Journal of Pharmaceutical Sciences 109 (2020) 1105-1114

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Journal of Pharmaceutical Sciences

journal homepage: www.jpharmsci.org

Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Role of Surface Characteristics of Mannitol in Crystallization of

Fenofibrate During Spray Drying
Poonam Singh Thakur, Samarth D. Thakore, Arvind K. Bansal*
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India

a r t i c l e i n f o a b s t r a c t

Article history: NanoCrySP™ is a novel spray-drying-based technology for the generation of nanocrystalline solid dis-
Received 12 July 2019 persions of active pharmaceutical ingredients embedded in the matrix of small molecule excipients.
Revised 22 October 2019 Active pharmaceutical ingredient first appears as an amorphous phase, which transforms to crystalline
Accepted 30 October 2019
phase during its passage in the drying chamber. Mannitol acts as a crystallization inducer for the in-
Available online 6 November 2019
termediate amorphous phase by primary heterogeneous nucleation. Heteronucleation is a surface-
assisted phenomenon and surface characteristics of mannitol were hypothesized to play important
Keywords:
crystallization role. This study investigates the role of surface characteristics of mannitol on crystallization kinetics of
mobility amorphous fenofibrate. Crystallization kinetics of amorphous fenofibrate was assessed on 2 surfaces of
surface chemistry mannitol having different porosity, roughness, and polarity. Fenofibrate showed faster crystallization in
solid state
the presence of rougher surface (tind < 1 min) compared with smooth surface (tind ¼ 49.28 min). This was
excipient(s)
attributed to higher porosity (75%) and surface polarity (~1.25-fold) of rough surface as compared with
smooth surface. Polar nature provided primitive sites for faster crystallization of amorphous fenofibrate.
These findings can be utilized for generating crystalline solid dispersions using spray drying in the
presence of mannitol. The crystalline solid dispersions can be used for the development of oral solid
dosage forms.
© 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Introduction Our laboratory has reported novel spray-drying-based tech-

Spray drying is an industrially viable technique, which involves
the generation of dry solid particles by rapid evaporation of solvent
from the atomized feed solution.1 The technique is well-established
for particle engineering and co-processing in pharmaceutical sci-
ences. Spray drying has been used for manufacturing of dosage
forms for parenteral, nasal, or pulmonary route.2-5 A fine balance
between rate of evaporation and solute diffusion has been reported
to generate hollow particles with reduced aerodynamic diameter.1,6
Spray-drying-based platform technologydPulmospheres™dhas
been reported to generate solid sponge-like particles by spray
drying of oil-in-water emulsion.7 Spray drying has been also used
to generate microparticles,8 metastable polymorphic form,3 amor-
phous solid dispersions,9 and cocrystals2 of active pharmaceutical
ingredients (APIs). Moreover, the technique could also serve as a
continuous manufacturing platform, where it can simultaneously
undertake drying, particle formation, and separation of the solid.3
This article contains supplementary material available from the authors by request
or via the Internet at https://doi.org/10.1016/j.xphs.2019.10.067.
* Correspondence to: Arvind K. Bansal (Telephone: þ91-172-2214682).
E-mail address: akbansal@niper.ac.in (A.K. Bansal).
nology, NanoCrySP™, for the generation of nanocrystalline solid
dispersion (NSD). A feed solution containing pre-dissolved API and
excipient is spray dried to generate particles into a size range of 2-
10 mm. Each particle consists of API nanocrystals of 10-1000 nm
embedded in the matrix of excipient.10 The latter plays a major role
in achieving the nanocrystalline size of API and is referred to as
crystallization inducing agents.11 Here, API first appears as an
amorphous phase and then converts to crystalline phase. This
process depends on the following: (1) inherent crystallization
tendency of API, (2) critical process parameters and formulation
variables, and (3) properties of co-sprayed excipients.10 The impact
of critical process and formulation variables have been investigated
and described elsewhere.11-13 Excipients promote the crystalliza-
tion of API by (1) reduction in glass transition temperature (plas-
ticization) of amorphous API and (2) pre-crystallized excipient
providing a heteronuclear site to the amorphous API. NSD of a wide
variety of poorly water-soluble APIs including celecoxib,13 hesper-
etin,11,14 naringenin,11 dipyridamole,15 and fenofibrate16 have been
generated using NanoCrySP™. They showed enhanced biophar-
maceutical performance in terms of solubility, dissolution, and
bioavailability.
Interestingly, mannitol has been frequently used as crystalliza-
tion inducing excipient for the generation of NSDs using

https://doi.org/10.1016/j.xphs.2019.10.067
0022-3549/© 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
1106 P.S. Thakur et al. / Journal of Pharmaceutical Sciences 109 (2020) 1105-1114
NanoCrySP™.11-13,16 Mannitol acts as a heteronucleant and pro-
motes primary heterogeneous nucleation of the amorphous API
obtained as an intermediate phase during spray drying.11,13 Primary
heterogeneous nucleation is a surface-assisted phenomenon and
the role of surface characteristics of heteronucleant-like surface
topography and surface functionality has been investigated for
crystallization using cooling and slow-solvent evaporation.17,18
Mechanisms including lattice matching,18 functional group in-
teractions,19 and pore-controlled nucleation20 have been investi-
gated for controlling the crystallization outcome. However, the role
of aforementioned surface characteristics has not been explored for
the crystallization of intermediate amorphous phase generated
during spray drying.
A recent study demonstrated generation of NSD of fenofibrate in
the presence of mannitol using NanocrySP™.16 Spray drying in the
absence of mannitol generated partially crystalline fenofibrate,
wherein the intermediate amorphous phase failed to completely
crystallize upon transit through spray drying chamber. Inclusion of
mannitol to the feed solution increased the crystallization kinetics
of intermediate amorphous phase and generated completely crys-
talline fenofibrate in the matrix of crystalline mannitol.16 Hence,
the present study was aimed to understand the impact of surface
characteristics of mannitol on solid-state crystallization kinetics of
amorphous fenofibrate, which appears as an intermediate phase
during spray drying.
To achieve the aforementioned objective, crystallization kinetics
of amorphous fenofibrate was investigated in the presence of 2
samples of mannitol having different surface characteristics (as
described in the Methods section). The experiments involve eval-
uation of non-isothermal crystallization, isothermal crystallization,
and molecular mobility behavior of amorphous fenofibrate in the
presence and absence of the aforementioned mannitol samples.
Differential scanning calorimetry and hot stage microscopy were
used for non-isothermal crystallization studies, while modulated
differential scanning calorimetry and broadband dielectric spec-
troscopy were used for isothermal crystallization and molecular
mobility studies, respectively. Surface topography was probed us-
ing scanning electron microscope and atomic force microscope,
while the surface chemical environment was retrieved using X-ray
photon correlation spectroscopy. Observed surface characteristics
like surface topography and surface chemical environment of the
mannitol samples were correlated with the experimental outcome
of isothermal and non-isothermal crystallization studies.
Materials and Methods
Materials
Fenofibrate was received as a gift sample from Lupin Ltd. (Pune,
India). b-(D) mannitol was supplied by Loba Chemie Pvt. Ltd.
(Mumbai, India). Acetone (99% purity) was purchased from Avra
Synthesis Pvt. Ltd. (Hyderabad, India). All other materials and sol-
vents were of analytical grade.
Methods
Generation of Solid Dispersions
Spray-dried solid dispersions of fenofibrate and mannitol were
generated using a laboratory scale spray dryer (LU228 advanced
model; Labultima Ltd., Waliv, India). The feed solution containing
2% w/w of fenofibrate and mannitol was prepared in acetone:water
(3:2) and sprayed using 2-fluid spray nozzle (orifice diameter of 0.7
mm). The process parameters were inlet temperature at 343 K, feed
rate of 3 mL/min, air atomization pressure of 1.20 kg/cm2, and
vacuum of 95-100 mm water column. The generated solid
dispersions were stored at 298 K/0% relative humidity (RH) in a
vacuum desiccator containing phosphorus pentoxide until further
use. The solid dispersions were generated at 2 different mannitol
contents as per the experimental requirement: (1) fenofibrate-
mannitol (50:50) solid dispersion for differential scanning calo-
rimetry, modulated differential scanning calorimetry, and hot stage
microscopy-based studies and (2) fenofibrate-mannitol (99.5:0.5)
solid dispersion for broadband dielectric spectroscopy-based
studies.
Sample Preparation
The study involved 5 experimental samples and following pro-
tocols were used for preparation of these samples:
(1) Preparation of amorphous fenofibrate (“AFNT”): Accurately
weighed crystalline fenofibrate was heated up to 373.15 K at
a heating rate of 20 K/min and held isothermally for 2 min in
differential scanning calorimeter (Q2000; TA Instruments,
New Castle, DE); the molten mass was rapidly cooled to
253.15 K at a cooling rate of 20 K/min to obtain AFNT (sup-
plementary material, Figs S1Ia and S1Ib).
(2) Preparation of AFNT dispersed in the matrix of spray-dried
mannitol (“AFNT-SDM”) from the solid dispersion: crystal-
line fenofibrate and mannitol have A melting point of 354 K
and 440 K, respectively. Fenofibrate-mannitol solid disper-
sion was heated up to 373.15 K at heating rate of 20 K/min
and held isothermally for 2 min in differential scanning
calorimeter, to melt fenofibrate while retaining the crystal-
line mannitol. The sample was cooled from 373.15 K to 253.15
K at a cooling rate of 20 K/min. This generated AFNT
dispersed in the matrix of mannitol obtained after “spray
drying” and it was coded as “AFNT-SDM” (supplementary
material, Figs S1IIa and S1IIb).
(3) Preparation of AFNT dispersed in the matrix of recrystallized
mannitol (“AFNT-RCM”) from the solid dispersion: Accu-
rately weighed fenofibrate-mannitol solid dispersion was
heated up to 473.15 K at a heating rate of 20 K/min and held
isothermally for 2 min in the differential scanning calorim-
eter, thus melting both fenofibrate and mannitol. The sample
was cooled from 473.15 K to 253.15 K at a cooling rate of 20 K/
min. The melted mannitol “recrystallized” during cooling
due to its faster crystallization tendency,13 while fenofibrate
remained amorphous. AFNT-RCM contained mannitol having
surface characteristics expectedly different from that origi-
nally present in the solid dispersion (supplementary mate-
rial, Figs S1IIIa and S1IIIb).
(4) Removal of fenofibrate from the solid dispersion to obtain
spray-dried mannitol (“SDM”): As stated earlier, fenofibrate-
mannitol solid dispersion had crystalline fenofibrate
dispersed in the matrix of crystalline mannitol generated
during spray drying. Fenofibrate is highly soluble in acetone,
while mannitol is practically insoluble in acetone.21,22 In
view of these solubility differences, fenofibrate-mannitol
solid dispersion was washed using 10 volumes of 20 mL of
acetone. Complete removal of fenofibrate was confirmed
using high-performance liquid chromatography16 analysis.
The sample obtained after 10 washings with acetone was
coded as “SDM” (i.e., spray-dried mannitol).
(5) Removal of fenofibrate from AFNT-RCM to obtain recrystal-
lized mannitol (“RCM’): AFNT-RCM was washed using 10
volumes of 20 mL of acetone and complete removal of
fenofibrate was confirmed using high-performance liquid
chromatography analysis. The sample obtained after 10
washings with acetone was coded as “RCM” (i.e., recrystal-
lized mannitol).
 P.S. Thakur et al. / Journal of Pharmaceutical Sciences 109 (2020) 1105-1114
Differential Scanning Calorimetry
Differential scanning calorimetry was used to evaluate non-
isothermal crystallization of AFNT, AFNT-SDM, and AFNT-RCM.
The experiments were conducted using differential scanning
calorimeter (Q2000; TA Instruments) equipped with a refrigerated
cooling system and operating with Universal Analysis 2000 soft-
ware (version 4.5A; TA Instruments). The sample cell was purged
with dry nitrogen at a flow rate of 50 mL/min. The instrument was
calibrated for temperature and heat flow using high purity indium
as a standard. The prepared samples (i.e., AFNT, AFNT-SDM, and
AFNT-RCM) were heated up to a melting point of fenofibrate at a
heating rate of 2 K/min. The obtained heating curves were analyzed
for presence of thermal events if any.
Hot Stage Microscopy
Hot stage microscopy was used as an orthogonal tool to differ-
ential scanning calorimetry. Non-isothermal crystallization of
AFNT, AFNT-SDM, and AFNT RCM was also evaluated using hot
stage microscopy. These experiments were performed using a Leica
DMLP polarized microscope (Leica Microsystems, GmbH, Wetzlar,
Germany) equipped with Linkam LTS 350. Samples (i.e., AFNT,
AFNT-SDM, and AFNT-RCM) were prepared in between 2 micro-
scopic glass slides using their respective protocol described in the
Sample Preparation section. The prepared samples were heated up
to a melting point of fenofibrate (~354 K) at a heating rate of 2 K/
min. Photomicrographs were acquired at 40 magnification using
JVC color video camera and Linksys32 software (version 1.8.9; Leica
Microsystems, GmbH).
Modulated Differential Scanning Calorimetry
Modulated differential scanning calorimetry was used for the
evaluation of isothermal crystallization kinetics of AFNT, AFNT-
SDM, and AFNT-RCM. The experiments were conducted using dif-
ferential scanning calorimeter (Q2000; TA Instruments) equipped
with a refrigerated cooling system and operating with Universal
Analysis 2000 software (version 4.5A; TA Instruments). The sample
cell was purged with dry nitrogen at a flow rate of 50 mL/min. The
instrument was calibrated for cell capacitance and cell resistance
using sapphire as a standard.
Accurately weighed 4-5 mg of AFNT, AFNT-SDM, and AFNT-RCM
were heated up to 288.15 K (Tg þ 35 K) and held isothermally for
180, 15, and 180 min, respectively. The samples were cooled to
233.15 K after a predefined time interval and the change in heat
capacity at Tg (DCp) was analyzed by heating from 233.15 K to 273.15
K. The analysis was performed at a heating rate of 2 K/min, mod-
ulation amplitude of ±0.5 K, and modulation period of 60 s. All the
experiments were performed in triplicate and DCp was reported as
a mean of 3 samples. Time-dependent change in the value of DCp
was used for the calculation of fraction crystallized with time for
the respective sample.
Broadband Dielectric Spectroscopy
Broadband dielectric spectroscopy was used to probe the mo-
lecular relaxation behavior of AFNT, AFNT-SDM, and AFNT-RCM.
The experiments were performed using broadband dielectric
spectrophotometer (Novocontrol Concept 40; Novocontrol Tech-
nologies, Montabaur, Germany). The instrument was operated with
WinDETA® version 5.69 and the data was analyzed by WinFIT®
version 3.2. Dielectric measurements were carried out as a function
of frequency at controlled temperatures (i.e., frequency sweep
mode). Spacers (thickness ¼ 1 mm) of polytetrafluoroethylene
were placed parallel on the lower side of the (on the base of the
cell) sample thus maintaining ~5 mm distance. The spacers pre-
vented direct contact between upper and lower electrodes when
1107
the sample was in the molten state and ensured the constant
thickness of the sample throughout the analysis.
About 1.2 g of powder was loaded to the sample cell and sam-
ples corresponding to AFNT, AFNT-SDM, and AFNT-RCM were
prepared as specified in the Sample Preparation section. Here,
samples were cooled by dipping into liquid nitrogen instead of a
cooling rate of 20 K/min. The cell loaded with sample was mounted
on cryostat pre-equilibrated at 234.15 K (~Tg ¼ 17.5 K). The samples
were scanned from 123.15 K to 243.15 K at a temperature interval of
10 K, and from 243.15 K to 273.15 K at temperature interval of 2.5 K.
The sample temperature was maintained to an accuracy level of
±0.1 K with a Novotherm® temperature controller using liquid
nitrogen dewar. The alternating current frequency of 102 to 107 Hz
was applied at each temperature. Resultant isothermal frequency
curves were utilized to calculate molecular relaxation time of AFNT
in the studied samples.
Powder X-Ray Diffraction
Powder X-ray diffraction (PXRD) was used to determine poly-
morphic form of “SDM” and “RCM.” “SDM” was mounted as a
compact on polymethyl methacrylate sample holder for PXRD
analysis. The compact of “SDM” was prepared by applying minimal
pressure to the sample layered between 2 layers of aluminum foil.
“RCM’ had sufficient size and was mounted on the sample holder
without any processing. The experiments were performed using
XPERT-PRO X-ray diffractometer (Karlsruhe, Germany) equipped
with Cu-Ka radiation (l ¼ 1.54 Ǻ) at 45 kV, 40 mA passing through a
nickel filter. The configuration of goniometer was kept at q/q
arrangement (where the stage was fixed) to preferentially collect
the data from the surface of the sample. Data were collected at
room temperature in continuous scan mode with a step size of
0.04 and with a step scan time of 0.4 s over an angular range of 3 -
40 2q. Crystallographic information file of b-D-mannitol was
retrieved from Cambridge structural database (DMANTL01; Cam-
bridge Crystallographic Data Center, Cambridge, UK) and powder
diffraction pattern was calculated from the same using Mercury
(version 2.3; Cambridge Crystallographic Data Center).
Scanning Electron Microscopy
Scanning electron microscopy was used for visualization of
surface morphology of “SDM” and “RCM.” The experiments were
conducted using scanning electron microscope (S-3400; Hitachi
Ltd., Tokyo, Japan), operated at an excitation voltage of 25 kV.
“SDM” and “RCM” were mounted onto a stainless steel stage using
double-sided adhesive tape and sputter coated with gold using ion
sputter (E-1010; Hitachi Ltd.), before analysis.
Atomic Force Microscopy
Atomic force microscopy was used to evaluate surface topog-
raphy and surface roughness of “SDM” and “RCM.” The experiments
were conducted using atomic force microscope (BioScope II; Veeco
Instruments, San Jose, CA). “SDM” was mounted as a compact and
“RCM” was mounted as is, for atomic force microscopic analysis,
where the compact was prepared using protocol specified in PXRD
analysis (“Powder X-Ray Diffraction” section). The mapping was
performed in tapping mode using an RTESP cantilever (Veeco In-
struments) with a force constant of 20-80 N/m. The surface topo-
graphical images obtained by atomic force microscope were
analyzed using image analysis software, Gwyddion (v2.52; Czech
Metrology Institute, Russia). The root-mean-square surface
roughness for each sample was reported as an average of three 10 
10 mm area measurements.
1108 P.S. Thakur et al. / Journal of Pharmaceutical Sciences 109 (2020) 1105-1114
X-Ray Photon Correlation Spectroscopy
X-ray photon correlation spectroscopy was used for the deter-
mination of surface atomic composition of “SDM” and “RCM.”
“SDM” was mounted as a compact and “RCM” was mounted as is for
X-ray photon correlation spectroscopic analysis, where the
compact was prepared using protocol specified in PXRD analysis
(Powder X-Ray Diffraction section). The samples were affixed to the
stage using double-sided tape. Analysis was performed using point
mode and takeoff angle was of 45 for the studied samples. X-ray
photoelectron spectra were recorded using high vacuum X-ray
photoelectron spectroscope (PHI 1257 model; PerkinElmer) with
Mg K X-ray source of 100 W (h ¼ 1253.6 eV) with the operating
voltage of 15 kV and vacuum pressure in analyzer chamber of
5  1010 Torr. The secondary electron energy was detected by a
hemispherical section analyzer capable of 25 meV resolution. The
natural linewidth of Mg K line used for X-ray photon correlation
spectroscopic analysis was with an energy resolution better than
0.1 eV (10% of full width at half maximum). Binding energy range
was from 0 to 1100 eV for regions of C 1s and O 1s, with average
peak binding energy of 286.0 and 533.0, respectively. All spectra
were baseline subtracted and fitted using a Gaussian function.
Fitting was performed using PeakFit® Version 4.12 (SeaSolver
Software, Inc., MA). The surface atomic composition was deter-
mined from integrated peak intensities and the corresponding
relative sensitivity factor.
Helium Pycnometry
Helium pycnometry was used to determine the true density of
“SDM.” Compacts of “SDM” were used as a sample for helium
pycnometry, which was prepared as specified in PXRD analysis
(Powder X-Ray Diffraction section). The experiments were per-
formed using helium pycnometer (Pycno 30; Smart Instruments,
Mumbai, India) operated at 298.15 ± K/40 ± 5% RH. Accurately
weighed “SDM” was loaded to the sample cell and volume of he-
lium replaced by the loaded sample was recorded. The measured
volume was further used as a denominator to the weight of “SDM”
and their ratio was reported as a true density of the sample.
Tapped Density Analysis
Tapped density of “SDM” was measured using graduated glass
cylinder and the measured value was further used for the calcula-
tion of true density of the sample. Accurately weighed compact of
“SDM” was added to the 10 mL graduated measuring cylinder. The
cylinder was tapped manually for 1500 times from the approximate
height of 3 ± 0.5 cm. The final volume was used as a denominator to
the weight of “SDM” and their ratio was reported as a tapped
density of the sample. Porosity is a derived property of powder and
was determined using Equation 1.
ðTrue density  Tapped densityÞ
% porosity ¼  100
True density
Dynamic Vapor Sorption
Dynamic vapor sorption was used to evaluate moisture uptake
behavior of “SDM” and “RCM.” The experiments were performed
using a dynamic vapor sorption instrument (Q5000SA; TA In-
struments). “SDM” was mounted as a compact and “RCM” was
mounted as is for dynamic vapor sorption analysis, where the
compact was prepared using protocol specified in PXRD analysis
(Powder X-Ray Diffraction section). The samples were dried over-
night at 333 K prior to storage in desiccator maintained at 0% RH
using anhydrous phosphorus pentoxide. The stored samples (25 ± 5
mg) were loaded onto a tared metal-coated quartz sample pan and
an empty quartz pan was used as a reference. The samples were
pre-dried at 313.15 K/0% RH for 60 min and the instrument was
programed for moisture sorption from 0% to >90% RH in 10% RH
steps at 298.15 ± 0.1 K using an equilibrium condition. The equi-
librium condition was set to <0.01% total mass change within
15 min with a maximum dwell time of 15 min for 0%-40% RH and
30 min for 40%-90% RH. All the experiments were performed in
duplicate.
Results and Discussion
Crystallization Behavior of Fenofibrate
Crystallization is a self-assembly of randomly distributed mol-
ecules, which arranges themselves in a structured crystalline phase
with long-range order. Although amorphous phase demonstrates
short-range order in contrast to the long-range order described for
crystalline phase and it serves as a starting point for generation of
crystalline material upon activation.23
Non-isothermal crystallization behavior of AFNT has been out-
lined in Figure 1a. AFNT showed calorimetric glass transition
temperature at 251.38 K. Despite the low calorimetric glass tran-
sition temperature, AFNT did not crystallize on subsequent heating
(Fig. 1a) up to the melting point of fenofibrate (i.e., ~354 K). These
observations were also consistent with hot stage microscopy re-
sults, where AFNT did not crystallize upon heating. Moreover, AFNT
did not crystallize upon isothermal hold up to 180 min during
isothermal crystallization at Tg þ 35 K (Fig. 2a).
Lack of crystallization tendency of fenofibrate has been attrib-
uted to the lack of hydrogen bonding functionality and arrange-
ment of molecules in the crystal lattice solely held by van der Waals
interactions (Figs. S2a and S2b).24 With these results, fenofibrate
was classified as class III crystallizer (having good glass-forming
ability and stability) with poor crystallization tendency.25
Crystallization Behavior of Fenofibrate in the Presence of Mannitol
This section outlines non-isothermal and isothermal crystalli-
zation behavior of AFNT, AFNT-SDM, and AFNT-RCM. The non-
isothermal crystallization behavior was evaluated using differen-
tial scanning calorimetry and hot stage microscopy, while modu-
lated differential scanning calorimetry was used to evaluate of
isothermal crystallization behavior of the aforementioned samples.
Non-isothermal crystallization studies served as a qualitative
tool for demonstrating the role of mannitol surface in crystalliza-
tion of AFNT. The obtained heating curves for non-isothermal
crystallization of AFNT-SDM and AFNT-RCM have been shown in
Figures 1b and 1c, respectively.
In the case of AFNT-SDM, the mannitol retained the surface
characteristics “as it was” present in spray-dried fenofibrate-
(1)
mannitol solid dispersion (Figs S1IIa and S1IIb). Here, AFNT crys-
tallized (Tc, onset) around 280.07 K (i.e., exothermic peak in the
heating curve; Fig. 1b), which was followed by melting at 351.45 K
corresponding to polymorphic form I of fenofibrate (Fig. 1b).
In the case of AFNT-RCM, the mannitol has surface characteris-
tics imparted due to in situ recrystallization during cooling.13 Here,
AFNT did not crystallize upon heating and was observed as amor-
phous phase in the vicinity of RCM (Fig. 1c). These observations
were also consistent with the results obtained with hot stage mi-
croscopy (Figs. 1b and 1c).
Isothermal crystallization studies provided time-dependent
crystallization behavior of AFNT-SDM and AFNT-RCM. The change
in heat capacity with isothermal crystallization at different
time periods was transformed to fraction crystallized (a) using
Equation 2.11
 P.S. Thakur et al. / Journal of Pharmaceutical Sciences 109 (2020) 1105-1114 1109

Figure 1. Non-isothermal crystallization of AFNT (a), AFNT-SDM (b), and AFNT-RCM (c) using differential scanning calorimetry and corresponding hot stage microscopy images.

DCp;0  DCp;t
aðtÞ ¼
DCp;0
where a(t) is the fraction crystallized at time t, DCp,0 is the change in
heat capacity of amorphous fenofibrate at Tg at t ¼ 0 min, and DCp,t
is the change in heat capacity after the isothermal hold of “t”
minute. AFNT-SDM showed 100% crystallization within 15 min
(Fig. 2a), while AFNT-RCM did not crystallize up to 45 min. How-
ever, the latter exhibited 80% crystallization within the experi-
mental time frame of 180 min (Fig. 2a).
Isothermal crystallization data were fitted to literature reported
models for solid state crystallization.26 Akaike’s information crite-
rion was used as a statistical indicator27 of linear fitting of integral
forms of various reaction models with time on the abscissa (Sup-
plementary material, Table S1). Crystallization of AFNT-SDM and
AFNT-RCM followed 3-dimensional diffusion proposed by Ginstling
and Brounshtein model.28 The model assumes that reaction, that is,
nucleation takes place from the boundary of the reactant, that is,
mannitol heterosurface, followed by diffusion-controlled particle
(2) growth. Furthermore, this model assumes concentration gradient
dependent flux of the molecule to the growing particle. Nucleation
process is dependent upon the amount of reactant left and the
amount of product formed during the reaction.29,30 This was also
evident from the qualitative data shown in Figure 1b, wherein
crystallization of fenofibrate in AFNT-SDM was initiated from the
surface of mannitol followed by crystal growth.
The data of fraction crystallized with isothermal hold time were
subjected to statistical analysis using Avrami11 (Eq. 3) and Finke-
Watzky31 (Eq. 4) model. The equations were fitted to the experi-
mental data using sigma plot version 12.0 (Systat Software Inc., San
Jose, CA).
 n

tti
tcr
aðtÞ ¼ 1  e (3)

Figure 2. (a) Fraction crystallized with time upon isothermal crystallization of AFNT, AFNT-SDM, and AFNT-RCM (n ¼ 3). The solid line indicates data fitted to the Avrami model.
(b) Plot of log-transformed relaxation time versus the inverse of corresponding temperature for a- and b-relaxation process.
1110 P.S. Thakur et al. / Journal of Pharmaceutical Sciences 109 (2020) 1105-1114
where ti is crystallization induction time, tcr is characteristic crys-
tallization time, and n is Avrami exponent. The data of isothermal
crystallization were also fitted to Finke-Watzky 2-step kinetic
model (Eq. 3) for deconvolution of nucleation (k1) and crystal
growth (k2) rate constants.
 
k1  k2
aðtÞ ¼ 1 
k2 þ k1 e½ðk1 þk2 Þt
where k1 and k2 are average nucleation and crystallization rate
constants with a unit of time1. The values of parameters obtained
after the fitting of experimental isothermal crystallization data to
Equations 3 and 4 are shown in Table 1. A significantly higher dif-
ference was observed in lag time for induction of crystallization,
where fenofibrate took less than a minute for induction of crys-
tallization in AFNT-SDM as compared with 49.28 min in AFNT-RCM.
These results were consistent with characteristic crystallization
time where fenofibrate took 5.85 min in AFNT-SDM as compared to
88.60 min in AFNT-RCM for crystallization of 50% of fenofibrate.
Value of the Avrami constant was near to 1 for both the samples. It
indicates constant nucleation from the surface of heteronucleant
with no crystallization from edge sites.11
The crystallization kinetics data were further deconvoluted into
nucleation and crystal growth rate constants using Finke-Watzky
model (Table 1). Crystallization from AFNT-SDM showed 46.26-
fold and 5.68-fold higher nucleation and crystal growth rate con-
stant, respectively, as compared with AFNT-RCM. The relative
nucleation rate (k1/k2) was 8.14-fold higher for AFNT-SDM. The k2/
k1 ratio was found to be 0.66 for AFNT-SDM as compared to 5.44 for
AFNT-RCM. The lower k2/k1 ratio indicates greater number of nuclei
followed by crystal growth of those nuclei. This can have implica-
tions in controlling the particle size of the fenofibrate during gen-
eration of NSD using NanoCrySP™.16 Qualitative and quantitative
crystallization data demonstrated that spray-dried mannitol (i.e.,
SDM in AFNT-SDM) had better capability to induce crystallization
of AFNT as compared with recrystallized mannitol (i.e., RCM in
AFNT-RCM).
Effect of Mannitol on Molecular Mobility of Fenofibrate
Differential scanning calorimetry based isothermal crystalliza-
tion studies highlighted differential crystallization tendency of
AFNT in the presence of SDM (i.e., AFNT-SDM) and RCM (i.e., AFNT-
RCM). AFNT failed to crystallize during the isothermal crystalliza-
tion experiments in the absence of mannitol and did not provide
any information about molecular behavior of fenofibrate on the
isothermal treatment. Crystallization from the amorphous phase is
controlled by thermodynamic (i.e., free energy) and kinetic factors
(i.e., molecular mobility).23 According to the Stokes-Einstein
equation, molecular mobility triggers diffusional jumps of the
molecules, depending on temperature and viscosity of the amor-
phous phase.23 Diffusion encourages molecular aggregation which
triggers nucleation and crystal growth. b-Relaxation involves non-
Table 1
Fitted Parameters of Avrami and Finke-Watzky Model to the Experimental Data of Isothermal Crystallization of Amorphous Fenofibrate in AFNT-SDM and AFNT-RCM
Model Parameter
Avrami model Induction time (min)
Characteristic crystallization time (min)
Avrami exponent (n)
Finke-Watzky model Nucleation rate constant (k1)
Crystallization rate constant (k2)
Relative rate of nucleation (k1/k2)
Relative rate of crystal growth (k2/k1)
cooperative local motions below and above Tg, while a-relaxation is
cooperative global motion responsible for the occurrence of Tg.
These molecular motions in AFNT, AFNT-SDM, and AFNT-RCM were
probed using broadband dielectric spectrometry.
b-Relaxation
(4) The response of b-relaxation of fenofibrate was initiated from
123.15 K and 153.15 K in AFNT-SDM and AFNT-RCM, respectively, as
compared to 163.15 K for AFNT. The dielectric response of b-
relaxation shifted to higher frequencies with an increase in tem-
perature for the studied samples (Fig. S3).
The molecular relaxation time of b-relaxation was retrieved by
fitting responses of imaginary permittivity to Havriliak-Negami
(HN) function32 (Supplementary Material). The b-relaxation time
retrieved from HN fit was used further to calculate activation en-
ergy for the b-relaxation process. Temperature dependence of b-
relaxation time (Fig. 2b) was described by Arrhenius behavior and
the data were fitted to Equation 5.33
Ea
t ¼ t∞ expRT (5)
where t the is molecular relaxation time, t∞ is a constant taken as
1014, Ea is the activation energy, R is the universal gas constant,
and T is the temperature. The order of activation energy for b-
relaxation was AFNT > AFNT-SDM > AFNT-RCM (16,190, 14,962, and
14,180 J/K*mol, respectively). These values suggest that hetero-
nucleants facilitated the process of b-relaxation. Presence of
mannitol had a marginal impact on b-relaxation time. However, the
activation energy for b-relaxation was similar for AFNT-SDM and
AFNT-RCM.
The dielectric permittivity is better known as the dielectric
constant of the capacitor. It shows the charge carrying capacity of
the material. The dielectric strength of the sample can be defined as
the difference between the values of real permittivity at the lowest
and highest experimental frequency.34 The order of dielectric
strength was AFNT < AFNT-RCM < AFNT-SDM (0.086, 0.160, and
0.474, respectively). The data suggest the increased local arrange-
ment and participation of fenofibrate molecules in AFNT-SDM and
AFNT-RCM. Thus, mannitol could have provided a primitive site for
“right” orientation of fenofibrate molecules which may arrange to
commence nucleation and subsequent crystal growth. This was
further investigated by studying surface characteristics of SDM and
RCM using scanning electron microscopy, atomic force microscopy,
and X-ray photon correlation spectroscopy.
a-Relaxation
Fenofibrate molecules showed initiation of the a-relaxation
process at 253.15 K in AFNT. Real and imaginary components of
dielectric permittivity at temperatures above Tg are shown in
Figure S4. The value of the real part of complex permittivity was in
equilibrium at lower frequencies and it decreased with an increase
in frequency. These values depend on the local order of molecules
in the sample, where increased order leads to the higher value of
AFNT-SDM AFNT-RCM Ratio of AFNT-SDM/AFNT-RCM
0.4724 49.2842 0.0096
5.8500 88.6075 0.0660
1.0064 1.0000 1.0064
0.1249 0.0027 46.2592
0.0835 0.0147 5.6802
1.4958 0.1837 8.1426
0.6685 5.4444 0.1227
 P.S. Thakur et al. / Journal of Pharmaceutical Sciences 109 (2020) 1105-1114
the real part of the complex permittivity. The molecules tend to
show increased mobility with increasing temperatures which was
evident by a shift in the peak toward higher frequencies in both real
and imaginary parts of the complex permittivity. The data showed
marginal increase in the values of the permittivity of fenofibrate in
AFNT-RCM. In contrast, a higher level of local ordering occurred in
AFNT-SDM, which was evident by the increased real and imaginary
permittivity of fenofibrate (Fig. S4).
The responses of the imaginary permittivity of a-relaxation
process were fitted to HN function from 253.15 K to 273.15 K, which
provided molecular relaxation time for a-relaxation. Temperature
dependence of molecular relaxation time for a-relaxation was
fitted to Vogel-Tammann-Fulcher model described in Equation 6.35
 
DT0
t ¼ t0 exp
T  T0
where t is the mean a-relaxation time, t0 is the pre-exponential
factor, D is the strength parameter, T is the temperature, and T0 is
the temperature of zero mobility. D and T0 are constants in Equation
6. The D values of <10 and >30 indicate fragile and strong nature of
the glass, respectively.36 T0 described as a temperature where
either viscosity or molecular relaxation time reached infinity.
Conceptually, T0 has been related to Kauzmann temperature (Tg ¼
50). The value of t0 was taken as 1014 s. The fitted value of strength
parameter for AFNT was 8.63, which indicates its fragile nature.36
Value of strength parameter did not change in AFNT-SDM and
AFNT-RCM and was 8.75 and 8.71, respectively.
Log-transformed molecular mobility underlying a-relaxation
was plotted as a function of the inverse of the respective temper-
ature and dielectric Tg,D was calculated by extrapolating mean
alpha-relaxation time to 100 s (Fig. 2b).33 The value of dielectric Tg,D
of AFNT was 249.3 K. The extrapolated Tg,D value was ~2 K lower
than that of calorimetric Tg (i.e., 251.25 K; Fig. 1). Tg of fenofibrate in
AFNT-SDM and AFNT-RCM remained similar, the extrapolated
values of Tg were 249.3 K and 249.2 K, respectively. Lack of plasti-
cization of amorphous fenofibrate in the presence of mannitol was
satisfactorily explained by solubility parameter37 of the respective
components.13 The calculated solubility parameter (dt) values of
fenofibrate and mannitol were 22.0 and 38.5 MPa1/2, respectively.
Both are immiscible in each other as the difference in their solu-
bility parameter value was more than 7 MPa1/2.37 Additionally, the
free energy of mixing (DG, 7.02 J/mol) was positive which indicates
unfavorable mixing. Lack of miscibility was also observed in hot
stage microscopy studies (Fig. 1c).
In brief, molecular mobility study revealed that heteronucleants
have reduced activation energy for b-relaxation, which indicates
increased local motion of the fenofibrate molecules in the presence
of mannitol. On other hand, mannitol did not affect a-relaxation,
which was a result of lack of plasticization, due to immiscibility of
the 2 components.
Characterization of Surface Heterogeneity of Mannitol Samples
The differential crystallization characteristics of AFNT in the
presence of SDM and RCM suggested the presence of differential
surface characteristics of the studied mannitol samples. Previous
studies demonstrating heteronucleation implicated the role of (1)
surface topography,19,20 which includes surface roughness, surface
pores, pore size and its geometry; (2) surface functionality,18 which
includes surface environment with respect to the exposed func-
tional groups; and (3) crystallographic features,18 which include
lattice characteristics like miller indices of heteronucleant in gov-
erning crystallization of API. Hence, topographical features and
surface environment of mannitol in AFNT-SDM and AFNT-RCM
1111
were studied to understand the role of surface heterogeneity on
crystallization kinetics of fenofibrate. Calculated PXRD diffracto-
gram of b-mannitol (from DMANTL01; CCDC, Cambridge, UK) was
in agreement with experimental diffractograms of SDM and RCM.
This confirmed the b-form of mannitol in both the samples
(Fig. 3III).
Scanning electron microscopic analysis of SDM showed tiny
particles with surface corrugations, while RCM showed flat and
smooth surface (Figs. 3Ia and 3Ib). The tiny particles of SDM also
demonstrate higher surface area of SDM as compared with RCM.
Atomic force microscopic images of the SDM and RCM are shown in
Figures 3IIa and 3IIb. The level of irregularity was higher in SDM as
compared to RCM (z-axis of 4.6 mm and 0.1 mm, respectively when
analyzed using atomic force microscope). These irregularities were
quantified as surface roughness and values were 732.80 ± 351.10
(6)
nm and 10.92 ± 0.81 nm for SDM and RCM, respectively. Surface can
be termed as smooth if the irregularity from the reference plane
calculated as roughness is less than 10 nm.38 Hence, RCM was
smooth and SDM was rough. Differential surface roughness has
been reported to modulate crystallization kinetics of small organic
molecules by intervention to the phase of nucleation.39 The
significantly higher surface irregularities in SDM were one of the
reasons for its higher efficiency for improved crystallization ki-
netics of AFNT in AFNT-SDM.
Besides the differential surface morphology and topography,
porosity of these samples remains another factor that can promote
crystallization within pore confinements.19,20 Page and Sear40,41
clearly demonstrated that the maximum crystallization rate can
be achieved between the pore size between the wide and narrow
range. These studies demonstrated that the surface with diverse
porosity acts as a huge random library of crystallization agents.
Moreover, some of the previous studies demonstrated that the pore
affects the nucleation kinetics through the alteration of the orien-
tation order of the crystallizing molecules near the corner of the
pore. The porosity of SDM and RCM was calculated (Eq. 1) and
found to be 75% and 0%, respectively. The significantly higher
porosity of SDM can be attributed to voids created by removal of
fenofibrate during preparation of SDM from AFNT-SDM (Sample
Preparation section). As described earlier, RCM was prepared by
in situ recrystallization of mannitol during cooling. Its crystalliza-
tion took place at ~375 K during cooling (Figs. S1IIIa and S1IIIb),
which led to denser and non-porous mass. Moreover, the surface of
RCM was smooth without any irregularities (Fig. 3IIa). Hence, the
crystal density of mannitol can be taken as the true density and
tapped density of RCM, which led to porosity of 0%. SDM had highly
porous surface, which could have provided more points of contact
for crystallization of fenofibrate.
Additionally, surface chemical environment of the exposed
surface of SDM and RCM was quantified using X-ray photon cor-
relation spectroscopy. The chemical formula of mannitol is C6H14O6,
which has only carbon (C), hydrogen (H), and oxygen (O). It has 6
hydroxyl groups, which can interact with chlorine and oxygen
functionality present in fenofibrate. Peak shape and chemical shift
for C and O were similar between SDM and RCM. However, the
relative abundance of surface elements shows a significant differ-
ence. The surface of SDM exhibited a relatively higher concentra-
tion of O (i.e., 49.45%) as compared with RCM (i.e., 44.58%). Surface
atomic composition of carbon was higher for RCM (i.e., 55.41) as
compared with SDM (i.e., 49.75%). The surface polarity,42 expressed
as ratio of % atomic composition of O to % atomic composition of C,
was 0.99 and 0.80 for SDM and RCM, respectively. This indicated a
higher relative abundance of hydroxyl functionality on the surface
of SDM as compared with RCM. Higher surface polarity can be
attributed to higher exposure of hydroxyl group on the surface of
SDM as compared with RCM.
1112 P.S. Thakur et al. / Journal of Pharmaceutical Sciences 109 (2020) 1105-1114
Figure 3. (I) Scanning electron microscopy and (II) atomic force microscopy images of (a) SDM and (b) RCM. (III) PXRD diffractogram of SDM, RCM, and b-mannitol (derived from
DMANTL01; CCDC, Cambridge, UK).
The impact of differential surface environment on interaction
capacity of mannitol was further confirmed by moisture sorption
behavior of SDM and RCM using dynamic vapor sorption analysis.
The results showed 4.00 ± 0.01% and 0.01% weight gain (at 90% RH)
for SDM and RCM, respectively. This difference in moisture sorption
behavior could be attributed to differential surface chemistry with
higher amount of hydroxyl functionality, surface roughness, and
higher porosity of SDM as compared to RCM.42 The different
moisture sorption behavior further strengthens significantly higher
heterogeneity of SDM over RCM.
Summary of Surface Governed Crystallization of Fenofibrate
A comprehensive overview of the current study is shown in
Figure 4. AFNT did not crystallize in the experimental time frame,
while it showed higher nucleation and lower crystal growth rate in
the presence of SDM as compared with RCM. On the basis of the
experimental evidences, we postulated a possible molecular
mechanism to interpret the role of mannitol heterosurfaces on the
crystallization behavior of fenofibrate.
The crystal lattice of fenofibrate is sustained with short-range
van der Waal forces due to lack of hydrogen bond donors.24 The
substrate (i.e., mannitol) has 6 hydrogen donors in its chemical
structure and exposure of these groups on the surface may govern
the arrangement of fenofibrate molecules on its surface.43 It has
been reported that crystal nucleation is preceded by molecular
cluster formation through density fluctuations and molecular re-
orientation through structure fluctuations. The rate of nucleation
of amorphous fenofibrate can be modified in the presence of rough,
porous surface having the “right” chemistry. Higher surface
roughness and polarity of SDM enables favorable surface in-
teractions with AFNT. Furthermore, the right surface chemistry (i.e.,
exposure of eOH) and preferred oriented multiple faces of SDM
initiated molecular recognition events between its surface and the
 P.S. Thakur et al. / Journal of Pharmaceutical Sciences 109 (2020) 1105-1114
Figure 4. Comprehensive summary of the impact of surface heterogeneity on the crystallization of fenofibrate.
fenofibrate molecules. Hence, the mannitol surface with higher
roughness, porosity, and exposed hydroxyl groups led to faster
crystallization of fenofibrate.
Conclusion
The current study systematically demonstrated the impact of
surface heterogeneity of mannitol on the crystallization of amor-
phous fenofibrate. Mannitol generated during the spray drying of
solid dispersion had significantly enhanced the nucleation kinetics
of amorphous fenofibrate as compared with mannitol recrystallized
during cooling. Mannitol surface generated during spray drying
had higher roughness, polar chemical environment, and higher
porosity. These surface characteristics facilitated the enhanced
molecular re-orientation of fenofibrate through the structural
fluctuation of the API at the mannitol surface. Hence, the surface
characteristics of heteronucleant can potentially serve as a critical
material attribute in governing the crystallization of poor crystal-
lizer during spray drying. It will be interesting to explore the utility
of these findings in a wider spectrum of APIs/excipients, where
crystalline solid dispersions can be generated using spray drying in
the presence of mannitol. Moreover, the generated crystalline solid
1113
dispersions can further find application in the development of oral
solid dosage forms.
Acknowledgments
The authors would like to thank Mr. Jagadish M. Sharma
(Department of Pharmaceutics, NIPER, SAS Nagar) and Ms. Tanya
Ralli (Jamia Hamdard, Delhi) for their valuable suggestions, support
in sample preparation, and analysis during the broadband dielectric
spectroscopic experiments. We also thank Mr. Dnyaneshwar P. Kale
for the helpful discussions. Ms. Poonam Singh Thakur would like to
thank DST (SERB) for providing her junior research fellowship and
financial assistance to carry out the project.
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