Evaluating the Effects of Different Molecular Weights of Polymers in Stabilizing Supersaturated Drug Solutions and Formulations Using Various Methodologies of the Model Drug- Fenofibrate

Delivered by Ingenta to: Guest User
IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Copyright: American Scientific Publishers
Copyright © 2015 American Scientific Publishers
All rights reserved
Printed in the United States of America
Article
Journal of
Pharmaceutical Sciences
and Pharmacology
Vol. 2, 259–276, 2015
www.aspbs.com/jpsp
Evaluating the Effects of Different Molecular Weights of
Polymers in Stabilizing Supersaturated Drug Solutions
and Formulations Using Various Methodologies of the
Model Drug: Fenofibrate
Smruti P. Chaudhari and Rutesh H. Dave∗
Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University,
Brooklyn, New York 11201, USA
Assessing the effect of the molecular weight of excipients like Hydroxypropyl methyl cellulose (HPMC) and Polyvinylpyrroli-
done (PVP) on their ability to attain and maintain the supersaturation of drug-based solutions and solid dispersion will
provide useful information for the design of solid dosage formulations. In this study, three grades of HPMC (HPMC E5,
HPMC E15 and HPMC E50) and PVP (PVP K12, PVP K29 and PVP K90) were chosen to study their effect as antiprecip-
itants on the model drug Fenofibrate. Two approaches were used in this study: a non-formulated drug method (solvent
shift) and a formulated drug method (a miniaturized solvent casting method and spray-dried solid dispersion). The effects
of accelerated temperature and humidity were also studied in the spray dried solid dispersions and the solvent casting
methods. Miniaturized testing of the polymer using the solvent shift and the solvent casting method suggest that HPMC
E5 is a favorable polymer that gives the best extend and stability for the formed supersaturated solutions in the screening
assay and also shows a better release profile in in-vitro assay. Out of all the grades of PVP studied, PVP K29 shows
the best extend and stability of a formed supersaturated solution; however, the spray-dried dispersions were vulnerable
to temperature and humidity. The stability of Fenofibrate spray-dried dispersion is dependent on the molecular weight of
the polymer and the amount of the polymer in the dispersion. A high molecular weight polymer shows good stability as
compared to a lower molecular grade polymer at higher drug loading; however, the polymer governs the dissolution of
high molecular weight of polymer dispersions.
KEYWORDS: Fenofibrate, Supersaturation, Spray-Dried Solid Dispersion, HMPC, PVP.
INTRODUCTION
Most of the drugs discovered in the past decade are
hydrophobic in nature. They belong to the Biopharmaceu-
tics Classification System (BCS) of Class II compounds,
which are characterized by high permeability and low
aqueous solubility (Friesen et al., 2008). Even though they
may not fit the “rule of five” (Lipinski et al., 1997), these
drugs are safe and efficacious, and hence, their devel-
opment is critical. Unfortunately, it is difficult to retain
the potency and efficacy of these drug candidates while
improving their solubility (Ruben et al., 2006). Two types
∗
Author to whom correspondence should be addressed.
Email: rutesh.dave@liu.edu
Received: 31 December 2015
Accepted: 2 March 2016
of approaches are used to address the low solubility chal-
lenges, which include chemical modification, such as salt
formation (Serajuddin, 2007), prodrug (Stella and Nti-
Addae, 2007), or formulation methods, such as lipid for-
mulations (Akhlaquer Rahman et al., 2011), cocrystals
formations (Thakuria et al., 2013), particle size reduc-
tion (Brittain, 2002), inclusion complexes with cyclodex-
trins (Moya-Ortega et al., 2011), amorphous dispersions
of drug and polymer (Serajuddin, 1999), nanocrystals
(Müller et al., 2011; Murdande et al., 2015) and nanopar-
ticles (Al-Nemrawi and Dave, 2014). Of these methods
amorphous solid dispersion is gaining momentum since
it increases the dissolution of these drugs and thereby
increases bioavailability (Singh et al., 2011), although
additional experiments are needed for each drugs. Addi-
tionally, solid dispersion offers the possibility of presenting
J. Pharm. Sci. Pharmacol. 2015, Vol. 2, No. 3 2333-3715/2015/2/259/018 doi:10.1166/jpsp.2015.1066 259

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Evaluating the Effects of Different Molecular Weights of Polymers Chaudhari and Dave
the drugs in solid dosage forms, which have high patient
compliance (Hancock and Zografi, 1997). Various meth-
ods are available to convert crystalline drugs into an amor-
phous form, such as mechanical milling (Peltonen and
Hirvonen, 2010), fusion (DiNunzio et al., 2010), hot melt
extrusion (Lakshman et al., 2008), spray-drying (Patel
et al., 2013; Patel et al., 2014; Alhalaweh et al., 2009),
freeze drying (Yang et al., 2008), and supercritical fluid
precipitation (Bouchard et al., 2008). Of these, hot melt
extrusion and spray drying are the most widely used meth-
ods for manufacturing of solid dispersions, since these
technologies are scalable. The spray drying method offers
two advantages over hot melt extrusion. First, the materi-
als are not exposed to extreme temperatures, and second,
it is possible to granulate material using the same equip-
ment (Hugo et al., 2013). In this research we have used
the spray drying method to convert crystalline drug into
an amorphous form.
In spite of several advantages of solid dispersion, sta-
bility and reproducibility have limited the commercial use
of solid dispersion. To address this issue, the BCS Class
II compound fenofibrate (FENO) was selected. FENO is
practically insoluble in water, has very low tg and is highly
lipophilic (logP = 5 24 (Vogt et al., 2008)) in nature.
In light of Fick’s first law, we know that if the permeability
is good, dissolution is the only rate limiting step. Several
reports in the literature have indicated that FENO has a
very low tg of −21.3 C (de Waard et al., 2008; Górniak
et al., 2011; Sanganwar and Gupta, 2008, Zhou et al.,
2002) and very high molecular mobility. As a result, it
shows a tendency for spontaneous recrystallization, which
in turn, affects the dissolution characteristics which means
it, has an unpredictable drug release profile. Different
polymers have been shown to be beneficial in inhibiting
drug crystallization, including polyvinylpyrrolidone (PVP)
(Khougaz and Clas, 2000), hydroxypropylmethyl cellulose
(HPMC) (Raghavan et al., 2001) and many others as well.
This polymer follows what is called a spring and parachute
approach. A spring is a high energy form of drug or self-
emulsifying system, which allows for the rapid dissolution
of poorly soluble drugs at a supersaturated concentration.
A formulation component which stabilizes the metastable
supersaturated system acts as a parachute, hindering nucle-
ation, or crystal growth (Guzmán et al., 2007; Guzman,
2004; Gao et al., 2004; Gao and Morozowich, 2006).
Sporanox (itraconazole) is an example of this stratagem
(Peeters et al., 2002). Itraconazole is a poorly water sol-
uble drug (∼1 ng/ml at ph7) with a logP > 5 and melt-
ing point of 167 C. The marketed formulation was based
on the development of the solid solution of the drug in a
polymeric matrix. HPMC was used as polymeric matrix.
The drug and HPMC were dissolved in a common sol-
vent and coated on sugar spheres. In this formulation,
HPMC acts as an inhibitor of drug nucleation and crystal
growth for a sufficient period of time, which leads to sig-
nificant absorptions and bioavailability. The optimization
of the system features will allow for sustained supersat-
uration, which in turn, leads to improved bioavailability.
The use of supersaturation approaches has been widely
reported in topical and transdermal therapies (Raghavan
et al., 2001; Raghavan et al., 2003; Davis and Hadgraft,
1991; Hadgraft, 1999) and has led to marketed products
(Strickley, 2004). Another approach used by scientists is
to increase the saturation solubility of drugs. In all of
these methods the selection of the excipient i.e., polymeric
matrix is the crucial step, which in turn, stabilizes the
high energy form of the drug. Some of the reports in the
literature have reported multiple in-vitro assays to eval-
uate supersaturation, precipitation or precipitation inhibi-
tion by use of the excipients, i.e., polymers. In this paper,
the solvent shift and solvent casting methods are used
to evaluate the supersaturation potential of the polymer.
These two techniques are miniaturized testing methods
involving g quantity of drug; hence spray dried solid
dispersions (SD) are prepared in order to evaluate their
effect of FENO on a large scale. Two polymer fami-
lies are used in this study: PVP (PVP K12, PVP K29
and PVP K90) and HPMC (HPMC E5, HPMC E15 and
HPMC E50).
MATERIAL AND METHODS
Materials
FENO was obtained from Sigma Aldrich. PVP K12
(Plasdone®
k12), PVP K29 (Plasdone®
K29); PVP
K90 (Plasdone®
K90) was received from ISP tech-
nologies and HPMC E5 (Methocel®
E5), HPMC
E15 (Methocel®
E15) and HPMC E50 (Methocel®
E50) were procured from Dow Chemicals. Sodium
taurocholate (Sigma Aldrich) and lecithin (Spectrum
Chemicals) were used for simulated intestinal fluid prepa-
ration. Chemicals such as Sodium dihydrogen phosphate
(NaH2PO4 , sodium chloride (NaCl), sodium hydrox-
ide (NaOH), hydrochloric acid (HCl) and HPLC grade
acetonitrile and water were obtained from Spectrum
Chemicals.
Quantification of FENO
High performance liquid chromatography (HPLC) was
used for quantification of FENO. HPLC analysis was per-
formed using an Agilent 1100 series HPLC system fitted
with a binary pump, with a plate auto sampler, a thermo-
stat in the column compartment and a diode array detec-
tor controlled by Chemstation, software version A.10 .02.
A Supleco C18 Column of 4.6 mm×150 mm with particle
size of 5 um was also used. The mobile phase was com-
posed of 90% acetonitrile and 10% water. The flow rate
was 1 ml/min. The column temperature was maintained at
25 C and UV detection was carried out at 291 nm and
the injection volume used was 10 uL with 6 min of run
time and retention time of 4.1 min.
260 J. Pharm. Sci. Pharmacol. 2, 259–276, 2015

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Chaudhari and Dave Evaluating the Effects of Different Molecular Weights of Polymers
Preparation of Media
In this study, the fasted state simulated intestinal fluid
(FaSSIF) was used as the test medium for the solvent
shift method and the solvent casting method. FaSSIF was
prepared according to the formula described in Vertzoni
et al. (Vertzoni et al., 2004). Drug release experiments
were also carried out in blank FaSSIF with 1% w/v
sodium lauryl sulfate (SLS) without sodium taurocholate
and lecithin. The composition of FaSSIF was as follows:
pH 6.5, 3 mM sodium Taurocholate, 0.75 mM Lecithin,
29 mM NaH2PO4, 13.8 mM NaOH, 106 mM NaCl. pH
was adjusted to 6.5 by 1 N NaOH or 1 N HCl.
Solubility Measurements
The solubility of FENO was assessed in an aqueous
medium by the shaking flask method: approximately
10 mg of FENO was dispersed in 5 ml of medium and
shaken for 24 hrs at room temperature (RT) and 37 C. The
undissolved materials were separated from the solution by
centrifugation (14000 rpm×10 mins). The supernatant was
diluted with mobile phase and analyzed by HPLC.
STABILIZING EFFECT OF POLYMER
Solvent Shift Method
Polymers were dissolved in FaSSIF at concentrations of
0.01%, 0.1 %, 1%, 2% w/v and FENO was dissolved
in dimethyl sulfoxide (DMSO) at a concentration of
50 mg/ml. Then 30 ml of polymer solution was placed in
a beaker and stirred continuously with the help of a mag-
netic stirrer. Organic solution was then added drop-wise to
the polymer solution until a visible precipitate was notice-
able. 1 ml samples were withdrawn after 5, 30, 60, 90, 120
minutes post drug addition. Samples were filtered using a
0.45 um GHP filter and diluted immediately with mobile
phase and analyzed in the HPLC. In every case, only 2%
of organic phase was added.
Viscosity Measurement
Viscosity measurements were also performed on AP solu-
tion using Gilmont Falling Ball viscometer, size 1. 5–10 ml
solution was filled in the viscometer and capped. The time
required by stainless steel ball to pass between two set of
fiduciary line is measured with a stop watch and viscosity
was calculated by
= K 1 − t (1)
Where, K = 0 3 (size 1), 1 = density of stainless
steel ball, = Density of the liquid, t = time of descent
(minutes).
Density of solution was measured with the help of glass
pycnometer.
Solvent Casting Method
The formulations were prepared in 96 well plates. Ethanol
was used as the solvent to prepare the excipient-drug stock
solution. Ethanol was chosen as the solvent since it dis-
solves all the excipients and drugs used in this study.
A stock solution with the drug excipient was prepared and
200 uL was dispensed in each plate. The drug concentra-
tion in each plate was kept at 0.1 mg/ml and the polymer
varied according to the drug load in each well. After dis-
pensing the liquid, the solvent was evaporated in a vacuum
oven at 50 C for 2.5 hrs. After drying, each well contained
a film or pellet, which was sealed with a paraffin film and
kept at room temperature overnight. This step was done to
give unstable formulation the opportunity to recrystallize.
Replicates of the plates were prepared and stored in room
temperature and humidity for three months and dissolu-
tion testing was performed again after 15 days, 1 month
and 3 months. Plates were also stored at accelerated sta-
bility conditions at 40 C and 75% relative humidity (RH)
(described below) and analyzed after 2 weeks, 4 weeks
and 6 weeks.
Drug Release Testing from Solvent Cast
The drug release testing from the solvent casts was per-
formed by adding 200 uL of FaSSIF (pH 6.5) in each
well and then the plates were shaken in the shaker for
0.5, 1 and 4 hrs at 95 rpm. After shaking, the contents
of the plates were transferred to the 0.45 um GHP mem-
brane filter plate (Pall Life Sciences). The samples were
pulled through the filter with the help of the vacuum.
100 uL of sample was diluted with the mobile phase
immediately to avoid precipitation. The drug release stud-
ies were carried out on the stability samples as well; the
plates were shaken for 4 hrs only to determine the drug
content.
Preparation of Spray Dried Solid Dispersion
The spray dried solid dispersion was prepared using
a Buchi spray dryer B-290 (Buchi Laboretechnik AG,
Flawil, Switzerland) equipped with an inert loop B-295.
The spray drying solution was prepared by dissolving the
excipient and the drug in ethanol. An 8% w/v feed con-
centration was used for PVP K12 and K29, a 3.2% w/v
feed concentration was used for HPMC E5, HPMC E15
and a 2% w/v feed concentration was used with HPMC
E50. The inlet temperature was set as 110 C and the solu-
tion was sprayed at a 10 ml/min flow rate. The aspirator
rate was set as 100% with a nozzle size of 0.7 mm and
drying air flow (473 L/Hr) was kept constant throughout
the experiment. The resulting spray dried powder was col-
lected and stored in tightly closed vials and stored over
desiccators at room temperature.
Stability Studies
Stability studies of the formulation were performed at
40 C in sealed glass chambers. A saturated NaCl salt
solution was prepared by using chemically pure NaCl
and distilled water. This solution was placed in glass
J. Pharm. Sci. Pharmacol. 2, 259–276, 2015 261

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
chambers and allowed to equilibrate at 40 C to main-
tain the accelerated stability condition of 40 C and 75%
RH. SD was stored in these glass chambers in open glass
vials. The samples were pulled after 1, 2 and 6 weeks.
The solid dispersion collected was gently separated and
screened through USP mesh no 30. All stability samples
were then thoroughly dried in a silica gel (0% RH) des-
iccator for 48 hrs and then stored in sealed glass vials in
0% RH desiccator until further analysis.
Drug Load Quantification
The FENO content in SD and stability samples were deter-
mined by suspending the amount of powder equivalent to
5 mg of FENO in 10 ml of DMSO and stirred with the
help of a magnetic stirrer for 4 hrs. After 4 hours, the sam-
ples were filtered through a 0.45 m PTFE syringe filter
and diluted appropriately and analyzed in HPLC.
CHARACTERIZATION OF SOLID
DISPERSION
Powder X-ray Diffraction
Powder X-ray diffraction (PXRD) was done using scan-
ning diffractometer (Advanced Diffraction System, Scintag
Inc., Model XI Cupertino, CA) controlled by a computer
with diffraction management system software for Windows
NT. The X-ray radiation used was generated by a copper
K filter with a wavelength of 1.54 A0 at 45 KV and
40 mA. Solid samples were placed on a sample holder with
dimensions of 2 cm × 2 cm × 2 mm. Powder was placed
on the holder using a spatula and then flattened. Samples
were scanned over a range of 5 to 50 2 degree using a
scan rate 2 /min and scan step of 0.05.
Modulated Differential Scanning Calorimetry
Modulated differential scanning calorimetry (MDSC) was
applied as an additional method to detect crystallinity in
the sample apart from X-ray. It has been reported in the lit-
erature that small crystals might not be detected by PXRD,
even if it is above the limit of detection (Munson, 2009).
MDSC analysis was performed using Q200 (TA Instru-
ments, USA) equipped with a cooling system. Nitrogen
was used as a purge gas with a flow rate of 50 ml/min.
5–10 mg samples were weighed into aluminum pans with
a pinhole on the lid and then hermetically sealed. Sam-
ples were heated from 20–200 C at a heating rate of
5 C/min with modulation of 1.59 C every 60 s. All the
data handling was performed using a Universal Analysis
2000 software package (TA Instruments).
Fourier Transform Infrared Spectroscopy
Fourier Transform Infrared Spectroscopy (FTIR) spectra
for all solid dispersion were obtained using MAGNA-IR-
60 Spectrophotometer (Nicolet Instrument Corp., Madi-
son, WI). A small quantity of each sample was triturated
with pure potassium bromide in a mortar and pestle and
compressed to form a semitransparent film. Each film was
scanned in the region of 400 to 4000 cm−1
. 64 scans were
collected for each sample.
Dissolution Testing
In-vitro release experiments were carried out in USP
Apparatus 2 (Distek Dissolution Systems 2100A, East
Brunswick, NJ). The release behavior of the SD, the physi-
cal mixture and the pure drug were assessed in two media:
FaSSIF and blank FaSSIF (without sodium taurocholate
and lecithin) with 1% SLS: to ensure sufficient wetting,
media was conditioned at 37 C with a stirring speed of
50 rpm. A sample amount equivalent to 25 mg of FENO
was used throughout the studies in 250 ml of media.
A sample volume of 3 ml was drawn through a stainless
steel cannula at 15, 30, 45, 60, 90 and 120 min. All sam-
ples were filtered through a 0.45 m PTFE syringe filter.
The first milliliter of the sample was discarded and rest of
the sample was diluted with mobile phase and analyzed in
HPLC.
Particle Size Analysis
Particle size analysis was performed using Flowcam
(Scarborough, ME) and data was analysed using Flowcam
software version 3.4.5. Drug particle and dispersions were
suspended in mineral oil and particle size analysis was per-
formed at a flow rate of 0.5 ml/min for 10 minutes using
a 4× optical lens.
RESULTS AND DISCUSSION
Solubility Studies
Solubility of FENO in water was found to be 0.3 g/ml±
0.01 g/ml at 25 C and 37 C, respectively. It was seen
that temperature did not affect the solubility of FENO
in water. Media plays an important role in solubility of
FENO. The solubility of FENO in FaSSIF (0.5 g/ml ±
0.02 g/ml at 25 C, 13.5 g/ml ± 0.3 g/ml at 37 C)
was significantly enhanced, as compared to blank FaSSIF
(0.3 g/ml at 25 C and 37 C), which indicates FENO
is solubilized in the micelles of the simulated intestinal
media. The significant increase in solubility upon addition
of taurocholate and lecithin corresponds with the docu-
mented positive food effect of FENO (Guichard, 2000;
Guivarc’h et al., 2004; Sauron, 2006; Yun et al., 2006).
The solubility of FENO is greatly enhanced with the addi-
tion of 1% w/v SLS to Blank FaSSIF (337 g/ml ±
14 g/ml at 37 C). The critical micelle concentration
(CMC) of SLS is 8 mM (Cheng et al., 2006; Dave et al.,
2012). We have used SLS above its CMC concentration,
and hence, the solubility of FENO is more in blank FaSSIF
with 1% w/v SLS. The excipient also has an effect on sol-
ubility (Rodríguez-hornedo and Murphy, 1999; Strickley,
2004). However, when the solubility of FENO in FaSSIF

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Table I. Physiochemical properties of polymers.
Viscosity in mpa·s
Polymer Tg ( C) Molecular weight (Da) 0.1 mg/ml (n = 3) 1 mg/ml (n = 3) 10 mg/ml (n = 3) 20 mg/ml (n = 3)
PVP K12 117 4 000 0.91 0.91 1 1 1 42
PVP K29 176 58 000 1.03 1.13 1 24 1 87
PVP K90 181 1 300 000 1.08 1.33 3 07 7 37
HPMC E5 150 28 700a
0.97 1.11 2 06 5 02
HPMC E15 154 60 000a
1.06 1.26 4 02 15 00a
HPMC E50 164 86 700a
1.03 1.38 ND 50 00a
Notes: a
values are taken from published literature (Keary, 2001), ND: not determined.
in the presence of 2% w/v excipient was tested, it was
found that the excipient does not have any effect on the
solubility of FENO (data not shown). The physiochemical
properties of the polymer are listed in Table I. Molecular
weight increases as we go from PVP K12 to PVP K90 for
PVP, and HPMC E5 to HPMC E15, which is associated
with the increase in glass transition temperature. The vis-
cosity of the solution is concentration dependent. Higher
molecular weight HPMC and PVP has the higher viscos-
ity. The viscosity of 10 mg/ml solution of HPMC E50 and
20 mg/ml solution of HPMC E15 and HPMC E50 was
not determined due to limitation of gilmont falling ball
viscometer, size 1.
STABILIZING EFFECT OF POLYMER
Solvent Shift Method
In the blank experiment, the supersaturation degree and
stability was determined for the supersaturated FENO
solution without any antiprecipitant. The supersaturation
degree, expressed as a concentration of FENO in solu-
tion after 5 min post drug addition, was 8.48 g/ml ±
0.03 g/ml. After 2 hrs, there was 3.19 g/ml ±
0.01 g/ml of FENO in the solution. These data sug-
gests that we can achieve a signiﬁcant degree of super-
saturation (DS) even without the addition of the excipient
compared to thermodynamic solubility. DS is expressed
Figure 1. Spring and parachute approach.
as shown in Eq. (2)
S =
C
Ceq
(2)
Where C is the drug concentration and Ceq is the equi-
librium drug concentration.
It also represents the state of drug
DS = 0, Drug is in a state of saturation,
DS < 1, Drug is in an unsaturated state,
DS > 1, Drug is in a supersaturated state.
To evaluate the extent of supersaturation produced and the
stability of the supersaturated solution, the excipient gain
factor (EGF) was calculated from Figure 1, Eq. (3)
Excipient Gain Factor =
Area A+Area B +Area C
Area A+Area B
(3)
For most of the polymers studied, the stability of supersat-
uration was superior compared to blank. Table II shows the
data for the degree of supersaturation achieved after 5 min
post drug addition. It is seen that K29 shows the highest
degree of supersaturation after 5 min post drug addition in
the PVP family, whereas HPMC E5 shows superior results
in the HPMC family. In general, increasing the polymer
concentration does not increase the supersaturation pro-
duced. However, it only increases the stability of supersat-
urated FENO in solution for PVP K12 and K29 polymers,
which is shown by an increase in the excipient gain fac-
tor until a polymer concentration of 1 mg/ml. Increasing
the concentration further has a reverse effect and stabil-
ity decreases, since EGF decreases, as shown in Table III.
Increasing the concentration of the HPMC polymer also
Table II. Supersaturation of drug created in the presence of
excipients.
Supersaturation produced after 5 mins post drug addition
0.1 mg/ml 1 mg/ml 10 mg/ml 20 mg/ml
(n = 3) (n = 3) (n = 3) (n = 3)
PVP K12 1.8 1.7 1.6 1.5
PVP K29 1.9 1.9 1.9 1.3
PVP K90 1.3 1.6 1.6 1.4
HPMC E5 3.1 2.7 2.2 1.9
HPMC E15 2.9 2.2 1.6 1.3
HPMC E50 2.0 1.5 1.5 0.9

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Table III. Stability of supersaturated drug solution at the end
of 2 hours.
Excipient gain factor
0.1 mg/ml 1 mg/ml 10 mg/ml 20 mg/ml
(n = 3) (n = 3) (n = 3) (n = 3)
PVP K12 1.45 1.47 1.44 1.43
PVP K29 1.45 1.46 1.45 1.42
PVP K90 1.49 1.44 1.45 1.42
HPMC E5 1.59 1.58 1.56 1.53
HPMC E15 1.56 1.51 1.49 1.40
HPMC E50 1.50 1.51 1.36 1.31
has a negative effect on the degree of supersaturation gen-
erated characterized by a decrease in EGF.
Solvent Casting Method
The miniaturized solvent casting method was used to
determine the efﬁciency of polymers. The casts prepared
by this method cannot be considered as formulation; how-
ever, their manufacturing technique does mimic solid dis-
persion and we can assume how polymer behaves. In this
study we have used solvent casts to perform the release
rate studies and to evaluate the stability of the drug in
polymers. The release studies carried out for HPMC sol-
vent casts reveal that HPMC E5 shows the fastest drug
release as compared to HPMC E15 and E50 at all the
drug load, Figure 2. It should be noted that none of the
polymer shows 100% drug release (i.e., concentration of
Figure 2. Drug release versus time proﬁle of FENO-HPMC solvent casts at various drug loading.
100 g/ml); the maximum drug release attained was 29%.
It is seen that at lower drug load more supersaturation
is achieved, HPMC E5 being the highest. All the sol-
vent casts show a concentration above saturation solubility;
however, at 80% w/w drug load, the HPMC E50 solvent
cast was not able to reach saturation concentration levels.
The release rate studies carried out on the PVP solvent
cast revealed that PVP K29 shows the highest drug release
as compared to K12 and K90. From Figure 3, it is seen
that initially PVP K12 and K29 show the same rate of
release; however, at the end of 4 hrs, K29 shows almost
16% drug release in contrast to the 7% release of PVP
K12 cast at 20% w/w drug loading. FENO is a very poor
water soluble drug. Even at 20% w/w drug loading, the
maximum release obtained was 16%. It should be noted
that the PVP K29 cast shows supersaturation at all the
drug loading and the DS ratio increases as we increase
the polymer content. However, PVP K12 and K90 solvent
casts did not attain saturation level at 80%, 60% and 40%
w/w drug loading. At the higher polymer concentrations,
i.e., 20% drug loading, they show DS > 1.
Stability Studies on Solvent Casts
The supersaturation ratio at the end of 4 hours is given in
Table IV. When these solvent casts are stored for a long
period of time, the solubility of the drug decreases for both
the storage conditions. HPMC E5 was able to maintain
DS of 4.7, even at 40 C for 4 weeks and then decreases
to 1.5 after 6 weeks of storage at 40 C and 75% RH.

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Figure 3. Drug release versus time profile of FENO-PVP solvent casts at various drug loading.
As we increase the drug content, the solubility decreases
in order HPMC E5 > E15 > E50, and at the higher drug
load of 80% w/w, the solubility reaches only at saturation
solubility levels, which suggest that the amount of polymer
is very critical. For PVP polymer, even at 20% w/w drug
loading, initial sample of PVP K12 achieved a mere DS of
1.5 and PVP K90 achieved DS of 1.6 whereas PVP K29
solvent casts achieved DS of 3.0. PVP K29 has the highest
solubility in the PVP family and on storage the solubility
decreases.
Table IV. Stability of solvent casts (n = 3).
40 C and 40 C and 40 C and 40 C and 40 C and 40 C and
RT15 RT 1 75% RH 75% RH 75% RH RT15 RT 1 75% RH 75% RH 75% RH
Polymer Initial days month 2 week 4 week 6 week Polymer Initial days month 2 week 4 week 6 week
20% drug loading 40% drug loading
PVP K12 2 0.8 0.7 1.4 0.6 0.6 PVP K12 0.9 1.0 0.7 1.0 0.6 0.6
PVP K29 3.0 3.0 0.7 3.0 0.8 0.7 PVP K29 1.2 1.2 0.6 1.2 0.7 0.7
PVP K90 1.6 1.6 0.5 1.3 0.7 0.5 PVP K90 0.8 0.8 0.6 0.8 0.6 0.6
HPMC E5 5.5 5.4 4.7 5.1 4.7 1.5 HPMC E5 4.4 4.3 4.2 2.5 2.1 1.2
HPMC E15 5.4 4.9 4.2 3.4 3.0 1.5 HPMC E15 4.1 3.7 3.7 2.9 2.0 1.0
HPMC E50 3.0 3.0 2.9 2.8 2.4 1.4 HPMC E50 2.7 2.5 2.2 2.5 2.1 1.0
60% drug loading 80% drug loading
PVP K12 0.8 0.8 0.7 0.8 0.6 0.6 PVP K12 0.8 0.7 0.5 0.7 0.4 0.5
PVP K29 1.2 1.2 0.6 1.2 0.7 0.6 PVP K29 1.0 1.1 0.6 1.1 0.6 0.6
PVP K90 0.8 0.7 0.6 0.7 0.6 0.6 PVP K90 0.7 0.8 0.6 0.8 0.6 0.5
HPMC E5 2.1 2.1 2.3 2.0 1.7 1.2 HPMC E5 1.2 1.2 1.2 1.1 1.2 1.1
HPMC E15 1.7 1.7 1.8 1.7 1.5 0.9 HPMC E15 1.1 1.1 1.1 1.1 1.2 1.0
HPMC E50 1.7 1.7 1.4 1.7 1.1 0.9 HPMC E50 0.8 0.8 0.8 0.8 0.8 0.8
Solid Dispersions Preparation
Solid dispersion was prepared by using a spray drying
process. This process has many factors, including: inlet
temperature, flow rate, solvent selection, nozzle size, dry-
ing gas flow rate and feed concentration, all which affect
the properties of the spray dried dispersion. However, in
order to minimize variation parameters, the inlet temper-
ature, flow rate, solvent, drying gas flow rate and noz-
zle size were kept constant. The feed concentration was
changed in order to increase processability. Since PVP

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Table V. % yield of FENO-SD.
25% w/w 10% w/w 5% w/w
drug loading drug loading drug loading
% yield % yield % yield
Polymer (n = 3) Stdev (n = 3) Stdev (n = 3) Stdev
PVP K12 50 1.58 75 3.02 73 1.97
PVP K29 70 1.47 71 1.20 72 2.57
HPMC E5 58 1.59 59 0.51 57 0.43
HPMC E15 42 1.57 51 0.69 43 0.21
HPMC E50 28 0.85 36 0.69 35 0.55
K90 and HPMC E50 have very high viscosity, we reduced
the feed concentration to 1% w/v for PVP K90 and to 2%
w/v for HPMC E50. Despite reducing the feed concentra-
tion, the processing parameters were inadequate for PVP
K90 and we did not get any product; thus the PVP K90
dispersion was not prepared. The % yield for FENO is
given in Table V. It is seen from Table V that the yield
of HPMC E50 is less, as compared to HPMC E15 and E5
in the HPMC family and the yield of PVP K12 is less,
as compared to K29. The viscosity of PVP K12 is less
as compared to PVP K29, and hence, in a dilute solu-
tion very small particles formed and which escaped the
cyclone and got deposited on the ﬁlter (Patel et al., 2013;
Patel et al., 2014). This explains the reason for the low
yield for PVP K12. The yield for HPMC E5 is higher as
compared to HPMC E15. HPMC E15 has a higher vis-
cosity as compared to HPMC E5 and hence, the viscosity
of the feed solution is higher for E15. Due to the higher
viscosity, most of the dispersion was lost due to stick-
ing in the drying chamber of the spray dryer and hence
we get lower yield. HPMC E50 shows very low yield as
compared to other HPMC E5, HPMC E50, the feed con-
centration of HPMC E50 was reduced to 1% w/v for better
Figure 4. Overlay of MDSC thermogram of FENO-SD (a) HPMC-SD (b) PVP-SD.
Figure 5. The effect of increase in drug loading on the glass
transition temperature of drug: polymer SD.
processability. However, owing to the high viscosity of the
HPMC E50, most of the dispersion was lost on drying
chamber of the spray dryer.
CHARACTERIZATION OF SOLID
DISPERSIONS
Modulated Differential Scanning Calorimetry and
Powder X-ray Diffraction
Many factors, such as glass transition temperature, plas-
ticization, storage temperature and humidity, as well
as viscosity play an important role in determining the
kinetic stability of high energy amorphous solid dosage
forms. Since FENO is prone to spontaneous recrystalliza-
tion, efforts were employed to physically stabilize FENO
through spray dried solid dispersion. In this study var-
ious polymers were evaluated as potential inhibitors of
recrystallization.
Three different grades of HPMC and PVP were investi-
gated as stabilizing agents based on their molecular weight

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Figure 6. The effect of temperature and humidity on FENO-
HPMC SD at 5% drug loading.
and three different drug loading i.e., 25%, 10% and 5%
w/w was used to test these polymers. All the polymers
used were able to convert crystalline FENO into an amor-
phous form, which is evident from the MDSC thermo-
grams, as noted in Figure 4. The PXRD was performed
Figure 7. DSC thermogram of FENO-HPMC solid dispersions at different drug loading and its stability samples stored in 40 C
% 75% RH for 1 week, 2 weeks, and 6 weeks.
on solid dispersion to check for presence of crystalline
fenoﬁbrate. The PXRD diffraction pattern did not show
the presence of crystalline FENO in the solid dispersion
and stability samples (data not shown).
It is well known that as the polymer content increases,
the tg increases, as seen in Figure 5. HPMC E5 shows
lower tg as compared to E15 and E50, which can be
explained due to the molecular weight difference between
HPMC polymers. It was demonstrated that the storage of
indomethacin at 40–50 C below tg prevents crystalliza-
tion for long periods of time (Yoshioka, 1995); hence, the
higher tg of dispersion is desired. At 5% of drug load-
ing, all HPMC polymers retain FENO in the amorphous
state even after storage at an elevated temperature and
humidity (40 C and 75% RH); however, a decrease in
tg was observed, see Figure 6. The tg of HPMC E5 dis-
persion with 5% FENO shows a decrease in tg to 109.55
after 6 weeks of storage; however, E50 doesn’t shows
much change in tg. Figures 7 and 8, show an overlay
of DSC thermogram of FENO-polymer SD at different
drug loading and their stability samples for HPMC and

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
PVP, respectively. In Figure 7, it can be seen that at 10%
w/w drug loading, HPMC E5 shows a decrease in tg after
1 week of storage samples; after that, 2 tg are observed,
which indicates immiscibility and we can see crystalline
FENO peak in 6 week samples. All the polymers were
able to form an amorphous form of FENO at 10% w/w
and below drug loading. At 25% w/w, drug loading all the
SD forms were crystalline characterized by peak near the
drug melting point as seen in Figures 7 and 8.
PVP polymer shows similar results as HPMC; an
increase in tg is observed as we increase the polymer con-
tent for both grades of PVP, as seen in Figure 5. FENO-
PVP K29 SD with 5% w/w drug loading shows tg of
155 C, which is the highest tg obtained for both HPMC
and the PVP series. However, the drug crystallizes out after
1 week of storage at 40 C and 75% RH. From Figure 8,
it is seen that PVP SD is more susceptible to temperature
and humidity than HPMC SD.
The percent crystallinity of the SD and its stability sam-
ples were calculated by Eq. (3) by pan (Pan et al., 2006;
Pan et al., 2008)
Crystallinity of drug substance
= A/Wt /H ×100% (4)
Where, A = area under the melting endotherm, Wt =
amount of FENO in the solid dispersion as measured by
HPLC and H = heat of fusion of pure crystalline FENO.
The % crystallinity was calculated for all the SD pre-
pared and shown in Figure 9. The SD prepared with
25% w/w drug loading shows 6% of crystallinity initially
Figure 8. DSC thermogram of FENO-PVP solid dispersions at different drug loading and its stability samples stored in 40 C %
75% RH for 1 week, 2 weeks, and 6 weeks.
Figure 9. FENO crystallinity in spray dried dispersions dur-
ing 6 weeks stability.
for HPMC E5 and 7% crystallinity for HPMC E15 and
E50. After storage of the samples, crystallinity increases
in all HPMC grades used; however, E15 and E50 were
most affected with 15% crystallinity in the 6-week storage

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
samples. HPMC dispersions with 10% w/w were amor-
phous in nature initially after storage while FENO crys-
tallizes out and shows 9% crystallinity in E50, and 7%
crystallinity in E15. E5 dispersion were amorphous at
10% w/w of drug loading even after storage. Increas-
ing the HPMC content further in dispersion increases the
stability with no crystallinity detected after 6 weeks of
storage.
PVP K12 forms amorphous dispersion at all the drug
loading studied; however, they were susceptible to elevated
temperature and humidity and show 18% crystallinity in
6 weeks of storage at 25% w/w drug loading and 11%
crystallinity at 10% and 5% w/w drug loading. In PVP
polymer PVP K12, dispersion was most affected. This may
be due to lower viscosity of PVP K12 as compared to
PVP K29.
Figure 10. FTIR spectra of FENO-HPMC physical mixtures and solid dispersions at different drug loading.
Fourier Transform Infrared Spectroscopy
To investigate the mechanism of forming amorphous solid
dispersion, FTIR was used to investigate potential inter-
actions between FENO and polymeric excipients. In high
energy form of drug i.e., SD, the interactions between the
drug and polymers may be relevant to stabilization of the
SD (Wang et al., 2009). FENO has four functional groups
that can act as proton acceptors: they have two hydroxyl
groups ((O–H) groups) and two oxygen atoms of carbonyl
(C O) but they lack a proton donor. Some scientist have
reported that FENO forms hydrogen bonds with polymers
typically used in the pharmaceutical industry (Yun et al.,
2006). The less resolved peaks and broader band shapes
in the FTIR spectra of FENO SD suggest the presence of
amorphous FENO (Heinz et al., 2009). Crystalline FENO
shows that carbonyl stretching peaks at 1729 cm−1
and

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
1652 cm−1
. A shift in peak position indicates the strength
of the FENO-polymer hydrogen bonding (Lynne S. Taylor,
1997). Physical mixtures (PM) of FENO-HPMC do not
show any change in peak positions at all drug loading,
i.e., no interaction between FENO and HPMC, as shown
in Figure 10. SD formed at 25% w/w drug loading in all
HPMC polymers show peak at 1730 cm−1
and 1652 cm−1
,
which is almost the same as crystalline FENO. Higher
polymer content shows a larger shift. At 10% w/w drug
loading, there is peak at 1733 cm−1
and 1657 cm−1
for
all HPMC polymer, as shown in Figure 10. SD containing
5% w/w FENO shows a similar peak shift to SD con-
taining 10% w/w FENO. From this data we can conclude
that FENO shows hydrogen bonding with the polymer at
the higher polymer content, i.e., 10% and 5% w/w drug
loading, owing to the larger spectral shifts. However, it
should be noted that all grades of HPMC show similar
results. These dispersions, when subjected to elevated tem-
perature and humidity, show a decrease in spectral shift
as compared to the initial shifts indicating a breakage
of the hydrogen bonds. From Figure 11, it is seen that
after 6 weeks at 25% w/w drug loading, the spectral shift
decreases to 1729 cm−1
and 1652 cm−1
, which is the same
as that of crystalline FENO. HPMC E15 and E50 SD
containing 10% w/w FENO show a decrease in spectral
shift to 1731 cm−1
and 1653 cm−1
after 6 weeks, and
HPMC E5 SD shows peaks at 1720 cm−1
and 1656 cm−1
.
Figure 11. FTIR spectra of FENO-HPMC solid dispersions at different drug loading and their stability at 1 week, 2 weeks, and
6 weeks of storage in 40 C % 75% RH.
The spectral shift is less in stability samples of E5 as
compared to E15 and E50. This data supports the fact that
E15 and E50 show greater crystallinity as compared to E5.
IR spectra of physical mixtures of FENO-PVP are
shown in Figures 12(a and b). PVP shows peak at
1678 cm−1
. It is seen that at 25% w/w drug loading, the
physical mixture of FENO-PVP shows peak same as that
of FENO. However, when we increase the polymer content
peak at 1729 cm−1
and 1652 cm−1
is seen as mere shoulder
in IR spectra of both the grades of PVP. SD of FENO-PVP
shows the larger spectral shift to 1679 cm−1
at 5% w/w
drug loading. The IR spectra of FENO-PVP, looks similar
to that of the PVP polymer, as seen in Figure 12. The shift
in FENO-PVP SD shows a similar trend as that of HPMC.
As we increase the drug content in SD, the spectral shift
decreases; peak at 1729 cm−1
in FENO is seen as shoulder
at 5% w/w and at 10% w/w drug loading. A decrease in
the spectral shift is observed when these dispersions are
subjected to elevated temperature and humidity, as noted
in Figure 13. The 1652 cm−1
is seen as shoulder after
1 week of storage in FENO-PVP at 25% w/w drug load-
ing; however, no such peak is seen at 10% or 5% w/w
drug loading.
Some reports have demonstrated that drug-polymer
interactions are important in order to stabilize solid disper-
sion (Lynne S. Taylor, 1997). It was found that the crys-
tallization tendency of a series of benzodiazepines with

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Figure 12. FTIR spectra of FENO-PVP physical mixtures and solid dispersions at different drug loading.
different functional groups was prevented only when the
compound was able to form a hydrogen bond with the car-
rier (phospholipid) (Konno and Taylor, 2006). It has also
been argued that the anti-plasticizing effect of the polymer
plays an important role in the stabilization of amorphous
drugs, in contrast to drug-polymer interactions. As the vis-
cosity of the drug polymer system is increased, the dif-
fusion of drug molecules is inhibited, which is necessary
for recrystallization (Van den Mooter et al., 2001). In the
Figure 13. FTIR spectra of FENO-PVP solid dispersions at different drug loading and their stability at 1 week, 2 weeks, and
6 weeks of storage in 40 C% 75% RH.
present study, the type of polymer and drug/polymer ratio,
rather than hydrogen bonding, affected the amorphous
character of FENO, since amorphous FENO in FENO-
PVP dispersion was the least physically stable.
Dissolution Studies
The solubility of FENO in blank FaSSIF with 1% w/v SLS
is 337 g/ml±14 g/ml at 37 C. The dose of FENO in
both the release media corresponds to a theoretical con-

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
centration of 100 g/ml. In FaSSIF, 100 g/ml represents
a supersaturated state. In blank FaSSIF with 1% SLS, sol-
ubility of FENO is 337 g/ml±14 g/ml at 37 C, with a
final concentration of 100 g/ml, sink condition was thus
maintained throughout the experiment.
Dissolution results could be well predicted with DSC
and FTIR analysis. The dissolution profile of SD of FENO
with HPMC and PVP, along with the stability sample in
blank FaSSIF with 1% SLS and FASSIF, is shown in
Figures 14–17. Comparing the dissolution profile of 25%
FENO with HPMC polymer in sink conditions, shows that
as the viscosity increases there is a decrease in the rate
of the release of the drug, Figure 14. The release from
HPMC E50 is the slowest in all the drug loading, fol-
lowed by HPMC E15 and E5. An increase in the rate of
drug release is observed from 25% to 10% w/w FENO for
all the HPMC polymers. However, when drug loading is
increased further, the rate of drug release slows down ini-
tially. A DSC thermogram of these SD shows that SD with
10% w/w FENO is amorphous in nature; increasing the
polymer concentration increases the stability of the disper-
sions. However, in sink conditions it is shown to slow the
dissolution as compared to SD with 10% FENO. In non-
sink conditions, Figure 15, it is seen that at 25% w/w drug
Figure 14. Comparison of dissolution profiles of FENO SD, PM and 6 weeks stability samples using various HPMC polymers at
different drug loading in blank FaSSIF with 1% SLS.
loading, the final concentration released in the media is a
mere 11.6 g/ml for HPMC E5 SD, 11.4 g/ml for E15,
and 9 g/ml for E50. The release from SD with 25% w/w
FENO is expected to be less as the drug was in crystalline
form. The release profile was improved in SD with 10%
w/w FENO; the maximum concentration achieved was
57 g/ml for E5, 40 g/ml for E15 and 33 g/ml for E50.
It is seen that E5 dispersion has a better release profile as
compared to E15 and E50. Further increasing the polymer
content in SD does not show slowing of the drug release
as seen in non-sink conditions. Overall, after the samples
are kept in stability, the release profile is decreased in both
sink as well as non-sink conditions.
FENO-PVP SD follows same trend as FENO-HPMC
SD. In blank FaSSIF with SLS, Figure 16 PVP K12 shows
better release when compared to PVP K29. PVP K12
shows 100% release in contrast to 90% release of PVP
K29 at 10% drug loading. However, when these disper-
sions were tested in FaSSIF, Figure 17, PVP K12, release
is slow as compared to PVP K29. At 25% drug load-
ing, K12 shows only 19% release, and at the same time,
K29 shows 40% drug release. As we increase the polymer
content, the drug release increases up to 10% w/w drug
loading; increasing the polymer content further does not

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Figure 15. Comparison of dissolution profiles of FENO SD, PM and 6 weeks stability samples using various HPMC polymers at
different drug loading in FaSSIF.
show much change in the release profile. With regard to
stability, PVP SD shows a slowing of the drug release
due to crystallization of the FENO, which was also shown
by MDSC.
Figure 16. Comparison of dissolution profiles of FENO SD, PM and 6 weeks stability samples using various PVP polymers at
different drug loading in blank FaSSIF with 1% SLS.
Particle Size
The particle size of FENO-SD is given in Table VI. FENO
has a mean particle size of 16.69 g ± 0.03 g. In gen-
eral the particle size was reduced to a certain extent in

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Figure 17. Comparison of dissolution profiles of FENO SD, PM and 6 weeks stability samples using various PVP polymers at
different drug loading in FaSSIF.
FENO SD. Since the parameters used for spray drying was
same, there is little difference in the particle size of differ-
ent drug loaded dispersions. FENO is known for increasing
its solubility on the reduction of the particle size to nano-
crystal range (Zuo et al., 2013). However, spray dried dis-
persion does not reduce particle size in nano range; there
is only a slight reduction of particle size as compared to
the pure drug, and hence, the difference in release pattern
and stability of solid dispersion in different solid disper-
sion formed is due to the polymer itself.
SUMMARY
In this study, two types of experiments are performed on
FENO: non-formulated drug and formulated drug. In non
formulated drug, two methods have been used: solvent
shift method and solvent casting method. In these method
ability to attain and maintain supersaturation in presence of
different molecular weight PVP and HPMC was studied.
The solvent casts prepared were subjected to drug release
testing and were also stored at elevated temperature and
Table VI. Mean particle size of FENO-SD.
25% 10% 5%
Particle Particle Particle
size size size
( g) ( g) ( g)
Polymer (n = 3) Stdev (n = 3) Stdev (n = 3) Stdev
PVP K12 18.41 0 17 15.17 0.12 15.09 0.09
PVP K29 17.90 17 75 12.40 0.01 16.33 0.98
HPMC E5 14.34 0 03 13.46 0.02 13.53 0.08
HPMC E15 14.43 0 07 13.79 0.02 13.96 0.05
HPMC E50 14.43 0 19 13.53 0.02 13.77 0.25
humidity. In formulated drug, solid dispersions were pre-
pared using different molecular weight PVP and HPMC.
Solid dispersions were prepared at 25%, 10% and 5% w/w
drug loading. These dispersions were also subjected to ele-
vated temperature and humidity. Physical characterizations
like mDSC, IR, PXRD and dissolution studies were per-
formed on these dispersions.
CONCLUSION
In this study we examined the anti-precipitant effect of
polymers using the solvent shift and the solvent casting
method. PVP and HPMC were able to generate supersat-
uration in simulated intestinal fluid by the solvent shift
method. However, the rapid crystallization tendency lim-
its the stabilization of the supersaturated solution when
FENO concentration drops below saturation solubility at
the end of experiment. The polymers were able to main-
tain a supersaturated state of FENO by the solvent casting
method. PVP K29 and HPMC E5 casts showed immedi-
ate drug release as compared to other grades used in their
respective categories. HPMC E5 shows superior results
as compared to PVP K29. However, these casts are vul-
nerable to elevated temperature and humidity. HPMC E5
casts show better stability than the other polymers used.
Spray dried dispersions of these polymers were prepared.
Although there are many factors, like inlet temperature,
flow rate, solvent selection, drying gas flow rate, nozzle
size and feed concentration that affect the properties of
spray dried dispersions, we tried to minimize the variations
by adjusting the fixed inlet temperature, drying gas, flow
rate constant and feed concentration to obtain product.
Analysis revealed that FENO is converted to an amorphous
form at 10% w/w and below drug loading. DSC analysis

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
revealed that 5% w/w, drug loaded HPMC SD was stable
even at 40 C and 75% RH. The SD prepared using PVP
shows immiscibility in storage. FTIR analysis revealed that
types of polymer and drug polymer ratios affect the amor-
phous nature of FENO. High viscosity polymer inhibits the
diffusion of FENO and increases stability. Non-sink media
used for dissolution gives a better correlation than sink
media in FENO dispersions. This study will help scientist
to understand the effect of the molecular weight of HPMC
and PVP on neutral drugs with very low water solubility.
Abbreviations
HPMC—Hydroxypropyl methyl cellulose
PVP—Polyvinylpyrrolidone
BCS—Biopharmaceutics classification system
FENO—Fenofibrate
NaH2PO4—Sodium dihydrogen phosphate
NaCl—Sodium chloride
NaOH—Sodium hydroxide
HCl—Hydrochloric acid
FaSSIF—Fasted state simulated intestinal fluid
DMSO—Dimethyl sulfoxide
HPLC—High performance liquid chromatography
SLS—Sodium lauryl sulfate
RH—Relative humidity
MDSC—Modulated differential scanning calorimetry
PXRD—Powder X-ray diffraction
FTIR—Fourier transform infrared spectroscopy
RT—Room temperature
DS—Degree of supersaturation
EGF—Excipient gain factor
PM—Physical mixture.
REFERENCES
Akhlaquer Rahman, M., Harwansh, R., Aamir Mirza, M., Hussain, S.,
and Hussain, A. (2011). Oral lipid based drug delivery system (LBDDS):
Formulation, characterization and application: A review. Current Drug
Delivery 8, 330–345.
Al-Nemrawi, N. K. and Dave, R. H. (2014). Formulation and charac-
terization of acetaminophen nanoparticles in orally disintegrating films.
Drug Delivery 1–10.
Alhalaweh, A., Andersson, S., and Velaga, S. P. (2009). Preparation of
zolmitriptan–chitosan microparticles by spray drying for nasal delivery.
European J. Pharm. Sci. 38, 206–214.
Bouchard, A., Jovanović, N., Hofland, G. W., Jiskoot, W., Mendes, E.,
Crommelin, D. J. A., and Witkamp, G.-J. (2008). Supercritical fluid
drying of carbohydrates: Selection of suitable excipients and process
conditions. European Journal of Pharmaceutics and Biopharmaceutics
68, 781–794.
Brittain, H. G. (2002). Effects of mechanical processing on phase com-
position. J. Pharm. Sci. 91, 1573–1580.
Cheng, Y., Ye, X., Huang, X. D. and Ma, H. R. (2006). Reentrant wet-
ting transition on surfactant solution surfaces. The Journal of Chemical
Physics 125, 164709.
Dave, R. H., Patel, A. D., Donahue, E., and Patel, H. H. (2012). To
evaluate the effect of addition of an anionic surfactant on solid dispersion
using model drug indomethacin. Drug Dev. Ind. Pharm. 38, 930–939.
Davis, A. F. and Hadgraft, J. (1991). Effect of supersaturation on mem-
brane transport: 1. Hydrocortisone acetate. Int. J. Pharm. 76, 1–8.
De Waard, H., Hinrichs, W. L. J., and Frijlink, H. W. (2008). A novel
bottom–up process to produce drug nanocrystals: Controlled crystalliza-
tion during freeze-drying. J. Controlled Release 128, 179–183.
Dinunzio, J. C., Brough, C., Hughey, J. R., Miller, D. A., Williams, III,
R. O., and Mcginity, J. W. (2010). Fusion production of solid dispersions
containing a heat-sensitive active ingredient by hot melt extrusion and
Kinetisol®
dispersing. European Journal of Pharmaceutics and Biophar-
maceutics 74, 340–351.
Friesen, D. T., Shanker, R., Crew, M., Smithey, D. T., Curatolo, W. J.,
and Nightingale, J. A. S. (2008). Hydroxypropyl methylcellulose acetate
succinate-based spray-dried dispersions: An overview. Molecular Phar-
maceutics 5, 1003–1019.
Gao, P. and Morozowich, W. (2006). Development of supersaturatable
self-emulsifying drug delivery system formulations for improving the oral
absorption of poorly soluble drugs. Expert Opinion on Drug Delivery
3, 97–110.
Gao, P., Guyton, M. E., Huang, T., Bauer, J. M., Stefanski, K. J., and
Lu, Q. (2004). Enhanced oral bioavailability of a poorly water solu-
ble drug PNU-91325 by supersaturatable formulations. Drug Dev. Ind.
Pharm. 30, 221–229.
Górniak, A., Wojakowska, A., Karolewicz, B., and Pluta, J. (2011). Phase
diagram and dissolution studies of the fenofibrate–acetylsalicylic acid
system. J. Therm. Anal. Calorim. 104, 1195–1200.
Guichard, J. P., Blouquin, P., and Qing, Y. (2000). A new formulation
of fenofibrate: Suprabioavailable tablets. Current Medical Research and
Opinion 16, 134–138.
Guivarc’h, P.-H., Vachon, M. G., and Fordyce, D. (2004). A new
fenofibrate formulation: Results of six single-dose, clinical studies of
bioavailability under fed and fasting conditions. Clinical Therapeutics
26, 1456–1469.
Guzman, H., T. M., Zhang Z., Ratanabanangkoon, P., Shaw, P.,
Gardner, C., Chen, H., Moreau, J., Almarsson, O., and Remenar, J.
(2004). A “spring and parachute” approach to designing solid celecoxib
formulations having enhanced oral absorption. AAPS J, T2189.
Guzmán, H. R., Tawa, M., Zhang, Z., Ratanabanangkoon, P., Shaw, P.,
Gardner, C. R., Chen, H., Moreau, J.-P., Almarsson, Ö., and Remenar,
J. F. (2007). Combined use of crystalline salt forms and precipitation
inhibitors to improve oral absorption of celecoxib from solid oral formu-
lations. J. Pharm. Sci. 96, 2686–2702.
Hadgraft, J. (1999). Passive enhancement strategies in topical and trans-
dermal drug delivery. Int. J. Pharm. 184, 1–6.
Hancock, B. C. and Zografi, G. (1997). Characteristics and significance of
the amorphous state in pharmaceutical systems. J. Pharm. Sci. 86, 1–12.
Heinz, A., Gordon, K. C., Mcgoverin, C. M., Rades, T., and Strachan,
C. J. (2009). Understanding the solid-state forms of fenofibrate—A spec-
troscopic and computational study. European Journal of Pharmaceutics
and Biopharmaceutics 71, 100–108.
Hugo, M., Kunath, K., and Dressman, J. (2013). Selection of excipient,
solvent and packaging to optimize the performance of spray-dried formu-
lations: Case example fenofibrate. Drug Dev. Ind. Pharm. 39, 402–412.
Keary, C. M. (2001). Characterization of METHOCEL cellulose ethers
by aqueous SEC with multiple detectors. Carbohydr. Polym. 45, 293–303.
Khougaz, K. and Clas, S.-D. (2000). Crystallization inhibition in solid
dispersions of MK-0591 and poly(vinylpyrrolidone) polymers. J. Pharm.
Sci. 89, 1325–1334.
Konno, H. and Taylor, L. S. (2006). Influence of different polymers on the
crystallization tendency of molecularly dispersed amorphous felodipine.
J. Pharm. Sci. 95, 2692–2705.

IP: 75.108.130.155 On: Mon, 30 May 2016 16:05:42
Lakshman, J. P., Cao, Y., Kowalski, J., and Serajuddin, A. T. M. (2008).
Application of melt extrusion in the development of a physically and
chemically stable high-energy amorphous solid dispersion of a poorly
water-soluble drug. Molecular Pharmaceutics 5, 994–1002.
Lipinski, C. A., Lombardo, F., Dominy, B. W., and Feeney, P. J. (1997).
Experimental and computational approaches to estimate solubility and
permeability in drug discovery and development settings. Advanced Drug
Delivery Reviews 23, 3–25.
Lynne S. Taylor, G. Z. (1997). Spectroscopic characterization of inter-
actions between PVP and indomethacin in amorphous molecular disper-
sions. Pharm. Res. 14, 1691–1698.
Moya-Ortega, M., Messner, M., Jansook, P., Nielsen, T., Wintgens, V.,
Larsen, K., Amiel, C., Sigurdsson, H., and Loftsson, T. (2011). Drug
loading in cyclodextrin polymers: Dexamethasone model drug. Journal
of Inclusion Phenomena and Macrocyclic Chemistry 69, 377–382.
Müller, R. H., Gohla, S., and Keck, C. M. (2011). State of the art of
nanocrystals—Special features, production, nanotoxicology aspects and
intracellular delivery. European Journal of Pharmaceutics and Biophar-
maceutics 78, 1–9.
Munson, E. J. (2009). Analytical techniques in solid-state characteri-
zation. Developing Solid oral Dosage Forms, edited by Qiu, Y. Y. C.,
Zhang, G. G. Z., Liu, L., Yu, L., Venkatramana Rao, and Porter, W.,
Academic Press, San Diego.
Murdande, S. B., Shah, D. A., and Dave, R. H. (2015). Impact of nanosiz-
ing on solubility and dissolution rate of poorly soluble pharmaceuticals.
J. Pharm. Sci. 104, 2094–2102.
Pan, X., Julian, T., and Augsburger, L. (2006). Quantitative measurement
of indomethacin crystallinity in indomethacin-silica gel binary system
using differential scanning calorimetry and X-ray powder diffractometry.
AAPS PharmSciTech. 7, E72–E78.
Pan, X., Julian, T., and Augsburger, L. (2008). Increasing the dissolution
rate of a low-solubility drug through a crystalline-amorphous transition:
A case study with indomethicin. Drug Dev. Ind. Pharm. 34, 221–231.
Patel, A. D., Agrawal, A., and Dave, R. H. (2013). Development of
polyvinylpyrrolidone-based spray-dried solid dispersions using response
surface model and ensemble artificial neural network. J. Pharm. Sci.
102, 1847–1858.
Patel, A. D., Agrawal, A., and Dave, R. H. (2014). Investigation of the
effects of process variables on derived properties of spray dried solid-
dispersions using polymer based response surface model and ensemble
artificial neural network models. European Journal of Pharmaceutics and
Biopharmaceutics 86, 404–417.
Peeters, J., Neeskens, P., Tollenaere, J. P., Van Remoortere, P.,
and Brewster, M. E. (2002). Characterization of the interaction of
2-hydroxypropyl- -cyclodextrin with itraconazole at pH 2, 4, and 7.
J. Pharm. Sci. 91, 1414–1422.
Peltonen, L. and Hirvonen, J. (2010). Pharmaceutical nanocrystals by
nanomilling: Critical process parameters, particle fracturing and stabi-
lization methods. J. Pharm. Pharmacol. 62, 1569–1579.
Raghavan, S. L., Schuessel, K., Davis, A., and Hadgraft, J. (2003). For-
mation and stabilisation of triclosan colloidal suspensions using super-
saturated systems. Int. J. Pharm. 261, 153–158.
Raghavan, S. L., Trividic, A., Davis, A. F., and Hadgraft, J. (2001).
Crystallization of hydrocortisone acetate: Influence of polymers. Int. J.
Pharm. 212, 213–221.
Rodríguez-Hornedo, N. and Murphy, D. (1999). Significance of control-
ling crystallization mechanisms and kinetics in pharmaceutical systems.
J. Pharm. Sci. 88, 651–660.
Ruben, A. J., Kiso, Y., and Freire, E. (2006). Overcoming roadblocks in
lead optimization: A thermodynamic perspective. Chemical Biology and
Drug Design 67, 2–4.
Sanganwar, G. P. and Gupta, R. B. (2008). Dissolution-rate enhancement
of fenofibrate by adsorption onto silica using supercritical carbon dioxide.
Int. J. Pharm. 360, 213–218.
Sauron, R., Wilkins, M., Jessent, V., Dubois, A., Maillot, C., and Weil, A.
(2006). Absence of a food effect with a 145 mg nanoparticle fenofibrate
tablet formulation. International Journal of Clinical Pharmacology and
Therapeutics 44, 64–70.
Serajuddin, A. T. M. (1999). Solid dispersion of poorly water-soluble
drugs: Early promises, subsequent problems, and recent breakthroughs.
J. Pharm. Sci. 88, 1058–1066.
Serajuddin, A. T. M. (2007). Salt formation to improve drug solubility.
Advanced Drug Delivery Reviews 59, 603–616.
Singh, A., Worku, Z. A., and Van Den Mooter, G. (2011). Oral formula-
tion strategies to improve solubility of poorly water-soluble drugs. Expert
Opinion on Drug Delivery 8, 1361–1378.
Stella, V. J. and Nti-Addae, K. W. (2007). Prodrug strategies to overcome
poor water solubility. Advanced Drug Delivery Reviews 59, 677–694.
Strickley, R. (2004). Solubilizing excipients in oral and injectable formu-
lations. Pharm. Res. 21, 201–230.
Thakuria, R., Delori, A., Jones, W., Lipert, M. P., Roy, L., and Rodríguez-
Hornedo, N. (2013). Pharmaceutical cocrystals and poorly soluble drugs.
Int. J. Pharm. 453, 101–125.
Van Den Mooter, G., Wuyts, M., Blaton, N., Busson, R., Grobet, P.,
Augustijns, P., and Kinget, R. (2001). Physical stabilisation of amorphous
ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Euro-
pean J. Pharm. Sci. 12, 261–269.
Vertzoni, M., Fotaki, N., Nicolaides, E., Reppas, C., Kostewicz, E.,
Stippler, E., Leuner, C., and Dressman, J. (2004). Dissolution media sim-
ulating the intralumenal composition of the small intestine: Physiological
issues and practical aspects. J. Pharm. Pharmacol. 56, 453–462.
Vogt, M., Kunath, K., and Dressman, J. B. (2008). Dissolution
enhancement of fenofibrate by micronization, cogrinding and spray-
drying: Comparison with commercial preparations. European Journal of
Pharmaceutics and Biopharmaceutics 68, 283–288.
Wang, R., Pellerin, C., and Lebel, O. (2009). Role of hydrogen bonding
in the formation of glasses by small molecules: A triazine case study.
J. Mater. Chem. 19, 2747–2753.
Yang, W., Tam, J., Miller, D. A., Zhou, J., Mcconville, J. T., Johnston,
K. P., and Williams III, R. O. (2008). High bioavailability from nebu-
lized itraconazole nanoparticle dispersions with biocompatible stabilizers.
Int. J. Pharm. 361, 177–188.
Yoshioka, M., Hancock, B. C., and Zografi (1995). Inhibition of
indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates.
J. Pharm. Sci. 84, 983–986.
Yun, H.-Y., Lee, E., Chung, S., Choi, S.-O., Kim, H., Kwon, J.-T., kang,
W., and Kwon, K.-I. (2006). The effects of food on the bioavailability of
fenofibrate administered orally in healthy volunteers via sustained-release
capsule. Clinical Pharmacokinetics 45, 425–432.
Zhou, D., Zhang, G. G. Z., Law, D., Grant, D. J. W., and Schmitt,
E. A. (2002). Physical stability of amorphous pharmaceuticals: Impor-
tance of configurational thermodynamic quantities and molecular mobil-
ity. J. Pharm. Sci. 91, 1863–1872.
Zuo, B., Sun, Y., Li, H., Liu, X., Zhai, Y., Sun, J., and He, Z. (2013).
Preparation and in vitro/in vivo evaluation of fenofibrate nanocrystals.
Int. J. Pharm. 455, 267–275.

Evaluating the Effects of Different Molecular Weights of Polymers in Stabilizing Supersaturated Drug Solutions and Formulations Using Various Methodologies of the Model Drug- Fenofibrate

More Related Content

What's hot (20)

Similar to Evaluating the Effects of Different Molecular Weights of Polymers in Stabilizing Supersaturated Drug Solutions and Formulations Using Various Methodologies of the Model Drug- Fenofibrate (20)

Evaluating the Effects of Different Molecular Weights of Polymers in Stabilizing Supersaturated Drug Solutions and Formulations Using Various Methodologies of the Model Drug- Fenofibrate