Beruflich Dokumente
Kultur Dokumente
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
38
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
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
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.
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.
Fig. 2. Perturbation plot showing inuence of individual factors on solubility (Y1) & Dissolution rate (Y2).
40
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)
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
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
42
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.
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.
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
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).
44
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.
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).
46
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.
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.
48
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.
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
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.
References
Ahuja, B.K., Jena, S.K., Paidi, S.K., Bagri, S., Suresh, S., 2015. Formulation, optimization and
in vitroin vivo evaluation of febuxostat nanosuspension. Int. J. Pharm. 478, 540552.
Akman, M.C., Erguder, T.H., Gndz, U., Erolu, ., 2015. Investigation of the effects of initial substrate and biomass concentrations and light intensity on photofermentative
hydrogen gas production by response surface methodology. Int. J. Hydrog. Energy
40, 50425049.
Alhijjaj, M., Bouman, J., Wellner, N., Belton, P., Qi, S., 2015. Creating drug solubilisation
compartments via phase separation in multi-component buccal patches prepared
by direct hot melt extrusion-injection moulding. Mol. Pharm. 12 (12), 43494362.
Alshahrani, S.M., Lu, W., Park, J.-B., Morott, J.T., Alsulays, B.B., Majumdar, S., et al., 2015.
Stability enhanced Hot-melt Extruded Amorphous Solid Dispersions via Combinations of Soluplus and HPMCAS-HF. AAPS PharmSciTech 111.
Alves, L.D.S., Soares, M.F.D., de Albuquerque, L.R., da Silva, C.T., Vieira, .R., Fontes, A.C.,
D.A.F., C., et al., 2014. Solid dispersion of efavirenz in PVP K-30 by conventional solvent and kneading methods. Carbohydr. Polym. 104, 166174.
Ambrogi, V., Perioli, L., Pagano, C., Marmottini, F., Ricci, M., Sagnella, A., et al., 2012. Use of
SBA-15 for furosemide oral delivery enhancement. Eur. J. Pharm. Sci. 46, 4348.
Charoo, N.A., Shamsher, A.A., Zidan, A.S., Rahman, Z., 2012. Quality by design approach for
formulation development: a case study of dispersible tablets. Int. J. Pharm. 423,
167178.
Crowley, M.M., Zhang, F., Repka, M.A., Thumma, S., Upadhye, S.B., Kumar Battu, S.,
McGinity, J.W., Martin, C., 2007. Pharmaceutical applications of hot-melt extrusion:
part I. Drug Dev. Ind. Pharm. 33, 909926.
Deng, W., Majumdar, S., Singh, A., Shah, S., Mohammed, N.N., Jo, S., et al., 2013. Stabilization of fenobrate in low molecular weight hydroxypropylcellulose matrices produced by hot-melt extrusion. Drug Dev. Ind. Pharm. 39, 290298.
Djuris, J., Ioannis, N., Ibric, S., Djuric, Z., Kachrimanis, K., 2014. Effect of composition in the
development of carbamazepine hot-melt extruded solid dispersions by application of
mixture experimental design. J. Pharm. Pharmacol. 66, 232243.
Ewing, A.V., Biggart, G.D., Hale, C.R., Clarke, G.S., Kazarian, S.G., 2015. Comparison of pharmaceutical formulations: ATR-FTIR spectroscopic imaging to study drug-carrier interactions. Int. J. Pharm. 495, 112121.
Fan, H., Mahjour, M., Moser, J., Rege, B., 2015. Formulations for Cathepsin K Inhibitors
Google Patents.
Feng, X., Vo, A., Patil, H., Tiwari, R.V., Alshetaili, A.S., Pimparade, M.B., Repka, M.A., 2015.
The effects of polymer carrier, hot melt extrusion process and downstream processing parameters on the moisture sorption properties of amorphous solid dispersions.
J. Pharm. Pharmacol. http://dx.doi.org/10.1111/jphp.12488.
Fong, S.Y.K., Ibisogly, A., Bauer-Brandl, A., 2015. Solubility enhancement of BCS Class II
drug by solid phospholipid dispersions: spray drying versus freeze-drying. Int.
J. Pharm. 496, 382391.
Fule, R., Dhamecha, D., Maniruzzaman, M., Khale, A., Amin, P., 2015. Development of hot
melt co-formulated antimalarial solid dispersion system in xed dose form
(ARLUMELT): evaluating amorphous state and in vivo performance. Int. J. Pharm.
496, 137156.
Fule, R., Paithankar, V., Amin, P., 2016. Hot melt extrusion based solid solution approach:
Exploring polymer comparison, physicochemical characterization and in-vivo evaluation. Int. J. Pharm. 499, 280294.
Gaur, P.K., Mishra, S., Bajpai, M., Mishra, A., 2014. Enhanced oral bioavailability of
efavirenz by solid lipid nanoparticles: in vitro drug release and pharmacokinetics
studies. BioMed. Res. Internat. 2014.
Gu, B., Linehan, B., Tseng, Y.-C., 2015. Optimization of the Bchi B-90 spray drying process
using central composite design for preparation of solid dispersions. Int. J. Pharm. 491,
208217.
Hancock, B.C., Parks, M., 2000. What is the true solubility advantage for amorphous pharmaceuticals. Pharm. Res. 17, 397404.
Hancock, B.C., Shamblin, S.L., Zogra, G., 1995. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm. Res. 12, 799806.
Kaur, P., Singh, S.K., Garg, V., Gulati, M., Vaidya, Y., 2015. Optimization of spray drying process for formulation of solid dispersion containing polypeptide-k powder through
quality by design approach. Powder Technol. 284, 111.
Knopp, M.M., Tajber, L., Tian, Y., Olesen, N.E., Jones, D.S., Kozyra, A., et al., 2015. Comparative study of different methods for the prediction of drugpolymer solubility. Mol.
Pharm. 12, 34083419.
Ko, W.-C., Chang, C.-K., Wang, H.-J., Wang, S.-J., Hsieh, C.-W., 2015. Process optimization of
microencapsulation of curcumin in -polyglutamic acid using response surface methodology. Food Chem. 172, 497503.
Lauer, M.E., Grassmann, O., Siam, M., Tardio, J., Jacob, L., Page, S., et al., 2011. Atomic force
microscopy-based screening of drug-excipient miscibility and stability of solid dispersions. Pharm. Res. 28, 572584.
Li, B., Konecke, S., Wegiel, L.A., Taylor, L.S., Edgar, K.J., 2013. Both solubility and chemical
stability of curcumin are enhanced by solid dispersion in cellulose derivative matrices. Carbohydr. Polym. 98, 11081116.
Li, M., Gogos, C.G., Ioannidis, N., 2015. Improving the API dissolution rate during pharmaceutical hot -melt extrusion I: effect of the API particle size, and the co-rotating, twinscrew extruder screw conguration on the API dissolution rate. Int. J. Pharm. 478,
103112.
49
Maddineni, S., Battu, S.K., Morott, J., Soumyajit, M., Repka, M.A., 2014. Formulation optimization of hot-melt extruded abuse deterrent pellet dosage form utilizing design of experiments. J. Pharm. Pharmacol. 66, 309322.
Mahesh, K.V., Singh, S.K., Gulati, M., 2014. A comparative study of top-down and bottomup approaches for the preparation of nanosuspensions of glipizide. Powder Technol.
256, 436449.
Maurin, M.B., Rowe, S.M., Blom, K., Pierce, M.E., 2002. Kinetics and mechanism of hydrolysis of efavirenz. Pharm. Res. 19, 517521.
Meer, T., Fule, R., Khanna, D., Amin, P., 2013. Solubility modulation of bicalutamide using
porous silica. J. Pharm Invest 43, 279285.
Patil, H., Feng, X., Ye, X., Majumdar, S., Repka, M.A., 2015. Continuous production of
fenobrate solid lipid nanoparticles by hot-melt extrusion technology: a systematic
study based on a quality by design approach. AAPS J. 17, 194205.
Pawar, J.N., Shete, R.T., Gangurde, A.B., Moravkar, K.K., Javeer, S.D., Jaiswar, D.R., Amin,
P.D., 2015. Development of amorphous dispersions of artemether with hydrophilic
polymers via spray drying: physicochemical and in silico studies. Asian J. Pharm.
Sci. http://dx.doi.org/10.1016/j.ajps.2015.08.012.
Qi, S., Gryczke, A., Belton, P., Craig, D.Q., 2008. Characterisation of solid dispersions of
paracetamol and EUDRAGIT E prepared by hot-melt extrusion using thermal,
microthermal and spectroscopic analysis. Int. J. Pharm. 354, 158167.
Qi, S., Belton, P., Nollenberger, K., Clayden, N., Reading, M., Craig, D.Q., 2010. Characterisation and prediction of phase separation in hot-melt extruded solid dispersions: a
thermal, microscopic and NMR relaxometry study. Pharm. Res. 27, 18691883.
Ranjan, D., Talat, M., Hasan, S., 2009. Biosorption of arsenic from aqueous solution using
agricultural residue rice polish. J. Hazard. Mater. 166, 10501059.
Raw, A.S., Lionberger, R., Lawrence, X.Y., 2011. Pharmaceutical equivalence by design for
generic drugs: modied-release products. Pharm. Res. 28, 14451453.
Rumondor, A.C., Stanford, L.A., Taylor, L.S., 2009. Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions. Pharm. Res. 26, 25992606.
Sarode, A.L., Sandhu, H., Shah, N., Malick, W., Zia, H., 2013. Hot melt extrusion (HME) for
amorphous solid dispersions: predictive tools for processing and impact of drug
polymer interactions on supersaturation. Eur. J. Pharm. Sci. 48, 371384.
Sathigari, S.K., Radhakrishnan, V.K., Davis, V.A., Parsons, D.L., Babu, R.J., 2012. Amorphousstate characterization of efavirenzpolymer hot-melt extrusion systems for dissolution enhancement. J. Pharm. Sci. 101, 34563464.
Shah, S., Maddineni, S., Lu, J., Repka, M.A., 2013. Melt extrusion with poorly soluble drugs.
Int. J. Pharm. 453, 233252.
Snorradttir, B.S., Gudnason, P.I., Thorsteinsson, F., Msson, M., 2011. Experimental design
for optimizing drug release from silicone elastomer matrix and investigation of transdermal drug delivery. Eur. J. Pharm. Sci. 42, 559567.
Stroyer, A., McGinity, J., Leopold, C., 2006. Solid state interactions between the proton
pump inhibitor omeprazole and various enteric coating polymers. J. Pharm. Sci. 95,
13421353.
Sun, D.D., Lee, P.I., 2015. Probing the mechanisms of drug release from amorphous solid
dispersions in medium-soluble and medium-insoluble carriers. J. Control. Release
211, 8593.
Sun, Y., Tao, J., Zhang, G.G., Yu, L., 2010. Solubilities of crystalline drugs in polymers: an
improved analytical method and comparison of solubilities of indomethacin and nifedipine in PVP, PVP/VA, and PVAc. J. Pharm. Sci. 99, 40234031.
Takano, R., Sugano, K., Higashida, A., Hayashi, Y., Machida, M., Aso, Y., Yamashita, S., 2006.
Oral absorption of poorly water-soluble drugs: computer simulation of fraction
absorbed in humans from a miniscale dissolution test. Pharm. Res. 23, 11441156.
Tanno, F., Nishiyama, Y., Kokubo, H., Obara, S., 2004. Evaluation of hypromellose acetate
succinate (HPMCAS) as a carrier in solid dispersions. Drug Dev. Ind. Pharm. 30, 917.
Tho, I., Liepold, B., Rosenberg, J., Maegerlein, M., Brandl, M., Fricker, G., 2010. Formation of
nano/micro-dispersions with improved dissolution properties upon dispersion of ritonavir melt extrudate in aqueous media. Eur. J. Pharm. Sci. 40, 2532.
Tian, Y., Booth, J., Meehan, E., Jones, D.S., Li, S., Andrews, G.P., 2012. Construction of drug
polyme thermodynamic phase diagrams using FloryHuggins interaction theory:
identifying the relevance of temperature and drug weight fraction to phase separation within solid dispersions. Mol. Pharm. 10, 236248.
Ueda, K., Higashi, K., Yamamoto, K., Moribe, K., 2013. Inhibitory effect of hydroxypropyl
methylcellulose acetate succinate on drug recrystallization from a supersaturated solution assessed using nuclear magnetic resonance measurements. Mol. Pharm. 10,
38013811.
Verma, G., Dhoke, S., Khanna, A., 2012. Polyester based-siloxane modied waterborne anticorrosive hydrophobic coating on copper. Surf. Coat. Technol. 212, 101108.
Vo, A.Q., Feng, X., Morott, J.T., Pimparade, M.B., Tiwari, R.V., Zhang, F., Repka, M.A., 2016. A
novel oating controlled release drug delivery system prepared by hot-melt extrusion. Eur. J. Pharm. Biopharm. 98, 108121.
Wang, J., Kan, S., Chen, T., Liu, J., 2014. Application of quality by design (QbD) to formulation and processing of naproxen pellets by extrusion-spheronization. Pharm. Dev.
Technol. 20, 246256.
Xu, X., Khan, M.A., Burgess, D.J., 2011. A quality by design (QbD) case study on liposomes
containing hydrophilic API: I. Formulation, processing design and risk assessment.
Int. J. Pharm. 419, 5259.
Yoshioka, M., Hancock, B.C., Zogra, G., 1994. Crystallization of indomethacin from the
amorphous state below and above its glass transition temperature. J. Pharm. Sci. 83,
17001705.
Yu, L., 2001. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv. Drug Deliv. Rev. 48, 2742.
Zhang, L., Yan, B., Gong, X., Lawrence, X.Y., Qu, H., 2013. Application of quality by design to
the process development of botanical drug products: a case study. AAPS
PharmSciTech 14, 277286.