2019

pharmaceutics
Article
The Self-Assembly Phenomenon of Poloxamers and
Its Effect on the Dissolution of a Poorly Soluble Drug
from Solid Dispersions Obtained by Solvent Methods
Joanna Szafraniec 1,2, * , Agata Antosik 1 , Justyna Knapik-Kowalczuk 3,4 ,
Krzysztof Chmiel 3,4 , Mateusz Kurek 1 , Karolina Gawlak 2 , Joanna Odrobińska 2 ,
Marian Paluch 3,4 and Renata Jachowicz 1
1 Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy,
Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;
[email protected] (A.A.); [email protected] (M.K.); [email protected] (R.J.)
2 Department of Physical Chemistry and Electrochemistry, Faculty of Chemistry, Jagiellonian University,
Gronostajowa 2, 30-387 Krakow, Poland; [email protected] (K.G.);
[email protected] (J.O.)
3 Division of Biophysics and Molecular Physics, Institute of Physics, University of Silesia, Uniwersytecka 4,
40-007 Katowice, Poland; [email protected] (J.K.-K.);
[email protected] (K.C.); [email protected] (M.P.)
4 Silesian Center for Education and Interdisciplinary Research, 75 Pulku Piechoty 1a, 41-500 Chorzow, Poland
* Correspondence: [email protected]; Tel.: +48-12-62-05-606

Received: 13 February 2019; Accepted: 15 March 2019; Published: 19 March 2019
Abstract: The self-assembly phenomenon of amphiphiles has attracted particular attention in recent
years due to its wide range of applications. The formation of nanoassemblies able to solubilize
sparingly water-soluble drugs was found to be a strategy to solve the problem of poor solubility of
active pharmaceutical ingredients. Binary and ternary solid dispersions containing Biopharmaceutics
Classification System (BCS) class II drug bicalutamide and either Poloxamer® 188 or Poloxamer® 407
as the surface active agents were obtained by either spray drying or solvent evaporation under
reduced pressure. Both processes led to morphological changes and a reduction of particle size,
as confirmed by scanning electron microscopy and laser diffraction measurements. The increase
in powder wettability was confirmed by means of contact angle measurements. The effect of an
alteration of the crystal structure was followed by powder X-ray diffractometry while thermal
properties were determined using differential scanning calorimetry. Interestingly, bicalutamide
exhibited a polymorph transition after spray drying with the poloxamer and polyvinylpyrrolidone
(PVP), while the poloxamer underwent partial amorphization. Moreover, due to the surface activity
of the carrier, the solid dispersions formed nanoaggregates in water, as confirmed using dynamic
light scattering measurements. The aggregates measuring 200–300 nm in diameter were able to
solubilize bicalutamide inside the hydrophobic inner parts. The self-assembly of binary systems was
found to improve the amount of dissolved bicalutamide by 4- to 8-fold in comparison to untreated
drug. The improvement in drug dissolution was correlated with the solubilization of poorly soluble
molecules by macromolecules, as assessed using emission spectroscopy.
Keywords: bicaludamide; poloxamer; evaporation; spray drying; dissolution enhancement;

nanoaggregates; self-assembly
Pharmaceutics 2019, 11, 130; doi:10.3390/pharmaceutics11030130 www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2019, 11, 130 2 of 22
1. Introduction
The issue of poor solubility of active pharmaceutical ingredients (APIs) is one of the biggest
limitations for drug development. It is a matter of concern, as the bioavailability depends on the
dissolution of drug in the gastrointestinal fluids. The main determinants of the dissolution kinetics
in vivo are solubility and surface area of the particles. The solubility is a function of the crystal lattice
energy and the affinity of solid phase to the solvent. Thus, three groups of strategies that have
been implemented to improve the rate of dissolution and solubility rely on: (1) the reduction of the
intermolecular forces in solid phase, (2) the enhancement of the solid–solvent interaction, and (3) the
increase of the surface area available for solvation (according to the Noyes–Whitney equation) [1].
Due to the fact that almost 50% of currently marketed drugs and over 70% of new chemical
entities exhibit low solubility in water, numerous techniques have been developed to overcome this
problem [2]. Common strategies include pH adjustment, formation of salts, cosolvency, formation
of cocrystals and inclusion complexes, particle size reduction, supercritical fluid technology (SCF),
and self-emulsification [3,4]. Recently, nanotechnology has emerged as a technique that leads to
the formation of robust delivery systems. Numerous attempts have been applied to obtain several
types of delivery systems, i.e., micelles [5], liposomes [6], capsules [7,8], protein nanocontainers [9],
and silica-based nanoparticles [10,11]. Poorly water-soluble drugs have been frequently processed with
hydrophilic polymers, as the molecular dispersion of drug molecules within the matrix provides better
dissolution of the drug. Moreover, when the systems were further formulated into the nanoparticles,
the results were more pronounced [12–14].
The main factors affecting the choice of a particular method are the physicochemical characteristics
of drugs and carriers. Solid dispersions are commonly formed to enhance the water solubility of APIs;
however, the number of marketed products arising from that strategy is rather low. This is a result of the
thermal instability of drug and carrier during preparation of systems, a poor in vitro–in vivo correlation,
and instability during storage [15]. However, the simplicity of preparation, low cost, and great
improvements in the dissolution of poorly water-soluble drugs have made the solid dispersions
widely investigated. Experimental and theoretical approaches have been involved to determine the
thermodynamic properties of APIs dispersed in polymer matrices as well as the mechanisms and
factors affecting their stability [16–18].
The concept of solid dispersion—one of the earliest methods of solubility enhancement—was
introduced in 1961 by Sekiguchi and Obi, who prepared eutectic mixtures containing microcrystalline
drug and a water-soluble carrier [19–22]. Although crystalline forms provide high stability and
chemical purity, the lattice energy barrier is the major limitation affecting the dissolution rate.
Thus, amorphous carriers such as polyvinylpyrrolidone (PVP) [23,24] and hydroxypropylmethyl
cellulose (HPMC) [25,26] have been introduced to prepare amorphous solid dispersions (ASDs).
The highly water-soluble amorphous carriers provide stabilization of APIs, increasing the wettability
and dispersibility of the drug [27–29]. They limit the precipitation of a drug in water; however,
the supersaturation may lead to precipitation and recrystallization of APIs, which negatively affects
the bioavailability of the drug. To face this problem, surface active agents or self-emulsifiers such as
poloxamers (PLXs) [30,31], Tween 80 [32], or sodium lauryl sulfate (SLS) [33] have been introduced.
They improve the dissolution rate as well as physical and chemical stability of the supersaturated
system. Surfactants or emulsifiers enhance the miscibility and thus limit the recrystallization rate of
the drug. Moreover, they are able to absorb onto the outer layer of drug particles or form micelles
encapsulating drug particles, effectively preventing drug precipitation [34]. On the other hand,
many surfactants can absorb moisture, which may result in phase separation during storage, an increase
in drug mobility, and conversion from the amorphous or metastable form to the more stable crystalline
one. They may change the physical properties of the matrix, increase the water content and cause
adverse side effects in vivo. [35] Thus, their use has to be cautious and their amounts well adjusted.
Among the strategies that allow for obtaining solid dispersions, solvent methods are often used.
In these techniques the drug and the carrier are dissolved in a volatile solvent such as ethanol [36] or
methylene chloride–ethanol mixture [37] that is further evaporated. It requires sufficient solubility
of the drug as well as the carrier in the solvent. Moreover, the type of used solvent, the temperature,
and rate of its evaporation are of key importance due to the fact that the concentration of residual
solvent needs to be below the detection limit after drying. One of the strategies utilized to fulfill that
requirement is the use of low-toxicity solvent mixtures, e.g., water with ethanol, which decreases
the amount of each solvent in dry formulation. However, this strategy sometimes fails due to
insufficient dissolution of components at a given ratio [35]. Usually, a second drying step is applied
to completely removed the solvent as it may lower the glass transition temperature, enhancing the
recrystallization tendency.
The common feature of evaporation approaches is the removal of small droplets or thin
layers of the solvent from different surfaces. It may lead to the crystal growth of oriented
morphology as described for droplet evaporative crystallization or microwave-accelerated evaporative
crystallization [38–40]. The crystallization of the celocoxib–PVP mixture was found to generate
drug crystals of improved dissolution characteristics [41]. Other approaches such as the evaporative
antisolvent method and supercritical carbon dioxide evaporation were applied to the formation of
nanoparticles, drug-loaded micelles, and liposomes characterized by improved dissolution of the
drug [42,43].
Commonly used solvent methods include vacuum drying using rotary evaporators [44],
spray drying [45], or freeze-drying [46], among others. In rotary evaporators, solvents are removed
under reduced pressure, limiting thermal decomposition of the components of the mixture as
organic solvent evaporation occurs at low temperature. Spray drying combines four processes, i.e.,
(1) atomization of the liquid containing dissolved or suspended drug, which is transported into the
nozzle and then sprayed onto fine droplets, (2) mixing the liquid with the drying gas, (3) evaporation,
and finally (4) separation of obtained particles from the gas using cyclone [47]. Generally, the spray
drying process can be applied for the generation of amorphous materials as well as a technique for
particle engineering, i.e., particle size reduction [48].
In the work reported herein, we study the self-assembly phenomenon of solid dispersions
containing either Poloxamer® 188 or Poloxamer® 407 and its effect on dissolution enhancement of
the poorly water soluble drug bicalutamide (BCL). Poloxamers are the nonionic surfactants widely
used in pharmaceutical formulations as emulsifiers, wetting agents and solubilizers. They have been
introduced into solid dispersions to enhance solubility and dissolution profiles of poorly water-soluble
APIs from solid dosage forms [49,50]. Bicalutamide was used as a model drug. It is a non-steroidal
antiandrogenic drug assigned to Biopharmaceutics Classification System (BCS) class II because of
poor water solubility (below 3.7 mg/L) and high membrane permeability (logP = 2.92) [51–53]. It is
known to exhibit polymorphism and undergo mechanical activation upon milling [54–58]. Obtained
results indicate that the formation of solid dispersions by means of solvent methods led to the changes
of particles in solid state, i.e., morphological features, increased wettability, phase transition (in case
of ternary solid dispersions containing PVP) and partial disruption of crystal lattice. Moreover,
the formation of nanoaggregates in aqueous media led to the 4- to 8-fold increase in the amount of
dissolved bicalutamide. Emission spectroscopy allowed for a correlation of the effect of dissolution
changes with the solubilization related to the variations of molecular structure of used poloxamers.
2. Materials and Methods
2.1. Materials
Bicalutamide (BCL, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-
hydroxy-2-methylpropanamide, 99.8%, Hangzhou Hyper Chemicals Limited, Zhejiang, China) was
used as a model drug. Poloxamer® 188, Poloxamer® 407 (BASF, Ludwigshafen am Rhein, Germany),
and polyvinylpyrrolidone K29/32 (PVP, Ashland, Covington, KY, USA) were used as excipients.
Sodium lauryl sulfate (SLS, BASF, Ludwigshafen am Rhein, Germany) was used to prepare dissolution
medium. Ethanol (absolute, 99.8%, pure p.a., Avantor Performance Materials, Gliwice, Poland)
and methanol (p.a., Chempur, Piekary Slaskie, Poland) were used as solvents. Cyclohexane (ACS,
pure p.a., Avantor Performance Materials, Gliwice, Poland) was used as a dispersant in laser
diffraction measurements. Perylene (Pe, p.a., Koch-Light Laboratories Ltd., Colnbrook, UK) and
pyrene (98%, Sigma-Aldrich, Darmstadt, Germany) were used in fluorescence emission measurements.
All chemicals were used as received. Distilled water was used to prepare all of aqueous solutions.
2.2. Methods of Preparation of Solid Dispersions
2.2.1. Solvent Evaporation (E)

Bicalutamide (2 g) was mixed with either Poloxamer® 188 or Poloxamer® 407 in a 1:1 and 2:1 wt.
ratio, placed in the round-bottomed flask, and dissolved in 200 mL of absolute ethanol. The solution
was heated up to 40 ◦ C in the water bath and after complete dissolution of the mixture the solvent was
evaporated using a Hei-VAP Value rotavapor (Heidolph, Schwabach, Germany). The rotational speed
was equal to 200 rpm and the pressure was reduced stepwise to ca. 40 mbar. The dry solid dispersion
was transferred to a container and dried under vacuum prior to further characterization. The systems
were further labeled as BCL-PLX188 1:1 (E), BCL-PLX188 2:1 (E), BCL-PLX407 1:1 (E) and BCL-PLX407
2:1 (E), respectively.
2.2.2. Spray Drying (SD)

An ethanolic solution containing bicalutamide mixed with the appropriate carrier or carrier
mixture (1:1 and 2:1 wt. ratio, respectively) was spray-dried using a Mini Spray Dryer B-191 (Büchi,
Flawil, Switzerland). The process was conducted using following parameters: Tinlet = 50–53 ◦ C,
Toutlet = 39–42 ◦ C, aspirator flow 100%, gas flow rate 600 L/min, liquid flow rate 3.4 mL/min, and a
0.7-mm diameter nozzle. The process was carried out under a constant control and the concentration of
ethanol was 10-times lower than the flammability limit. The samples were further dried under vacuum
to remove residual solvent. The systems were labeled as BCL-PLX188 1:1 (SD), BCL-PLX188 2:1 (SD),
BCL-PLX407 1:1 (SD) and BCL-PLX407 2:1 (SD), BCL-PLX188-PVP 2:1:1 (SD), BCL-PLX188-PVP 4:1:1
(SD), BCL-PLX407-PVP 2:1:1 (SD), and BCL-PLX407-PVP 4:1:1 (SD), respectively.
2.2.3. Scanning Electron Microscopy (SEM)

A Phenom Pro desktop electron microscope (PhenomWorld, Thermo Fisher Scientific, Waltham,
MA, USA) equipped with a CeB6 electron source and backscattered electron detector was used to
determine the morphological features of the samples. The acceleration voltage was equal to 10 kV and
the magnification was 750× for evaporated samples, 5000× for spray-dried ternary solid dispersions,
and 10,000× for zoomed sections. The powder was placed on the conductive adhesive tape previously
glued to the specimen mount. The holder for non-conductive samples was used. The excess of sample
(loosely bound to the tape) was removed using a stream of argon. The samples were not sputtered
prior to the measurement.
2.2.4. Differential Scanning Calorimetry (DSC)

A DSC 1 STARe System (Mettler–Toledo, Greifensee, Switzerland) was used in order to examine
the thermal properties of the samples. The measuring device was equipped with a HSS8 ceramic
sensor with 120 thermocouples and a liquid nitrogen cooling station. The apparatus was calibrated for
temperature and enthalpy using zinc and indium standards. Melting points were determined as the
onset of the peak, with the glass transition temperatures as the midpoint of the heat capacity increment.
The samples were measured in an aluminum crucible (40 µL). All measurements were carried out with
a heating rate equal to 10 K/min.
2.2.5. Powder X-ray Diffraction (PXRD)

The diffraction patterns of the samples were registered using an X-ray diffractometer Mini Flex II
(Rigaku, Tokyo, Japan). The angular range 3–70◦ 2θ was scanned with a scan speed of 5◦ /min and a
step size equal to 0.02. The measurements were carried out using monochromatic Cu Kα radiation
(λ = 1.5418 Å) at ambient temperature. The samples in form of powder were placed in a standard glass
sample holder without milling prior the measurement.
2.2.6. Laser Diffraction Measurements

A Mastersizer 3000 equipped with a HydroEV unit (Malvern Instruments, Malvern, UK) was
used to determine the particle size distribution. The samples were analyzed by the wet method using
cyclohexane (reflective index, RI = 1.426) as a dispersant. The cyclohexane was filtered through the G5
sintered disc filter funnel and placed in the beaker. The rotational speed of the mixer was 1500 rpm.
The sample in powder form was added until the obscuration reached the given value (between 5%
and 20%) and then the measurement was carried out. A Fraunhofer diffraction theory was applied
to find the relationship between particle size and light intensity distribution pattern. Reported data
represent the averages from 10 series of measurements for each sample.
2.2.7. Fourier Transform Infrared Spectroscopy (FTIR)

A Nicolet iS10 FT-IR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) equipped
with a Smart iTR™ ATR (Attenuated Total Reflectance) sampling accessory with diamond as an ATR
crystal was used to collect the vibrational spectra of powders. Spectra were collected within the
range 600–4000 cm−1 with 4 cm−1 resolution. Presented data represent average from 128 scans for
each sample.
2.2.8. Dynamic Light Scattering Measurements (DLS)

The size distribution of aggregates formed by the solid dispersions obtained by either evaporation
or spray drying was determined using a Zetasizer Nano ZS instrument (Malvern Instruments, Malvern,
UK) working at a 173◦ detection angle. The distribution analysis was performed at 25 ◦ C using the
general purpose mode. The powder was weighted, dissolved in water (cPLX = 2.5 mg/mL) and shaken
using a KS 130 Basic orbital shaker (IKA, Staufen im Breisgau, Germany) for 24 h. After that the sample
was filtered through the 0.45-µm syringe filter and measured without further dilution. The reported
data represent the averages of three series of measurements (10–100 runs each) of hydrodynamic
diameter and their standard deviations.
2.2.9. Emission Spectroscopy

A SLM 8100 spectrofluorometer of L-geometry (Aminco, Silver Spring, MD, USA) equipped with
a 450W xenon lamp as a light source was used to capture the emission spectra. The microliter quantities
of the molecular probes (c ≈ 10−4 M), i.e., methanolic perylene solution or ethanolic pyrene solution
were slowly injected into a milliliter volume of aqueous PLX188 or PLX407 solutions (cPLX = 5 mg/mL)
as well to the solid dispersions solutions previously filtered through a 0.45-µm syringe membrane
filter and vigorously stirred. The residues of organic solvents were removed by purging the solution
with nitrogen. The samples were equilibrated in the dark for at least 12 h and diluted 10 times before
the measurement.
2.2.10. Contact Angle Determination

The wettability of binary systems was assessed by the contact angle measurements performed
using a DSA255 drop shape analyzer (Krüss, Hamburg, Germany). The sessile drop technique was
used. The droplet of distilled water of volume equal to 2 µL was deposited on the surface of powders
compressed using an AtlasTM manual 15Ton hydraulic press (Specac, Kent, UK) with a load pressure
of 1.5 tons that was applied for each sample for 15 s.
2.2.11. Dissolution Study

Pharmaceutics 2019, 11, x FOR PEER REVIEW 6 of 22
Dissolution of BCL was carried out according to the method recommended by the FDA for
Vision
BCL Elite (1000
tablets 8 (Hanson
mL of Research,
1% SLS, 37 Chatsworth,
± 0.5 ◦ C, 50 CA,rpm)USA) equipped
in the with a VisionG2
pharmacopeial AutoPlus
paddle dissolution
Autosampler.
apparatus TheElite
Vision sink8conditions were maintained.
(Hanson Research, Chatsworth, PureCA,drug
USA)and binary systems
equipped (solid dispersions,
with a VisionG2 AutoPlus
physical mixtures), equivalent of 50 mg of BCL were placed
Autosampler. The sink conditions were maintained. Pure drug and binary systems (solidinto the beakers. The samples were
dispersions,
analyzed mixtures),
physical spectrophotometrically
equivalent of at 50 272
mg nm using
of BCL a UV-1800
were placed intospectrofotometer
the beakers. The (Shimatzu,
samplesKioto,
were
analyzed spectrophotometrically at 272 nm using a UV-1800 spectrofotometer (Shimatzu,triplicate
Japan) equipped with the flow-through cuvettes. The tests were carried out in and
Kioto, Japan)
presented results represents averages with their standard deviations.
equipped with the flow-through cuvettes. The tests were carried out in triplicate and presented results
represents averages with their standard deviations.
3. Results and Discussion
3. Results and Discussion
3.1. Solid State Characterization
3.1. Solid State Characterization
3.1.1. Size Distribution and Morphology of Particles of Solid Dispersions
3.1.1. Size Distribution and Morphology of Particles of Solid Dispersions
The effect of applied processes on the particle size and morphology was studied using both
scanning effect
The electronof microscopy and laser
applied processes on diffraction
the particlemeasurements.
size and morphology The analysis of size distribution
was studied using both
of BCL-PLX solid dispersions obtained via evaporation in rotavapor confirmed the heterogeneity of
scanning electron microscopy and laser diffraction measurements. The analysis of size distribution
particle
of BCL-PLX size (Figure 1A). Long obtained
solid dispersions tails of the viadistribution
evaporationcurves in the region
in rotavapor of small
confirmed the particles were
heterogeneity
well pronounced. Moreover, the shape of the distribution suggests that several fractions of particles
of particle size (Figure 1A). Long tails of the distribution curves in the region of small particles
of different
were sizes were present
well pronounced. Moreover,in the thesample,
shape of as the
more than one maximum
distribution suggests thatcanseveral
be noticed. This of
fractions is
particularly noticeable for the BCL-PLX188 1:1 (E) system, which exhibits a bimodal long-tailed
particles of different sizes were present in the sample, as more than one maximum can be noticed.
distribution
This of particle
is particularly size. for
noticeable This
theisBCL-PLX188
reflected by1:1 great differences
(E) system, whichinexhibits
Dx(90) avalues
bimodal between the
long-tailed
samples, i.e.of
distribution the point in
particle theThis
size. sizeisdistribution,
reflected by up to differences
great which 90% in of Dx(90)
the total volume
values of material
between in the
the samples,
sample
i.e., is included.
the point in the sizeThe value wasup
distribution, 1190.0 μm 90%
to which for BCL-PLX188 1:1 (E)ofsolid
of the total volume dispersion,
material while is
in the sample it
varied between 630–730 μm for the other evaporated systems. The Dx(10) and Dx(50) values
included. The value was 1190.0 µm for BCL-PLX188 1:1 (E) solid dispersion, while it varied between
representing
630–730 µm for thethediameter of particles
other evaporated whereThe
systems. 10% and aand
Dx(10) half of thevalues
Dx(50) particle population
representing thelie below,
diameter
respectively, did not vary between the corresponding samples; however, the values are greater for
of particles where 10% and a half of the particle population lie below, respectively, did not vary between
BCL-PLX188
the corresponding1:1 (E) and BCL-PLX407
samples; however, the 2:1values
(E), which also exhibit
are greater long tails in1:1the
for BCL-PLX188 (E)region of particles
and BCL-PLX407
that exceeded 1000 μm in length.
2:1 (E), which also exhibit long tails in the region of particles that exceeded 1000 µm in length.
Figure 1.
Figure 1. Particle
Particlesize
sizedistribution
distributionof of
solid dispersions
solid obtained
dispersions by evaporation
obtained technique
by evaporation (A) and
technique (A)
sprayspray
and drying of binary
drying (B) and
of binary (B) ternary systems
and ternary (C). BCL:
systems bicalutamide;
(C). BCL: PLX: poloxamer;
bicalutamide; PVP:
PLX: poloxamer;
polyvinylpyrrolidone.
PVP: polyvinylpyrrolidone.
In spray
In spray drying,
drying, the
the liquid
liquid is
is dispersed
dispersed in
in aa form
form of
of droplets and dried
droplets and with a
dried with a hot
hot air. This leads
air. This leads
to aa formation
to formation of
of particles
particles of
of consistent
consistent size
size distribution,
distribution, usually
usually of
of spherical
spherical or
or ruptured
ruptured spheres
spheres
shape of
shape of diameter
diameter below
below 1010 micrometers.
micrometers. TheThe data
data presented
presented in
in Table
Table 11 indicates
indicates that
that spray-dried
spray-dried
binary systems exhibited particles of greater size that those obtained via evaporation technique.
However, the span values (calculated using Equation (1)) are a bit smaller in case of spray-dried
systems, which indicates that the distributions are narrower. The tails of the distribution suggest that
the particles aggregated during the process, probably due to the fact of low melting temperature of
poloxamer. This may also result from the fact that some amount of drying samples adhered to the
binary systems exhibited particles of greater size that those obtained via evaporation technique.
However, the span values (calculated using Equation (1)) are a bit smaller in case of spray-dried
systems, which indicates that the distributions are narrower. The tails of the distribution suggest that
the particles aggregated during the process, probably due to the fact of low melting temperature of
poloxamer. This may also result from the fact that some amount of drying samples adhered to the
inner wall of spray dryer, which additionally leads to the decrease in the process yield. The Dx(90)
value of particles of PLX 188-based (SD) solid dispersions are bigger than systems containing PLX407.
Interestingly, BCL-PLX407 2:1 (SD) system exhibited the smallest particles among all investigated
systems, as seen in Figure 2B and the SEM image (Figure 3). The size distributions of PLX407-based
solid dispersions were narrower, with well resolved maxima as compared to those obtained for systems
containing PLX188. Moreover, the maximum of particle size distribution of the system containing
twice as much bicalutamide as PLX407 in binary solid dispersions was shifted towards bigger particles
(Dx(10) = 126.0 µm and Dx(90) = 380.0 µm). All of examined systems exhibited a tailed distribution
towards lower values of particle size.
Dx (90) − Dx (10)
Span = (1)
Dx (50)
Table 1. Particle size of solid dispersions obtained using the laser diffraction method. PLX188:
Poloxamer® 188, PLX407: Poloxamer® 407.
BCL:polymers
Method Carrier Dx(50) ± SD (µm) Span
wt. Ratio
1:1 247.0 ± 55.9 4.698
PLX188
2:1 227.0 ± 30.7 2.719
Evaporation
1:1 203.0 ± 23.1 2.971
PLX407
2:1 159.0 ± 53.1 4.438
1:1 196.0 ± 27.2 4.405
PLX188
2:1 355.0 ± 64.7 2.876
1:1 445.0 ± 28.7 1.771
PLX407
2:1 154.0 ± 13.7 2.167
Spray-drying
2:1:1 78.0 ± 0.8 3.339
PLX188-PVP
4:1:1 55.6 ± 1.5 3.907
2:1:1 48.6 ± 2.2 5.153
PLX407-PVP
4:1:1 54.2 ± 2.1 4.098
Interestingly, the addition of PVP to BCL-PLX systems led to the formation of fine powders with
the particle size distribution maxima located between 50 and 120 µm. However, the span reaches
greater values than for binary solid dispersions, which may be a consequence of the distributions tailed
towards smaller particles. Obtained ternary systems were also characterized with better flowability
than platelet-like particles of binary solid dispersions. Particle size distributions of all the systems were
more unified; moreover, the formation of a fraction of particles of size below 1 µm was also noticeable
(Figure 1C).
An SEM analysis indicates that the crystals of neat bicalutamide adopt hexagonal shape and
particles of smooth surface exhibiting ca. 160 µm in length [57]. The evaporation process led to the
noticeable changes in the surface and morphology of obtained binary solid dispersions. During the
rotation of the flask, the surface area of solvent increases. This leads to an enhancement of evaporation
rate and fast recrystallization of dissolved bicalutamide. Thus, the formation of sharp-edged aggregates
2:1 159.0 ± 53.1 4.438
1:1 196.0 ± 27.2 4.405
PLX188
2:1 355.0 ± 64.7 2.876
1:1 445.0 ± 28.7 1.771
PLX407
2:1 154.0 ± 13.7 2.167
Spray-drying
Pharmaceutics 2019, 11, 130 2:1:1 78.0 ± 0.8 3.339 8 of 22
PLX188-PVP
4:1:1 55.6 ± 1.5 3.907
2:1:1 48.6 ± 2.2 5.153
not exceeding 100 µm in case ofPLX407-PVP
BCL-PLX407 1:1 (E)
4:1:1and 200 µm54.2
for the
± 2.1other systems
4.098 was observed
(Figure 2). The systems comprised particles of wide size distribution, as seen in the SEM images as
well Interestingly, the addition
as plots obtained of PVP
using laser to BCL-PLX
diffraction systems
technique led to
(Figure the formation of fine powders with
1A).
the particle size distribution maxima located between 50 and 120 μm.
A spray drying process usually leads to the formation of spherical However,
particles withthe span reaches
a consistent size
greater values than for binary solid dispersions, which may be a consequence of the distributions
distribution. The SEM micrographs of ternary solid dispersions show that obtained particles formed
tailed
spherestowards smaller
of diameter particles. Obtained
not exceeding ternaryhowever
several microns, systems they
weretended
also characterized
to agglomeratewith better
(Figure 3).
flowability than platelet-like particles of binary solid dispersions. Particle size distributions of all the
In combination with the recrystallization that also occurred it led to the particle size distribution
systems
determinedwerebymore unified;
means moreover,
of laser the formation
diffraction measurementsof a fraction of particles
being much greaterof as
sizethe
below 1 μm
Dx(90) was
values
also noticeable (Figure 1C).
varied between 227 µm and 273 µm.
An SEM analysis indicates that the crystals of neat bicalutamide adopt hexagonal shape and
particles of smooth surface exhibiting ca. 160 μm in length [57]. The evaporation process led to the
noticeable changes in the surface and morphology of obtained binary solid dispersions. During the
rotation of the flask, the surface area of solvent increases. This leads to an enhancement of
evaporation rate and fast recrystallization of dissolved bicalutamide. Thus, the formation of sharp-
edged aggregates not exceeding 100 μm in case of BCL-PLX407 1:1 (E) and 200 μm for the other
systems was observed
Figure
(Figure 2). systems
The systems comprised particles of wide size distribution, as seen
Figure 2.
2. SEM
SEMimages
imagesofofbinary
binary systemscontaining
containing bicalutamide
bicalutamideand
andeither PLX188
either in 1:1
PLX188 (A) (A)
in 1:1 andand
2:1
in the(B)
SEM
2:1 wt.
images
ratio
(B) wt. ratio
as wellinas1:1
or PLX407
or PLX407
plots
in (C)
obtained
and
1:1 (C) 2:1 (D)
and
using laser
wt. wt.
2:1 (D) ratio diffraction
obtained
ratio using
obtained
technique
evaporation
using
(Figure
method.
evaporation
1A).
method.
Figure
Figure 3.
3. SEM
SEMimages
imagesof ofternary
ternarysystems
systemscontaining
containingbicalutamide,
bicalutamide, PVP
PVP and
andeither
either PLX188
PLX188 in
in4:1:1
4:1:1(A)
(A)
and 2:1:1 (B) wt. ratio or PLX407 in 4:1:1 (C) and 2:1:1 (D) wt. ratio obtained using spray drying.
and 2:1:1 (B) wt. ratio or PLX407 in 4:1:1 (C) and 2:1:1 (D) wt. ratio obtained using spray drying.
A spray drying process usually leads to the formation of spherical particles with a consistent
size distribution. The SEM micrographs of ternary solid dispersions show that obtained particles
formed spheres of diameter not exceeding several microns, however they tended to agglomerate
(Figure 3). In combination with the recrystallization that also occurred it led to the particle size
distribution determined by means of laser diffraction measurements being much greater as the
Dx(90) values varied between 227 μm and 273 μm.
3.1.2. X-Ray Powder Diffractometry (XRPD)

The XRPD studies were performed to characterize the molecular structure of binary systems.
Obtained results indicate that both of applied processes led to the changes in molecular structure of
the systems (Figure 4). The diffraction pattern of raw bicalutamide indicated by numerous distinctive
Braggs peaks (2θ = 12.18◦ , 16.88◦ , 18.92◦ , 23.82◦ , 24.66◦ , and 24.94◦ ) confirms that the drug exhibited
highly-ordered arrangement on molecular level. The data confirm that bicalutamide existed as a form
I polymorph (according to the 2014 Cambridge Crystallographic Data Centre (CCDC)). The decrease
in crystallinity of the drug after co-processing with poloxamers is manifested by the reduction of
the relative intensities of peaks. This suggests that the crystal lattice was partially destructed during
processing. Moreover, the crystalline diffraction peaks are superimposed on the slightly noticeable
amorphous halos. This indicates that the sample is amorphous to a very small extent. No transition to
metastable polymorph was observed as no shifts in diffraction peaks appeared. This confirms that
used poloxamers did not stabilize the disordered system at low concentration, in agreement with a
previously published
Pharmaceutics 2019, 11, x paper [59].
FOR PEER REVIEW 9 of 22
Figure
Figure 4. X-ray
4. X-ray diffraction
diffraction patterns
patterns of of binary
binary systems
systems containing
bicalutamide and
and either
either PLXPLX188188
or or
PLX 407 (1:1 and 2:1 wt. ratio) obtained using evaporation technique (E) and spray drying
PLX 407 (1:1 and 2:1 wt. ratio) obtained using evaporation technique (E) and spray drying (SD). (SD).
Interestingly,thethediffraction
Interestingly, diffractionpatterns
patternswere
weremore morestructured
structuredin inspray-dried
spray-driedsystems
systemsthan
than
evaporated
evaporated ones.Moreover,
ones. Moreover,the the obtained
obtained ternary
ternary solid
solid dispersions
dispersions exhibited
exhibited oneone more
more important
important
feature,
feature, thetransition
the transitionofofBCL
BCLfromfromform
formIIinto
into form
form IIII polymorph
polymorph [60].
[60]. This
Thisisisclearly
clearlymarked
markedininthe
thediffractograms
diffractograms presented
presentedin in
Figure 5 and
Figure manifested
5 and manifested by the additional
by the intense
additional peakpeak
intense between 25.08°
between
and◦ 25.86°
25.08 and 25.86 ◦ 2θ, which does not appear in the diffractogram of raw BCL. No such solid–solid
2θ, which does not appear in the diffractogram of raw BCL. No such solid–solid transition
of bicalutamide–poloxamer
transition solid dispersions
of bicalutamide–poloxamer has been described
solid dispersions so far. Theso
has been described diffraction patterns also
far. The diffraction
suggest
patterns that
also ternary
suggest thatsystems contain contain
ternary systems a fraction of amorphous
a fraction phase
of amorphous as the
phase diffractograms
as the diffractogramsare
aresuperimposed
superimposed onon
the amorphous
the amorphous halo further
halo furtherassigned
assigned toto
partial amorphization
partial amorphization of of
poloxamers
poloxamers(see
Section 3.1.4).
(see Section 3.1.4).
diffractograms presented in Figure 5 and manifested by the additional intense peak between 25.08°
and 25.86° 2θ, which does not appear in the diffractogram of raw BCL. No such solid–solid transition
of bicalutamide–poloxamer solid dispersions has been described so far. The diffraction patterns also
suggest that ternary systems contain a fraction of amorphous phase as the diffractograms are
superimposed
Pharmaceutics 2019,on
11, the
130 amorphous halo further assigned to partial amorphization of poloxamers
10 (see
of 22
Section 3.1.4).
3.1.3. Vibrational Spectroscopy

FTIR spectroscopy
Figure
Figure 5. X-ray
5. haspatterns
X-ray diffraction
diffraction been applied
patterns of ternaryto
of ternary determine
systems
systems the bicalutamide,
containing
containing molecular structure
bicalutamide, PVP,
PVP, and and PLX
and either
either possible
PLX
interactions
188 or between
188 or PLX
PLX 407 BCL and
407 obtained
obtained by the carriers
by spray
spray drying. in solid dispersions. The intensity, shape and position of
drying.
peaks (the presence of shifts) were evaluated with an emphasis placed on the vibrations within the
3.1.3. Vibrational Spectroscopy
carbonyl and amine functional groups (Figure 6). Well-resolved bands at 3335 cm−1 correspond to
N–HFTIRstretching vibrations,
spectroscopy andapplied
has been the broad band with
to determine theamolecular
maximumstructure
at 1687 and
cm−1possible
originates in C=O
interactions
stretchingBCL
between vibrations.
and theThe spectra
carriers of binary
in solid solid dispersions
dispersions. do notshape
The intensity, differand
significantly
position from those
of peaks of
(the
pure drug, suggesting that BCL does not interact with any of used poloxamers or that the strength of
presence of shifts) were evaluated with an emphasis placed on the vibrations within the carbonyl and
the interactions
amine functional is negligibly
groups (Figuresmall. The new band
6). Well-resolved thatat appears
bands 3335 cm−in1 correspond
the range of to 2860–3000 cm−1
N–H stretching
corresponds
vibrations, to the
and the broad
stretching
bandvibrations of aliphatic
with a maximum C–H
at 1687 cm group
− 1
in poloxamers.
originates in C=O stretching vibrations.
Noticeable differences were observed for ternary solid dispersions as the
The spectra of binary solid dispersions do not differ significantly from those ofband
pure corresponding
drug, suggestingto
carbonyl
that BCL group vibration
does not interactis with
broadened
any ofand
used thepoloxamers
maximum red-shifted. This indicates
or that the strength of thethe existence of
interactions is
strong intermolecular
negligibly small. The interactions
new band that between BCLinand
appears thePVP
rangeas of
we2860–3000
previouslycm showed [57]. Moreover,
−1 corresponds to the
the O–H band

stretching is fuzzy,
vibrations which confirms
of aliphatic partial
C–H group in amorphization
poloxamers. of the system.
Figure 6. FTIR spectra of raw bicalutamide and binary and ternary solid dispersions.
Figure 6. FTIR spectra of raw bicalutamide and binary and ternary solid dispersions.
Noticeable differences were observed for ternary solid dispersions as the band corresponding to
3.1.4. Thermal Properties of Solid Dispersions
carbonyl group vibration is broadened and the maximum red-shifted. This indicates the existence of
The
strong thermal properties
intermolecular of raw
interactions systems
between BCL (i.e.,
andBCL, PLX188,
PVP as PLX407,showed
we previously and PVP),
[57]. the binary
Moreover,
formulations
the O–H bandcontaining BCL confirms
is fuzzy, which and either PLX407
partial or PLX188 of
amorphization polymer (that were obtained by two
the system.
different methods—evaporation (E) and spray drying (SD)), and the ternary, spray-dried
formulations of BCL, PLX, and PVP have been examined by means of the differential scanning
calorimetry (DSC) technique. The DSC curves obtained during heating with a rate equal to 10 °C/min
are presented in Figure 7.
As can be seen in the panel (C) of Figure 7, the DSC trace of raw BCL reveals a single sharp peak
with an onset at 194 °C. This endothermal process corresponds to the melting of the investigated
antiandrogen and is in a perfect agreement with the literature data [61]. Both DSC curves of PLX188
as well as PLX 407 exhibit two thermal events. The first (barely visible on the DSC thermograms
3.1.4. Thermal Properties of Solid Dispersions

In the panels (A) and (B) of Figure 7, the DSC traces of binary drug-polymer compositions
prepared by evaporation
The thermal (panel
properties A),systems
of raw and spray
(i.e.,drying
BCL, (panel
PLX188, B) PLX407,
are shown.andAs can the
PVP), be seen
binaryall
investigated formulations reveals three thermal events—Tg, Tm1, and Tm2—in the temperature range
formulations containing BCL and either PLX407 or PLX188 polymer (that were obtained by two
from −80methods—evaporation
different °C to 210 °C. Because the glassspray
(E) and transition
dryingevent (Tand
(SD)), g) is the
almost invisible
ternary, in the scale
spray-dried of Figure
formulations
7,BCL,
of the data
PLX,from the temperature
and PVP region: −75
have been examined °C to −40
by means °C differential
of the are presented in a separate
scanning figure
calorimetry (see
(DSC)
◦ C/min are presented
Figure 8). In Table 2 the values of all investigated thermal events of all examined systems have been
technique. The DSC curves obtained during heating with a rate equal to 10
collected..
in Figure 7.
Figure7.7.The
Figure TheDSC
DSCthermograms
thermogramsof:of:binary
binarysystems
systemscontaining
containingbicalutamide
bicalutamideand
andeither
eitherPLX188
PLX188or
or
PLX407obtained
PLX407 obtained using
usingthe
theevaporation
evaporation method
method (A)
(A)and
andspray
spraydrying
drying(B),
(B),raw
rawbicalutamide
bicalutamideand
and
polymers(C),
polymers (C),and
andternary
ternaryspray-dried
spray-driedsystems
systemscontaining
containingBCL,
BCL,poloxamer,
poloxamer,and
andPVP
PVP(D).
(D).
Since
As can(1)
be the
seenglass
in thetransitions
panel (C)ofofBCL-PLX
Figure 7,188
the systems
DSC trace areoflocated
raw BCLat the samea temperature
reveals single sharp as the
peak
◦ C. This endothermal process corresponds to the melting of the investigated
Tg of raw PLX 188, and (2) the glass transitions of the BCL-PLX 407 systems are located at the same
with an onset at 194
temperature as
antiandrogen andthe
is Ting of raw PLX
a perfect 407, one with
agreement can conclude that data
the literature the glass
[61]. transition
Both DSCevent
curvesregistered
of PLX188in
binary
as formulations
well as PLX 407 exhibitoriginates
two from the events.
thermal amorphousThe fraction of the
first (barely PLXs on
visible (poly(ethylene oxide) PEO
the DSC thermograms
blocks). Comparing the values of the onsets of the thermal events which have been marketed in
Figure 7A,B as Tm1, one can identify them as the melting of the crystalline part of the polymer which
presented in Figure 7C) is step-like transition occurring in the vicinity of −60 ◦ C associated with the
glass transition of the amorphous part of PLXs (poly(propylene oxide), PEO blocks). The second,
located at around 50 ◦ C, is a sharp endothermal peak originating from the melting of the crystalline
part of the polymers (poly(propylene oxide), PPO block). Two thermal events have been also observed
in the DSC trace of the neat PVP polymer, when measured as received. The first, very broad, thermal
event that is2019,
Pharmaceutics located in the
11, x FOR range
PEER of 20–100 ◦ C is associated with water evaporation (note the absence
REVIEW 12 of of
22
this process, when the sample is re-heated). The second step-like transition (barely visible in Figure 7C)
exists in the
occurring solid
in the dispersions.
vicinity of 172 ◦ CThe third thermal
is associated withevent that hasglass
the polymer been registered during the DSC
transition.
measurements
In the panelsof (A)
the and
BCL-PLX systems
(B) of Figure is located
7, the DSC tracesin the temperature
of binary range from
drug-polymer 130 °C toprepared
compositions 200 °C.
This endothermal
by evaporation peakA),
(panel corresponds
and sprayto the melting
drying (panel of B) the
are BCL contained
shown. As can in bethe
seensolid dispersions.
all investigated
Therefore,
formulations onereveals
can observed that itsevents—T
three thermal enthalpyg ,(ΔH
Tm1m2, )and
decreases
Tm2 —inwith decreasing amounts
the temperature of the
range from −80 BCL
◦C
in the system.
to 210 ◦ As can
C. Because the be seen,
glass the onset
transition of T(T
event g )shifts
m2 towards
is almost lower
invisible in temperatures with 7,
the scale of Figure increasing
the data
amounts
from the of PLX in theregion:
temperature formulation.
−75 ◦This
C to might
−40 ◦ Cbeareconnected
presented with
in athe dissolution
separate figureof(see
the drug
Figurein8).
a
liquid
In Tablepolymer.
2 the values of all investigated thermal events of all examined systems have been collected..
Figure
Figure 8.
8. The
The zoomed
zoomed fragment
fragment of
of DSC
DSC thermograms
thermograms presented
presented in
in the
the Figure
Figure 77 of
of raw
raw bicalutamide
bicalutamide
and
and poloxamers
poloxamers (A),
(A), binary
binary systems
systems containing
bicalutamide and
and either
either PLX188
PLX188 oror PLX407
PLX407 obtained
obtained
using evaporationmethod
using evaporation method(B)(B)and
andspray
spray drying
drying (C),(C),
andand ternary,
ternary, spray-dried,
spray-dried, systems
systems containing
containing BCL,
BCL, poloxamer,
poloxamer, and(D1,D2).
and PVP PVP (D1 and D2) .
In the panel (D) of Figure 7, the DSC traces of ternary drug–polymer–polymer compositions
(prepared by spray drying) are shown. As can be seen, the investigated formulations reveal five
thermal events which are marked in Figure 7D as Tg-PLX, Tg-PVP, Tm1, Tm2, and water evaporation.
Since both Tg-PLX and Tg-PVP are almost invisible in the scale of Figure 7, the data from the
temperature regions −80 °C to −40 °C and 110°C to 160°C are presented in the separate figures (see
Figure 7 D1 and D2). From the comparison of the DSC traces of ternary systems to either raw and
Table 2. Comparison of the Tg , Tm1 , and Tm2 values of raw BCL, poloxamers, PVP, binary systems
containing bicalutamide and either PLX188 or PLX407 (obtained using evaporation method (E) and
spray drying (SD)), and ternary systems containing bicalutamide, PLX, and PVP.
Tg-PLX (◦ C) Tg-PVP (◦ C) Tm1 (◦ C) ∆Hm1 Tm2 (◦ C) ∆Hm2

System
(midpoint) (midpoint) (onset) (J/g) (onset) (J/g)
Raw BCL - - - - 194 110.8
Raw PVP - 172 - - - -
Raw PLX 188 −60 - 53 134.9 - -
Raw PLX 407 −65 - 56 117.3 - -
BCL-PLX 188 1:1 E −60 - 50 65.7 160 39.6
BCL-PLX 188 2:1 E −61 - 49 45.7 176 42.4
BCL-PLX 188 1:1 SD −61 - 49 66.6 160 39.2
BCL-PLX 188 2:1 SD −61 - 48 42.3 176 42.6
BCL-PLX 407 1:1 E −65 - 52 59.6 160 39.5
BCL-PLX 407 2:1 E −65 - 52 39.2 182 52.4
BCL-PLX 407 1:1 SD −66 - 52 58.9 165 39.6
BCL-PLX 407 2:1 SD −66 - 52 38.9 181 49.2
BCL-PLX-PVP 188 2:1:1 SD −61 142 47 188 135 27
BCL-PLX-PVP 188 4:1:1 SD −62 146 45 120 134 50
BCL-PLX-PVP 407 2:1:1 SD −67 141 47 140 135 26
BCL-PLX-PVP 407 4:1:1 SD −67 142 47 95 137 48
Since (1) the glass transitions of BCL-PLX 188 systems are located at the same temperature as
the Tg of raw PLX 188, and (2) the glass transitions of the BCL-PLX 407 systems are located at the
same temperature as the Tg of raw PLX 407, one can conclude that the glass transition event registered
in binary formulations originates from the amorphous fraction of the PLXs (poly(ethylene oxide)
PEO blocks). Comparing the values of the onsets of the thermal events which have been marketed
in Figure 7A,B as Tm1 , one can identify them as the melting of the crystalline part of the polymer
which exists in the solid dispersions. The third thermal event that has been registered during the DSC
measurements of the BCL-PLX systems is located in the temperature range from 130 ◦ C to 200 ◦ C.
This endothermal peak corresponds to the melting of the BCL contained in the solid dispersions.
Therefore, one can observed that its enthalpy (∆Hm2 ) decreases with decreasing amounts of the BCL
in the system. As can be seen, the onset of Tm2 shifts towards lower temperatures with increasing
amounts of PLX in the formulation. This might be connected with the dissolution of the drug in a
liquid polymer.
In the panel (D) of Figure 7, the DSC traces of ternary drug–polymer–polymer compositions
(prepared by spray drying) are shown. As can be seen, the investigated formulations reveal five thermal
events which are marked in Figure 7D as Tg -PLX, Tg -PVP, Tm1 , Tm2 , and water evaporation. Since
both Tg -PLX and Tg -PVP are almost invisible in the scale of Figure 7, the data from the temperature
regions −80 ◦ C to −40 ◦ C and 110◦ C to 160◦ C are presented in the separate figures (see Figure 7 D1
and D2). From the comparison of the DSC traces of ternary systems to either raw and binary systems
one can conclude that: (1) Tg -PLX originates from the amorphous fraction of the PLXs (PEO blocks);
(2) Tg -PVP is associated with the glass transition temperature of PVP polymer; (3) Tm1 reflects the
melting of the crystalline part of the PLX polymer which exists in the system; and (4) Tm2 corresponds
to the melting of the BCL. Note that with increasing amount of API in the system, ∆Hm1 and ∆Hm2
are changing.
3.1.5. Wettability of Solid Dispersions

Powder wettability is an important issue in pharmaceutical sciences as the solid–liquid interfacial
interactions can affect drug dissolution, solubilization, and disintegration [62]. Given the heterogeneity
of the surface properties resulting from a specific surface chemistry, variations between polymorphic
and amorphous forms have been reported thus far [63]. They affect the level of supersaturation of
molecularly-disordered systems and physical stability; thus, the assessment of wetting properties
plays a significant role in the systems containing fine particles.
The wetting behavior of raw compounds as well as binary and ternary solid dispersions were
assessed by contact angle measurements using the sessile drop technique. The difference between
the two used poloxamers is clearly visible (Figure 9). The values of measured contact angle were
equal to 56.8 ± 1.8◦ and 64.7 ± 0.02◦ for PLX188 and PLX407, respectively. The difference may result
from the differences in molecular composition of both polymers, i.e., higher amount of hydrophobic
poly(propylene oxide) units and greater molar mass of PLX407 [49]. Interestingly, no significant effects
of either the type of applied poloxamer or the process on the wettability of binary solid dispersions
were observed. All the systems exhibited improved wettability expressed by the decreased contact
angle in comparison with raw BCL (θ = 74.1 ± 0.3◦ ) with slightly higher values determined for systems
containing PLX407. Interestingly, the addition of PVP to ternary solid dispersions obtained by spray
drying led to well pronounced increase in wetting behavior of the systems. While the values of contact
angle for binary systems ranged between 60◦ –65◦ , for the systems comprising polyvinylpirrolidone
they reached ca. 42◦ –45◦ . Moreover, the effect of molecular structure of poloxamers was less significant
as lower values of the contact angle were obtained for PLX407-based systems. This is of particular
importance as the improved wettability and surface activity of poloxamers can strongly affect the
Pharmaceutics 2019,
improvement in11, x FOR PEER REVIEW
bicalutamide dissolution. 14 of 22
Figure
Figure 9. The values
9. The values of
of contact
contact angles
angles of
of raw
raw bicalutamide and poloxamers,
bicalutamide and binary and
poloxamers, binary and ternary
ternary
systems
systems containing bicalutamide, poloxamers, and PVP obtained using either evaporation method
containing bicalutamide, poloxamers, and PVP obtained using either evaporation or
method or
spray
spray drying.
drying.
3.2. Characterization of Solid Dispersions in Solution
3.2. Characterization of Solid Dispersions in Solution
3.2.1. Self-Assembly of Poloxamers in Solid Dispersions
3.2.1. Self-Assembly of Poloxamers in Solid Dispersions
The assembly phenomenon of amphiphilic polymers has been intensively studied in recent
yearsThe assembly
[64–66]. phenomenon
Their aggregationofleads
amphiphilic polymers has
to the formation been intensively
of hydrophobic studiedthat
domains in recent years
are able to
[64–66]. Their
solubilize aggregation
sparingly leads tomolecules.
water-soluble the formation Thisofreduces
hydrophobic domains thatofare
the agglomeration able
drug to solubilize
molecules and
sparingly the
increases water-soluble
dissolutionmolecules.
of API. This reduces the agglomeration of drug molecules and increases
the dissolution of API.
Poloxamers are low-meltable triblock copolymers consisting of hydrophobic chain of
Poloxamersoxide)
poly(propylene are bound
low-meltable
with two triblock copolymers
hydrophilic chains ofconsisting of oxide)
poly(ethylene hydrophobic chain of
able to solubilize
poly(propylene oxide) bound with two hydrophilic chains of poly(ethylene oxide)
hydrophobic molecules [67]. While PLX188 contains ca. 15% of PPO, PLX407 is composed of ca. 35% able to solubilize
hydrophobic
of PPO, whichmolecules
may affect[67].
the While
assemblyPLX188 contains ca.
of copolymer 15% of
in polar PPO,[68].
media PLX407 is composed of ca. 35%
of PPO, which may affect the assembly of copolymer in polar media [68].
The size of molecular assemblies of both used poloxamers did not exceed 6 nm, however the
The of
diameter size of molecularparticles
PLX407-based assemblies
is ca.of30%
bothgreater
used poloxamers did not
than those formed byexceed 6 nm,
PLX188, whichhowever the
may result
diameter
from of PLX407-based
the higher particles
content of PPO is Physical
units. ca. 30% greater
mixtures than those
also formedin
assembled byparticles
PLX188,of
which may below
diameter result
from the higher content of PPO units. Physical mixtures also assembled in particles of diameter below
6 nm; however, the mixtures containing equal amounts of BCL and PLX formed particles of ca. 10–
12% greater diameter than those containing the excess of the drug (Figure 10).
The mean hydrodynamic diameters of all solid dispersions based on PLX188 are smaller than
those containing PLX407, regardless of the method of preparation and the number of system
constituents. Moreover, solid dispersions containing 50% of the carrier exhibited aggregates of
6 nm; however, the mixtures containing equal amounts of BCL and PLX formed particles of ca. 10–12%
greater diameter than those containing the excess of the drug (Figure 10).
Figure
Figure 10. Hydrodynamic diameters
10. Hydrodynamic diameters of
of aggregates
aggregates formed
formed inin aqueous
aqueous solutions
solutions of
of poloxamers,
poloxamers,
physical mixtures, and binary systems obtained using either the evaporation method or spray drying.
physical mixtures, and binary systems obtained using either the evaporation method or spray drying.
Insert: zoomed data corresponding to raw PLXs and physical mixtures.
Insert: zoomed data corresponding to raw PLXs and physical mixtures.
The mean hydrodynamic diameters of all solid dispersions based on PLX188 are smaller than those
The DLS measurements confirmed monomodal and rather narrow distribution of particle size
containing PLX407, regardless of the method of preparation and the number of system constituents.
(Figure 11) with maxima slightly shifted towards greater values for PLX407-based systems,
Moreover, solid dispersions containing 50% of the carrier exhibited aggregates of greater diameter
regardless of the method of solid dispersion preparation. The long tail of distribution of the BCL-
than those with the excess of bicalutamide, similarly to physical mixtures. However, the differences
PLX407 1:1 (E) binary system assigned to the formation of several aggregated structures that
reached up to 39% for the BCL-PLX407 1:1 (E) system. No significant variations occurred between
disrupted the measurement explains the variation in particle size in comparison with the other
the PLX188-based binary systems of corresponding compositions obtained by the two methods.
systems. The size of the formed aggregates was determined to be almost 40% greater than for BCL-
The systems containing the excess of the drug exhibited particles of ca. 170 nm in diameter, while
PLX407 2:1 (E) system, similarly to BCL-PLX407-PVP 2:1:1 (SD) compared with BCL-PLX407-
the size of aggregates formed by 1:1 systems was equal to 225 nm. The great variation in particle
PVP 4:1:1 (SD) solid dispersions. This confirms that the effect of the applied method of solid
size was noticed in BCL-PLX407 systems, especially the evaporated one containing an equal amount
dispersion preparation is negligible when considering that the solution and the composition are the
of the drug and the carrier. The diameter of these particles reached 350 nm in diameter, while the
most important factors.
aggregates of spray-dried solid dispersion did not exceed 250 nm in diameter (Figure 10). Similar
behavior was observed for BCL-PLX407-PVP 2:1:1 (SD) which exhibited particles much greater that
the other ternary systems. The addition of PVP to solid dispersions did not affect the self-assembly
behavior. The differences in hydrodynamic diameters values follows the same trend as for binary
systems, with slightly greater values for solid dispersions containing equal amount of BCL and the
carriers (PLX and PVP).
The DLS measurements confirmed monomodal and rather narrow distribution of particle size
(Figure 11) with maxima slightly shifted towards greater values for PLX407-based systems, regardless
of the method of solid dispersion preparation. The long tail of distribution of the BCL-PLX407
1:1 (E) binary system assigned to the formation of several aggregated structures that disrupted the
measurement explains the variation in particle size in comparison with the other systems. The size of
Figure 11. Number-weighted particle size distribution of aqueous solutions of evaporated (A), spray-
the formed aggregates was determined to be almost 40% greater than for BCL-PLX407 2:1 (E) system,
dried binary (B), and ternary (C) solid dispersions.
similarly to BCL-PLX407-PVP 2:1:1 (SD) compared with BCL-PLX407-PVP 4:1:1 (SD) solid dispersions.
This
3.2.2.confirms that the
Solubilization ofeffect of theProbes
Molecular applied method of solid dispersion preparation is negligible when
considering that the solution and the composition are the most important factors.
Fluorescence spectroscopy has been applied to the determination of micropolarity,
microviscosity and solubilization ability. Two molecular probes were used due to the act that their
fluorescent properties vary depending on physical parameters of nanoassemblies.
Perylene exhibits unique properties, i.e., low solubility in water (c = 1.6 × 10−9 M) and lack of
fluorescence in polar environment [69]. The presence of characteristic emission bands indicates that
the probe experienced non-polar environment and confirms that the probe is solubilized within
hydrophobic packets formed by self-assembled poloxamer molecules (Figure 12).
disrupted the measurement explains the variation in particle size in comparison with the other
systems. The size of the formed aggregates was determined to be almost 40% greater than for BCL-
PLX407 2:1 (E) system, similarly to BCL-PLX407-PVP 2:1:1 (SD) compared with BCL-PLX407-
PVP 4:1:1 (SD) solid dispersions. This confirms that the effect of the applied method of solid
dispersion2019,
Pharmaceutics preparation
11, 130 is negligible when considering that the solution and the composition are
16 ofthe
22
most important factors.
Figure11.
Figure 11. Number-weighted
Number-weightedparticle
particlesize distribution
size of aqueous
distribution solutions
of aqueous of evaporated
solutions (A), spray-
of evaporated (A),
dried binary
spray-dried (B), and
binary (B),ternary (C) solid
and ternary dispersions.
(C) solid dispersions.
3.2.2. Solubilization of Molecular Probes

3.2.2. Solubilization of Molecular Probes
Fluorescence spectroscopy has been applied to the determination of micropolarity, microviscosity
Fluorescence spectroscopy has been applied to the determination of micropolarity,
and solubilization ability. Two molecular probes were used due to the act that their fluorescent
microviscosity and solubilization ability. Two molecular probes were used due to the act that their
properties vary depending on physical parameters of nanoassemblies.
fluorescent properties vary depending on physical parameters of nanoassemblies. −9
Perylene exhibits unique properties, i.e., low solubility in water (c = 1.6 × 10−9 M) and lack
Perylene exhibits unique properties, i.e., low solubility in water (c = 1.6 × 10 M) and lack of
of fluorescence in polar environment [69]. The presence of characteristic emission bands indicates
fluorescence in polar environment [69]. The presence of characteristic emission bands indicates that
that the probe experienced non-polar environment and confirms that the probe is solubilized within
the probe experienced non-polar environment and confirms that the probe is solubilized within
Pharmaceutics 2019,
hydrophobic
hydrophobic 11, x formed
packets
packets FOR PEER
formed
byREVIEW
self-assembled poloxamer molecules (Figure 12).
by self-assembled poloxamer molecules (Figure 12). 16 of 22
Figure
Figure 12.12.Emission
Emissionspectra
spectraof of perylene
perylene solubilized
solubilized byby either
either Poloxamer
Poloxamer ®188
® 188 or or Poloxamer
Poloxamer ®407
® 407
solution
solution (λex
(λex = =405
405nm).
nm).
TheTheemission
emissionspectrum
spectrumofofpyrene pyreneyields
yieldsinin the the informationabout
information aboutthethepolarity
polaritysensed
sensedbybythethe
probe
probe inin
thethe solubilization
solubilization site.
site. TheThe intensity
intensity ofof
thethe vibronic
vibronic fine
fine structure
structure ofofthethe monomeric
monomeric form
form ofof
pyrene
pyrene depends
depends ononthethe polarity
polarity of theof the microenvironment
microenvironment [70].[70]. In polar
In polar media
media therethere
is an is an increase
increase in thein
the intensity of the 0-0 band (peak I), whereas band III is affected only slightly [71]. The ratio of the
intensity of the 0-0 band (peak I), whereas band III is affected only slightly [71]. The ratio of the emission
emissionIIII
intensities intensities
(at 386 nm)IIII and
(at 386
II (atnm) 374 and
nm) Iwas
I (atused
374 to nm) wasenvironmental
study used to studychangesenvironmental
experiencedchanges
by
theexperienced by the probe. The values presented in Table 3 indicate that the probe experienced less
probe. The values presented in Table 3 indicate that the probe experienced less polar environment
polar
while environment
solubilized withinwhile
any ofsolubilized
examined systemwithin in any of examined
comparison system
to water. in comparison
However, the increaseto inwater.
the
IIIIHowever,
to II ratiothe increase
is rather lowininthe IIII todispersions
solid II ratio is rather low inthe
(especially solid dispersions
spray-dried (especially
ones), which the spray-dried
suggests that
theones), which suggests that the systems formed loosely packed nanoasseblies easily penetrable by
systems formed loosely packed nanoasseblies easily penetrable by water molecules.
water molecules.
Table 3. The IIII to II ratio calculated based on the fluorescence emission spectra of pyrene solubilized
in aqueous solutions of either pure compounds or solid dispersions (λex = 330 nm).
System IIII/II System IIII/II

Water 0.351 BCL-PLX 188 1:1 (SD) 0.442
Raw PLX188 0.516 BCL-PLX 188 2:1 (SD) 0.430
Raw PLX407 0.503 BCL-PLX 407 1:1 (SD) 0.435
BCL-PLX 407 2:1 (SD) 0.442
Table 3. The IIII to II ratio calculated based on the fluorescence emission spectra of pyrene solubilized
in aqueous solutions of either pure compounds or solid dispersions (λex = 330 nm).
System IIII /II System IIII /II

Water 0.351 BCL-PLX 188 1:1 (SD) 0.442
Raw PLX188 0.516 BCL-PLX 188 2:1 (SD) 0.430
Raw PLX407 0.503 BCL-PLX 407 1:1 (SD) 0.435
BCL-PLX 407 2:1 (SD) 0.442
BCL-PLX 188 1:1 (E) 0.508 BCL-PLX 188-PVP 2:1:1 (SD) 0.556
3.2.3. Dissolution Study

The methods aimed at the enhancement of the dissolution of bicalutamide have been already
considered in several papers. Solvent evaporation under reduced pressure was applied to obtain
solid dispersions containing bicalutamide and PVP in 1:3, 1:4, and 1:5 drug-to-polymer ratios,
respectively [59,72]. The formation of binary systems led to the amorphization of BCL; however,
a great excess of PVP was required. The authors concluded that such a high proportion of the carrier
may lead to the increase in bulkiness and tablet weight during the development of a formulation.
Solid dispersions with poloxamer were obtained by melting [73] and supercritical carbon dioxide
method [74]. The samples containing 83.8% of the carrier were found to be amorphous, however
gelling properties of PLX retarded the dissolution of the drug from the systems containing high
concentration of the polymer. The increase in the amount of poloxamer in solid dispersions was
concluded not to offer any advantage for the dissolution improvement.
Due to the aforementioned problems caused by the excess of poloxamer, we prepared binary and
ternary systems containing either equal amounts of bicalutamide and polymer or twice as much BCL
as the carriers. The dissolution profiles presented in Figure 13 showed a significant improvement
(from 4- to 8-fold) of the drug dissolution in comparison with raw BCL and BCL-PLX physical
mixtures. Only 8.2% of crystalline bicalutamide dissolved after 1 h of the dissolution test. Moreover,
the formation of the systems in which BCL was physically mixed with the readily soluble carrier
affected the dissolution of the drug only slightly as less than 12.6% of bicalutamide dissolved from
physical mixture containing PLX407 and ca. 8% from PLX188-based systems (Figure 13C).
The dissolution profiles of solid dispersions were found to be independent on the applied
processes. The amount of bicalutamide dissolved from binary systems processed in 2:1 wt. ratio varied
between 36.0% for BCL-PLX407 (SD) and 37.2% for BCL-PLX188 (E) to 44.6% for BCL-PLX188 (SD)
and 46.3% for BCL-PLX188 (E). Solid dispersions containing equal amounts of the drug and the carrier
exhibited better dissolution than those containing the excess of the drug, as 51.3% of bicalutamide
dissolved from BCL-PLX188 (E), 53.3%% from BCL-PLX407 (E), and 54.8% from BCL-PLX407 (SD).
The variation was observed only for BCL-PLX188 1:1 (SD) solid dispersion as 69.6% of the drug
dissolved after 1 h. Interestingly, dissolution curves obtained for spray-dried systems with both
binary and ternary solid dispersions (Figure 13B,D) showed an opposite tendency in comparison
to evaporated systems (Figure 13A), as in evaporated systems more bicalutamide dissolved from
PLX407-based solid dispersions, while after spray drying, systems containing PLX188 exhibited better
dissolution. Importantly, the addition of PVP seems to positively affect BCL dissolution, as 77% of
BCL dissolved from both systems containing PLX188, while 75.6% and 57.3% dissolved from the 2:1:1
and 4:1:1 PLX407-based systems, respectively.
BCL as the carriers. The dissolution profiles presented in Figure 13 showed a significant improvement
(from 4- to 8-fold) of the drug dissolution in comparison with raw BCL and BCL-PLX physical
mixtures. Only 8.2% of crystalline bicalutamide dissolved after 1 hour of the dissolution test.
Moreover, the formation of the systems in which BCL was physically mixed with the readily soluble
carrier affected
Pharmaceutics 2019, 11,the
130 dissolution of the drug only slightly as less than 12.6% of bicalutamide dissolved
18 of 22
from physical mixture containing PLX407 and ca. 8% from PLX188-based systems (Figure 13C).
Figure13.13.Dissolution
Figure Dissolution of
of binary
binary and
and ternary
ternarysystems
systemscontaining
containingbicalutamide,
bicalutamide, poloxamers andand
poloxamers PVP
(in (in
PVP case of ternary
case systems)
of ternary obtained
systems) using
obtained thethe
using evaporation technique
evaporation technique(A),(A),
spray drying
spray (B and
drying D),
(B,D),
and physical mixing
and physical mixing (C). (C).
The dissolution profiles of solid dispersions were found to be independent on the applied
4. Conclusions
processes. The amount
The obtained results of bicalutamide
indicate dissolved from
that co-processing of BCL binary
withsystems processed
PLXs leads in 2:1 wt. ratio
to an improvement
of bicalutamide dissolution from 4- to 8-times in comparison with the pure drug. ThatBCL-PLX188
varied between 36.0% for BCL-PLX407 (SD) and 37.2% for BCL-PLX188 (E) to 44.6% for effect was
(SD) andto46.3%
assigned for BCL-PLX188
the formation (E). Solid dispersions
of nanoaggregates. containing
Surface activity equal amounts
of poloxamers leadsoftothe
thedrug and the
formation
of hydrophobic packets in which bicalutamide was solubilized. Importantly, physical mixtures didof
carrier exhibited better dissolution than those containing the excess of the drug, as 51.3%
bicalutamide
not form aggregatesdissolved
withfrom BCL-PLX188
bicalutamide and(E), 53.3%%
thus from BCL-PLX407
no significant enhancement (E), in
anddrug
54.8% from BCL-
dissolution
PLX407
was (SD). While
observed. The variation was observed
no variations only for
in dissolution BCL-PLX188
between systems 1:1obtained
(SD) solidbydispersion
either spray as drying
69.6% of
the drug dissolved after 1 hour. Interestingly, dissolution curves obtained for
or evaporation processes were noted, some differences in physicochemical characteristics appeared. spray-dried systems
with
The mostboth binary and
important ternary issolid
observation that dispersions (Figure
the drug partially 13B,D)
lost showed an opposite
its highly-ordered moleculartendency
structurein
comparison to evaporated systems (Figure 13A), as in evaporated systems
after preparation of solid dispersions. The changes in diffractograms were more pronounced in more bicalutamide
dissolved from
evaporated PLX407-based
systems. The decrease solid
in dispersions,
crystallinity while after spray
was expressed bydrying, systems
the decrease in containing PLX188
relative intensity
exhibited
and better peaks.
lack of several dissolution. Importantly,
Moreover, the of
the addition addition
PVP and offormation
PVP seems to positively
of ternary affect BCL
solid dispersions
dissolution, as 77% of BCL dissolved from both systems containing PLX188,
by spray drying led to the transition of polymorph I into polymorphic form II of bicalutamide. while 75.6% and 57.3%
dissolved from the 2:1:1 and 4:1:1 PLX407-based systems, respectively.
This confirms that the interplay between the process parameters and properties of both drug and
carrier is important to obtain solid dispersion of desired characteristics without a great excess of the
4. Conclusions
auxiliary compounds.
The obtained
The type results
of polymer wasindicate that
found to co-processing
affect of BCL with PLXs
the size of nanoaggregates leadsbytosolid
formed an improvement
dispersions inof
anbicalutamide
aqueous medium.dissolution from 4- to 8-times
The self-assembly of systemsin containing
comparisonPLX188
with the
led pure
to thedrug. Thatofeffect
formation was
smaller
assignedregardless
particles, to the formation of nanoaggregates.
the applied Surface
technique of solid activitypreparation.
dispersion of poloxamers leads
This maytobe
the formation
a result of
the composition of the macromolecule, as it contains ca. 15% PPO hydrophobic mers, while PLX407
contains ca. 35%.
Thermal analysis confirmed that poloxamers were partially amorphous in solid dispersions,
which indicates that the drug antplasticizes the Tg of the polymer. This would be connected with the
dissolution of the drug in a liquid polymer.
Author Contributions: Conceptualization, J.S.; investigation, J.S., A.A, J.K.-K., K.G., M.K., J.O., and K.C.;
writing—original draft preparation, J.S. and J.K.-K.; writing—review and editing, R.J. and M.P.; visualization,
J.S. and J.K.-K.; supervision, R.J. and M.P.
Funding: This research was funded by the Polish National Science Centre (grant Symfonia 3 no
2015/16/W/NZ7/00404).
Conflicts of Interest: The authors declare no conflict of interest.
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pharmaceutics

Keywords: bicaludamide; poloxamer; evaporation; spray drying; dissolution enhancement;

Pharmaceutics 2019, 11, 130; doi:10.3390/pharmaceutics11030130 www.mdpi.com/journal/pharmaceutics

2. Materials and Methods

2.2. Methods of Preparation of Solid Dispersions

2.2.1. Solvent Evaporation (E)

2.2.2. Spray Drying (SD)

2.2.3. Scanning Electron Microscopy (SEM)

2.2.4. Differential Scanning Calorimetry (DSC)

2.2.5. Powder X-ray Diffraction (PXRD)

2.2.6. Laser Diffraction Measurements

2.2.7. Fourier Transform Infrared Spectroscopy (FTIR)

2.2.8. Dynamic Light Scattering Measurements (DLS)

2.2.9. Emission Spectroscopy

2.2.10. Contact Angle Determination

2.2.11. Dissolution Study

Pharmaceutics 2019, 11, x FOR PEER REVIEW 8 of 22

3.1.2. X-Ray Powder Diffractometry (XRPD)

Pharmaceutics 2019, 11, x FOR PEER REVIEW 10 of 22

3.1.3. Vibrational Spectroscopy

the O–H band

Pharmaceutics 2019, 11, x FOR PEER REVIEW 11 of 22

3.1.4. Thermal Properties of Solid Dispersions

Tg-PLX (◦ C) Tg-PVP (◦ C) Tm1 (◦ C) ∆Hm1 Tm2 (◦ C) ∆Hm2

3.1.5. Wettability of Solid Dispersions

3.2.2. Solubilization of Molecular Probes

System IIII/II System IIII/II

System IIII /II System IIII /II

3.2.3. Dissolution Study

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