European Journal of Pharmaceutical Sciences 88 (2016) 3749

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European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps

Solubility and dissolution enhancement of efavirenz hot melt extruded

amorphous solid dispersions using combination of polymeric blends: A
QbD approach
Jaywant Pawar , Apurva Tayade, Avinash Gangurde, Kailas Moravkar, Purnima Amin
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, University under Section-3 of UGC Act-1956, Elite Status & Centre of Excellence - Govt. of Maharashtra, N. P. Marg, Matunga, Mumbai 400019, India

a r t i c l e

i n f o

Article history:
Received 22 December 2015
Received in revised form 12 February 2016
Accepted 1 April 2016
Available online 2 April 2016
Keywords:
Efavirenz
Soluplus
HPMCAS-HF
Hot melt extrusion
Solubility
FTIR imaging

a b s t r a c t
Efavirenz is a non-nucleoside reverse transcriptase inhibitor and categorized in to BCS class II drug. The aim of the
present investigation was to apply quality by design approach to enhance the solubility, dissolution and stability
of amorphous solid dispersions (ASDs) of efavirenz using a combination of Soluplus and HPMCAS-HF polymers.
In design of experiments, the user dened quadratic model was used to study the effect of variable concentrations of Soluplus and HPMCAS-HF for the formation of ASDs of efavirenz. Similarly, a prototype ASD was
made using Soluplus as a carrier with efavirenz loading of 30%. The efavirenz ASDs granular extrudates were
evaluated for saturation solubility as well as dissolution rate studies. X-ray powder diffraction, Differential scanning calorimetry, Fourier transform infrared, Atomic force microscopy and FTIR imaging to determine the solid
state of efavirenz in the ASDs. DSC and XRD data conrmed that bulk crystalline efavirenz transformed to the
amorphous form during the hot melt extrusion processing. Prototype ASD batch showed instability upon storage
as per ICH guidelines over a period of 6 months, observations inferred from DSC, XRD and in vitro dissolution
studies. The maximum dissolution rate was observed when Soluplus and HPMCAS-HF was in ratio of (60:20)
as optimized by design of experiments study. Moreover, the optimized ASDs batch were stable at 40C, 75% RH
for a period of 6 months without any dissolution rate changes, and remained into amorphous state.
2016 Elsevier B.V. All rights reserved.

1. Introduction
The Unites States Food and Drug Administration initiated Quality by
design (QbD) approach in the product development that considers
both, formulation and process-related factors that affect the quality attributes of the nal product (Raw et al., 2011). QbD approach pave
way in enhancing pharmaceutical development through design efforts
from product development conceptualization to its commercialization.
Design of experiments (DoE) is a systematic and scientic approach to
study the interaction between dependent and independent variables
which helps in reducing the number of trials and to make the experiments more informative (Snorradttir et al., 2011).
A complete QbD study involves four major steps: (1) establishing
quality target product prole based on literature and scientic knowledge; (2) establishing critical quality attribute formulation factors and
then establish design space through DoE; (3) design product or formulation manufacturing process to meet predened targets; (4) control
strategy of manufacturing process to produce consistent quality of
product over a time by operating within an proven control space, ensuring the quality is incorporated into the product (Wang et al., 2014; Xu
Corresponding author.
E-mail address: jaywantpawar.ict@gmail.com (J. Pawar).

http://dx.doi.org/10.1016/j.ejps.2016.04.001
0928-0987/ 2016 Elsevier B.V. All rights reserved.

et al., 2011). Literature shows several articles of application of QbD protocol to various pharmaceutical processes, such as tablet compression
(Charoo et al., 2012), hot melt extrusion (Patil et al., 2015), spray drying
(Gu et al., 2015), nanosuspensions (Ahuja et al., 2015), pellets
manufacturing (Maddineni et al., 2014; Wang et al., 2014) and several
others. In case of pharmaceutical application of DoE the input factors
are raw material attributes, formulation parameters and output is Critical Quality Attributes. The design space can be termed as the multidimensional combination and interaction of input variables and process
parameters that have been demonstrated to provide assurance of quality (Zhang et al., 2013). Henceforth, using DoE we can establish a design space (DS) for the experimental study.
Response surface methodology (RSM) is one of the techniques used to
estimate possible effects, their interaction, shape of response surface and
quadratic effects. Application of RSM for pharmaceutical development is
advantageous, because there can be a variation of only one parameter at
a time, by keeping other parameters constant although the interactions
of two or more variables can be studied simultaneously (Akman et al.,
2015; Ko et al., 2015; Ranjan et al., 2009). Use of RSM results in reduced
process variability, higher percentage yields, less treatment time with
minimum costs. It estimates the relative signicance of different variables.
Amorphous solid dispersions (ASDs) are a known as highly supersaturated category of drug delivery systems. ASDs have attracted a lot

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J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

Table 1
Variables in RSM study for ASDs of EFZ.
Factor code
X1
X2
Y1
Y2

Independent factors

Levels

HPMCAS-HF ratio
Soluplus ratio
Dependent factors
Solubility (mg/mL)
Dissolution rate (%)

Low (1)
Medium (0)
20
40
20
40
Constraints
Maximum solubility
Target up to 100

High (+1)
60
60

of research interest, both in pharmaceutical industry and in academic

research because of their ability to improve solubility and oral bioavailability compared to that of poorly water-soluble crystalline drug (Sun
and Lee, 2015; Yu, 2001). The high internal free energy of ASDs frequently results in fast recrystallization with the subsequent loss of dissolution rate and solubility advantages (Sun et al., 2010). To improve
the kinetic stability of ASDs drug is incorporated into a polymer with a
higher glass transition temperature (Tg), resulting into increase in Tg
of resulting mixture, thereby reducing molecular mobility, thus nucleation and crystal growth of the drug (Hancock et al., 1995). The molecular dispersion of drug in an amorphous polymer matrix is termed as
amorphous solid dispersions (ASDs). Although, it is promising approach, the physical stability of the ASDs during storage is a critical factor as some drugs tend to crystallize at temperature below the Tg of the
system (Yoshioka et al., 1994). In any experimental approach, to stabilize
a molecular system thermodynamically, one has to consider the complete miscibility of drug in the polymeric system below its saturation solubility, and therefore drug-polymer miscibility is of great importance for
the rational development of ASDs (Knopp et al., 2015; Tian et al., 2012).
In comparison to traditional methods of preparation of ASDs, hot melt extrusion is the most promising solvent-free, continuous and industry feasible and scalable process for preparation of ASDs (Shah et al., 2013).
Hot melt extrusion (HME) is efciently utilized in preparation of
solid dispersion systems, by converting crystalline drug into amorphous
form or by forming a molecularly dispersed solid solution (Crowley
et al., 2007). The transformation of drugs from amorphous to crystalline
counterpart raises a concern regarding the physical instability of the developed ASDs as reported earlier in literature (Alshahrani et al., 2015; Qi
et al., 2008). This all has resulted into limited numbers of marketed formulations made by HME extruded ASDs. There is strong need to formulate physically stable ASDs with desired solubility and dissolution rate
enhancement.
Efavirenz (EFZ), a widely prescribed HIV-I specic non-nucleoside
reverse transcriptase inhibitor (NNRTI), used as part of highly active antiretroviral therapy (HAART). EFZ belongs to BCS class II and exhibit
Table 2
Experimental design of EFZ ASDs.
Batch
code

RSM
run

Factor
A X1

Factor
B X2

Response 1 solubility
(mg/mL) Y1

Response 2
dissolution (%) Y2

ASD1
ASD2
ASD3
ASD4
ASD5
ASD6
ASD7
ASD8
ASD9
ASD10
ASD11
ASD12
ASD13
ASD14
ASD15
ASD16
ASD17
ASD18

2
5
8
1
4
3
9
6
7
16
13
12
11
14
18
17
10
15

40
40
40
20
20
60
60
60
20
20
20
60
40
40
60
40
20
60

20
40
60
20
40
20
60
40
60
60
40
20
20
40
60
60
20
40

0.987
1.054
1.591
0.839
0.987
1.168
1.38
1.322
1.712
1.702
0.984
1.169
0.978
1.0678
1.392
1.597
0.821
1.387

46.20
78.02
91.41
51.98
75.14
56.30
83.57
68.94
99.44
99.64
75.01
57.03
48.44
76.03
76.05
92.55
49.34
69.11

poor aqueous solubility and high permeability with dissolution rate dependant absorption resulting into low and variable oral bioavailability
(Fong et al., 2015; Maurin et al., 2002; Sathigari et al., 2012; Takano
et al., 2006). There is strong need to overcome the issue of poor solubility of EFZ. In this context, ASDs of EFZ has been prepared by HME technology using a blend of polymeric system comprised of Soluplus,
(polyvinyl caprolactam polyvinyl acetate polyethylene glycol graft copolymer), and HPMCAS-HF (Hydroxypropylmethylcellulose acetate
succinate). Soluplus is an amphiphilic polymer that can work as solubilizing agent as it forms micelles in solution furthermore have been
used to enhance the solubility of poorly water soluble APIs by forming
solid solution (Fule et al., 2016) and solid dispersion (Djuris et al.,
2014; Li et al., 2015). As reported in literature it is used to improve physicochemical stability of ASDs (Alshahrani et al., 2015; Qi et al., 2010) to
form a stabilized solid dispersion formulation. HPMCAS-HF is used as a
polymer with high glass transition temperature (Fan et al., 2015).
HPMCAS-HF polymer cannot be extruded alone due to its high glass
transition temperature Tg = 133 C (Stroyer et al., 2006). It was reported in literature (Li et al., 2013) polymers with high glass transition temperature can potentially prevent recrystallization by delayed kinetics. In
addition, HPMCAS also restricts nucleation and crystal growth of the
APIs during storage of ASDs as well as after reaching supersaturation
levels in gastrointestinal uid (Rumondor et al., 2009). Nevertheless,
blending of Soluplus (SOL) with HPMCAS-HF facilitates the extrusion
by increasing its Tg, subsequently enhancing physical stability.
In this context, objective of the study was to develop amorphous
solid dispersions of EFZ with enhanced solubility and stability by
implementing Quality by design (QbD) approach. We have demonstrated the user dened quadratic model as a part of RSM technique of design of experiments to study formulation of amorphous solid
dispersions (ASDs) of EFZ using HME technology.
2. Material and methods
2.1. Materials
Efavirenz (EFZ) was a kind gift from Laurus Labs, India; and Hydroxypropyl methyl cellulose acetate succinate (HPMCAS-HF) was supplied by Shin-Etsu Chemical Co. Soluplus, a hydrophilic graft
copolymer of poly-vinyl caprolactam - polyvinyl acetate polyethylene
was donated by BASF Corporation, Mumbai, India. EFVIR (Efavirenz
capsules) a marketed product of Cipla Pvt. Ltd. was bought from
retailer's chemist shop in Mumbai, India. Hard gelatin capsules IP
were donated by ACG associated capsules Pvt. Ltd. Mumbai, India. All
other chemicals and solvents used were of analytical grade and were
procured from SD ne Chemicals, Mumbai, India. Puried water was
used throughout the study.
2.2. Design of experiments
The HME experimental design and data analysis was conducted
using licensed version of Design expert software (version 9.0.4.1; M/
s, Stat-Ease, Minneapolis, USA). The blend of polymeric system consists
of SOL and HPMCAS-HF has been used for the preparation of ASDs of
EFZ. Based on the number of factors and their level, user dened response surface methodology was analyzed using multiple regression
statistics. A full quadratic model was tted to collect responses, and p
values for each of the factors were used to determine their signicance
on HME process (Maddineni et al., 2014). The effect of independent variables [Soluplus concentration (X1) and HPMCAS-HF concentration
(X2)] on dependent variable [Solubility (Y1) and dissolution enhancement (Y2)] was studied as shown in Table 1. The linear equation of the
model is as follows:
Y b0 b1 X 1 b2 X 2 b3 X 3 b4 X 4 ::bn X n

J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

39

Fig. 1. QbD (Quality by Design) steps applied to the hot melt extrusion process.

where Y is the response, b0 is the constant and b1 b2 bn is the coefcient of factor X1, X2. Xn is representing the effect of each ordered
within 1, +1.
The DoE software designed eighteen experimental runs as mentioned in Table 2. One-way ANOVA and multilinear regression analysis
were performed to test the signicance of model and factor coefcients.
In order to validate and to check reproducibility of each batch allexperimental runs (formulations) were prepared in duplicate.

As we have used different weight ratios of polymers, different temperature processing ranges from 130 C140 C were applied to obtain semisolid, transparent extrudates for each formulation suitable for downstream processing of EFZ ASDs. The obtained powder of EFZ ASDs was
stored in a desiccator at room temperature for further physicochemical
characterization. The powdered extrudes were lled in the capsule for
in vitro dissolution study. The EFZ loading was kept 30% and the independent variables i.e. polymer ratios were varied as shown in Table 2.

2.3. Hot-melt extrusion

2.4. Physicochemical characterization of EFZ ASDs

Amorphous Solid dispersions of EFZ were prepared using a SingleScrew Lab Hot Melt Extruder (S.B. Panchal and Co., India) equipped
with stainless steel Single Screw with diameter of 24.5 mm and length
of 5.8 in. The barrels have feeder, conveyer, mixing sections, and carrier
zone with internal diameter 25.5 mm and length of 6 in. attached with a
round shaped die (4 mm in diameter). Prior to processing EFZ and
HPMCAS-HF and SOL were passed through #60 sieve and mixed in a
blender with batch size of around 30 g. The propylene glycol (PG)
used as a plasticizer at 5% ratio w/w, when the HPMCAS-HF loads was
on higher ratio of 40% and 60% in the blend as per DoE runs. All 18
batches were processed as suggested by DoE runs. The blend was fed
and processed in to the barrel. The processing temperatures were selected based on Tg of the blend of polymeric system i. e. 131 C and melting point of API i.e. 139140 C in order to obtain well-solidied
extrudates. A batch of ASD was also prepared by using only SOL as a carrier system to study the chemical and thermal stability further referred
as prototype ASD. The extrusion of EFZ using HPMCAS-HF as a carrier
system was not possible because its high glass transition temperature
Tg = 133 C (Stroyer et al., 2006) moreover, it's not extrudable alone.

2.4.1. Saturation solubility study

Saturation solubility study was carried out for neat EFZ and ASDs of
EFZ in dissolution medium containing 0.2% SLS in 0.1 N HCl maintained
at 37 0.5 C. Excess quantities of API and ASDs were added to 10 mL of
respective dissolution media and capped glass test tubes were kept in a
shaking hot tub (Boekel scientic, USA) at 37 0.5 C, 30 rpm for 72 h.
The solutions in the test tubes were vortexed and kept for centrifugation
at 6000 rpm for 10 min. The supernatant layer was then ltered through
0.45 m millipore membrane lter and suitably diluted and analyzed for
drug content. The study was carried out in triplicate.
2.4.2. In vitro dissolution studies
The dissolution studies were conducted using a USP type II dissolution apparatus. An amount equivalent to 100 mg of EFZ was lled into
capsules and capsules were then placed in the dissolution medium
within the apparatus for 90 min. The dissolution studies were performed under sink conditions in 1000 mL of dissolution media containing 0.2% SLS in 0.1 N HCl maintained at 37 0.5 C and the paddle
rotation speed was 50 rpm. ASDs equivalent to 100 mg of EFZ were

Fig. 2. Perturbation plot showing inuence of individual factors on solubility (Y1) & Dissolution rate (Y2).

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J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

taken along with EFZ neat drug (100 mg) subjected to the same dissolution study (Sathigari et al., 2012). At various time points like 15, 30, 45,
60 and 90 min, the samples were withdrawn and an equal amount of
fresh medium was added to ongoing dissolution medium vessel.
These samples were analyzed using UV-spectrophotometer at 248 nm.
The dissolution studies were performed in triplicate. The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum
of squared error, is a measurement of similarity in the percent dissolution between the two curves, and is expressed as in Eq. (2). An f2
value larger than 50 indicates that the two dissolution proles are similar (Deng et al., 2013).
(
)
0:5


1
n
2
f 2 50  log 1
 100
t1 Rt  T t 1
n

where,
n number of time points
Rt dissolution value of the reference [prechange] batch at time t
Tt dissolution value of the test [postchange] batch at time t.
2.4.3. Differential scanning calorimetry (DSC)
DSC analysis was performed to check the solid state of ASDs of EFZ
with respect to neat EFZ and HPMCAS and SOL respectively using
Pyris-6 DSC Perkin Elmer, USA. Approximately 34 mg of sample was
hermetically sealed in aluminum pan. To measure glass transition temperature samples were heated from 30 C300 C at the rate of 10 C/
min1 under an inert atmosphere was maintained purging nitrogen
gas at a ow rate of 18 mL/min. An empty aluminum pan was used as
a blank. The Pyris manager software was used for post experimental
analysis.
2.4.4. X-ray powder diffraction (XRPD) analysis
XRPD was used to determine the solid state of ASDs made from
extrudates along with bulk materials using a Bruker D8 Advance in
thetatheta mode. For PXRD study's purpose, a Cu anode at 40 kV and
20 mA current was set, Soller slits (0.04 rad) were used in the incident
and diffracted beam path and sample rotation at 15 rpm were used.
Each sample was scanned from 2 to 50 2 with a step size of 0.02 2
and a counting time of 0.3 s per step. The samples were placed in a
zero background sample holder and incorporated on a spinner stage.
2.4.5. Structural analysis by FTIR
FTIR analysis was done to investigate the molecular structures of
EFZ, HPMCAS-HF, SOL and ASDs of EFZ. The samples were analyzed for
their functional groups using Shimadzu MIRACLE IR Afnity-1 FTIR
spectrophotometer. The samples were premixed with KBr using mortar
and pestle and KBr disks were prepared by means of a hydraulic press.
The scanning range was 4000 to 500 cm1 resolution of 4 cm1.
Table 3
Analysis of variance (ANOVA) for all responsesa.
Source

Model
A
B
AB
A2
B2

Solubility (mg/mL)

2.4.6. FTIR spectroscopic imaging

The optimized ASD formulation was characterized using FTIR imaging (Vertex 80/Hyperion 3000, Bruker, Germany) with liquid nitrogen
cooled single mercury-cadmium-telluride (MCT) focal plane array detector 128 128, (Santa Barbara Focal plane, Goleta, California) at
range: 4000900 cm 1 (Verma et al., 2012). Thin lm sample was
placed on the temperature-controlled stage; position of the accessory
was adjusted such that a good focused image was obtained. The spectrometer was setup in Attenuated Total Reectance (ATR) mode using
a diamond internal reection element (IRE). The images were acquired
with a spectral resolution of FTIR 0.2 cm1, and 32 co-added scans with
the help of OPUS 6.5 software with an acquisition time of approximately 2 min.

Dissolution in 60 min (%)

Mean square

f Value

p Value

Mean square

f Value

p Value

0.27
0.050
0.97
0.22
2.941E-003
0.083

27.72
5.20
101.73
22.72
0.31
8.65

b0.0001
0.0435
b0.0001
0.0006
0.5904
0.0134

1021.57
106.21
4668.91
308.76
0.15
23.85

107.19
11.14
489.91
32.40
0.015
2.50

b0.0001
0.0066
b0.0001
0.0001
0.9034
0.1420

ANOVA for Response Surface Quadratic model.

a
Signicant effect (p value b0.5) of factors on individual responses are shown as different ratios of; A: SOL and B: HPMCAS-HF.

2.4.7. Atomic force microscopy (AFM) characterization

Sample for AFM was prepared by cutting freshly prepared
extrudates with smooth surfaces (Cross section of extrudates) by a
razor blade. All extrudates with cylindrical rods of 20 mm and 50 mm
were selected, and placed on a petri dish. The at bed of sample was
then afxed on an optical glass slide by use of a 2-component epoxy
resin, which get hardened within 3 min. The sample placed such that
it should keep its position horizontally, as this is required for to get
non-destructive imagining by atomic force microscope operations
(Tho et al., 2010). AFM analysis was carried out using AFM instrument
of DFRT-PFM on a commercial SPM system (Asylum Research MFP-3D,
California, USA) with a nitrogen ow cell positioned above an inverted
optical microscope. Extrudate sample was mounted on glass on the micrometer positioning stage of a dimension icon of AFM with accelerating
voltage up to 220 V and imaging at ac voltages up to 110 Vpp (in the
dual-excitation mode) at frequencies of 300400 kHz. Voltages were
applied between the ITO substrate and the conductive probe tips, and
the current was recorded by the AFM's preamplier (Asylum Research
ORCA head model59). The light source used in the AFM instrument is
Superluminescent diode (SLD), classied as Class 1M light source
(Lauer et al., 2011). This enables polarization switching in extrudes
samples and imaging of the samples with maximum resolution and
magnication. An AFM scans the surface of a specimen with a sharp
tip mounted to a cantilever (Olympus TR400PB cantilevers), the deections are directly related to the surface micro scale topography and its
physical properties (Fule et al., 2015). About 2030 regions per sample
were scanned by the programmed move in tapping mode. Height,
phase and amplitude images were collected simultaneously, using
Platinum-coated, contact-mode AFM tips were used, with the tip diameter of b 25 nm (Budget Sensors, BS-ElectriCont). AFM images with
areas of 10 10 mm were recorded at higher resolution. The result
data was processed using Open user interface based on IGOR Pro software with OpenGL 3D for advanced image display.
2.4.8. Analytical method (HPLC)
The assay of ASDs was assessed using high-performance liquid chromatography (HPLC) system of JASCO corporation equipped with auto
sampler (AS-2055 plus, intelligent sampler), photodiode array detector
(JASCO corp.). A Phenomenex Luna reverse-phase C18 column
(150 4.6 mm; 5 m particles) was used as a stationary phase. The mobile phase was composed of a mixture of buffer (Ammonium acetate
buffer, pH maintained at 7.5): acetonitrile in the ratio 40:60 (v/v). The
buffer was prepared by dissolving ammonium acetate in 1000 mL of
water; maintain the pH at 7.5 0.05. The ow rate was 1.5 mL/min,
with injection, volume was 20 L and the detection of EFZ was done at
248 nm with the retention time of 3.38 0.05 min. Drug content uniformity was assessed by accurately weighing ASDs equivalent to
10 mg of EFZ were dissolved in 10 mL of methanol and appropriately diluted. These samples further centrifuged (Centrifuge Eppendorf) for
5 min at 5000 rpm and drug content was quantied using previously
delineated HPLC procedure.

J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

41

Table 4
Predicted vs Experimental values of optimized ASDs.
Response

Predicted values

Std dev

Experimental
values

Std dev

Dissolution
in 60 min
Solubility
in mg/mL

99.654

3.087

99.64

3.68

1.6703

0.097

1.702

0.074

2.4.9. Stability studies

The impact of temperature and humidity conditions on chemical
and physical stability of the EFZ ASDs was determined in HDPE bottles
according to ICH guidelines. A portion of EFZ ASDs were stored in a
HDPE bottles to at 40 C/75% relative humidity (RH) for 6 months. Differential scanning calorimetry and powder X-ray diffraction studies
were carried out to determine the crystallinity of EFZ ASDs at 0 and
6 months. The in vitro dissolution studies also carried out to study the
percentage drug release of developed ASDs. The dissolution proles at
the different time points were matched using the f2 similarity factor.

term indicates an antagonistic effect upon the response. ANOVA table

conrms the variables responses are signicant subsequently conrms
competence of the model (i. e. f b 0.05) as shown in Table 3. Mathematical relationships, generated using MLRA (Multiple linear regression
analysis), has been used to generate the counter plots for independent
factors (Kaur et al., 2015). The results shown in respective gures, conrmed that a curvature or a steep slope in a plot shows the response is
sensitive to particular factor. A relatively at line shows lack of dependence of response on the said variable factor (Mahesh et al., 2014).

3. Result and discussions

3.1.3. Post analysis and optimization

The DoE optimization study was carried out to nd out the level of
independent factors A & B, which gives Y1 in range of 95101%, and Y2
in range of 1.601.80 mg/mL. The optimization results have inferred
that 20% HPMCAS-HF and 60% SOL batch had given the best results. To
validate the experimental models, the optimized formulation was prepared in triplicate by using these values of independent factors
(Table 4).

3.1. Design of experiments

3.1.1. RSM experimental design
The ICH guideline Q8 outlines the terms and steps involved in a
pharmaceutical QbD process, all steps involved in this study are
shown in Fig.1. A total of 18 experiments were carried out to study
the effect of different ratios of SOL and HPMCAS-HF on dissolution
rate and solubility enhancement of EFZ ASDs. The experimental results
i.e. response data for all experiments are given in Table 2. The ratio of
maximum to minimum amount of SOL and HPMCAS-HF was from 20%
to 60% for each of the polymer mixture system. The values of responses
(Y1 = Solubility in mg/mL), (Y2 = Dissolution rate in percentage) varies
from lowest to highest values ranging from 0.821 0.68 to 1.712
0.49 mg/mL and 46 3.05 to 100.40 2.81% respectively. Ratio of maximum to minimum for the two responses is 1.83 and 1.42 respectively.
Hence there is no requirement of power transformation, usually a value
of 10 of the difference indicates requirement of power transformation.
The Perturbation plots for the independent factors and responses are
shown in Fig.2. It is important to mention here that a steep slope in a
plot infers the response is sensitive to that particular independent factor. A moderately at line indicates lack of dependence of response on
the said factor (Mahesh et al., 2014).
3.1.2. Data analysis and optimization of formula
The independent factor and response variables were interrelated
using a polynomial equation with statistical analysis raties that the
most signicant factors affecting Y1 & Y2 are ratio of SOL and HPMCASHF through Design-Expert version 9.0.4.1 software. Analysis of variance (ANOVA) was applied to determine the effects of variables and
their interactions on responses. Final mathematical model in terms of
coded factors as determined by Design-Expert software are as follows:
Y 1 Dissolution rate 73:462:98  A 19:73  B6:71
 AB0:19  A2:44  B

Y 2 Solubility 1:120:064  A 0:28  B0:16  AB 0:027

 A 0:14  B

where A represent amount of SOL and B represents amount of HPMCASHF.

The polynomial equations consist of coefcients for intercept, interaction term, rst-order main effects, and related higher order effects. A
positive sign of coefcient indicate a synergistic effect while negative

3.1.4. Effect of independent factors on saturation solubility (Y2) study

The response (Y2), negative coefcients of factor B (i.e. lower concentration of SOL) indicates a decrease in saturation solubility of EFZ
ASD. However, positive coefcients of factor A (i.e. higher concentration
of HPMCAS-HF) also result in less solubility of ASDs. Saturation solubility study of EFZ ASDs prepared by HME showed increase in the drug solubility with polymers. The saturation solubility of EFZ in dissolution
medium was found to be 0.312 0.32 mg/mL and further solubility
values found higher in ASDs with higher concentration of SOL. The solubility of drug was reached maximum in ASD containing 60% SOL and
20% HPMCAS-HF. When the amount of SOL is decreased in formulations,
the solubility of drug decreases. The increase in apparent solubility of
drug was may be attributed due to formation of ASD, which converted
drug from crystalline state to amorphous state (Pawar et al., 2015).
The hydrophilic polymeric system improved the wettability of the
drug by decreasing surface tension of ASDs. Solubility of neat EFZ and
ASDs are shown in Fig. 3.

Fig. 3. Saturation solubility plot of EFZ ASDs.

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J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

Fig. 4. Response surface 3D plot (A) and contour plot (B) showing effect of different levels of SOL and HPMCAS-HF on saturation solubility of ASDs.

3.1.5. Effect of independent factors on dissolution rate (Y1) studies

In case of response (Y1), positive coefcients of factor B (i.e. higher
concentration of SOL) shown maximum dissolution rate of EFZ ASD. In
addition, negative coefcients of factor A (i.e. lower concentration of
HPMCAS-HF) shown better dissolution rate. The dissolution prole
curves of plain EFZ, optimized batches of EFZ ASDs and marketed product of EFZ (EFAVIR) is shown in Fig.6. EFZ is a poor water soluble drug
with a solubility of only 5.2 2.3 g/mL in water (Maurin et al.,
2002). Due to extreme low solubility of EFZ, 1000 mL 0.1 N HCl containing 0.2% SLS was used as a dissolution medium to maintain the sink conditions, nevertheless at the end of 60 min it exhibits b 20% of dissolution.
In this study, ASDs showed good increase in dissolution rate of EFZ. All
the dissolution rate values in percentages are shown in Table 2, i.e. in response column. As shown in Fig. 6, optimized batches ASD9 and ASD10
(composition as EFZ: SOL: HPMCAS-HF 30:60:20) showed N 91% drug
release within 45 min, which is approximately 3.7 fold higher than
pure EFZ alone and corresponding physical mixture which only shows
about 32% drug release which is statistically signicant (p 0.05,
Fig. 6). The enhancement in dissolution rate of ASDs is may be due to
the amorphous state of drug that offers a lower thermodynamic barrier
to dissolution. The glassy solution of EFZ ASDs gives the highest solubility and dissolution rate because the drug is molecularly dispersed in
polymer mixture system resulting into formation of amorphous system
(Hancock and Parks, 2000). Other different factors that might contribute
to increase in dissolution rate of EFZ are increased wettability, greater
hydrophilicity, improved dispersibility, and reduction in particle size

of the drug. The ASD9 and ASD10 exhibited similar drug release proles
compared to that of the marketed formulation of EFVIR with similarity
(f2) values of 71.03 and 73.63 respectively hence there was no statistical
signicance (p 0.02) in the drug release. The physical mixture showed
a little improved drug release compared to that with pure EFZ. The little
marked difference in dissolution rate for physical mixture was maybe
due to creation of hydrodynamic layer surrounding the drug particles
in early stages of dissolution process resulting into local solubilization
action in the respective microenvironment. The 3D counter plots for
all factors and responses are shown in Figs 4 & 5.
The differences in dissolution prole among these ASDs were perhaps due to the solubility/dissolution rate of polymers and their respective ratios, as mentioned above in the DoE study. In above in vitro
dissolution rate study of ASDs wherever SOL loads was higher, the respective drug release of EFZ ASDs were found maximum as inferred
from the results as, ASD3 = 91%, ASD16 = 92%, ASD9 = 99% approx.
As SOL ratio was improved in polymer mixture system, the respective
ASDs showed maximum drug release, our results are in resemblance
as reported previously in literature for carbamazepine drug processed
by hot melt extrusion with polymer mixture system (Alshahrani et al.,
2015).
3.2. DSC analysis
DSC is a predictive tool to inspect the melting temperature and recrystallization behaviour of crystalline material. DSC thermograms as

Fig. 5. Response surface 3D plot (A) and contour plot (B) showing effect of different levels of SOL and HPMCAS-HF on dissolution rate of ASDs.

J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

43

Fig. 6. In vitro release studies of neat EFZ, Optimized batches ASD9, ASD10, and marketed capsule EFAVIR.

shown in Fig. 7 were recorded for EFZ, SOL, HPMCAS-HF and optimized
ASDs to check the amorphousness of extrudates. EFZ was characterized
by thermogram showing a single, sharp melting endothermic peak at
139.60 C indicating crystalline nature of drug, whereas SOL and
HPMCAS did not show any melting endotherm because of its amorphous nature. ASDs of EFZ showed a complete decrease in H and no
peak sign, the result data is in accordance with PXRD data (Sarode
et al., 2013). The drug is found in complete amorphous state results inferred from the DSC thermograms. The physical mixtures of EFZ and
polymers showed an endotherm peak between 137 and 142 C, while
the ASDs prepared using HME showed no thermal peak of EFZ indicating complete conversion of EFZ into amorphous form. A prototype
ASD made using only SOL with 30:70 ratio upon 6-month stability
showed a sharp melting endotherm, showing the instability of EFZ
ASD made up using SOL due to recrystallization effect. Optimized ASD
batch with EFZ: SOL: HPMCAS at (30:60:20) ratios respectively showed
stable ASD up to end of 6 months too. This result depicts that crystalline
nature of EFZ was diminished by HME technology, over converting it

into a stable ASDs using a blend of polymeric system of SOL and

HPMCAS-HF.
3.3. XRD analysis
The X-ray diffractograms of pure EFZ, SOL, HPMCAS and physical
mixtures of above polymers with EFZ and ASDs of EFZ kept at 6month stability studies has been shown in Fig. 8. EFZ showed sharp multiple peaks, indicating the crystalline nature of the drug. As shown in
Fig. 8, pure EFZ showed characteristic PXRD pattern with sharp peak
at diffraction angle (2) values of 6.11,10.43, 10.98, 12.27, 13.25,
14.20, 16.92, 20.14, 21.25, and 24.93 indicating crystalline nature
of EFZ the data resembles with results available in literature (Alves
et al., 2014). However, the physical mixtures of EFZ and blend of polymeric system exhibited relatively less intense but more diffused peaks
at respective 2 angles. This is may be due to the dilution effect imparted
by bipolymer system on drug, and the unchanged diffused peaks indicate drug is still available in its crystalline form in the physical mixture.

Fig. 7. DSC thermograms of EFZ (a), SOL + HPMCAS-HF mixture (b), PM of EFZ + SOL + HPMCAS-HF (c), prototype ASD (d), prototype ASD (6 month stability) (e) ASD10 (0 day analysis)
(f), ASD10 (6 month stability analysis) (g).

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J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

Fig. 8. PXRD diffractograms of EFZ (a), SOL + HPMCAS-HF mixture (b), PM of EFZ + SOL + HPMCAS-HF (c), ASD10 (0 day analysis) (d), ASD10 (6 month stability analysis) (e), prototype
ASD (0 day analysis) (f) and prototype ASD (6 month stability analysis) (g).

In case of melt extrudate formulations, did not showed any characteristics peak at respective 2 angles. The characteristic peaks of EFZ disappeared and crystallinity found decreased. From the XRD studies of
ASD formulations conrms the amorphous nature of EFZ with the
bipolymer system. A prototype ASD made up of only EFZ:SOL (30:70)
ratio showed complete amorphous nature initially but upon 6-month
stability showed some peaks at respective 2 values, indicating the instability of ASD made up of using only SOL due to recrystallization effect,
the data is in resemblance with the DSC results as discussed previously.
The ASD batch with EFZ: SOL: HPMCAS (30:60:20) ratios respectively
showed stable formulations, as in that crystalline drug has not been detected conrmed from the PXRD diffractogram at the end of 6 month
stability analysis. This result depicts that crystalline nature of EFZ was
diminished using HME technology, by converting it into a stable ASDs
using the blend of polymeric system of SOL and HPMCAS-HF. The amorphous system contains more free energy which assists as a driving potential for solubility enhancement, therefore the solubility of these
systems is more as matched to their crystalline counterpart (Meer
et al., 2013).

between the drug and the polymer mixture system but they would
have formed molecular dispersions with slight shifting of certain
peaks compared to pure EFZ. SOL and HPMCAS-HF both of these polymers have proton donating such as OH and proton accepting groups
(higher number of electron reach O\\H) as functional groups. These
groups may prove a potential site of intermolecular interaction, which
causes broadening of the peaks in case of ASDs.
The formation of hydrogen bonds between drugs and polymers by
forming weak interactions has been reported in literature (Pawar
et al., 2015; Rumondor et al., 2009). The another hydrogen bond formation by hydrogen bonding with the hydroxyl group of polymeric mixture system resulting into a broad peak at 30003400 cm 1 (Ueda
et al., 2013). The SOL and HPMCAS-HF blend of polymer mixture system
showed a hydrophilic surface with maximum number of hydrophilic
groups, resulting into diffusion of dissolution medium and accelerated
release of EFZ ASDs. The hydrogen bond formation due to weak interactions between drug and polymers which could be easily broken in biological uids and works synergistically resulting into fast drug release
(Ambrogi et al., 2012) and increase in solubility and drug release of
the developed EFZ ASD formulations.

3.4. FTIR analysis

3.5. AFM analysis
The ATR-FTIR spectra of EFZ, SOL, HPMCAS and ASD3 and ASD10 are
shown in Fig.9. The FTIR spectra of EFZ showed characteristics peak of
689 and 652 cm 1 (CF stretch), 1096, 1057, 1074 cm 1 (C\\O\\C
stretch vibration), 3314 cm1 (NH stretch vibration), 1742 cm 1
(C_O stretching vibration), 1492 cm1 (C`C of benzene ring
stretching vibration), 1240 cm1 (CN stretch), 1165 cm 1 (CO
stretching vibration) (Gaur et al., 2014). In case of both the polymers
SOL and HPMCAS showed IR stretch at C_O stretch at 1738 cm1 and
1632 cm1, and aliphatic C\\H stretch at 2932 cm 1. A broad band
around 30003400 cm1 attributed for the presence of more number
of OH stretching groups. The physical mixtures of EFZ with blend of
polymeric system showed no intermolecular interaction (Fig.9d). The
IR peaks of ASDs showed the presence of drug and no change in drugs
functional group properties after the ASDs formation. The addition of
polymeric blend by HME process should not have affected the respective drugs stretching vibrations. There was no chemical interaction

The extrudates lms were analyzed by AFM, with respect to their

morphological surface interactions, the results are illustrated in
Fig. 10ad. The molecular fracture roughness data displayed in (Fig
10A&B) and the 3D surface image shown in (Fig. 10D). AFM characterization techniques have been proven for its potential to identify formed
molecular disperse mixture in ASDs. All the AFM images were calculated
from at least a 20 images on each samples, illustrating the morphological surface interactions in detail. The phase images illustrated that there
is no phase separation between the components indicating EFZ had
made molecular disperse with the blend of polymeric mixture system
of SOL and HPMCAS-HF (Lauer et al., 2011). Cross sectional and 3D topography views of AFM analysis of the optimized batch of EFZ ASDs
showed that there are morphological surface interactions leading to
amorphosization of drug inside polymer mixture system (Fule et al.,
2015; Lauer et al., 2011). Nevertheless, there was no sign of

J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

45

Fig. 9. FTIR of EFZ (a), SOL (b), HPMCAS-HF (c), physical mixture of EFZ with polymer mixture of EFZ + SOL + HPMCAS-HF polymer mixture system (d), ASD9 (e), ASD9 (f).

crystallization on the surface, which also infers that EFZ is in amorphous

state within the bipolymeric system. Molecular dispersion at homogeneous state is directly related with the amorphousness in case of ASD

systems. The extrudate showed complete molecular homogeneity,

which infers that AFM images should show different molecular structure roughness in the cross-sectional extrudate as shown in (Fig 10C)

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J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

Fig. 10. AFM microscopic images of ASD9 Height phase (A), Amplitude phase (B), Roughness (C) and Height 3D phase image (D).

with values of Sdev(Rq) = 1.386 nm and Adev (Ra) = 1.070 nm. AFM
probes at nanoscale were used to study the distribution and characterization of components within the ASD system. The two phases were variegated at molecular level as imitated from the AFM images (Height and
amplitude images) and 3D image processed via AFM conrming the
molecular homogeneity.

3.6. FTIR chemical imaging analysis

FTIR imaging results has been shown in (Fig. 11) the 3D image and IR
reectance spectrum of the point of interest of HME ASDs with 25% w/w
loading of EFZ specifying surface compositional homogeneity. Use of
FTIR imaging spectrum to understand distribution of API at microscale

J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

47

Fig. 11. FTIR image (left), optical image (right), and the IR reectance spectrum of the point of interest of optimized EFZ ASDs showing the surface compositional homogeneity. Red: EFZ.
Green: SOL + HPMCAS-HF polymer mixture system.

level been reported in literature (Alhijjaj et al., 2015; Ewing et al., 2015;
Feng et al., 2015; Vo et al., 2016).
FTIR imaging was constructed based on ATR mode using a diamond
internal reection element (IRE). To understand the homogeneity of
EFZ in the blend of polymeric system at the microscale level; the
extrudate was characterized by FTIR chemical imaging. Random spots
on the extrudates were analyzed by ATR. The wave number of
2243 cm1 corresponding to the CN stretch, uniquely distinguishes

in EFZ in the ASDs (Fig. 11C) was used to generate the FTIR chemical images. We have selected the peak range at 2212 cm1 to 2299 cm1 as
the chemical imaging reectance spectrum. Fig. 11A and B represents
the 3D image and the reectance spectrum (Vo et al., 2016). The 3D
graph is illustrated by homogeneity of the EFZ by red colors and blend
of polymeric system by pink color. It is worth studying here in these results, for amorphousness determination viz. DSC and XRD spectroscopy
have different sensitivity and detection limitations, henceforth results

Fig. 12. Drug content of all 18 batches as per DoE runs at day 1 and 3, 6 months after storage at 40 C and 75% RH.

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J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

Fig. 13. In vitro release proles of optimized ASDs (top) and prototype ASDs (bottom)
stored at 40 C and 75% RH on fresh extrudates and 3, 6 month stability.

obtained by FTIR imaging could be a versatile analytical technique for

characterization of ASDs for the distribution of API in polymer system
by HME process (Vo et al., 2016).

and ASD10 shown analogous drug release proles at accelerated stability conditions of 40 C and 75% RH at 0, 3 and 6 months (Fig. 13 top). The
similarity factor values (f2) according FDA guidelines for ASD9 and
ASD10 were found 70.73 and 73.61 respectively infers similar release
proles. DSC and XRD data reveals ASD9 and ASD10 did not show any
sign of morphology change or recrystallization after a storage period
of 6 months (Fig.13 top). The prototype ASD (only SOL added) demonstrated fast drug release of EFZ initially, but samples of 3 and 6-month
stability study indicates the drug release proles declined (Fig. 13 bottom). This decrease in drug release prole was may be due to the recrystallization of EFZ during storage, the results are conrmed by the DSC
and XRD studies. DSC thermogram shows small endotherm peak
(Fig. 7e) showing the instability of prototype EFZ ASD. In addition, the
2-theta value of EFZ arisen at 6 month prototype ASD formulation
(Fig. 8g). These results are same as reported previously in literature
(Alshahrani et al., 2015).
According to these results, polymer mixture blend consisting of SOL
in HPMCAS-HF based ASDs were able to stabilize chemically the amorphous form of EFZ in the extrudates. This improved stability was due to
high Tg and low hygroscopic nature of HPMCAS-HF, ensuing no moisture uptake leading to no recrystallization. HPMCAS-HF is available in
different specic grades, which can be differentiated by the ratio between acetyl and succinoyl groups (Tanno et al., 2004) In the present
context, we have used HPMCAS-HF, which has lowermost level of
succinoyl groups and the highest acetyl substituent level, in comparison
with other HPMCAS-HF grades. In literature, it has been reported that
succinoyl substituent level in HPMCAS-HF polymers induce strong afnity with hydrophobic drug surface, leading to crystal growth inhibition of the API (Rumondor et al., 2009). This lowermost level of
succinoyl groups in HPMCAS-HF decreased the recrystallization of EFZ
by increasing the hydrophobic interaction with EFZ, which will reduce
the moisture uptake and subsequently inhibit the recrystallization by
inhibiting molecular mobility within ASDs (Ueda et al., 2013). The ndings of results are in resemblance with previous literature (Alshahrani
et al., 2015).
4. Conclusions

3.7. Drug content by HPLC analysis

Analytical method validation was carried out as per ICH and FDA
guidelines. The linear calibration range of 10200 g/mL, with the coefcient of regression (R2) value of 0.997. The retention time for EFZ was
~3.38 0.05 min. The percent relative standard deviation (RSD) of the
replicate was b2%, demonstrating relative reproducibility of this method. After extrusion, each ASD was analyzed for the drug content using
HPLC. ASD samples equivalent to 30 g/mL were taken randomly for
the drug content analysis. All ASDs were found in acceptable range as
per US Pharmacopoeia for EFZ capsule. Nevertheless, drug content
was also carried out for the samples for fresh and 3, 6-month storage
conditions (Fig. 12). It was found that the drug content of the optimized
ASDs found between 97.02 and 101.34%. This infers that EFZ was chemically stable in case bipolymer system of EFZ for 6 months (at 40 C and
75% RH). The standard deviation value of was in range between 0.99 and
2.23% for fresh ASD and after a storage of 6 months. This illustrated that
HME processing conditions divulged excellent content uniformity of
EFZ with high chemical stability.
3.8. Stability studies
The developed ASDs were evaluated for the chemical, thermal stability and their in vitro dissolution studies. The primary screening tests inferred that extrusion of EFZ in the blend of polymer mixture system
with 30% EFZ loads. As per DoE runs when HPMCAS-HF ratio was higher
we had used polyethylene glycol as a plasticizer to facilitate the extrusion process. The optimized ASDs were selected based on the solubility
and their dissolution results (Table 2). The optimized batches of ASD9

The study represents application of quality by design in optimization

of ASDs formulation and process variables for EFZ ASDs prepared by
HME technique. It was observed that ratio of SOL to HPMCAS-HF significantly affected the solubility and dissolution rate of EFZ ASDs. HME was
successfully explored, as a versatile and robust technique for the formation of ASDs of EFZ in blend of polymeric system to produce immediate
release EFZ capsule dosage form. This research work has reconnoitered
a new combination mixture of polymer system that can be used as a
simple and effective polymer system for hot melt extrusion process
for enhancing the solubility and stability for up-to 6 months at accelerated stage. The dissolution rate of developed ASDs gave comparable and
signicantly higher dissolution rate compared to the marketed product,
which released 100% drug in less than 1 h. The solid-state characteristics
of EFZ were conrmed in ASD using DSC, PXRD, FTIR, AFM and FTIR imaging analysis. SOL was favoring increased dissolution rate and
HPMCAS-HF acts as a stabilizer due to its high Tg and least hygroscopic
nature. The research outcomes from this study accentuate the importance of selecting a suitable blend of polymeric carrier system for the development of a stable ASDs formulation with improved dissolution rate
prole, with no change in physical and chemical status even after 6month storage at accelerated conditions 40 C/75% RH.
Acknowledgments
The author is thankful to University grants commission India for providing the research fellowship no. UGC-SAP/ICT-DPST/2012-13/1115.
The authors want to acknowledge Laurus Labs, Hyderabad, India for
genuine gift sample of Efavirenz. Author is thankful to Asylum Research,

J. Pawar et al. / European Journal of Pharmaceutical Sciences 88 (2016) 3749

Mumbai India facility for carrying out the AFM analysis. The authors are
thankful to S.A.I.F., Department, Indian Institute of Technology, Mumbai
for FTIR imaging analysis and interpretation.

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