and polymers [41]. Although many investigations have
been carried out on techniques to predict drug-polymer solubility and miscibility, there are still some limitations
associated with methods that are currently being used [43–48].
Amorphous carriers improve the solubility and dissolution rate of the drug since they cannot only increase the
wettability and dispersibility of drugs, and inhibit the precipitation process but also due to the rapid dissolution
rate because of their low thermodynamic stability [49]. The amorphous carriers that are used to prepare this type
of SDs can be classified into polymers of complete synthesis and polymers based on natural products. The first
group includes PVP, PEG, crospovidone (PVP-CL), PVP-VA and polymethacrylates. Polymers based on natural
products are composed of cellulose derivatives such as HPMC, HPC, HPMC-AS and hydroxypropylmethylcellulose
phthalate (HPMC-P), starch (corn starch, potato starch) and sugars as trehalose, sucrose, and inulin. Among all
the polymers mentioned, HPMC, PEG and PVP are the most commonly used [28,50–52].
Recently, Suzuki et al. prepared amorphous SDs of meloxicam using HPMC and polyacrylates and polymethacry-
lates as carriers. On the basis of the results obtained, meloxicam in both amorphous SDs formulations was mainly
presented as an amorphous material, leading to an improvement in the dissolution behavior of the drug. Both SDs
formulations of meloxicam exhibited much better dissolution behavior than crystalline meloxicam. Both prepared
SDs showed significant improvement in dissolution behavior of meloxicam at gastric pH value, whereas only
orally taken SDs of meloxicam using HPMC as carrier exhibited much greater systemic exposure of meloxicam as
compared with crystalline meloxicam [53].
Chlortetracycline hydrochloride SDs using hydrophilic polymers like PVP and copovidone were prepared using
different methods by Apiwongngam et al. Physicochemical properties and antimicrobial susceptibility were evaluated
for the obtained SDs. Authors found that spray drying was the most successful method of preparation. Interestingly,
SDs increased almost tenfold chlortetracycline hydrochloride solubility, what can be probably explained by the
amorphous nature of the SDs observed, suggesting the occurrence of intermolecular interactions. Moreover, SDs
maintained the microbiological effectiveness of the drug [54].
Second-generation SDs were also prepared to carry posaconazole and benznidazole by the solvent evaporation
method using water-soluble carriers as PVP K-30 and PVP-VA 64. Results from in vitro dissolution tests showed that
the PVP-VA was the most effective vehicle for the combination of 50:50 fixed doses of both drugs to increase their

solubility and the dissolution rate. Physicochemical characterization revealed that exists a threshold drug loading
level at about 30% of both drugs below which SDs are obtained and above which a certain degree of crystallinity
tends to result. Thus, the obtained SD combines two synergistic antichagasic agents stabilized in the PVP-VA
matrix in amorphous form and enhances the dissolution behavior, potentially improving their bioavailability and
therapeutic activity in Chagas disease treatment [55].
Third-generation SDs
Advances in the development of this pharmaceutical area have conducted to the formulation of third-generation
SDs incorporating polymers with surfactant properties or a mixture of amorphous polymers and surfactants [56,57].
These SDs are designed to obtain the highest degree of solubility enhancement and to prevent morphological
changes during administration and storage [58]. The third-generation SDs are like the previous generation and
amorphous dispersions, but the surfactant nature of the carriers allowed to improve the SDs behavior by enhancing
dissolution rate, improving stability and preventing precipitation under supersaturation [51].
Surfactants or emulsifiers are used as carriers themselves or as process adjuvants and additives to improve
the biopharmaceutical performance of the supersaturation systems, the physical and chemical stability, and the
dissolution profile of the drug. Moreover, the miscibility of the drug and the carrier, and the prevention of
drug recrystallization can also be improved by the use of surfactants with an amphiphilic structure [34,59]. In
addition, the surfactants or emulsifiers increase the wettability of the drugs and prevent the precipitation thereof
due to supersaturation by absorbing the outer layer of the drug particles or forming micelles to encapsulate the
drugs [49,51]. Dissolution rate as well as bioavailability degree, and stability are increased mainly due to the inclusion
of surface activity [34].
The most commonly used surfactants are gelucire 44/14, compritol 888 ATO, poloxamer and inutec SP1.
Other surfactants and emulsifiers that have been also used as additives in SDs include sucrose laurate, Tween 80,
D-α tocopheryl polyethylene glycol 1000 succinate and sodium lauryl sulfate among others [51]. The use of inutec
SP1, compritol 888 ATO, gelucire 44/14 and poloxamer 407 as carriers was shown to be effective in originating
high polymorphic purity and enhanced in vivo bioavailability [28,60].
An example of third-generation SDs was the one prepared by Tambe and Pandita [61] to enhance the solubility and
dissolution of boswellic acids (BAs) using poloxamer 188 and 407 as hydrophilic polymeric carriers by kneading and
solvent evaporation methods. Phase solubility studies revealed that both poloxamers acted as solubility enhancers
for BAs. On the other hand, in vitro drug release studies of acetyl-keto-β-boswellic acid from the SDs showed an
improved release performance. The SDs based on poloxamer 188 were able to release more than 84% of the drug
within 1 h at pH 6.8, whereas the acetyl-keto-β-boswellic acid released from a BA extract was found to be 35%
at the end of 8 h. While poloxamer 188 SDs were able to achieve highest solubility and release in the 1:2 ratios,
poloxamer 407 SDs showed better results with 1:1 ratio. Comparing the methods of synthesis, kneading was found
to be superior over solvent evaporation for both poloxamers. These results suggest that SDs could possibly help in
enhancing BAs oral bioavailability [61].
Pyrimethamine SDs were prepared by Khatri et al. using different carriers by solvent evaporation technique.
Intrinsic dissolution studies demonstrated that the dissolution rate of pyrimethamine SD using poloxamer 188 as
carrier at a ratio of 1:3 could be markedly improved. Furthermore, stability studies indicated no significant change
in the physical nature of pyrimethamine in SD up to 5 months [62].
Another interesting approach was performed by Jiménez de los Santos et al., who evaluated the role of gelucire
50/13 as carrier in albendazole SDs prepared by the fusion method. Solid-state characterization techniques indicated
that there was no miscibility, and there were no interactions in the solid phase. In vitro studies showed that SDs could
be an alternative to improve bioavailability and to reduce the dosage of the currently marketed formulations [63].
On the other hand, Tran et al. studied the effect of adding polyethylene oxide (PEO) to a third-generation SD of
aceclofenac, gelucire 44/14, poloxamer 407 and pH modifier (Na2 CO3 ). The authors observed that the immediate
release SDs containing the pH modifier greatly enhanced the drug dissolution rate to approximately 100%, while
the presence of PEO in the SD allowed a controlled release of the drug [64].
Fourth-generation SDs
The SDs belonging to the fourth-generation were developed as controlled release dispersions [49] due to a need
to improve the performance of drugs that are poorly soluble in water with a short biological half-life and/or a
narrow therapeutic margin. The fourth-generation SDs improve the solubility of the poorly water-soluble drug while

delaying the release of the drug in the dissolution medium due to the use of water insoluble or swellable polymers [34].
These dispersions allow an adequate amount of drug to be administered over a prolonged period of time and offer
advantages such as better patient compliance due to a decrease in dosing frequency, lesser development of side
effects and prolonged therapeutic effect for poorly water soluble drugs. The mechanisms by which the drug can
be released in fourth-generation SDs are diffusion and erosion [49,51]. To prepare fourth-generation SDs, polymers
such as ethyl cellulose, HPC, Eudragit R
RS, RL, poly(ethylene oxide), carboxyvinylpolymer (Carbopol R
) and
R
Soluplus can be used.
This strategy was used by Guo et al. [65] to prepare berberine hydrochloride SDs using Eudragit R
S100 as
carrier by the solvent evaporation method. The ratio of drug and polymer was optimized to 1:4 and the SDs were
characterized. Results showed that berberine hydrochloride and Eudragit R
S 100 interacted to form a new complex
in amorphous form and in vitro cytotoxicity studies indicated the SD demonstrated lower IC50 values than free
berberine hydrochloride. Authors concluded that the SD improved berberine hydrochloride efficacy, providing a
basis for further development of berberine hydrochloride as a potential new candidate for colon cancer therapy and
prevention.
Another study on SDs based on Soluplus R
as carrier was conducted by Shamma et al. [66]. Authors investigated
the applicability of different industrially scalable techniques in the preparation of carvedilol SDs by solvent
evaporation, freeze drying and spray drying in different drug: carrier ratios. The highest saturation solubility value
was obtained for the SD prepared by freeze drying method at 1:10 ratio. Solid state characterization indicated the
complete transformation of the drug in the SD from crystalline to an amorphous state. Selected carvedilol SD
was further incorporated into an orodispersable tablet. Authors concluded that the development of carvedilol SDs
using Soluplus R
as orodispersable tablets could be used as a promising approach for improving the solubility and
oral bioavailability of poorly water-soluble drugs.
Drug release from SDs

Drug release mechanism from SDs is complex and depends on the nature not only of the drug dispersed in the
matrix but also of the polymer serving as carrier [67]. Because of such complexity, the development of a biorelevant
in vitro dissolution testing method becomes even more complicated. The variability in physiological factors and in
dosage forms makes difficult to establish an in vitro/in vivo correlation.
The dissolution test is the standardized method for scientific and regulatory purposes that is used to determine
the rate of solubilization or release of a drug from solid oral formulations and other dosage forms. Knowing and
controlling this rate is of utmost importance when the release of the drug is the limiting step of the absorption rate
and the pharmaceutical effect, since it can result in variations in bioavailability and safety or efficacy problems. The
dissolution test allows to assess the most important attributes of the components of the formulation (active agent
and excipients), and also serves to evaluate the manufacturing process, as well as the physicochemical changes of
the pharmaceutical product during storage or subjected to aging or stress. In the case of formulations containing
amorphous SDs, the in vitro dissolution performance of the drug is influenced by the carrier dissolution properties
and behavior. Therefore, drug release can be manipulated by polymer properties, including the type of polymer and
its molecular weight, particle porosity and wettability. When a dissolution study is carried out to test the particle
size of the released drug, the simulated gastric fluid or simulated intestinal fluid (the one with the lowest solubility
capacity for the drug) can be selected as dissolution medium, or even purified water as another alternative. Although
the drug would not dissolve in such a dissolution medium, the in vivo performance can be correlated with the
particle size of the released drug and the formulation concentration.
The Noyes and Whitney [68] and the Nernst models [69] are usually used to describe the dissolution rate of a solid,
but they cannot be extended to more complex systems, such as two-component systems or binary mixtures. In this
regard, Higuchi et al. [70] developed a theory for the dissolution rate of polyphase mixtures and applied it to several
cases, stablishing relationships to describe experimental data, based on physical models involving simultaneous
diffusion and rapid equilibria.
An interesting model that can lump together both diffusional and polymer relaxation steps present in drug
release process was proposed by Fernández-Colino et al. [71] and validated later by Romero et al. [72]. It was used
to fit experimental data obtained from dissolution profiles of SDs of albendazole [73] and benznidazole [74] using
poloxamer 407 as carrier, reaching good correlation coefficients (R2 > 0.90), and allowing to easily estimate different
parameters of pharmaceutical relevance.

Spray drying KinetiSol
Fluid bed
granulation/
Coprecipitation
layering/
film coating
Milling
Melt extrusion (Biorise™)
Solvent- Fusion-
based based
methods Supercritical methods
Rotating jet fluid-based
spinning technologies
Melt Deposition
Cryogenic granulation (Meltdose™)
Electrospinning
processing
Figure 3. Commonly used processing technologies in the manufacture of solid dispersions.
Deep analysis about the theories of the carrier- and drug-controlled dissolution of SDs was critically assessed by
Craig [67] who proposed a model to describe the release behavior of the drug from the SD considering that it can
be carrier- or drug-controlled. The process begins with the formation of a polymer-rich diffusion layer between the
dissolution medium and the SD. When the dissolution is mediated by the carrier, the drug diffuses first into this
polymer-rich layer, and later it is released into the dissolution medium either as solvated molecules or as amorphous
particles at a rate controlled by the carrier. On the other hand, when the dissolution rate is controlled by the drug,
the polymer-rich phase is not formed due to the high solubility of the carrier in the dissolution medium and the
drug is dissolved directly through diffusion from the dispersion to the dissolution medium at a rate dependent on
the aqueous solubility of the drug.
The drugs present in the SDs can form supersaturated solutions which can precipitate over time. Depending
on the particle size of the precipitate, the drug could redissolve during GI transit, increasing its bioavailability.
Determining the nature of the precipitated drug, that is, its morphology and physical form should be helpful when
assessing the in vivo performance of SDs [56].
Methods for SD preparation

As reviewed by Serajuddin [22], one of the main challenges in the development of SDs is the need for adequate
manufacturing techniques that can be extended to commercial production. The commercial-scale manufacturing of
SDs has received significant attention over the past decade, and various techniques became available for large-scale
manufacturing.
The two methods most widely described in the literature for SDs preparation are solvent evaporation and melt
extrusion (fusion-based method). A scheme showing the different alternatives involved in these methods are shown
in Figure 3.
Figure 4 shows the rising number of published articles using different keywords ‘solid ‘solid dispersion and spray
drying’, ‘solid dispersion and hot melt extrusion’ in two databases (PubMed and Science Direct) in the period from
2008 to 2018, illustrating the increasing scientific interest in this technology.
Despite the fact that among solvent evaporation methods, spray drying remains an important technology and is
the most studied at the research level, industrially the technological list is led by hot-melt extrusion (HME) with
high commercial success. This is mainly explained by the specific advantages of the HME process, such as the
possibility of a continuous mode of operation, modularity, solvent-free process and ability to produce an almost
final product.
Melting methods
Among the advantages of melting techniques, they are less expensive than solvent evaporation methods, the
equipment involved has a smaller footprint, no solvents are required, and they can be coupled at one stage in

500
Number of published articles
400
300
200
100
0
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Years
Hot melt extrusion Spray drying Solid dispersions
Figure 4. Articles published using as keywords ‘solid dispersion’, ‘solid dispersion and spray drying’, and ‘solid
dispersion and hot melt extrusion’ in two databases (PubMed and Science Direct) in the period from 2008 to 2018.
a continuous process, what is of great importance since the pharmaceutical industry is increasingly focused on
the speed and efficiency of continuous over batch processing [75,76]. However, some limitations must be taken
into account in order to apply this method. At first, it is necessary that the drug not only exhibits sufficient
thermostability at the process temperature but also be miscible with the co-melting polymer. Noteworthy, the
polymer has also to be selected considering its thermostability. If the drug and the carrier are not compatible,
phase separation can occur which will result in a nonhomogeneous product. This problem can also occur during
cooling [51].
Besides that, the molten polymer provides a medium in which the drug is either solubilized or dispersed during
melting processing, stabilizing the amorphous form. To prepare a SD by this method, the drug and the carrier must
be melted together at a temperature above the eutectic point of the mixture, and then the homogeneous mixture is
cooled and solidified. The resulting solid is pulverized and sieved. Alternatively, the homogeneous mixture can be
injected into dosage forms before cooling, avoiding the grinding process [49]. Another modification of the fusion
method consists in dispersing the drug in the previously melted carrier, thus reducing the temperature of the
process [28]. To cool and solidify the molten mixture, different alternatives can be used such as stirring in an ice
bath [77], spreading on thin layer of stainless steel cooled by air or water [36], putting the samples in a desiccator [78],
immersing in liquid nitrogen [79], spreading on plates placed over dry ice [80] and spray freezing [81].
To overcome the limitations of this method, some variants were proposed, such as HME [82], Meltrex™ [83] and
melt agglomeration [84], Melt-Dose R
and Lidose R
[49].
Although numerous patents and research papers on HME in the pharmaceutical field have been published since
the 1980s [85], extrusion technology is a highly developed platform widely used in the polymer and food industries.
Extrusion is used to make various plastic products, such as plastic bags, pipes, electrical cables and medical tubes,
among others. In the pharmaceutical area, HME is used in the processing of products designed to favor oral
absorption and sustained release [86] and targeted release [87,88].
The HME is a continuous melt-fabrication process [89], through which one or more drugs are mixed with at
least one molten excipient in an extruder, giving an extruded product (or HME product) where the drug may be
in its crystalline or amorphous state. This method involves the mixing of the drug and the carrier, its subsequent
heating, melting, homogenization, and extrusion in the form of rods, tablets or granules, or grinding and blending
with other excipients. The drug particles in the molten polymer completely disintegrate due to the intense mixing
and forced agitation by the rotating screw, producing a homogeneous dispersion [34]. Taking into account that

carriers should be selected such that they do not degrade at such elevated temperatures and pressures, polymers
such as PVP, HPMC, polymethacrylate polymers (e.g., Eudragit EPO), poly(ethylene oxide) PEO, HPMC-AS,
were successfully used during HME in the preparation of SDs.
In order to avoid the risk of drug or carrier alteration at elevated temperatures, a modified technique reduces the
time for heating by dispersing the drug in the molten carrier instead of heating both of the components to obtain
the molten mixture. Two processes that employ this adaptation were patented, one called MeltDose R
by Lifecycle
R
R
Pharma A/S and the other, Lidose by SMB laboratory. The MeltDose technology consists in spraying a ‘melt’
solution of the active drug onto an inert particulate carrier using a patented nozzle, which is the originality of this
process. The obtained particles solidify into a state of solid solution, and the resulting granulate can be compressed
into tablets or capsules. On the other hand, the Lidose R
technology is based on a drug delivery system formed by
a hard capsule, containing the drug melted together with the carrier and then cooled under specific conditions.
Another patented process also based on the fusion method is Meltrex™. In this technology, a special twin screw
extruder and independent hoppers are used where the temperature can be different [28]. In the melt agglomeration
process, a high shear mixer is used and the mixture can be prepared in different ways. An alternative is to add a
molten mixture of the carrier and the drug to the excipients that are under heating. The molten carrier can also be
added to a mixture of drugs and excipients while heating or a mixture of the drug, carrier and excipients can be
heated to a temperature close to the melting point of the carrier [49].
Solvent method
In SD development, it is essential to eliminate the crystallinity of the drug. This requirement can be achieved by
dissolving it in a suitable solvent. Although a pure amorphous drug can sometimes be obtained, a polymer that
stabilizes the amorphous state of the drug through physicochemical and mechanical interactions is generally used
during processing. The solvent method consists of a first stage in which the drug and the carrier are solubilized in a
volatile solvent, and in its subsequent evaporation at low temperature, minimizing the risk of thermal decomposition
of both the drug and the carrier [28], to obtain as a result a SD [90].
The design of a SD formulation process obtained by solvent evaporation involves the selection of the solvent first,
then the polymer and additives, and finally the evaporation method. Normally, the choice between the different
alternatives available depends to a large extent on the solubility of the drug in organic solvents.
One of the disadvantages of this method is that the complete elimination of the solvent is almost impossible, and
the remains of it in the dispersion after evaporation can cause toxicity. Other disadvantages are the environmental
problems, the high cost of production and the protection against explosions, and low scalability [34]. This method
requires a sufficient solubility of both the drug and the vehicle in the solvent or co-solvent, what makes it difficult
to search a suitable nontoxic solvent since the carriers are usually hydrophilic while the drugs are hydrophobic [51].
Different methods were developed for fast solvent removal, such as heating on a hot plate [91], vacuum drying [92],
rotary evaporation [93], freeze drying [94], spray freeze drying [95], spray drying [96], ultra rapid freezing [97] and the
use of supercritical fluids [98].
One of the widely used methods for solvent evaporation is spray drying [99,100], which consists in solubilizing
the drug in an organic solvent (also aqueous or a mixture) with low boiling temperature, and spraying the material
through a high-pressure or two-fluid nozzle at a temperature above the solvent’s boiling point. The addition
of polymers in the dispersion helps to stabilize the material, preventing recrystallization, as well as improving the
solubility. Spray drying can be fully automatized under a continuous mode of operation and adapted to the different
capacities that may be required by the pharmaceutical industry. The selection of the scale depends mainly on the
performance of the target process and the lot size requirements.
In the last 20 years, the technology of supercritical fluids (SCF) has been widely studied by pharmaceutical
researchers because it offers promising options in the development of drug delivery systems, such as in the design
of nanoparticles and SDs, among other applications. The SCF have the advantage that they are highly versatile due
to their properties similar to liquids and gases, allowing the solubilization of compounds employing low amounts
of solvents. In the preparation of SDs, SCF can fulfill the function of solvent or antisolvent, according to the
properties of the drug and the polymer. There are numerous types of applications where SCF can be introduced
in the development of SDs. For example, they can be used during processing in HME technology, reducing the
viscosity of the melt, lowering the processing temperature and increasing the solubility of the drug in the molten
polymer, thereby improving the dissolution and compression properties. On the other hand, SCF can also be used
in spray drying technology, acting as an extraction solvent to extract residual solvents from the material.

The versatility of the SCF technology has allowed new alternatives to emerge over the years, oriented mainly
to particle engineering, such as supercritical antisolvent precipitation [101], rapid expansion of supercritical solu-
tions [102], precipitation with compressed fluid antisolvent [103], gas antisolvent precipitation [104], precipitation
from gas-saturated solutions [105] and solution-enhanced dispersion by supercritical fluids [98,106].
Although there are numerous articles related to the use of SCF in applications related to particle engineering,
they are still limited in the area of SD design. Varshosaz et al. [107] used the rapid expansion of supercritical solutions
technology to prepare amorphous particles containing cefuroxime axetil. A similar work was carried out by Pathak
et al. [108] in the vehiculization of ibuprofen and indomethacin. Regarding SAS techniques, they were used to
prepare SDs of rifampin [109], itraconazole [110] and amoxicillin [111].
As already mentioned, the solubility of the drug and the polymer are key to properly select the SCF technology
in the development of SDs, with the supercritical CO2 being the most commonly used SCF. In some cases, it
may also be necessary to incorporate excipients in the formulation in order to achieve a desired particle size and
morphology and thereby improve the dissolution rate of the drug.
Another interesting approach is based on the combination of the solvent and fusion methods. This alternative
consists of dissolving the drug in an appropriate solvent, which is subsequently mixed with the molten polymer
vehicle. In the next step, the solvent is removed, obtaining a solid form. This method allows operating at lower
temperatures and shorter times, compared with the fusion method, avoiding the thermal degradation of the drug
and the polymer [51].
SDs limitations
Despite the many advantages of SDs in pharmaceutical development, the successful administration of a SD dosage
form still remains a challenge because being in a metastable state SDs have the intrinsic tendency of spontaneously
reverting to a more stable crystalline state due to both thermodynamic and kinetic driving forces. Any physical
instability that leads to phase transformations may result in poor performance of dosage forms, including changes
in dissolution rates and oral bioavailability. On the other hand, since the drug is either molecularly dispersed or
mixed with the carrier, there is a possibility of greater chemical interaction between them. For all these reasons,
both chemical and physical stability must be conveniently evaluated to assure it during process and aging of SDs.
Chemical instability
The SD preparation usually involves treatments at high temperature, so thermal degradation of high sensitive
drugs may occur [112]. Another common chemical stability problem presented by SDs is the formation of reactive
intermediates (e.g., peroxides) secondary to excipient degradation [113,114], leading to changes in dissolution rate
and thus, in drug bioavailability. For these reasons, careful monitoring of the stability of not only the drug but
also of the carriers and excipients used in SDs is needed during stressed stability studies to ensure adequate drug
stability and reproducible performance of a product during shelf life.
A suitable drug-excipient compatibility screening technique such as the one described by Serajuddin et al. [22]
may be applied to identify any potential incompatibility between drug and carrier or any other agents used in the
formulation.
Physical instability
The physical instability of SDs due to crystallization of drugs was widely described by many authors [22]. In SDs
not only the drug but also the polymer can be present in different states, for example, a part of the drug can be
molecularly dispersed in the carrier forming a solid solution while the excess of the drug can crystallize out, form
a supersaturated solution or separate out as an amorphous phase, which both can also crystallize out overtime. On
the other hand, the carrier can also undergo changes during aging since it may be present in a thermodynamically
unstable state. Physical instability in SDs generally leads to drug crystallization during storage, which is usually
manifested by a decrease in drug dissolution rate. Such drug crystallization is more prominent in the presence
of moisture, which enhances the molecular mobility [115,116] and thus, it is a major concern during storage of
amorphous pharmaceutical products [117]. It should also be considered that polymers used in SDs usually can
absorb moisture, what would lead to phase separation, loss of amorphous state or crystal growth, resulting in
decreased dissolution rate and solubility [118].
Improving physical stability of SDs has been a subject of discussion for many years [119]. There are two main factors
that impact on the physical stabilization of amorphous SDs: interactions between drug and polymer molecules and

molecular mobility. In general, inhibition of crystallization is affected by more than one factor. Different phenomena
are involved in the stabilizing capacity of a polymer, such as its ability to decrease molecular mobility, increase
the Tg , stabilize the drug–polymer interactions and interrupt the drug–drug molecular interactions. Moreover,
the stability of amorphous dispersions is also influenced by the intrinsic tendency of the pure amorphous drug to
crystalize [120]. Drug–polymer interactions, such as hydrogen bonding, hydrophobic interactions and in some cases
ionic interactions, are fundamental in amorphous SDs stabilization. On the other hand, the presence of a polymer
usually limits the mobility of the drug molecule, decreasing then the crystallization tendency. The Tg is also related
to the mobility of a material and the relative strength of adhesive and cohesive interactions. The addition of a
polymer with high Tg increases the glass transition of the system and may help in the stabilization of an amorphous
SD [121,122].
Other factor influencing the stability of the amorphous SD is the extent of drug–polymer miscibility. Systems
containing drug–polymer mixtures are considered miscible if they have a single Tg . More than one glass transition
represents phase separation, resulting in a less stable system. The formation of single or multiple phases depends upon
the initial concentration of drug and the nature of the drug–polymer interaction. Drug–polymer miscibility allows
to predict the physical stability of drug–polymer mixtures and can be measured by various techniques including
Flory–Huggins interaction parameter, solubility parameters, Tg measurements by DSC, computational analysis of
x-ray diffraction data, solid state nuclear magnetic resonance spectroscopy and atomic force microscopy [47,123].
Commercial products based on SDs

Over time, SD technology evolved and was not limited only to the laboratory scale, but the commercial production
of water-insoluble drugs was developed using this technique. It should be noted that the process of US FDA
approval of drug products based on SDs is simpler than that of a new drug entity, since in general, SDs are
designed to improve the bioavailability of previously approved generic drugs with aqueous limited solubility, whose
safety and efficacy have already been established [124]. Polymers or matrix formers are the major ingredients of
SD formulations and so, they should also meet regulatory requirements. The most commonly used carriers are
food or pharmaceutical-grade materials and classified ‘Generally Regarded As Safe’ by the FDA. Based on these
considerations, the most important difference in the FDA approval process for SDs compared with new drugs is
that clinical and preclinical trials are usually not required.
Due to the different problems related to the preparation, formulation, and stability of the final product, the
amount of commercial products based on the SD technique is not large, despite its various advantages. Table 2
presents a complete list of commercial products that use SD techniques [10,34,125,126].
Commercial products based on SDs are generally administered by oral route as coated and non-coated tablets
or as capsules, either soft or hard. They can be used in the treatment of different diseases, either alone or in
combination with other drugs or drugs delivery systems. For example, Sporanox R
, OnmelR
and Gris-PEG R
are
used as antifungals, whereas Isoptin SR , Nivadil , Afeditab CR and Adalat-XL are indicated for the treatment
R R R R
of heart conditions, such as hypertension and angina pectoris. On the other hand, Cesamet R
is used as antiemetic
R
before the administration of chemotherapeutic agents and Pro-Graf is recommended after transplants to reduce
the risk of organ rejection. Interestingly, Kaletra R
, IntelenceR
and Norvir R
are indicated in combination with
other antiretroviral agents for the treatment of HIV. Another product based on SDs is Kalydeco R
, indicated for
cystic fibrosis, which is available in different presentations, like tablets for adults and granules for children, and can
be used as monotherapy or combined with other therapeutic agents.
While the pace of new product launches using SD technology has increased in recent years, amorphous dispersions
present certain risks and require certain considerations unlike crystalline drugs. Their used is limited in commercial
products, mainly because of crystallization risks during processing or storage [41,118]. Therefore, for the complete
exploitation of SDs, their stabilization and a sound scientific understanding of scale-up for defining a robust
manufacturing process are still necessary.
With the successful advance in research and a better understanding of SDs, an increase in the number of drugs
formulated as a SD is expected in the coming years. Studies on SDs are a guarantee to continue since almost
60–70% of the new chemical entities have a limited solubility in water, and more drug compounds formulated as
SDs will reach the pharmaceutical market in the future.

Conclusion & future perspective

Over the past two decades, the pharmaceutical industry has made significant progress in the field of the drug
discovery and design that has led to a number of potential drug candidates with poor or limited solubility and,
therefore, limited bioavailability. An adequate aqueous solubility of new drugs is one of the key properties required
for the successful development of a pharmaceutical formulation. The SDs have clearly demonstrated, in many
cases, advantages to enhance the dissolution rate and absorption of drugs.
The SDs are currently considered as an effective method to improve the low bioavailability of poorly water-
soluble drugs; however, decades of research has only resulted in a handful of marketed pharmaceutical products.
The main reasons for the low transfer of this technology to market are explained by their physical instability during
manufacturing, storage and dissolution, and by the lack of accessibility of commercially available manufacturing
facilities.
Technical challenges involved in the development of SDs as a drug delivery technology are related to the
preparation method, the processing capacity of the material and the variability of the dosage form. Through an
adequate selection of materials and formulation, SD technology can be applied to a wide range of compounds
with different physicochemical properties. The preparation of SDs may become easily achieved at both laboratory
and large scales along with the advances in the development of novel manufacturing process technologies such as
HME, spray drying and freeze-drying technologies. However, these technologies are limited to thermally stable
drug molecules or compounds soluble in volatile organic solvents.
Advances in improving the physical stability of SDs and the ability to prolong the supersaturation of the drug in
GI fluids are the two main drivers to increase the future application of SDs. Taking these limitations into account
in the development plan of these materials will contribute to increasing the number of marketed pharmaceutical
products based on SD technology.
Executive summary
• Among the different strategies to improve drugs solubility and dissolution rate, solid dispersions (SDs) have
gained more attention in the last 10 years and been intensively investigated over the last half-century.
Classification of solid dispersions
• Based on the advancement of knowledge and the complexity of these systems, they are categorized in first-,
second-, third and fourth-generation SDs.
Drug release from solid dispersions
• The release behavior of drugs from SDs can be either carrier- or drug-controlled, or their interaction.
Methods for solid dispersions preparation
• The methods used to prepare SDs are based on solvent evaporation and melt extrusion technologies.
Solid dispersions limitations
• The main disadvantage of SDs is their physical instability since the drug tends to recrystallize due to both
thermodynamic and kinetic driving forces.
Commercial products based on solid dispersions
• Despite the numerous advantages of SDs, decades of research have only resulted in a handful of marketed
pharmaceutical products.
Conclusion & future perspective
• The exploitation of the full potential of SDs requires an improvement in their physical stability and the ability to
prolong the drug supersaturation in GI fluids, and a better scientific understanding of scale-up for defining a
robust manufacturing process.
Financial & competing interests disclosure

Authors would like to thank for the financial support to Agencia Nacional de Promoción Cientı́fica y Tecnológica (ANPCyT)
(grant number PICT 2012-2643) and Consejo de Investigación Universidad Nacional de Salta (CIUNSa; grant numbers 2199, 2398
and 2392). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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Solid Dispersion Technology As A Strategy To Improve The Bioavailability of Poorly Soluble Drugs

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Solid dispersion technology as a strategy to

Dissolution rate of drug

Solubility limitations for current therapeutics

Strategies to improve drug solubility

Emergence of solid dispersion technology

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Table 1. US Pharmacopeia solubility criteria.

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Tablet/capsule Solid dispersion/solution

Large solid particles (Super)saturation/colloidal particles/

dissolution Systemic drug absorption dissolution

Considerations in the use of SDs for drug development

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Table 2. Marketed products based on solid dispersions techniques.

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Feature first generation Feature second generation

First generation Second generation

Fourth generation Third generation

Feature fourth generation Feature third generation

Mixture of surfactants and

Figure 2. Classification of solid dispersions.

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Drug release from SDs

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Spray drying KinetiSol

Figure 3. Commonly used processing technologies in the manufacture of solid dispersions.

Methods for SD preparation

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Hot melt extrusion Spray drying Solid dispersions

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Commercial products based on SDs

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Conclusion & future perspective

Financial & competing interests disclosure

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