pharmaceutics

Article
Applying Supercritical Fluid Technology to Prepare
Ibuprofen Solid Dispersions with Improved
Oral Bioavailability
Fei Han 1 , Wei Zhang 1 , Ying Wang 2,3 , Ziyue Xi 1 , Lu Chen 1 , Sanming Li 1 and Lu Xu 1, *
1 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China;
[email protected] (F.H.); [email protected] (W.Z.); [email protected] (Z.X.);
[email protected] (L.C.); [email protected] (S.L.)
2 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education,
Shenyang Pharmaceutical University, Shenyang 110016, China; [email protected]
3 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016,
China
* Correspondence: [email protected]; Tel.: +86-024-4352-0583




Received: 4 January 2019; Accepted: 31 January 2019; Published: 3 February 2019


Abstract: In this study, supercritical fluid (SCF) technology was applied to prepare reliable solid
dispersions of pharmaceutical compounds with limited bioavailability using ibuprofen (IBU) as
a model compound. Solid-state characterization of the dispersions was conducted by differential
scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM).
The PXRD and DSC results suggested that the amorphous form of IBU was maintained in the solid
dispersions. Furthermore, in vitro dissolution and in vivo pharmacokinetic (PK) studies in rats were
also performed. The dissolution performance of the SCF-prepared IBU dispersions was significantly
improved compared to that of the physical mixtures of crystalline IBU and a polymer. In addition,
the PK results revealed that the SCF-prepared IBU dispersions produced remarkably high blood
drug concentrations (both the AUC and Cmax ) and a rapid absorption rate (Tmax ). Finally, molecular
modeling was used to evaluate the binding energy of interactions between IBU and the polymers.
The negative binding energy suggests a relatively stable system. Hence, SCF technology can be used as
a very effective approach to prepare IBU solid dispersions with good physical stability and enhanced
in vitro and in vivo performance.

Keywords: ibuprofen; supercritical fluid; solid dispersion; bioavailability

1. Introduction
Ibuprofen (IBU), a poorly water-soluble drug, is widely used as one of the best-tolerated
nonsteroidal anti-inflammatory drugs for treatment of rheumatoid arthritis, osteoarthritis, and mild to
moderate pain [1]. However, the poor aqueous solubility of IBU significantly limits its bioavailability
and therapeutic activity [2]. In recent years, many approaches have been applied to improve
solubility and bioavailability, such as encapsulation into liposomes, nanoparticles, co-milling, solid
dispersion, nano-emulsification, etc. [3–5]. Among them, amorphous solid dispersions (ASDs) have
been extensively used due to their superior solubilization [6–10]. Supercritical fluid (SCF) technology,
a way to prepare ASDs, exhibits many unique advantages, including mild preparation conditions,
environmental friendliness, controllable processing conditions, and good reproducibility. In particular,
rapid expansion of a supercritical solution does not require an organic solvent as a mixing medium and
can directly produce microparticles even without milling. Using supercritical carbon dioxide (scCO2 )
as a medium to prepare artemisinin dispersions can reportedly enhance the drug’s in vitro dissolution

Pharmaceutics 2019, 11, 67; doi:10.3390/pharmaceutics11020067 www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2019, 11, 67 2 of 13

rate and intestinal absorption [11]. A solid dispersion of oxeglitazar with improved dissolution kinetics
was prepared using supercritical antisolvent and spray-freezing techniques [12]. An SCF anti-solvent
process was also applied to prepare telmisartan solid dispersions (SDs) using polyvinylpyrrolidone
and hydroxypropyl methylcellulose as carriers [13]. Compared to conventional methods, and owing
to these advantages, the use of SCF technology avoids the toxicity and pollution problems related to
organic solvent usage and reduces the risk of high-energy-induced phase transitions. SCF technology
with scCO2 as media can easily eliminate and recover the final product by controlling the pressure,
temperature, aspect ratio, etc. [14]. The Kollidon grades are manufactured by a polymerization process
in water without any organic solvents to form a popcorn polymer. A Kollidon system, crosslinked
polyvinylpyrrolidone, including Kollidon VA 64, Kollidon CL, Kollidon CL-SF, Kollidon SR, etc. has
been widely used to prepare SDs and improve oral bioavailability [15,16]. However, studies on the
use of Kollidon system SDs on improving oral adsorption and bioavailability via an SCF method are
still rare.
In this study, SCF technology was applied as a solvent-free manufacturing approach to prepare
SDs of IBU with Kollidon system-based polymeric carriers at the lab scale. Kollidon CL and
Kollidon CL-SF were selected as model polymers in the dispersions because they are reportedly
good candidates for use as drug carriers and superdisintegrants in SDs to improve the dissolution rate
for immediate-release dosage forms. The optimal conditions (i.e., temperature, pressure, and reaction
time) for using SCF technology to prepare SDs were investigated. The solid-state forms of IBU in the
SDs were investigated using powder X-ray diffraction (PXRD) and differential scanning calorimetry
(DSC). Molecular modeling was also applied to predict the binding energy, which is valuable for
evaluating and analyzing the interaction between SDs and poorly water-soluble drugs. Furthermore,
both in vitro dissolution tests and in vivo pharmacokinetic studies in rats were conducted. The in vitro
and in vivo performance of the SCF-prepared ASDs was shown to be superior to that of a drug–polymer
physical mixture (PM).

2. Materials and Methods

2.1. Materials
IBU was obtained from Knoll Co. Ltd. (Purity >98%, Bad Saulgau, BW, Germany). Kollidon CL
and Kollidon CL-SF (The volume average diameter was 110–130 µm and 10–30 µm, respectively) were
obtained from BASF AG (Ludwigshafen, Germany). Industrial-grade carbon dioxide was purchased from
Jingquan Gas Factory (Purity 99%; Shenyang, China). Deionized water was prepared by ion exchange.
All other chemicals were of analytical grade and used as required without further purification.

2.2. Preparation of SDs

IBU-Kollidon SDs were prepared using an SCF instrument (Shenyang Dongyu Supercritical
Extraction Co. Ltd., Shenyang, China). The PMs in different ratios were placed in an scCO2 -permeable
bag, and the bag was then placed in the high-pressure vessel of the SCF instrument and processed,
as shown in Scheme 1. When the vessel was closed and sealed, sufficient CO2 was pumped into the
vessel to reach 25 MPa at 40 ◦ C. These reaction conditions had to be maintained for at least 18 h to
enable sufficient mixing of the drug and polymer in the scCO2 medium. Next, CO2 was gradually
discharged from the vessel through a valve. The solid powders of IBU-Kollidon CL and IBU-Kollidon
CL-SF (Named as IBU-CL SD and IBU-CL-SF SD) were collected and dried in an oven at 40 ◦ C for at
least 24 h.
 Pharmaceutics 2019, 11, 67 3 of 13
Pharmaceutics 2019, 11, x 3 of 12

Flow
Scheme1.1.Flow
Scheme chart
chart ofof supercriticalfluid
supercritical fluidtechnology.
technology.

2.3. Scanning Electron Microscopy (SEM)

2.3. Scanning Electron Microscopy (SEM)
SEM images were obtained using a scanning electron microscope (Type SM-T20, JEOL, Tokyo„
SEM images were obtained using a scanning electron microscope (Type SM-T20, JEOL, Tokyo,,
Japan) to analyze the surface morphology of the particles. Samples (pure IBU, IBU-Kollidon PMs,
Japan) to analyze the surface morphology of the particles. Samples (pure IBU, IBU-Kollidon PMs,
and IBU-Kollidon SDs) were mounted on metal stubs using double-sided adhesive tape and sputtered
and IBU-Kollidon SDs) were mounted on metal stubs using double-sided adhesive tape and
with a thin layer of gold under the vacuum.
sputtered with a thin layer of gold under the vacuum.
2.4. Differential Scanning Calorimetry (DSC)
2.4. Differential Scanning Calorimetry (DSC)
Thermal analysis of the IBU SDs was performed using a differential scanning calorimeter (Q1000,
Thermal analysis
TA Instruments, of the DE,
New Castle, IBUUSA).
SDs was performed 5using
Approximately mg of aa sample
differential scanning
was placed calorimeter
in an aluminum
(Q1000, TA Instruments, New Castle,
◦ DE,
◦ USA). Approximately
pan and heated from 25 to 150 C at 10 C/min to obtain DSC curves. 5 mg of a sample was placed in an
aluminum pan and heated from 25 to 150 °C at 10 °C/min to obtain DSC curves.
2.5. Powder X-Ray Diffraction (PXRD)
2.5. Powder X-Ray Diffraction (PXRD)
The X-ray diffraction (XRD) patterns of SD samples, the pure drug, and PMs samples stressed at
◦The
25 C and X-ray
65%diffraction (XRD) patterns
RH were measured of SD samples,
by a powder the pure drug,
X-ray diffractometer and PMs
(X’pert PRO,samples stressed
PANalytical B.V.,
atAlmelo,
25 °C andThe 65% RH wereequipped
Netherlands) measuredwithby aa powder X-ray diffractometer
Cu Kα radiation (X'pert PRO,
source. The experiments PANalytical
were conducted
B.V.,
underAlmelo,
ambient Theconditions
Netherlands)
in theequipped with a Cu
Bragg–Brentano Kα radiation
geometry source.ranging
at 2θ values from 5◦ to were
The experiments 45◦ in
◦
conducted under ambient conditions in the Bragg–Brentano geometry
0.01 steps. The voltage and current were set to 40 kV and 20 mA, respectively. at 2θ values ranging from 5°
to 45° in 0.01° steps. The voltage and current were set to 40 kV and 20 mA, respectively.
2.6. Dissolution Studies
2.6. Dissolution Studies
Dissolution tests of the SD samples were performed using a dissolution test machine (Shanghai
Huanghai Medicament
Dissolution tests of theTest
SDInstrument
samples were Factory, Shanghai,
performed usingChina) applying
a dissolution test amachine
USP II (Shanghai
dissolution
apparatusMedicament
Huanghai [17,18]. The paddle rotation speed
Test Instrument andShanghai,
Factory, temperature wereapplying
China) fixed at 50a rpm
USPand 37 ± 0.5 ◦ C,
II dissolution
respectively.
apparatus SDs The
[17,18]. containing
paddlethe equivalent
rotation speedofand100temperature
mg of IBU were wereplaced
fixed in 900rpm
at 50 mL and
of distilled
37 ± 0.5water.
°C,
Samples (5 SDs
respectively. mL) containing
of the dissolution medium
the equivalent were
of 100 mgwithdrawn
of IBU were atplaced
predetermined
in 900 mLtime intervals
of distilled (1, 2,
water.
3, 4, 5, 10,
Samples 15, 20,
(5 mL) 30,dissolution
of the 45, 60, 90, medium
and 120 min), and each was
were withdrawn compensated by
at predetermined timeadding 5 mL
intervals (1,of
2, the
3,
4,corresponding
5, 10, 15, 20, 30,fresh45,buffer.
60, 90,Next,
and the
120samples
min), andwere filtered
each was through
compensated a 0.45 by membrane
µmadding 5 mLfilter and
of the
analyzed by high-performance
corresponding fresh buffer. Next,liquid chromatography
the samples (HPLC)
were filtered at 220
through nm. μm membrane filter and
a 0.45
analyzed by high-performance liquid chromatography (HPLC) at 220 nm.
2.7. Pharmacokinetic Studies in Rats
2.7. Pharmacokinetic Studiesfrom
Animals were bought in Rats
Laboratory Animal Center of Shenyang Pharmaceutical University
andAnimals
the guidelines were approved
were bought by Shenyang
from Laboratory Pharmaceutical
Animal UniversityPharmaceutical
Center of Shenyang completely. TenUniversity
male Wistar
ratsthe
and (200 ± 20 g) were
guidelines werefasted for 12by
approved h but allowedPharmaceutical
Shenyang free access to water. They were
University dividedTen
completely. randomly
male
and equally into two groups for intragastric administration; one group received an IBU-CL-SF
Wistar rats (200 ± 20 g) were fasted for 12 h but allowed free access to water. They were divided PM
equivalent to 25 mg/kg of IBU, and the other received an IBU-CL-SF SD equivalent
randomly and equally into two groups for intragastric administration; one group received an IBU- to 25 mg/kg
of IBU
CL-SF PMprepared by SCF
equivalent to 25methods
mg/kg of[19].
IBU,After ether
and the anesthesia,
other received0.5
an mL of bloodSD
IBU-CL-SF was collectedtofrom
equivalent 25
the retro-orbital plexus at 5, 10, 15, 30, 45, 60, 90, 120, 240, and 360 min after dosing
mg/kg of IBU prepared by SCF methods [19]. After ether anesthesia, 0.5 mL of blood was collectedand transferred
from the retro-orbital plexus at 5, 10, 15, 30, 45, 60, 90, 120, 240, and 360 min after dosing and
transferred immediately to a heparinized centrifuge tube. All blood samples were centrifuged at
Pharmaceutics 2019, 11, 67 4 of 13

immediately to a heparinized centrifuge tube. All blood samples were centrifuged at 10,000 g for 10 min
to obtain the plasma, which was transferred to a centrifuge tube and stored at –20 ◦ C until analysis.
Plasma samples were processed as follows: exactly 0.2 mL of a plasma sample was transferred
to a 1.5 mL plastic tube with a stopper and mixed with 0.1 mL of an internal standard solution
(cinnamic acid, 38.1 µg/mL), 0.1 mL of methanol, and 0.2 mL of acetonitrile. After vortexing for 5 min,
the mixture was further centrifuged at 10,000 g for 10 min, and a 20 µL aliquot was analyzed using
a HPLC system.

2.8. HPLC Analysis of IBU

HPLC analyses were performed using a Shimadzu HPLC system (Kyoto, Japan) equipped with
an LC-10AT pump, a UV detector (PD-10AV) at 220 nm, and an Inertsil ODS-3 reverse-phase column
(5 µm, 46 mm × 150 mm, GL Science Inc., Tokyo, Japan) maintained at 35 ◦ C. The mobile phase was
methanol/phosphate buffer (pH 3.0) solution (75:25, v/v), and the flow rate was 1.0 mL/min.

2.9. Molecular Docking

The 3D structures of both IBU and the polymer were built using the SYBYL 6.9.1 software package
(Tripos Inc. St. Louis, MO, USA). The optimal parameters were as follows: The maximum number of
iterations was 10,000, and the change in energy was 0.005 kcal/(mol × Å).
AutoDock Tools (1.5.4) were applied to transfer both the polymer and the molecule into PDBQT
format and define the binding site for a further molecular docking study. The docking results were
analyzed using the docking conformations with the highest percentage frequency and the lowest
binding energy as representatives.
The optimized parameters of the AutoDock 4.0 software were as follows: the maximum number
of energy evaluations was increased to 25,000,000 per run, the iterations of the Solis and Wets local
search were 3000, the number of individuals in a population was 300, and the number of generations
was 100. Results differing by <2 Å in a positional root mean square deviation were clustered together.
In each group, the lowest binding energy configuration with the highest percentage frequency was
selected as the group representative. All other parameters were maintained at the default values [20].
Discovery Studio Visualizer 4.5 (BIOVIA) was used for molecular interaction analysis.

2.10. Statistical Analysis

The unpaired student’s t-text was applied to do a statistical analysis. Data were presented as
mean ± SD and the significant level was set at a probability of p < 0.001.

3. Results

3.1. Optimization of Preparation Conditions

SDs of IBU-CL-SF were prepared at different conditions and the same temperature by applying
SCF technology, as shown in Table 1. The drug release profiles of SDs (Figure 1) indicated that the
cumulative percentage of drug release in the IBU-CL-SF SD increased with increasing preparation time,
pressure, and drug-to-carrier ratio. Both Group 5 and Group 7 had a relative higher drug release
percentage. However, IBU in scCO2 exhibited higher solubility under a higher preparation pressure,
resulting in better interaction between the drug and carriers to yield the desired SDs. Considering all
the factors, the IBU-CL-SF SDs were prepared at a drug-to-carrier ratio of 1:5, a reaction pressure of
25 MPa, and a reaction time of 18 h.
Pharmaceutics 2019, 11, 67 5 of 13

Pharmaceutics
Table 1.2019, 11, x
Cumulative percentage of drug release from carriers at different conditions (reaction pressure,5 of 12
reaction time, drug-to-carrier ratio).
Table 1. Cumulative percentage of drug release from carriers at different conditions (reaction
pressure,Pressure
reaction (MPa)
time, drug-to-carrier ratio). Cumulative Percentage
Group Reaction Time (h) Drug-to-Carrier Ratio
of Drug Release (%)
Group Pressure (MPa) Reaction Time (h) Drug-to-carrier ratio Cumulative Percentage of Drug Release (%)
1
1 Pharmaceutics202019,
2011, x 6
6 1:5
1:5 73.21
73.21 5 of 12
2
2 20
20 12
12 1:5
1:5 80.44
80.44
3 Table 1. Cumulative
20 percentage18 of drug release from carriers
1:5 at different conditions (reaction
87.90
3 20 18 1:5 87.90
4 pressure, reaction
15 time, drug-to-carrier
18 ratio). 1:5
4 15 18 1:5 80.58 80.58
5 5 Group 25 25
Pressure (MPa) Reaction 18
18 Time (h) Drug-to-carrier 1:5
1:5 ratio Cumulative Percentage of 91.05 91.05 (%)
Drug Release
66 1 20 2020 18 6 18 1:5
1:1 1:1 73.21 77.45 77.45
77 2
20 2020 18 12 18 1:5
1:3 1:3 80.44
91.45 91.45
3 20 18 1:5 87.90
4 15 18 1:5 80.58
5 25 18 1:5 91.05
6 20 18 1:1 77.45
7 20 18 1:3 91.45

Figure1.1.Dissolution
Figure Dissolutionprofiles
profilesofofIbuprofen
IbuprofenKollidon
KollidonCL-SF
CL-SFsolid
soliddispersion
dispersion(IBU-CL-SF
(IBU-CL-SFSD)SD)systems
systems
prepared by the supercritical fluid (SCF) method with different preparation times (A),
prepared by the supercritical fluid (SCF) method with different preparation times (A), preparation preparation
Figureand
pressure 1. Dissolution profiles of Ibuprofen Kollidon CL-SF solid dispersion (IBU-CL-SF SD) systems
pressure(B),
(B), andratio
ratio(C).
(C).
prepared by the supercritical fluid (SCF) method with different preparation times (A), preparation
3.2. Characterization(B), and ratio (C).
pressure
3.2. Characterization
3.2. Characterization
3.2.1. SEM Results
3.2.1. SEM Results
The3.2.1.
SEM SEM Resultsin Figure 2 show the surface morphology of pure IBU and Kollidon, together
images
The SEM
with that ofThe images
theSEM in Figure
IBU-Kollidon PMs 2 show the surface morphology of pure IBU and powder
Kollidon,exhibited
together
images in Figure 2and
showSDs. As shown
the surface in Figure
morphology 2A,B,E,
of pure theKollidon,
IBU and IBU together
with that
rod-shaped of the
with crystals, IBU-Kollidon
that of thewhereas PMs
Kollidon
IBU-Kollidon and
PMs and SDs.
CLSDs. As
andAs shown
Kollidon in
shown inCL-SF Figure
Figurewere 2A,B,E,
observed
2A,B,E, the IBU powder
to haveexhibited
the IBU powder exhibited
rough surfaces
rod-shaped crystals,
rod-shaped whereas
crystals, Kollidon
whereas KollidonCL
CL and
and Kollidon
Kollidon CL-SF
CL-SF were
were
and irregularly shaped agglomerates of different sizes. Notably, free crystals of IBU observed
observed to haveto have
rough rough
weresurfaces
surfaces clearly
and irregularly
observed and irregularly
in the PMs shaped
but agglomerates
shaped
not agglomeratesofofdifferent
in the two SDs,different sizes.Notably,
sizes.
which demonstratedNotably, freefree
IBUcrystals
that crystals
in of
theIBU ofwere
IBUclearly
amorphous were clearly
state was
observedobserved
in the inPMs
the PMs
but but
not not
in in
thethetwo
twoSDs,
SDs, which
which demonstrated
demonstrated thatthat
IBU IBU
in theinamorphous
the state
amorphous state
present was
in the IBU-CL
present
and IBU-CL-SF SDs prepared by the SCF method.
was present in theinIBU-CL
the IBU-CL
andand IBU-CL-SFSDs
IBU-CL-SF SDs prepared
preparedbyby thethe
SCFSCF
method.
method.

Figure 2. SEM images of samples. (A) IBU; (B) Kollidon CL; (C) Kollidon CL-SF; (D) IBU-CL SD;
Figure 2. SEM images of samples. (A) IBU; (B) Kollidon CL; (C) Kollidon CL-SF; (D) IBU-CL SD; (E)
(E) IBU-CL physical mixture (PM); (F) IBU-CL-SF SD. (G) IBU-CL-SF PM. Scale bar is shown in the graph.
IBU-CL physical mixture (PM); (F) IBU-CL-SF SD. (G) IBU-CL-SF PM. Scale bar is shown in the graph.

Figure 2. SEM images of samples. (A) IBU; (B) Kollidon CL; (C) Kollidon CL-SF; (D) IBU-CL SD; (E)
IBU-CL physical mixture (PM); (F) IBU-CL-SF SD. (G) IBU-CL-SF PM. Scale bar is shown in the graph.
Pharmaceutics 2019, 11, 67 6 of 13
Pharmaceutics 2019, 11, x 6 of 12

Pharmaceutics 2019, 11, x 6 of 12

3.2.2. PXRD Analysis
3.2.2. PXRD Analysis
3.2.2.As
PXRD
As Analysis
aa complementary
complementary method,
method, PXRD
PXRD cancan provide
provide direct
direct evidence
evidence of of IBU
IBU crystallization.
crystallization. Powder
Powder
X-ray diffractograms
X-rayAsdiffractograms
a complementary of pure
of pure IBU and
IBUPXRD
method, the
and the IBU-Kollidon
canIBU-Kollidon
provide directPM PM and
and SD
evidence SD systems
systems
of IBU are shown
are shownPowder
crystallization. in Figure
in Figure 3.
3.
Characteristic
Characteristic
X-ray diffraction
diffraction
diffractograms of purepeaks
peaks ofIBU
IBU of
and IBU were
thewere clearlyobserved
clearly
IBU-Kollidon observed
PM and in SDin
thethe IBU-Kollidon
IBU-Kollidon
systems are shown PMs PMs
in butbut
not3.not
Figure in
in the
the SDs, suggesting
SDs, suggesting
Characteristic that IBU
that IBUpeaks
diffraction was
was of transformed
transformed into
into an
IBU were clearly an amorphous
amorphous
observed in thestate state in
in the SDs
IBU-Kollidon the
PMs SDs
of butof
IBU-CLIBU-CL
not inand and
the IBU-
IBU-CL-SF
SDs,
CL-SF obtained
suggesting
obtained that
by thebySCF
IBU the
wasSCF method,
transformed
method, whichwhich
into anis
is in in agreement
amorphous
agreement with
state
with theSDs
in the
the DSC DSC ofstudy.
study. IBU-CL and IBU-
CL-SF obtained by the SCF method, which is in agreement with the DSC study.

Figure 3. Powder X-ray diffraction patterns of the IBU-Kollidon different grade PM and SD systems
Figure 3. Powder X-ray diffraction patterns of the IBU-Kollidon different grade PM and SD systems
prepared
prepared by
bythe
by the
the SCF
SCF
SCF
method.
method.
method. (A)
(A)
(A)
IBU;
IBU;
IBU;
(B)(B)
(B) IBU-CL
IBU-CL
IBU-CL PM;PM;
PM;
(C) (C)
(C)
IBU-CL
IBU-CL
IBU-CL
SD; SD; (D)SD; (D)PM;
IBU-CL-SF
IBU-CL-SF
(D) IBU-CL-SF PM;IBU-
(E)
PM;
(E) IBU-
(E) IBU-CL-SF
CL-SF
CL-SF SD.
SD. SD.

3.2.3. DSC Analysis

3.2.3. DSC
3.2.3. DSCAnalysis
Analysis
To demonstrate the presence or absence of the crystalline drug, a DSC analysis was conducted.
ToTo demonstrate
demonstratethe thepresence
presence oror absence
absence of of
thethe crystalline
crystalline drug,
drug, a DSC
a DSC analysis
analysis was was conducted.
conducted.
DSC thermograms of pure IBU and SDs composed of IBU-Kollidon obtained by the SCF method are
DSC thermograms of pure IBU and SDs composed of IBU-Kollidon obtained
DSC thermograms of pure IBU and SDs composed of IBU-Kollidon obtained by the SCF method by the SCF method are are
shown
shown in
in Figure 4. IBU is a crystalline compound exhibiting a single, sharp endothermic peak at
shown inFigure
Figure4.4.IBU
IBUisisa acrystalline
crystallinecompound
compound exhibiting
exhibitinga single, sharp
a single, endothermic
sharp peakpeak
endothermic
◦ C, which corresponds to the melting point of IBU. An endothermic peak was detected in the PMs,
at 80.3
at 80.3
80.3
°C,
°C, which
whichcorresponds
correspondstotothe themelting
melting point
pointof ofIBU. AnAn
IBU. endothermic
endothermic peakpeak
was was
detected in theinPMs,
detected the PMs,
confirmingthe
confirming the existenceofofa acrystalline
crystalline phase, although thethe endothermic behavior
was was weaker
than than
confirming theexistence
existence of a crystalline phase,
phase, although
although endothermic
the endothermic behavior
behavior weaker
was weaker than
that of
that pure IBU. This was in contrast toto itsits
crystalline phase in the PMs, in which the two
the SDs exhibited
that ofof pure
pure IBU.
IBU.This
Thiswas
wasinincontrast
contrast to crystalline
its crystallinephase
phasein the PMs,
in the in which
PMs, in which two
the SDs
two SDs
the amorphous
exhibited state instead. Therefore, the drug–carrier interactions appeared to be effective
to beto for
exhibited the the amorphous
amorphousstate stateinstead.
instead.Therefore,
Therefore, thethe
drug–carrier
drug–carrier interactions appeared
interactions appeared be
inhibiting drug crystallization.
effective for inhibiting drug crystallization.
effective for inhibiting drug crystallization.

Differentialscanning
Figure 4.4. Differential
Figure scanning calorimetry
calorimetry curves
curves of IBU-CL
of IBU-CL different
different grade
grade PM SD
PM and andsystems
SD systems
prepared by the SCF method (A) IBU; (B) IBU-CL PM; (C) IBU-CL SD; (D) IBU-CL-SF PM; (E) IBU- PM;
prepared by the SCF method (A) IBU; (B) IBU-CL PM; (C) IBU-CL SD; (D) IBU-CL-SF
Figure 4. Differential scanning calorimetry curves of IBU-CL different grade PM and SD systems
(E) IBU-CL-SF
CL-SF SD. SD.
prepared by the SCF method (A) IBU; (B) IBU-CL PM; (C) IBU-CL SD; (D) IBU-CL-SF PM; (E) IBU-
CL-SF SD.
Pharmaceutics 2019, 11, x 7 of 12

3.3. Dissolution Studies

Pharmaceutics 2019, 11, 67 7 of 13

The dissolution profiles of IBU in the PMs and SDs prepared with different carriers (Kollidon
3.3. Dissolution Studies
CL and Kollidon CL-SF) were investigated and are shown in Figure 5. In contrast to the
corresponding The PM,dissolution
the SD profiles of IBU inenhanced
significantly the PMs andthe
SDsdissolution
prepared withrate
different carriersAs
of IBU. (Kollidon
shownCLin the
and Kollidon CL-SF) were investigated and are shown in Figure 5. In contrast to the corresponding
dissolution profiles, in the first 5 min, 60.0% and 83.7% of the IBU in the Kollidon CL and Kollidon
PM, the SD significantly enhanced the dissolution rate of IBU. As shown in the dissolution profiles,
CL-SF SDs inwas dissolved; these values are 15.9 times and 22.3 times those of pure IBU and the
the first 5 min, 60.0% and 83.7% of the IBU in the Kollidon CL and Kollidon CL-SF SDs was dissolved;
corresponding
thesePM,
valuesrespectively.
are 15.9 times Moreover,
and 22.3 timesthe selection
those of the
of pure IBU and carrier during SD
the corresponding PM,preparation
respectively. was
also critical. In thisthestudy,
Moreover, Kollidon
selection CL-SF
of the carrier duringproduced a more
SD preparation remarkable
was also improvement
critical. In this study, Kollidonin the
dissolution rate of IBU than IBU-CL; thus, the cumulative percentages of IBU in theIBU-CL;
CL-SF produced a more remarkable improvement in the dissolution rate of IBU than thus, and
IBU-CL-SF
the cumulative percentages of IBU in the IBU-CL-SF and IBU-CL SDs reached 94% and 80%, respectively,
IBU-CL SDs reached 94% and 80%, respectively, within 15 min. Considering all of the above results,
within 15 min. Considering all of the above results, the IBU-CL-SF SD was the optimal choice for
the IBU-CL-SF SD was the optimal choice for improving the solubility and in vitro dissolution of IBU.
improving the solubility and in vitro dissolution of IBU.

Figure 5. Dissolution profiles of IBU-Kollidon different grade SD systems prepared by the SCF method.
Figure 5. Dissolution profiles of IBU-Kollidon different grade SD systems prepared by the SCF
method. Release kinetic modeling was conducted by using DDSolver software [21], including zero-order,
first-order, Weibull, Makoid-Banakar, Peppas-Sahlin, and Korsmeyer-Peppas [22–24], as is shown in
Table
Release 2. The
kinetic release profile
modeling wasofconducted
IBU and IBU-CL-SF
by SD were fit into a first-order kinetic model, zero-order,
whose

using DDSolver software [21], including
equations were F = 57.736 × 1 − e−0.009t , r2 = 0.9915 and F = 90.550 × 1 − e−0.862 t , r2 = 0.9980,


first-order, Weibull, Makoid-Banakar, Peppas-Sahlin, and Korsmeyer-Peppas [22–24], as is shown in
respectively. Among the following equations, the Makoid-Banakar equation was the best one for IBU-CL
Table 2. TheSDrelease profile
(F = 39.238 of IBU
× t0.251 × e−and
0.004t , IBU-CL-SF
r2 = 0.9906),SD werePM
IBU-CL fit(Finto a first-order
= 8.811 × t0.455 × e−kinetic
0.004t , r2model,
= 0.9969whose
)
.
equations andwere IBU-CL-SF F (F
= =57.736 ×t 1 −×𝑒e
19.688 × 0.244 − 0.002t , )r, 𝑟
2 = 0.9915
= 0.9844 ). and F = 90.550 × 1 − 𝑒 . 𝑡), 𝑟 =
0.9980, respectively. Among the following equations, the Makoid-Banakar equation was the best one
for IBU-CL SD ( F = 39.238 × 𝑡 . × 𝑒 . , 𝑟 = 0.9906 ), IBU-CL PM ( F = 8.811 × 𝑡 . ×
𝑒 . , 𝑟 = 0.9969) and IBU-CL-SF (F = 19.688 × 𝑡 . × 𝑒 . , 𝑟 = 0.9844).

Table 2. Release rate constants and r2 coefficients obtained from drug release profile based on kinetic
equations.
Equations IBU-CL SD IBU-CL-SF SD IBU IBU-CL PM IBU-CL-SF PM
Zero-order F = 51.441 + 0.376t F = 71.947 + 0.266t F = 2.131 + 0.332t F = 16.276 + 0.369t F = 25.417 + 0.288t
F = C + kt r2 = 0.2997 r2 = 0.0875 r2 = 0.9769 r2 = 0.7279 r2 = 0.5396
F = 78.064 × (1 − F = 90.550 × (1 − F = 57.736 × (1− F = 45.904 × (1− F = 44.493 × (1 −
First-order
e−0.366t) e−0.862t) e−0.009t) e−0.076t) e−0.247t)
F = a × (1 − e-kt)
r2 = 0.9474 r2 = 0.9980 r2 = 0.9915 r2 = 0.9328 r2 = 0.9328
F = 100 × {1 − F = 100 × {1 − F= 100 × {1 − F = 100 × {1 − F = 100 × {1 −
Weibull
e[− (t^0.294) / 1.873]} e[− (t^0.278) / 0.934]} e[− (t^0.869) / 128.345]} e[− (t^0.410) / 9.318]} e[ −(t^0.248) / 4.333]}
F = 100×{1 − e[-(t^β) / α]}
r2 = 0.9630 r2 = 0.9742 r2 = 0.9912 r2 = 0.9858 r2 = 0.9794
F = 39.238 × t0.251 × F = 66.349 × t0.135 × F = 0.637 × t0.936 × F = 8.811 × t0.455 × F = 19.688 × t0.244 ×
Makoid-Banakar
e−0.004t e−0.003t e−0.003t e−0.004t e−0.002t
F = k × tn × e-bt
r2 = 0.9906 r2 = 0.9870 r2 = 0.9910 r2 = 0.9969 r2 = 0.9844
F = 26.104 × t0.5 − F = 34.669 × t0.5 − F = 1.237 × t0.5 + F = 8.968 × t0.5 − F =12.862 × t0.5 −
Peppas-Sahlin
1.821t 2.603t 0.223t 0.404t 0.794t
F = k1 × t0.5 + k2t
r2 = 0.8292 r2 = 0.3378 r2 = 0.9875 r2 = 0.9967 r2 = 0.8805
Korsmeyer-Peppas F = 45.960 × t0.140 F = 72.461 × t0.064 F = 1.020 × t0.766 F = 11.220 × t0.329 F = 21.366 × t0.192
F = k × tn r2 = 0.9294 r2 = 0.9460 r2 = 0.9895 r2 = 0.9771 r2 = 0.9762
Pharmaceutics 2019, 11, 67 8 of 13

Table 2. Release rate constants and r2 coefficients obtained from drug release profile based on kinetic equations.

Equations IBU-CL SD IBU-CL-SF SD IBU IBU-CL PM IBU-CL-SF PM

Zero-order F = 51.441 + 0.376t F = 71.947 + 0.266t F = 2.131 + 0.332t F = 16.276 + 0.369t F = 25.417 + 0.288t
F = C + kt r2 = 0.2997 r2 = 0.0875 r2 = 0.9769 r2 = 0.7279 r2 = 0.5396
First-order F = 78.064 × (1 − e−0.366t ) F = 90.550 × (1 − e−0.862t ) F = 57.736 × (1−e−0.009t ) F = 45.904 × (1−e−0.076t ) F = 44.493 × (1 − e−0.247t )
F = a × (1 − e−kt ) r2 = 0.9474 r2 = 0.9980 r2 = 0.9915 r2 = 0.9328 r2 = 0.9328
Weibull F = 100 × {1 − e[− (tˆ0.294) / 1.873] } F = 100 × {1 − e[− (tˆ0.278) / 0.934] } F= 100 × {1 − e[− (tˆ0.869) / 128.345] } F = 100 × {1 − e[− (tˆ0.410) / 9.318] } F = 100 × {1 − e[ −(tˆ0.248) / 4.333] }
F = 100×{1 − e[−(tˆβ) / α] } r2 = 0.9630 r2 = 0.9742 r2 = 0.9912 r2 = 0.9858 r2 = 0.9794
Makoid-Banakar F = 39.238 × t0.251 × e−0.004t F = 66.349 × t0.135 × e−0.003t F = 0.637 × t0.936 × e−0.003t F = 8.811 × t0.455 × e−0.004t F = 19.688 × t0.244 × e−0.002t
F = k × tn × e−bt r2 = 0.9906 r2 = 0.9870 r2 = 0.9910 r2 = 0.9969 r2 = 0.9844
Peppas-Sahlin F = 26.104 × t0.5 − 1.821t F = 34.669 × t0.5 − 2.603t F = 1.237 × t0.5 + 0.223t F = 8.968 × t0.5 − 0.404t F =12.862 × t0.5 − 0.794t
F = k1 × t0.5 + k2 t r2 = 0.8292 r2 = 0.3378 r2 = 0.9875 r2 = 0.9967 r2 = 0.8805
Korsmeyer-Peppas F = 45.960 × t0.140 F = 72.461 × t0.064 F = 1.020 × t0.766 F = 11.220 × t0.329 F = 21.366 × t0.192
F = k × tn r2 = 0.9294 r2 = 0.9460 r2 = 0.9895 r2 = 0.9771 r2 = 0.9762
SF SD after administration are shown in Figure 6, while Table 3 shows the pharmacokinetic
parameters of the IBU-CL-SF PM and SD systems.
After oral administration, IBU was quickly detected in plasma, and the maximum concentrations
Cmax of IBU-CL-SF PM and IBU-CL-SF SD were rapidly achieved, with values of 6.98 ± 0.18 within 48
min and 20.6
Pharmaceutics ± 5.4
2019, within 33 min, respectively. Compared with those in the IBU-CL-SF PM, the9 C
11, 67 ofmax
13
value of IBU was 2.95 times higher, and Tmax decreased by 15 min in the IBU-CL-SF SD. These
phenomena may result from the enhanced solubility and improved dissolution rate of IBU in the
3.4. In Vivo Pharmacokinetic Evaluation
IBU-CL-SF SD during in vitro release.
The profiles
All these of the
results mean plasmathat
demonstrated concentration versus time for
the oral bioavailability the IBU-CL-SF
of IBU PM andenhanced
was significantly IBU-CL-SF in
SD
ratsafter administration
owing are shown
to the increased in Figure
dissolution 6, while
amount andTable
rate3ofshows thethe
IBU in pharmacokinetic parameters
IBU-CL-SF solid of
dispersion
the IBU-CL-SF
prepared by thePM SCF and SD systems.
method.

Figure
Figure 6.6. The
The profiles
profiles of
of mean
mean plasma
plasma concentration-time. (Mean ±
concentration-time. (Mean SD, nn == 5,
± SD, 5, biological
biological replicates).
replicates).
Statistical significance is represented by *** p < 0.001.
Statistical significance is represented by ***p < 0.001.
Table 3. Pharmacokinetic parameters of IBU-CL-SF PM and SD systems.
Table 3. Pharmacokinetic parameters of IBU-CL-SF PM and SD systems.
Parameters IBU-CL-SF PM IBU-CL-SF SD
Parameters IBU-CL-SF PM IBU-CL-SF SD
Cmax (mg/L)Cmax (mg/L) 6.98 ± 0.18
6.98 ± 0.18 20.6 ± 5.4
20.6 ± 5.4
Tmax (min) T max (min) 48 ± 6.7 48 ± 6.7 33 ±
33 12.55
± 12.55
AUC (mg/L × min) 1476.4 ± 411.7 3203.7 ± 450.9
AUC(0–t) (mg/L ×(0–t)
min) 1476.4 ± 411.7 3203.7 ± 450.9
MRT(0–t) (min) 140.5 ± 30.8 115.7 ± 23.8
MRT(0–t) (min) 140.5 ± 30.8 115.7 ± 23.8

After oral administration,

3.5. Drug–Polymer InteractionsIBU was quicklyDocking
in Molecular detectedSimulation
in plasma, and the maximum concentrations
Cmax of IBU-CL-SF PM and IBU-CL-SF SD were rapidly achieved, with values of 6.98 ± 0.18 within
Kollidon affects the dispersibility of the drug and the particle size. Small particles can ensure
48 min and 20.6 ± 5.4 within 33 min, respectively. Compared with those in the IBU-CL-SF PM,
uniform distribution of the drug and easily form a water-soluble complex, accelerating drug
the Cmax value of IBU was 2.95 times higher, and Tmax decreased by 15 min in the IBU-CL-SF SD.
dissolution and improving bioavailability. The sizes of Kollidon CL and Kollidon CL-SF are 110 to
These phenomena may result from the enhanced solubility and improved dissolution rate of IBU in
130 μm and 10 to 30 μm, respectively. As shown in the literature [25], binding of the drug to Kollidon
the IBU-CL-SF SD during in vitro release.
was simulated by 1-methyl-2-pyrrolidone (Etp), which is similar in structure to the Kollidon unit.
All these results demonstrated that the oral bioavailability of IBU was significantly enhanced
Here, as shown in Figure 7, the interactions of IBU with Kollidon systems were represented at the
in rats owing to the increased dissolution amount and rate of IBU in the IBU-CL-SF solid dispersion
molecular level with both the polymer and molecule in three dimensions. Generally, the polymer
prepared by the SCF method.
effectively undergoes a hydrophobic interaction with the drug; from a thermodynamic point of view,
a negative
3.5. free energy
Drug–Polymer (△G < 0)
Interactions in suggests
MolecularaDocking
relatively stable system, whereas a positive △G indicates
Simulation
that an unstable system was formed when the molecule complexed with the polymer. The binding
Kollidon affects the dispersibility of the drug and the particle size. Small particles can ensure
energy (△G) obtained in the molecular docking simulation, which was −5.71 kcal/mol, was used to
uniform
evaluatedistribution of thebetween
the interactions drug and easily
IBU andform a water-soluble complex, accelerating drug dissolution
the polymers.
and improving bioavailability. The sizes of Kollidon CL and Kollidon CL-SF are 110 to 130 µm and 10
to 30 µm, respectively. As shown in the literature [25], binding of the drug to Kollidon was simulated
by 1-methyl-2-pyrrolidone (Etp), which is similar in structure to the Kollidon unit. Here, as shown in
Figure 7, the interactions of IBU with Kollidon systems were represented at the molecular level with
both the polymer and molecule in three dimensions. Generally, the polymer effectively undergoes
a hydrophobic interaction with the drug; from a thermodynamic point of view, a negative free energy
(4G < 0) suggests a relatively stable system, whereas a positive 4G indicates that an unstable system
was formed when the molecule complexed with the polymer. The binding energy (4G) obtained in
the molecular docking simulation, which was −5.71 kcal/mol, was used to evaluate the interactions
between IBU and the polymers.
Pharmaceutics 2019, 11, 67 10 of 13
Pharmaceutics 2019, 11, x 9 of 12

Figure 7. Docking conformation of ibuprofen complexed with polymers. Ibuprofen is shown in the
Figure
3D 7. Docking
structure conformation
representation (left).ofThree
ibuprofen complexed
close-up views ofwith polymers.
integral Ibuprofen
and local is shownrelevant
conformations in the
3D structure representation (left). Three close-up views of integral and local conformations
with the polymer, named Kollidon System and IBU-Kollidon solid dispersion, are displayed with therelevant
with the polymer,
molecule named
and polymer Kollidon
shown System and IBU-Kollidon solid dispersion, are displayed with the
as stick.
molecule and polymer shown as stick.
4. Discussion
4. Discussion
SCF technology, an experimental friendly process, minimized the particle size distribution,
damage SCFbytechnology,
shear forces, an etc.,
experimental friendly
in comparison process,
with minimized
conventional the particleIt size
approaches. distribution,
is categorized by
adamage by shear forces,
rapid expansion etc., in comparison
of supercritical solutions,with conventional
supercritical approaches.
antisolvents, It is categorized
gaseous antisolvents, by aparticle
rapid
expansionfrom
formation of supercritical
gas-saturation, solutions,
and so on supercritical
[26]. Among antisolvents,
the processes gaseous
above, antisolvents,
SCF technology particle
using
formation from gas-saturation, and so on [26]. Among the processes
scCO2 was greatly advantageous, since scCO2 is easier to remove from the system and the limitedabove, SCF technology using
scCO2 was
amount greatly would
remaining advantageous, since scCO
not be dangerous is easier As
to2 patients. to remove
shown in from the system
Scheme 2, pointandA isthethelimited
critical
amount remaining would not be dangerous
3 to patients. As shown in
point of CO2 (304.2 K, 7.39 × 10 kPa), and when the system is above the critical pressure andScheme 2, point A is the critical
point of CO2the
temperature, (304.2 K, 7.39
interface × 103 kPa),
between the gas and when
phase andthethesystem
liquid is above
phase the criticalthis
disappears; pressure
is called andthe
temperature, the interface between the gas phase and the liquid phase disappears;
supercritical state. IBU is a crystalline drug. The pressure of supercritical fluid has a great influence on this is called the
supercritical
the solubility ofstate.
IBU.IBU Theisdensity
a crystalline
of COdrug. The pressure of supercritical fluid has a great influence
2 increases as the pressure increases, and the ability to dissolve
on the solubility of IBU. The density of CO 2 increases as the pressure increases, and the ability to
substances is proportional to its density. Therefore, the solubility of IBU was improved significantly.
dissolve
The substances
XRD results is proportional
suggested to its peak
that the crystal density. Therefore,
of the the solubilitydisappeared,
drug-loaded-carrier of IBU was or improved
the large
significantly. The XRD results suggested that the crystal peak of the drug-loaded-carrier disappeared,
amount of the carrier masked the peak of the crystalline drug. Therefore, we further adopted DSC
or the large amount of the carrier masked the peak of the crystalline drug. Therefore, we further
characterization and molecular simulation to prove that the drug can be spontaneously loaded in the
adopted DSC characterization and molecular simulation to prove that the drug can be spontaneously
carrier to form a stable system (4G < 0). IBU, indeed, converted to amorphous, which is beneficial
loaded in the carrier to form a stable system (△G < 0). IBU, indeed, converted to amorphous, which
to the dissolution of the drug [27–29]. In the supercritical CO2 , hydrogen bond dimers formed
is beneficial to the dissolution of the drug [27–29]. In the supercritical CO2, hydrogen bond dimers
between the molecules of IBU. The high fluid density caused the dimerization balance between the
formed between the molecules of IBU. The high fluid density caused the dimerization balance
monomers to shift, which weakened the bonding and increased solubility. In this process, IBU-CL-SF
between the monomers to shift, which weakened the bonding and increased solubility. In this process,
SDs were prepared at the same supercritical state (40 ◦ C) but with different reaction times, pressure,
IBU-CL-SF SDs were prepared at the same supercritical state (40 °C) but with different reaction times,
and drug-to-carrier ratio. The results indicate that the cumulative percentage of the drug released
pressure, and drug-to-carrier ratio. The results indicate that the cumulative percentage of the drug
with the extension of the three conditions. Prolonging the reaction time was preferable to obtain ideal
released with the extension of the three conditions. Prolonging the reaction time was preferable to
solid dispersions, since the drug and carriers were more thoroughly dissolved and dispersed in scCO2 .
obtain ideal solid dispersions, since the drug and carriers were more thoroughly dissolved and
The cumulative percentage of drug release in IBU-CL-SF SDs increased with the rise of preparing
dispersed in scCO2. The cumulative percentage of drug release in IBU-CL-SF SDs increased with the
pressure. This could be attributed to the fact that IBU in scCO2 possessed
rise of preparing pressure. This could be attributed to the fact that
higher solubility under
IBU in scCO2 possessed higher
higher preparing
solubility pressure,
under higher resulting
preparing in the more
pressure, thorough
resulting interaction
in the more thoroughbetween drug between
interaction and carriers drugto
obtain desirable solid dispersions. Considering the comprehensive factors, optimized
and carriers to obtain desirable solid dispersions. Considering the comprehensive factors, optimized conditions were
determined. In addition, IBU has a relatively low melting point and boiling
conditions were determined. In addition, IBU has a relatively low melting point and boiling point. point. This makes IBU
easy
Thistomakes
sublimate and istoalso
IBU easy the reason
sublimate andfor is its
alsohighthesolubility.
reason forSolubility
its high of poor water-soluble
solubility. Solubility of drugs
pooris
significant for enhancing oral bioavailability. Therefore, the preparation of
water-soluble drugs is significant for enhancing oral bioavailability. Therefore, the preparation ofibuprofen solid dispersion
by a supercritical
ibuprofen fluid static
solid dispersion byreaction method
a supercritical is astatic
fluid very reaction
feasible method.
method isWe believe
a very that method.
feasible Kollidon
system SDs prepared by SCF technology will potentially become a carrier
We believe that Kollidon system SDs prepared by SCF technology will potentially become a carrier with good biocompatibility
and
withhigh
good drug delivery efficiency.
biocompatibility and high drug delivery efficiency.
 Pharmaceutics 2019, 11, 67 11 of 13
Pharmaceutics 2019, 11, x 10 of 12

Scheme
Scheme 2. Phase
2. Phase diagram
diagram of CO
of CO 2 . Critical
2. A: A: Critical point;
point; B: Three-phase
B: Three-phase point.
point.

5. Conclusions
5. Conclusions
IBUIBU SDswere
SDs wereformulated
formulated with
with Kollidon
KollidonCL CLandandKollidon CL-SF
Kollidon carriers
CL-SF in SCF
carriers in media. The obtained
SCF media. The
results suggest that IBU-Kollidon CL-SF solid dispersion prepared by SCF technology
obtained results suggest that IBU-Kollidon CL-SF solid dispersion prepared by SCF technology markedly improves
in in vitro
markedly and in vivo
improves performance.
in in vitro and inMoreover, a molecularMoreover,
vivo performance. docking simulation
a molecular showed that intermolecular
docking simulation
interaction occurred and also suggested a relatively stable system. Using SCF technology
showed that intermolecular interaction occurred and also suggested a relatively stable system. combined with
Using
SCFa Kollidon system
technology to prepare
combined solid
with a dispersions is a promising
Kollidon system approach
to prepare solid todispersions
improving theis aabsorption
promising and
oral bioavailability of water-insoluble drugs. We hope our study may open a new window
approach to improving the absorption and oral bioavailability of water-insoluble drugs. We hope our for designing
different
study formulations
may open to improve
a new window bioavailability
for designing in theformulations
different future. to improve bioavailability in the
future.
Author Contributions: Conceptualization, L.X. and F.H.; methodology, W.Z.; software, Y.W.; validation, W.Z.,
Z.X. and
Author L.C.; writing—original
Contributions: draft preparation,
Conceptualization, F.H. methodology,
L.X. and F.H.; and L.X.; writing—review andY.W.;
W.Z.; software, editing, L.X. and W.Z.,
validation, S.L.
and L.C.;This
Funding:
Z.X. research received
writing—original nopreparation,
draft external funding.
F.H. and L.X.; writing—review and editing, L.X. and S.L.
Conflicts
Funding: of research
This The authors
Interest: received declare funding.
no external no conflict of interest.

Conflicts of Interest: The authors declare no conflict of interest.

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