Hindawi

Advances in Pharmacological and Pharmaceutical Sciences

Volume 2022, Article ID 5916013, 17 pages
https://doi.org/10.1155/2022/5916013

Review Article
Current Trends on Solid Dispersions: Past, Present, and Future

Ruba Malkawi ,1 Walla I. Malkawi,2 Yahia Al-Mahmoud,1 and Jawad Tawalbeh3

1
School of Pharmacy, Jadara University, P.O. Box 733, Irbid 21110, Jordan
2
School of Pharmacy, Iowa State University, Ames, IA 50011, USA
3
School of Business, Teesside University, Campus Heart, Southfield Rd, Middlesbrough TS1 3BX, UK

Correspondence should be addressed to Ruba Malkawi; [email protected]

Received 12 July 2022; Revised 10 August 2022; Accepted 21 September 2022; Published 22 October 2022

Academic Editor: Srinivas Mutalik

Copyright © 2022 Ruba Malkawi et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Solid dispersions have achieved significant interest as an effective means of enhancing the dissolution rate and thus the bio-
availability of a range of weakly water-soluble drugs. Solid dispersions of weakly water-soluble drugs with water-soluble carriers
have lowered the frequency of these problems and improved dissolution. Solid dispersion is a solubilization technology em-
phasizing mainly on, drug-polymer two-component systems in which drug dispersion and its stabilization is the key to for-
mulation development. Therefore, this technology is recognized as an exceptionally useful means of improving the dissolution
properties of poorly water-soluble drugs and in the latest years, a big deal of understanding has been accumulated about solid
dispersion, however, their commercial application is limited. In this review article, emphasis is placed on solubility, BCS
classification, and carriers. Moreover, this article presents the diverse preparation techniques for solid dispersion and gathers
some of the recent technological transfers. The different types of solid dispersions based on the carrier used and molecular
arrangement were underlined. Additionally, it summarizes the mechanisms, the methods of preparing solid dispersions, and the
marketed drugs that are available using solid dispersion approaches.

1. Introduction Pharmaceutical scientists have two approaches to im-

proving the oral bioavailability of pharmacologically active
The oral route is the most convenience route for drug agents: (i) improving the solubility and dissolution rate of
adminstration and favore mode of delivery [1]. From the poorly water-soluble medications, and (ii) improving the
patient’s standpoint, swallowing and medication is a com- permeability of poorly permeable drugs [4].
fortable and familiar method of taking medication. As a result, In the pharmaceutical literature, a variety of strategies have
orally delivered drugs are often more effective than alternative been used to improve the dissolving capabilities of weakly
modes of administration, such as parenteral, in terms of water-soluble medications other than solid dispersions. Some
patient compliance and drug treatment. When an active of these strategies are salt creation, complexation with cyclo-
substance is given orally, it must first dissolve in the stomach dextrins, solubilization of pharmaceuticals in solvent(s), and
and/or intestinal fluids before it can pass through the GI particle size reduction; however, each of these procedures has
tract’s membranes and reach systemic circulation [2]. significant limitations, such as poor yield, expensive, time
Therefore, water solubility and/or membrane permeability of consuming, and very low drug solubility [5]. On the other
the drug molecule are significant contributors to drug ab- hand, formulating pharmaceuticals as solid dispersions pro-
sorption from the gastrointestinal (GI) tract, which causes low vides several processing and excipient alternatives, allowing for
medication bioavailability of the medications. Consequently, greater flexibility for formulating oral delivery systems of
a drug with weak aqueous solubility usually shows a disso- poorly tolerated water-soluble medications [6].
lution rate of limited absorption, while a drug with weak Much of the research that has been published on solid
membrane permeability usually shows a permeation rate of dispersion technologies includes medications that are poorly
limited absorption [3]. water-soluble and highly permeable to biological membranes
2 Advances in Pharmacological and Pharmaceutical Sciences

Table 1: The definitions of various solubility terms [9].

Solubility assigned
Description forms (solubility definition) Parts of solvent required for one part of solute Solubility range (mg/ml)
(mg/ml)
Very soluble <1 >1000 1000
Freely soluble (FS) 1 to 10 100–1000 100
Soluble 10–30 33–100 33
Sparingly soluble 30–100 10–33 10
Slightly soluble 100–1000 1–10 1
Very slightly soluble 1000–10000 0.1–1 0.1
Practically insoluble >10000 <0.1 0.01

as with these drugs dissolution is the rate-limiting step to Table 2: Classification of drugs as per the BCS system [7].
absorption. As a result, the rate of in vivo absorption will be
Class Permeability Solubility
enhanced in tandem with an increase in the drug dissolution
rate. Medications having limited water solubility and strong Class I High High
Class II High Low
membrane permeability are classified as class II drugs in the
Class III Low High
biopharmaceutical classification system (BCS). As a result, Class IV Low Low
solid disperion technology has many promises to enhance the
oral absorption of BCS Class II drugs and thier bioavailability
[7]. Bioavailability may be improved by enhancing the solu-
The weak solubility of many discovered drugs is a barrier bility and dissolving rate of the class II medication in the
to their possible therapeutic activity. According to statistical gastrointestinal fluids. Medication release is a critical and
reports, it has been estimated that 40 per cent of the novel limiting step for oral drug bioavailability, especially for
chemical entities identified today are water-insoluble [8]. medicines with limited gastrointestinal solubility. Optimizing
Unfortunately, many of these prospective medications are the drug release profile of these drugs makes it feasible to
abandoned in the early phases of development due to sol- improve their bioavailability and reduce side effects [11, 12].
ubility difficulties. As a result, it is becoming increasingly The World Health Organization’s (WHO) model list of
crucial to identify new ways to overcome solubility limits so essential medicines has assigned a biopharmaceutical clas-
that the potential therapeutic benefits of these active com- sification system categorization based on publicly available
pounds can be realized [9]. data. Unfortunately, only 61 of the 130 orally given medi-
Solid dispersion formulation is one of the most prom- cations on the WHO list could be classified with accuracy.
ising and practical approaches for increasing solubility. Eighty-four percent of these medications are classified as
According to Chiou and Riegelman [3], solid dispersion class I, seventeen percent as class II, forty-nine percent as
systems are “the solid-state dispersion of one or more active class III, and ten percent as class IV [10].
substances in an inert carrier or matrix generated by the
fusion, solvent evaporation, or melting-solvent process.”
Matrix is hydrophilic, whereas the medication is hydro- 2.2. Mechanisms Involved in Enhancing Drug Solubilization by
phobic. Simple eutectic mixtures, solid solutions, glass so- Solid Dispersion Technique. Although the mechanism is not
lutions, and glass suspensions, amorphous precipitation in a well understood yet, the basic principle includes the com-
crystalline carrier, compound, or complicated forms are plete removal of drug crystallinity and molecular dispersion
solid dispersion types [3]. of the poorly soluble compound in a hydrophilic polymeric
carrier [13]. When the solid dispersion is exposed to the
2. Solubility aqueous media, the carrier dissolves and the drug is released
as fine colloidal particles. This increases the surface area of
At a particular temperature and pressure, the solubility of a the dissolution rate and hence the bioavailability of poorly
substance is the amount that has entered the solution when water-soluble drugs. The drug is a soluble hydrophilic carrier
an equilibrium is reached between the solution and the and has a better dissolution rate due to the reduction of the
excess, that is, an undissolved substance. The dissolved particle size and the increase of the particle porosity. The
substance is referred to as the “solute,” and the dissolving potential advantage of this technique is enormous. Recently,
fluid in which the solute is dissolved is referred to as the surfactants were included to improve formulations, as in
solvent, and the two together are referred to as the solution many cases. However, thermodynamic instability and re-
[10]. Table 1 lists the definitions of various solubility terms. crystallization of the drug became a problem. Hence, sur-
factants are used to avoid recrystallization and to potentiate
their solubility [14].
2.1. Biopharmaceutical Classification System (BCS). The
biopharmaceutical classification system was first devised in
1995 by Amidon and his co-workers [7]. According to the 2.3. The Justification behind the Use of the Solid Dispersion
biopharmaceutical classification system, drug substances can Technique in the Pharmaceutical Industry. The primary
be classified as shown in Table 2. purposes of using this technique in pharmaceuticals are [15]
Advances in Pharmacological and Pharmaceutical Sciences 3

First generation

Second generation
On the basis of
the carrier
used [8]
Third generation

Fourth generation

Types of Solid
Dispersions Eutectics Systems

Glass solutions and

On the basis of suspensions
their molecular
arrangement [9]
Solid Solutions

Amorphous precipitation in
a crystalline carrier

Figure 1: Schematic representation of the solid dispersion types [15].

Table 3: Different carriers used in solid dispersion [16].

Category Carriers
Sugars Dextrose, sucrose, galactose, sorbitol, maltose, xylitol, mannitol, and lactose
Acids Citric acid and succinic acid
Polyvinyl pyrrolidine (PVP), polyethene glycol (PEG), hydroxypropyl methylcellulose (HPMC),
Polymeric materials methylcellulose (MC), hydroxyethyl cellulose, cyclodextrin, hydroxypropyl cellulose, pectin, and
galactomannan
Insoluble or enteric
Hydroxy propyl methylcellulose phthalate (HPMCP), EudragitL100, Eudragit E100, Eudragit RL, Eudragit RS
polymer
Surfactants Polyoxyethylene stearate, poloxamer 188, deoxycholic acid, tweens, and spans
Miscellaneous Pentaerythritol, pentaerythrityl tetraacetate, urea, urethane, and hydroxy alkyl xanthine

(i) Enhancing drug solubility (v) It should be able to preferably increase the aqueous
(ii) Enhancing drug stability solubility of the drug
(iii) Masking the bitter taste of drugs (vi) Ideally, it should be able to boost the medication’s
(iv) Gaining the desired release profile. water solubility and be chemically compatible with
the drug and should not form a firmly bound
complex with it [17]
2.4. Types of Solid Dispersions. Figure 1 summarizes the
different types of solid dispersion. Based on the carrier used, solid dispersions can be
classified into the following four generations [18]:
2.5. Based on the Carrier Used. A carrier must meet the First generation: Solid dispersions were formed as the
following criteria to be appropriate for enhancing the dis- first carriers to be applied in solid dispersions [19]. In
solution rate of a drug. Materials used as carriers are given in this generation, crystalline carriers are used such as
Table 3. sugars and urea. The disadvatange of the first gener-
ation is the presence of crystalline nature of the carrier.
(i) freely water-soluble with intrinsic quick-dissolving In which they are thermodynamically stable, and the
capabilities drug will not be released as fast as the amorphous form
(ii) nontoxic and pharmacologically inert [20].
(iii) The melting process must be heat stable and it Second generation: This generation involves the use of
should have a low melting point amorphous carriers which are usually polymers [21].
(iv) It must be soluble in a wide range of solvents These polymers could be synthetic such as polyethene
4 Advances in Pharmacological and Pharmaceutical Sciences

Solid dispersion

Eutectics Amorphous
Solid solution
mixture precipitation

Substitutional Continuous Interstitial Discontinuous

solid solutions solid solutions solid solutions solid solutions

Solute molecule
Solvent molecule
Figure 2: Classifications of solid dispersion [25].

glycols (PEG), povidone, polyvinyl pyrrolidine, and but in the solid state only to a very limited extent. It is
polymethacrylates or natural-based polymers, such as prepared through fast solidification of the fused melt of the
ethyl cellulose, hydroxypropyl methylcellulose two compounds, giving a complete liquid miscible product
(HPMC), and starch derivatives such as cyclodextrins and very little solid-solid solubility. Such a system is ther-
or hydroxypropyl cellulose [22]. modynamically intimately mixed with the physical mixture
Third generation: It has been proved that the dissolution of its two crystalline compounds [26].
profile can be enhanced by using a carrier with surface
active agent properties. As a result, the use of surface-active
agents such as poloxamer 407, compritol 888, ATO, inutec 2.6.2. Glass Solution and Suspensions. Glass solution refers
SP1, gelucire 44/14, and inulin as carriers was revealed to to the homogeneous glassy system in which a solute is
be effective in achieving a high purity level of the poly- dissolved in a glass carrier, whereas the glass suspensions, in
morphic and for increasing in vivo bioavailability [23]. which the precipitated particles are present, are suspended in
glass solvent. The lattice energy in such systems is low, and
Fourth generation: This type of dispersion is described as the melting point is not sharp, examples of carriers that form
controlled release solid dispersion. It contains poorly water- glass solutions and suspensions are urea, citric acid, poly-
soluble drugs with a short biological half-life. The carriers ethene glycol, polyvinyl pyrrolidine, and sugars such as
used are either water-soluble carriers or insoluble water dextrose, sucrose, and galactose [26].
carriers. Solubility enhancement and extended drug release
in a controlled manner are the two targets in controlled-
release solid dispersion. The water-soluble carriers used in 2.6.3. Solid Solution. In this system, when the two com-
controlled-release solid dispersion include ethyl cellulose, ponents crystallize together, they form a single homoge-
Eudragit, Hydroxypropyl cellulose, and others [24]. neous phase system. The drug particle size is decreased to its
molecular size in the solid solution. As a result, a faster rate
2.6. Based on their Molecular Arrangement. Solid dispersions of dissolution will be achieved in the solid solution than in
can be categorized into the following types (Figure 2): the corresponding eutectic mixture. The solution can be
categorized (as continuous or discontinuous) depending on
the level of miscibility of the two compounds or how the
2.6.1. Eutectics Systems. This mixture composes of two solvate molecules are circulated (substitutional, interstitial,
compounds in the liquid state that are completely miscible or amorphous) [26].
Advances in Pharmacological and Pharmaceutical Sciences 5

Method of Prepration

Hot-melt Co- Super

Solvent Spray Electro-
Fusion extrusion precipitati Critical Kneading
Method drying spinning
method on Fluid

Figure 3: Various methods of solid dispersion preparation [11].

(i) Continuous solid solutions: performed. To reach the desired particle size, the solid mass
The components are miscible in all proportions in a is crushed, pulverized, and sieved. Despite its popularity,
continuous solid solution. Hypothetically, this in- several drawbacks to employing this process in making solid
dicates that the bonding strength between the two dispersions are present. These drawbacks include a lack of
components is greater than the bonding strength drug-polymer miscibility at the heating temperature.
between the molecules of each individual compo- However, surfactants may be used to avoid this issue. Ad-
nent. However, solid solutions of this type have not ditionally, medications and polymers must be thermally
been reported in the pharmaceutical world to date stable at melting temperatures, therefore lower production
[27]. temperatures are desirable. In addition, the fused mixture
must be resistant to recrystallization and phase separation
(ii) Discontinuous solid solutions:
[11]. Table 4 shows examples of decent case studies for the
In the case of discontinuous solid solutions, the preparation of solid dispersion using the fusion method.
solubility of each component in the other compo-
nent is limited [27].
(iii) Substitutional solid solutions: 3.2. Hot-Melt Extrusion Method. The hot-melt extrusion
method is the modern version of the fusion method in which
This type of solid solution occurs only if the size of
the extruder induces intense mixing of the components.
the solute molecules is variable by less than 15% or
Compared with the traditional fusion method, melt extru-
so from the solvent particles [28].
sion offers the potential to shape the molten drug-polymer
(iv) Interstitial solid solutions: mixture into implants, pellets, or oral dosage forms [4].
In interstitial solid solutions, the soluble particles fill However, this method requires the complete miscibility of
the interstitial gaps between the solvent molecules in the drug and the polymer in the molten state. Solubility
the crystal lattice. Therefore, the solute molecule parameter phase diagrams can be used to predict miscibility
diameter should be less than 0.59 times that of the and to rationally select the compatible polymer [11].
solvent molecular diameter [28]. This process has various advantages, which includes the
following [11]:
2.7. Amorphous Precipitation in the Crystalline Matrix. In the (1) Fewer processing steps because the components are
crystalline carrier, the drug may also precipitate in an not compressed and the product is not dried, making
amorphous form instead of simultaneous crystallization of this procedure simple, continuous, and efficient.
the drug and the carrier (eutectic system). High dissolution (2) Entire mixing at a high shear rate and temperature
rates are usually produced in this form because of the high disaggregates the particles, resulting in a uniform
energy of the drug in the amorphous state [25]. distribution of tiny drug particles in the polymer
matrix and molecular level dispersion.
3. Method of Preparation (3) In addition, unlike the classical fusion approach, this
technique allows for continuous manufacturing,
Several techniques for preparing solid dispersion are listed in making it appropriate for large-scale production.
Figure 3. Generally speaking, there is no best method in solid HPMC, HPMCAS, PVP, PVP, vinyl acetate, and
dispersion to enhance poorly water-soluble drugs. It de- polyethylene oxide are some of the most often uti-
pends on factors such as the hydrophilicity-hydrophobicity lized polymeric materials in hot-melt extrusion [4].
balance of the drug, drug dose, and drug molecular weight.
Therefore, trial and error is the best approach the check the Over the last decade, hot-melt extrusion (HME) has
proper method that could enhance the drug solubility. developed as an effective technique for drug delivery and has
started to host such molecules previously considered un-
viable as drugs. Hot-melt extrusion is an efficient technology
3.1. Fusion. Sekiguchi and Obi proposed the fusion method for creating solid molecular dispersions and has been proven
in 1961, also known as the melt method. A physical mixture to produce sustained, modified, and targeted drug delivery
of drug and polymer is heated to generate a molten mixture, after improved drug bioavailability [34]. Nonsteroidal anti-
which is then cooled and hardened while vigorous stirring is inflammatory drugs (NSAID) and paracetamol were
6 Advances in Pharmacological and Pharmaceutical Sciences

Table 4: Shows examples of decent case studies for the preparation of solid dispersion using the fusion method.
Solubility of the Solubility of the Drug release of the Drug release percentage of
Drug name pure drug (mg/L) solid dispersed pure drug at 37°C the solid dispersed drug at Polymer used Reference
at 25°C drug at 25°C after an hour 37°C after an hour
Polyethene
Spironolactone 0.02354 0.06173 27.25 74.24 [29]
glycol 4000
Carvedilol 0.002 0.012 42.6 93.214 Poloxamer 188 [30]
Cefuroxime
0.412 5.886 10 92 Poloxamer 188 [31]
axetil
−5
1.93 × 10 (at Polyethylene
Luteolin — 13.11 97.78 [32]
20°C) glycol 4000
Polyethylene
Atorvastatin <1 — 60 99 [33]
glycol 6000

Add anti-solvent

Filtration/centrifugation
and washing
Drug and polymer
Controlled Precipitation Anti-solvent residue
Dissolved in a common
removed
Solvent
Drying

Powder
Figure 4: Schematic presentation coprecipitation process [37].

prepared as orally disintegrating tablets using the hot-melt pestle and mortar [37]. Figure 4 shows a demonstration of
extrusion method [35]. Paracetamol was prepared using the the process. Table 5 shows examples of decent case studies
hot-melt extrusion method through granulation para- for the preparation of solid dispersion using the fusion
cetamol and filler excipients with different low molecular method.
weight polyethylene glycol using the hot-melt extrusion Ibuprofen is one of the examples of medication that
process. The granules achieved were then mixed with dis- undergoes solubility enhancement using a coprecipitation
integrants and lubricant and were compacted into tablets. process. The solubility and the dissolution rate were im-
The HME granules showed an enhanced drug release profile proved by two-fold and one-fold, respectively.
as compared to the original tablets. More than 80% of the
drug was released by tablets that contained 15% of poly-
ethylene glycol within 30 minutes [36], which is the needed 3.4. Solvent Method. The solvent approach entails dissolving
amount for paracetamol tablets in the USP 30. both the medication and the polymer in a single solvent and
then removing the solvent to create a solid dispersion. This
method allows for molecule-level mixing, which is favored
3.3. Coprecipitation Method (Coevaporate). The carrier is for improving product solubility and stability [37].
accurately weighed and dissolved in water, while the The fundamental advantage of this approach is that it
medication is dissolved in an organic solvent. The aqueous avoids drug and polymer thermal degradation, which is
carrier solution is then added to the organic drug solution common when organic solvents are evaporated at low
after complete dissolution. After that, the solvents are temperatures. When utilizing this strategy, however, for-
ejected. The dispersion is crushed, sieved, and dried using a mulation scientists face two obstacles [48]. The first issue is
Advances in Pharmacological and Pharmaceutical Sciences 7

Table 5: Shows examples of decent case studies for the preparation of solid dispersion using the solvent evaporation method.
Drug release
Solubility of Solubility of Drug release
percentage of the
the pure drug the solid percentage of the
Drug name solid dispersed Polymer or carrier used Reference
(mg/L) at dispersed drug pure drug at 37°C
° ° drug at 37°C after
25 C at 25 C after an hour
an hour
Nisoldipine 0.005 5 18 75 Polyvinylpyrrolidone [38]
Nebivolol 0.0403 1.8135 20 98.17 Kleptose HPB, PEG 6000 [39]
Carvedilol 0.002 0.07 7 79 Polyvinylpyrrolidone K 30 [40]
Dutasteride 0.00006 0.0187 60 95.1 PEG 6000 [41]
Cefpodoxime
0.07211 0.171 20 70 Urea [42]
proxetil
Famotidine 0.405 10.436 80 after 35 min 100 after 35 min Xyloglucan and hyaluronic acid [43]
Clarithromycin 0.33 — 10 100 Urea [44]

Ebastine 0.0017 0.014 22 99.68

® ®
Avicel PH101, Avicel PH 102,
croscarmellose sodium(CCS), and [45]
sodium starch glycolate (SSG)
Lovastatin 0.0013 0.00372 30 75 Locust bean gum [46]
Poloxamer 407 and polyvinyl
Butein 0.0031 0.114 10 after 24 min 100 after 24 [47]
pyrrolidine K-30

to combine the medication and the polymer in a single in the polymer matrix. Drugs with limited water solubility can
solvent, which can be challenging if the polarity differences be spray-dried into extremely fine particles if they are soluble in
are large. Surfactants are sometimes developed to facilitate certain spray-drying solvents. However, the chemical prop-
medication or polymer solubility in certain solvents. erties of the medication influence the nature of the solid
However, their amount in the final dosage form is frequently particles generated and spray drying can result in amorphous
large, reducing drug loading capacity and potentially causing material, crystalline forms, imperfect crystals, or metastable
issues if they are not well tolerated in the body. In addition, crystals. Indeed, Mahlin and Bergstrom [51] studied various
this method is expensive due to the necessity to evaporate a drug compounds and found that developing an amorphous
substantial amount of the solvent [40]. The second issue is form is more dependent on the chemical composition of the
phase separation, which can occur when the solvent is re- medications than on process variables. However, the stability of
moved. The solution is usually dried by vacuum drying. A the amorphous forms depends on the process variables. Spray
rotary evaporator is sometimes used to accomplish rapid drying provides excellent control over powder characteristics,
drying. The use of higher drying temperatures reduces the and it has become the most popular solvent-based production
time for phase separation. The high molecular mobility of process due to lower manufacturing costs, simplicity of scale-
medicine and polymers at high temperatures may speed up, and continuous batch production. Table 6 shows a few
phase separation [37]. Table 5 shows examples of decent case examples of decent case studies for the preparation of solid
studies for the preparation of solid dispersion using the dispersion using the spray drying method.
solvent evaporation method. One study used solid dispersion (SD) techniques and
One study was performed with furosemide as it had modified the locust bean gum (MLBG) as a carrier to en-
limited bioavailability, poor solubility, and permeability. The hance lovastatin drug solubility. Solubility and dissolution
research study intended to assess coprecipitation, kneading, studies were used, respectively, to examine the effects of
and solvent evaporation by solubility and dissolution en- polymer concentration and preparation methods on solu-
hancement methods. All the approaches were found to en- bility enhancement. According to the solubility study’s
hance the solubility to some extent; however solvent findings, lovastatin’s solubility increased as MLBG con-
evaporation gave the best results. However, the following order centration increased. It was discovered that the method used
was observed; solvent evaporation > kneading > physical mix- for making the solid dispersions affected the dissolution rate
tures > coprecipitation [49]. of lovastatin. According to dissolution research, among the
different ways of preparing solid dispersions, modified
solvent evaporation is the most practical and successful
3.5. Spray Drying. Spray drying has become a prominent method for improving the solubility of weakly water-soluble
processing method for creating solid drug dispersions. It is lovastatin. The kneading method improves the dissolution
used to turn a liquid or a suspension into a dry powder in one rate better than that of coprecipitation because it has other
step. This method allows for more precise control of process trituration influences on the drug. Spray drying improves
factors, resulting in powders with the required size, shape, the dissolution rate of lovastatin due to enhanced wettability
density, flow characteristics, and crystalline forms [50]. In of drug particles and a significant decrease in particle size in
spray drying, the solvent evaporates at a rapid rate, resulting in the spray drying procedure. The explanation for the greater
a dramatic increase in viscosity and trapping of drug molecules dissolution rate of solvent evaporation in comparison with
8 Advances in Pharmacological and Pharmaceutical Sciences

Table 6: Shows examples of decent case studies for the preparation of solid dispersion using the spray drying method.
Drug release
Solubility of the Solubility of the Drug release percentage
Drug percentage of the pure Polymer or carrier
pure drug (mg/L) solid dispersed ° of the solid dispersed drug Reference
name drug at 37 C after an used
at 25°C drug at 25°C at 37°C after an hour
hour
Celecoxib 0.003–0.007 — 59 100 PEG 6000 [52]
Practically Hydroxypropyl
Ritonavir 0.161 8 100 [53]
insoluble in water methylcellulose
Apigenin 0.002 0.016 23 85 Poloxamer [54]

other solid dispersions could be due to the availability of substances and operating conditions. Response surface
increased surface area of particles in the suspension [46]. methodology was utilized for the optimization of the out-
comes, and it was shown that the smallest particle size may
be achieved at a temperature of 50°C, a pressure of 17.7 MPa,
3.6. Supercritical Fluid (SCF) Method. Supercritical fluids
and a spray distance of 10 cm [59].
have both liquid and gas characteristics. Materials exhibit
liquid-like solvent characteristics and gas-like viscosity,
diffusivity, and thermal conductivity under supercritical 3.7. Kneading Method. In a glass, a mixture of precisely
conditions. While the solvent properties are advantageous weighed medication and carriers is wetted with a solvent and is
for drug/polymer solubilization, the gas-like properties thoroughly kneaded for sometime [16]. In the kneading
considerably improve the fluids’ mass transport character- method, the liquid (which may be water or a hydroalcoholic
istics [55]. This approach is most commonly used with mixture) is added dropwise while the drug and polymers are
supercritical carbon dioxide (CO2) as a drug and polymer triturated in a pestle and mortar. This results in the formation
solvent or as an antisolvent. The polymer and medicine are of a slurry and the reduction of particle size, which increases
dissolved in supercritical CO2 and blasted into a low- bioavailability because of the kneading action. Then, the
pressure zone through a nozzle, generating adiabatic CO2 mixture is dried and placed through the mesh to bring the
expansion and fast cooling. As a result, this approach enables contents into homogeneity [60]. Satranidazole-cyclodextrin
the creation of drug particles with much smaller particle complexes were made. Following the examination of this
sizes. The rapid expansion of supercritical solutions is the complexation, it was discovered that there had been a no-
common name for this technology (RESS) [56]. Current ticeable increase in solubility [61]. In one study, Olmesartan
supercritical fluid approaches have shown the ability to medoxomil inclusion complexes were created using the
generate nanoparticulate suspensions of particles with sizes kneading approach and were introduced as mouth-dissolving
ranging from 5–2000 nm. This process is considered envi- tablets. Complexation increased the solubility and the me-
ronmentally friendly because it does not require the use of chanical stability of the tablets as well as their solubility and
organic solvents and the small amount of residual CO2 dissolution [62]. Efavirenz in PVP K-30 was prepared by two
trapped inside the polymer causes no risk to patients. CO2’s methods, that is, kneading and conventional solvent methods.
propensity to plasticize and swell polymers can also be The two formulations were characterized by DSC, FT-IR, SEM,
exploited. However, the limited solubility of most medicinal XRD, and dissolution profile.
chemicals in CO2 prevents this method from being used in A higher dissolution rate has been seen in solid dis-
practice. Several supercritical fluid-processing approaches persions made by the kneading technique [63]. By kneading
have been developed to address specific parts of these flaws approach, Patel created etoricoxib-cyclodextrin complexes.
and to increase solubility. These approaches involve pre- For each material, phase solubility studies were performed to
cipitation with a compressed antisolvent, supercritical fluid- design the phase solubility diagram. Inclusion complexes
enhanced dispersion, supercritical antisolvent processes, gas from this approach showed a significant increase in solu-
antisolvent recrystallization, and an aerosol supercritical bility [64]. By adopting the complexation through kneading
extraction system [57]. The drug solubility in supercritical approach, nimesulide dissolution was improved [65]. In one
CO2 has a huge effect on the diameter ranges of the particles study, a BCS class II medication was identified called azi-
formulated by the RESS process. This was demonstrated in a thromycin using physical characterization and melting point
study by Kim et al. [58] when they utilized RESS for the determination. Melting, kneading, and solvent evaporation
formulation of ultrafine drug particles by applying super- were used to generate azithromycin’s solid dispersions.
critical CO2, with no organic solvent. Three different drugs From the study’s findings, it can be determined that the
were used (lidocaine, griseofulvin, benzoic acid) with var- melting and kneading approaches successfully increased the
ious solubilities in supercritical CO2, and orifice disks and solubility of the azithromycin to the maximum compared to
capillary tubes were fitted as an expansion apparatus. The the solvent evaporation method [66].
drug solubilities in supercritical CO2 and the impacts of
different operating parameters on the physical characteris-
tics of the particles formulated by the RESS procedure were 3.8. Electrospinning Method. This technology combines solid
experimentally studied. The results showed that the average dispersion technology with nanotechnology to be used in the
particle diameter reduced with the solubility for all the drug polymer industry. This technique exposes a liquid stream of
Advances in Pharmacological and Pharmaceutical Sciences 9

Table 7: Different characterization methods to assess solid dispersion [6].

Characterization Technique Purpose [69]
Differential scanning
calorimetry (DSC),
Used for studying biological reactions and for the validation of production
Fourier transform infrared
Drug-carrier interactions materials and identification of unknown compounds. It is also used for
spectroscopy (FTIR),
detecting any new interaction
Raman spectroscopy, and
solid-state NMR studies
Hot-stage microscopy (HSM),
differential scanning calorimeter
(DSC), Used for identifying thermal transition and for achieving a three-
Drug-carrier miscibility
X-ray diffraction (XRD), dimensional model
and nuclear magnetic resonance
(NMR)
Dynamic vapour sorption, Used for supplying details on particle surface thermodynamic properties,
inverse gas chromatography, such as surface free energy, acid-base interactions, enthalpy, and entropy.
Surface properties
atomic force microscopy, and Moreover, it is also used for providing details of the solvent quantity that
Raman microscopy was absorbed on the sample surface
Scanning electron microscopy,
surface area analysis,
surface properties,
Physical structures dynamic vapour sorption, Used for determining the area or pore size of the surfaces sample surface
inverse gas chromatography,
atomic force microscopy, and
Raman microscopy
Humidity studies,
isothermal calorimeter,
differential scanning calorimeter
Stability Used for measuring the reaction between the sample molecules
(DSC),
dynamic vapour sorption, and
saturated solubility studies
Differential scanning
calorimeter (DSC),
hot-stage microscopy (HSM),
Amorphous state in solid Used for providing a humid environment and for studying the surface
humidity stage microscopy,
dispersion properties of the amorphous compounds
polarized light optical
microscopy, and
powder X-ray diffraction
Dissolution studies,
Dissolution rate intrinsic dissolution, and Used for studying the dissolution profile
dynamic solubility studies

a drug/polymer solution to a voltage between 5 and 30 kV. ketoprofen alone (p < 0.05). In a different investigation,
Fibres of submicron diameter arise when electrical forces indomethacin and griseofulvin were combined in an
exceed the surface tension of the drug/polymer solution at amorphous form using the electrospinning technique and
an air contact [67]. The generated fibres can be collected on a the PVP was the carrier. For eight months, this mixture
screen to make a woven fabric, or they can be gathered on a remained stable in a desiccator [68].
spinning mandrel as the solvent evaporates. Surface tension,
dielectric constant, feeding rate, and electric field strength all 4. Solid Dispersion Characterization
influence the fibre diameter. Because it is the simplest and
cheapest technology for preparing nanofibers and control- In solid dispersions, the medication in the matrix can take on
ling the release of medicines, it has enormous potential. In a variety of molecular configurations. The molecular ar-
the future, this approach could be used to make solid dis- rangement in solid dispersions has been studied in several
persions [16]. The simplicity and low cost of this method ways. However, much work has gone into distinguishing
make it advantageous. This technique works well for making between amorphous and crystalline materials [16]. For this
nanofibers and managing the release of biomedical treat- purpose, many approaches exist to detect the amount of
ments. By electrospinning, a nanofiber of polyvinyl alcohol crystalline material in the dispersion. The amount of
(PVA) : ketoprofen (1 : 1, w/w) was created. The dissolution amorphous material in a sample can never be directly
rate of this nanofiber was significantly greater than that of measured, but it can be estimated based on the amount of
10 Advances in Pharmacological and Pharmaceutical Sciences

Table 8: Marketed products [70].

Product name Drug name Carrier used Method used Company name Reference
Melt process, the exact process is
®
Grispeg Griseofulvin PEG
unknown
Pendinal pharm inc. [71]
Cesamet
® Nabilone PVP
Hypromellose, HMPC, PEG
Process is unknown Eli lilly [71]
Sproranox
® Itraconazole
20000
Spray layering Janssen [71]
Rezulin
® Troglitazone PVP
Hepatitis type Amorphous adefovir dipivoxil
Melt-extrusion
Amorphous adefovir in solid
Pfizer [71]
Hepcure
® b in solid dispersion dispersion
CJ CheilJedang [22]
Keletra
® Lopinavir PVPV Melt-extrusion Abbott [71]
Afeditab
® Nifedipine Poloxamer or PVP Melt/absorb on the carrier Elan corp, Ireland [71]
Certican
® Everolimus HPMC Melt or spray drying Novartis, Switzerland
Life cycle pharma,
[71]
Fenoglide
® Fenofibrate PEG Unknown process
Denmark
[22]
Fujisawa
Nivadil
® Nivaldipine HPC/HPMC Solvent method
pharmaceuticals co., ltd
[72]
Nimotop
® Nimodipine PEG Unknown process Bayer [73]
Torcetrapib
® Torcetrapib HPMC Pfizer, USA
Ibuprofen
® Ibuprofen PEG, HPMC, and PVP Melt-extrusion Soliqs, Germany [71]
Incivek
® Telaprevir HPMC as Spray drying Vertex
Fujisawa
[74]
Prograf
® Tacrolimus HPMC Wet granulation
pharmaceuticals co., ltd
[74]
Cymbalta
® Duloxetine HPMC AS Unknown process Lilly, USA
Noxafil
® Posaconazole HPMC AS Melt extrusion Merck [74]
Intelence
® Etravirine HPMC Spray drying Tibotec, Yardley, PA
Janssen pharmaceutica,
[71]
Incivo
® HPMC Spray drying
Belgium
[74]
Isoptin SRE-
Verapamil Various Melt-extrusion Soliqs, Germany [71]
240
® HPC/HPMC HPC/HPMC Abbott Laboratories,
Isoptin SR-E
® Verapamil
Abbott
Spray drying
USA,
[75]
Crestor
® Rosuvastatin HPMC Solvent evaporation AstraZeneca [76]
Zelboraf
® Vemurafenib HPMC as Coprecipitation Roche [71]
Zortress
® Everolimus HPMC Spray drying
New solvate of ivacaftor, processes,
Novartis, Switzerland [74]
Kalydeco
® Ivacaftor HPMC as
exact process unknown
Vertex [77]

PVP: polyvinylpyrrolidone; HPMC: hydroxypropylmethylcellulose; PEG: polyethyleneglycol; HPC: hydroxypropylcellulose; and HMPC AS: hydrox-
ypropylmethylcellulose acetylsuccinate.

crystalline material present. It should be highlighted that In Vitro studies

using crystallinity to measure the amount of amorphous 9
drug makes it impossible to distinguish whether the drug is 8
7
present as amorphous drug particles or as molecularly 6
5 9
dispersed molecules. Table 7 summarizes the different 4
3 5 5
methods applied to characterize solid dispersions [6]. 2
1 1 1 1
0
Antiparasitic
Anticancer

Gastro/Hepatoprotective
Antioxidant
Antimicrobial

Anti-inflammatory

4.1. Marketed Products Used the Solid Dispersion Approach.

Several drugs are already on the market and have been
prepared using the various approaches of solid dispersion
[12]. Some of the products are shown in Table 8.
Different approaches can perform solid dispersion. As a
result, solid dispersion methods have been extensively used to Figure 5: Quantification and classification of in vitro studies on
improve the solubility of poorly water-soluble drugs. Table 6 solid dispersions published in the period from 2009 to 2020 [78].
shows the Praziquantel drugs that have been studied using
different solid dispersion methods with various carriers.
synthetic medicines and drug candidates [78]. The synthesis
4.2. Solid Dispersion in Polymeric Matrices for In Vitro Studies. and usage of SDs have been reported in many in vitro in-
This section covers solid dispersions (SDs) used to improve vestigations, which have been numerically quantified and
the characteristics and release of poorly soluble natural and categorized in Figure 5 based on the biological activities of
Advances in Pharmacological and Pharmaceutical Sciences 11

Table 9: In vitro studies on solid dispersion.

Drug name Carrier used Method used Activity Reference
Niclosamide OHPP Spray drying Anticancer [79]
Paclitaxel OHPP Spray drying Anticancer [80]
Paclitaxel PVP/VA TPGS Spray drying Anticancer [81]
®
Brij L4 Chrysin Solvent evaporation Anticancer
Anticancer enzyme inhibitory/
[82]
Curcumin (CM) Poloxamer 407 Solvent evaporation [83]
antioxidant anti-inflammatory
Zn (II)-curcumin
PVP K30 Solvent evaporation Anticancer [84]
complex
Telaprevir HPMC, PVP K30, PEG 6000 Kneading Anticancer [85]
Angelica gigas nakai
Berberine
Soluplus
® Hot melting extruder Anticancer [86]
Eudragit S-100 Solvent evaporation Anticancer [87]
hydrochloride (HB)
IIIM-290 PVP K30 Scanning electron microscopy Cytotoxic [88]
Benznidazole Poloxamer 407 Solvent evaporation Antichagasic [89]
Benznidazole Low-substituted HPC Solvent evaporation Antichagasic [90]
Ursolic acid Gelucire 50/13 Solvent evaporation Antichagasic [91]
PVP K30, PVP/VA, kollidon-cl-
Praziquantel Solvent evaporation Antischistosomal [92]
m, and sodium starch glycolate
Praziquantel PVP K30 Spray congealing Antischistosomal [93]
Soluplus, PEG 400, lutrol F127,
Artemether Hot-melt extrudate Antimalarial [94]
and lutrol F68
Soluplus, kollidon VA64, and
Lumefantrine Hot-melt extrudate Antimalarial [95]
plasdone S630
Abietic acid Chitosan Solvent evaporation Antimicrobial, antioxidant [96]
Gatifloxacin Pluronic F127 Solvent evaporation Antimicrobial [97]
Curcumin PVP K30 Coprecipitation Antimicrobial [98]
Curcumin HPMC Coprecipitation Antimicrobial [99]
Curcumin Poloxamer 407 Coprecipitation Antioxidant [100]
Quercetin PVP K25 Solvent evaporation Antioxidant [101]
Coenzyme Q10 Mannitol Solvent evaporation Antioxidant [102]
Usnic acid PVP K30 Spray drying Antioxidant [103]
Solvent evaporation, fusion,
Luteolin PEG 4000 Antioxidant [32]
and microwave irradiation
α, β-amyrin PVP K30, PEG 6000, and HPMC Kneading Anti-inflammatory [104]
Curcumin HPMC Solvent evaporation Cytoprotective [105]
OHPP, octenylsuccinate hydroxypropyl phytoglycogen; IC50, half inhibitory concentration; PVP/VA, polyvinylpyrrolidone/vinyl acetate; TPGS, D-
α-tocopherol polyethylene glycol-1000-succinate; PVP, polyvinylpyrrolidone; SD, solid dispersion; AChE: acetylcholinesterase; BChE, butyrylcholinesterase;
CM, curcumin; GST, glutathione S-transferase; MAO, monoamine oxidase; LPS, lipopolysaccharide; NO, nitric oxide; PEG, polyethylene glycol; HPMC,
hydroxypropyl methylcellulose; ITG (chloroquine-resistant cell line); DPPH, 2,2-diphenyl-1-picryl-hydrazyl-hydrate; HPMCAS, hydroxypropyl methyl-
cellulose acetate succinate; MIC, minimum inhibitory concentration; ROS, reactive oxygen species; and t-BHP, tert-butylhydroperoxide.

their active compounds, with the major information from In Vivo studies

this research summarized in Table 9. 9

8
7
6
5 9
4
3 5 5
4.3. In Vivo Studies on Solid Dispersions in Polymeric Matrices. 2 3
1 1 1 1 1
As previously indicated, solid dispersions (SDs) have been 0
Anticancer

Antiparasitic

Gastro/Hepatoprotective
Antimicrobial

Antioxidant

Antidiabetic

Antinociceptive
Anti-inflammatory

employed in pharmaceutical technology to overcome

some of the limits posed by pharmaceuticals and new
bioactive substances, such as the limited solubility and
bioavailability [78]. In this regard, as seen in Figure 3 and
quantitatively quantified in Figure 6, this section discusses
in vivo studies on SDs with various biological activities.
Table 10 summarizes the most important aspects of this Figure 6: Quantification and classification of in vivo studies on
research. solid dispersions published from 2009 to 2020 [78].
12 Advances in Pharmacological and Pharmaceutical Sciences

Table 10: In vivo studies with solid dispersion.

Drug name Carrier used Method used Activity Reference
IIIM-290 PVP K30 Solvent evaporation Anticancer [88]
9-nitrocamptotheci
(−)-oleocanthal
Soluplus
®
(+)-xylitol
Solvent evaporation
Hot melt fusion
Anticancer
Anticancer
[97]
[106]
Zinc(II)-curcumin complex PVP K30 Solvent evaporation Anticancer [84]
Selaginella doederleinii hieron PVP K30 Coprecipitation Anticancer [107]
Benznidazole Low substituted HPC Solvent evaporation Antichagasic [90]
Curcumin (CM) PVP K30 Coprecipitation Antimicrobial [98]
Taurine-zinc complex PVP K30 Spray drying Antioxidant [108]
Triacetylated andrographolide (TA) Kollidon (VA64) Solvent evaporation Anti-inflammatory [109]
Curcumin PVP K30, poloxamer 188 Solvent evaporation Anti-inflammatory [110]
Aceclofenac Crospovidone Solvent evaporation Anti-inflammatory [111]
Curcumin
Curcumin
®
Gelucire 50/13-aerosil
HPMC, lecithin and isomalt
® Hot melt fusion
Hot melt extrusion
Anti-inflammatory
Anti-inflammatory
[112]
[113]
Ibuprofen PEG 8000 Fusion method Anti-inflammatory [114]
Flurbiprofen Urea and mannitol Fusion method Anti-inflammatory [115]
Meloxicam Paracetamol Coprecipitation Anti-inflammatory [116]
Chelerythrine (CHE) PVP K30 Solvent evaporation Anti-inflammatory [117]
Curcumin HPMC Solvent evaporation Hepatoprotective [105]
Nobiletin HPC Spray drying Hepatoprotective [118]
Silymarin PVP K30 Solvent evaporation Hepatoprotective [119]
Repaglinide Poloxamer 188 Fusion method Antihyperglycemic [120]
Glimepiride Soluplus1 and PEG 4000 Solvent evaporation Antidiabetic [121]
Pioglitazone PVP K17 Spray drying Antihyperglycemic [122]
Hecogenin acetate HPMC Kneading Antinociceptive [63]
PVP, polyvinylpyrrolidone; SD, solid dispersion; HPC, hydroxypropyl cellulose; CM, curcumin; CM/PVP SD, curcumin/polyvinylpyrrolidone solid dis-
persion; SOD, superoxide dismutase; PEG, polyethylene glycol; TNF-α, tumour necrosis factor alpha; IL, interleukin; NO, nitric oxide; HPMC, hydrox-
ypropyl methylcellulose; and AST, aspartate aminotransferase.

5. Drawbacks of Solid Dispersions dispersion systems have proven to be a valuable method for
increasing the dissolving properties of poorly water-soluble
There are several drawbacks that limit the use of solid medications. Solid dispersion technology has gained much
dispersion in the drug formulation process, including [18] knowledge in recent years, but its practical use is still limited.
the following: Several ways have recently been tried to overcome limitations
(i) Demanding and costly techniques of preparation and make the preparation more realistic. In addition, the
issues involved in incorporating dosage forms into formu-
(ii) Physicochemical properties reproducibility lation have been increasingly resolved with the development
(iii) Difficulty merging dosage forms into the of various solutions. Spraying sugar beads and directly filling
formulation capsules are two examples. This study has addressed the aim
(iv) Scaling up of the manufacturing process as well as objectives. This research study was performed by
(v) Stability of medications and solvent using a review design. There were some major limitations in
the study. This research study has no specific methodology
section, where the design was specifically described and
6. Conclusion evidenced. This article has also not talked about any of the
The oral route of medicine administration is the most processes by which data were collected and the number of
common and preferred form of delivery due to its simplicity articles selected for data collection. These limitations should
and convenience of oral administration. From the patient’s be addressed in future research studies.
perspective, ingesting medicine is a convenient and accus- Although there are significant challenges to solve, such
tomed way to take medicines. As a result, oral medication as scale-up and production costs, solid dispersion tech-
delivery is frequently more efficient in terms of patient nology has considerable potential for improving the drug
compliance and drug therapy than alternate modes of ad- release profile of poorly water-soluble medicines.
ministration, such as parenteral. When taken orally, an
active drug must dissolve in the stomach and/or intestinal Data Availability
fluids before it can cross the GI tract’s membranes and enter
the bloodstream. It is a review of articles with no hyperlinks are applicable.
As a result, low medication bioavailability is caused by
low drug absorption from the gastrointestinal (GI) tract, Conflicts of Interest
which is significantly influenced by the drug’s molecule’s
water solubility and membrane permeability. Solid The authors declare that they have no conflicts of interest.
Advances in Pharmacological and Pharmaceutical Sciences 13

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