MINIREVIEW

Crystallization from the Amorphous State: Nucleation–Growth

Decoupling, Polymorphism Interplay, and the Role of Interfaces
MARC DESCAMPS, EMELINE DUDOGNON

University Lille 1, UMET (Unité Matériaux et Transformations) UMR CNRS 8207, Bat P5 F-59655, Villeneuve d’Ascq, France

Received 26 February 2014; revised 21 April 2014; accepted 23 April 2014

Published online 5 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24016

ABSTRACT: The physical stability of the amorphous state is governed by crystallization, which results from the complex interplay of
nucleation and growth processes. These processes can be further complicated by the preferred initial nucleation of less-stable phases, and
interpretation requires the evaluation of the relative roles of structure, dynamics, and thermodynamics on the kinetics of the recrystallization.
As a contribution to this issue, we reanalyze data sets concerning recrystallization of two pharmaceutical compounds: L-arabitol and RS
ibuprofen. These compounds share the property of being good glass formers and present monotropic polymorphism. In the present analysis,
we are mainly focusing on the localization of nucleation and growth zones and the role of a transient crystallization of the metastable
phase. On the basis of the elementary theories, the results offer the opportunity to discuss the impact of interfacial energies, molecular
mobility, crystal disorder, liquid short-range order, and crack formation in the glass.  C 2014 Wiley Periodicals, Inc. and the American

Pharmacists Association J Pharm Sci 103:2615–2628, 2014

Keywords: crystallization; amorphous; nucleation; kinetics; polymorphism; crystal growth

INTRODUCTION stability is that these rates both have a maximum at some de-
gree of undercooling. The existence of such maxima is essential
Preparing poorly soluble drugs in the amorphous state is con-
for the capability of vitrifying a melt by cooling it at sufficiently
sidered to be one of the more attractive methods of enhanc-
high rate. The two maxima do not necessarily occur at the same
ing dissolution and dilution properties.1,2 The most important
temperature (see Fig. 1b). The relative temperature positioning
drawback of using pharmaceuticals in the amorphous state is
of the nucleation and growth zones is the basic feature that de-
their inherent instability to crystallization upon storage, which
termines whether a compound is or is not a good glass former.
eventually leads to the loss of the beneficial dissolution proper-
Simple evidence of this is that often undercooled pharmaceu-
ties. Moreover, avoiding crystallization is of course the decisive
ticals are more prone to crystallization upon reheating than
stage in the amorphization process itself.
upon cooling because of the maximum rate of nucleation being
Amorphization can be achieved via several routes in addition
at a significantly lower temperature than that of growth. At
to the conventional quench cooling of the melt (milling, fast con-
any temperature, the global kinetics of recrystallization will be
densation, spray drying, and so on).3 Whatever the amorphiza-
dictated by the rates of both nucleation and growth processes.
tion route, recrystallization of an amorphous compound can
Controlling the stability of an amorphous pharmaceutical, and
occur throughout the temperature domain of the undercooled
optimizing the amorphization process, thus requires the iden-
melt (T < melting temperature, Tm ), which is a metastable
tification of the temperature domain of preferred occurrence of
state of matter (this state can even be unstable below the glass
each process and the temperatures corresponding to maximum
transition temperature, Tg ). An amorphous undercooled com-
rates. Such a determination can provide a better insight into
pound can be maintained in a metastable state for an amount
the rate of global crystallization and kinetic laws themselves,
of time that depends strongly on temperature. An understand-
but is difficult in practice because as the critical size of nuclei
ing of the lifetime of metastability requires the investigation of
is of the order of a few nm, the initial stage of nucleation is not
the kinetics of recrystallization at each temperature. Crystal-
observable in situ.
lization of an undercooled amorphous melt in fact results from
The crystallization process is complicated by the fact that
the complex interplay of nucleation and growth processes (see
molecular compounds are often polymorphic. Nucleation does
Fig. 1a). Nucleation is the process by which crystalline clus-
not necessarily correspond initially to that of the more stable
ters having a minimum critical size appear randomly, but at
phase. This has been popularized by the empirical Ostwald’s
some given rate N [with dimension t−1 L−3 in the usual three-
rule of stages,4,5 which states-without theoretical foundation–
dimensional (3D) space], within the amorphous matrix. Once
that the first phase to appear is the one which is closest in free
formed, the crystalline grains grow with a domain wall velocity
energy to the parent phase.
V (with dimension t−1 L). The rates of these two processes have
The investigation of the crystallization of indomethacin poly-
their proper temperature variations. The most important fea-
morphs from the amorphous state by Zografi and coworkers6,7
ture with regard to amorphization capability and amorphous
is particularly illustrative of the main factors that influence
recrystallization. By a direct microscopic observation of crys-
tal particle number density (see Figs. 1a and 1b), it was
Correspondence to. Marc Descamps (Telephone: +33-3-20-43-49-79;
E-mail: marc.descamps@univ-lille1.fr) demonstrated that the nucleation rate of phase " has a max-
Journal of Pharmaceutical Sciences, Vol. 103, 2615–2628 (2014) imum above Tg , whereas the growth rate maximum is lo-

C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association cated at higher temperature somewhere between Tg and Tm .

Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014 2615

2616 MINIREVIEW
Figure 1. Photomicrograph of the indomethacin "-crystal form grown from the amorphous phase. Reproduced from Andronis and Zografi7 with
permission from Elsevier. (b) Nucleation and growth rates for the indomethacin "-crystal as a function of temperature. (Adapted from Figs. 7
and 8 of Andronis and Zografi7 with permission from Elsevier).
Furthermore, it was shown that these positions are different
for the two known polymorphs of indomethacin, which is the
essential feature of their selection during crystallization. Fi-
nally, the potential important role of the crystal—amorphous
interface energy in this polymorph selection was stressed.
In line with these previous works, the purpose of the present
paper is to exemplify the recrystallization process of two molec-
ular compounds studied in our group: L-arabitol8,9 and RS
ibuprofen.10,11 These compounds share the property of being
good glass formers and present monotropic polymorphism.
More specifically, we will pay attention to a possible separation
between zones of preferred nucleation and preferred growth
and to the interplay of crystallization of the metastable poly-
morphs.
This new analysis offers an opportunity:
r to draw a TTT (temperature, time, transformation rate)
diagram, which is a familiar concept in the domain of met-
allurgy but less so in pharmaceutical science;
r to show the interest of a scaling analysis of the transfor-
mation curves for identifying changes of kinetic regimes;
r to define a simple differential scanning calorimetry (DSC)
protocol which allows the preferred zones of nucleation
and growth to be located;
r to highlight the role of a transient polymorphic form as a
facilitator of nucleation and (or) growth of the stable form;
r to point out the role of cracks as sources of heterogeneous
nucleation.
RS ibuprofen is particularly illustrative of the resistance of
an ordered racemic compound against nucleation in contrast
with the relative ease of nucleating a more disordered form at
low temperature. Results obtained from the two compounds al-
low the important role played by the interfacial energy in the
separation of nucleation and growth, and on phase selection,
to be stressed. The order/disorder contrast between the crys-
tallized phase and the parent undercooled melt is certainly of
great importance in modifying the entropic contribution of the
free energy surface. A possible link with modification of molec-
ular mobility at the interface will be briefly addressed.
Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
MATERIALS AND METHODS
Compounds were purchased from Sigma–Aldrich and used
without further purification.
Differential scanning calorimetry experiments were carried
out in DSC Q10 and DSC Q1000 calorimeters from TA Instru-
ments with a heating rate of 10 K/min. A small amount of sam-
ple (less than 5 mg) was enclosed in a hermetic aluminum pan.
Measurements were performed under dry helium (at flow rate
of 25 mL/min) to improve the thermal conductivity. A liquid
nitrogen cooling system was used in order to reach temper-
atures as low as −130◦ C. Temperatures and enthalpies were
calibrated using indium at the same heating rate and the same
environmental conditions as the experiments.
Powder X-ray diffraction (PXRD) experiments were per-
formed with an INEL CPS 120 diffractometer (8Cu K"1 = 1.54056
Å) equipped with a 120◦ curved position sensitive detector cou-
pled to a 4096 channel analyzer. A Cryostream Plus controller
from Oxford Cryosystems was used to regulate the tempera-
ture. Samples were placed into Lindemann glass capillaries
(Ø = 0.7 mm).
RECRYSTALLIZATION OF L-ARABITOL
L-Arabitol is liquid above Tm I = 101◦ C8,9 and can be deeply
undercooled even at rates as low as 2◦ C/min to give rise to a
calorimetric glass transition at Tg ≈ −14◦ C (scan rate 5◦ C/min).
Recrystallization can only be observed upon reheating after su-
percooling to a sufficiently low temperature and using a suffi-
ciently slow heating rate (see, for example, Fig. 3).
Overall Crystallization Kinetics of the Undercooled Melt
To determine the overall crystallization rates, amorphous L-
arabitol was prepared by quenching the melt at different tem-
peratures ranging from Tg to Tm . The recrystallization was fol-
lowed isothermally using DSC. In this condition, the exothermic
heat flow is directly proportional to the enthalpy release rate
and thus to the crystallization kinetic rate. At each anneal-
ing temperature, the samples were followed for periods of up to
20 h. For T > 50◦ C, no recrystallization could be detected during
a reasonable annealing time. At lower temperatures, however,
the annealing duration was enough to recrystallize totally the
initial amorphous phase. Figure 2 shows a typical isothermal
DOI 10.1002/jps.24016
 MINIREVIEW 2617

Figure 2. Typical DSC isothermal thermogram (T = 25◦ C) showing recrystallization of L-arabitol and corresponding time dependence of the
fractional volume X(t) recrystallized.

T (°C)
Maximum rate
60
of growth

50 ● ●●
5% ● ● ● 90%
40 ● ● ●

● ● ●

30 ● ●●

●● ●

20 ● ● ●

● ● ●
Figure 3. Temperature dependency of the time evolution of the frac-
tional volume X(t) of recrystallized L-arabitol in phase I. The different 10
temperatures are that reached after a quench from the melt (obtained Maximum rate
from DSC isothermal measurements). Nmax
of nucleation

DSC signal (at T = 25◦ C) with a peak in the enthalpy release at
time tpeak ≈ 115 min, which corresponds to the maximum rate
of crystallization. Time integration and normalization of this
signal gives the time (t) evolution of the fraction of material
transformed X(T,t), which has a typical sigmoidal shape. X(t)
varies from 0 to 1 during the crystallization. The observed time
evolutions of X(t) for various temperatures between 15◦ C and
50◦ C are summarized in Figure 3. The progress of the isother-
mal crystallization as a function of time and temperature is con-
veniently represented by the TTT diagram shown in Figure 4.
The TTT diagram is constructed from the X(T,t) curves and
shows a nose-shaped feature of most rapid isothermal crystal-
lization at about 30◦ C, where 1 h is enough to fully crystallize
the DSC sample. When cooling the melt, the temperature range
of this nose must be passed quickly in order to successfully vit-
rify the sample. The overall behavior can be understood by the
fact that the crystallization rate is obviously zero at the equilib-
rium melting temperature Tm , where an infinite time would be
needed to crystallize the sample because the thermodynamic
driving force disappears at this temperature. The crystalliza-
200 400 600 800
Time (min)
Figure 4. (L-Arabitol) TTT (Temperature, Time, Transformation
rate) diagram derived from Figure 3. Each line corresponds to a given
value (5%, 50%, 90%) of the fraction of material transformed.
tion time then decreases when temperature decreases because
the thermodynamic driving force increases. At temperatures
lower than that of the nose, the crystallization time increases
as molecular mobility decreases when approaching Tg .
Localization of Preferred Temperatures of Nucleation and Growth
Scaling Analysis of the Growth Curves
There are several factors that combine to determine X(T,t) and
the overall crystallization kinetics. Among these factors are the
nucleation rate (N) and the growth rate (V = linear velocity).
When both events occur together during the recrystallization,

DOI 10.1002/jps.24016 Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
2618 MINIREVIEW
1.2
X (t / t0.5)
1.0
0.8
0.6
0.5
0.4
0.2
15°C T 40°C
0.0
45°C
–0.2
0.0 0.2 0.4 0.6 0.8
Figure 5. (L-Arabitol) The scaled curves of X(t) (corresponding to those shown in Fig. 3) plotted in terms of the scaled time t/t0.5 .
the most simple model for X(t), which takes into account at the
same time the effective decrease of the nucleation efficiency as
the untransformed fraction 1 − X(t) decreases and the impinge-
ment of neighboring grains at the end of crystallization, is that
of JMAK (Johnson, Mehl, Avrami, and Kolmogorov).12
For homogeneous nucleation and isotropic 3D growth:
X(t) = 1 − exp[−6(t/t0 )4 ](6 = 4B/3)
This is a universal sigmoidal function of the time scale:
3 −1/4
t0 = (NV )
where 4 (= d + 1 where d is the dimensionality of the space in
which the nucleation and growth transformation is proceeding)
is the Avrami exponent. X(t) is an almost symmetric sigmoid
on both sides of the half transformation point (occurring for
t0.5 ≈ t0 ). As a result, we expect that X(t) considered at different
temperatures—with very different values for N and V giving
different values of t0 —can be scaled onto a universal curve
once plotted versus t /t0.5 .
Figure 5 shows the X(T,t) curves corresponding to those of
Figure 3 plotted against a scaled time parameter (t/t0.5 ). At the
lowest temperatures (15◦ C ≤ T ≤ 40◦ C), scaled curves super-
impose rather well showing that scaling is well satisfied. This
suggests that in this temperature domain, the recrystallization
kinetics obey the same law and correspond to a nucleation and
growth process. This plot reveals that kinetics recorded at the
highest temperatures (45◦ C and 50◦ C) deviate strongly from the
universal sigmoidal symmetric shape. The 50◦ C growth curve
has a pronounced step like behavior associated to a long time
lag followed by a very fast crystallization. This could only be de-
scribed by an unphysically high value of the Avrami exponent
d + 1 > 10. Such behavior indicates that on approaching Tm nu-
cleation and growth do not occur simultaneously in a continu-
ous process, and also shows that there are no preexisting nuclei
Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
15°C
20°C
25°C
30°C
35°C
40°C
50°C 45°C
50°C
1.0 1.2 1.4 1.6 1.8 2.0 2.2
t / t0.5
t/t(1/2)
from which crystallization could propagate by growth (in that
case an Avrami exponent d + 1 < 4 would be expected). This
simple scaling analysis provides insight into the mechanism of
crystallization at the highest temperature: the nucleation rate
is very small: about 7 h are needed for one nucleus to appear
in the DSC sample. Growth from this nucleus is comparatively
fast and the sample is fully crystallized in less than 1 h. From
this analysis, we can conclude that N and V have their maxima
in distinct temperatures ranges.
Maxima of Nucleation and Growth Rates of the Stable Phase I
We have used a DSC instrument working in temperature scan-
ning mode to locate the approximate temperature ranges of the
respective maxima of N(T) and V(T). In the following experi-
ments, crystalline L-arabitol samples were heated and held at
117◦ C (≈Tm + 15◦ C) for 15 min to ensure complete melting.
Melted samples were then cooled to different temperatures Ta
< Tm at the highest achievable cooling rate allowed by the DSC
(>20◦ C/min). The samples were then kept for 60 min at Ta and
afterward reheated at 2◦ C/min by DSC.
Figure 6 shows the DSC curves recorded upon heating sam-
ples cooled to temperatures Ta ranging from −83◦ C to 82◦ C.
No calorimetric events can be observed on the DSC heat-
ing curves for samples annealed at Ta > 35◦ C. The absence of
a melting endotherm in particular shows that no crystalliza-
tion process occurred during the cooling/heating cycle. For Ta
< −10◦ C, we observe a very small endothermic manifestation
of melting, which shows that only an extremely limited recrys-
tallization (less than 3%) occurs during the cooling/heating cy-
cle. Throughout this Ta range, the enthalpy of melting is very
small and independent of Ta preventing any variability from
being detected. Furthermore, crystallization exotherms on the
DSC curves are not detectable. On these curves, we can see
the localization of the glass transition temperature at Tg ≈
−12◦ C. These results show that the sample was totally amor-
phized during cooling, which is consistent with what can be
DOI 10.1002/jps.24016

Figure 6. (L-Arabitol) DSC curves recorded upon heating (heating
rate of 2 K/min) for samples undercooled at temperatures Ta ranging
from −83◦ C to 82◦ C and annealed for 60 min at this temperature.
predicted from the global TTT representation and the position
of the nose of most rapid crystallization. In particular, no signif-
icant nucleation occurred in this low temperature domain. On
the contrary, for annealing temperatures Ta ranging between
−5◦ C and 30◦ C, pronounced crystallization exotherms, followed
by melting endotherms, are observed. The exotherms have their
maxima located not far below the melting point, in the range
60◦ C–95◦ C, that is, at temperatures clearly separated from the
annealing Ta domain. The preceding analysis of isothermal ki-
netics - particularly that recorded at 50◦ C demonstrates that
above 50◦ C, we enter a temperature range where growth ve-
locity is increasing strongly, and nucleation in a volume as
small as that of the DSC sample becomes negligible during
the time taken to cross the recrystallization exotherm. The in-
terpretation is that the exotherms correspond to the growth of
crystals nucleated at significantly lower temperature. If so, as
exotherms occur in the same temperature range, V(T) values
are expected to be similar. The measured enthalpy of recrystal-
lization is roughly proportional to the number of nuclei formed
at lower temperature. The maximum enthalpy of recrystalliza-
tion is obtained for an annealing performed at Ta = 5◦ C, and so
this is the temperature where the maximum of N is expected.
Transient Metastable Phase
Careful investigations of the crystallization conditions allow
the detection of the transient appearance of a new metastable
form of L-arabitol (which will be referred to below as phase II).
We report two experiments (PXRD and DSC) that display this
additional complexity and the influence of this less stable form
on the crystallization of form I.
Figure 7 shows DSC heating scans obtained after applying
isothermal annealing of different durations ta to samples of L-
arabitol quenched from the melt to Ta = 20◦ C (a temperature
situated in the domain of favored nucleation of phase I). Be-
fore recording the DSC scans, in order to amplify the transfor-
DOI 10.1002/jps.24016 Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
MINIREVIEW 2619
Figure 7. (L-Arabitol) DSC heating scans after applying isothermal
annealing of different short durations ta to samples quenched from the
melt to Ta = 20◦ C.
mations that have occurred at Ta , the annealed samples were
heated to 70◦ C and held at this temperature for 30 min where
growth only is expected. In the hope of learning something
about the nucleation mechanism itself, ta durations smaller
than that which was used in the production of Figure 6 were
employed. After a short annealing time, a small melting peak
is observed at Tm II = 80◦ C (onset), which is significantly lower
than the value observed initially. Increasing ta gives rise to
the progressive appearance of a melting peak at Tm I and a de-
crease in the amplitude of that occurring at Tm II . These results
show that annealing initially induces nucleation of metastable
form II of L-arabitol, which melts at lower temperature. When
ta is increased, the nuclei of phase II progressively disappear,
whereas the nuclei of the stable phase I form and cause melting
at the higher temperature. The existence of a metastable phase
for L-arabitol has been postulated previously.13
A sample fully converted to form II can be obtained by
quenching L-arabitol from the melt to a low temperature (20◦ C)
and holding it there for 2 min followed by a rapid increase to
70◦ C (Tm II – 10◦ C) where growth of phase II is maximum. Full
crystallization at this temperature occurs in less than 2 h. No
contamination by phase I is observed during this process, which
once again confirms that nucleation of phase I only operates at
low temperature and after a long enough time. Phase II has
lower melting temperature (Tm II = 80◦ C), lower melting en-
thalpy (Hm ≈ 28.8 kJ/mol) and melting entropy (Sm ≈ 81
J/mol K) than phase I (Tm I ≈ 101◦ C, Hm ≈ 36.5 kJ/mol and
Sm ≈ 98 J/mol K). This is sufficient information to conclude
that phases I and II form a monotropic set.
To get an insight into the features of this transient
metastable phase, long isothermal (at Ta = 0◦ C) time-resolved
X-ray measurements were performed for durations of up to 14 h.
In order to increase the intensities of Bragg peaks and to help
in resolving the kinetics, a procedure was employed to enhance
nucleation. The melted sample was quenched in liquid nitrogen
(to well below Tg ) before investigation. The associated thermal
shock produces cracks in the glassy sample, which then sup-
port heterogeneous nucleation upon reheating. The occurrence
and effect of cracks as nucleation facilitators will be discussed
and visualized in more detail below for the case of Ibupro-
fen. X-ray results are shown in Figure 8a. During the isother-
mal annealing, peaks characteristic of the metastable phase II
2620 MINIREVIEW
Figure 8. (a) (L-Arabitol) Time sequence of the X-ray diffraction pat-
terns during the recrystallization at Ta = 0◦ C. To speed up the evo-
lution, the melted sample was previously quenched in liquid nitrogen
to induce cracks and heterogeneous nucleation before recording. Peaks
arrowed in blue and red are for phase II and phase I, respectively.
(b) (L-Arabitol) Time evolutions of the sum of the integrated intensities
of the representative Bragg peaks shown in Figure 8a (normalization
to the max observed for phase II).
appear initially and then disappear when Bragg peaks of phase
I progressively increase. To investigate quantitatively the time
evolutions of the amounts of phases II and I, we have selected
three specific Bragg peaks for each phase, which are sufficiently
spatially resolved and intense. Peaks arrowed in blue and red in
the figure were used for phase II and phase I, respectively. The
time evolution of the amounts of these two phases is thus repre-
sented by the evolutions of the sum of the integrated intensities
of the three representative Bragg peaks. Figure 8b shows the
parallel evolutions of these quantities (normalized for clarity
Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
Figure 9. (RS ibuprofen) DSC curves recorded upon heating (heating
rate 10 K/min) for samples undercooled at different temperatures and
annealed for 360 min at this temperature.
to the maximum value observed for phase II during anneal-
ing). Clearly, phase II develops first and its rate of evolution
decreases when phase I starts to grow. Phase I then develops
to the detriment of phase II. Finally, phase I only remains and
continues to crystallize even after phase II has disappeared.
RECRYSTALLIZATION OF RS IBUPROFEN
The investigation of the recrystallization and polymorphism of
racemic ibuprofen (ra-Ibu)10,11 provides additional understand-
ing and insight into factors that have an impact on nucleation
and growth. The typical feature distinguishing the crystal state
of the initial compound (hereafter designated by phase I) is
that the unit cell contains an equal number of molecules of
each enantiomer S(+) and R(−), which are positioned in an or-
dered manner. ra-Ibu is representative of a large class of active
ingredients. The racemic compound I has significantly higher
melting temperature (Tm I ≈ 71◦ C), greater melting enthalpy
(Hm ≈ 26.9 kJ/mol) and melting entropy (Sm ≈ 78 J/mol K)
than each S(+) or R(−) crystalline isomer (Tm ≈ 46◦ C–52◦ C,
Hm ≈ 18 kJ/mol and Sm ≈ 55 J/mol K).14 In addition to the
stable ordered racemic compound I, the existence of another
metastable crystalline form II that melts at Tm II ≈ 17◦ C has
been shown.10,11,15 We present a brief account of the crystalliza-
tion conditions of these two phases and their relationship10,11
with the aim of deriving trends linked to the bicomponent na-
ture of the compound.
Crystallization of Stable Phase I
In order to locate the preferred zones of nucleation and growth
of phase I, we have applied the protocol described above for L-
arabitol (see Fig. 6) consisting of a cycle of melting—quenching
to various annealing temperatures Ta and holding at that tem-
perature for a given duration ta and reheating. Figure 9 shows
that an exotherm of recrystallization is detectable at high tem-
perature (between 35◦ C and 65◦ C) upon heating, only if the
sample has been previously annealed for a sufficient period
DOI 10.1002/jps.24016

Figure 10. (a) (RS ibuprofen) DSC heating curve obtained after un-
dercooling of the melt well below Tg (typically to −130◦ C) then reheat-
ing to 0◦ C for a 30 min. annealing. It reveals successive melting of
phase II and I. (b) (RS ibuprofen) Gibbs diagram.
between −40◦ C and −10◦ C. This recrystallization is that of
the racemic crystal (phase I) as melting occurs at 71◦ C. These
results show that nucleation and growth zones are very well
separated, which is consistent with the very good glass forming
nature of ra-Ibu (Tg ≈ −45◦ C). Nmax is located at about −30◦ C,
not far above Tg . Vmax is obviously impossible to locate precisely
in a DSC heating scan, but the temperature range where rapid
growth is expected is situated not far below melting. It should
be noted that an annealing duration as long as ta = 360 min was
necessary to trigger a noticeable nucleation. As will be shown
below, the initial crystallization of phase II can significantly
increase further formation of phase I.
Crystallization of Metastable Phase II
A new crystalline polymorph (II) was found for which nucle-
ation and growth from the melt were favored at temperatures
significantly lower than that which control crystallization of
phase I. Figure 10a shows the most efficient operational method
of rapidly and completely recrystallizing the quenched liquid
into form II.10 This method consists of the following steps: un-
dercooling of the melt well below Tg (typically to −130◦ C) then
heating to 0◦ C for a 30 min. period of annealing. It is this proto-
col that was initially used to prepare powder samples suitable
for structural analysis of phase II.15 It should be noted that
phase II can also be crystallized after directly cooling to 0◦ C,
but this process takes about a day and involves a long time lag
of unpredictable duration (typically 14 h).16 The difference in
crystallization behavior with these two protocols is associated
with the fact that deep undercooling below Tg induces cracks
in the glass, which favor heterogeneous nucleation during the
reheating step. The presence of cracks in a glassy sample has
been recognized as being a factor which significantly affects
nucleation.17 The DSC sample is thus more highly nucleated
and less than 1 h is enough to crystallize phase II at 0◦ C. As
cracks are cured not far from Tg = −45◦ C, the efficient - crack
assisted - heterogeneous nucleation process is expected to be
DOI 10.1002/jps.24016 Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
MINIREVIEW 2621
effective only between −130◦ C and approximately −40◦ C. As
may be deduced from Ref.16, nucleation of phase II well above
Tg (at 0◦ C) is much more homogeneous and slow. The long,
irreproducible time lag preceding crystallization after a direct
quench to 0◦ C, and the following 8–10 h needed to grow nucleus
of phase II, are in fact consistent with a rare, homogeneous nu-
cleation event. The rather short recrystallization exotherm at
0◦ C obtained after cooling a sample to low temperature (see
Fig. 11a) is thus mainly linked to the growth process of a rela-
tively highly nucleated amorphous sample. Interestingly, such
a growth process occurs not far below the melting temperature
of phase II (Tm II ≈ 17◦ C). The present experiment further sug-
gests that even if the rate of nucleation of phase II is increased
by cracks, it may occur below Tg .
Relationship Between Crystallizations of Stable (I) and Metastable
(II) Phases
It should be noted that even if heterogeneities promote nu-
cleation of phase II, they do not invert the order of appear-
ance of the phases. The initial transformation to phase II, how-
ever, accelerates the subsequent transformation toward phase
I. Isothermal DSC (Fig. 11a) shows the chain of the different
steps when annealing is continued. The exotherm takes a bi-
modal aspect whose second bump corresponds to the II to I
conversion. The latter develops on a longer timescale than the
initial crystallization of phase II. Hot-stage microscopy (Fig.
11b) allows the visualization of the crystallizations and their
intertwining at 0◦ C after a similar melt-cool-heat treatment.
Part of the sample is sandwiched between two cover slips (be-
tween the dashed lines in the Fig. 11b) and was free of cracks
that instead appear in the nonconfined area. This setup allows
visualization of homogeneity or heterogeneity of the nucleation
and growth process. The succession of slides shows that a ma-
jority of crystals of phase II develop in the outer part and pro-
gressively grow into the confined amorphous sample (in black).
After 2 h, phase I starts developing at the expense of phase
II (interface delimited by dotted line). Heating the partially
converted sample allows the identification of the two phases
by their melting temperatures. After a direct quench to 0◦ C,
the same succession of transformations is observed, but over a
much longer time scale.16
Specificities of Phase II
Phase II has a significantly lower melting temperature (Tm II
= 17◦ C), smaller melting enthalpy (Hm ≈ 8.8 kJ/mol) and
melting entropy (Sm ≈ 30 J/mol K) than racemic phase I.
Figure 10b shows a schematic Gibbs free energy (also known
as free enthalpy on account of its functional definition: G =
H – T·S) diagram, which situates phase I and II as well as
the liquid phase. Slopes were calculated from the evaluation
of the melting entropies of the crystalline phases. Schematic
curves are plotted assuming that the entropies are tempera-
ture independent. The picture is that of a monotropic situation
where the metastable phase appears to be unusually close in
entropy to the liquid. There are a number of features that show
that the crystalline structure of the metastable phase II of RS
Ibuprofen is highly disordered. Refinement of the crystalline
structure from X-ray data using the hypothesis of an ordered
arrangement was only possible by introducing an anomalously
high effective Debye Waller factor.15 Disorder is indicated in X-
ray diffractograms, which show a very rapid decrease of peak
2622 MINIREVIEW
Figure 11. (a) (RS ibuprofen) DSC thermogram for isothermal recrystallization recorded at 0◦ C after deep undercooling to −130◦ C (induction of
cracks). Successive crystallizations of phase II and I are appearing. (b) (RS ibuprofen) Corresponding time sequence of micrographies. Dash lines
delimit part of the sample between two microscope slides. Dotted lines delimit the growing phase I. The figure shows the progressive development
first of phase II then of phase I at the expense of phase II.
intensities with increasing Bragg angle. Low-frequency Raman
data of the metastable phase also show the features of a disor-
dered crystal.18
DISCUSSION
Remarks about Behaviors Identified for L-Arabitol and RS
Ibuprofen
The two compounds exhibit monotropic polymorphism. The
metastable phase II of ra-Ibu, however, has a significantly lower
Tm II with regard to Tm I and a much smaller melting enthalpy
(and entropy). This is an indication of the significant degree
of disorder characteristic for phase II of ibuprofen. Concern-
ing the recrystallization from the melt of the stable forms, it
was concluded in both cases that the maxima of N and V (Nmax
and Vmax ) are set well apart from each other. Nmax is situated
slightly above Tg , whereas Vmax is located slightly below the
melting temperature. This separation is clearly the origin of
the high propensity of both compounds to form glasses. The
kinetics of recrystallization of the stable phase is, however, sig-
nificantly faster with L-arabitol. As a result, a TTT diagram
for crystallization of phase I could be plotted, and its nose lo-
calized, which would be practically impossible with ra-Ibu. It is
important to note that Nmax and Vmax are situated on either side
of the TTT nose. This is a consequence of the fact that the char-
acteristic times for nucleation and growth combine in an actual
effective characteristic time t0 for global recrystallization. This
shows clearly that it will not be possible to extract activation
energy for the global phenomena as is sometimes attempted.
We have shown the interest of using a scaling analysis de-
rived from a simple model of nucleation and growth to local-
ize temperature ranges where kinetics obey the same phys-
ical law. It is very useful to identify scaling violations, that
reveal changes of regimes, to prevent the attribution of erro-
Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
neous time-scale evolutions where it is the physical law itself
that is changing.
Analysis of the first stage of crystallization in the tem-
perature domain where the maximum of nucleation Nmax of
phase I of both compounds (typically not far above Tg ) is ob-
served gives insights into the nucleation pathway of the stable
form. In both cases, it generally involves a first step of forma-
tion of a more disordered metastable form (phase II), which
only emerges transiently. This is another example of cross-
nucleation between polymorphs.19 We may however suspect a
double effect: that of a secondary nucleation on the less-stable
phase, which occurs concomitantly with a II to I transforma-
tion. Phase II thus facilitates nucleation of form I. However, the
temperature where the maximum rate of the latter is found to
occur is largely decoupled from temperatures of fast growth
velocity.
In both cases, we have seen that initial formation of cracks
in the deeply quenched glass is able to promote substantial
heterogeneous nucleation even below Tg , particularly with ra-
Ibu. This is not incompatible with more homogeneous, less fre-
quent, nucleation above Tg . Heterogeneities simply amplify the
nucleation rates in the temperature domain where homoge-
neous nucleation slows down significantly because of the lack
of molecular mobility. The presence of cracks should certainly
be taken into consideration when investigating the stability of
solid amorphous compounds.
Remarks about Mechanisms and Data Analysis
The kinetics of first order transformations such as recrystal-
lizations is a very complex and challenging question both in
physics and in material science. It is out of the question to at-
tempt an in-depth analysis of our observations. Nevertheless,
they can be used to gain insights using the most elementary
models.
DOI 10.1002/jps.24016

Classical Nucleation and Growth Picture in Brief
Homogeneous nucleation is a thermally activated process
by which some crystalline clusters have to be formed in order
to enable a phase transformation to occur.20–22 In the conven-
tional Becker-Döring capillarity theory (see for example 23 ), the
free enthalpy of formation of the cluster is assumed to result
from the competition between an unfavorable positive interfa-
cial free enthalpy (() and the negative bulk driving force (G).
G is the free enthalpy (Gibbs free energy) difference between
the parent melt and product crystalline phase. Interfacial en-
ergy prevails for small crystalline clusters (nuclei). The latter
have a good chance of growing if they exceed a certain criti-
∗
cal size r3D (T) and overcome the nucleation barrier g∗3D (T).
Nucleation events thus occur with a steady rate:
N(T) = f 0 (T)exp(−g∗ /RT)
where f0 is an “attempt frequency” for the addition of molecules
from the metastable melt to the stable crystal across the inter-
face. For a spherical 3D nucleus:
∗
r3D = 2(/G and g∗3D = 16B(3 /3G2
If we assume that the driving force G is proportional to the
undercooling T = Tm – T:
G ≈ Sm · T = Hm · T/Tm
where Hm and Sm are respectively the latent heat and en-
tropy of melting, then:
∗
r3D (T) ∼ 1/T and g∗3D (T) ∼ 1/T2 .
In a first approximation, and on a short temperature inter-
val, we can consider that f0 (T) decreases with temperature in an
Arrhenius way and scales roughly with the diffusion constant
of the bulk liquid. The effect of f0 (T) becomes significant near
the glass transition. The two terms of N(T) vary with tempera-
ture in opposite directions and a maximum Nmax is expected at
some temperature above Tg .
If the nucleus forms in contact with other phases, impurity
sites, or containers walls, the interfacial free enthalpy term is
reduced, and the heterogeneous nucleation barrier is smaller
than g∗3D by a catalytic potency factor f < 1. As will be discussed
below, cracks, which may form in the molecular vitreous solid,
can strongly enhance crystal nucleation in a temperature do-
main (T < Tg ) where slow molecular mobility is expected to
freeze the nucleation process.
Growth Process. Once a viable supercritical nucleus is
formed, it will continue to grow during isothermal annealing. In
the following, we consider only the case where density change
and component redistribution are negligible (a process con-
trolled by the interface). There are two types of crystal/liquid
interfaces: an interface which is rough (or diffuse) at the molec-
ular level or a flat (or smooth) sharply defined interface24,25 .
Taking into account the estimations made by Jackson,26,27 flat
interface is expected for compounds having high entropy of
melting (Sm > 4R ∼ = 33 J/mol K), whereas rough interfaces
are expected for substances having low Sm values (Sm <
2R ∼= 16.6 J/mol K). To these different types of interfaces corre-
DOI 10.1002/jps.24016 Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
MINIREVIEW 2623
spond different modes of crystal growth: normal (or continuous)
growth for diffuse interfaces, lateral growth for sharp inter-
faces. The latter can be itself subdivided in two main different
types: spiral (or dislocation) and 2D nucleation.24,25 These dif-
ferent mode of growth give rise to different expression of the
temperature-dependent linear growth rate V(T). V(T) can be ex-
pressed in a compact form, which summarizes the results given
in the literature7,24 for the different modes of crystal growth. It
is derived from the initial semi-phenomenological expression of
Turnbull20 and can be written in the form:
V(T) ∝ V0 (T) ·  · [1 − exp(−G/RT)]
To cross the interface, a molecule must overcome an acti-
vation free energy Ga , which is roughly that of the diffu-
sion coefficient of a molecule in the liquid, so that: V0 (T) ∝
exp(−Ga /RT)].  is a function of G, which depends of the
specific mechanism of growth. The term inside the brackets ex-
presses the influence of the thermodynamic driving force G
on the net flux from liquid to crystal.
r For normal growth, molecules are directly incorporated
at the growth sites of the crystal surface. In that case: 
∼
= const. ( proportional to the relative number of growth
sites). This specific form of the equation predicts a quasi
linear increase in growth velocity with decreasing tem-
perature (increasing T) at small undercoolings and a
decrease at much lower temperatures as the viscosity in-
creases. As for N(T), a maximum Vmax is thus expected
at some undercooling. It should be noted that, contrary to
the case of nucleation, the interface free energy ( has no
explicit effect on the normal growth velocity, and thus on
the position of Vmax .
r For lateral growth of a dislocation clean surface, nucle-
ation of a 2D disc-shaped layer is a prerequisite for the
continuation of the process. Critical radius and nucle-
ation barriers associated to this 2D process are now given
by:
∗ (
r2D = and g∗2D = B(2 h/G
G
where h (of the order of nm) is the height of the 2D nuclei.
The limitation associated to the 2D nucleation is taken into
account in the expression of  ∼ = const. × exp(−g∗2D /RT).
The interface energy ( may that time have an influence on
the position of Vmax . Vmax is expected at a temperature some-
what lower than for normal growth. To get an idea of the pos-
sible influence of the interface energy on the proximity of Nmax
and Vmax , we calculate the ratio of the nucleation barriers:
g∗2D /g∗3D = (3/16)(G × h)/(
Taking the numerical values available for the " phase of
indomethacin (Fig. 9 of Ref. 7): 0 (at Tm ) < G (kJ/m3 ) < 2.5 ×
104 (at Tg ), ( ∼
= 0.02 J/m2 , h ∼
= 1 nm, we find:
0(at Tm ) < g∗2D /g∗3D < 1/4(at Tg )
This simple evaluation shows that the 2D nucleation barrier
is significantly lower than the 3D one on all the temperature
range situated between melting and glass transition. The 2D
2624 MINIREVIEW

nucleation which is associated to a lateral growth should thus

have a limited influence on the position of Vmax with regard to
the position of Nmax .

Impact of the Interface Free Enthalpy

Nmax and Vmax are both the result of the competition between
the increasing thermodynamic driving force and the decreas-
ing molecular mobility. Their temperature positions, however,
differ mainly because of the effect of the surface tension (. As
we just saw, this should be valid whatever the growth mech-
anism. Concerning recrystallization, ( has a double influence:
first on the separation between Nmax and Vmax then on the phase
selection.
( has a strong impact on the nucleation rate via g∗3D (T), but
has no (or limited for lateral growth) explicit influence on the Crystal Liquid
growth rate (except in the very early stage of growth). Because
of (, the decrease in growth velocity due to the slowing down of Hl
molecular mobility occurs at a smaller undercooling than the TMSl
corresponding decrease in nucleation rate. Nmax is expected at a TM S
T S (interf)
temperature lower than Vmax . A high value of ( and thus of g∗3D
(T) strongly reduces the influence of the driving force G(T) TM S (bulk)
on nucleation and contributes to an increase in the distance = HM
between the two maxima. As a result, undercooling and glass
formation become easier. Hc
The phase selection during recrystallization of an under-
TMSc
cooled melt is strongly dependent on the structure dependence
of (. For a stable phase, the driving force G(T) is higher than Figure 12. Schematic representation of the crystal/liquid interface
for a metastable phase. At a given T < Tm , the nucleation bar- showing short-range molecular ordering. Corresponding evolution of
rier may, however, be smaller for the metastable phase if ((T) is entropy that illustrates the negentropic approach of Spaepen (see
sufficiently small, resulting in the preferred nucleation of the Ref. 28)
metastable phase.
According to this picture, the stability of the amorphous state
Figure 12 shows a schematic representation of the evolution
(via nucleation/growth decoupling), phase selection, and ulti-
of molecular ordering in the liquid, at the interface, and of the
mately the Ostwald rule of stages have mainly a kinetic origin
corresponding physical quantities: enthalpy H and entropy S.
modulated by the interface.
For simplicity, the temperature is taken to be Tm so that there
At a given T < Tm , the mobility of molecules within the bulk
is a balance between bulk high enthalpy and high entropy:
amorphous state is the same irrespective of the crystallized
Hm = Tm Sm . At the interface, the balance is no longer sat-
phase, and has thus a priori little influence on this modulation.
isfied, which gives rise to the excess free energy (. Obviously,
We will mention below that molecular mobility in the liquid
the maximum value of ( is Hm = Tm Sm (bulk). Molecular or-
near the interface can, however, be modified as a result of the
ganization in the interface locally reduces the configurational
structural short-range organization of the molecules needed to
entropy jump, which becomes:
adjust to the configurational constraints of the crystal plane.

Influence of Disorder and Correlations on the Interface Free
Enthalpy
It must be remembered that the surface tension ( is a free
enthalpy (Gibbs free energy) and as such has an energetic and
entropic contribution. Turnbull,20 then Spaepen28 and Oxtoby29
pointed out that atoms or molecules of the liquid have to in-
crease ordering near the crystal boundary in order to optimize
fitting with the translational order of the crystal and even-
tually to allow an ordered embryo to grow. The entropy loss
corresponding to this interface ordering is mainly at the origin
of the crystal melt interfacial free enthalpy. Spaepen justified
the fact (at least for atomic compounds) that entropy rises more
slowly than enthalpy when going from crystal to bulk liquid.
The only available model for ( which takes into account struc-
tural aspects is the negentropic model,28,30 which provides an
interesting guide to understanding the important potential role
of relative disordering in the crystal embryo and relative order-
ing in the surrounding liquid.
S(interface) < S(bulk).
At Tm , the difference in free enthalpy (per molecule at the
interface) of the liquid, which develops an interface, and that
of the reference bulk is: Tm [S(bulk) − S(interface)].
Spaepen28 proposed the following formal expression for (:
( ∝ " T Sm with "
= [S(bulk) − S(interface)]/Sm (< 1)
This model has been successfully used mainly for atomic
systems and to our knowledge only once for molecular sys-
tems: n-alkane liquids. Turnbull remarked that the relative
undercoolings for several n-alkane liquids are almost an order
of magnitude smaller than those for other simple molecular
melts or for Hg.31 This is related to a very high crystal nucle-
ation frequency and interfacial energies an order of magnitude
smaller than for Hg or H2 O.21,32,33 An immediate consequence

Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014 DOI 10.1002/jps.24016

of the small undercooling is the difficulty of forming glasses
of the n-alkanes. Turnbull and Spaepen attribute this effect to
the high probability for occurrence of linear configurations in
the melt. Such correlations existing in the bulk mean that the
entropy loss in adjusting to the crystal plane is minimized, re-
sulting in rather small values of ". A negentropic model28,30
based on this model34 can give a satisfying estimate of the
crystal-melt tension.
If ( is small, crystallization is easier. From the negentropic
model this can be understood for two main reasons: (1) if a liq-
uid is locally organized, (in a way which mimicks the crystalline
order), it does not need much further organization at the inter-
face, leading to a weak value for ", which for n-alkanes was
found to decrease with increasing n. (2) The other possibility is
that of a disordered crystal giving a relatively low value of Hm
= TSm , meaning that the first nuclei to form are those of the
metastable phase, as is found for phase II of our systems. The
latter have the lowest melting enthalpies and thus the highest
crystalline entropies (as visualized by slopes in the Gibbs dia-
gram). This applies in particular to the highly disordered phase
II of ra-Ibu, which appears prior to phase I. In contrast, the cor-
responding liquid phase is a multicomponent one (mixture of R
and S species), which increases the melting entropy. Ordering
at the interface to adjust to the ordered racemic structure I is
all the more costly in entropy, which hinders nucleation of this
stable phase.
Nucleation from the Melt and from the Glass: Influences of
Cracks and Mobility
A metastable amorphous melt (Tg < T < Tm ) and an unsta-
ble amorphous glass (T < Tg ) obviously differ by their molec-
ular mobilities. Molecular compounds are often fragile glass
formers35 and exhibit a very fast slowing down of the main
" relaxation at the approach of Tg . Below Tg , the amorphous
system becomes solid with ultraslow bulk " relaxations and re-
maining secondary $ relaxations. Molecular mobility can never
be a driver of nucleation, which is thermodynamic in nature. It
only plays the role of a facilitator. Obviously, some mobility is
necessary for crystallization to occur, but simply because mobil-
ity slows down with temperature, this cannot explain by itself
that some nucleation rates seem to rise somewhere in the glassy
state. When attempting to find or to predict the origin of the in-
stability of an amorphous glass with regard to crystallization, it
is important to pay attention to the homogeneous or heteroge-
neous nature of the nucleation. The examples presented above
help to show that, because of its brittle nature, the amorphous
glass is prone to crack some tens of ◦ C below Tg . This is a fre-
quently observed phenomenon with molecular compounds that
can give spikes in the DSC thermogram. Crack generation sub-
stantially increases the specific surface area of the compound
which in turn enhances the possibilities of heterogeneous nu-
cleation. Heterogeneous nucleation rates can be considerably
accelerated by the effective reduction of interfacial energy.21,22
As a result, even if a homogeneous bulk nucleation rate is in-
trinsically slow in the glassy state, the presence of cracks can
multiply this rate substantially. This is to be expected when
reheating the cracked glass and approaching Tg from below.17
Such an effect will no longer occur if cracks are cured near Tg
when fluidity starts appearing. Nucleation assisted by cracks
can only occur at temperature lower that the curing tempera-
ture. It must be mentioned that molecular mobility may amplify
DOI 10.1002/jps.24016 Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
MINIREVIEW 2625
the phenomenon. It has been shown recently36,37 that at the sur-
face of a glassy molecular compound, diffusion of molecules can
be higher than that in the bulk by six orders of magnitude. This
surface mobility is ascribed to the fact that surface molecules
obviously experience interactions that are different from those
in the bulk because of a smaller number of neighbors.
Growth Velocity and a Possible Change of Mobility Near the
Interface
Both systems studied show that metastable (more disordered)
crystals have not only a tendency to be more rapidly nucleated,
but also to grow more rapidly than those of the stable phase.
Several reasons can be invoked. To simplify, we consider the
crystal growth of the metastable form at a point away from the
very early stage where curvature and capillary effect could slow
down the growth.
r If the Sm of the metastable phase is much lower than that
of the stable phase, a change in the mode of growth mech-
anism can be expected, to become (more) continuous and
faster. It could be the case for phase II of ra-Ibu. For phase
II, Sm ∼ = 30 J/mol K. It is a value intermediate between
4R and 2R. For such substances, a transition temperature
from lateral to normal growth is to be expected.24
r In the case of L-arabitol, the Sm of phase II is lower than
that of phase I. However, both are much greater than 4R.
Lateral growth is to be expected for both phases. For phase
I, the driving force G(T) is higher than for phase II, which
would contribute to a decrease of the growth velocity of the
metastable phase. The 2D nucleation barrier for surface
nucleation may, however, be smaller for the metastable
phase if ((T) is sufficiently small, resulting in a faster
lateral growth of the metastable phase.
From the Turnbull equation for interface-controlled growth,
the remaining factor that influences growth velocity is that of
the “jump” frequency of liquid molecules across the liquid–solid
interface. Molecules must overcome an activation energy Ga
by thermal activation, which, in a first approximation is that
which opposes the diffusion of molecules in the liquid, that is,
that involved in viscosity.
The jump frequency is proportional to exp(−Ga /RT). How-
ever, such a term has to be multiplied by the probability (p)
for a molecule to be accommodated on the crystal surface. It is
expected that because of the crystallographic structure, not all
these molecules will find a suitable site to stick to the surface.
The effective flux of molecules from the liquid to the crystal
will be ∝ p exp(−Ga /RT). This induces an apparent modifi-
cation of the activation energy which depends on the degree
of molecular organization on both sides of the interface. There
will be a similar flux in the reverse direction, but modified by
the thermodynamic driving force G. The situation for racemic
ibuprofen is easy to imagine. The liquid is a disordered mixture
of the two enantiomer molecules (R) and (S). At a given T < Tm ,
the activation jump barrier may be effectively smaller for the
metastable phase II if p is large enough. This would result in
a faster growth velocity for the metastable phase. Indeed, we
can imagine that the probability of molecular accommodation
is larger if there is a substitutional disorder between R and S
molecules on the crystal side. The positional molecular order
2626 MINIREVIEW
which is proper to phase I is much less easy to accommodate.
These different considerations show that several factors can
combine to make growth of metastable phases faster.
There is another factor that may slow down mobility near the
interface to a greater or lesser extent. As some molecular or-
dering of the liquid is expected near the crystal boundary, the
which is highly disordered. Recrystallization of phase II of RS
free energy of activation for boundary migration is certainly
ibuprofen is close to this situation.
higher than the free energy Ga for self-diffusion within the
liquid. The mobility involved locally in the growth mechanism
is thus decreased depending both of the degree of accommo-
dation needed to achieve a jump and of the degree of short
range ordering in the liquid side of the interface. Mobility at
the free surface of an amorphous system is the object of intense
activity.36,37 It would be highly useful to improve understand-
ing of the mobility at the crystal/liquid interface. In the case
of confinement of molecular liquids in nanoporous materials, it
is known that some slowing down of the molecular motions at
the interface with the confining material can be observed. In a
fully similar way, we may expect a modification of the molec-
ular mobility at the interface with the growing crystal, which
depends on the nature of the crystalline polymorph.
CONCLUDING REMARKS
Many factors can influence the recrystallization from the melt
and thus the stability of the amorphous systems. If we try to
categorize these factors, we can say broadly that:
1. Thermodynamic is the driver.
2. Molecular mobility is the facilitator.
3. Interface energy is the modulator.
4. Heterogeneities and cracks are amplificators.
From the discussion above, it becomes clear that the molec-
ular entropy of melting Sm , which measures the degree of
similarity between crystal and the melt, plays a pivotal role in
controlling several above quoted factors.
Three types of systems provide useful benchmarks for esti-
mating the tendency of a molecular compound to recrystallize
from the melt more or less easily. Unlike the last type, the first
two are that of bad glass formers:
1. The first type corresponds to molecular crystals, which
have a low entropy of melting such as:
Cyclohexanol (Sm ∼ = 5.72 J/mol K, Tm ∼ = 25◦ C38 ); CBr4
(Sm ∼ = 10.88 J/mol K, Tm ∼ = –10◦ C38 ); succinonitrile (Sm ∼
=
11.1 J/mol K, Tm ∼ = 61◦ C39 ).These compounds have all a plas-
tic crystal phase at high temperature (rotationally disordered
crystalline phase). It is this phase which melts. Melting entropy
is low because the crystalline state is already partly disordered.
All these systems show very poor undercooling ability for two
reasons:
r The nucleation barrier is small, as Sm , which fixes the
maximum value of the surface tension, is small. Molecules
of the melt situated at the crystal/melt interface adapt
with relative ease to the disordered molecules of the
crystal.
Descamps and Dudognon, JOURNAL OF PHARMACEUTICAL SCIENCES 103:2615–2628, 2014
r Because Sm ≤ 2R (16.6 ∼ J/mol K), normal (or continu-
ous) growth of rough interfaces is the only possible mech-
anism. Plastic crystals grow rapidly from the melt.
Such a behavior is expected for recrystallization in a phase
2. Other type of bad glass formers are systems that behave
like the n-alkanes with n ranging from 16 to 32. As men-
tioned above, the resistance to crystal nucleation of these
compounds is very weak. They behave in a way which is
closely similar to that of plastic crystals and show very
reduced undercooling. However, their melting entropy is
high: for Eicosane (n = 20) Sm ∼ = 226 J/mol K.40 In that
case, it is the entropy loss incurred by the melt when
it adjusts to the constraints of the crystal plane, which
determines the surface tension. If similar intermolecular
correlations exist in the bulk and in the interface, they
will not reduce the interface entropy relative to its bulk
value. At Tm , for example, the interface entropy term (Tm
Sm ) will quite fully compensate enthalpy (Hm ) as it
does in the bulk. It results in a low surface tension and a
low nucleation barrier. The result is a weak value of the
scaled interfacial tension. It is the situation considered
in the negentropic model of Spaepen30,34 (see Fig. 12).
3. The third type is that we have found for phases I of L-
arabitol and RS ibuprofen. It is also the situation found
for salol and other good molecular glass formers. The sit-
uation of salol is well documented because it is a model
of fragile glass former. Crystallization from the melt is
slow. For this compound, Sm ∼ = 60 J/mol K, Tm ∼ = 41◦ C,
∼
Tg = −58 C◦ 38,41
. Substantial nucleation rate was detected
at temperatures close to Tg (∼ = −53◦ C).42 At this tem-
perature, undercooled salol was found to crystallize by
coalescence of small crystalline embryos rather than by
usual growth of one initial super critical cluster. Normal
crystal growth was found to occur at higher tempera-
tures. This behavior shows that maxima of nucleation
and growth rate are largely decoupled with nucleation
rate having a maximum near Tg . As for our systems, eas-
ier recrystallization can be observed on heating. Large
interface energy (connected to large Sm ) leads to the
necessity to undercool the compound deeply in order to
attain a sufficiently small value of the nucleation critical
size and nucleation barrier. As is expected for such high
value of Sm , the growth rate of salol at small under-
cooling exhibits a lateral growth and surface nucleation-
limited behavior. As a consequence, the growth rate
increases more slowly than linear with decreasing tem-
perature (increasing T) at small undercoolings. Neu-
mann and Micus27,43 have however shown that a maxi-
mum rate of growth rate (Vmax ) due to viscosity increase
is reached at about 24◦ C (T ∼ = 18◦ C). The maximum
of growth rate thus occurs at a rather low value of un-
dercooling. It shows that even if growth is limited by
2D nucleation, the corresponding barrier g∗2D is not high
enough to push the position of Vmax to temperatures as
low as that of Nmax . Salol is another example of separa-
tion of the two maxima, which is at the origin of the good
glass forming ability of the compound.
DOI 10.1002/jps.24016

To this last type of good glass formers can be added a less
frequently found situation, which gives rise to a very stable un-
dercooled liquid or glass. It is typically that of meta-toluidine.17
It was found that the undercooled liquid phase of this com-
pound persists during extremely long times without showing
any sign of recrystallization. No crystallization is observed
even at extremely low cooling rate of 10◦ C/day. Even cycling
the system between Tg and Tm does not reveal recrystalliza-
tion. This allowed to investigate the temperature evolution of
the amorphous structure using very long X-ray experiments.44
Crystallization requires prior deep temperature excursion well
below Tg where cracks are formed and trigger the formation
of a very small number of nuclei. Crystallization is then de-
tectable upon reheating in the temperature domain where
growth is fast enough (i.e., slightly below Tm ). X-ray44 and
neutron scattering45 investigations of undercooled m-toluidine
show the existence of a pre-peak in the structure factor, which
reveals an important short-range clustering of the molecules.
The origin of the difficulty involved in homogeneous nucleation
is most probably linked to the need to destroy this local orga-
nization in order to allow adaptation to the crystal in the crys-
tal/liquid interface. A significant local increase of entropy could
help to explain the apparent effective high value of the interface
energy.
ACKNOWLEDGMENTS
The authors thank the EU INTERREG IV A 2 Mers-Seas-
Zeeën Crossborder Cooperation Programme for funding. They
are very grateful to Professor G. Zografi for giving permission to
use a nice photomicrograph of amorphous indomethacin in the
course of crystallization (from Ref. 5). They thank colleagues of
the group (F. Affouard, N. Correia, L. Carpentier, F. Danède, P.
Derollez, A. Hedoux, Y. Guinet, L. Paccou, and J.F. Willart) for
their cooperation and interaction. They also thank the master’s
students C. Avellaneda and K. Filali for their participations
in the measurements. The authors are deeply indebted to Dr.
Mark Eddleston for his kind attentive improvement of the En-
glish version.
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