Pharmaceutical Dispersion Techniques For Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs

pharmaceutics
Review
Pharmaceutical Dispersion Techniques for
Dissolution and Bioavailability Enhancement of
Poorly Water-Soluble Drugs
Xingwang Zhang 1 ID
, Huijie Xing 2 , Yue Zhao 2 and Zhiguo Ma 1, *
1 Department of Pharmaceutics, College of Pharmacy, Jinan University, 601 West Huangpu Avenue,
Guangzhou 510632, China; zhangxw@jnu.edu.cn
2 Institute of Laboratory Animals, Jinan University, 601 West Huangpu Avenue, Guangzhou 510632, China;
huijie920326@163.com (H.X.); tsukimoon@126.com (Y.Z.)
* Correspondence: mzg1979@126.com

Received: 27 May 2018; Accepted: 19 June 2018; Published: 23 June 2018
Abstract: Over the past decades, a large number of drugs as well as drug candidates with poor
dissolution characteristics have been witnessed, which invokes great interest in enabling formulation
of these active ingredients. Poorly water-soluble drugs, especially biopharmaceutical classification
system (BCS) II ones, are preferably designed as oral dosage forms if the dissolution limit can be
broken through. Minimizing a drug’s size is an effective means to increase its dissolution and
hence the bioavailability, which can be achieved by specialized dispersion techniques. This article
reviews the most commonly used dispersion techniques for pharmaceutical processing that can
practically enhance the dissolution and bioavailability of poorly water-soluble drugs. Major interests
focus on solid dispersion, lipid-based dispersion (nanoencapsulation), and liquisolid dispersion
(drug solubilized in a non-volatile solvent and dispersed in suitable solid excipients for tableting or
capsulizing), covering the formulation development, preparative technique and potential applications
for oral drug delivery. Otherwise, some other techniques that can increase the dispersibility of a drug
such as co-precipitation, concomitant crystallization and inclusion complexation are also discussed.
Various dispersion techniques provide a productive platform for addressing the formulation challenge
of poorly water-soluble drugs. Solid dispersion and liquisolid dispersion are most likely to be
successful in developing oral dosage forms. Lipid-based dispersion represents a promising approach
to surmounting the bioavailability of low-permeable drugs, though the technique needs to traverse
the obstacle from liquid to solid transformation. Novel dispersion techniques are highly encouraged
to develop for formulation of poorly water-soluble drugs.
Keywords: poorly water-soluble drug; pharmaceutical dispersion; dissolution; bioavailability
1. Introduction
Drugs with poor aqueous solubility are still an ongoing challenge in the successful formulation of
therapeutic products due to their low oral bioavailability. It is a hard nut to crack that has discouraged
pharmaceutical practitioners for many years. In the 1990s; the biopharmaceutical classification system
(BCS) was introduced to characterize various drugs according to their solubility and permeability [1].
It reports that over 70% of drugs and active entities are poorly water-soluble compounds (BCS II or BCS
IV) due to the considerable involvement of high throughput screening and combinatorial chemistry [2].
These active pharmaceutical ingredients (APIs) often suffer from formulation challenges because of
limited dissolution and/or low permeability. Accordingly; applicable formulation techniques are
highly aspired to improve the apparent solubility or dissolution of poorly soluble drugs and thus
enable them become bioavailable.
Pharmaceutics 2018, 10, 74; doi:10.3390/pharmaceutics10030074 www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2018, 10, 74 2 of 33
A variety of formulation strategies have been explored to overcome the poor aqueous solubility of
drugs, including micronization [3], nanocrystalization [4], salification [5], cyclodextrin inclusion [6,7],
cocrystallization [8], micelle solubilization [9], solid dispersion [10], liquisolid technique [11], and
encapsulation in nanoparticles [12]. Generally, there are two methods to prepare nanodrug, namely
top-down and bottom-up techniques. The former is a straightforward approach to reducing a drug’s
size by the mechanical force (grinding or crushing); the latter is a simple and self-dispersion process
where the drug is embedded or dissolved in carrier excipients/vehicles in molecular or amorphous
state by solubilization or self-assembly [13]. Of course, recrystallization from molecular solution by
antisolvent precipitation also represents a bottom-up technique for preparing drug nanocrystals [14].
However, the products produced by the top-down technique tend to result in broad size distribution
and insufficient physical stability due to potential Ostwald ripening, which limits its potential
application of this technique. The bottom-up technique, dispersion starting from molecules, almost can
maximize the dispersion of a drug and lead to more stable dispersion systems (amorphous, molecular
or colloidal). Therefore, the bottom-up dispersion technique represents the most promising approach
for pharmaceutical processing.
Pharmaceutical engineering involves all sorts of dispersion systems, including suspension system,
colloidal system and solution system, in which a drug can be dispersed by itself or in a solid matter,
a semisolid matter, a solvent or nanoparticles. Among these, solid dispersion (SDs), lipid-based
dispersion and liquisolid dispersion are well-developed and more commonly used pharmaceutical
dispersion techniques. These dispersion systems have been widely applied to formulation of poorly
water-soluble drugs to address the issues related to solubility and permeability. Solid dispersion
technology is a method of dispersing a drug in an inert carrier excipient (normally a water-soluble
polymer) in the solid form. This technique allows complete removal of drug crystallinity and molecular
dispersion of a poorly soluble drug in a hydrophilic polymeric carrier [15]. In solid dispersions, the
specific surface area of drug is dramatically amplified and the drug is always in high-energy state,
which greatly facilitates the dissolution. The performance of SDs as bioavailability enhancer has been
widely evaluated for different drugs with encouraging results [16]. Lipid-based formulations are a
series of preparations consisting of oils or lipids as basic excipients [17], in which the drug is highly
dispersed or completely solubilized in the lipophilic core. In addition to providing a supersaturated
drug concentration in the gastrointestinal tract, lipid formulations have the advantages of motivating
intestinal lymphatic drug transport and optimizing enterocyte-based drug transport and disposition
whereby to reduce the first-pass effect and increase the lipophilic drug’s absorption [18]. The potential
utility of lipid formulations as a means of bioavailability enhancer for poorly water-soluble drugs has
been critically reviewed [19,20].
Liquisolid system as a viable alternative to the conventionally used dispersion techniques for
dissolution and bioavailability improvement has received considerable attention in recent years [21].
Liquisolid formulations involve liquid medication in solid powdered form that possess a drug
delivery mechanism similar to soft capsules [22]. In the liquisolid systems, a drug is completely
dissolved in a non-volatile solvent and molecularly dispersed in suitable carrier and coating
materials. Liquisolid system breaks away from the constraint of Van der Waals’ attraction and
hydrophobic interaction between drug particulates, thus presenting the highest dispersibility and
physical stability among various dispersion systems. Better bioavailability for an orally administered
poorly water-soluble drug can be achieved through a liquisolid formulation since the drug is already in
solution. Of course, other dispersion techniques are also in active development, such as co-precipitation,
concomitant crystallization and inclusion complexation. These techniques provide flexible options to
tackle the low bioavailability of “problem” drugs caused by poor aqueous solubility.
In this article, a comprehensive survey on the use of solid dispersion, lipid-based solubilization
and liquisolid technique for dissolution and bioavailability enhancement of poor water-soluble
drugs are carried out. Specific aspects focus on the formulation development, excipient application,
preparative techniques and oral delivery efficiency of these dispersion-based formulations. In addition,
Pharmaceutics 2018, 10, x FOR PEER REVIEW 3 of 32
Pharmaceutics out.10,Specific
are carried2018, 74 aspects focus on the formulation development, excipient application, 3 of 33
preparative techniques and oral delivery efficiency of these dispersion-based formulations. In

addition,
other other dispersion
dispersion techniquestechniques that canthe
that can improve improve the dissolution
dissolution as well as bioavailability
as well as bioavailability are
are also briefly
also briefly outlined. It is strongly recommended that these promising pharmaceutical
outlined. It is strongly recommended that these promising pharmaceutical dispersion techniques can dispersion
techniques
well canthe
serve for well serve for the
development ofdevelopment of oral
oral dosage forms ofdosage
poorly forms of poorly
water-soluble water-soluble drugs.
drugs.
2. Interrelation between Dispersion and Drug Dissolution/Absorption

Dissolution/Absorption
Dispersion is
Dispersion is aatechnique
techniqueresulting
resultinginina asubstance
substancedispersed
dispersedoror embedded
embedded in in another
another molecule
molecule or
or continuous phase. A dispersion can be classified in a number of ways according to
continuous phase. A dispersion can be classified in a number of ways according to the size and the the size and the
of dispersed
state of dispersed matter.
matter.Generally,
Generally,there
thereare
arethree
threemain
maintypes
typesofofdispersions
dispersionsasas depicted
depicted inin Figure
Figure 1:
1: coarse dispersions (suspensions); colloidal dispersions (nanoparticles); and molecular
coarse dispersions (suspensions); colloidal dispersions (nanoparticles); and molecular dispersions dispersions
(true solution,
(true solution, liquid
liquid or or solid
solid state).
state). The term “dispersion” does not involve involve covalent
covalent bonds,
bonds, and
and
instead generates
instead generatesa areversible
reversible agglomerate
agglomerate containing
containing twotwo or more
or more substances
substances by van byder
van der forces,
Waals Waals
hydrogen bond, hydrophobic interaction and/or physical entanglement [23]. Dispersing a drug ina
forces, hydrogen bond, hydrophobic interaction and/or physical entanglement [23]. Dispersing
drug in material
another another material is an means
is an effective effective
to means
overcome to overcome the intermolecular
the intermolecular force betweenforcedrug
between drug
molecules
molecules
and realizeand realize
a quick a quick dissolution.
dissolution.
Figure 1. Dimension and physical properties of different

different kinds
kinds of
of dispersions.
dispersions.
Drug dissolution
Drug dissolutionrefers referstotoa aprocess
processthat that the
the interaction
interaction between
between drugdrug molecules
molecules is displaced
is displaced by
by the
the between
one one between the drugthe and
drugdissolution
and dissolution
medium medium [24].
[24]. If the If the intermolecular
intermolecular force betweenforcedrug
between drug
molecules
molecules is prematurely minimized, the dissolution will be significantly
is prematurely minimized, the dissolution will be significantly speeded up. Weak interactions between speeded up. Weak
interactions
drug and carrierbetween druginand
formed carrier formed
dispersions not onlyin dispersions
well maintain not only well maintain
the dispersion statethe
of dispersion
a drug in
state of a drug in a carrier, but also produce a higher internal energy
a carrier, but also produce a higher internal energy between drug and carrier than between drug between drug and carrier than
between drug molecules. This high-energy state greatly contributes
molecules. This high-energy state greatly contributes to the drug dissolution. Drug dissolution to the drug dissolution. Drug
dissolution
from from formulations
formulations is particularly is important
particularly forimportant
those drugs forwith
those drugsabsorption
a short with a short absorption
window, since
window, since they might have passed their absorptive sites
they might have passed their absorptive sites by the time they have dissolved. Dissolution by the time they have dissolved.
is the
Dissolution of
prerequisite is drug
the prerequisite
absorption by ofthe
drug absorption by
gastrointestinal the gastrointestinal
epithelia. Low aqueous epithelia. Low aqueous
solubility always results
solubility always results in a slow drug dissolution rate in the coarse
in a slow drug dissolution rate in the coarse dispersion systems. Formulating poorly soluble drugs dispersion systems. Formulating
poorly
into soluble
ultrafine drugs into
dispersions canultrafine
lower thedispersions
energy barrier canforlower the energy
dissolution barrier
in advance andfor dissolution
thus enhance the in
advance andrate.
dissolution thusForenhance
BCS IIthe dissolution
drugs, rate. For
it is a feasible wayBCStoIIpromote
drugs, ittheis aoral
feasible way toby
absorption promote
preparing the
oral absorption by preparing dissolution-unconfined dispersions.
dissolution-unconfined dispersions. However, for BCS IV drugs, it is not enough to improve the However, for BCS IV drugs, it is
not enough to improve the absorption extent utilizing a dispersion
absorption extent utilizing a dispersion strategy that merely overcomes the dissolution limit [25]. strategy that merely overcomes
the
It dissolution
must limit [25].
simultaneously It mustthe
surmount simultaneously
dissolution and surmount
absorption thebarriers.
dissolution and absorption
Formulation barriers.
techniques that
Formulation techniques that have the function of dispersion plus absorption-promoting
have the function of dispersion plus absorption-promoting effect are intrinsically required to develop. effect are
intrinsically required to develop. In this respect, lipid-based formulations
In this respect, lipid-based formulations have demonstrated great potential in absorption betterment have demonstrated great
potential
due to highinbiocompatibility
absorption betterment due towith
and interaction high thebiocompatibility
cell membrane [26]. andOfinteraction
course, lipid with the cell
dispersions,
membrane [26]. Of course, lipid dispersions, often in the form of
often in the form of nanoparticles, do not have to experience a dissolution process for subsequent nanoparticles, do not have to
experience aAnyhow,
absorption. dissolution process for
formulating subsequent
a poorly solubleabsorption. Anyhow,
drug into eligible formulating
dispersions can acreate
poorly soluble
favorable
drug into eligible dispersions can
conditions for its dissolution and absorption. create favorable conditions for its dissolution and absorption.
3. Solid Dispersion Technique

Technique
3.1. Solid Dispersions

3.1. Solid Dispersions
Solid
Solid dispersions
dispersions are are aa dispersion
dispersion mixture
mixture of of one
one oror more
more active
active ingredients
ingredients in in an
an inert
inert carrier
carrier at
at
the solid state prepared by melting, solvent, solvent-melting or other methods.
the solid state prepared by melting, solvent, solvent-melting or other methods. The approaches used The approaches used
for
for preparing
preparing SDs SDs are referred as
are referred solid dispersion
as solid dispersion techniques.
techniques. According
According to to Noyes–Whitney
Noyes–Whitney equation,
equation,
the
the dissolution
dissolution rate rate of
of aa drug
drug in in aa given
given medium
medium depends
depends on on thethe concentration
concentration difference
difference between
between
the
the dissolving interface and the bulk solution. For poorly water-soluble drugs, thethe
dissolving interface and the bulk solution. For poorly water-soluble drugs, dissolving
dissolving raterate
on
on
thethe interface
interface is positively
is positively associated
associated withwith the particle
the particle size size of drug,
of drug, especially
especially above above
100 nm100[27].
nm [27].
SDs
SDs can maximize
can maximize the the reduction
reduction of aofdrug‘s
a drug‘s size
size byby dispersing
dispersing it itinina alarge
largequantity
quantityof ofcarrier
carrier excipient,
excipient,
thus
thus increasing the absorption area, hence the bioavailability. In SDs, the drug can be in presence as
increasing the absorption area, hence the bioavailability. In SDs, the drug can be in presence as
molecular,
molecular,amorphous,
amorphous, microcrystal
microcrystal or colloidal state (Figure
or colloidal 2), which
state (Figure 2),is which
dependent on the formulation
is dependent on the
and preparative
formulation and process thereof.
preparative The high-energy
process thereof. The or metastableor
high-energy state of drug in
metastable SDsofmakes
state drug it intend
SDs
to dissolve in a medium, as opposed to the bulk drug. Apart from
makes it tend to dissolve in a medium, as opposed to the bulk drug. Apart from drug solubilization, drug solubilization, SDs can
also
SDs improve
can also the improvegastrointestinal absorptionabsorption
the gastrointestinal of poorly soluble
of poorly drugs
solubleby affecting
drugs bythe absorptive
affecting the
epithelia, in particular those surfactant-based and absorption enhancer-containing
absorptive epithelia, in particular those surfactant-based and absorption enhancer-containing SDs. SDs. Currently, the
scale-up
Currently, manufacturing of SDs has no longer
the scale-up manufacturing of SDsbeen
has noa limitation
longer been factor that hinders
a limitation factortheir
thatsuccess
hinderstotheir
the
clinical application. SDs can either serve as a pharmaceutical intermediate
success to the clinical application. SDs can either serve as a pharmaceutical intermediate used for used for preparation of
various dosage forms such as tablets, capsules and granules, or
preparation of various dosage forms such as tablets, capsules and granules, or as a final as a final pharmaceutical product,
e.g., pellets produced
pharmaceutical product,by one-step granulation
e.g., pellets producedinbyfluidized
one-stepbed. During the
granulation past decades,
in fluidized bed. there
During more
the
than ten commercial SDs-based products have been marketed [10].
past decades, there more than ten commercial SDs-based products have been marketed [10]. SDs areSDs are presenting an inspiring
vision to solve
presenting the dissolution
an inspiring vision and bioavailability
to solve issuesand
the dissolution of poorly soluble drugs.
bioavailability issues of Solid dispersion
poorly soluble
technique
drugs. Solid dispersion technique is more suitable for those drugs with low viscosity,glass
is more suitable for those drugs with low viscosity, less hygroscopicity and high less
transition
hygroscopicitytemperature.
and high glass transition temperature.
Figure 2.
Figure 2. Physical
Physicalstate
stateofofdrug
drugininsolid
soliddispersions:
dispersions:(a)(a)
molecular
molecularstate, forming
state, solid
forming solution;
solid (b)
solution;
amorphous
(b) amorphousstate, forming
state, forming amorphous
amorphous dispersions; (c)(c)microcrystal
dispersions; microcrystalstate,
state,forming
formingsimple
simpledispersions;
dispersions;
(d) colloidal state, forming colloidal dispersions.
(d) colloidal state, forming colloidal dispersions.
3.2. Carrier Excipients of SDs

3.2. Carrier Excipients of SDs
Carrier excipients play an essential role in formation of SDs, drug dissolution and absorption,
Carrier excipients play an essential role in formation of SDs, drug dissolution and absorption, and
and stability of SDs. Pharmaceutical excipients that have been used for production of SDs are
stability of SDs. Pharmaceutical excipients that have been used for production of SDs are exhaustively
exhaustively collected in Table 1. The carrier excipients of SDs are generally classified into low-
collected in Table 1. The carrier excipients of SDs are generally classified into low-molecular-weight
molecular-weight carriers, polymeric carriers and surfactant carriers [28]. They are highly water-
carriers, polymeric carriers and surfactant carriers [28]. They are highly water-soluble or hydrophilic
soluble or hydrophilic in nature in the case of poorly water-soluble drugs. In physical property, low-
in nature in the case of poorly water-soluble drugs. In physical property, low-molecular-weight
molecular-weight carriers are generally crystalline (e.g., saccharides), amphiphilic copolymer carriers
carriers are generally crystalline (e.g., saccharides), amphiphilic copolymer carriers are semi-crystalline
are semi-crystalline (e.g., Poloxamer), and homopolymer carriers are amorphous, such as
(e.g., Poloxamer), and homopolymer carriers are amorphous, such as polyethylene glycol (PEG) and
polyethylene glycol (PEG) and polyvidone (PVP). In the early development of SDs, low-molecular-
polyvidone (PVP). In the early development of SDs, low-molecular-weight carriers were tentatively
weight carriers were tentatively used, such as urea, saccharides and organic acids. These carrier
used, such as urea, saccharides and organic acids. These carrier excipients have high requirements for
excipients have high requirements for drug and solvent used. Moreover, the resulting SDs tend to
drug and solvent used. Moreover, the resulting SDs tend to become aging and unstable. In some cases,
become aging and unstable. In some cases, the low-molecular-weight compounds such as glucose
the low-molecular-weight compounds such as glucose and lactose negatively affect the gastrointestinal
and lactose negatively affect the gastrointestinal absorption of API, since the body preferably takes
up the nutrients rather than the non-nutritive excipients. Compared to low-molecular-weight
carriers, polymeric carriers possess larger molecular weight that can afford higher dispersibility and
absorption of API, since the body preferably takes up the nutrients rather than the non-nutritive
excipients. Compared to low-molecular-weight carriers, polymeric carriers possess larger molecular
weight that can afford higher dispersibility and stronger recrystallization inhibition for drugs. For this
end, polymeric carriers are currently widely used for the preparation of SDs, such as PEG, PVP and
hydroxypropylmethylcellulose (HPMC). Nevertheless, the high viscosity, plasticity and hygroscopicity
associated with macromolecules that make problems for production compromise their application in
SDs. Polymeric carriers, not including surfactants, have inadequate absorption-promoting effect for
poorly permeable drugs, which just provide necessary dispersibility. Carriers that possess a surfactant
property, beyond dispersion powder, have the advantage of increasing drug absorption through
interaction with the absorptive epithelia and inhibiting drug efflux transporters. To improve the
performance of polymeric carriers, copolymers and functionalized polymers (e.g., PEGylated polymers)
are developed for SDs. These novel carrier excipients are provided with excellent amphiphilicity,
formability, solubilization or absorption-promoting characteristics. Examples include fatty acid
macrogolglycerides (e.g., Gelucire 44/14 and Gelucire 50/13), poly(vinylpyrrolidone-co-vinyl acetate)
(PVP/VA), and poly(vinyl acetate-co-vinyl caprolactame-co-ethylene glycol) (Soluplus® ).
Table 1. Summary of the commonly used excipients for preparation of solid dispersions.
Carrier Excipients Example Comments Reference

Sucrose
Glucose Ordinary dispersibility; having potential
Saccharides [29–33]
Lactose effect on drug absorption.
Dextrose
Mannitol Ordinary dispersibility; weak [34,35]
Alcohols
Sorbitol absorption-promoting effect. [36]
Citric acid Effervescent dispersion;Simple dispersing [37,38]
Organic acids
Tartaric acid material, not applicable for acid-labile API. [39]
PEG 4000 High dispersibility; able to solubilize drug [40]
Polyethylene glycol
PEG 6000 and delay aging of SDs. [41,42]
PVP k15 High dispersibility; able to inhibit [42]
Polyvidone
PVP k30 recrystallization. [23,43,44]
HPMC [45,46]
High dispersibility; less plasticity and
Cellulose derivative HPC [47,48]
hygroscopicity, easy to process.
MC [49]
Poly(oxyethylene–co Poloxamer 188 High dispersibility; able to solubilize drug [50,51]
-oxypropylene) Poloxamer 407 and having absorption-promoting effect. [52]
Carbopol 947 Ionic polymers; good dispersibility; rapid [53]
Carboxypolymethylene
Carbopol 907 drug release in the intestine. [54]
Polyoxyethylene (40) Fine dispersibility; contribute less to
Polyoxyethylene stearate [55]
stearate dissolution; used rarely.
Functional dispersing materials; either able
Gelucire 44/14 [56,57]
Fatty acid macrogolglycerides to enhance dissolution or to promote
Gelucire 50/13 [58,59]
drug absorption.
Poly(vinylpyrrolidone-co-vinyl Fine dispersibility but low hygroscopicity;
PVP/VA [60,61]
acetate) superior to PVP in function.
Poly(vinyl acetate-co-vinyl Novel dispersing material; excellent
Soluplus® [62,63]
caprolactame-co-ethylene glycol) capability to form solid solution.
Gelucire 44/14 and Gelucire 50/13 are non-ionic water dispersible surfactants composed
of well-characterized PEG-esters, a small glyceride fraction and free PEG, which are able to
self-emulsify upon contact with aqueous media, forming a fine dispersion [64]. The surface
activity of such PEGylated carriers can improve the solubility and wettability of API in vitro and
in vivo. Enhanced bioavailability was reported to be related with strong inhibition of P-glycoprotein
efflux and metabolizing enzyme CYP3A4 [65]. Furthermore, this kind of carriers have good
thermoplasticity suitable for use in the melt process. PVP/VA copolymers possesses proper flexibility,
bioadhesion, water
Pharmaceutics 2018, 10, xremoistenability
FOR PEER REVIEWand hardness, and have found usage in SDs as carrier excipient [60].
6 of 32
In comparison with PVP, PVP/VA has a lower hygroscopicity but higher bioadhesion, conferring it
processing
easy and good
processing and good absorption-promoting
absorption-promoting capacity. These
capacity. advantages
These advantages make it more
make suitable
it more for
suitable
preparation
for preparation of SDs
of SDsfor for
oraloral
drug delivery.
drug Soluplus
delivery. ®
Soluplus , a polyethylene
® , a polyethylene glycol, polyvinyl
glycol, acetate
polyvinyl and
acetate
polyvinylcaprolactame-based
and polyvinylcaprolactame-based graftgraft
copolymer, has has
copolymer, been extensively
been extensivelyinvestigated
investigated forfor
preparation
preparation of
SDs [62,63]. Soluplus ® is ®
a transparent solid excipient and can form solid
of SDs [62,63]. Soluplus is a transparent solid excipient and can form solid solutions with many solutions with many drugs
[66]. Soluplus
drugs ® is an®innovative excipient that enables new levels of solubility and bioavailability for
[66]. Soluplus is an innovative excipient that enables new levels of solubility and bioavailability
poorly soluble APIs. Soluplus
for poorly soluble APIs. Soluplus ® shows superior
® shows performance
superior performance in forming solidsolid
in forming solutions in theinhot
solutions themelt
hot
extrusion process thanks to its high flowability and excellent extrudability.
melt extrusion process thanks to its high flowability and excellent extrudability. The resulting solid The resulting solid
solution makes
solution makes API available in
API available in aa dissolved
dissolved state,
state, resulting
resulting in in significantly
significantly enhanced
enhanced bioavailability
bioavailability
in vivo. The products above-mentioned represents the latest development in carrier excipients of
in vivo. The products above-mentioned represents the latest development in carrier excipients of SDs,
SDs,
which will
which will become
become the the dominant
dominant excipients
excipients for
for production
production of of SDs
SDs inin the
the future
future[67].
[67].
3.3. Preparative Processes of SDs

There are many kinds of techniques available for the production of SDs (Figure 3) [67], including
solvent
melting, solvent evaporation,
evaporation, solvent-melting,
solvent-melting, milling,milling, spray-drying,
spray-drying, hot-meltsupercritical
hot-melt extrusion, extrusion,
supercritical
fluid fluidKinetiSol
processing, ®
processing,
, etc.KinetiSol , etc. some
Among these,
® Among these, some
are applicable are applicable
to scale-up to scale-up
production of SDs,
production
while othersofjust
SDs,can
while others just caninbethe
be implemented implemented
laboratory. in
Inthe
thelaboratory.
following In the following
section, we givesection,
a brief
we give a brief
discussion on a discussion on a varietyprocesses
variety of preparative of preparative processes
involved in SDs.involved in SDs.
Figure
Figure 3.
3. Commonly
Commonly used
used preparative techniques for
preparative techniques for solid
solid dispersions.
dispersions.
3.3.1. Melting Method

3.3.1. Melting Method
Melting method is the earliest technique used for SDs preparation proposed by Sekiguchi and
Melting method is the earliest technique used for SDs preparation proposed by Sekiguchi and
Obi in 1961. They prepared sulfathiazole SDs by melting the drug with urea and investigated the
Obi in 1961. They prepared sulfathiazole SDs by melting the drug with urea and investigated the drug
drug absorption in the form of eutectic mixture [68]. In this process, drug and carrier are mixed evenly
absorption in the form of eutectic mixture [68]. In this process, drug and carrier are mixed evenly
and then heated to make all components molten. Subsequently, the molten materials are subjected to
and then heated to make all components molten. Subsequently, the molten materials are subjected
quenching against a cold plate to obtain the congealed mass. Melting method is a straightforward
to quenching against a cold plate to obtain the congealed mass. Melting method is a straightforward
and solvent-free process that is suitable for heat-stable drugs. But, this technique possesses some
and solvent-free process that is suitable for heat-stable drugs. But, this technique possesses some
shortfalls such as high-temperature operation and difficulty in the later processing (e.g., product
shortfalls such as high-temperature operation and difficulty in the later processing (e.g., product
harvesting and pulverization) that limits its success in industrial production. Nevertheless, melting
harvesting and pulverization) that limits its success in industrial production. Nevertheless, melting
method can yet be regarded as a convenient preparative process for preliminary survey on the
method can yet be regarded as a convenient preparative process for preliminary survey on the
suitability of solid dispersion if the candidate is thermostable. For example, Alhayali et al. prepared
suitability of solid dispersion if the candidate is thermostable. For example, Alhayali et al. prepared
ezetimibe/PVP/Poloxamer SDs by melt-quenching method [69]. The resulting SDs were more soluble
ezetimibe/PVP/Poloxamer SDs by melt-quenching method [69]. The resulting SDs were more soluble
than that produced by spray-drying.
than that produced by spray-drying.
3.3.2. Solvent Evaporation Method
Solvent evaporation method circumvents the suffering of high temperature, thus suitable for
heat-labile APIs. In this process, both drug and carrier are dissolved in organic solvent. After
3.3.2. Solvent Evaporation Method

Solvent evaporation method circumvents the suffering of high temperature, thus suitable for
heat-labile APIs. In this process, both drug and carrier are dissolved in organic solvent. After dissolving,
the solvent is evaporated using a special apparatus, rotatory evaporator. The solid mass is ground,
sieved and dried. It requires that the drug and selected carrier excipient can completely dissolve in
the solvent so as to form amorphous dispersions or solid solution. Of course, this approach likewise
confronts challenges from two aspects: to remove the residual solvent and to harvest the SDs. Ethanol is
the proposed solvent to use in the production of SDs. But, in some cases, other harmful solvents have
to be adopted in order to dissolve some water-insoluble drugs. If the issues of solvent residue and
product harvesting in the evaporator can be overcome, solvent evaporation method may after all
be accepted as workable technology for manufacturing SDs. With this technique, Dos Santos et al.
developed SDs of β-lapachone using PEG 6000 and PVP k30 as hydrophilic polymers and evaluated
the dissolution rate in aqueous medium [70].
3.3.3. Solvent-Melting Method

Solvent-melting method is an improvement to melting method and solvent evaporation method.
In this process, API is first dissolved in a small quantity of solvent and then added into the molten
carrier excipient. The solvent used can be removed through instant evaporation upon contacting
with the hot carrier or through an evaporator. This technique overcomes the disadvantages of high
temperature and the use of larger volume of solvent, which is suitable for moderately thermostable and
practically insoluble APIs. However, it also requires the therapeutic dose of API to be low. For instance,
Chen et al. prepared emulsified SDs containing docetaxel by three approaches, i.e., melting method,
solvent-melting method and solvent method [71]. It was shown that the dissolution of docetaxel from
SDs prepared by the solvent-melting method was higher than that prepared by the melting method.
3.3.4. Milling Method

Milling method, also known as co-grinding method, refers to a preparative process of SDs by
exploiting external mechanical power to knead the drug and carrier together. The drug and carrier are
physically mixed for some time in a blender and then charged into the chamber of a colloid mill or
fluid-energy mill to grind strongly with or without a small amount of solvent. The resulting dispersions
are collected, dried and pulverized ready for use. As an example, chlordiazepoxide and mannitol SDs were
produced by this method [72]. Of note, SDs prepared by this technique generally exhibit inferior dissolution
improvement than does the solvent evaporation or melting processes. Nevertheless, this technique is more
suitable for scale-up production of SDs, which can be easily carried out using a grind machine.
3.3.5. Spray-Drying Method

Spray-drying method refers to the preparation of SDs by dissolving or suspending the drug and
carrier in a common solvent or solvent mixture and then drying it in a hot air stream to remove the
solvent, which can be deemed as an improvement on the solvent method. Upon atomization, the
solvent promptly evaporates and SDs are formed simultaneously. Spray-drying method can directly
obtain SDs powders with good flowability or pellets by co-precipitating on the surface of blank beads
using fluid-bed coating. It can completely yield drugs in the amorphous or molecular state [23], though
sometimes drug crystallization partially takes place during the processing [73]. Spray-drying method
provides a high feasibility for scale-up production of SDs using spraying dryers, especially using a
fluidized equipment.
3.3.6. Supercritical Fluid Processing

Supercritical fluid (SCF) technology shows tremendous advantages and favorable operating
conditions (low temperature and high dissolving power), making the method more attractive for SDs
production. The most commonly used SCF for a variety of pharmaceutical applications is supercritical
carbon dioxide (CO2 ). Apart from lower critical temperature (Tc = 31.1 ◦ C) and pressure (Pc = 73.8 bar),
CO2 is nontoxic, nonflammable and inexpensive for use. In general, two basic SCF techniques can be
utilized to prepare SDs [74], namely rapid expansion of supercritical solution (RESS) and gas antisolvent
precipitation (GAS). In RESS technique, a solution containing drug and carrier in the supercritical state
is expanded rapidly through a nozzle. Due to rapid changes in density and solvent power, the solution
becomes highly supersaturated and consequently SDs are immediately formed [75]. In GAS technique,
drug and carrier are first dissolved in an organic solvent in a vessel. The solution is then pressurized
with a supercritical fluid, resulting in precipitation of the solid as a fine powder upon solvent extraction
by SCF [76]. Yin et al. prepared itraconazole SDs with HPMC, Pluronic F-127 and L-ascorbic acid
using GAS in an attempt to enhance its dissolution and bioavailability [77]. Powder X-ray diffraction
and Fourier transform infrared spectra indicated that itraconazole existed as an amorphous state in
SDs. SCF technology provides a novel alternative approach to preparing SDs with high surface area,
excellent flowability property and low solvent residue. This technology is equally applicable for scale-up
production of SDs and can avoid most of the drawbacks associated with the routine methods.
3.3.7. Hot-Melt Extrusion

Hot-melt extrusion is a process of applying heat and pressure to melt a polymer or mixture and
force it through an orifice in a continuous process, which was introduced into the pharmaceutical field
for SDs manufacturing in 1980s. The drug/carrier mixture is simultaneously melted, homogenized and
then extruded with a twin-screw extruder. The resulting intermediates can be further processed into
conventional dosage forms, such as tablets and capsules. The prominent advantage of hot-melt
extrusion lies in the shorter subjection to high temperature, approximately for 1~2 min, which
secures APIs that are somewhat heat-labile. Hot-melt extrusion has been successfully explored for the
preparation of Soluplus® /artemisinin SDs [63]. Although artemisinin is a thermolabile drug, it can
be processed under 110 ◦ C to produce the SDs. Hot-melt extrusion can be regarded as an innovation
toward the melting method, which reduces the difficulty of follow-up processing of SDs and is suitable
for mass production likewise.
3.3.8. KinetiSol® Technique

KinetiSol® technology represents a new processing paradigm for amorphous SDs, which can
satisfy some unmet needs. Poorly soluble drugs that have high melting point and low solubility in
organic solvents are becoming commonplace. KinetiSol® dispersing is a new fusion-based process that
has been developed to rapidly form SDs by exerting high shear and friction force without external
heat input [78]. It can be conducted in a custom built compounder designed for pharmaceutical
processing. The unit consists of a product containment vessel with a rotating shaft that has several
blades facing outward from it. During operation, the blades rotate at a high velocity that rapidly
processes the materials through the heat developed by shear and frictional motion of product within
the vessel. The fusion mode is unique among various possessing technologies of SDs where no
external energy input is required. This thermo-kinetic mixing is termed as KinetiSol® dispersing.
KinetiSol® dispersing rapidly transfers drug and polymer blends into a molten state that thoroughly
mixes the API with selected carrier excipient on a molecular level to achieve a single-phase amorphous
system. The real-time temperature of dispersions is monitored by a computer-controlled module.
Once reaching the designated end point, the molten material is immediately ejected from the unit.
The total processing time is generally less than 20 s, and elevated temperature is typically not more
than 5 s before discharge and cooling. KinetiSol® provides technical supplement to the hot-melt
extrusion and spray-drying processes when the API is thermally labile or unstable in organic solution.
For example, LaFountaine et al. utilized this technique to formulate ritonavir, a drug with thermal,
rheological and soluble limitations, into amorphous SDs using polyvinyl alcohol as carrier and
confirmed the feasibility of this processing for production of SDs [79]. KinetiSol® dispersing can be
operated semi-continuously in a custom built device with the product throughput up to 1000 kg/h.
Therefore, the technique is incredibly applicable to the commercial processing of SDs.
3.4. SDs-Based Dissolution and Bioavailability Enhancement

For poorly water-soluble drugs, especially BCS II ones, the limited step of gastrointestinal
absorption is the dissolution process of drugs from their preparations. According to Noyes-Whitney
equation, the dissolution rate is proportional to the surface area of dissolution. Reducing the particle size
or enhancing the dispersibility of drug is an effective means to increase the surface area of dissolution.
Solid dispersion technique not only can enhance the drug dispersibility, hence the surface area, but
also can result in a high-energy state of drug (e.g., amorphous, molecular or colloidal crystal state) that
largely facilitates the drug dissolution. In addition, some carrier excipients such as Poloxamer and
Gelucire have the abilities of promoting drug absorption and inhibiting drug efflux. These advantages
impart SDs excellent performances for oral delivery of various therapeutic agents [80].
Piperine, an alkaloid with poor water solubility, has been prepared into SDs with sorbitol, PEG
and PVP by solvent evaporation method [36]. Piperine SDs with three different kinds of carriers all
exhibited superior performance for enhancement of dissolution compared to physical mixtures and
pure piperine. The transformation from crystalline to amorphous form as well as the assistance of
hydrophilic carriers was assumed responsible for dissolution improvement. Deng et al. developed
SDs formulations using Pluronic F68 and PEG as carriers to enable the oral delivery of α-asarone, a
phytomedicine with poor solubility and bioavailability [81]. SDs prepared using hydrophilic polymers
significantly enhanced the dissolution in vitro and oral bioavailability in vivo of α-asarone, showing a
great potential for developing oral dosage form of α-asarone. In another example, SDs formulations
consisting of itraconazole and Soluplus®were produced by hot-melt extrusion [82]. Higher maximum
plasma concentration (Cmax ) and area under plasma concentration-time curve (AUC) were achieved
through SDs after oral administration compared to the levels resulting from a marketed product
(Sporanox® ). Efonidipine hydrochloride ethanolate (NZ-105) is a novel API with calcium antagonist
activity, but has a very low solubility in water. Otsuka et al. employed the microwave technology,
a modified melting method, to prepare NZ-105 SDs using hydroxypropyl methylcellulose acetate
succinate as a carrier and urea as an auxiliary component [83]. It was showed that SDs prepared through
such technique resulted in eightfold improvement in oral bioavailability compared with NZ-105 alone
in beagle dogs. These cases indicated that SDs as a dosage form or intermediate have become a viable
option for addressing the dissolution and bioavailability issues of poorly water-soluble drugs.
4. Lipid Dispersion Technique

Lipid dispersion refers to formation of nanoparticles using lipid excipients. Distinct from solid
dispersion, the products resulting from lipid excipients are generally in the form of liquid dispersion.
Even though solidified by spray-drying or lyophilization, they possess poor powder property, low
storage stability, and great difficulty to pulverize. Nonetheless, formulating drug into lipid carriers
represents an effective dispersion technique that can enhance the dispersibility of drug and create a
supersaturated concentration in the gastrointestinal lumen for drug absorption. Herein, it is obviously
inappropriate using the terms of solubility and dissolution to describe the dissolution characteristics
of lipid-formulated drugs. Solubilization and release turn into the descriptors to characterize the
drug lipid dispersions. Lipid dispersion technique is more applicable for formulation of highly
lipophilic, low-melting-point, and poorly permeable drugs. These drugs are easily prepared into lipid
nanoparticles with satisfactory physiochemical stability.
4.1. Lipid Dispersions Accomplished by Lipid Nanoparticles

Dispersion of drug can either be accomplished through excipient-free top-down (milling) and
bottom-up (recrystallizing) methods that forms drug nanocrystals [84], or through excipient-assisted
nanosizing that forms nanoparticles [85]. The drug dissolves or disperses in the hydrophobic
excipients followed by being formulated into a variety of lipid-based nano-formulations. In general,

the hydrophobic excipients are lipids or amphiphilic materials containing lipid moiety. A liquid
formulation containingnanoparticles
formulation containing nanoparticlesorornanocarriers
nanocarriers is normally
is normally termed
termed as “nanosuspensions”,
as “nanosuspensions”, too.
too. From the viewpoint of dispersion, the nanosuspensions resemble
From the viewpoint of dispersion, the nanosuspensions resemble the drug nanocrystals the drug nanocrystals where
where the
the difference is only that the drug is dispersed in the lipid core rather than
difference is only that the drug is dispersed in the lipid core rather than in the bulk solution. On the in the bulk solution.
On thehand,
other othernanosuspensions
hand, nanosuspensions can also canbealso be transferred
transferred into theinto the solid
solid modality
modality by dehydration.
by dehydration. The
The
solidified or dried products are the same as SDs made from polymers with respect totodispersibility.
solidified or dried products are the same as SDs made from polymers with respect dispersibility.
Poorly
Poorly water
water soluble
soluble drugs
drugs cancan completely
completely form form highly
highly dispersed
dispersed lipid
lipid dispersions
dispersions with
with suitable
suitable
excipients.
excipients. However, lipid dispersions both in the form of nanosuspensions and lyophilized state
However, lipid dispersions both in the form of nanosuspensions and lyophilized state are
are
different
different from
from SDs
SDs with respect to
with respect to drug
drug release,
release, absorption
absorption feature,
feature, processibility,
processibility, usage
usage and
and storage.
storage.
The
The most
most predominant
predominant difference
difference is is the
the drug
drug transport
transport process
process where
where drugdrug release
release does
does not
not have
have toto
take
take place for lipid dispersions and the active ingredient can be assimilated through nanocarriers or
place for lipid dispersions and the active ingredient can be assimilated through nanocarriers or
reconstituted
reconstituted colloidal
colloidalparticles [86].[86].
particles SDs SDs
accelerate the drug
accelerate thedissolution and absorption
drug dissolution by improving
and absorption by
the apparent
improving thesolubility
apparent and dissolving
solubility rate of drug,
and dissolving ratewhile
of drug,lipid dispersions
while augmentaugment
lipid dispersions the surface
the
area for drug
surface area absorption by providing
for drug absorption bysupersaturated drug concentration
providing supersaturated drug in the gastrointestinal
concentration in the
lumen (Figure 4). Lipid dispersion and solid dispersion achieve the same
gastrointestinal lumen (Figure 4). Lipid dispersion and solid dispersion achieve the same goal by goal by different means.
Lipid-based formulations
different means. Lipid-based provide a straightforward
formulations provide aand ready-to-useand
straightforward dispersion for drug
ready-to-use absorption
dispersion for
that undergoes no disintegration and dissolution processes.
drug absorption that undergoes no disintegration and dissolution processes.
Figure 4. Schematic illustration of supersaturated state of drug in nanoparticle dispersion system.

Figure 4. Schematic illustration of supersaturated state of drug in nanoparticle dispersion system.
4.2. Commonly used Lipid Dispersion Systems

4.2. Commonly Used Lipid Dispersion Systems
4.2.1. Solid Lipid Nanoparticles
4.2.1. Solid Lipid Nanoparticles
Solid lipid nanoparticles (SLNs) represent the first generation of lipid nanoparticles composed
Solid lipid nanoparticles (SLNs) represent the first generation of lipid nanoparticles composed
of a high-melting-point solid lipid and a small number of surfactant, which are developed on the base
of a high-melting-point solid lipid and a small number of surfactant, which are developed on the
of from O/W emulsions [20]. SLNs present a solid state both at room and body temperature, thus
base of from O/W emulsions [20]. SLNs present a solid state both at room and body temperature,
possessing high physical stability. They show multiple advantages as drug delivery system, such as
thus possessing high physical stability. They show multiple advantages as drug delivery system,
high drug loading, sustaining drug release, facilitating drug absorption, and ease of scale-up
such as high drug loading, sustaining drug release, facilitating drug absorption, and ease of scale-up
production [87]. These features of SLNs make them more suitable for formulating poorly water-
production [87]. These features of SLNs make them more suitable for formulating poorly water-soluble
soluble drugs to ameliorate their oral bioavailability. High-pressure homogenization (HPH) is the
drugs to ameliorate their oral bioavailability. High-pressure homogenization (HPH) is the most
most frequently used technique for the production of SLNs [88]. SLNs have become as a potential
frequently used technique for the production of SLNs [88]. SLNs have become as a potential enhancer
enhancer of bioavailability for various poorly soluble drugs [26].
of bioavailability for various poorly soluble drugs [26].
4.2.2. Nanostructured
4.2.2. Lipid Carriers
Nanostructured Lipid Carriers
SLNs exclusively
SLNs exclusively involve
involve solid
solid lipids
lipids that
that have
have aa high
high crystallinity
crystallinity in
in the
the lipid
lipid core,
core, thus
thus existing
existing
potential drug expulsion upon storage [89]. The solid lipids typically exhibit low capacity
potential drug expulsion upon storage [89]. The solid lipids typically exhibit low capacity of dissolving of
dissolving
poorly poorly
soluble drugssoluble drugs
compared compared
with with In
liquid lipids. liquid lipids. Innanostructured
this context, this context, nanostructured lipid
lipid carriers (NLCs)
carriers (NLCs) are invented to overcome the limitations associated with SLNs owing to
are invented to overcome the limitations associated with SLNs owing to the highly ordered structure. the highly
ordered structure. NLCs are derived from SLNs by incorporating spatially incompatible liquid lipid
into the solid core. The participation of liquid lipid creates an imperfect crystal matrix, resulting in
higher drug loading and drug/lipid compatibility [90]. Depending on superb solubilizing and
NLCs are derived from SLNs by incorporating spatially incompatible liquid lipid into the solid core.
The participation of liquid lipid creates an imperfect crystal matrix, resulting in higher drug loading
and drug/lipid compatibility [90]. Depending on superb solubilizing and dispersing capacities, NLCs
have turned into a promising nanocarrier and have been widely investigated for oral drug delivery [91].
4.2.3. Nanoemulsions
Pharmaceutical nanoemulsions are generally O/W emulsions in the nanometer scale made up
of oil phase, water phase, emulsifier, and a selected co-emulsifier. By virtue of facile preparation and
smaller particle size, nanoemulsions have been getting considerable attention in recent years as smart
drug delivery system [92]. The oil used in the nanoemulsions formulation is a liquid lipid, which
provides a great practicality for high load of poorly soluble drugs. Nanoemulsions can spontaneously
form in the presence of massive surfactants (~20% of the oil phase, w/w) [93]. The excellence in
particle size (<100 nm) renders nanoemulsions a high dispersibility for drug and a great surface
area for absorption. Nanoemulsions can either be water-containing formulation or water-free
formulation. An example as water-free formulation is the self-microemulsifying drug delivery system
(SEDDS), generally being developed into the dosage form of soft capsules [94]. Drug dispersing
(molecularly dissolving) in the oil phase of nanoemulsions is equivalent to dispersing in the solid
carrier. They just appear in different state and dispersibility, but have no substantial distinction.
Therefore, nanoemulsions containing liquid lipid (oil) are also a kind of efficient dispersing vehicle.
4.2.4. Liposomes and Phytosomes

Liposomes are spherical vesicles consisting of one or more bilayers formed by phospholipid
and cholesterol. Due to flexible controllability and good biocompatibility, liposomes have become a
talented drug delivery system, and several liposomal products are clinically available at present [95].
Liposomes not only can encapsulate hydrophilic molecules but also encapsulate hydrophobic
molecules [96–99], thanks to holding both aqueous cavity and hydrophobic bilayer in structure.
Among various preparative processes of liposomes, the film hydration method is the commonly used
and more mature technique. In the process of lipid film formation, the drug is utterly dispersed in the
lipid mixture. Liposomes as oral delivery vehicle have been extensively explored for a variety of active
therapeuticals and have shown a huge potential for enhancement of bioavailability [100].
Unlike liposomes, phytosomes are not vesicle-based drug carrier. They are phospholipid
dispersions containing a natural active ingredient [101]. Phytosomes are chemically conjugated
drug-phospholipid complexes prepared by reacting a botanical active ingredient with phospholipid
in an opportune solvent, which can be considered as novel entities [102]. The plant extracts or its
monomers are firmly bound to phosphatidylcholine, a main constituent of phospholipids, resulting in
a lipid compatible molecular complex. Phytosomes can significantly improve the pharmacokinetic
and pharmacodynamic profiles of phytomedicines compared to the unmodified modalities [103].
Phytosomes are originally developed for handling the water-soluble phytomedicines with poor oral
absorption due to their large molecular size and lack of lipophicity, but now not limited to water-soluble
active compounds. Some highly hydrophobic molecules have been successfully formulated into
phytosomes, such as silymarin [104], curcumin [105], and apigenin [106]. Phytosome technology has
been widely utilized to potentiate various active ingredients including phytomedicines and chemical
drugs, and has proven to be a useful tool for strengthening the potency of poorly water-soluble drugs.
4.3. Lipid Excipients

Lipids are substances consisting of fatty acids and their derivatives, including oils, fats, waxes,
sterols, monoglycerides, diglycerides, triglycerides, and phospholipids. Lipid-based drug delivery
systems are mostly constructed upon lipid vesicles or matrixes. The lipid excipients have abilities
to solubilize, disperse, encapsulate and stabilize lipophilic drugs that are poorly water-soluble in
nature, thus enhancing their bioavailability. The unique characteristics of lipid excipients have been
motivating the pharmaceutical practitioners to develop various lipid-based formulations for coping
with challenges from compounds with inadequate solubility and permeability [107]. Apart from the
true solution and simple dosage forms, almost all colloidal dispersion systems are largely dependent
on the use of lipid excipients. For instance, in the formulation of emulsions, the hydrophilic drugs are
solubilized in the inner oil phase of emulsion droplets. In the case of liposomes, the hydrophilic drugs
are entrapped into the lipid bilayer of vesicles. In SLNs and NLCs, the hydrophilic drugs are dissolved
or dispersed in the lipid core of nanoparticles. For phytosomes, the natural compounds are physically
coupled or chemically conjugated with the phospholipids. Lipid excipients are generally inert, in vivo
biodegradable and biocompatible with the body, thus possessing high safety and accessibility for drug
delivery. Many kind of lipid excipients have been approved by the regulatory agency (Food and Drug
Administration, FDA) for use in pharmaceutical products [108]. Meanwhile, severe adverse reactions
have not been reported on lipid excipients or formulations as yet. Table 2 lists the commonly used
lipid excipients at large that are involved in the lipid-based formulations. With the advancement of
excipients, it will usher in the rapid development of lipid-based formulations to revitalize poorly
soluble and/or permeable drugs.
Table 2. Commonly used lipid excipients in lipid-based nanocarriers.
Lipid Excipient Chemical Carrier Type Comments Reference

Liquid, high biocompatibility,
Nanoemulsions;
Soybean oil Long-chain triglycerides negligible physiological effect, [109–112]
NLCs
solubilizing capacity a little weak.
Liquid, good health benefits,
Nanoemulsions;
Olive oil Long-chain triglycerides containing more monounsaturated [110,113–116]
NLCs
fatty acid, easy to emulsify.
Liquid; rich in essential fatty acids,
Medium/long-chain having tocopherols, tocotrienols,
Hemp oil triglycerides blended with Nanoemulsions phytosterols, phospholipids, etc., [93,117]
low-molecular-weight lipids excellent hydrophilicity and
self-emulsifiability.
Liquid, fine solubilizing capacity,
Caprylic/capric Nanoemulsions;
Medium-chain triglycerides good compatibility with other lipids, [118–123]
triglycerides NLCs
easy to emulsify.
liquid, fine solubilizing and
Medium/short-chain Nanoemulsions;
Captex® series emulsifying capacities, miscible with [124–126]
triglycerides SEDDS; NLCs
other lipids.
Liquid, excellent solvent powder for
Medium-chain Nanoemulsions;
Capmul MCM many organic compounds, can use [127–130]
mono/diglycerides SEDDS; NLCs
as emulsifier.
Nanoemulsions; Liquid, properties similar to that of
Capmul MCM C8 Glyceryl monocaprylate [131–133]
SEDDS; NLCs Capmul MCM.
Liquid, solubilizer, bioavailability
Maisine TM 35-1 Glyceryl monolinoleate SEDDS [134–137]
enhancer, oil phase in SEDDS.
SEDDS; NLCs; Liquid, lipid dispersion agent,
PeceolTM Glyceryl monooleate [138–140]
Cubosomes; oil-soluble surfactant, moisturizer.
Liquid, water insoluble surfactant of
Nanoemulsions; SEDDS, solubilizer, bioavailability
Lauroglycol® 90 Propylene glycol monolaurate [141–143]
SEDDS; NLCs enhancer, skin penetration
solubilizer enhancer.
Propylene glycol Nanoemulsions; Liquid, properties similar to that of
CapryolTM series [144–146]
monocaprylate SEDDS; NLCs Lauroglycol® 90.
Liquid, water dispersible surfactant,
Nanoemulsions; able to self-emulsify, good miscibility
Labrafil M 1944 CS Oleoyl polyoxyl-6 glycerides [147–149]
SEDDS; NLCs with other lipids, bioavailability
enhancer, solubilizer, co-emulsifier.
Liposomes; Semi-solid, an amphiphilic lipid, used
Phosphatidylcholine blended
phytosomes; sorts as vesicles-forming material,
Lecithin with a small amount of other [150–154]
of lipid solubilizing, emulsifying, and
lipid components.
nanoparticles stabilizing agents.
Table 2. Cont.
Lipid Excipient Chemical Carrier Type Comments Reference

Semi-solid, non-ionic water soluble
Lipid blends consisting of surfactant for solid/semi-solid
mono-, di-, or triglycerides SEDDS; SLNs; dispersions and SEDDS,
Gelucire® series [146,155,156]
and fatty acid NLCs bioavailability enhancer,
macrogolglycerides micelles-forming material,
solubilizing and wetting agent.
Solid, lipid matrix for SLNs and
Monostearin Glyceryl monostearate SLNs; NLCs NLCs; thickening, solidifying and [133,157]
control release adjusting agent.
NLCs, hydrophobicity and melting
Precirol® ATO 5 Glyceryl distearate SLNs; NLCs [158,159]
point greater than
glyceryl monostearate.
Solid, high melting point lipid, used
Compritol® 888 SLNs; NLCs; solid for preparation of SLNs and NLCs,
Glyceryl behenate [160–162]
ATO lipid dispersions lipid matrix for sustained release,
used as atomized powders.
Trilaurin Glyceryl trilaurate SLNs; NLCs; NLCs, sustained release material, [163–165]
thickening agent.
Solid, wax-like substance, used for
Cetyl palmitate Palmityl palmitate SLNs; NLCs; [166,167]
preparation of SLNs and NLCs.
Solid, as lipid matrix of SLNs and
Tripalmitin Glyceryl tripalmitate SLNs; NLCs; [168,169]
NLCs, skin-conditioning agent.
4.4. Lipid Nanocarriers-Based Enhancement of Bioavailability

The merits of lipid-based formulations for oral drug delivery have been profoundly
reviewed [2,107,170]. Lipid-based formulations, in most cases, are colloidal dispersion systems that
circumvent the rate-limiting steps of drug absorption related to conventional solid dosage forms, such
as tablets, capsules and granules. It does not require the formulations to disintegrate and dissolve for
drug absorption. Lipid-based formulations in the form of nanosuspensions provide a sufficiently large
surface for drug absorption in the gastrointestinal gut. Even being digested, they can also result in a
supersaturated drug concentration by way of reconstitution into micelles [171]. These characteristics create
favorable conditions for drug absorption. Oral bioavailability of lipophilic drugs such as itraconazole can
be improved even though they are co-administered with a fat-rich meal or vegetable oil. Lipid nanocarriers
have positive effects on drug absorption by making supersaturated drug concentration, preventing drug
precipitation, enhancing membrane permeability, inhibiting efflux transporters, reducing CYP enzymes,
providing bioadhesion to the absorptive epithelia, stimulating secretion of chylomicrons and improving
lymphatic transport [172]. As a result of lipid dispersion, it greatly augments the absorption rate and extent
of lipophilic drugs. Oral route is the most preferred option that patients take a medication. Taking full
advantage of the potential of lipid nanocarriers will enable some drug candidates that are normally
believed unpromising to stay away from suspension or abortion.
To ameliorate the oral bioavailability, various lipid nanocarriers have been explored for oral
delivery of poorly water-soluble drugs. For instance, Wang et al. utilized SLNs to orally delivery
sorafenib, an anticancer agent for hepatocarcinoma, in order to achieve a desirable liver targeting [173].
The designed sorafenib-loaded SLNs possessed a smaller particle size and high entrapment efficiency
and resulted in enhancement of drug selectivity and bioavailability after oral administration compared
with its suspensions. In our group, we developed different kinds of NLCs for the oral delivery of
oridonin and tripterine, two natural active ingredients. A biotin-modified NLCs formulation was first
investigated for its performance in bioavailability enhancement of oridonin [174]. Compared with the
common NLCs, biotin-modified NLCs apparently improved the absorption rate of oridonin rather than
absorption extent. However, both biotinylated NLCs and common NLCs significantly enhanced the
bioavailability of oridonin relative to the suspensions formulation. The second typical example is the
broccoli lipid-based NLCs for the oral delivery of tripterine. We extracted the lipidic components from
broccoli using 1-octanol as solvent in an attempt to further the intestinal permeability of NLCs [175].
The results showed that the intestinal permeability and bioavailability of tripterine were largely
improved through such functional NLCs. Nanoemulsions, another representative lipid nanocarrier,
have also demonstrated a great potential in promoting oral absorption of poorly water-soluble drugs.
Yin et al. developed biocompatible nanoemulsions using hemp oil and less surfactants for the oral
delivery of baicalein [93], and Chavez-Zamudio et al. prepared lysophosphatidylcholine-stabilized
nanoemulsions for the oral delivery of curcumin [176]. The constructed nanoemulsion systems
unexceptionally enhanced the oral bioavailability of payloads in comparison with their coarse
dispersions. A nanoemulsion system loading dabigatran etexilate phospholipid complex was also
proposed for use to improve the lipophilicity and oral bioavailability of drug [177]. In terms of
liposomes, there were also some reports related to their use in the oral delivery of poorly water-soluble
drugs [100]. As an example, Rushmi et al. formulated black seed oil (Nigella sativa) into liposomes
using the ethanol injection method aiming to enhance the oral bioavailability and improve the
therapeutic activity of such analgesic in small animal studies of analgesia [178]. The in vivo studies
showed that the liposomal formulation demonstrated a significant analgesic activity in mice. In recent
years, phytosomes (phospholipid complexes) are also being widely used for oral drug delivery [103].
For example, Freag et al. developed self-assembled phytosomal nanocarriers for improving the
solubility and oral bioavailability of celastrol [151], and Telange et al. developed apigenin-loaded
phytosomes to improve the drug’s aqueous solubility, dissolution, in vivo bioavailability, and
antioxidant activity [106]. It demonstrates that phytosome technique is a promising and viable
formulation strategy for enhancing the delivery efficiency of poorly water-soluble drugs.
Although lipid carriers have been proven to be potential as oral delivery vehicles, it should
be noted that the lipolysis of lipid carriers substantially takes place in the gastrointestinal transport
process. As a matter of fact, the in vivo degradation of lipid nanoparticles is not contradictory with their
absorption-promoting effect, since lipids can facilitate drug absorption by co-transport and cytosis in the
form of intact nanoparticles or reconstituted micelles [20]. The in vivo lipolysis-reconstitution mechanism
of lipid nanocarriers have been confirmed by Wu’s laboratory utilizing an environment-responsive
probe [179,180]. The fact that water-quenched fluorescent dye encapsulated in lipid nanoparticles can
be rekindled by the reconstitution of lipolytic products after lipolysis of nanoparticles provides pivotal
evidence for the gastrointestinal disposition of lipid nanocarriers.
4.5. Translation of Liquid Lipid Dispersions into Solid Formulations

Lipid-based formulations are generally liquid preparations that have low physiochemical stability,
which will cause inconveniences for storage and quality control. Although lipid nanocarriers belong
to colloidal dispersion system, they are just stable on a short-term basis. When storing for a long time,
the phenomena of nanoparticle aggregation and precipitation would inevitably occur due to particle
collision and gravitational settling [181]. The stability study for lipid nanoparticles in literature is relatively
insufficient, and the investigation period for reserved samples is also short, oftentimes not more than
one month. For oral delivery, the physical instability of lipid dispersions is not a serious problem, unless
rancidity or contamination takes place in the formulation. However, in aqueous conditions, the lipid
excipients and drugs tend to deteriorate and degrade, resulting in harmful chemical molecules. In view of
safety and conveniences for storage and use, it is best to solidify the liquid preparations. Despite numerous
merits, one long-standing historical challenge for the practical application of lipid nanocarriers remains
unmet: redispersibility after drying. How to realize the translation of liquid lipid dispersions into solid
formulations has gotten into the research focus of nanomedicine [182].
4.5.1. Freeze Drying

Freeze drying is a practicable technique to settle the long-term storage of colloidal nanoparticles.
By removing the water from the aqueous dispersions, a dried form of lipid dispersions is harvested
whereby to improve the physiochemical stability of colloidal nanoparticles. Freeze drying of
nanosuspensions not only requires consideration for the formulation factors, but also the lyophilization
process. The process conditions have a crucial effect on the stability of nanoparticles during and after freeze
drying. During lyophilization, the nanoparticles will be subjected to various stresses, such as particles
agglomeration and desiccation, which may be detrimental to the stability of nanoparticles. Therefore, a
proper cryoprotectant and optimized lyophilization process must be adopted so as to minimize damage to
the nanostructures. For example, Howard et al. tested nine kinds of cryoprotectants and different freeze
drying conditions to optimize lyophilization process of solid lipid nanoparticles loading dexamethasone
palmitate for improving the long-term stability [183]. The resulting lyophilized SLNs exhibited slightly
larger but acceptable particle size and polydispersity index. Drug loading and particle shape were well
maintained by lyophilization. The lyophilized SLNs possessed a consistent particle size and less drug
content loss during a three month period. To improve the dissolution and intestinal permeability of
diosmin, Freag et al. utilized the lyophilization technique to prepare diosmin-loaded phytosomes [184].
The lyophilized phytosomal nanocarriers exhibited the lowest particle size to 316 nm, adequate ζ-potential
for stabilization of colloidal particles, and good in vitro stability. Phytosomes obtained by freeze drying
significantly improved the drug’s dissolution and permeation characteristics. Freeze drying is proven to
be an effective means to achieve a long-term stability of lipid nanocarriers.
4.5.2. Spray Drying

Spray drying is proposed for use as a promising alternative to stabilize and preserve the colloidal
nanoparticles in a dried form. In spraying drying, the liquid is promptly evaporated when the liquid
lipid dispersions are sprayed into the hot air stream, in which solid micropowders such as starch and
aerosil or blank pellets are pre-charged. The nanoparticles immediately precipitate on the surface
of carriers upon water evaporation. This dehydration-solidification technique intended for lipid
nanoparticles is normally termed as nano spray drying [185,186]. It is worth noting that spray drying
of lipid nanoparticles must prevent particle adhesion, coalescence, and fusion. It requires the spray
speed, temperature and carrier excipients to be of optimal conditions. By controlling the processing
parameters precisely, the maintenance of colloidal characteristics of nanoparticles can be substantiated
through spray drying. For instance, Tian et al. investigated and characterized solidification of
nanostructured lipid carriers (NLCs) onto pellets by spray drying using a fluid-bed [187]. To achieve
good coating and redispersibility of nanoparticles, PVP k17 was used as the carrier dispersant to load
the solidified NLCs. It was found that reconstituted NLCs had spherical morphology similar to the
original modality, but had an augmented particle size. Nevertheless, both solidified NLCs and original
NLCs showed parallel in vitro lipolysis profiles and pharmacokinetics in beagle dogs. The study
indicates that spray drying is a practicable approach to solidifying lipid nanoparticles [188].
4.5.3. Self-Emulsifying
Self-emulsifying drug delivery systems (SEDDS) are emulsifiable water-free formulations made
up of oil and emulsifier with or without hydrophilic co-solvent. SEDDS are utilized to solve
low bioavailability issues of poorly soluble and highly permeable drugs [189]. Self-emulsifying
formulations can rapidly disperse in the gastrointestinal tract in contact with the digestive fluids
under the agitation of gastrointestinal peristalsis to spontaneously form nanoemulsions, so-called
in situ self-emulsification. SEDDS are physically stable formulations and can be manufactured into the
semisolid soft capsules (e.g., Sandimmun® ) [190] or liquisolid tablets [191]. Water-free formulations
offer an opportunity to realize the commercial success of nanoemulsions.
4.5.4. Developing Liquisolid Hybrid Formulations

This approach converts liquid lipid nanoparticles into powdered form and then formulates them
into tablets or capsules, which differs from the following liquisolid system directly developed from
a drug solution. The liquid lipid dispersions must be concentrated to a relatively small volume that
can be fully adsorbed by additional adjuvants, such as microcrystalline cellulose (MCC) and aerosil.
Liquisolid compact tablets or capsules can be obtained after lipid dispersions are loaded into adsorptive
excipients and form dry-looking, freely flowing and compressible powders. For example, Nnamani et al.
developed low-dose liquisolid tablets of artemether-lumefantrine (AL) from NLCs and estimated their
Pharmaceutics
potential 2018,
for 10, delivery
oral x FOR PEERofREVIEW
AL in malariogenic Wistar mice [192]. The results highlighted 16 of 32
that
AL-loaded NLCs could be further processed into oral tablets to improve the patient’s compliance.
5. Liquisolid Dispersion Technique
5. Liquisolid Dispersion Technique
5.1. Overview of Liquisolid System
5.1. Overview of Liquisolid System
Molecular solution represents the highest dispersion of drug in a variety of formulations. In SDs,
Molecular
a poorly water solution
soluble represents
drug can form the highest dispersion
solid solution withof drug in a variety
a suitable carrier of formulations.
excipient. Solid
In SDs, a poorly water soluble drug can form solid solution with
pharmaceutical intermediates are readily processed into a final dosage form, such as tablets and a suitable carrier excipient.
Solid pharmaceutical
capsules. Accordingly,intermediates
there should be areareadily processed
possibility by which intoliquid
a final dosage form,
substances can be such as tablets
changed into
and solid
the capsules.
form.Accordingly, there should
Liquisolid dispersion be a possibility
technique by which
is the right means liquid substances solidification
to materialize can be changed of
into the solid form. Liquisolid dispersion technique is the right means to
liquefied drug. A liquisolid system refers to formulation implemented by conversion of lipophilic materialize solidification of
liquefied
drug in a drug. A liquisolid
nonvolatile solvent system refers to formulation
into dry-looking, implemented
freely flowing by conversion
and compressible of lipophilic
powders drug
by blending
aindrug
a nonvolatile
solutionsolvent into dry-looking,
with adsorptive freely
excipients flowing by
followed andprocessing
compressible intopowders
suitableby blending
dosage formsa drug
(as
solution with
illustrated adsorptive
in Figure excipients
5) [193]. followed by
The liquisolid processing
system greatlyinto suitablethe
maintains dosage forms (as
molecular illustrated
dispersion of
in Figure 5)
candidate [193].
drug andThe liquisolid
provides the system greatly maintains
most favorable dissolution thecondition,
molecularfreelydispersion of candidate
diffusing into the
drug and provides
dissolution medium.the most favorable
Therefore, dissolution
the liquisolid system condition,
possessesfreely diffusing
a number into the dissolution
of advantages: (1) drug
medium. Therefore,
dispersion in the solidthe liquisolid
formulation system possesses aliquid
as solubilized number of advantages:
form; (2) enabling (1)solidification
drug dispersion in the
of liquid
solid formulation
drug; as solubilized
(3) quicker drug dissolution liquid
fromform; (2) enabling
formulations duesolidification
to superior of liquid drug;
wettability and(3)miscibility;
quicker drug (4)
dissolution from formulations due to superior wettability and miscibility; (4)
low cost of production; and (5) liquisolid dispersions able to be developed either into immediately- low cost of production; and
(5) liquisolid
release or intodispersions able to be
sustained-release developed either
preparations. intothese
Besides immediately-release or into sustained-release
advantages, it requires the dose of drug
preparations.
for developing Besides these advantages,
a liquisolid system to beit relatively
requires the low dose of drugthat
in order for the
developing a liquisolid
drug solution can be system
fully
to be relatively
loaded within the lowsolid
in order thatLiquisolid
carriers. the drug solution
dispersion cantechnique
be fully loaded withinanthe
is becoming solid carriers.
innovative and
Liquisolid dispersion
promising formulation technique
strategyisthat
becoming an innovative
can improve and promising
the dissolution formulation strategy
and bioavailability of poorly that can
water
improve the dissolution and bioavailability of poorly water soluble drugs
soluble drugs [194]. Liquisolid dispersion technique is mainly implemented to enable the formulation[194]. Liquisolid dispersion
technique
of is mainlydrugs.
amphiphobic implemented to enable
These drugs tendthe to
formulation
precipitate of amphiphobic
from carriers, drugs.
evenThese
thoughdrugs tendare
they to
precipitate
temporarilyfrom carriers,ineven
entrapped though they are temporarily entrapped in nanoparticles.
nanoparticles.
Figure
Figure 5.5.Formulation
Formulationstrategy
strategy of poorly
of poorly waterwater soluble
soluble drugsthe
drugs using using the liquisolid
liquisolid dispersion dispersion
technique.
technique.
5.2. Formulation Components of Liquisolid System
5.2. Formulation Components of Liquisolid System
Liquisolid dispersion system is developed based on the principle of converting liquid medication into
freelyLiquisolid dispersion
flowing, readily systemand
compressible is apparently
developeddry based on the
powders principle
by physical of converting
adsorption liquid
using selected
medication into freely flowing, readily compressible and apparently dry powders by
excipients. In addition to common excipients involved in tablets or capsules, a liquisolid dispersion physical
adsorption usingconsists
system generally selected excipients. solvent,
of non-volatile In addition tomaterial
carrier common andexcipients involved
coating material. Theinformulation
tablets or
capsules, a liquisolid dispersion system generally consists of non-volatile solvent, carrier
composition of a typical liquisolid system (e.g., liquisolid compact tablets) is generalized in Table material
3.
and coating material. The formulation composition of a typical liquisolid system (e.g., liquisolid
compact tablets) is generalized in Table 3.
Table 3. Components generally involved in a liquisolid formulation.
Excipients Type Characteristics Function Examples Reference

PEG series; glycerin; propylene glycol;
Inert, water-miscible, compatible
Non-volatile solvent acts as a solvent and polysorbate; Cremophor® EL;
Non-volatile solvent with drug candidate, excellent [195–202]
a binding agent in a liquisolid system. Transcutol HP; CapryolTM 90;
dissolving powder.
2-pyrrolidone; Labrasol, etc.
Microcrystalline cellulose (MCC, e.g.,
Avicel® , Ceolus® , Vivapur® ,
Porous, large specific surface area, Carrier material plays a fundamental role
Emcocel® ); lactose; mannitol;
Carrier material sufficient adsorption ability, good in forming the dry form of powders from [196,197,203–207]
Magnesium Aluminometasilicate
flowability and compressibility. liquid medication.
(Neusilin® ); Dibasic calcium phosphate
anhydrous (Fujculin® );
Coating material contributes to covering
Colloidal silicon dioxide (e.g., Aerosil® ,
Ultrafine and highly adsorptive the wet surface of particles by adsorbing
Coating material Cab-O-Sil® M5); Neusilin® ; Calcium [195,196,204,208,209]
particles, good flow-aided effect. excess liquid to ensure a good flowability
Silicate (Florite® )
of powders.
Disintegrant, lubricant, release Sodium starch glycolate (CMS-Na);
The selected adjuvants can improve the
Other adjuvants modifiers, flavoring and coloring crospovidone; L-HPC; PVP k25; PEG [22,210]
quality of solid dosage forms.
agents, etc. 6000; HPMC; Eudragit.
Non-volatile solvent
Non-volatile solventused usedin in liquisolid
liquisolid systems
systems should
should be inert,
be inert, lowlylowlyviscous, viscous, preferably
preferably water-
water-miscible and meanwhile have a strong solvent power as liquid
miscible and meanwhile have a strong solvent power as liquid vehicle. Various solvents with high vehicle. Various solvents with
high boiling
boiling point point are explored
are explored for thefor the formulation
formulation of liquisolid
of liquisolid systems, systems,
including including PEG, propylene
PEG, propylene glycol,
glycerin, and polysorbate. The non-volatile solvent simultaneously acts as a solventaand
glycol, glycerin, and polysorbate. The non-volatile solvent simultaneously acts as solvent and a
a binding
agent in the liquisolid formulation. It has been shown that the solvent had a significant effect on effect
binding agent in the liquisolid formulation. It has been shown that the solvent had a significant drug
on drug release from the liquisolid system [211]. For rapid-release purpose,
release from the liquisolid system [211]. For rapid-release purpose, a liquid vehicle in which the API a liquid vehicle in which
themost
is API soluble
is most is soluble
normallyis normally
selected.selected.
In the case In the case of sustained-release
of sustained-release preparation,preparation, the solvent
the solvent with a
with a highly viscosity is usually used to dissolve the drug, such as glycerin and Cremophor ® EL.
highly viscosity is usually used to dissolve the drug, such as glycerin and Cremophor EL. Of course, ®
Of course, other hydrophilic or amphipathic ® ® ® are

other hydrophilic or amphipathic solvents solvents
such assuch as Transcutol
Transcutol ®, Solutol , Solutol and Labrasol
® and Labrasol ® are also
also oftentimes
oftentimes involved
involved in theinliquisolid
the liquisolid systems.
systems.
In the
In theliquisolid
liquisolidsystem,
system, carrier
carrier materials
materials playplay the role
the key keyinrole in gaining
gaining the dry the formdry form of
of powders
powders from the solubilized liquid drug. Carrier materials mainly contribute
from the solubilized liquid drug. Carrier materials mainly contribute to liquid adsorption. It requires to liquid adsorption.
It requires
that the carrierthatshould
the carrier
be porous should and be porous
possess largeand possess
enough largesurface
specific enough area specific surface
(SSA) [212]. area
Carrier
(SSA) [212].
selection Carrier
depends selection
on its depends on
liquid adsorption its liquid
capacity, adsorption
flowability capacity,and
of powders flowability of powders
compressibility. The
most commonly used carriers in liquisolid formulations include MCC (e.g., Avicel® andMCC
and compressibility. The most commonly used carriers in liquisolid formulations include Ceolus(e.g.,
®),
Avicel ® and Ceolus® ), lactose, sorbitol, anhydrous dibasic calcium phosphate (Fujicalin® ), amorphous
lactose, sorbitol, anhydrous dibasic calcium phosphate (Fujicalin ), amorphous magnesium ®
magnesium aluminometasilicate ® ), etc. Among these, Fujicalin® and Neusilin® represent the
aluminometasilicate (Neusilin®),(Neusilin
etc. Among these, Fujicalin® and Neusilin® represent the newly-
newly-developed carrier materials,
developed carrier materials, which exhibit especiallywhich exhibit especially large
large SSA,SSA, upuptoto40 40 mm22/g/gand
and 300
300 m 2
m2/g,
/g,
respectively [210]. Neusilin ® not only can be used as a carrier material, but also function as a coating
respectively [210]. Neusilin not only can be used as a carrier material, but also function as a coating
®
material by
material by virtue
virtue of of excellent
excellent adsorption
adsorption and and flowability
flowability properties
properties [204].
[204].
Coating material
Coating material playsplays aa keykey role
role in
in covering
covering the the wet
wet carrier
carrier particles
particles to to form
form dry-looking
dry-looking and and
freely flowing powders. It should be a material possessing fine and
freely flowing powders. It should be a material possessing fine and highly adsorptive micropowders highly adsorptive micropowders
that can
that can adsorb
adsorb excess
excess liquid
liquid to to ensure
ensure goodgood flowability
flowability of of the
the admixture.
admixture. In In the
the liquisolid
liquisolid system,
system,
coating material
coating material and and carrier
carrier material
material mustmust be be used
used in in conjunction
conjunction in in order
order to to enhance
enhance the the flowing
flowing
and compressing properties of powders as illustrated in Figure
and compressing properties of powders as illustrated in Figure 6. Currently, the most commonly 6. Currently, the most commonly
used coating
coating material
material in in the ® and
used the liquisolid
liquisolid formulation
formulation is is colloidal
colloidal silicon
silicon dioxide,
dioxide, such such as as Aerosil
Aerosil® and
Cab-O-Sil®
Cab-O-Sil M5. Amorphous
® M5. Amorphous silica silica gel
gel (e.g., Syloid®
(e.g., Syloid Neusilin®®,,calcium
), Neusilin
®), calcium silicate (Florite®®)) and
silicate (Florite and ordered
ordered
mesoporous silicates that have suitable flowability and compressibility
mesoporous silicates that have suitable flowability and compressibility can also be used to prepare can also be used to prepare
liquisolid formulation
liquisolid formulation [11]. [11].
Figure
Figure 6.6.Formation process
Formation of dry-looking,
process freelyfreely
of dry-looking, flowing and compressible
flowing powderspowders
and compressible in the liquisolid
in the
system.
liquisolid system.
Apart from non-volatile solvent, carrier and coating materials, the liquisolid system usually use
Apart from non-volatile solvent, carrier and coating materials, the liquisolid system usually use
some other additives to develop solid dosage forms. Tablets or capsules normally experience the
some other additives to develop solid dosage forms. Tablets or capsules normally experience the
disintegration process before dissolution. Therefore, disintegrants such as sodium starch glycolate,
disintegration process before dissolution. Therefore, disintegrants such as sodium starch glycolate,
croscarmellose sodium, and low-substituted hydroxypropyl cellulose (L-HPC) are generally
croscarmellose sodium, and low-substituted hydroxypropyl cellulose (L-HPC) are generally included
included in liquisolid formulation to allow a fast disintegration. In addition, release modifier (e.g.,
in liquisolid formulation to allow a fast disintegration. In addition, release modifier (e.g., HPMC) and
HPMC) and crystal growth inhibitor (e.g., PVP) are frequently contained in the liquisolid compact
crystal growth inhibitor (e.g., PVP) are frequently contained in the liquisolid compact tablets [203,213].
tablets [203,213]. These additives improve the dissolution profile and physical stability of liquisolid
These additives improve the dissolution profile and physical stability of liquisolid systems.
systems.
5.3. Preparation of Liquisolid Compacts

A given powder can only retain limited amount of liquid medication while maintaining
acceptable flowability and compressibility. Before preparation, it generally performs the pre-
5.3. Preparation of Liquisolid Compacts

A given powder can only retain limited amount of liquid medication while maintaining acceptable
flowability and compressibility. Before preparation, it generally performs the pre-formulation studies,
including solubility study, determining the flowable liquid retention potential (Φ-value), calculating
the liquid load factor (Lf), and measuring the repose angle of admixture. Theory on liquisolid system
was developed in 1992 by Spireas and his colleagues based on the concept of powdered solution [214].
According to the pre-formulation’s information, the candidate drug is dissolved in the required
quantity of nonvolatile solvent, and then the resulting drug solution is incorporated into the calculated
amounts of carrier and coating materials. Generally, the mixing process is carried out in three steps as
proposed by Spireas and Bolton [215]. During the first stage, the liquid medication and carrier material
were mixed using a blender at a speed of 60 rpm for 1 min around in order to evenly distribute the
liquid mixture in the powders. Afterwards, the coating material in calculated amount is added and
blended homogeneously. In the second stage, the resulting admixture was evenly spread as a uniform
layer on the surfaces of a mortar and left standing for approximately 5 min to facilitate a complete
adsorption of liquid medication by the powder particles. In the third stage, the powders were scraped
off from the mortar surface and then blended with a suitable disintegrant at a higher rate for another
several minutes. Finally, the prepared liquisolid system that has been subjected to critical evaluation
for flowability and compressibility can be further compressed or encapsulated into a specific solid
dosage form [216].
5.4. Liquisolid System-Based Enhancement of Dissolution and Bioavailability

Liquisolid dispersion technique has been widely used to improve the dissolution and
bioavailability of poorly water-soluble drugs with a low dose [210]. A liquisolid formulation
allows an insoluble drug to be solubilized, almost molecularly dispersed in a solid dosage form,
which greatly enhances the dissolution rate of solubility-limiting drugs due to ameliorative wetting
property and dissolution surface area, hence the oral bioavailability. There a great number of poorly
water-soluble drugs have been developed into liquisolid formulations in an attempt to enhance their
dissolution and/or bioavailability, including Rosuvastatin [195], Aprepitant [217], Fenofibrate [218],
Curcumin [198], Indomethacin [219], Griseofulvin [205], Loperamide [208], Ketoprofen [220],
Olmesartan Medoxomil [207], Loratadine [221], Nimesulide [222], Furosemide [223], Lovastatin [224],
Carbamazepine [203], Telmisartan [200], Valsartan [225], and Mosapride Citrate [196].
Sharma et al. developed a liquisolid system to improve the dissolution rate and bioavailability
of curcumin using PEG as liquid vehicle, Avicel® PH102 as carrier material and Aerosil® as coating
material [198]. The systems were screened for pre-compression properties before being compressed to
liquisolid tablets, followed by post-compression tests and in vitro dissolution. The optimized formulation
exhibited a higher accumulative drug release than directly compressed tablets. Ex vivo permeation
of curcumin was significantly enhanced, and the oral bioavailability was increased 18.6-fold in New
Zealand rabbits. The authors concluded that solubility promotion of curcumin in liquisolid tablets
contributed significant enhancement to its permeation and bioavailability. Fexofenadine hydrochloride
(FXD) possesses poor water solubility and pharmacokinetic property. To increase its oral bioavailability
and shorten the time to reach the maximum plasma concentration, Yehia et al. formulated FXD into
liquisolid tablets with propylene glycol or Cremophor® EL, Avicel® PH102 and Aerosil® 200 as functional
excipients [199]. It was found that Cremophor-based liquisolid powders showed acceptable to good
flow property suitable for compaction. The physicochemical properties and disintegration time were
appropriate for tablet qualities. Dissolution of prepared tablets could be completed within 5 min, and the
oral bioavailability of FXD was enhanced by 62% relative to commercial tablets (Allegra® ).
In another work, Khames et al. developed risperidone liquisolid formulation using versatile
solvents (Transcutol HP, Labrasol and Labrasol/Labrafil (1:1) mixture) as liquid vehicles and evaluated
its dissolution and bioavailability [202]. The results showed that liquisolid tablets prepared using
Labrasol/Labrafil (1:1) mixture as liquid vehicle with 10% risperidone was a compatible formula
with low drug crystallinity and higher dissolution rate (100% in 25 min). The oral bioavailability of
risperidone was significantly enhanced through liquisolid tablets in comparison to the conventional
tablets (1441.711 µg·h/mL vs. 321.011 µg·h/mL in AUC). The examples above indicate that liquisolid
technique was a potential tool in increasing dissolution and bioavailability of poorly water-soluble drugs.
6. Other Dispersion Techniques
6.1. Co-Precipitation Technique

Co-precipitation technique refers to a process by dissolving a drug in a solvent containing an
insoluble adsorbing material and then evaporating them to result in drug precipitation onto the
surface or the internal pore of the absorbing material, thus forming solid dispersions [226]. It is
different from the solvent evaporation method used for preparation of SDs. In this process, the drug is
completely dissolved in a volatile solvent, but the carrier material is suspended in the selected solvent.
The carrier materials are generally water insoluble and possess strong adsorptive capacity and high
porosity. The commonly used carrier materials include crospovidone (PVPP), sodium starch glycolate
(CMS-Na), L-HPC, mesoporous silica, mesoporous carbons, etc. Upon the solvent evaporating,
the drug precipitates onto the carrier excipient to form drug/excipient dispersions. The viscosity of
dispersions produced by such technique is lower than that prepared by the solvent evaporation method,
but the drug dispersibility is lower than the latter. Shin et al. prepared coprecipitates of furosemide and
crospovidone by a solvent evaporation method [227]. The dissolution rate of furosemide was markedly
enhanced by coprecipitating with crospovidone. They confirmed that physicochemical modifications
at the molecular level have taken place between furosemide and crospovidone in the coprecipitates that
changed the thermal property and increased the dissolution of furosemide. Planinsek et al. prepared
carvedilol/porous silica dispersions from acetone solution through evaporating the solvent to cause
drug precipitation and adsorption into the pores of silica [228]. The dispersions resulted in a significant
improvement in drug dissolution compared with raw material and its physical mixture. It was shown
that amorphous form of carvedilol in the dispersions, improved wettability and weak interactions
between the drug and carrier contributed to dissolution enhancement.
6.2. Concomitant Crystallization Technique

In recent years, pharmaceutical cocrystals have gained increasing attention to developing drug in
solid-state formulations [229], which can be achieved through a concomitant crystallization technique.
Cocrystal complexes structurally contain drug candidate and co-crystallizing agent (coformer).
Cocrystals are formed by intermolecular interactions or synthons between the drug and co-crystal
former, which results in the creation of supramolecular assembly. The physiochemical properties of
drug depends on its molecular order in the solid form, and changes in intermolecular interactions
have important effects on these properties, including melting point, stability, solubility and dissolution.
From the micromilleu of drug being, co-crystals can be viewed as a kind of pharmaceutical dispersions.
Although the drug is always crystallized in the cocrystals, the physiochemical properties can be
greatly modified through developing cocrystals. For poorly soluble drugs, the most predominant
changes in cocrystal system refer to its apparent solubility and dissolution improvement [230].
Pharmaceutical cocrystals can be manufactured by two basic methods: (1) solvent-free technique
(grinding, solvent-assisted grinding and sonication) and (2) solvent-based technique (slurring, solvent
evaporation, and antisolvent cocrystallization). For example, Du et al. successfully obtained
two novel cocrystals of lamotrigine with 4,40 -bipyridine and 2,20 -bipyridine as coformer by neat
grinding and liquid assisted grinding [231]. The resulting cocrystals exhibited significantly improved
solubility and dissolution rate in comparison with the monocrystal drug. In another case, a highly
soluble carbamazepine (CBZ) cocrystal with glutaric acid (GLA) was developed by Yamashita and
Sun through solvent evaporation [232]. The dissolution rate of CBZ was improved in the case
of CBZ/GLA cocrystals due to solubility increase and precipitation inhibition during dissolution.
Pharmaceutical co-crystals provide new opportunity to modify the physicochemical properties of

poorly water-soluble drugs whereby to enhance their dissolution rate and bioavailability.
6.3. Inclusion Complexation Technique

In most cases, inclusion complexes are not regarded as a pharmaceutical dispersion. However, it is
unreasonable to exclude inclusion complexes from pharmaceutical dispersions, since the guest molecule
(drug) is fully incorporated into the cavity of host molecule that results in a complete dispersion of drug.
It is merely that, in solid dispersions, the drug is embedded between carrier molecules, but in inclusion
complexes, the drug is embedded within the molecule. In addition, solid dispersions and cyclodextrin
inclusion complexes shared some common preparative techniques, such as kneading method and solvent
evaporation method. From these points of view, drug inclusion into another molecule can be deemed
as a practicable dispersion technique. Cyclodextrin complexation, but not limited to cyclodextrins, has
shown the potential to precisely improve the aqueous solubility, dissolution rate, and bioavailability of
poorly water-soluble drugs [233]. For instance, Ezawa et al. prepared piperine/cyclodextrin inclusion
complexes by the co-grinding method and tested their solubility and dissolution [7]. They found that
piperine could form inclusion complexes with α-cyclodextrin and γ-cyclodextrin in a stoichiometric ratio
of 1/2 and 1/1, respectively, and the complexes of piperine/α-cyclodextrin exhibited higher solubility
than that of piperine/γ-cyclodextrin. Mady et al. utilized a coprecipitation method to investigate the
complexing effect of finasteride, a BCS II drug, with different kinds of β-cyclodextrin derivatives [234].
It was found that the dimethyl-β-cyclodextrin (DM-β-CYD) inclusion system gave rise to the highest
complexation efficiency for solubility improvement and hence the bioavailability. These cases indicate
that dispersion resulting from inclusion complexation can act as the enhancement of pharmacokinetics of
poorly water-soluble drugs [235].
7. Conclusions
To date, oral administration remains the most preferred route that patients take the
medicine, and solid dosage forms are the prevalent modality of pharmaceutical preparations.
Pharmaceutical processing always results in a dispersion of a drug in the solid, semisolid or liquid
excipient in particulate, colloidal, amorphous or molecular state. Super-advanced dispersion can
engender additional benefits for dissolution and bioavailability of poorly soluble drugs, which, of
course, greatly depends on effective dispersion techniques. It has been shown that solid dispersion,
lipid-based dispersion and liquisolid dispersion are becoming useful tools to solve the formulation
challenges of poorly soluble drugs.
Author Contributions: H.X. and Y.Z. collected the materials, X.Z. wrote the original manuscript and Z.M.
reviewed and edited the article.
Funding: This research was funded by the National Natural Science Foundation of China (81673604), the
Fundamental Research Funds for the Central Universities (21617473), the Natural Science Foundation of
Guangdong Province (2016A030310085) and the Scientific Research Cultivation and Innovation Foundation
of Jinan University (21616319; 21616317).
Conflicts of Interest: The authors declare no conflict of interest.
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Pharmaceutical Dispersion Techniques For Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs

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pharmaceutics

Keywords: poorly water-soluble drug; pharmaceutical dispersion; dissolution; bioavailability

Pharmaceutics 2018, 10, 74; doi:10.3390/pharmaceutics10030074 www.mdpi.com/journal/pharmaceutics

preparative techniques and oral delivery efficiency of these dispersion-based formulations. In

2. Interrelation between Dispersion and Drug Dissolution/Absorption

Figure 1. Dimension and physical properties of different

3. Solid Dispersion Technique

3.1. Solid Dispersions

3.2. Carrier Excipients of SDs

Carrier Excipients Example Comments Reference

3.3. Preparative Processes of SDs

3.3.1. Melting Method

3.3.2. Solvent Evaporation Method

3.3.3. Solvent-Melting Method

3.3.4. Milling Method

3.3.5. Spray-Drying Method

3.3.6. Supercritical Fluid Processing

3.3.7. Hot-Melt Extrusion

3.3.8. KinetiSol® Technique

3.4. SDs-Based Dissolution and Bioavailability Enhancement

4. Lipid Dispersion Technique

4.1. Lipid Dispersions Accomplished by Lipid Nanoparticles

excipients followed by being formulated into a variety of lipid-based nano-formulations. In general,

Figure 4. Schematic illustration of supersaturated state of drug in nanoparticle dispersion system.

4.2. Commonly used Lipid Dispersion Systems

4.2.4. Liposomes and Phytosomes

4.3. Lipid Excipients

Table 2. Commonly used lipid excipients in lipid-based nanocarriers.

Lipid Excipient Chemical Carrier Type Comments Reference

Lipid Excipient Chemical Carrier Type Comments Reference

4.4. Lipid Nanocarriers-Based Enhancement of Bioavailability

4.5. Translation of Liquid Lipid Dispersions into Solid Formulations

4.5.1. Freeze Drying

4.5.2. Spray Drying

4.5.4. Developing Liquisolid Hybrid Formulations

Table 3. Components generally involved in a liquisolid formulation.

Excipients Type Characteristics Function Examples Reference

Of course, other hydrophilic or amphipathic ® ® ® are

5.3. Preparation of Liquisolid Compacts

5.3. Preparation of Liquisolid Compacts

5.4. Liquisolid System-Based Enhancement of Dissolution and Bioavailability

6. Other Dispersion Techniques

6.1. Co-Precipitation Technique

6.2. Concomitant Crystallization Technique

Pharmaceutical co-crystals provide new opportunity to modify the physicochemical properties of

6.3. Inclusion Complexation Technique

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