Andrographolide solid dispersions formulated by Soluplus to enhance

interface wetting, dissolution, and absorption

Bing Song,1 Jian Wang,2 Si-Jing Lu,3 Li-Na Shan 3
1
Department of Endocrinology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China
2
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Shenyang, 110016, China
3
Department of Respiratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China
Correspondence to: L. N. Shan (E-mail: shanlina123@163.com) and S. J. Lu (E-mail: sxbsln@163.com)

ABSTRACT: Andrographolide (ADG) had profound functions as drug health-care product. To improve ADG application in medical care, solid
dispersion technique was introduced. Initially, several polymers were chosen to prepare ADG solid dispersion using hot-melt extrusion. Work-
ing mechanisms of ADG solid dispersion, which include molecular docking and wetting property, were studied. The strongest molecular bind-
ing energy of ADG with Soluplus contributed to carrier-controlled mechanism, leading to its highest drug dissolution. Soluplus as solid
dispersion excipient could significantly improve drug absorption. In addition, ADG solid dispersions formulated by Soluplus were prepared
and studied, and the ratios of drug to polymer were 1:5, 1:7, 1:9, and 1:12, respectively. It demonstrated that hydrogen bond interactions were
formed between ADG and Soluplus based on infrared (IR) spectroscopy analysis. The characteristic peaks of crystal state of ADG at 11.97
,
14.95
, 15.86
, and 9.78
disappeared in ADG solid dispersion, demonstrating that excipient was efficient in transforming drug crystal state to
amorphous phase by interacting with ADG. ADG-Soluplus solid dispersion of 1:7 turned out to be the best with maximum cumulative release
amount of more than 80%, whereas other ADG solid dispersions were in the range of 60–70%. The cumulative release amount of pure
ADG was below 20%. Comparing with the oral administration of pure ADG, we found that the mean Cmax and AUC values of ADG for ADG-
Soluplus solid dispersion were approximately increased 1.96- to 2.53-fold. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 48354.

KEYWORDS: andrographolide; hot-melt extrusion; solid dispersion; Soluplus

Received 23 March 2019; accepted 13 July 2019

DOI: 10.1002/app.48354

INTRODUCTION
Andrographolide (ADG) is one of the main active components
isolated from the Chinese herb Andrographis paniculata. ADG
has many pharmacological actions, including anti-inflammatory,1,2
anti-infection,3–5 anticancer,6–8 anti-hyperglycemia,9 anti-angio-
genesis,10,11 hepato-protection,12,13 antifertility,14 and anti-HIV15,16
effects. However, its high lipophilicity (log P = 2.63), low aqueous sol-
ubility (74 μg mL−1), and poor stability seriously limit its applica-
tion.17 ADG can be normally made into tablet, capsule, and dropping
pill, whereas its oral bioavailability is low due to its low solubility
(74 μg mL−1).18 In order to tackle this problem, soluble salt and
superfine grinding have been used. Various formulation techniques,
including nanoemulsion,19 cyclodextrin inclusion complexes,20 and
liposomes,21,22 have been also applied. Among them, solid dispersion
turns out to be an outstanding strategy to improve dissolution and
bioavailability of ADG. Solid dispersion is designed as drug dispersion
system that drug is highly dispersed in a suitable solid carrier, which
can effectively change drug physical state from crystalline to amor-
phous phase owing to the advantages of carriers in enlarging area
surface and interacting with drug molecules.23 Many polymers, such
as polyoxyethylene pyrrolidone K30,24 polyethylene glycol,25,26
Eudragit series,27,28 hydroxy propyl cellulose,29 poloxamer,30 and
Soluplus,31,32 have been considered as excipients for forming solid
dispersion.
In this article, ADG solid dispersion was prepared by hot-melt
extrusion. Hot-melt extrusion method was first used in the field
of pharmaceutical preparations in 1970s.33 It requires no solvent
participation, has few operation steps, and is suitable for large-
scale industrial production.34,35 Since the application of various
new auxiliary materials and pharmaceutical equipment, the appli-
cation frequency of this method has been increasing in the past
40 years. However, it is difficult to apply this method for ther-
mally unstable excipients and drugs, typically as albendazole.36,37
In the process of research work, we screened out the suitable
polymer and drug/polymer ratio for preparing ADG solid disper-
sion, analyzed their molecular interaction through IR spectros-
copy, and studied crystal form using X-ray diffraction (XRD).
Further, the current study focused on interface wetting property

Additional Supporting Information may be found in the online version of this article.
© 2019 Wiley Periodicals, Inc.

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of as-synthesized ADG solid dispersion through measuring
dynamic contact angle.
EXPERIMENTAL
Materials
ADG with purity above 99% was purchased from Wuhan Dong-
kangyuan Technology Co., Ltd. (Wuhan, China). Polyethylene glycol
6000 (PEG 6000), polyvinylpyrrolidone VA64 (PVP VA64), and pol-
oxamer 188 (F68) were purchased from Sigma-Aldrich Chemical
Co. (St. Louis, MO). Soluplus was provided by BASF Company
(Ludwigshafen, Germany). Other chemical agents were obtained
from Tianjin Bodi Chemical Holding Co., Ltd. (Tianjin, China).
Preparation Process and Working Mechanism
ADG was physically mixed with different polymers. All chemical
structures were shown in the Supporting Information Figure S1.
The ratios of ADG/polymer (w/w) and temperature settings were
listed in Table I. The weight ratios of ADG and carrier were set
at 1:5, 1:7, 1:9, and 1:12, respectively. Extrusion process of all
ADG and polymer physical mixtures was conducted using a
Thermo Scientific Haake MiniLab II conical, co-rotating, twin-
screw microcompounder (Thermo Electron, Karlsruhe, Ger-
many). The screw speed was set at 50 rpm.
The 3D structures of macromolecules were optimized using the
Sybyl 6.9.1 software package. The parameters that included energy
change (0.005 kcal mol−1) and max iterations (10 000) were also
optimized. All other parameters were kept at the default values.
Molecular docking was studied using the AutoDock 4.0 software.
Energy evaluations were set at 25 000 000 per run. Discovery Studio
4.0 was used to understand the binding interactions between the
drug and polymers as well as molecular binding energy.
In vitro Dissolution
In vitro dissolution tests for screening suitable polymer and optimal
ADG/polymer ratio for ADG solid dispersion were performed using
stirring paddle method (50 rpm, 37
C) with a RCZ-6C3 tester
(Huanghai, China) according to 2015 Chinese pharmacopeia.38
Since small intestine was the main absorption site for ADG, samples
were exposed to pH 6.8 phosphate buffer solutions (250 mL). At pre-
determined time intervals, 5 mL of sample medium was withdrawn
and an equivalent amount of fresh medium was added into the disso-
lution cup. Sample medium administered through a 0.45 μm micro-
porous membrane was determined by a Shimadzu LC-20AT HPLC
system (Shimadzu Corporation, Kyoto, Japan) equipped with a
Table I. The Ratios of ADG/Polymer (w/w) and Temperature Settings
Drug–polymer Process
Sample ID system w:w temperature (
C)
1 ADG:F68 1:7 150
2 ADG:PEG 6000 1:7 130
3 ADG:PVP VA64 1:7 170
4 ADG:Soluplus 1:7 150
5 ADG: Soluplus 1:5 150
6 ADG: Soluplus 1:9 150
7 ADG: Soluplus 1:12 150
48354 (2 of 7)
Shimadzu Inertsil ODS-3 column (4.6 mm × 150 mm, 5 μm) at a
wavelength of 220 nm. The HPLC working conditions for ADG
analysis were (1) methanol:water (0.1% formic acid) = 51:49, v/v;
(2) flow rate of 1.0 mL min−1; and (3) column temperature of
30
C  1
C.
Infrared Spectroscopy
The IR spectroscopy (Spectrum 1000; Perkin Elmer) spectra of
10 scans, including ADG, Soluplus, physical mixtures (ADG and
Soluplus with weight ratio of 1:5, 1:7, 1:9, and 1:12) and solid dis-
persions (ADG:Soluplus = 1:5, 1:7, 1:9, and 1:12, respectively)
were obtained over the spectral region of 400–4000 cm−1. All the
samples were made with KBr.
X-ray Diffraction
XRD of ADG, Soluplus, and ADG solid dispersion formed by
Soluplus with different drug/polymer ratios was analyzed using a
Shimadzu XRD-6000 diffractometer (Shimadzu Corporation)
equipped with a Cu-Ka source and set in Bragg–Brentano geome-
try, scanning between 5
C and 50
C 2θ at 2
C min−1 with a
0.04
step size.
Contact Angle Measurement
The interface wetting property of ADG solid dispersion formu-
lated by Soluplus was studied by dynamic contact angle measured
using an automatic contact angle meter model JCY series
(Shanghai, China) with operation manual.39 Briefly, 200 mg sam-
ple was weighed and compressed using a circular stainless steel
punch and die to get tablet with flat surface. A drop of dissolu-
tion medium (2 μL) was placed on tablet as the start of measure-
ment. Tangent method was explored to calculate the contact
angle of tested sample.40
Pharmacokinetics Study
Thirty male Wister rats (200–250 g) were obtained from the Labora-
tory Animal Center of Liaoning Medical University. The study pro-
tocols were approved by the Institutional Animal Ethics Committee.
The rats were divided randomly into five groups (n = 6 per group)
for the administrations of a single dose of ADG, ADG-F68 1/7 solid
dispersion, ADG-Soluplus 1/7 solid dispersion, ADG-PEG 6000 1/7
solid dispersion, and ADG-PVP AV64 solid dispersion. The ADG or
ADG solid dispersions were dissolved in physiological saline solu-
tions to form suspensions. Each group of rats was orally dosed at
50 mg kg−1 of ADG. The blood samples (0.3 mL) were collected
from orbital venous plexus into dried heparinized tubes at 5, 15,
30, 45, 60, 90, 120, 180, 240, 360, 480, and 720 min and were cen-
trifuged at 4000 rpm for 10 min at 4
C to obtain the plasma samples.
The plasma (0.1 mL) was mixed with 200 μL of acetonitrile and cen-
trifuged at 12 000 rpm for 20 min at 4
C. The supernatant was col-
lected and an aliquot of 20 μL of the solution was analyzed by
LC/MS/MS system.
The LC–MS/MS system (Waters Corporation, Milford, MA) was
fitted with an Acquity UPLC BEH C18 column (2.1 mm × 100 mm,
1.7 μm; Waters Co. Ltd., Milford, MA). The mobile phases consisted
of LC grade water with 0.1% formic acid (A) and LC grade methanol
(B) with the following gradient profile: 0.0–1.5 min from 60 to
90% B, 1.5–2.5 min from 90 to 90% B, 2.5–3.0 min 90 to 60% B, and
3.0–5.0 min at 60% B. Mass detection of ADG was performed in neg-
ative, and quantification was performed using the multiple reaction
J. APPL. POLYM. SCI. 2019, DOI: 10.1002/APP.48354
ARTICLE WILEYONLINELIBRARY.COM/APP
monitoring (MRM) method with the transitions of m/z 349.1 ! m/
z 287.1 for ADG. According to preliminary experiments (data not
shown), the performance parameters that include specificity, linear-
ity, accuracy, precision, decision limit, quantification limit, and sta-
bility proved that the validated method was qualified for the
determination of ADG.
RESULTS AND DISCUSSION
Superior Polymer for ADG Solid Dispersion
The photograph of the prepared ADG-Soluplus solid dispersion was
shown in Figure 1. ADG-Soluplus solid dispersion was uniformly
powder particles, which was favorable for obtaining solid dispersion
with high drug dispersity. According to drug dissolution result
[Figure 2(a)], it was obvious that Soluplus was the best choice among
these excipients with highest cumulative drug release amount of
more than 80% while others were lower than 70% (the dissolution of
ADG solid dispersion made by PVP VA64, F68 and PEG 6000 were
almost 60, 20, and 20%, respectively). The cumulative release amount
of pure ADG was below 20%. In order to illustrate this result, molec-
ular docking strategy was applied to calculate the binding energy
between drug and excipient. The binding modes of the four com-
plexes that were proved to be the most stable one with the lowest
binding energy were analyzed further. Figure 3(a) described the
molecular docking result of Soluplus with ADG, and the binding
affinity of the complex was calculated as −4.73 kcal mol−1, which
was the lowest among the four complexes. It observed that there were
two hydrogen bonds formed between the dihydroxyl group of ADG
with the ether oxygen atoms on ester group of Soluplus, additionally,
and hydrophobic contacts were found between the met-
hylenecyclohexyl group of ADG and caprolactam group on Soluplus.
Figure 3(b) showed the molecular interaction between ADG and
PEG 6000, the binding affinity of which was calculated as
−4.18 kcal mol−1, and the hydrogen bonds formed by three hydroxyl
group of ADG with the oxygen atoms on PEG 6000 were the major
contacts in this complex. Figure 3(c) represented the molecular inter-
action of Pluronic F68 with ADG generated by molecular docking
studies, the binding affinity of them was calculated as
−4.28 kcal mol−1, and two hydrogen bonds can be found in this
complex were formed by the dihydroxyl group with oxygen atoms
Figure 1. The photograph of the prepared ADG-Soluplus solid dispersion.
[Color figure can be viewed at wileyonlinelibrary.com]
48354 (3 of 7)
on Pluronic F68. Figure 3(d) showed the molecular docking results
of ADG with PVP-VA64, and the corresponding binding affinity
was calculated as −4.37 kcal mol−1. As for their binding mode, a
hydrogen bond formed by a hydroxyl group of ADG with PVP
VA64 was observed, and the hydroxyl group also formed an intra-
molecular hydrogen bond with another hydroxyl group at its ortho-
position. In a summary, it was found that ADG can interact with the
four types of material mainly through hydrogen bond formed by the
hydroxyls of the small molecule. Besides, several hydrogen bonds
were also formed with Soluplus, the binding affinity of which was
proved to be the highest, followed by PVP VA64, F68, and PEG 6000
according to their binding affinities. Therefore, the stronger binding
affinity between ADG and PVP VA64 contributed to its obvious
higher drug dissolution.
The wetting property of ADG and ADG solid dispersions prepared
by these excipients was studied to elucidate their working mecha-
nism. It is well known that drug release mechanisms of solid disper-
sion divide into drug-controlled and carrier-controlled mechanism.
Carrier becomes the controller when drug molecularly disperses
within polymer layer and releases along with carrier. On the con-
trary, when drug releases faster than polymer diffusion layer, drug
manages dissolution process and is mainly influenced by its charac-
teristics (size, physical form, etc.). Carrier-controlled mechanism is
superior to drug-controlled mechanism. As shown in Figure 2(b),
the initial time period of contact angle of ADG solid dispersions for-
mulated by PEG 6000 and F68 was close to ADG (contact angle
values of ADG, ADG-PEG solid dispersion, and ADG-F68 solid dis-
persion were in the range of 75
–88
), while ADG solid dispersion
formulated by Soluplus and PVP VA64 became easier to be wetted
(contact angle values of ADG-Soluplus solid dispersion and ADG-
PVP VA64 solid dispersion were 48.88
and 66.23
, respectively). It
demonstrated that ADG controlled its release in the former two solid
dispersions and led to their low drug cumulative release. Polymer
of Soluplus and PVP VA64 exerted functions in bringing out
ADG along with its dissolution. The obtained wetting property
result confirmed in vitro dissolution result, which was in agreement
with the conclusions from related literature that carrier-controlled
mechanism is superior to drug-controlled mechanism.41 The disso-
lution mechanism was related with molecular binding energy mea-
sured using molecular docking technique. The molecular binding
energies of Soluplus and PVP VA64 with ADG were −4.73 and
−4.37 kcal mol−1, respectively, and they were higher than PEG 6000
and F68 with ADG (−4.18 and −4.28 kcal mol−1). The contact angle
result was in agreement with in vitro drug release result, demonstrat-
ing that the stronger binding affinity between ADG and carrier con-
tributed to its better wetting ability and therefore higher dissolution.
The result further confirmed the reason why Soluplus can be chosen
as the final excipient for preparing ADG solid dispersion. The eluci-
dation of working mechanism of ADG solid dispersion provided
valuable instruction when screening proper excipient and clearly
presented the important information of drug and excipient in solid
dispersion.
Pharmacokinetic Study
The concentration–time curves of ADG and ADG solid dispersion
were shown in Figure 4 and the pharmacokinetics parameters were
shown in Table II. The area under the plasma concentration–time
J. APPL. POLYM. SCI. 2019, DOI: 10.1002/APP.48354
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Figure 2. The in vitro dissolution (a) and contact angle (b) of ADG and ADG solid dispersion. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3. Molecular docking of ADG with Soluplus (a), PEG 6000 (b), F68 (c), and PVP-AV64 (d). [Color figure can be viewed at wileyonlinelibrary.com]

curve (AUC) and the ADG peak plasma concentration (Cmax) characteristic bands that belonged to ─OH, ester, carbanyl group,
differed markedly between different samples (the mean AUC values CH2 at 3399.0, 2928.8, 1727.6, 1673.7, 1408.5, and 1033.0 cm−1,
of ADG, ADG-PEG 6000, ADG-F68, ADG-PVP AV64, ADG- respectively.42 It also presented C─O─C band at 1010.0 cm−1,
Soluplus were 2.72, 3.36, 3.41, 4.76, and 8.72 mg L−1*h, respectively, C─H stretching vibration band at 981.2 cm−1, and C C rocking
and their mean Cmax values were 0.86, 0.91, 0.96, 1.59, and vibration band at 702.8 cm−1.43 The characteristic bands OH group
2.91 mg L−1 respectively). It should be first noted that the oral bio- from soluplus showed the characteristic band at 3445.9 cm−1 and
availability of these four ADG solid dispersions were higher than ester group exhibited the characteristic band at 2930.4 cm−1.44
ADG evidenced by their higher AUC compared with ADG
according to Table II, demonstrating that solid dispersion was an
effective strategy to improve ADG bioavailability. Comparing with
the oral administration of pure ADG, we found that the mean Cmax
and AUC values of ADG for ADG-Soluplus solid dispersion were
approximately increased 1.96- to 2.53-fold, confirming the superior-
ity of Soluplus as ADG solid dispersion carrier owing to the strong
binding affinity between ADG and Soluplus. Compared to other
ADG solid dispersions, the ADG-Soluplus solid dispersion 1:7 had
significant high oral bioavailability.18,29 Other solid dispersion,
including ADG-PEG 6000, ADG-PVP VA64, and ADG-F68,
showed little effect on AGD absorption. Thus, Soluplus is a good
solid dispersion excipient to increase drug absorption. Good drug
absorption of ADG-Soluplus solid dispersion may be related to the
highest cumulative drug release in media.

Infrared Figure 4. Plasma concentration–time curves of ADG after oral administra-

The interaction between ADG and excipient was studied through IR tion of ADG and ADG solid dispersions. Data are expressed as mean  SD
analysis. The IR spectra are presented in Figure 5. ADG showed its (n = 6). [Color figure can be viewed at wileyonlinelibrary.com]

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Table II. The Main Pharmacokinetic Parameters of ADG Solid Dispersions in Rats
Solid dispersions
ADG ADG-PEG 6000
AUC(0-∞) (mg/L*h) 2.72  0.15 3.36  0.23
t1/2 (h) 2.33  0.59 2.38  0.36
Tmax (h) 0.75  0.24 1.03  0.25
Cmax (mg L−1) 0.86  0.12 0.91  0.13
Carbanyl group exhibited two characteristic bands at 1739.3 cm−1
and 1636.7 cm−1. In addition, its CH2 presented two bands at
1442.4 cm−1 and 1241.1 cm−1.45 Whereas Soluplus had aliphatic
ether (─O─) stretching band at 973.4 cm−1. After mixing ADG with
Soluplus or preparing ADG solid dispersion, the stretching vibration
of C─H from ADG cannot be observed while the band of aliphatic
ether from Soluplus still presented in IR spectra, indicating that
the C─H of ADG was covered by aliphatic ether band of Soluplus.
According to molecular docking result of ADG with Soluplus, hydro-
gen bonding interaction was mainly formed. ADG showed its char-
acteristic bands at 3399.0, 1727.6—, and 1631.5 cm−1, which can be
assigned to ─OH and C O groups, respectively. The spectrum of
Soluplus displayed classical bands at 3445.9, 1739.3, and
1636.7 cm−1, which belonged to ─OH and C O groups. After
mixing ADG with Soluplus, C O groups of Soluplus can be
observed while ─OH groups were assigned to ADG, indicating that
the ─OH of ADG interacted with C O group of Soluplus. As for
ADG solid dispersion, both ─OH and C O groups originated from
Soluplus, which possibly demonstrated that ─OH group of Soluplus
had molecular interaction with C O groups of ADG apart from the
hydrogen bonding formed between ─OH group of ADG with C O
group of Soluplus. In this case, stronger molecular interaction can be
formed for ADG solid dispersion.
Figure 5. IR spectra of raw ADG, Soluplus, ADG solid dispersions and ADG
physical mixtures. [Color figure can be viewed at wileyonlinelibrary.com]
48354 (5 of 7)
ADG-F68 ADG-PVP AV64 ADG-Soluplus
3.41  0.36 4.76  0.28 8.72  1.36
2.43  0.21 2.52  0.32 2.23  0.21
1.23  0.24 1.13  0.68 1.02  0.11
0.96  0.26 1.59  0.32 2.91  0.12
X-ray Diffraction
The XRD spectra of ADG, excipient, physical mixtures and ADG
solid dispersions formulated by Soluplus were shown in Figure 6.
Crystal ADG displayed its characteristic peaks at 9.78
, 11.97
,
14.95
, and 15.86
2θ. After mixing with Soluplus, intensity of
drug peaks was weakened because the excipient was able to cover
these peaks by interacting with ADG according to the wavelength
movement of physical mixture of IR result. However, the pres-
ence of many characteristic peaks illustrated that crystal ADG
was remained in mixture samples. The situation was changed
when ADG was loaded into Soluplus using solid dispersion strat-
egy. The characteristic peaks of crystal state of ADG at 11.97
,
14.95
, 15.86
, and 9.78
disappeared in ADG solid dispersion,
demonstrating that excipient was efficient in transforming drug
crystal state to amorphous phase by interacting with ADG. The
amorphous state of ADG with stronger energy than crystal ADG
can be better wetted and released from solid dispersion carrier.
Further, compared to physical mixing ADG with Soluplus, solid
dispersion technique was effectively in enhancing molecular
interaction and performing functions.
Drug Dissolution and Wetting Property
The drug dissolution result was shown in Figure 7(a). It was clear
that ADG solid dispersion formulated by different amount of Sol-
uplus was able to improve drug release owing to the drug amorphous
phase in solid dispersion evidenced by XRD analysis. The amor-
phous ADG had stronger energy to be dissolved than raw ADG
because crystal ADG was harder to be wetted and dissolved, leading
Figure 6. XRD patterns of raw ADG, Soluplus, ADG solid dispersions and
ADG physical mixtures. [Color figure can be viewed at wileyonlinelibrary.com]
J. APPL. POLYM. SCI. 2019, DOI: 10.1002/APP.48354
ARTICLE WILEYONLINELIBRARY.COM/APP

Figure 7. The results of drug release (a) and contact angle (b,c) of samples. (c) The magnifying line chart of contact angle of ADG solid dispersions. [Color
figure can be viewed at wileyonlinelibrary.com]

to enhanced drug dissolution of ADG solid dispersion (the drug property of ADG solid dispersion of 1:7 was the best among these
release of ADG solid dispersion was at least three times higher than formulations [Figure 7(c)], giving evidence for its highest drug
ADG). Among all these formulations, ADG-Soluplus solid disper- dissolution. After fitting the dynamic wetting profiles (Table III),
sion of 1:7 turned out to be the best with maximum cumulative the fitting equations of ADG solid dispersions were all binomial
release amount of more than 80%, while others (ADG-Soluplus solid expressions, which turned to be different from fitting equations
dispersion with weight ratio between drug and carrier of 1:5, 1:9, and of ADG (y = −1.561ln(x) + 72.19) and Soluplus
1:12) were in the range of 60–70%. The wetting property study will (y = 22.754x−0.117). It demonstrated that ADG solid dispersion
address the further reason why ADG solid dispersion of 1:7 was the was able to improve wetting property by lowing contact angle of
best formulation. ADG and changing fitting equation type. All these contributions
were made due to strong hydrogen bonding formed by ADG and
Figure 7(b) described dynamic wetting process of ADG, Soluplus,
Soluplus with capacity to convert crystal ADG to amorphous
mixture of ADG and Soluplus, and ADG solid dispersions. Over-
ADG. Furthermore, the dynamic contact angle measurement
all, the contact angle of dissolution medium on tablets gradually
turned out to be an effective method to reflect the binding affin-
decreased with time. The extreme high contact angle of ADG
ity between drug and carrier and to elucidate the dissolution
reflected that it was hard to be wetted. On the contrary, Soluplus
mechanism of solid dispersion. The final results demonstrated
can be easily wetted using dissolution medium. The contact angle
that Soluplus was the best choice for preparing ADG solid disper-
profiles of physical mixture of ADG and Soluplus were lower
sion. The best drug/polymer ratio can be determined to 1:7. The
than ADG but higher than ADG-Soluplus solid dispersions, dem-
interface wetting and dissolution of this formulation turned out
onstrating that (1) the adding of Soluplus was favorable in
to be optimal ADG solid dispersion, which is certain to have
enhancing wetting property of ADG and (2) solid dispersion was
huge value for industrialization development of ADG. The eluci-
an effective method to get better ADG wetting property than
dation of working mechanism of ADG solid dispersion provided
physical mixture. After forming solid dispersion, the contact
valuable instruction when screening proper excipient.
angle profiles were between ADG and physical mixtures, showing
that the wetting property was enhanced compared with ADG and
so did its drug dissolution. According to the previous discussion CONCLUSIONS
in the section “Superior polymer for ADG solid dispersion,” the
In summary, ADG solid dispersion was prepared using hot-melt
dissolution mechanism of ADG solid dispersion formulated by
extrusion method. PEG 6000, F68, Soluplus, and PVP VA64 were
Soluplus belonged to carrier-controlled mechanism. It was obvi-
initially screened as excipient for ADG solid dispersion. These
ous that the contact angles of ADG solid dispersions prepared
results confirmed that the strongest molecular binding energy of
using different ratios of Soluplus were significantly lower than
ADG with Soluplus contributed to carrier-controlled mechanism
ADG and physical mixtures, demonstrating that these solid dis-
and led to its highest drug dissolution. Soluplus as solid disper-
persions all fitted to carrier-controlled mechanism. The wetting
sion excipient could significantly improve drug absorption. ADG
solid dispersion formulated by Soluplus with various weight
ratios was further focused. According to XRD measurement,
Table III. The Fitting Wquations of ADG, Soluplus, and ADG Solid
amorphous ADG was remained in solid dispersion and led to the
Dispersions
enhancement of drug release. ADG solid dispersion of 1:7 with
best ability to be wetted turned out to be the best ADG solid dis-
Sample Fitting curve R2
persion. It is believed that the elucidation of working mechanism
ADG y = −1.561ln(x) + 72.19 0.9479 of ADG solid dispersion provided valuable instruction for the
Soluplus y = 22.754x−0.117 0.8299 development of solid dispersion technology.
1:5 y = 0.0804x2–1.5167x + 51.847 0.9895
1:7 y = 0.1241x2–2.1005x + 50.525 0.9757
ACKNOWLEDGMENTS
2
1:9 y = 0.0091x –0.4847x + 47.667 0.9785
This research was supported by Youth Found of National Natural
1:12 y = 0.0189x2–0.6238x + 47.744 0.8911
Science Foundation (81700050).

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REFERENCES
1. Liu, L.; Yan, Y.; Zheng, L.; Jia, H.; Han, G. Nat. Prod. Res.
2019, 1, https://doi.org/10.1080/14786419.2018.1501689.
2. Tao, L.; Zhang, L.; Gao, R.; Jiang, F.; Cao, J.; Liu, H. Front.
Neurosci. 2018, 12, 657.
3. Ekalaksananan, T.; Sookmai, W.; Fangkham, S.;
Pientong, C.; Aromdee, C.; Seubsasana, S.; Kongyingyoes, B.
Nutr. Cancer. 2015, 67, 687.
4. Wintachai, P.; Kaur, P.; Lee, R. C.; Ramphan, S.;
Kuadkitkan, A.; Wikan, N.; Ubol, S.; Roytrakul, S.; Chu, J. J.;
Smith, D. R. Sci. Rep. 2015, 5, 14179.
5. Yan, Y. Y.; Shi, G. X.; Shao, J.; Wang, T. M.; Wang, C. Z.
Zhongguo Zhong Yao Za Zhi. 2013, 38, 3819.
6. Khan, I.; Khan, F.; Farooqui, A.; Ansari, I. A. Nutr. Cancer.
2018, 70, 787.
7. Peng, Y.; Wang, Y.; Tang, N.; Sun, D.; Lan, Y.; Yu, Z.;
Zhao, X.; Feng, L.; Zhang, B.; Jin, L.; Yu, F.; Ma, X.; Lv, C.
J. Exp. Clin. Cancer Res. 2018, 37, 248.
8. Zhai, Z.; Qu, X.; Li, H.; Ouyang, Z.; Yan, W.; Liu, G.;
Liu, X.; Fan, Q.; Tang, T.; Dai, K.; Qin, A. Mol. Med. Rep.
2015, 11, 1139.
9. Ji, X.; Li, C.; Ou, Y.; Li, N.; Yuan, K.; Yang, G.; Chen, X.;
Yang, Z.; Liu, B.; Cheung, W. W.; Wang, L.; Huang, R.;
Lan, T. Mol. Cell. Endocrinol. 2016, 437, 268.
10. Dai, J.; Lin, Y.; Duan, Y.; Li, Z.; Zhou, D.; Chen, W.;
Wang, L.; Zhang, Q. Q. Int. J. Biol. Sci. 2017, 13, 660.
11. Guo, X.; Zhao, M.; Lin, Y.; Chen, W.; Wang, S.; Dai, J.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2018, 43, 821.
12. Das, S.; Pradhan, G. K.; Das, S.; Nath, D.; Das, S. K. Chem.
Biol. Interact. 2015, 242, 281.
13. Mishra, N.; Yadav, K. S.; Rai, V. K.; Yadav, N. P. AAPS
PharmSciTech. 2017, 18, 381.
14. Akbarsha, M. A.; Murugaian, P. Phytother. Res. 2000, 14, 432.
15. Tang, C.; Liu, Y.; Wang, B.; Gu, G.; Yang, L.; Zheng, Y.;
Qian, H.; Huang, W. Arch. Pharm. (Weinheim). 2012, 345, 647.
16. Uttekar, M. M.; Das, T.; Pawar, R. S.; Bhandari, B.;
Menon, V.; Nutan; Gupta, S. K.; Bhat, S. V. Eur. J. Med.
Chem. 2012, 56, 368.
17. Parveen, R.; Ahmad, F. J.; Iqbal, Z.; Samim, M.; Ahmad, S.
Drug Dev. Ind. Pharm. 2014, 40, 1206.
18. Zhang, Y.; Hu, X.; Liu, X.; Dandan, Y.; Di, D.; Yin, T.;
Zhang, S.; Tang, X. Int. J. Pharm. 2015, 493, 214.
19. Yen, C. C.; Chen, Y. C.; Wu, M. T.; Wang, C. C.; Wu, Y. T.
Int. J. Nanomed. 2018, 13, 669.
20. Zhang, T.; Zhu, L.; Li, M.; Hu, Y.; Zhang, E.; Jiang, Q.;
Han, G.; Jin, Y. Mol. Pharm. 2017, 14, 1718.
21. Li, M.; Zhang, T.; Zhu, L.; Wang, R.; Jin, Y. Int. J. Pharm.
2017, 528, 163.
22. Suo, X. B.; Zhang, H.; Wang, Y. Q. Biomed. Chromatogr.
2007, 21, 730.
23. Fan, N.; Ma, P.; Wang, X.; Li, C.; Zhang, X.; Zhang, K.;
Li, J.; He, Z. Carbohydr. Polym. 2018, 199, 492.
48354 (7 of 7)
24. Bothiraja, C.; Shinde, M. B.; Rajalakshmi, S.; Pawar, A. P.
J. Pharm. Pharmacol. 2009, 61, 1465.
25. Alagdar, G.; Oo, M. K.; Sengupta, P.; Mandal, U. K.;
Jaffri, J. M.; Chatterjee, B. Int. J. Pharm. Invest. 2017,
7, 142.
26. Ogawa, N.; Hiramatsu, T.; Suzuki, R.; Okamoto, R.;
Shibagaki, K.; Fujita, K.; Takahashi, C.; Kawashima, Y.;
Yamamoto, H. Eur. J. Pharm. Sci. 2018, 111, 205.
27. Higashi, K.; Seo, A.; Egami, K.; Otsuka, N.; Limwikrant, W.;
Yamamoto, K.; Moribe, K. J. Pharm. Pharmacol. 2016,
68, 655.
28. Ueda, K.; Kanaya, H.; Higashi, K.; Yamamoto, K.;
Moribe, K. Int. J. Pharm. 2018, 538, 57.
29. Ma, Y.; Yang, Y.; Xie, J.; Xu, J.; Yue, P.; Yang, M. Int.
J. Nanomed. 2018, 13, 3763.
30. Wu, Q.; Kennedy, M. T.; Nagapudi, K.; Kiang, Y. H. Int.
J. Pharm. 2017, 521, 1.
31. Lavra, Z. M.; Pereira, D. S. D.; Re, M. I. Drug Dev. Ind.
Pharm. 2017, 43, 42.
32. Penumetcha, S. S.; Gutta, L. N.; Dhanala, H.; Yamili, S.;
Challa, S.; Rudraraju, S.; Rudraraju, S.; Rudraraju, V. Drug
Dev. Ind. Pharm. 2016, 42, 1609.
33. Patil, H.; Tiwari, R. V.; Repka, M. A. AAPS PharmSciTech.
2016, 17, 20.
34. Agrawal, A.; Dudhedia, M.; Deng, W.; Shepard, K.;
Zhong, L.; Povilaitis, E.; Zimny, E. AAPS PharmSciTech.
2016, 17, 214.
35. Barea, S. A.; Mattos, C. B.; Cruz, A. C.; Chaves, V. C.;
Pereira, R. N.; Simoes, C. M.; Kratz, J. M.; Koester, L. S.
Drug Dev. Ind. Pharm. 2017, 43, 511.
36. Dinunzio, J. C.; Brough, C.; Hughey, J. R.; Miller, D. A.;
Williams, R. R.; McGinity, J. W. Eur. J. Pharm. Biopharm.
2010, 74, 340.
37. Hengsawas, S. S.; Keen, J. M.; Huang, S.; Zhang, F.;
McGinity, J. W.; Williams, R. R. Drug Dev. Ind. Pharm.
2017, 43, 797.
38. Zeng, C.; Jiang, W.; Tan, M.; Yang, X.; He, C.; Huang, W.;
Xing, J. Eur. J. Pharm. Sci. 2016, 85, 123.
39. Li, J.; Fan, N.; Wang, X.; Li, C.; Sun, M.; Wang, J.; Fu, Q.;
He, Z. Eur. J. Pharm. Sci. 2017, 106, 244.
40. Li, J.; Guo, Y. Mater. Sci. Eng. C Mater. Biol. Appl. 2017,
73, 670.
41. Li, J.; Wang, X.; Li, C.; Fan, N.; Wang, J.; He, Z.; Sun, J.
Mol. Pharm. 2017, 14, 2781.
42. Guo, L.; Kang, L.; Liu, X.; Lin, X.; Di, D.; Wu, Y.; Kong, D.;
Deng, Y.; Song, Y. Eur. J. Pharm. Sci. 2017, 104, 13.
43. Ansari, M. T.; Pervez, H.; Shehzad, M. T.; Mahmood, Z.;
Razi, M. T.; Ranjha, N. M.; Khanum, N. Pak. J. Pharm. Sci.
2012, 25, 447.
44. Obaidat, R.; Alnaief, M.; Jaeger, P. Pharm. Dev. Technol.
2018, 23, 697.
45. Zi, P.; Zhang, C.; Ju, C.; Su, Z.; Bao, Y.; Gao, J.; Sun, J.;
Lu, J.; Zhang, C. Eur. J. Pharm. Sci. 2019, 134, 233.
J. APPL. POLYM. SCI. 2019, DOI: 10.1002/APP.48354