International Journal of Pharmaceutics 456 (2013) 480488

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Benzocaine polymorphism: Pressuretemperature phase diagram

involving forms II and III
Ins Gana a,b,c , Maria Barrio d , Bernard Do b , Josep-Llus Tamarit d ,
Ren Colin a,d , Ivo B. Rietveld a,
a
EAD Physico-chimie Industrielle du Mdicament (EA4066), Facult de Pharmacie, Universit Paris Descartes, 4, Avenue de lObservatoire, 75006 Paris,
France
b
Etablissement Pharmaceutique de lAssistance Publique-Hpitaux de Paris, Agence Gnrale des Equipements et Produits de Sant, 7, rue du Fer Moulin,
75005 Paris, France
c
Laboratoire de chimie analytique, Facult de Pharmacie, rue Ibn Sina, 5000 Monastir, Tunisia
d
Grup de Caracteritzaci de Materials (GCM), Departament de Fsica i Enginyeria Nuclear, Universitat Politcnica de Catalunya, ETSEIB, Diagonal 647,
08028 Barcelona, Spain

a r t i c l e

i n f o

Article history:
Received 10 June 2013
Received in revised form 13 August 2013
Accepted 15 August 2013
Available online 28 August 2013
Keywords:
Thermodynamics
Physical stability
Phase diagram
Pressure
X-ray powder diffraction
Polymorphism

a b s t r a c t
Understanding the phase behavior of an active pharmaceutical ingredient in a drug formulation is
required to avoid the occurrence of sudden phase changes resulting in decrease of bioavailability in a
marketed product. Benzocaine is known to possess three crystalline polymorphs, but their stability hierarchy has so far not been determined. A topological method and direct calorimetric measurements under
pressure have been used to construct the topological pressuretemperature diagram of the phase relationships between the solid phases II and III, the liquid, and the vapor phase. In the process, the transition
temperature between solid phases III and II and its enthalpy change have been determined. Solid phase
II, which has the highest melting point, is the more stable phase under ambient conditions in this phase
diagram. Surprisingly, solid phase I has not been observed during the study, even though the scarce literature data on its thermal behavior appear to indicate that it might be the most stable one of the three
solid phases.
2013 Elsevier B.V. All rights reserved.

1. Introduction
1.1. Stability hierarchy between polymorphs
Benzocaine, p-aminobenzoic acid ethyl ester or ethyl 4aminobenzoate (Fig. 1) is a local anesthetic in use for more than
a century (Ritsert, 1925) and it is known to possess at least three
crystalline forms;(Chan et al., 2009b) however, the phase relationships between the different polymorphs have not been resolved
yet.
Knowledge about the physical stability of polymorphs is
important for the preformulation stage in drug development. To
determine the stability hierarchy between two different phases, a
so-called topological method has been developed, based on calorimetric and volumetric data obtained under ordinary conditions
and on the Clapeyron equation (Barrio et al., 2002; Ceolin et al.,
1992, 1993, 1996; Ceolin and Rietveld, 2010; Espeau et al., 2005;

Corresponding author. Tel.: +33 1 53739675.

E-mail address: ivo.rietveld@parisdescartes.fr
(I.B. Rietveld).
0378-5173/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.031

Gana et al., 2012; Giovannini et al., 2001; Toscani et al., 1996,

2002). More recently, the topological method has been compared
against data of phase equilibria obtained by high-pressure measurements to verify its results and to investigate in more detail the
effects of pressure on phase equilibria. It has been shown in several papers that the topological method can be used to construct
reliable pressuretemperature phase diagrams, if the experimental
data collected under ordinary conditions are sufciently accurate
(Barrio et al., 2009, 2012; Ceolin et al., 2008; Ledru et al., 2007;
Rietveld et al., 2011). In the present paper, data from direct measurements under pressure as well as inferences by the topological
method will be presented and a pressuretemperature phase diagram will be constructed for two of the three known polymorphs
of benzocaine.
1.2. Benzocaine literature data: structural data and specic
volumes
Benzocaine exhibits polymorphism, and three different crystal
structures have been solved to date. The rst structure that was
solved and thus named form is orthorhombic with space group
P21 21 21 (Sinha and Pattabhi, 1987). Later Gruno et al. demonstrated

I. Gana et al. / International Journal of Pharmaceutics 456 (2013) 480488

481

Fig. 1. Chemical structure of benzocaine, C9 H11 NO2 , M = 165.19 g mol1 .

that another solid form, thus named form , transforms endothermically into form (Gruno et al., 1993). The latter melts around
362 K (Gruno et al., 1993).
Lynch and McClenaghan published the crystal structure of a
monoclinic, P21 /c, form of benzocaine in 2002, which appears to be
the same form found by Gruno et al. judging from the position of
the diffraction peaks (Lynch and McClenaghan, 2002). In 2009, Chan
et al. revisited the crystal structures of the benzocaine polymorphs
and solved the structure of a third form (Chan et al., 2009a,b). They
also proposed a new nomenclature taking into account the results
of Gruno et al. (1993) and Schmidt (2005): form I, previously form
, is the monoclinic P21 /c polymorph, form II, previously form ,
is the orthorhombic P21 21 21 polymorph, and form III is the monoclinic form P21 found by Chan et al. at low temperature (Chan et al.,
2009a). With the data found in references (Chan et al., 2009a,b;
Gruno et al., 1993; Lynch and McClenaghan, 2002; Schmidt, 2005;
Sinha and Pattabhi, 1987), the specic volumes of forms I, II and III
have been calculated. They have been compiled in Table 1.
Specic volume inequalities between different solid forms are
most reliably determined from crystallographic data collected as
a function of temperature and on the same equipment. The literature data are not adapted for comparison between the specic
volumes of the different solid forms, but with a few approximations an estimate of the inequalities can be obtained. Only for form I,
the specic volume had been determined at different temperatures
(Fig. 2). Under the assumption that the inequalities are independent of temperature, it may tentatively be inferred that vII > vIII > vI
(Fig. 2).
1.3. Benzocaine literature data: calorimetry
Literature data concerning calorimetric properties for these
polymorphs is limited and the data compiled in Table 2 are mainly
based on the work of Schmidt (2005). The melting temperature
of benzocaine has been reported by Schwartz and Paruta (1976),
Manzo and Ahumada (1990), and Yalkowsky et al. (1972); however,
polymorphism was not mentioned in the latter three publications.
According to Gruno et al., form I (or ) transforms endothermically into Form II (or ) at about 352 K as observed by DSC (Gruno
Table 1
Specic volumes of benzocaine polymorphs from literature data.
T/K

vspec /cm3 g1

Form I (), monoclinic P21 /c

0.7946
120
300
0.8257
a
Form II (), orthorhombic P21 21 21
b
R.T.
0.8287
300
0.8334
R.T.b
0.8286
Form III, monoclinic P21
150
0.8021
a
b

Form I in Ref. (Schmidt, 2005).

R.T. = room temperature

Reference
Lynch and McClenaghan (2002)
Chan et al. (2009b)
Sinha and Pattabhi (1987)
Chan et al. (2009a)
Gruno et al. (1993)
Chan et al. (2009a)

Fig. 2. Specic volumes of forms I (solid spheres), II (solid squares) and III (solid diamond), as a function of temperature from literature data. Broken lines are estimates
based on the assumption that the specic volumes increase parallel to that of form
I: vI /cm3 g1 = 0.7739 + 0.0001728 T/K.

et al., 1993). In addition, they remark that form I does not transform for at least several months of storage (presumably at room
temperature) (Gruno et al., 1993). Using X-ray powder diffraction
as a function of temperature, they observe the appearance of formII-specic peaks in a form I sample at 308 K (Gruno et al., 1993).
Schmidt deduced from the DSC curves published by Gruno et al. that
the enthalpy of this transition (I II) is approximately +1 kJ mol1
(Gruno et al., 1993; Schmidt, 2005).
Gruno et al. obtained form II by slow crystallization from butyl
acetate solutions and form I by fast crystallization from butyl
acetate or chloroform solutions (Gruno et al., 1993). Chan et al.
obtained the two forms by evaporation from ethanol solutions at
room temperature (Chan et al., 2009b). Schmidt has listed a number of solvents, from which form I can be obtained (Schmidt, 2005).
She also mentioned that form II can be obtained from the supercooled melt below 337 K (Schmidt, 2005). Furthermore, Chan at al.
observed a reversible transition of form II into form III by decreasing
the temperature down to 150 K (Chan et al., 2009a). Schmidt however, did not observe any solidsolid transition for a commercially
available form II in the range of 40 to 100 C (Schmidt, 2005).
Heat capacities of solid, Cp,S , and liquid, Cp,L , benzocaine have
been determined by Neau et al. (Neau and Flynn, 1990). The data
Table 2
Calorimetric data from literature of the melting behavior of some benzocaine
polymorphs.
Tfus /K

fus H/kJ mol1

Form I (), P21 /c

21.5a

Form IIb () P21 21 21

363

361.8
20.5
363.4
21
362.85
22.3
363
23.6
363.05
20.51
363
22.26
361363
21.05
362.7
23.56
363
19.75
362.8
21.6
a
b

Reference

Gruno et al. (1993)

Schmidt (2005)
Pena et al. (2004)
Nordstrom and Rasmuson (2009)
Chickos et al. (2002)
Garmroodi et al. (2004)
Neau et al. (1989)
Schwartz and Paruta (1976)
Manzo and Ahumada (1990)
Yalkowsky et al. (1972)
Average

Calculated in Ref. (Schmidt, 2005) from data in Ref. (Gruno et al., 1993).
Form I in Ref. (Schmidt, 2005).

482

I. Gana et al. / International Journal of Pharmaceutics 456 (2013) 480488

have been compiled in Table S1 (in the Supplementary Materials).

Unfortunately, the polymorphic form was not mentioned in the
text; hence, it may be either form I or form II. The following two
expressions have been derived from the heat capacity data as a
function of the temperature T:
Solid :
Liquid :

Cp,S /J g1 K1 = 0.0044(3)T/K + 0.11(11)

Cp,L /J g1 K1 = 0.0025(4)T/K + 1.11(14)

(1)
(2)

The values between parentheses are the uncertainties in the last

digits they follow.
1.4. The topological method
Traditionally in pharmaceutical solid-state studies, the conclusion whether a phase relationship between two phases is
enantiotropic or monotropic is based on the rules proposed by
Burger and Ramberger, 1979a,b. Interestingly, the basis for those
rules has been established about a century before the Burger rules
and they lead to the same conclusions. It is the Le Chatelier Principle. The principle states that a system tends to compensate changes
in its environment. It applies to chemical reactions as well as phase
changes (and other exchanges of matter and energy).
To determine whether two phases in a system have an enantiotropic or a monotropic relationship, their enthalpy difference
and the direction of the transition need to be known. Thus, if a
solid phase form I transforms into form II with increasing temperature at temperature T = T1 and enthalpy difference H = H1 > 0
(endothermic transition), it indicates that the system takes up heat
from the environment with increasing temperature. This is exactly
what would be expected thermodynamically, because an increase
in the temperature of the environment signies an increase in its
heat content. Therefore, such a process must be thermodynamically
stable and it is to be expected that at decreasing the temperature,
the system will relax back into form I while releasing heat into
the environment. Such a transition is considered reversible and the
two phases have an enantiotropic relationship. The two phases may
even be enantiotropic if the transition back into form I does not
occur; i.e. the system may not revert back. The word reversible
reects a thermodynamic characteristic of the transition, whereas
the verb to revert reects a kinetic characteristic. The system may
be kinetically hindered to transform into the lower energetic state
and thus a solidsolid transition may not be observed, even if thermodynamically speaking the system remains in a metastable state.
Therefore non-reverting is not synonymous with non-reversible
(or irreversible).
In the case that H = H2 < 0 (exothermic transition) for a transition of form I into form II with increasing temperature, the system
releases energy into the environment, while the environment is
increasing its heat content. Obviously, the system does not compensate the external increase in heat, which means that the system
cannot have been stable in the rst place. It indicates that form II
is the more stable form of the two phases even at lower temperatures; thus phase I behaves monotropically with respect to phase II,
which is the only stable phase. Such transitions may happen when
a system is stuck in a metastable state and the thermal energy of
heating provides the system with enough energy to pass barriers
to nd a more stable, lower energetic state.
In the discussion above, the stability of the system is only considered as a function of the temperature. In thermodynamics, two
running variables determine the state of the system; in the case of
the Gibbs energy, which is mainly used when considering stability, the two variables are temperature and pressure. Applying the
Le Chatelier principle to the effects of pressure, one would expect
the system to decrease its volume against an outer pressure (and

thus increase its internal pressure); thus stable transitions that

occur under increasing pressure have a negative volume change
(the density increases).
The Le Chatelier principle leads to the same conclusions as
the Burger and Ramberger rules. However, there are a few
situations where the Burger and Ramberger rules run into exceptions (in such a case application of the Le Chatelier principle
would remain inconclusive) and that is caused by the fact that
temperature and pressure are not combined to construct a complete pressuretemperature (PT) phase diagram. In the end,
the Gibbs energy is determined by both the contribution of
the temperature and the contribution of the pressure. An additional advantage of constructing the PT phase diagram is that
it demonstrates whether any possibility exists of conversion of
a stable phase into a high-pressure phase during processing.
Nonetheless, the main reason to construct a phase diagram is
to improve overall understanding of the systems phase behavior.
The pressuretemperature behavior of transitions and thus
the position of a two-phase equilibrium can be determined by
direct measurement with high-pressure differential thermal analysis (HP-DTA) as used below. However, in the absence of such
equipment, use can be made of the Clapeyron equation, which can
be considered as a numerical version of the Le Chatelier principle
(even if the Le Chatelier principle had been developed after the
Clapeyron equation). The Clapeyron equation provides the slope of
a two-phase equilibrium in the pressuretemperature plane at the
P,T-coordinates, where the transition has been observed:
h
dP
=
dT
T v

(3)

h is the specic enthalpy change associated to the transition, T is

the transition temperature and v is the change in specic volume
associated to the phase change. In combination with the Le Chatelier principle, the Clapeyron equation can be used to construct a
PT phase diagram. In addition, the equation can be used to verify
the consistency of the data, as will be carried out below.
1.5. Estimation of an unobserved transition temperature
Yu has demonstrated that using a thermodynamic cycle the
transition temperature between two solid phases can be calculated,
when the transition itself has not been observed (Yu, 1995). In the
approach, the temperature of a solidsolid transition can be estimated, when the melting points and melting enthalpies of the two
solid forms are known (Yu, 1995). It is based on the evaluation of
the difference in the Gibbs energy between the two solid phases,
AB G. By evaluating the temperature at which the AB G is equal
to zero (equilibrium), an expression can be derived to determine
the transition temperature TAB , which can be found here in its
simplest form: (Yu, 1995)
TAB =

AL h BL h
(AL h/TAL ) (BL h/TBL )

(4)

For the melting transition of A, AL h is the specic enthalpy

change and TAL the temperature, and likewise for the melting of
B.
The approach is thermodynamically sound; however, lack of
certain data often requires the use of approximations. In the case
of Eq. (4), the right-hand side of the equation has been simplied by leaving out the heat capacities. Eq. (4) is therefore only a
valid approximation if all the transition temperatures are within
a few degrees of each other, or if the heat capacity changes and
differences are small.
In the present case of benzocaine, the melting point of form III
has not been observed and Eq. (4) needs to be rewritten to reect

I. Gana et al. / International Journal of Pharmaceutics 456 (2013) 480488

the known quantities. The necessary equations have been derived

in a slightly different way than Yu (1995). Details can be found in
the supplementary materials. Without taking into account the heat
capacity, the following equation can be obtained that will provide
the melting point of A directly:
TAL =

BL h + AB h
(BL h/TBL ) + (AB h/TAB )

(5)

If the heat capacities are important, they will need to be taken

into account. In the case of benzocaine, for the solid state only one
series of heat capacities is known (Table S1); therefore, the heat
capacities for the different solid forms are considered equal (by
lack of data). That leads to the following expression:
AL G(T ) = BL h + AB h T



BL


h

TBL



AB


h

TAB

12 a(TBL T )2 b(TBL T + T ln(T/TBL ))

(6)

a and b are coefcients describing the difference in heat capacity

between the solid and the liquid state as a function of temperature:
aT + b = Cp,L Cp,B . Cp,L and Cp,B are the heat capacities of the liquid
and form B, respectively. AL G(T) represents the Gibbs energy
of the transition of solid A into liquid at temperature T at constant pressure, which is not necessarily the melting point. With
expression (6), the melting point of solid A can be found by setting
AL G(T) equal to zero, because that is implied by an equilibrium
between the phases liquid and solid A. The temperature of fusion of
A (if AL G(T) = 0, T = TAL ) can subsequently be found by numerical methods. A similar approach can also be found in a publication
by Bennema et al. (2008).

483

Table 3
Lattice parameters and specic volume of form III (low temperature, monoclinic
P21 ) of benzocaine as a function of temperature.
T/K

a/

b/

c/

/

Vcell /3

vspec /cm3 g1

200
220
245
260

8.2112
8.2176
8.2333
8.2393

10.695
10.714
10.752
10.764

20.559
20.591
20.658
20.694

99.403
99.411
99.527
99.576

1781.2
1788.6
1803.6
1809.7

0.81165
0.81502
0.82186
0.82466

3. Results
3.1. Crystals
Benzocaine crystals were grown at room temperature from the
following solvents: ethanol, p-xylene, butyl acetate, chloroform,
and diethyl ether. Only form II crystals were obtained in this way.
No crystals of form I were observed even after repeated crystallization attempts.
3.2. Calorimetric data
On heating from room temperature, form II melts at
362.4 0.5 K (onset) with an enthalpy change of 141 2.4 J g1 (see
Table S2 in the supporting information for the measurement values
obtained by DSC). In addition, an exothermic solidsolid transition
was observed on cooling from room temperature to 200 K. This
transition reverts endothermically on reheating at 265.3 0.5 K
(onset) with an enthalpy change of 3.0 1.0 J g1 (Table S2) and
its transition temperature is virtually independent of the heating
rate (Table S3 in the supplementary materials).

2. Materials and methods

Benzocaine was purchased from Fluka (99% by HPLC) and used
as such, after preliminary X-ray diffraction showed that the powder
consisted of the orthorhombic form P21 21 21 (form II).
Differential scanning calorimetry (DSC) experiments were performed on a Q100 analyzer from TA Instruments (New Castle,
DE, USA). Different quantities (210 mg) of benzocaine and different heating rates from 0.2 up to 10 K min1 were used. The
measurements were carried out on samples sealed in aluminum
pans.
High-resolution X-ray powder diffraction patterns were
obtained as a function of temperature from 200 K up to the liquid
state with a CPS120 diffractometer from INEL (France) equipped
with a liquid nitrogen 700 series Cryostream Cooler from Oxford
Cryosystems (Oxford, UK). Data were collected for at least 1 h per
diffraction pattern. The heating rate between the measurements
was 1.3 K min1 and before data collection the sample temperature was left to stabilize for at least 15 min. The lattice parameters
as a function of temperature have been determined with Pawley ts to the known unit cells using TOPAS Academic (Coelho,
2007).
The observed transitions in benzocaine have been studied with
high-pressure differential thermal analysis (HP-DTA). An in-house
constructed HP-DTA, similar to the apparatus previously built by
Wringer (1975) with temperature and pressure ranges from 203
to 473 K and 0 to 300 MPa, respectively, was used. Samples were
sealed in cylindrical tin pans and to ensure that in-pan volumes
were free from residual air, specimens were mixed with an inert
peruorinated liquid (Galden from Bioblock Scientics, Illkirch,
France) before sealing. HP-DTA scans were carried out with a heating rate of 2 K min1 . In addition, DSC runs at ordinary pressure
(i.e., in standard aluminum pans) with mixtures of benzocaine and
peruorinated liquid were carried out to verify that the latter was
inert.

3.3. Powder diffraction and specic volume

The lattice parameters of benzocaine have been determined as
a function of temperature from 200 K up to the melting point. They
have been compiled in Tables 3 and 4. On heating, a phase change
was observed between 260 and 270 K (Fig. 3); by comparing the
diffraction patterns available in the CSD, the low and high temperature phases were found to be form III and form II, respectively. The
diffraction pattern at 265 K possesses Bragg peaks of both phases,
an observation that matches the transition temperature obtained
by DSC.
The lattice parameters lead to the following two expressions for
the specic volume, vspec , as a function of temperature obtained by
tting the data in Tables 3 and 4, respectively
Form III :

vIII /cm3 g1 = 0.766(3) + 2.2(2) 104 T/K

(7)

Form II :

vII /cm3 g1 = 0.762(2) + 2.53(8) 104 T/K

(8)

Table 4
Lattice parameters and specic volume of form II (high temperature, orthorhombic
P21 21 21 ) of benzocaine as a function of temperature.
T/K

a/

b/

c/

Vcell /3

vspec /cm3 g1

270
280
300
310
320
330
345
355
360

8.2430
8.2458
8.2592
8.2598
8.2652
8.2736
8.2813
8.2867
8.2873

5.3057
5.3039
5.3187
5.3246
5.3304
5.3375
5.3462
5.3522
5.3548

20.853
20.885
20.928
20.940
20.966
20.997
21.049
21.082
21.099

911.99
913.41
919.31
920.93
923.69
927.20
931.91
935.02
936.31

0.83116
0.83246
0.83784
0.83932
0.84183
0.84503
0.84932
0.85216
0.85333

484

I. Gana et al. / International Journal of Pharmaceutics 456 (2013) 480488

4. Discussion
4.1. Consistency of the obtained data

Fig. 3. X-ray powder diffraction patterns demonstrating the phase change occurring
between 260 and 270 K. Diffraction peaks of both phases can be observed in the
pattern obtained at 265 K.

3.4. High-pressure differential thermal analysis (HP-DTA)

The pressures and the onset temperatures of the transitions
III II and II L have been compiled in Table S4. The HP-DTA peaks
are presented in Fig. 4a. The curves obtained by HP-DTA (Fig. 4b)
representing the III-II and II-L equilibria clearly converge as pressure increases. They intersect at the III-II-L triple point, which is
according to these results located at high pressure and high temperature. Fitting the data by linear regression results in the following
two expressions for the respective equilibria:
III II :

P/MPa = 722(18) + 2.70(6)T/K

II L :

P/MPa = 2166(50) + 5.99(13)T/K

(9)
(10)

The various data obtained by measurement in relation to the

observed transitions have been summarized in Table 5.

The temperature of the III II transition under ordinary conditions equals 265.3 K as found by DSC, which coincides with the
observations by X-ray diffraction. Simultaneously X-ray diffraction
indicates that the transition is accompanied by a positive volume
change; v = vII vIII equals 0.82893 0.82596 = 0.00297 cm3 g1
(Table 5).
With the Clapeyron equation (Eq. (3)), the consistency of the
data of the III II transition obtained by the different methods can
be veried. The experimental error being smallest over the transition temperature and the dP/dT slope (Eq. (9) and Table 5), their
product should be equal to the ratio of h over v, the quantities
with relatively the largest experimental errors (Eq. (3)). The product
equals 715 15 MPa and the ratio equals 1020 476 MPa; hence
the two values are equal within error. It is clear that the experimental uncertainty is much larger over the transition enthalpy
and the specic volume change, which can be explained by their
small absolute values. One would expect that the enthalpy change
is probably somewhat smaller and the volume change somewhat
larger.
In the case of the II L transition (fusion of form II), the consistency check cannot be carried out, because the specic volume of
the liquid is not known; however the Clapeyron equation (Eq. (3))
can be used to calculate the volume change associated with the
melting transition. The volume change is equal to the ratio h/(T
(dP/dT)), which has a value of 0.065 0.002 cm3 g1 . In this case,
the relative error is much smaller, because the relative experimental error over the enthalpy change is much smaller. The specic
volume of solid form II at the melting point can be calculated with
Eq. (3) and equals vII (362.4 K) = 0.8535 0.0007 cm3 g1 . With this
information, the specic volume of the melt can be calculated;
it equals vL = 0.92 0.03 cm3 g1 . The ratio vL /vII now equals
1.076 0.0036, which is in agreement with previous ndings for
other active pharmaceutical ingredients. The average ratio of vL /vII
at Tfus is 1.10 based on data from several APIs (active pharmaceutical compounds) (Ceolin and Rietveld, 2010; Rietveld et al., 2012,
2013). If by lack of data, the ratio 1.10 is used to calculate the slope
of the II L equilibrium using the Clapeyron equation (Eq. (3)), a

Fig. 4. (a) High-pressure differential thermal analysis curves as a function of pressure. The onset of the peaks indicates the temperature of transition under the imposed
pressure. Main gure: fusion of form II, inset: III II transition. (b) Linear ts to the HP-DTA data for the solidsolid III II transition (solid circles) and the fusion II L (open
circles). Error bars over T fall within the symbols.

I. Gana et al. / International Journal of Pharmaceutics 456 (2013) 480488

485

Table 5
Calorimetric, volumetric, and dP/dT data for selected phase transitions.
Transition

T/K

H/J g1

v/cm3 g1

dP/dT/MPa K1

III II
II L (fusion)

265.3 0.5
362.4 0.5

3.0 1.0
141.0 2.4

0.0030 0.0010

2.70 0.06
5.99 0.13

slope of 4.56 MPa K1 would be found. Although the latter value is

smaller than the slope obtained by the PT measurements, it is still
much larger than the slope for the solidsolid transition III II
(Table 5). Hence topologically speaking, the conclusion on the
phase behavior would remain the same, because the intersection
of the two equilibrium curves III-II and II-L still occurs at high
pressure and high temperature.
The intersection of the equilibrium curves III-II and II-L corresponds to the location in the pressuretemperature plane, where
the three phases III, II and L are in equilibrium. The intersection
must therefore be the III-II-L triple point implying the intersection of a third curve, that of the III-L equilibrium, or the fusion of
form III. The coordinates of the triple point can be calculated by
setting the two expressions for the measured PT curves Eqs. (9)
and (10) equal; this leads to 439 K and 463 MPa. Strictly speaking, these coordinates are estimates, as they have been obtained
by extrapolation and the trajectories of the phase equilibria above
the measurement range are not known; because the lines within
the measurement range are reasonably linear, the extrapolation
has been based on those linear expressions. The two equilibrium curves and the triple point can be found in the topological
pressuretemperature phase diagram of forms II and III of benzocaine (Fig. 5).

because if one scrutinizes Eq. (6), it can be seen that the effect
of the heat capacity only depends on the distance of the melting
temperature of form III from the melting point of form II, which
appears to be very small. The difference between the two solid heat

4.2. The position of the III-L equilibrium

The system concerning forms II and III is enantiotropic under
ordinary conditions. Form III is stable at low temperature and
form II is stable at higher temperature and melts eventually. With
increasing pressure, at ambient temperature, form III becomes the
more stable form with respect to form II. Moreover above the triple
point III-II-L, form III possesses a stable melting equilibrium and
form II becomes metastable. Hence, at higher pressures form II
becomes monotropic with respect to form III. However, the position
of the melting curve of form III is not known, because the melting
transition has never been observed.
There are two approaches to determine the position of the melting curve of form III. The rst is an approach similar to that by Yu
(1995), Eqs. (4)(6), and the second makes use of the thermodynamic relationships in the pressuretemperature phase diagram.
Both approaches will be used and their outcomes will be compared
to verify their mutual consistency.
For the rst approach, an estimate of the melting point of form
III will be calculated by Eq. (5) neglecting the inuence of the heat
capacities. Phase A is replaced by solid form III and phase B by
solid form II in the equation. The enthalpy changes and the transition temperatures as given in Table 5 are used. This leads to a
temperature of fusion for form III, TIIIII , of 359.6 K, just below the
temperature of fusion for form II (362.4 K).
The heat capacities for the solid phase of benzocaine and its
liquid can be found in Table S1 and the resulting expressions for
their temperature dependence are Eqs. (1) and (2). As indicated
below Eq. (6) in the introduction, it is the difference Cp,L Cp,III that
is used; hence Eq. (1) is subtracted from Eq. (2) resulting in:
Cp,L Cp,III (T )/J g1 K1 = 0.0019T/K + 1.0

(11)

Employing Eq. (6), leads to a temperature of fusion for form

III of 359.6 K, which is identical to the value found without taking into account the heat capacities. It is not surprising however,

Fig. 5. Topological pressuretemperature phase diagram of the stability hierarchy

of the benzocaine polymorphs III and II. (a) Measured curves, solid line: equilibrium
curve II-L (L = liquid), dotted line: equilibrium curve III-II, and broken line (just left
of II-L): equilibrium curve III-L (obtained by thermodynamic calculation). The stable
phases are indicated in their respective phase domains (III, II, and L). (b) Entire topological diagram not to scale with all equilibrium curves and triple points between
phases III, II, L, and V (vapor phase). Black solid lines: most stable phase equilibria,
gray broken lines: metastable phase equilibria, and dotted lines: supermetastable
equilibria. Solid black circles: stable triple points, gray circle: metastable triple point.
The phase equilibria have been marked by III-II, III-L, III-V, II-L, II-V, and L-V and the
triple points by III-II-V, III-II-L, III-L-V, and II-L-V. If a two-phase equilibrium (line)
crosses a triple point (circle), the equilibrium must change its stability hierarchy e.g.
the supermetastable III-V equilibrium on the right-hand side (dotted line) passes
through the metastable triple point III-L-V (gray circle) and becomes metastable
(gray broken line), then it passes through the stable triple point III-II-V (solid black
circle) and it turns stable (solid black line), the stable sublimation curve of the solid
form III.

486

I. Gana et al. / International Journal of Pharmaceutics 456 (2013) 480488

capacities may be more important, but due to lack of data it needs

to be assumed negligible. Moreover, the only occurrence of the
transition temperature between the two solid phases is in the
denominator of its ratio with the heat of transition of the solidsolid
transition. The transition enthalpy being very small, it is mainly the
quantities related to the fusion of form II that determine the position of the temperature of fusion of form III. This is clearly reected
in the results of Eqs. (5) and (6).
The results of Eqs. (5) and (6) can be veried by an unrelated
method, using the Clapeyron equation (Eq. (3)). The Clapeyron
equation provides the slope of a transition in the pressure temperature plane at a given temperature. This slope can be extrapolated
to nd the coordinates of a given equilibrium at a different pressure or temperature. Thus, the slope of the III-L equilibrium can
be calculated and by extrapolation the melting point of form
III (i.e. the melting transition under ordinary conditions) can be
obtained.
The Clapeyron equation needs a temperature, an enthalpy of
transition, and the volume change associated with the transition. The most judicious choice for the temperature is the melting
point of form II, 362.4 K. The melting enthalpy of form III is
expected to be fairly close to that of form II, because the transition enthalpy between the two solid phases is only 3 J g1 (Table 5).
Even if this value changes as a result of a difference between
heat capacities, the largest part of the melting enthalpy of form
III will be given by the melting enthalpy of form II, which is
141 J g1 and which is exactly known at its own melting point.
The melting enthalpy of form III at the temperature of fusion of
form II can therefore be estimated as 144 J g1 . Another advantage
of choosing TIIL as the temperature to evaluate the Clapeyron
equation for phase III, is that the specic volume of the liquid
phase has been calculated at this temperature with the experimental dP/dT slope. It resulted in vL = 0.9185 cm3 g1 . Moreover
the specic volume of form III can be obtained by extrapolation of Eq. (7). It leads to 0.8478 cm3 g1 . Hence, IIIL v equals
0.0707 cm3 g1 . The slope dP/dT becomes 5.62 MPa K1 . The known
point on this equilibrium curve is the triple point III-II-L, which
has been determined above. Using the coordinates 439 K and
463 MPa, the following equation for the melting curve of form III is
obtained:
P/MPa = 5.62T/K 2006

(12)

By setting the pressure to 0 MPa, the melting point under ordinary conditions is found to be 357 K. This value is very close to the
one obtained by Eqs. (5) and (6) and it validates the temperature
coordinate of the melting point of form III. It is hard to say, which of
the two results is closer to the correct value. There may be a small
contribution of the solid heat capacity differences that decreases
the melting point calculated by Eqs. (5) and (6), however using the
Clapeyron equation (Eq. (3)) involves a long extrapolation from the
triple point to 0 MPa. Nonetheless, the result of the two methods is
consistent for the melting point of form III.
In the case that the melting point obtained by Eq. (5) is used, the
expression for the pressure dependence of the III-L equilibrium (Eq.
(12)) should be adjusted. It means that the equilibrium curve must
intersect the coordinates [359.6 K, 0 MPa] and [439 K, 463 MPa], the
melting point of form III and the triple point III-II-L, respectively.
This leads to the following expression:
P/MPa = 5.80T/K 2086

(13)

The two Eqs. (12) and (13) can be considered as the error margin
of the position of the III-L equilibrium curve.

5. The pressuretemperature phase diagram including the

vapor phase
In a system with two solid phases, a liquid phase and a vapor
phase, six two-phase equilibrium curves exist. If curves with a coinciding phase meet, necessarily three phases are in equilibrium at
that point, which is a so-called triple point. It also implies that three
different curves must cross in a triple point. With six different equilibrium curves, four triple points exist (Riecke, 1890), in the present
case: III-II-L, III-II-V, III-L-V, and II-L-V; the roman numerals II and
III stand for the solid forms II and III, L stands for liquid and V for
vapor. The triple point III-II-L has been determined and has the
coordinates 439 K and 463 MPa. It is the intersection of both melting equilibrium curves and the solidsolid equilibrium curve. II-L-V
contains the melting equilibrium of form II in the presence of the
vapor phase. A DSC capsule contains always some dead volume,
which will be lled by benzocaine vapor during the heating run,
because some benzocaine will sublime. It means that when form
II melts, it happens in the presence of the vapor phase and thus
this transition, if not on the triple point, must be very close to it.
The same is valid for the other transitions containing the vapor
phase. They can be interpreted as the conditions in a closed DSC
capsule and that implies that all four triple points are known: IIIII-V (265.3 K, 0 MPa), III-L-V (259.6 K, 0 MPa), and II-L-V (362.4 K,
0 MPa), and the coordinates of the triple point III-II-L given just
above.
The value 0 MPa expresses the fact that the vapor pressure is relatively small in comparison with the pressures to reach the triple
point III-II-L and also the fact that the vapor pressures have never
been measured. Nonetheless, most experiments on APIs will take
place under ordinary conditions and that means under the vapor
pressure of the API, how small it may be. In addition, the vapor pressure of a compound is directly related to its Gibbs energy. Therefore,
it is of interest to investigate the order of magnitude of the vapor
pressure involved.
As to our knowledge no vapor pressure data of benzocaine exist,
the following method has been used to evaluate the vapor pressure of benzocaine. With ACDLabs (ACDLabs) the boiling point and
the enthalpy of vaporization can be estimated, Tb = 583.8 15 K and
vap H = 55.16 3 kJ mol1 , respectively. The normal boiling point
of a liquid is reached once the vapor pressure of the liquid is equal
to 1 bar or 105 Pa (0.1 MPa). With this information the vapor pressure of the liquid can be described as a function of temperature:

General expression :

ln P =

vap H
+ Bvap
RT

(14)

with P the pressure of the vapor taken in Pa, R the gas constant
(8.3145 J K1 mol1 ) and Bvap a tting constant that can be determined with the information just above Eq. (14). It is clear that
this equation only provides an estimate of the benzocaine vapor
pressures, because the enthalpy of vaporization is considered constant with pressure and temperature. Vapor pressures are another
means to compare the Gibbs energies of the different phases with
the phase possessing the lowest vapor pressure, necessarily the
more stable phase under isochoric conditions. Thus the following calculations constitute an additional way to study the phase
relationships while completing the topological phase diagram. It
is worth mentioning that with the word topological is meant that
the phase diagram represents the positions of the different phase
domains, two-phase equilibria, and triple points in relation to each
other; such a diagram does not pretend to represent an absolute
phase diagram, for which all possible phases should be known and
all triple points and phase equilibria should have been conrmed
experimentally. The vapor pressures calculated in this text are

I. Gana et al. / International Journal of Pharmaceutics 456 (2013) 480488

487

Table 6
The coordinates of the triple points for the pressuretemperature phase diagram of the solid forms II and III of benzocaine and the vapor pressures of the different phases at
those coordinates (the more stable phases have been indicated by a vapor pressure given in bold and italic).
Triple point

Temperature
/K

III-II-V
III-L-V
II-L-V
III-II-L

265
360
362
439

Pressure
/Pa

III
P/Pa
0.007
84
102
463 106

0.007
84
96
463 106

therefore estimates in the absolute sense, but completely acceptable for comparison in the relative sense.
For liquid benzocaine, the expression for the vapor pressure as
a function of temperature becomes:
Vapor pressure :

ln(Pvap /Pa) =

55160
+ 22.88
RT

(15)

At triple point II-L-V, solid form II, the liquid, and the vapor
are in equilibrium, which means that the vapor pressure of form
II equals that of the liquid. With Eq. (15), the vapor pressure
of the liquid at TIIL (362.4 K = TII-L-V ) can be calculated resulting in 96 Pa. This pressure provides a value for the sublimation
pressure of form II, the sublimation enthalpy being equal to
the sum of the vapor pressure enthalpy and that of the melting transition: sub,II H = vap H + fus,II H = 78445 J mol1 . Using the
sublimation enthalpy, the sublimation constant Bsub,II can be calculated (Bsub,II = 30.60). It results in the following expression for the
sublimation pressure of form II:
Sublimation pressure form II :

ln(Psub,II /Pa) =

78445
+ 30.60
RT
(16)

The same can be done for the sublimation pressure

curve of form III: Psub,III (TIIIL = TIII-L-V = 359.6 K) = 84 Pa,
sub,III H = vap H + IIIL H = 78946 J mol1 , and the sublimation constant Bsub,III becomes 30.83. It results in the following
expression for the sublimation pressure of form III:
Form III :

78946
+ 30.83
ln(Psub,III /Pa) =
RT

(17)

Either Eq. (16) or (17) can be used to calculate the sublimation pressure of form III and form II at their solidsolid transition
temperature of 265.3 K; the pressure equals 0.007 Pa.
The latter calculations provide all details for the triple points; the
coordinates can be found in Table 6. Besides the temperature and
the pressure of the triple points, the vapor pressures of the different
phases have been given at those triple points. It can be seen that in
most cases the vapor pressure of the stable phases (lowest vapor
pressure) equals that of the triple point and thus those triple points
are stable. Only in the case of the triple point III-L-V, form II has a
lower vapor pressure, which is indeed the more stable phase. The
topological phase diagram taking all information into account has
been presented in Fig. 5.
The phase diagram in Fig. 5 represents the phase behavior of
form III and form II. During the present experiments, form I did
not crystallize, despite repeated efforts; therefore, no new data has
been obtained next to the already existing literature data including the crystal structure and an uncertain transition temperature
with an even more ill-dened transition enthalpy. Considering the
uncertainties over the transition parameters and avoiding speculation, form I has not been incorporated in the present phase
diagram.

II
P/Pa
0.007
79
96
463 106

L
P/Pa
0.12
84
96
463 106

6. Conclusion
The benzocaine phase transition between the previously
reported monoclinic P21 (form III) and the orthorhombic form
P21 21 21 (form II) has been located for the rst time. The transition temperature is 265.3 0.5 K and the enthalpy change equals
3.0 1.0 J g1 .
The equilibrium curves of the III-II and the II-L equilibria in the
pressuretemperature phase diagram have been obtained by highpressure differential thermal analysis. They intersect at 439 K and
463 MPa, which are the coordinates where form III, form II, and the
liquid are in equilibrium with each other, i.e. the triple point III-II-L.
With the triple point coordinates, the position of the equilibrium
between form III and the liquid has been determined followed by
the complete topological phase diagram with respect to phases III,
II, liquid, and vapor.
Surprisingly, form I has not been obtained during the investigation despite repeated efforts reminiscent of what Dunitz
and Bernstein named disappearing polymorphs (Dunitz and
Bernstein, 1995). Its disappearance is surprising, because the sparse
calorimetric data on this form appear to indicate that it may be the
most stable phase of the three known solid phases under ambient conditions. Nonetheless, even if form I would turn out to be
the most stable phase, the phase relationships between the other
phases presented in Fig. 5 will remain valid.
Acknowledgments
M.B. and J.-Ll. T. were supported by the Spanish Ministry of
Science and Innovation (Grant FIS2011-24439) and the Catalan
Government (Grant 2009SGR-1251).
Appendix A. Supplementary data
Supplementary material related to this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.ijpharm.2013.
08.031.
References
ACDLabs, Advanced Chemistry Development (ACD/Labs) Software, V11.02 ed.
ACD/Labs.
Barrio, M., de Oliveira, P., Ceolin, R., Lopez, D.O., Tamarit, J.L., 2002. Polymorphism
of 2-methyl-2-chloropropane and 2,2-dimethylpropane (neopentane): Thermodynamic evidence for a high-pressure orientationally disordered rhombohedral
phase through topological PT diagrams. Chem. Mater. 14, 851857.
Barrio, M., Espeau, P., Tamarit, J.L., Perrin, M.A., Veglio, N., Ceolin, R., 2009. Polymorphism of progesterone: relative stabilities of the orthorhombic phases I
and II inferred from topological and experimental pressuretemperature phase
diagrams. J. Pharm. Sci. 98, 16571670.
Barrio, M., Maccaroni, E., Rietveld, I.B., Malpezzi, L., Masciocchi, N., Ceolin, R., Tamarit,
J.-L., 2012. Pressuretemperature state diagram for the phase relationships
between benuorex hydrochloride forms I and II: a case of enantiotropic behavior. J. Pharm. Sci. 101, 10731078.
Bennema, P., van Eupen, J., van der Wolf, B.M.A., Los, J.H., Meekes, H., 2008. Solubility of molecular crystals: polymorphism in the light of solubility theory. Int. J.
Pharm. 351, 7491.

488

I. Gana et al. / International Journal of Pharmaceutics 456 (2013) 480488

Burger, A., Ramberger, R., 1979a. Polymorphism of pharmaceuticals and other

molecular-crystals. 1. Theory of thermodynamic rules. Mikrochim. Acta 2,
259271.
Burger, A., Ramberger, R., 1979b. Polymorphism of pharmaceuticals and other
molecular-crystals. 2. Applicability of thermodynamic rules. Mikrochim. Acta
2, 273316.
Ceolin, R., Agafonov, V., Louer, D., Dzyabchenko, V.A., Toscani, S., Cense, J.M., 1996.
Phenomenology of polymorphism. 3. P, T diagram and stability of piracetam
polymorphs. J. Solid State Chem. 122, 186194.
Ceolin, R., Rietveld, I.B., 2010. Phenomenology of polymorphism and topological
pressuretemperature diagrams. J. Therm. Anal. Calorim. 102, 357360.
Ceolin, R., Tamarit, J.L., Barrio, M., Lopez, D.O., Nicola, B., Veglio, N., Perrin, M.A.,
Espeau, P., 2008. Overall monotropic behavior of a metastable phase of biclotymol, 2,2 -methylenebis(4-chloro-3-methyl-isopropylphenol), inferred from
experimental and topological construction of the related PT state diagram. J.
Pharm. Sci. 97, 39273941.
Ceolin, R., Toscani, S., Agafonov, V., Dugue, J., 1992. Phenomenology of Polymorphism. 1. Pressure temperature representation of trimorphism general rules
application to the case of dimethyl 3,6-dichloro-2,5-dihydroxyterephthalate.
J. Solid State Chem. 98, 366378.
Ceolin, R., Toscani, S., Dugue, J., 1993. Phenomenology of Polymorphism. 2. Criteria for overall (P, T) monotropy applications to monochloroacetic acid and to
hydrazine monohydrate. J. Solid State Chem. 102, 465479.
Chan, E.J., Rae, A.D., Welberry, T.R., 2009a. On the polymorphism of benzocaine: a
low-temperature structural phase transition for form (II). Acta Crystallogr. B 65,
509515.
Chan, E.J., Welberry, T.R., Goossens, D.J., Heerdegen, A.P., Beasley, A.G., Chupas,
P.J., 2009b. Single-crystal diffuse scattering studies on polymorphs of molecular crystals. I. The room-temperature polymorphs of the drug benzocaine. Acta
Crystallogr. B 65, 382392.
Chickos, J.S., Nichols, G., Ruelle, P., 2002. The estimation of melting points and
fusion enthalpies using experimental solubilities, estimated total phase change
entropies, and mobile order and disorder theory. J. Chem. Inf. Comput. Sci. 42,
368374.
Coelho, A.A., 2007. TOPAS Academic Version 4. 1 (Computer Software). Coelho Software, Brisbane.
Dunitz, J.D., Bernstein, J., 1995. Disappearing polymorphs. Acc. Chem. Res 28,
193200.
Espeau, P., Ceolin, R., Tamarit, J.L., Perrin, M.A., Gauchi, J.P., Leveiller, F., 2005.
Polymorphism of paracetamol: relative stabilities of the monoclinic and
orthorhombic phases inferred from topological pressuretemperature and
temperaturevolume phase diagrams. J. Pharm. Sci. 94, 524539.
Gana, I., Ceolin, R., Rietveld, I.B., 2012. Phenomenology of polymorphism: the
topological pressuretemperature phase relationships of the dimorphism of
nasteride. Thermochim. Acta 546, 134137.
Garmroodi, A., Hassan, J., Yamini, Y., 2004. Solubilities of the drugs benzocaine,
metronidazole benzoate, and naproxen in supercritical carbon dioxide. J. Chem.
Eng. Data 49, 709712.
Giovannini, J., Ter Minassian, L., Ceolin, R., Toscani, S., Perrin, M.A., Louer, D., Leveiller,
F., 2001. Tetramorphism of fananserine: P, T diagram and stability hierarchy
from crystal structure determinations and thermodynamic studies. J. Phys. IV
11, 123126.
Gruno, M., Wulff, H., Pegel, P., 1993. Polymorphism of benzocaine. Pharmazie 48,
834837.
Ledru, J., Imrie, C.T., Pulham, C.R., Ceolin, R., Hutchinson, J.M., 2007. High pressure
differential scanning calorimetry investigations on the pressure dependence of
the melting of paracetamol polymorphs I and II. J. Pharm. Sci. 96, 27842794.

Lynch, D.E., McClenaghan, I., 2002. Monoclinic form of ethyl 4-aminobenzoate (benzocaine). Acta Crystallogr. E 58, O708O709.
Manzo, R.H., Ahumada, A.A., 1990. Effects of solvent medium on solubility. 5.
Enthalpic and entropic contributions to the free-energy changes of disubstituted
benzene-derivatives in ethanol water and ethanol cyclohexane mixtures. J.
Pharm. Sci. 79, 11091115.
Neau, S.H., Flynn, G.L., 1990. Solid and liquid heat-capacities of normal-alkyl paraaminobenzoates near the melting-point. Pharm. Res. 7, 11571162.
Neau, S.H., Flynn, G.L., Yalkowsky, S.H., 1989. The inuence of heat-capacity assumptions on the estimation of solubility parameters from solubility data. Int. J.
Pharm. 49, 223229.
Nordstrom, F.L., Rasmuson, A.C., 2009. Prediction of solubility curves and melting
properties of organic and pharmaceutical compounds. Eur. J. Pharm. Sci. 36,
330344.
Pena, M.A., Bustamante, P., Escaler, B., Reillo, A., Bosque-Sendra, J.M., 2004.
Solubility and phase separation of benzocaine and salicyclic acid in 1,4dioxanewater mixtures at several temperatures. J. Pharm. Biomed. Anal. 36,
571578.
Riecke, E., 1890. Spezielle Flle von Gleichgewichterscheinungen eines aus
mehreren Phasen zusammengesetzten Systemes. Z. Phys. Chem. (Munich) 6,
411.
Rietveld, I.B., Barrio, M., Do, B., Tamarit, J.L., Ceolin, R., 2012. Overall stability for
the ibuprofen racemate: experimental and topological results leading to the
pressuretemperature phase relationships between its racemate and conglomerate. J. Phys. Chem. B 116, 55685574.
Rietveld, I.B., Barrio, M., Tamarit, J.-L., Nicolai, B., Van de Streek, J., Mahe, N.,
Ceolin, R., Do, B., 2011. Dimorphism of the prodrug l-tyrosine ethyl ester:
pressuretemperature state diagram and crystal structure of phase II. J. Pharm.
Sci. 100, 47744782.
Rietveld, I.B., Perrin, M.A., Toscani, S., Barrio, M., Nicolai, B., Tamarit, J.L., Ceolin,
R., 2013. Liquidliquid miscibility gaps in drug-water binary systems: crystal
structure and thermodynamic properties of prilocaine and the temperaturecomposition phase diagram of the prilocaine-water system. Mol. Pharmaceut.
10, 13321339.
Ritsert, E., 1925. Development of anesthesine. Pharm. Ztg. 70, 10061008.
Schmidt, A.C., 2005. Structural characteristics and crystal polymorphism of three
local anaesthetic bases crystal polymorphism of local anaesthetic drugs: part
VII. Int. J. Pharm. 298, 186197.
Schwartz, P.A., Paruta, A.N., 1976. Solution thermodynamics of alkyl-paraaminobenzoates. J. Pharm. Sci. 65, 252257.
Sinha, B.K., Pattabhi, V., 1987. Crystal-structure of benzocaine a local-anesthetic.
Proc. Indian Acad. Sci. (Chem. Sci.) 98, 229234.
Toscani, S., de Oliveira, P., Ceolin, R., 2002. Phenomenology of polymorphism IV. The
trimorphism of ferrocene and the overall metastability of its triclinic phase. J.
Solid State Chem. 164, 131137.
Toscani, S., Dzyabchenko, A., Agafonov, V., Dugue, J., Ceolin, R., 1996. Polymorphism
of sulfanilamide. 2. Stability hierarchy of alpha-, beta- and gamma-forms from
energy calculations by the atom-atom potential method and from the construction of the P, T phase diagram. Pharm. Res. 13, 151154.
Wringer, A., 1975. Differential thermal-analysis under high-pressure IV. Lowtemperature DTA of solidsolid and solidliquid transitions of several
hydrocarbons up to 3 kbar. Ber. Bunsen-Ges. Phys. Chem. 79, 11951201.
Yalkowsky, S.H., Slunick, T.G., Flynn, G.L., 1972. Importance of chain-length on
physicochemical and crystalline properties of organic homologs. J. Pharm. Sci.
61, 852857.
Yu, L., 1995. Inferring thermodynamic stability relationship of polymorphs from
melting data. J. Pharm. Sci. 84, 966974.