PHARMACEUTICAL TECHNOLOGY

Physicochemical Properties of the Amorphous Drug, Cast Films,

and Spray Dried Powders to Predict Formulation Probability of
Success for Solid Dispersions: Etravirine
ILSE WEUTS,1 FREDERIC VAN DYCKE,1 JODY VOORSPOELS,1 STEVE DE CORT,1 SIGRID STOKBROEKX,1 RUUD LEEMANS,1
MARCUS E. BREWSTER,1 DAWEI XU,2 BRIGITTE SEGMULLER,2 YA TSZ A. TURNER,3 CLIVE J. ROBERTS,3
MARTYN C. DAVIES,3 SHENG QI,4 DUNCAN Q.M. CRAIG,4 MIKE READING4
1
Chemical and Pharmaceutical Development, Johnson & Johnson, Beerse, Belgium
2
Analytical Development, Johnson & Johnson Pharmaceutical R&D, LLC, Raritan, New Jersey 08869
3
Laboratory of Biophysics and Surface Analysis, School of Pharmacy, University of Nottingham, University Park, Nottingham,
NG7 2RD, United Kingdom
4
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, United Kingdom

Received 31 January 2010; revised 23 April 2010; accepted 26 April 2010

Published online 22 June 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22242

ABSTRACT: Solid dispersion technology represents an enabling approach to formulate poorly

water-soluble drugs. While providing for a potentially increased oral bioavailability secondary to
an increased drug dissolution rate, amorphous dispersions can be limited by their physical
stability. The ability to assess formulation risk in this regard early in development programs can
not only help in guiding development strategies but can also point to critical design elements in
the configuration of the dosage form. Based on experience with a recently approved solid
dispersion-based product, Intelence1 (etravirine), a three part strategy is suggested to predict
early formulate-ability of these systems. The components include an assessment of the amor-
phous form, a study of binary drug/carrier cast films and the evaluation of a powder of the drug
and polymer processed in a manner relevant to the intended final dosage form. A variety of
thermoanalytical, spectroscopic, and spectrophotometric approaches were applied to study the
prepared materials. The data suggest a correlation between the glass forming ability and
stability of the amorphous drug and the nature of the final formulation. Cast films can provide
early information on miscibility and stabilization and assessment of processed powders can help
define requirements and identify issues with potential final formulations. 2010 Wiley-Liss, Inc.
and the American Pharmacists Association J Pharm Sci 100:260274, 2011
Keywords: solid dispersion; characterization; amorphous; etravirine; HPMC

INTRODUCTION in contemporary drug pipelines are thought to

The development of new pharmaceutical agents
is often confounded by their poor water solubility
which impacts a number of derivative properties
including poor dissolution rate.1,2 Inadequate solu-
bility or dissolution rate can significantly reduce both
the rate and extent of drug absorption deleteriously
affecting oral bioavailability. Several factors rooted
Correspondence to: Ilse Weuts (Telephone: 32-14-608205;
Fax: 32-14-607083; E-mail: iweuts@its.jnj.com)
Journal of Pharmaceutical Sciences, Vol. 100, 260274 (2011)
2010 Wiley-Liss, Inc. and the American Pharmacists Association
contribute to this overall decrease in drugability
including the manner in which drugs are discovered
and the chemically allowed space of the drug target.
As reviewed by Lipinski,1,3 high throughput screen-
ing has tended to select for compounds with lower
water-solubilities, higher lipophilicities and higher
molecular weights. Furthermore, many drug targets
have structure-activity relationship (SAR) require-
ments that do not overlap with properties known to
provide for good oral bioavailability resulting in poor
develop-ability and high attrition.4,5 While expanding
the chemical space of the target is the purview of
medicinal chemistry, pharmaceutical scientists can

260 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011

 PREDICTION OF FORMULATION PROBABILITY OF SUCCESS FOR SOLID DISPERSIONS
contribute to enlarging the oral drug bioavailability
space through the use of technologies that increase
apparent solubility and dissolution rate. A number
of approaches are available for increasing the
formulate-ability of BCS Class II compounds includ-
ing but not limited to complexation, micronization or
nanonization, use of cosolvents and structured lipid
systems.68 Solid amorphous dispersions provide a
unique opportunity in this regard.911 While theore-
tically of benefit in any number of situations, the
physical instability of solid amorphous dispersions
often conspires to limit their usefulness. Early
assessments of factors likely to impact on the
applicability of a dispersion based approach such as
stability, are important components in any develop-
ment program centered around such a formulation
concept. We suggest herein a three pronged approach
for assessing dispersion fitness using the recently
approved drug, Intelence1 (etravirine) as an illus-
trative example.
Etravirine (Fig. 1) is a novel second generation non-
nucleoside reverse transcriptase inhibitor (NNRTI)
which acts by molecularly blocking the viral reverse
transcriptase enzyme. It achieves this by preventing
the enzyme from converting its genetic material
(RNA) into proviral DNA and thus preventing
incorporation of the viral genome into the human
host cell.12,13 The physicochemical properties of
etravirine are challenging with regard to dosage
form configuration as indicated in Table 1. A variety
of technologies were screened to optimize bioavail-
ability, however most did not add significant value.
For example, oral dosing of a nanosuspension
resulted in negligible blood levels in dog. The best
enhancement of GI uptake was provided by systems
based on an amorphous drug substance and specifi-
cally, amorphous dispersions of the compound in a
glassy carrier.911,14,15
These initial screening elements were the inputs
for a development program to fabricate a viable
formulation for etravirine. In devising this program,
factors thought to contribute to, or detract from
success were posited. The philosophy adopted
included (1) a study of the pure amorphous drug
phase, (2) an evaluation of cast films of the drug and a
glassy polymer (HPMC), and (3) an assessment
Figure 1. Chemical structure of etravirine.
DOI 10.1002/jps
261
Table 1. Physicochemical and Solubility Properties of
Etravirine
Property Value
Molecular weight (g/mol) 435
Molecular formula C20H15BrN6O
Melting point 2608C (dec.)
log p >5
pKa (base) <3
S (water) 1 mg/mL
S (0.1 N HCl) 1 mg/mL
S (PEG400) 74 mg/mL
of powders prepared using scaled-down processes
simulating those likely to apply to the finished dosage
form. Thus, this communication examines the proper-
ties of amorphous etravirine,16 the characteristics of
solvent cast films containing the drug and HPMC and
assessments of the physical state of the drug and its
miscibility with the polymer as a function of drug/
polymer ratio in spray dried powders.15,1720 These
assessments required a number of appropriate
and complementary analytical methods such as
powder X-ray diffraction (XRD), infrared spectro-
scopy (IR), differential scanning calorimetry (DSC),
modulated temperature differential scanning calori-
metry (M-DSC) and solid state nuclear magnetic
resonance (SS-NMR). Imaging techniques such as
field emission gun-environmental scanning electron
microscopy (FEG-ESEM) and atomic force micro-
scopy (AFM)2123 allowed the spatial assessment of
pharmaceutical formulations with resolution up to
the nanometer scale.
EXPERIMENTAL
Materials
Etravirine (Fig. 1) was obtained from Janssen
Pharmaceutica (Beerse, Belgium). The hydroxypro-
pylmethyl cellulose (HPMC) was 2910 grade with a
viscosity of 5 mPa s and was purchased from Dow
Chemical (Plaquemine, LA). Amorphous etravirine
was prepared by cryomilling the crystalline drug
substance for 3 h at
1968C. Other methods such
as spray drying, freeze drying, and ball milling
were unsuccessful in generating stable amorphous
etravirine (data not shown). Stability was assessed
using FT-IR as described in the literature.16
Film Casting
A screening study found two useful solvent mixtures
including dichloromethane (DCM)-ethanol (80:20)
and various compositions of dimethylformamide
(DMF)-methanol (80:20, 50:50, and 40:60). Drug
and polymer (HPMC) were dissolved in the solvent
mixture of interest and the solutions were filtered and
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
262 WEUTS ET AL.
cast onto a Teflon plate (15 cm  15 cm). The solvent
was evaporated in a vacuum oven at between 85 and
1258C for several days until a constant weight was
obtained. Films were then subjected to M-DSC for
determination of Tg and the enthalpy of relaxation as
well as XRD for assessing crystallinity.
Spray-Dried Powders
Solid dispersions of various compositions were prepared
by spray drying on a laboratory scale instrument
(NIRO atomizer mobile minor, Soeberg, Denmark).
Etravirine and HPMC were dissolved in an organic
solvent mixture (dichloromethane (DCM)/ethanol),
after which the solvent was removed by spray drying.
A dual fluid nozzle with a diameter of 1 mm was
applied. Solutions were sprayed using a feed rate of
34 kg/h, an atomization pressure of 0.8 bars, an inlet
temperature of 1108C and an outlet temperature of
708C. These parameters were maintained for the
different dispersions. However, the solvent composi-
tion and the concentration of etravirine and HPMC
in the feed solutions varied (generating changes in
solvent evaporation rate and solution viscosity).
Powders with the following etravirine/HPMC ratios
(w/w) were prepared: 1:12, 1:9, 1:6, 1:5, 1:3, 1:2, 1:1,
1:0.5, 1:0.3, 1:0.1, and 0:1.
Physical mixtures were prepared by gently mixing
amorphous, cryomilled etravirine and spray dried
HPMC using a pestle and mortar. Powders with
the following etravirine/HPMC ratios (w/w) were
prepared: 1:3, 1:1, and 1:0.5.
Modulated Temperature Differential Scanning
Calorimetry (M-DSC)
The cast films or powder samples were analyzed using
a TGA Q-1000 MDSC (TA Instruments, Crawley, UK)
with a heating rate of 28C/min, an amplitude of
0.3188C and a period of 60 s. Standard aluminum DSC
pans (TA Instruments) were used without crimping.
Differential Scanning Calorimetry (DSC)
The assessment of the Tg of the amorphous etravirine
could most easily be performed using thermal
analysis without temperature modulation. The pow-
der was heated in the same pan type as for the M-DSC
measurements but higher heating rates were applied
(from 10 up to 1008C/min).
Powder X-Ray Diffraction Analysis (P-XRD)
P-XRD-analyses were performed on a Philips XPert
PRO MPD diffractometer PW3050/60 with a PW3040
generator (PANalytical, Almelo, The Netherlands).
The instrument is equipped with a Cu LFF X-ray tube
PW3373/10. The cast films or powders were applied to
a zero background holder and placed on a spinner
stage with a spinner revolution time of 1 s. For
quantitation of crystalline content including the
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
preparation of calibration curves, a sample holder
with a cavity of 16 mm diameter was implemented.
This methodology provided for improved robustness,
increased sensitivity and was less susceptible to
preferred orientation effects than the zero back-
ground holder. Bragg-Brentano geometry was
applied using monochromatic Cu Ka-radiation and
soller slits (0.04 rad) for the incident and diffracted
beam path. The instrument was operated at a voltage
of 45 kV and a current of 40 mA. The scan range was
from 3 to 508 2u with a step size of 0.028 and a counting
time of 60 or 100 s per step. Crystallinity was
estimated by constructing a standard curve in which
spray-dried powders of HPMC and crystalline etra-
virine were mixed with amorphous powders providing
a range from 0% to 100% crystalline content. The
peak area associated with the diffraction peak
between 8 and 108 2u (see Fig. 3b) was assessed as
a function of the percent crystalline content. There
was a good linear response (r  0.99) and low
variability (samples of the calibration curve were
measured in triplicate) at crystalline contents up to
approximately 30% or 40%. At higher crystalline
compositions, the linear fit of the data decreased and
variability increased. The limit of detection was
approximately 2% and the lower limit of quantitation
was approximately 6%.
Fourier-Transform Infra-Red Spectroscopy (FT-IR)
FT-IR spectra were measured using a Nicolet Nexus
670 FT-IR spectrometer (Thermo Fisher Scientific,
Waltham, MA) equipped with micro attenuated total
reflectance (microATR). Thirty two scans were taken
for each sample in the spectral range from 400 to
4000 cm
1 with a spectral resolution of 1 cm
1.
Fourier-Transform Raman Spectroscopy (FT-Raman)
The powders were transferred to a glass capillary cell
and spectra were recorded on a Nicolet FT-Raman
module (Thermo Fisher Scientific). 128 or 256 scans
were taken for each sample in the spectral range
from 100 to 4000 cm
1 with a spectral resolution of
4 cm
1.
Solid State-Nuclear Magnetic Resonance
Spectroscopy (SS-NMR)
The number of samples that were analyzed using this
technique was limited to the following: pure compo-
nents (Etravirine (both amorphous and crystalline)
and HPMC), solid dispersions (ratios 1:3, 1:1, and
1:0.5) and physical mixtures of the same ratios.
Solid-state carbon CP/MAS NMR data were collected
using a Bruker Avance 400 MHz widebore NMR
spectrometer equipped with a 4 mm MAS probe
(Bruker BioSpin Corporation, Billerica, MA), with
the Etravirine formulation samples spun at 5000 Hz
and a contact time of 3.5 ms at 258C. Measurements
DOI 10.1002/jps
 PREDICTION OF FORMULATION PROBABILITY OF SUCCESS FOR SOLID DISPERSIONS
of amorphous Etravirine and of its physical mixtures
with HPMC were performed at low temperature
(
508C), due to the thermal instability of the
amorphous state in these samples. Proton spin-
lattice relaxation times (T1 and T1r) were measured
as well.
Field Emission Gun Environmental Scanning Electron
Microscopy (FEG-ESEM)
The powders were sprinkled onto double sided carbon
attached to a standard SEM platform, and any excess
powder on the surface was removed by a stream of
nitrogen. The uncoated samples were studied using
a Philips FEI XL30 ESEM-FEG under a stream of
nitrogen gas. The vapor pressure was kept between
1.8 and 1.9 Torr to minimize interference. A low
accelerating voltage of 10 kV at a working distance of
10 mm and a beam current of 34 nA were employed.
Atomic Force Microscopy (AFM)
A small amount of powder was sprinkled on to the
surface of a thin layer of araldite glue. After 10 min,
excess powder was removed under a gentle stream of
nitrogen. Topographic height and phase images were
simultaneously obtained using tapping mode AFM
(TM-AFM) with a Nanoscope IIIa Multimode AFM
system equipped with either an E or J scanner (Veeco
InstrumentsTM, Santa Barabra, CA) in air. NP tips on
125 mm silicon cantilevers (Tap300, Budget SensorTM,
Sophia, Bulgaria) with a resonant frequency between
200 and 400 kHz were used. Scan rates between 1 and 2 Hz
were used to help minimize tip-sample interactions.
RESULTS
Amorphous Drug Substance
The availability and study of pure amorphous
etravirine would add value to the characterization
of solid dispersions by not only providing a standard
to assess drugpolymer mixtures but also as a tool to
gauge the nature of the formulation challenge and
suggest the best development options to address these
issues.2426 A number of approaches were attempted
to generate the amorphous material. Based on the
thermal lability some of these were not appropriate
for this compound such as those related to melting
and melt quenching. Spray-drying, ball milling,
freeze-drying, rapid precipitation and rapid solvent
evaporation (using a variety of conditions including
flash evaporation using hyper-DSC) all provided for
material containing significant crystalline content.
The amorphous material was ultimately prepared by
cryomilling (3 h at
1968C).16 The amorphous nature
of the material was confirmed by spectroscopic (FT-
IR, FT-Raman, SS-NMR) and thermal techniques
(DSC, M-DSC) as well as powder XRD. The IR- and
DOI 10.1002/jps
263
Raman-spectra clearly show a distinct spectrum for
the forms of interest in which the amorphous material
was characterized by the absence of sharp absorption
bands which are typical for crystalline systems.
The FT-IR spectra of cryomilled etravirine and the
crystalline polymorphic Forms I and II are shown in
Figure 2. Three regions where the different forms
demonstrate the greatest divergence in spectral
characteristics have been highlighted. Similarly,
peak broadening is observed in SS-NMR-13C-spectra
(data not shown). XRD-analysis showed the absence
of discrete diffraction peaks. A halo, typical for
materials that lack long range order, is observed.
The diffraction pattern of amorphous etravirine and
two of its crystalline forms are shown in an overlay in
Figure 3a and b. M-DSC-analysis indicates a glass
transition (Tg) at 998C however the Tg observed in
the reversible heat flow signal is accompanied by
recrystallization of the drug (exothermic event in the
irreversible and total heat flow signal). In order to
ensure that the phenomenon ascribed to the Tg
observed in the reversible heat flow is a true Tg and
not an artifact caused by a spurious deconvolution of
the total heat flow associated with the reversible and
nonreversible components, nonmodulated DSC mea-
surements were also performed. High heating rates
can inhibit kinetic phenomena such as cold crystal-
lization or delay them to higher temperatures.27
Figure 4 shows the DSC-curves that were recorded
at different heating rates. A Tg around 998C was
observed, supporting the assumption that the phe-
nomenon that was observed in the reversible heat
flow curve of the M-DSC, is the glass transition. The
anomalously high DCp at 1008C/min may be asso-
ciated with better differentiation of the glass transi-
tion and cold crystallization events which may
overlap at lower scanning rate.
The generated thermoanalytical data can shed
light on the stability of the amorphous phase (Tab. 2).
The Tg/Tm ratio for a variety of pharmaceutical glass
formers falls in a range of 0.720.79 and can provide a
general sense of glass fragility and the tendency to
crystallize.2833 This value is difficult to generate for
etravirine based on the fact that compound melting
occurs coincident with degradation. To estimate the
melting point, DSC experiments using high to very
high scanning rates were employed. These data
suggested a Tg/Tm of 0.69 which could suggest a
fragile system.28 The stability of the generated form
was next assessed. Anecdotal information found that
the amorphous material began to crystallize when
stored in open conditions at ambient temperature
in a few days. This was confirmed by a controlled
assessment using FT-IR to assess spectral changes as
a function of time. Even when the material was stored
at 308C below its glass transition temperature,
significant and rapid form conversion occurred.16
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
264 WEUTS ET AL.
Figure 2. FT-IR spectra (from top to bottom): cryomilled etravirine, etravirine poly-
morph II, and polymorph I.
DrugHPMC Cast Films
Screening studies were performed to select an optimal
common solvent from which drugpolymer (HPMC)
films could be cast.31 DCM-ethanol allowed for useful
films but only to a drug loading of 20% w/w. Above this
drugpolymer ratio, a crystalline component in the
glass was evident upon casting. Improved results
were found with DMF-methanol which allowed
amorphous films with up to a 70% w/w drug loading
to be prepared. This finding was interesting in that
even though the evaporation rate of this solvent
systems is likely to be lower than that of the DCM
ethanol mixture (based on the differences in solvent
vapor pressures) which would be expected to aid drug
crystallization, the solubility of the components in
the DMFmethanol solvent was higher, reducing the
extent of supersaturation and the crystallization
driving force. Films were therefore prepared using
this solvent at different drug and HPMC composi-
tions.31 The Tg varied as a function of drugpolymer
ratio suggesting that a higher polymer content
increased Tg (drug/polymer ratio 1:1; Tg 1068C,
1:2 ratio; Tg 1118C and 1:3 ratio; Tg 1148C). The
cast films were then evaluated using M-DSC to assess
the enthalpies of relaxation. The extent of relaxation
at three drug to polymer ratios namely 1:1, 1:2, and
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
1:3 was assessed (Tab. 3). As a function of annealing
temperature (i.e., storage temperature below Tg) and
time, the extent of relaxation varied consistent with
theory. Furthermore, the rank order suggested that
the higher the polymer content, the lower the extent
of relaxation and the greater the thermodynamic
stability. While devitrification appears to be disfa-
vored at higher polymer ratios, other kinetic factors
can drive drug crystallization.32 To assess these, XRD
was applied to the cast films and the approximate
extent of crystallization assessed (using a standard
curve). The conditions examined included storage
temperatures above the Tg such that crystallization
disconnected from relaxation could be studied. Within
the limitations of this method (see the Experimental
Section), a higher polymer content resulted in a
longer induction period when the films were stored
at Tg (Tab. 4) and on a lower crystalline content and
crystallization rate at temperature above their Tg.
These data point to the dramatic stabilizing effect of
the polymer when the drug is made amorphous by
film casting in HPMC in comparison to the cryomilled
(amorphous) API.
Processed DrugHPMC Powders
Drugpolymer powders prepared using the proces-
sing technique of interest were assessed. Powders
DOI 10.1002/jps
 PREDICTION OF FORMULATION PROBABILITY OF SUCCESS FOR SOLID DISPERSIONS 265

Figure 3. (a) Overlay of XRD-patterns of amorphous dispersions with different

etravirine/HPMC ratio (from top to bottom: etravirine/HPMC 1:3, 1:1, 1:0.5, amorphous
etravirine, spray-dried HPMC). (b) Overlay of XRD-patterns of partially amorphous
dispersions with different etravirine/HPMC ratio (from top to bottom: etravirine/HPMC
1:0.3, 1:0.1, etravirine polymorph II, polymorph I).

were prepared by spray-drying the drug at different
ratios (etravirine/HPMC) specifically: 1:12, 1:9, 1:6,
1:5, 1:3, 1:2, 1:1, 1:0.5, 1:0.3, 1:0.1, and 0:1 w/w (spray
dried HPMC). In addition, physical mixtures of the
drug and HPMC were also generated at ratios of 1:3,
1:1, and 1:0.5. Figure 5 shows an overlay of the
reversing heat flow curves of etravirine/HPMC
dispersions with varying drug/polymer ratio. All
the dispersions exhibit a single Tg that falls in
between the Tgs of the two dispersed components
(998C for etravirine and 1478C for HPMC), which
indicates that all the dispersions are at least partially
amorphous. Importantly, these data do not exclude
the presence of some crystalline etravirine in the
samples. In any case, the Tg was found to increase
with decreasing drug/polymer ratio which implies
that the composition of the amorphous phase is
dependent on the drug/polymer ratio. In Figure 6, the
measured Tg-values are plotted as a function of drug
concentration. The Tg changes with composition
especially in polymer rich dispersions. In the drug-
rich dispersions (greater than 1:1 drug/polymer) Tgs
in the range of the pure amorphous phase were
recorded and the changes in Tg as a function of

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
266 WEUTS ET AL.

Figure 4. DSC thermograms assessing Tg at different heating rates for cryomilled

(amorphous) etravirine.

composition were less dramatic. Figure 6 also gives be approximated by the SimhaBoyer rule:34
the theoretical Tg-values calculated using the
GordonTaylor equation.33 This relationship can be r1 Tg1
K
used to estimate the Tg in binary mixtures; however, r2 Tg2
this relationship gives accurate predictions only in
the case of ideal mixing, that is, when two conditions where r1 and r2 are the densities of the API and
are being met: both components are mixed at the the polymer. The Tg values and true densities for
molecular level (no phase separation) and mixing is etravirine and HPMC are 373 K (Tab. 2), 1.439 g/cm3
not accompanied by volume changes, that is, homo- (density of crystalline etravirine) and 413 K and
and heteromolecular forces are of equal strength. The 1.326 g/cm3 for HPMC. The density of amorphous
GordonTaylor equation is given as: etravirine was estimated as 0.95 that of the crystal-
line density based on the literature, resulting in a
w1 Tg1 Kw2 Tg2 value of 1.515 g/cm3.35
Tgmix
w1 Kw2
Table 3. The Extent of Relaxation (%) as a Function of
where w1 and w2 are the weight fractions of etravirine Annealing Temperature and Storage Time in Cast Films of
and HPMC and Tg1 and Tg2 are their glass transition Etravirine and HPMC
temperatures. Tg,mix is the glass transition tempera-
ture of the solid dispersion. K is a constant which can Drug/Polymer Drug/Polymer Drug/Polymer
Time (h) 1:1 (%) 1:2 (%) 1:3 (%)

Tg
25 K
Table 2. Thermal Properties Related to Amorphous 8 44 26 3.2
Etravirine and Itraconazole 24 49 40 5
170 54 48 11
Property Etravirine Itraconazole4042 570 61 52 22
Tg
35 K
Melting point 537 Ka 440.3 K 8 31 12 1
Glass transition temp. (Tg) 373 K 332.4 K 24 37 20 2
Heat capacity (Cp) at Tg 0.23 J/g K 0.43 J/g K 170 40 23 4
Enthalpy of fusion (DHfus) 100 J/ga 84.5 J/g 570 55 30 6
Tm/Tg 0.69 0.76 Tg
45 K
Activation energy of structural 905 kJ/mol 8 7 1 0
relaxation at Tg 24 11 4 0
Fragility parameter (m) 103 170 26 6 1
a
570 30 10 2
Melts with decomposition.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011 DOI 10.1002/jps
 PREDICTION OF FORMULATION PROBABILITY OF SUCCESS FOR SOLID DISPERSIONS 267

Table 4. The Extent of Crystallization (%) as a Function It is clear from Figure 6 that the experimental Tgs
of Temperature and Storage Time in Cast Films of deviate from the calculated values.
Etravirine and HPMC Figure 7 shows an overlay of the total heat
flow curves of the spray-dried dispersions with
Drug/Polymer Drug/Polymer Drug/Polymer
Time (h) 1:1 (%) 1:2 (%) 1:3 (%) different drug/polymer ratios. They illustrate that
once the temperature is above the Tg, etravirine
Tg 25 K crystallizes causing the observed exothermic event in
3 16 9 8
8 23 14 12
the DSC-curves. The data indicate that the barrier
24 30 22 18 to crystallization increases as the polymer load
96 31 30 30 increases, that is, crystallization takes place at higher
120 36 36 31 temperature.
144 38 36 31 Melting of etravirine takes place above 2008C
193 43 37 31
Tg 10 K
(temperature region not included in the graph)
3 4a <LOD <LOD and is accompanied by decomposition. Hence heats
8 7 4a <LOD of fusion had to be estimated by rapid scanning
24 12 7 5a techniques. As a consequence, the presence of
96 14 12 10 crystalline etravirine in the spray dried dispersions
120 23 14 10
144 24 15 12
cannot be accurately assessed by comparing the heat
193 25 16 12 of fusion in the dispersions to the crystallization
Tg enthalpy of the drug. The DSC-analyses, therefore,
3 <LOD <LOD <LOD suggest that the etravirine/HPMC materials consist
8 <LOD <LOD <LOD of one amorphous phase (only one Tg is measured for
24 3a <LOD <LOD
96 6 <LOD <LOD
the dispersions). Thermal analysis does not exclude
120 6 4a 3a the possibility that in addition to this amorphous
144 6 4a 3a phase, crystalline etravirine is present in the dis-
193 7 5a 5a persions. In the spray-dried powder, even at the
LOD, limit of detection. lowest assessed ratio (etravirine/HPMC 1:0.1), a
a
Estimated value (between the limit of detection and the limit of clear, single Tg is observed, suggesting that most
quantitation).
material is in the amorphous state. In order to assess
whether small amounts of crystalline drug substance
were present, other analytical techniques were

Figure 5. Overlay of reversing heat flow curves for etravirine/HPMC spray dried
formulations of different composition.

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
268 WEUTS ET AL.
Figure 6. Tg temperature-concentration profiles of
spray-dried powders of etravirine and HPMC (~ experi-
mentally determined values; & values calculated using the
GordonTaylor equation).
applied including powder XRD, FT-IR/FT-Raman,
and SS-NMR.
Figure 3a and b shows an XRD overlay of the
diffraction patterns of different dispersions. Only
the spray-dried powders with a drug/polymer ratio
of 1:0.1 and 1:0.3 exhibit discernable diffraction
Figure 7. Overlay of the total heat flow curves of etravirine/HPMC spray dried
powders at different compositions.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
patterns that are characteristic for crystalline etra-
virine (polymorph Form I). Even in these cases,
however, the XRD-patterns show only minor peaks
that are superimposed on a halo that originates from
the amorphous material present in the sample. These
XRD-analyses confirm the M-DSC-results, that is, the
1:0.3 and 1:0.1 formulations are predominantly
amorphous. FT-IR and FT-Raman analyses do not
indicate the presence of crystalline etravirine in any
of the dispersions. This suggests that these spectro-
scopic techniques are less sensitive than XRD in
detecting low levels of crystalline drug.
SS-NMR analysis was only performed on samples
containing an etravirine/HPMC ratio of 1:0.5, 1:1, and
1:3. The CP-MAS-13C-measurements supported the
conclusion that the drug was largely amorphous
in these samples.36,37 Specifically, proton T1 and T1r-
values were measured both for the drug and the
polymer (Tab. 5). The same was done for the physical
mixtures (PM) of amorphous (cryomilled) etravirine
and HPMC. In the solid dispersions, etravirine and
HPMC have similar T1 and T1r-values, pointing
to effective spin diffusion of the components and
miscibility. The physical mixtures on the other hand,
show a considerable difference in the 1H T1r-values of
drug and polymer, confirming the heterogeneous
nature of these materials.
Visualization techniques were also applied to better
characterize the spray-dried dispersions. Microscopic
images generated with FEG-ESEM (Fig. 8), indicate
that the dispersions consist of a mixture of spherical
structures which were found to be hollow after
focused ion beam scanning electron microscopy
(FIB-SEM) assessment. The size of these spheres
and the extent to which they have collapsed is
DOI 10.1002/jps
 PREDICTION OF FORMULATION PROBABILITY OF SUCCESS FOR SOLID DISPERSIONS
Table 5. Relaxation Parameters of the Etravirine/HPMC
Spray Dried Powders (SD) and Physical Mixtures (PM)
Measured with SS-NMR
1 1
H T1 (s) H T1r (ms)
Sample
Etravirine/HPMC Etravirine HPMC Etravirine
SD 1/0.5 1.43 1.47 14.72
SD 1/1 1.48 1.46 14.81
SD 1/3 1.39 1.34 16.85
PM 1/0.5 0.581 0.584 22.82
PM 1/1 0.538 0.552 24.08
PM 1/3 0.546 0.524 17.98
dependent on the etravirine/HPMC ratio and the
manufacturing process parameters. As mentioned
in the Experimental Section, solvent composition,
concentration of API and HPMC (and linked to this
viscosity) were variables that were not the same for
all prepared spray dried materials. It is well known
for instance that spray drying under wet conditions
(slow evaporation of the solvent) results in more
collapsed spheres. Temperature settings were kept
constant for the preparation of the samples but
the solvent composition was not. Having more or
less of the most volatile solvent present in this
case would relate to more or less wet conditions. In
addition, the feed solutions that were used had
different viscosities which impacts particle size. The
more viscous the feed, the larger the particles that
are formed. No particles with other morphologies
were observed.
In Figure 9, AFM images of etravirine powders,
ranging from high to low drug loading, are shown
both as 3D topography (odd numbered images) and
phase-based renderings (even numbered images).
The topography and phase images of the relatively
low polymer-loaded spray-dried powders, that is,
etravirine/HPMC 1:0.1 (i and ii) and 1:0.3 (iii and iv),
show distinct phase-separated areas and evidence
of some ordered crystalline material. The AFM-
analyses confirm the predominantly amorphous
nature of these samples which was established with
the techniques outlined above (M-DSC, FT-Raman,
FT-IR, and XRD). The AFM images also confirm the
presence of some crystalline drug as was suggested
by XRD. The spray-dried powder (drug/HPMC)
1:0.5 (v and vi) show some phase-separated domains
but no crystalline material. Powders containing 1:1 to
1:9 (drug/HPMC) (images viixvi) all show homo-
genous topography with no indication of phase-
separation or crystalline material.
DISCUSSION
The optimal development strategy for solid dis-
persions, in general, and the etravirine dispersion,
DOI 10.1002/jps
269
in particular, is best predicated using a number of
early, efficient, and predictive screening experiments.
These include, but are not limited to, those which
probe physical stability. To configure a suitable
roadmap, factors thought to contribute to, or detract
HPMC from stability need to be identified, assays need to be
developed and the aggregate information has to be
14.59
14.85 interpreted to provide an estimation of technical risk
15.86 as well as advice on the best excipients and processing
8.54 tools. The approach suggested herein includes three
7.82 evaluation elements including: (1) an assessment of
7.03
the pure amorphous phase, (2) an evaluation of
binary glasses cast from an appropriate solvent and
(3) the study of processed powders using down-scaled
production methods. The first component of this
roadmap assesses the enablement likely required to
generate a pharmaceutically relevant dispersion. The
properties of the amorphous glass and its impact on
the final dispersion depend on a number of factors
including the domain size in the dispersion and
miscibility, the possible molecular interaction of
the amorphous phase with the glassy carrier and
the mixing Tg systems and storage conditions.911,29
The greater the instability of the glass, the more
important these stabilizing factors become. The
data on etravirine presented here, as well as that
presented in the literature16 indicate that it is difficult
to form a glass and once the glass is formed it is
unstable even given its apparent high Tg and taking
the Tg
50 rule into account.38,39 It is interesting to
compare these properties with those of another
drug that has been marketed as a solid dispersion
or solution. Itraconazole, for example, can be easily
converted to an amorphous phase using any number
of techniques including melt quenching, spray
drying, lyophilization rapid precipitation, milling,
etc. (Tab. 2). Furthermore, even with a measured Tg
of 598C, the prepared amorphous phase is stable to
crystallization, even in open conditions for months to
years.4042 The stability of the amorphous form may
be suggested by its Tg/Tm value of 0.76 (compared to
0.69 for etravarine), its high energy of activation
for glassy to super-cooled liquid transition and by
analysis using WilliamsWatts formalism where
storage of the material at 308C below the Tg provide
for a t value of 245 days and when stored at 408C
below Tg a t value of 80 years was calculated.41,42
This stability is thought to be related to the ability of
itraconazole to form a chiral nematic mesophase
(i.e., a two dimensionally structured glass) and this
finding directly impacts dispersion robustness and
processing possibility.40,43,44 The practical conse-
quence of the relative stability of the itraconazole
amorphous phase is that a number of formulation
concepts can increase oral bioavailability relative to
the crystalline drug including those based on com-
plexation, bead coating, melt extrusion, spray-drying
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
270 WEUTS ET AL.

Figure 8. FEG-ESEM images of etravirine/HPMC 1:1 (a and b), etravirine/HPMC 1:3

(c and d), etravirine/HPMC 1:6 (e and f) and broken particles to demonstrate the hollow
nature of the spheres (g and h).

and even tableting the amorphous form per se.4550 By
contrast, the properties of etravirine strongly suggest
that the number of formulation options may be
limited and that stabilization of the amorphous phase
will be paramount to achieving success. The data
generated in this first part of the suggested roadmap
therefore triggers a number of additional early
screens and assessments.
The examination of a cast film provides insight
into general miscibility and compatibility and pro-
vides an easily testable, standardized matrix for
assessing thermal properties, enthalpic relaxation

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011 DOI 10.1002/jps
 PREDICTION OF FORMULATION PROBABILITY OF SUCCESS FOR SOLID DISPERSIONS 271

Figure 9. AFM-images of formulations etravirine/HPMC with ratios 1:0.1 (i and ii),

1:0.3 (iii and iv), 1:0.5 (v and vi), 1:1 (vii and viii), 1:2 (ix and x), 1:3 (xi and xii), 1:5 (xiii
and xiv), and 1:9 (xv and xvi).

(thermodynamic factors) and crystallization (kinetic
factors)/phase separation within certain limits.31
Studies on etravirine and HPMC films pointed to
the stabilizing effects of a HMPC-based dispersion on
the drug glass and that increasing the polymer
component increased the relative stability. This was
manifested by an increasing Tg as the drug/polymer
ratio decreases, meaning that molecular mobility
is reduced at a given storage temperature. The
measured values (see the Results Section) deviate
from the theoretical Tgs calculated using the
GordonTaylor equation. The deviation could
have several causes including limited miscibility or
phase separation.51,52 Having considered this, the
mixing Tgs, being intermediate between the Tgs of
HPMC and amorphous etravirine, suggested a drug/
polymer dispersion. Also, the fact that a discernable
Tg for HPMC was not present suggests that a pure
polymer phase was absent. Another cause for this
deviation may be the fact that the zero volume change
on mixing assumption is not met.51,52 Violation from
the free volume theory may be driven be differences
in molecular interactions such that the homo- and
heteromolecular associations are different.
A derivative parameter that can give insight into
dispersion stability is the extent of relaxation or the
degree to which the glass approaches its theoretical
equilibrium condition (DH1 lim(t!1)DH which can
be estimated by DH1 (Tg
T)DCp).29,53,54 Relaxa-
tion is assessed by annealing samples at different
storage temperatures below the Tg and then asses-
sing the change in relaxation enthalpy. Ordinarily
the enthalpy of relaxation increases with increasing
storage time and decreases with lower temperature in
a nonlinear fashion. The WilliamsWatts relation-
ship is a two parameter relationship (Ft 1
(DH/
DH1) exp
(t/t)b) that can suggest the time course
of the relaxation process allowing a prediction of
thermodynamic stability through the derived t (mean
relaxation time constant) value.11,55 Enthalpy of
relaxation measurements for etravirine in cast
HPMC films suggested that there was a dramatic
effect of polymer content and annealing temperature.
In the 1:3 drug/polymer glasses, the extent of
relaxation was 2%, 6%, and 22% after 24 days of
storage at 45, 35, and 258C below Tg, respectively. For
the same conditions in the 1:1 drug/polymer system,
these values were 30%, 55% and 61% demonstrating

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
272 WEUTS ET AL.
the stabilizing effect of the polymer, the reduced
molecular mobility and expected long t value.
However, it should be noted that thermodynamic
processes are only part of the picture and building a
dispersion only based on relaxation stability may be
inappropriate as the kinetic components may be more
important depending on the particular system of
interest.32 Kinetically, factors that impede crystal-
lization include vitrification of the amorphous drug in
the glassy polymer preventing the formation of a
crystalline lattice. In order to investigate this aspect
of dispersion stability, the rate and extent of crystal-
lization were assessed. This was conducted at
temperatures at, or above the Tg, a domain where
relaxation does not, theoretically, occur. These are
accelerated studies and the kinetic component of
crystallization from the dispersion may or may not
mimic that at ambient temperature, however these
approaches do provide a way to assess the effect of
polymer content in the cast films on induction time
and crystallization extent. These parameters were
estimated by preparing a standard curve for XRD
analysis. The data show that the 1:3 drug/polymer
systems crystallized more slowly than the 1:2 which
in turn was more stable than the 1:1 drug/polymer
dispersions. This is associated with the extent of
crystallization at the end of the experiments (200 h)
for the 1:3 systems measured at Tg, Tg 10 and
Tg 25 of 5% (96 h indication time), 12% (8 h
indication time) and 31% (crystalline detected at
the first sampling point), respectively. The compar-
able data for the 1:1 drug/polymer system was 7% (8 h
induction time), 25% and 43% (crystalline detected at
the first sampling point in the latter two cases) at Tg,
Tg 10 and Tg 25, respectively. These experiments,
based on the cast films, suggest that both thermo-
dynamic (by a reduction in the enthalpy of relaxation
with time) and kinetic (by reduced crystallization at
and above the Tg) contributions could be responsible
for the stabilization of the formed dispersions.32 It is
important to mention that while useful in screening
mode, the cast films can contain large amounts of
residual solvent significantly affecting the mixing
Tgs and related properties. This suggests that these
data should be used qualitatively to suggest trends in
drug stabilization. The advantage of this decision-
making element includes the fact that the approach
is fast, automatable in a 96-well format and
information-rich, however they should not be over-
interpreted.
To better assess the role of processing and to
provide a clearer view of the stability of the possible
formulation components, down-scaled techniques are
suggested to prepare powders for analytical scrutiny.
This last component of the evaluation roadmap is
important given that many amorphous dispersions,
even when containing the same excipients at the
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
same levels, often manifest different stability and
biopharmaceutical properties based on how they were
generated.56,57 Examples of down-scaled processes
include the use of film forming or mini-fluid bed
systems for coated bead systems, mini-extrusions for
melt extrusion and the use of mini-spray-driers for
this production technique. Similar to the approach
suggested in the case of the film study, data derived
from spray-dried powders indicated an increasing Tg
with increasing polymer content which was asso-
ciated with higher stability and lower crystalline
content (Figs. 5 and 6). As with the films, the data
deviated from GordonTaylor behavior suggesting
factors associated with homo- and heteromolecular
forces may be in play. Interestingly, the measured
Tgs were comparable for the 1:1 spray-dried
drug/polymer mixture (1078C vs. 1068C for the cast
film) but tended to be progressively higher in value
at the 1:2 (1138C (powder) vs. 1118C (film)) and
1:3 compositions (1188C (powder) vs. 1148C (film))
lending some credence to the proposition that
the processing technique could play a role in
dispersion structure and performance. Factors that
may be germane in this regard may include the
efficiency of solvent evaporation or the nature of
drugpolymer mixing, that is, domain size and drug
distribution.
CONCLUSIONS
Solid dispersions can allow for important drugs to
reach the market by overcoming biopharmaceutical
limitations imposed by NoyesWhitney and Ficks
First Law effects. Poor physical stability is one
factor that can limit the use of these potentially
enabling systems and whether this property impacts
dispersion applicability should be screened as early
in the development cycle as possible to increase
efficiency and probability of formulation success.
Three inputs are suggested in making these afore-
mentioned predictions including the stability and
characteristics of the pure amorphous phase, the
behavior of the amorphous drug when cast in films
containing a glassy carrier and when dispersed in a
polymer using a relevant process approach. The data
suggest that etravirine is a poor glass former and the
amorphous phase is unstable even given its high Tg.
By contrast, itraconazole manifests a much lower Tg
and yet forms a particularly stable amorphous phase.
While highly unstable as such, cast drug/HPMC films
resulted in a dramatic stabilization of amorphous
etravirine with high polymer contents yielding
progressively more stable dispersions. This informa-
tion may point to the fact that multiple dispersion
formulation are possible with itraconazole while only
the spray-dried dosage form provided good oral
DOI 10.1002/jps
 PREDICTION OF FORMULATION PROBABILITY OF SUCCESS FOR SOLID DISPERSIONS
bioavailability for etravirine (when compared to other
amorphous systems). The generation and study of
spray-dried powders allowed for a useful under-
standing of the formulation elements such that the
ultimate formulation could be optimally designed and
produced.
REFERENCES
1. Lipinski CA. 2000. Drug-like properties and the causes of poor
solubility and poor permeability. J Pharmacol Toxicol Methods
44:235249.
2. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 2001.
Experimental and computatorial approaches to estimate solu-
bility and permeability in drug discovery and development
settings. Adv Drug Deliv Rev 46:326.
3. Lipinski CA. 2001. Avoiding investment in doomed drugs. Curr
Drug Discov 1:1719.
4. Lipinski C, Hopkins A. 2004. Navigating chemical space for
biology and medicine. Nature 432:855862.
5. Lipinski CA. 2006. The anti-intellectual effect of intellectual
property. Curr Opin Chem Biol 10:380383.
6. Liu R. 2000. Water insoluble drug formulation. Interpharm
Press. Denver, CO.
7. Dressman J, Butler J, Hempenstall J, Reppas C. 2001. The
BCS: Where do we go from here? Pharm Tech 25:6876.
8. Brewster M, Loftsson T. 2007. Cyclodextrins as pharmaceutical
solubilizers. Adv Drug Deliv Rev 59:6456766.
9. Leuner C, Dressman J. 2000. Improving drug solubility for oral
delivery using solid dispersion. Eur J Pharm Biopharm 50:
4760.
10. Serajuddin AT. 1999. Solid dispersion of poorly water-soluble
drugs. Early promises, subsequent problems and recent break-
throughs. J Pharm Sci 88:10581066.
11. Hancock BC. 2002. Disordered drug delivery: Destiny,
dynamics and the Deborah number. J Pharm Pharmacol 54:
737746.
12. Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M,
Heeres J, Janssen P, De Corte B, Vingerhoets J, Pauwels R,
de Bethune MP. 2004. TMC125, a novel next-generation non-
nucleoside reverse transcriptase inhibitor active against non-
nucleoside reverse tgranscriptase inhibitor-resistant human
immunodeficiency virus type 1. Antimicrob Agents Chemother
48:46804686.
13. Vingerhoets J, Azijn H, Fransen E, De Baere I, Smeulders L,
Jochmans D, Andries K, Pauwels R, de Bethune MP. 2005.
TMC125 displays a high genetic barrier to the development
of resistance: Evidence from in vitro selection experiments.
J Virol 79:1277312782.
14. Habib MJ. 2000. Fundamentals of solid dispersions. In: Habib
MJ, editor. Pharmaceutical solid dispersion technology. Boca
Raton, FL: CRC Press. pp 736.
15. Craig DQM. 2002. The mechanisms of drug release from solid
dispersions in water-soluble polymers. Int J Pharm 231:131
144.
16. Qi S, Weuts I, De Cort S, Stokbroekx S, Leemans R, Reading M,
Belton P, Craig DQM. 2009. An investigation into the crystal-
lization behavior of an amorphous cryomilled pharmaceutical
material above and below the glass transition. J Pharm Sci
99:196208.
17. Shah B, Kakumanu VK, Bansal AK. 2006. Analytical techni-
ques for quantification of amorphous/crystalline phases in
pharmaceutical solids. J Pharm Sci 95:16411665.
18. Six K, Murphy J, Weuts I, Craig DQM, Verreck G, Peeters J,
Brewster M, Van den Mooter G. 2003. Identification of phase
DOI 10.1002/jps
273
separation in solid dispersions of Itraconazole and Eudragit1
E100 using microthermal analysis. Pharm Res 20:135138.
19. Bauer-Brandl A. 1996. Polymorphic transition of cimetidine
during manufacture of solid dosage forms. Int J Pharm 140:
195206.
20. Shi HG, Farber L, Michaels JN, Dickey A, Thompson KC,
Shekular SD, Hurter PN, Reynolds SD, Kaufman MJ. 2003.
Characterization of crystalline drug nanoparticles using
atomic force microscopy and complementary techniques.
Pharm Res 20:479484.
21. Zhang J, Ebbens S, Chen X, Jin Z, Luk S, Madden C, Patel N,
Roberts CJ. 2006. Determination of the surface free energy of
crystalline and amorphous lactose by atomic force microscopy
adhesion measurements. Pharm Res 23:401407.
22. Ward S, Perkins M, Zhang J, Roberts CJ, Madden CE, Luk SY,
Patel N, Ebbens SJ. 2005. Identifying and mapping surface
amorphous domains. Pharm Res 22:11951202.
23. Price R, Young PM. 2004. Visualization of the crystallisation of
lactose from the amorphous state. J Pharm Sci 93:155164.
24. Hancock BC, Zografi G. 1997. Characteristics and significance
of the amorphous state in pharmaceutical systems. J Pharm Sci
86:112.
25. Yu L. 2001. Amorphous pharmaceutical solids: Preparation,
characterization and stabilization. Adv Drug Deliv Rev 48:
2742.
26. Ping G. 2008. Amorphous pharmaceutical solids: Character-
ization, stabilization and development of marketable formula-
tions of poorly water soluble drugs with improved oral
absorption. Mol Pharm 5:903904.
27. Mathot VBF. 2001. New routes for thermal analysis and calori-
metry as applied to polymeric systems. J Therm Anal Cal 64:
1535.
28. Chawla G, Bansal AK. 2007. A comparative assessment of
solubility advantage from glassy and crystalline forms of a
water-insoluble drug. Eur J Pharm Sci 32:4557.
29. Crowley KJ, Zografi G. 2001. The use of thermal methods for
predicting glass-former fragility. Thermochim Acta 380:79
93.
30. Wang L, Angell CA, Richert R. 2006. Fragility and thermo-
dynamics in nonpolymeric glass-forming liquids. J Chem Phys
125:074505.
31. Verreck G, Six K, Van den Mooter G, Baert L, Peeters J,
Brewster ME. 2003. Characterization of solid dispersions of
itraconazole and hydroxypropylmethylcellulose prepared by
melt extrusionPart 1. Int J Pharm 251:165174.
32. Bhugra C, Pikal MJ. 2008. Role of thermodynamic, molecular
and kinetic factors in crystallization from the amorphous state.
J Pharm Sci 97:13291349.
33. Gordon M, Taylor JS. 1952. Ideal copolymers and the second-
order transitions of synthetic rubbers. I. Non-crystalline copo-
lymers. J Appl Chem 2:493501.
34. Simha R, Boyer RF. 1962. On a general relation involving the
glass temperature and coefficients of expansion of polymers.
J Chem Phys 37:10031007.
35. Van den Mooter G, Van den Brande J, Augustijns P, Kinget R.
1999. Glass forming properties of benzodiazepines and co-eva-
porate systems with poly(hydroxyethyl methacrylate). J Therm
Anal Calor 57:493507.
36. Lubach J, Xu D, Segmuller B, Munson EJ. 2007. Investigation
of the effects of pharmaceutical processing upon solid-state
NMR relaxation times and implications to solid-state stability.
J Pharm Sci 96:777787.
37. Geppi M, Mollica G, Borsacchi S, Veracini CA. 2008. Solid-state
NMR studies for pharmaceutical systems. Appl Spectrosc Rev
43:202302.
38. Hancock BC, Shamlin SL, Zografi G. 1995. Molecular mobility
of glassy pharmaceutical solids. Pharm Res 12:799806.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
274 WEUTS ET AL.
39. Franks F. 2003. Scientific and technological aspects of aqueous
glasses. Biophys Chem 105:251261.
40. Six K, Verreck G, Peeters J, Binnemans K, Berghmans H,
Augustijns P, Kinget R, Van den Mooter G. 2001. Investigation
of thermal properties of glassy itraconazole: Identification of a
monotropic mesophase. Thermochim Acta 376:175181.
41. Six K, Verreck G, Peeters J, Augustijns P, Kinget R, Van den
Mooter G. 2001. Characterization of glassy itraconazole: A
comparative study of its molecular mobility below Tg with that
of structural analogs with MTDSC. Int J Pharm 213:163173.
42. Weuts I, Kempen D, Six K, Peeters J, Verreck G, Brewster M,
Van den Mooter G. 2003. Evaluation of different calorimetric
methods to determine the glass transition temperature and
molecular mobility below Tg for amorphous drugs. Int J Pharm
259:1725.
43. Bunjes H, Rades T. 2005. Thermotropic liquid crystalline
drugs. J Pharm Pharmacol 57:807816.
44. Stevenson CL, Bennett DB, Lechuga-Ballesteros D. 2005.
Pharmaceutical liquid crystals: The relevance of partially
ordered systems. J Pharm Sci 94:18611880.
45. Gilis PA, De Conde V, Vandecruys R. 1997. Beads having a core
coated with an antifungal and a polymer. US patent 5633015.
46. Brewster ME, Vandecruys R, Verreck G, Noppe M, Peeters J.
2002. A novel cyclodextrin-containing glass thermoplastic sys-
tems (GTS) for formulating poorly water soluble drug candi-
dates: Preclinical and clinical results. J Incl Phenom Macro
Chem 44:3538.
47. Six K, Berghmans H, Leuner C, Dressman J, Van Werde K,
Mullens J, Benoist L, Thimon M, Meublat L, Verreck G, Peeters
J, Brewster M, Van den Mooter G. 2003. Characterization of
solid dispersions of itraconazole and hydroxypropylmethyl-cel-
lulose prepared by melt extrusionPart II. Pharm Res 20:
10471054.
48. Peeters J, Neeskens P, Tollenaere JP, Van Remoortere P,
Brewster ME. 2002. Characterization of the interaction of
2-hydroxypropyl-b-cyclodextrin with itraconazole at pH 2,
4 and 7. J Pharm Sci 91:14141422.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 1, JANUARY 2011
49. Cha B, Oh J. 1998. An itraconazole exhibition an improved
solubility, a method of preparing the same a pharmaceutical
composition for oral administration comprising the same.
WO9857967.
50. Peeters J, Verreck G, Vandecruys R, Brewster M. 2008.
Dissolution and human bioavailability in supersaturating drug
delivery systems: Formulations of itraconazole. 2008 American
Association of Pharmaceutical Scientists (AAPS) Annual Meet-
ing and Exposition, Abstract No. T2097.
51. Tajber L, Corrigan OI, Healy AM. 2005. Physicochemical eva-
luation of PVP-thiazide diuretic interactions in co-spray dried
compositesAnalysis of glass transition composition relation-
ships. Eur J Pharm Sci 24:553563.
52. Gupta P, Bansal AK. 2005. Molecular interactions in celecoxib-
PVP-meglumine amorphous systems. J Pharm Pharmacol 57:
303310.
53. Craig DQM, Royall PG, Kett VL, Hopton ML. 1999. The rele-
vance of the amorphous state to pharmaceutical dosage forms:
Glassy drugs and freeze dried systems. Int J Pharm 179:179
207.
54. Kawakami K, Pikal MJ. 2005. Calorimetric investigation
of the structural relaxation of amorphous materials: Evaluat-
ing validity of the methodologies. J Pharm Sci 94:948
965.
55. Shamblin SL, Hancock BC, Dupuis Y, Pikal MJ. 2000. Inter-
pretation of relaxation time constants for amorphous pharma-
ceutical systems. J Pharm Sci 89:417427.
56. Weuts I, Kempen D, Decorte A, Verreck G, Peeters J, Brewster
M, Van den Mooter G. 2004. Phase behavior analysis of solid
dispersions of loperamide and two structurally related
compounds with the polymers PVP-K30 and PVP-VA64. Eur
J Pharm Sci 22:375385.
57. Weuts I, Kempen D, Decorte A, Verreck G, Peeters J, Brewster
M, Van den Mooter G. 2005. Physical stability of the amorphous
state of loperamide and two fragment molecules in solid
dispersions with the polymers PVP-K30 and PVA-VA64. Eur
J Pharm Sci 25:313320.
DOI 10.1002/jps