indo amorphous
TRANSCRIPT
-
8/4/2019 Indo Amorphous
1/13
-
8/4/2019 Indo Amorphous
2/13
when the drug is dissolved at a molecular level,
that is, when the drug forms one phase system
with polymer. In order to qualify as solid solution,
the drug/polymer system should satisfy the
following criteria:
(a) The mixtures of drug and polymer shouldshow single glass transition temperature.
(b) The drug should be present in amorphous
form.12,13
The improvement in bioavailability with solid
solution is primarily improvement in the dissolu-
tion rates and solubility due to the presence of
high-energy amorphous form.14 Comparing crys-
talline and amorphous solids, the three-dimen-
sional long range order that normally exists in a
crystalline material does not exist in the amor-
phous state. In other words, the amorphous solidshave macroscopic properties of a solid with the
microscopic structure of a liquid. By the virtue of
high internal energy, the amorphous solids
possess enhanced thermodynamic properties,
molecular motions, and chemical reactivity as
compared to crystalline solids.14
Since molecules in the amorphous state are
thermodynamically metastable as compared to
crystalline state, the potential for crystallization
during processing and storage is always present.
Hancock et al. have published extensive informa-
tion regarding the factors affecting stabilization of
amorphous state.1416 The critical factors affect-
ing stability of amorphous state are the Tg,hygroscopicity, purity and storage conditions.
The presence of moisture can show plasticization
effect and lower the Tg, which can increase theprobability of conversion of amorphous state to
crystalline state. The Tg of the drug can beincreased by adding polymers with high Tgvalues.In drug/polymer system, the stability of the
amorphous form primarily depends on criteria
such as drug and polymer interaction, viscosity of
polymer, and glass transition temperature of the
mixture.1719 The literature has shown thathigher glass transition temperature and higher
viscosity of polymers usually show superior
stability for the amorphous drug.14,15 The specific
interactions between drug and polymer are
important considerations for stabilization of the
amorphous formulation. Therefore the evaluation
and selection of polymer is a key factor in
developing solid solution.
For this study the hot-melt extrusion technology
was utilized to prepare solid solution of the poorly
water-soluble model drug. This technology employs
application of high shear and high temperature to
formulate solid solutions. This technology has
many advantages over traditional processing
techniques such as spray drying or coevaporation
which involves organic solvents. Some of the
important advantages are solvent free continuousprocess and relatively smooth scale-up.
The primary objective of this study was to
obtain stable solid solution of poorly water soluble
and low Tg model drug with water insoluble/ionicpolymer and water soluble/non ionic polymers.
The secondary objective was to evaluate perfor-
mance attributes of solid solutions as a function of
polymer-type and concentrations.
INM was selected as the poorly water-soluble
model drug and Eudragit EPO (EPO), polyvinyl-
pyrrlidonevinyl acetate (PVPVA), and polyvi-
nylpyrrolidone K30 (PVPK30) were selected ashydrophilic polymers.
MATERIALS AND METHODS
Materials
INM was purchased from Ria International LLC.
(Whippany, NJ). EPO was purchased from Rohm
America (Degussa Corporation, Parsippany, NJ).
PVPVA (Plasdone S630) was supplied by ISP
Corporation (Wayne, NJ) and PVP K30 was
purchased from BASF Corporation (FlorhamPark, NJ). All other chemicals used were of
analytical grade. The physicochemical proper-
ties of the drug and polymers used in the study are
tabulated in Table 1.
Methods
Preparation of Physical Mixtures
The drug and polymers were passed through a 60-
mesh screen and mixed thoroughly in a mortar
with pestle. These mixtures were further mixed inturbula mixer for additional 20 min. The different
ratios of drug to polymer prepared for the study
were: 30:70, 50:50, and 70:30.
Preparation of Melt Extrudates
Hot-melt extrusion was performed in Micro-18
twin screw corotating extruder (American Leis-
tritz Extruder Corporation, Somerville, NJ). The
extrusion barrel was divided in eight temperature
zones. The extrusion temperatures varied for
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008
STABILIZATION OF LOW GLASS TRANSITION TEMPERATURE INDOMETHACIN FORMULATIONS 2287
-
8/4/2019 Indo Amorphous
3/13
various polymers although they were kept above
Tgof the polymers. The extrusion screw speed waskept at 5560 rpm and K-Tron-automated gravi-
metric feeder was used to feed the material in melt
extruder at 56 g/min. The process parameters
such as motor load and melt pressures were
recorded for each formulation (Tab. 2). INM was
extruded with various polymers such as EPO,
PVPVA, and PVPK30 as binary mixtures at drug
to polymer ratios of 70:30, 50:50, and 30:70.
Milling of Hot-Melt Extrudates
The resultant extrudates were cooled on air
conveyor belt and milled using FitzMill1 Commi-
nutor (South Plainfield, NJ). The milling process
consisted of two passes, first pass with a sieve # 2
(sieve size 0.065 inch, coarse milling) and second
pass with a sieve # 1 (sieve size 0.033 inch, fine
milling).
Thermal Analysis
Thermal analysis was carried out using a SII 5200
DSC (TA Instruments, Newcastle, DE), equipped
with a liquid nitrogen-cooling accessory. Samples
(510 mg) were prepared in sealed pans. The
samples were scanned at a heating rate of 108C/
min. The data were treated mathematically using
the DSC 5200 Disk Station Analysis program.
Powder X-Ray Diffraction (PXRD)
The various samples were analyzed by PXRD
(Scintag Inc., Cupertino, CA) using Cu Karadiation to determine the crystalline or amor-
phous state of the drug in the melt extrudate. The
PXRD patterns were collected in the angular
range of 1< 2u< 408 in step scan mode (step width
0.028, scan rate 1 deg/min).
FT-IR Spectroscopy
These studies were helpful in elucidating the
interaction between the drug and polymers. IR
absorbance spectra were obtained using Perkin
Elmer, Spectrum GX series spectrometer
equipped with DTGS detector. The test solid
(0.81%) was mixed with KBr and analyzed using
the diffuse reflectance method. Fifty scans were
collected for each sample at a resolution of 4 cm1
over wave number region 4000400 cm1.
Solubility Studies
The solubility of the various melt extrudates were
performed in simulated gastric fluid (SGF) at
pH 1.5 (SGF) and simulated intestinal fluid at
pH 6.8 (SIF). An excess amount of formulation
was mixed with 20 mL of dissolution medium and
was shaken at ambient conditions in a mechanical
Table 1. PhysicoChemical Properties of the Drug and Polymers
PhysicoChemical Properties INM Eudragit EPO PVPVA PVPK30
Aqueous solubility Poorly soluble ($0.004 mg/mL) Soluble at pH
-
8/4/2019 Indo Amorphous
4/13
shaker. The solubility of drug was measured after
24 and 72 h. The UV spectroscopy was used to
determine the solubility of the drug in dissolution
medium at 316 nm.
Dissolution StudiesIntrinsic dissolution or constant surface area
dissolution was studied using a Woods apparatus.
About 100 mg of the powder was compressed in
Woods apparatus die ($diameter 0.8 cm) using a
Carver Press at 4000 psi pressure and a dwell time
of 10 s. Dissolution was performed using a USP
Dissolution Apparatus II (Distek Inc., North
Brunswick, NJ) connected to HP UVVis spectro-
photometer Model 8452 (Hewlett-Packard Co.,
Palo Alto, CA) with a 900 mL of SGF with pH 1.5
and simulated intestine fluid (SIF) with pH 6.8 as
dissolution mediums at 378
C and a paddle speed of50 rpm.
Stability Studies
The accelerated stability studies were conducted
to determine the effect of high temperature and
humidity on the physical stability of the drug in
various formulations. The hot-melt extrudates
with various polymers and the drug as is were
stored at 408C/75% RH for 3 months in open glass
vials. For comparison purpose these formulations
were stored at controlled room temperature in
closed vials. Various analytical methods such asDSC, PXRD, and intrinsic dissolution studies
were used to access the stability of the formula-
tion.
RESULTS AND DISCUSSION
Evaluation of HME Process
The critical process parameters for various for-
mulations are listed in Table 2. The extrusion
temperature gradient, feed rate, and screw speed
were input parameters and motor load and meltpressures were output parameters. The extrusion
temperatures were dependent on glass transition
temperatures (Tg) of the polymers and thetemperature gradient across the barrel were kept
constant for each drug/polymer systems. The
extrusion temperatures were below the melting
point of INM. Feed rate and screw speed were kept
constant at 56 g/min and 5560 rpm, respec-
tively, for all formulations to ensure a constant fill
and shear in the extruder.20 Thus, motor load and
melt pressure were dependent on molecular mass
and viscosity of polymer and drug polymer
interactions.
The binary mixture with drug and polymer ratio
30:70 showed higher motor load and melt pressure
as compared to 50:50 and 70:30. Increasing the
concentration of drug decreased the motor loadand melt pressure, indicating a reduction in
viscosity of the polymer due to solubilization of
the drug. Since the molecular mass of EPO is
higher as compared to PVPVA and PVPK30
(Tab. 1), formulations with EPO showed higher
motor load.
Thermal Analysis
DSC was carried out to determine glass transition
temperature of the melt extrudates.
The crystalline INM showed an endotherm at
1658C and amorphous INM after heating and
quenching showed a glass transition temperature
(Tg) at 428C. EPO, PVPVA, and PVPK30 areamorphous in nature and showed Tg at 45, 109,and 1628C, respectively.
In case of melt extrudates with EPO, a single Tgwas observed suggesting the formation of solid
solution that is one phase system. However, the Tgof melt extrudate increased as a function of drug
concentration suggesting an antiplasticization
effect due to intermolecular interaction between
INM and EPO21 (Fig. 1). A similar effect was
observed with regards to the effect of temperatureon viscosity for INM and EPO system.22 Since
EPO is cationic and INM is a weak acid, a
potential for ionic interaction exists between
them23, however, no experimental evidence could
be obtained to confirm this hypothesis.
In case of melt extrudates with PVPVA and
PVP K30, a single Tg was observed indicatingformation of solid solution that is drug and
polymers were present in a one phase system.
INM acted as plasticizer for PVPVA and PVP
K30 and the Tgof melt extrudates were in between
the pure drug and pure polymers (Fig. 1).
Powder X-ray Diffraction Studies
Powder X-ray diffraction (PXRD) is an essential
technique in studying the crystalline or amor-
phous nature of the drug in solid solutions. The
PXRD for INM showed distinctive peaks at 10, 12,
13, 17, 19, 20, 21, 22, 23, 24, 27, and 29 degrees
indicating its crystalline nature as shown in
Figure 2. This figure also compares the corre-
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008
STABILIZATION OF LOW GLASS TRANSITION TEMPERATURE INDOMETHACIN FORMULATIONS 2289
-
8/4/2019 Indo Amorphous
5/13
sponding PXRD of the INM, physical mixture, and
melt extrudate with EPO. The presence of drug
peaks in PXRD of physical mixture indicated
crystalline nature of the drug while absence of
peaks in melt extrudate suggested amorphous
nature of the drug in the melt extrudate.
Melt extrudates with various ratios of drug/
EPO, drug/PVPVA, and drug/PVPK30 showed
the absence of drug peaks, which indicated that
INM was present in an amorphous form (Fig. 3).
This observation further supported thermal ana-
lysis in confirming the formation of solid solution
of the drug with these polymers.
Based on thermal analysis and PXRD, it was
confirmed that INM formed one phase system
with these polymers and drug was present in
high-energy amorphous form.
FT-IR Studies
FT-IR studies were performed on various melt
extrudates to elucidate interactions between INM
and polymer and to confirm the crystalline or
amorphous nature of drug in the melt extrudate.
The crystalline INM showed strong CO bond
stretch at 1718 and 1692 cm1.When the INM was
converted to the amorphous form the C O bond
stretch shifted to 1709 and 1683 cm1.
The FT-IR studies of melt extrudates with EPO,
PVPVA, and PVPK30 showed the presence of
amorphous INM; however, there was no evidence
of interaction between drug and polymers.
Solubility Studies
INM is a weak acid (pKa 4.5) and shows pH-
dependent solubility. The INM solubility
increases with the increase in pH.22 The EPO is
cationic polymer and is soluble at pH less than 4
but permeable at higher pH. The PVPVA and
PVPK30 are nonionic polymers and has pH-
independent solubility. Therefore the solubility
studies were performed in two different pH
conditions: SGF pH 1.5 and phosphate buffer
SIF pH 6.2. The drug solubility from the various
formulations in SGF and SIF are shown in
Table 3.
The pure drug has negligible solubility in SGF,
however, shows a solubility of 1.06 mg/mL in SIF.
The melt extrudates with EPO showed
increased solubility in SGF. The increase in
solubility was dependent on EPO concentration.
The higher amount of EPO in the melt extrudate
increased the drug solubility in SGF. The melt
extrudate with drug to EPO ratio of 30:70 showed
significant increase in solubility compared to puredrug and 320-fold increase in solubility compared
to corresponding physical mixture after 72 h
(Tab. 3). The melt extrudates with drug to EPO
ratio of 70:30 and 50:50 showed lower solubility at
72h ascompared to 24h. Asshown in Figure 4 the
decrease in solubility may be attributed to the
partial conversion of amorphous drug to crystal-
line form in SGF at 72 h. However, there was no
change in solubility for 30:70 formulation even
after 72 hours suggested that amorphous drug
Figure 1. Phase diagram of melt extrudates with
EPO, PVPVA, and PVPK30. [Color figure can be seen
in the online version of this article, available on the
website, www.interscience.wiley.com.]
Figure 2. PXRD comparing INM, physical mixture,
and melt extrudate with EPO (drug:polymer 50:50).
[Color figure can be seen in the online version of this
article, available on the website, www.interscience.
wiley.com.]
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008 DOI 10.1002/jps
2290 CHOKSHI ET AL.
-
8/4/2019 Indo Amorphous
6/13
showed superior stability at high polymer con-
centration.
As shown in Table 3, the improvement of the
drug solubility in melt extrudate with INM/EPO
in SIF was significantly lower as compared to
SGF. In addition, the increase in solubility was
inversely related to polymer concentration. This
can be attributed to the poor solubility of EPO and
good solubility of the drug in SIF rather than the
instability of the amorphous form. This was
further confirmed by PXRD.The melt extrudates with PVPVA and PVPK30
did not show any significant improvement in
solubility in SGF indicating the instability of
amorphous form. The conversion of amorphous
form to crystalline form was confirmed by PXRD of
excess solids after 24 and 72 h (Fig. 5).
The melt extrudates with PVPVA and PVPK30
showed significant increase in solubility in SIF at
24 h (from 20-folds to 30-folds). However, the
solubility decreased at 72 h suggesting conversion
of the amorphous form to crystalline form. The
observed increase in solubility was inversely
related to polymer concentration at 24 h, which
was attributed to the high viscosity at high
Figure 3. PXRD of various melt extrudates with (a)
EPO (b) PVPVA (c) PVPK30. [Color figure can be seen
in the online version of this article, available on thewebsite, www.interscience.wiley.com.]
Table 3. Solubility of Various Formulations in SGF
and SIF after 24 and 72 h
Formulation
Solubility in
SGF in mg/mL
Solubility in
SIF in mg/mL
24 h 72 h 24 h 72 h
Indomethacin N/A N/A 1.06 1.0
Formulation with EPO, PM, and HME (drug:polymer)
PM 70:30 0.05 0.02 0.45 0.54
PM 50:50 0.07 0.04 0.36 0.47
PM 30:70 4.71 0.12 0.18 0.19
HME 70:30 0.21 0.15 2.74 2.68
HME 50:50 6.52 0.14 0.77 1.99
HME 30:70 41.72 38.31 0.26 0.22
Formulation with PVPVA, PM, and HME
(drug:polymer)
PM 70:30 0.00 0.00 1.77 1.53
PM 50:50 0.00 0.00 2.37 2.16
PM 30:70 0.01 0.00 2.51 2.70HME 70:30 0.00 0.03 14.27 3.91
HME 50:50 0.01 0.01 33.22 5.44
HME 30:70 0.01 0.02 8.87 6.37
Formulation with PVPK30, PM, and HME
(drug:polymer)
PM 70:30 0.00 0.00 1.35 1.25
PM 50:50 0.00 0.00 1.65 1.54
PM 30:70 0.01 0.00 1.55 1.61
HME 70:30 0.00 0.02 38.55 4.28
HME 50:50 0.04 0.05 34.31 4.00
HME 30:70 0.1 0.29 19.39 4.98
N/A, could not be detected; PM, physical mixture; HME,hot-melt extrudate.
Figure 4. PXRD of the various melt extrudate with
EPO in SGF after 72 h. [Color figure can be seen in the
online version of this article, available on the website,
www.interscience.wiley.com.]
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008
STABILIZATION OF LOW GLASS TRANSITION TEMPERATURE INDOMETHACIN FORMULATIONS 2291
-
8/4/2019 Indo Amorphous
7/13
polymer concentration. Despite the conversion to
crystalline form, the equilibrium solubility from
melt extrudates was higher than the pure drug or
the corresponding physical mixtures. This may be
related to the stabilization of dissolved drug by the
polymer in the solution.
In summary, the melt extrudate with EPO
showed significant increase in solubility in SGF,
however, marginal increase was observed in SIF.
The high polymer concentration (EPO) helped in
stabilizing amorphous form of the drug even after
72 h during stability studies. On the contrary
PVPVA and PVPK30 did not show any signifi-
cant increase in solubility in SGF but these
formulations showed improved solubility in SIF.
However, the improved solubility could not bemaintained at 72 h.
Intrinsic Dissolution Studies
The intrinsic dissolution rates (IDR) of drug and
various formulations in SGF and SIF are sum-
marized in Table 4.
The IDR of the drug was 0.001 mg /cm2 min in
SGF, however, the dissolution rate increased by
40-folds in SIF.
The intrinsic dissolution profiles for melt
extrudate containing the drug and EPO are
shown in Figure 6. The thermal and PXRDanalysis of melt extrudate had shown that the
drug is present in amorphous form. Correspond-
ingly, the IDR of melt extrudates was found to be
significantly higher as compared to the pure drug
and the physical mixture in SGF. Furthermore,
the IDR were found to be dependent on polymer
concentration. The highest IDR was observed
with drug/EPO ratio of 50:50. The dissolution rate
increased by 2000-folds as compared to the pure
Figure 5. PXRD of the various melt extrudate with
PVPVA in SGF after 72 h. [Color figure can be seen in
the online version of this article, available on the web-
site, www.interscience.wiley.com.]
Table 4. Intrinsic Dissolution Rates for Various Formulations in SGF and SIF
Formulations IDR in mg/cm2 min in SGF IDR in mg/cm2 min in SIF
INM 0.0010.0005 0.040.01
Formulation with EPO, PM, and HME (drug:polymer)
PM 70:30 0.010.001 0.080.004
PM 50:50 0.060.01 0.050.002
PM 30:70 0.040.01 0.020.001
HME 70:30 1.470.04 0.010.002
HME 50:50 2.210.13 0.010.001
HME 30:70 1.790.21 0.010.002
Formulation with PVPVA, PM, and HME (drug:polymer)
PM 70:30 0.010.001 0.080.003
PM 50:50 0.010.001 0.170.01
PM 30:70 0.010.003 0.270.01
HME 70:30 0.010.001 0.940.16HME 50:50 0.010.002 1.130.19
HME 30:70 0.010.001 0.650.09
Formulation with PVPK30, PM, and HME (drug:polymer)
PM 70:30 0.0030.001 0.080.004
PM 50:50 0.010.003 0.140.01
PM 30:70 0.010.001 0.260.06
HME 70:30 0.010.002 1.040.05
HME 50:50 0.010.003 0.910.07
HME 30:70 0.010.003 0.300.01
PM, physical mixture; HME, hot-melt extrudate.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008 DOI 10.1002/jps
2292 CHOKSHI ET AL.
-
8/4/2019 Indo Amorphous
8/13
drug and 35-folds as compared to the correspond-
ing physical mixture (Tab. 4). The increase in IDR
was directly related to the EPO concentration up
to 50:50. The IDR was slightly lowered at higher
polymer concentration (70%), which could be
attributed to high polymer viscosity and thus
lower drug diffusivity (Tab. 4 and Fig. 6).
The dissolution profiles of melt extrudates
showed tendency to revert back to crystalline
form in SGF. This finding is consistent withliterature data where metastable amorphous form
has been shown to crystallize out from super-
saturated solution. For the drug/EPO formula-
tions, the conversion to crystalline form were
directly related to the polymer concentration. The
time to reversion increased with increase in the
polymer concentration. In spite of the reversion,
the equilibrium solubility of the drug in dissolu-
tion medium was higher than the pure crystalline
form.
The IDR of drug/EPO melt extrudate in SIF were
lower than the pure drug, despite the higher drug
solubility of the drug in SIF (Tab. 4). A decrease in
IDR from melt extrudate indicates that the drug is
bound to polymer and the low dissolution rate is due
to the insolubility of the polymer in SIF and not the
physical instability of INM.
The melt extrudates with PVPVA and PVPK30
did not show significant improvement in IDR as
compared to the pure drug and the correspondingphysical mixture in SGF (Tab. 4). The low
dissolution rate was attributed to the conversion
of amorphous drug to stable crystalline form
during the dissolution.
The melt extrudates with PVPVA and PVPK30
showed an improved IDR as compared to pure drug
and corresponding physical mixtures in SIF. In the
case of PVPVA, the melt extrudate at the ratio of
50:50 showed 28-folds higher IDR as compared to
the pure drug and 7-folds higher as compared to
Figure 6. Dissolution profile comparing various compositions of melt extrudates with
EPO in SGF. [Color figure can be seen in the online version of this article, available on
the website, www.interscience.wiley.com.]
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008
STABILIZATION OF LOW GLASS TRANSITION TEMPERATURE INDOMETHACIN FORMULATIONS 2293
-
8/4/2019 Indo Amorphous
9/13
the corresponding physical mixture (Tab. 4). In the
case of PVPK30, the melt extrudate at the ratio of
50:50 showed 23 fold higher IDR as compared to
the pure drug and 7 fold higher as compared to
corresponding physical mixture (Tab. 4). The
increasing polymer concentration showed decrease
in IDR (Figs. 7 and 8). Despite the similarity in
PVPK30 and PVPVA system, the different trends
were observed for IDR as a function of polymer
concentration. The PVPVA system showed an
increase in IDR up to 50% polymer concentration
followed by a decrease in IDR at 70% polymer
Figure 7. Dissolution profile comparing various compositions of melt extrudates with
PVPVA in SIF. [Color figure can be seen in the online version of this article, available on
the website, www.interscience.wiley.com.]
Figure 8. Dissolution profile comparing various compositions of melt extrudates with
PVPK30 in SIF. [Color figure can be seen in the online version of this article, available on
the website, www.interscience.wiley.com.]
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008 DOI 10.1002/jps
2294 CHOKSHI ET AL.
-
8/4/2019 Indo Amorphous
10/13
concentration. However, in the case of PVPK30,
IDR decreased as function of polymer concentra-
tion from 30% to 70 %. This can be attributed to
higher glass transition temperature and thus lower
drug mobility of the drug in PVPK30 system as
opposed to PVPVA system.
To confirm the physical stability of the INM
during dissolution, a small amount of surface
material was recovered and was analyzed by
PXRD. The melt extrudates with EPO at all ratios
showed the presence of amorphous drug in SGF
and SIF (Fig. 9). However, the drug in melt
extrudate with PVPVA and PVP K30 was
converted to crystalline form at the surface during
the dissolution studies (Fig. 10).
The solid solutions with EPO, PVPVA, and
PVPK30 showed improved dissolution rate due to
conversion to the high-energy amorphous form of
the drug. The amorphous INM in solid solutions
showed tendency to convert back to crystalline
form, which was dependent on dissolution media,
nature, and concentration of polymer.
Stability Studies
Stability studies were carried out to establish the
physical stability of the amorphous drug at the
accelerated conditions. All formulations were
stored at 408C and 75% relative humidity condi-
tions for 3 months in an open vial. Various
analytical techniques were used to monitor the
physical stability of the amorphous drug, such as
DSC, PXRD, and IDR studies.
After 3 months accelerated stability, the melt
extrudate of drug with EPO showed no depression
in glass transition temperature as compared to
the initial samples (Tab. 5). PXRD also confirmed
the amorphous nature of INM on stability. The
consistent solid-state properties after storage ataccelerated conditions suggest that amorphous
IND was stable in melt extrudate with EPO. This
was further confirmed by IDR studies showing
similar dissolution rates for initial and stability
samples (Tab. 6 and Fig. 11).
The melt extrudates with PVPK30 and PVPVA
stored at accelerated conditions displayed a
slightly lower glass transition temperature com-
pared to the initial samples (Tab. 5). That can be
attributed to the hygroscopic nature of the
Figure 9. PXRD of melt extrudates with EPO in SIF.
[Color figure can be seen in the online version of this
article, available on the website, www.interscience.
wiley.com.]
Figure 10. PXRD of melt extrudates with PVPK30 in
SGF. [Color figure can be seen in the online version of
this article, available on the website, www.interscience.
wiley.com.]
Table 5. Glass Transition Temperature Comparing
Initial and 3 Months 408C/75% RH Formulations
Formulations
Tg in 8C
Initial
Tg in 8C 3 Months
408C/75% RH
Formulation with EPO HME (drug:polymer)
HME 70:30 62.30.3 63.6 0.2HME 50:50 55.30.7 57.20.5
HME 30:70 45.90.5 47.80.6
Formulation with PVPVA HME (drug:polymer)
HME 70:30 59.40.7 58.80.4
HME 50:50 71.10.3 69.70.3
HME 30:70 80.80.9 76.50.6
Formulation with PVPK30 HME (drug:polymer)
HME 70:30 74.80.3 72.90.7
HME 50:50 92.90.6 90.20.9
HME 30:70 115.20.8 110.50.8
HME, hot-melt extrudate.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008
STABILIZATION OF LOW GLASS TRANSITION TEMPERATURE INDOMETHACIN FORMULATIONS 2295
-
8/4/2019 Indo Amorphous
11/13
polymer. However, PXRD confirmed the amor-
phous nature of the drug in stability samples. The
IDR after 3 months storage at accelerated
condition were similar to that of initial formula-
tions with lower concentration of polymer that is
drug to polymer ratio of 70:30 and 50:50 (Tab. 6).
However, the formulation with higher amount of
polymer (30:70) showed slight decrease in IDR in
SIF (Tab. 6, Figs. 12 and 13). The observed
decrease in IDR for 30:70 ratio was 1.6-fold and
15-folds for PVPVA and PVPK30 system, respec-
tively. This could be attributed to the hygroscopic
nature of the polymer. The higher concentration of
polymer will absorb more water and hence less
protection is provided to the amorphous drug.
To further evaluate this hypothesis, the moisture
content of stressed samples was determined by Karl
Fischer technique. As shown in Figure 14, the melt
extrudates with higher amount of polymer tend to
absorb more water, thus mediating the conversion
of amorphous drug to crystalline form.
Furthermore, PVPK30 system showed biphasic
dissolution profile. During the dissolution 1.8-fold
decrease in IDR (from 0 to 40 min and 4080 min)
was observed for both initial and stability sample
(Fig. 13). This observed decrease in dissolution
Table 6. IDR Comparing Initial and 3 Months 408C/75% RH Formulations in SGF
and SIF
Formulations IDR in mg/cm2 min Initial
IDR in mg/cm2 min
3 Months 408C/75% RH
Formulation with EPO HME in SGF drug:polymer
HME 70:30 1.470.04 1.520.12HME 50:50 2.210.13 2.130.21
HME 30:70 1.790.21 1.630.06
Formulation with PVPVA HME in SIF drug:polymer
HME 70:30 0.940.16 0.920.01
HME 50:50 1.130.19 1.090.16
HME 30:70 0.650.09 0.420.06
Formulation with PVPK30 HME in SIF (drug:polymer)
HME 70:30 1.040.05 1.100.11
HME 50:50 0.910.07 0.980.17
HME 30:70 0.300.01 0.020.01
HME, hot-melt extrudate.
Figure 11. The dissolution profile comparing initial
and 3 months 408C/75% RH melt extrudate with EPO in
SGF. [Color figure can be seen in the online version of
this article, available on the website, www.interscience.
wiley.com.]
Figure 12. The dissolution profile comparing initial
and 3 months 408C/75% RH melt extrudate with PVP
VA in SIF. [Color figure can be seen in the online version
of this article, available on the website, www.
interscience.wiley.com.]
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008 DOI 10.1002/jps
2296 CHOKSHI ET AL.
-
8/4/2019 Indo Amorphous
12/13
rates suggested that the rate-controlling mechan-
ism is consistent for both samples but different
from storage-mediated changes. This could be due
to differential dissolution rate of drug and
polymers resulting in drug-enriched surface layer
during dissolution.
SUMMARY AND CONCLUSION
The hot-melt extrusion was proven to be efficient
technology to formulate and stabilize the solid
solutions of low Tg model drug INM with theselected polymers such as EPO, PVPVA, and
PVPK30.
The drug formed one phase system that is solid
solution with EPO, PVPVA, and PVPK30 and
was found to be present in amorphous form at
various ratios.
The IDR and solubility were significantly
improved in case of solid solution that was
attributed to the high-energy amorphous form
of the drug. Although, melt extrudates with EPO
showed comparatively lower glass transition
temperature, these formulations showed superiorstability. Higher amounts of EPO in the formula-
tions facilitated stabilization of the amorphous
form of the drug. The melt extrudates with PVP
VA and PVPK30 showed higher glass transition
temperatures, however, these formulations were
more susceptible to conversion during dissolution
or storage stability.
In conclusion, the solid solutions improved the
solubility and IDR of the poorly water-soluble
model drug. The glass transition temperature was
Figure 13. The dissolution profile comparing initial and 3 months 408C/75% RH melt
extrudate with PVPK30 in SIF. [Color figure can be seen in the online version of this
article, available on the website, www.interscience.wiley.com.]
Figure 14. The moisture content of the melt extru-
dates comparing initial and stability samples. [Color
figure can be seen in the online version of this article,
available on the website, www.interscience.wiley.com.]
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008
STABILIZATION OF LOW GLASS TRANSITION TEMPERATURE INDOMETHACIN FORMULATIONS 2297
-
8/4/2019 Indo Amorphous
13/13
not the only factor determining the stability of the
formulations but also nature and concentration of
polymer played a vital role in stabilizing the
amorphous nature of the drug.
Thus, the model drug with low Tg such as INM(428C) can be stabilized by the appropriate
selection of polymer and concentration.
REFERENCES
1. Lipinski CA, Lombardo F, Dominyl BW, Feeney PJ.
1997. Experimental and computational approaches
to estimate solubility and permeability in drug dis-
covery and development settings. Adv Drug Deliv
Rev 23:325.
2. Atkinson RM, Bedford C, Child KJ, Tomich EG.
1962. The effect of griseofulvin particle size on blood
levels in man. Antibiot chemother 12:232238.
3. Charman WN. 2000. Lipids, lipophilic drugs, and
oral drug deliverysome emerging concepts. J Pharm Sci 89:967978.
4. Ford JL. 1986. The current status of solid disper-
sion. Pharm Acta Helv 61:6988.
5. Serajuddin ATM. 1999. Solid dipserison of poorly
water soluble drugs: Early promises, subsequent
problems, and recent breakthroughs. J Pharm Sci
88:10581066.
6. Dittgen M, Fricke S, Gerecke H, Osterwals H. 1995.
Hot spin mixing: A new technology to manufacture
solid dispersions. Pharmazie 50:225226.
7. Jung J, Yoo S, Lee S, Kim K, Yoon D, Lee K. 1999.
Enhanced solubility and dissolution rate of intra-
conazole by solid dispersion technique. Int J Pharm187:209218.
8. Sekikawa H, Arita T, Nakano M. 1978. Dissolution
behavior and gastrointestinal absorption of pheny-
toin-polyvinylpyrolidone and dicumarol-beta-cyclo-
dextrin. Chem Pharm Bull 26:118126.
9. Sekikawa H, Fukyda W, Takada M, Ohtani K, Arita
T, Nakano M. 1983. Dissolution behavior and
gastrointestinal absorption of dicumarol from solid
dispersion systems of dicumarol-polyvinylpyrolidone
and dicumarol-beta-cyclodextrin. Chem Pharm Bull
31:13501356.
10. Nozawa Y, Mizumoto T, Higashide F. 1985. Roll-
mixing of formulation. Pharm Acta Helv 60:175177.
11. Nozawa Y, Mizumoto T, Higashide F. 1986. Improv-ing dissolution rate of practically insoluble drug
kitasamycin by forcibly roll mixing with additives.
Pharm Ind 8:967969.
12. Goldberg AH, Gibaldi M, Kanig JL. 1965. In-
creasing dissolution rates and gastrointestinal
absorption of drugs via solid solutions and eutectic
mixtures I- theoretical considerations and dis-
cussion of the literature. J Pharm Sci 54:1145
1148.
13. Goldberg AH, Gibaldi M, Kanig JL. 1966. Increas-ing dissolution rates and gastrointestinal absorp-
tion of drugs via solid solutions and eutectic
mixtures IIExperimental evaluation of eutectic
mixtures: Urea-acetoaminophen system. J Pharm
Sci 55:482487.
14. Hancock BC, Zografi G. 1997. Characteristics and
significance of the amorphous state in pharmaceu-
tical systems. J Pharm Sci 86:112.
15. Hancok BC, Shamblin SL, Zografi G. 1995. Molec-
ular mobility of amorphous pharmaceutical solids
below their glass transition temperatures. Pharm
Res 12:799806.
16. Andronis V, Zografi G. 1998. The molecular mobi-
lity of supercooled amorphous Indomethacin as afunction of temperature and relative humidity.
Pharm Res 15:835842.
17. Taylor LS, Zografi G. 1997. Spectroscopy character-
ization of interactions between PVP and indo-
methacin in amorphous molecular dispersion.
Pharm Res 14:16911698.
18. Matsumoto T, Zografi G. 1999. Physical properties
of solid molecular dispersions of indomethacin with
poly vinylpyrrolidone and poly (vinylpyrrolidone-
covinyl-acetate) in relation to indomethacin crystal-
lization. Pharm Res 16:17221728.
19. Breitenbach J. 2003. Two concepts, one technology,
controlled release and solid dispersion with MeltrexTM. In: Michael Rathbone, Jonathan Hadgraft,
Michael Roberts, editors. Modified release drug
delivery technology. New York, NY: Marcel,
Dekker, pp. 125134.
20. Ghebre-Sellassie I, Martin C. 2003. Pharmaceutical
extrusion technology. New York: Marcel, Dekker.
21. Painter PC, Coleman MM. 1997. Fundamentals of
polymer science, an introductory text. 2nd edition.
New York: CRC press.
22. Chokshi R, Sandhu HK, Iyer RM, Shah NH,
Malick AW, Zia H. 2005. Characterization of
physico-mechanical properties of indomethacin
and polymers to assess their suitability for hot-melt
extrusion processs as a means to manufacture soliddispersion/solution. J Pharm Sci 94:24632474.
23. OBrien M, McCauley J, Cohen E. 1984. Indometha-
cin. Anal Profiles Drug Sub 13:211238.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008 DOI 10.1002/jps
2298 CHOKSHI ET AL.