International Journal of Pharmaceutics 456 (2013) 480488

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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 a b s t r a c t

Article history: Understanding the phase behavior of an active pharmaceutical ingredient in a drug formulation is
Received 10 June 2013 required to avoid the occurrence of sudden phase changes resulting in decrease of bioavailability in a
Received in revised form 13 August 2013 marketed product. Benzocaine is known to possess three crystalline polymorphs, but their stability hier-
Accepted 15 August 2013
archy has so far not been determined. A topological method and direct calorimetric measurements under
Available online 28 August 2013
pressure have been used to construct the topological pressuretemperature diagram of the phase rela-
tionships between the solid phases II and III, the liquid, and the vapor phase. In the process, the transition
Keywords:
temperature between solid phases III and II and its enthalpy change have been determined. Solid phase
Thermodynamics
Physical stability
II, which has the highest melting point, is the more stable phase under ambient conditions in this phase
Phase diagram diagram. Surprisingly, solid phase I has not been observed during the study, even though the scarce lit-
Pressure erature data on its thermal behavior appear to indicate that it might be the most stable one of the three
X-ray powder diffraction solid phases.
Polymorphism 2013 Elsevier B.V. All rights reserved.

1. Introduction
1.1. Stability hierarchy between polymorphs
Benzocaine, p-aminobenzoic acid ethyl ester or ethyl 4-
aminobenzoate (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 relation-
ships 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 calori-
metric 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;
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 mea-
surements to verify its results and to investigate in more detail the
effects of pressure on phase equilibria. It has been shown in sev-
eral 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 mea-
surements under pressure as well as inferences by the topological
method will be presented and a pressuretemperature phase dia-
gram 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

Corresponding author. Tel.: +33 1 53739675. structures have been solved to date. The rst structure that was
E-mail address: ivo.rietveld@parisdescartes.fr solved and thus named form is orthorhombic with space group
(I.B. Rietveld). P21 21 21 (Sinha and Pattabhi, 1987). Later Gruno et al. demonstrated

0378-5173/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.031
 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 endother-

mically 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
Fig. 2. Specic volumes of forms I (solid spheres), II (solid squares) and III (solid dia-
and solved the structure of a third form (Chan et al., 2009a,b). They
mond), as a function of temperature from literature data. Broken lines are estimates
also proposed a new nomenclature taking into account the results based on the assumption that the specic volumes increase parallel to that of form
of Gruno et al. (1993) and Schmidt (2005): form I, previously form I: vI /cm3 g1 = 0.7739 + 0.0001728 T/K.
, is the monoclinic P21 /c polymorph, form II, previously form ,
is the orthorhombic P21 21 21 polymorph, and form III is the mono-
et al., 1993). In addition, they remark that form I does not trans-
clinic form P21 found by Chan et al. at low temperature (Chan et al.,
form for at least several months of storage (presumably at room
2009a). With the data found in references (Chan et al., 2009a,b;
temperature) (Gruno et al., 1993). Using X-ray powder diffraction
Gruno et al., 1993; Lynch and McClenaghan, 2002; Schmidt, 2005;
as a function of temperature, they observe the appearance of form-
Sinha and Pattabhi, 1987), the specic volumes of forms I, II and III
II-specic peaks in a form I sample at 308 K (Gruno et al., 1993).
have been calculated. They have been compiled in Table 1.
Schmidt deduced from the DSC curves published by Gruno et al. that
Specic volume inequalities between different solid forms are
the enthalpy of this transition (I II) is approximately +1 kJ mol1
most reliably determined from crystallographic data collected as
(Gruno et al., 1993; Schmidt, 2005).
a function of temperature and on the same equipment. The liter-
Gruno et al. obtained form II by slow crystallization from butyl
ature data are not adapted for comparison between the specic
acetate solutions and form I by fast crystallization from butyl
volumes of the different solid forms, but with a few approxima-
acetate or chloroform solutions (Gruno et al., 1993). Chan et al.
tions an estimate of the inequalities can be obtained. Only for form I,
obtained the two forms by evaporation from ethanol solutions at
the specic volume had been determined at different temperatures
room temperature (Chan et al., 2009b). Schmidt has listed a num-
(Fig. 2). Under the assumption that the inequalities are indepen-
ber of solvents, from which form I can be obtained (Schmidt, 2005).
dent of temperature, it may tentatively be inferred that vII > vIII > vI
She also mentioned that form II can be obtained from the super-
(Fig. 2).
cooled melt below 337 K (Schmidt, 2005). Furthermore, Chan at al.
observed a reversible transition of form II into form III by decreasing
1.3. Benzocaine literature data: calorimetry the temperature down to 150 K (Chan et al., 2009a). Schmidt how-
ever, did not observe any solidsolid transition for a commercially
Literature data concerning calorimetric properties for these available form II in the range of 40 to 100 C (Schmidt, 2005).
polymorphs is limited and the data compiled in Table 2 are mainly Heat capacities of solid, Cp,S , and liquid, Cp,L , benzocaine have
based on the work of Schmidt (2005). The melting temperature been determined by Neau et al. (Neau and Flynn, 1990). The data
of benzocaine has been reported by Schwartz and Paruta (1976),
Manzo and Ahumada (1990), and Yalkowsky et al. (1972); however,
Table 2
polymorphism was not mentioned in the latter three publications.
Calorimetric data from literature of the melting behavior of some benzocaine
According to Gruno et al., form I (or ) transforms endothermi- polymorphs.
cally into Form II (or ) at about 352 K as observed by DSC (Gruno
Tfus /K fus H/kJ mol1 Reference

Form I (), P21 /c

Table 1 21.5a
Specic volumes of benzocaine polymorphs from literature data. Form IIb () P21 21 21
363 Gruno et al. (1993)
T/K vspec /cm3 g1 Reference
361.8 20.5 Schmidt (2005)
Form I (), monoclinic P21 /c 363.4 21 Pena et al. (2004)
120 0.7946 Lynch and McClenaghan (2002) 362.85 22.3 Nordstrom and Rasmuson (2009)
300 0.8257 Chan et al. (2009b) 363 23.6 Chickos et al. (2002)
a
Form II (), orthorhombic P21 21 21 363.05 20.51 Garmroodi et al. (2004)
b
R.T. 0.8287 Sinha and Pattabhi (1987) 363 22.26 Neau et al. (1989)
300 0.8334 Chan et al. (2009a) 361363 21.05 Schwartz and Paruta (1976)
R.T.b 0.8286 Gruno et al. (1993) 362.7 23.56 Manzo and Ahumada (1990)
Form III, monoclinic P21 363 19.75 Yalkowsky et al. (1972)
150 0.8021 Chan et al. (2009a) 362.8 21.6 Average
a
Form I in Ref. (Schmidt, 2005). a
Calculated in Ref. (Schmidt, 2005) from data in Ref. (Gruno et al., 1993).
b
R.T. = room temperature b
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 : Cp,S /J g1 K1 = 0.0044(3)T/K + 0.11(11)
Liquid : Cp,L /J g1 K1 = 0.0025(4)T/K + 1.11(14)
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 con-
clusion 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 Princi-
ple. 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 enan-
tiotropic 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 temper-
ature 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 ther-
modynamically 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 tran-
sition 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 com-
pensate 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 tempera-
tures; 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 con-
sidered 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 stabil-
ity, 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 excep-
(1) tions (in such a case application of the Le Chatelier principle
would remain inconclusive) and that is caused by the fact that
(2) temperature and pressure are not combined to construct a com-
plete 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 addi-
tional 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 behav-
ior.
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 anal-
ysis (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:
dP h
= (3)
dT T v
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 Chate-
lier 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 esti-
mated, 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)
AL h BL h
TAB = (4)
(AL h/TAL ) (BL h/TBL )
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 simpli-
ed 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 483

the known quantities. The necessary equations have been derived Table 3
Lattice parameters and specic volume of form III (low temperature, monoclinic
in a slightly different way than Yu (1995). Details can be found in
P21 ) of benzocaine as a function of temperature.
the supplementary materials. Without taking into account the heat
capacity, the following equation can be obtained that will provide T/K a/ b/ c/ / Vcell /3 vspec /cm3 g1
the melting point of A directly: 200 8.2112 10.695 20.559 99.403 1781.2 0.81165
220 8.2176 10.714 20.591 99.411 1788.6 0.81502
BL h + AB h
TAL = (5) 245 8.2333 10.752 20.658 99.527 1803.6 0.82186
(BL h/TBL ) + (AB h/TAB ) 260 8.2393 10.764 20.694 99.576 1809.7 0.82466

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 3. Results
capacities for the different solid forms are considered equal (by
lack of data). That leads to the following expression: 3.1. Crystals
 h
  h

AL G(T ) = BL h + AB h T
BL
T
AB Benzocaine crystals were grown at room temperature from the
TBL TAB following solvents: ethanol, p-xylene, butyl acetate, chloroform,
and diethyl ether. Only form II crystals were obtained in this way.
12 a(TBL T )2 b(TBL T + T ln(T/TBL )) (6)
No crystals of form I were observed even after repeated crystalliza-
a and b are coefcients describing the difference in heat capacity tion attempts.
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
3.2. Calorimetric data
and form B, respectively. AL G(T) represents the Gibbs energy
of the transition of solid A into liquid at temperature T at con-
On heating from room temperature, form II melts at
stant pressure, which is not necessarily the melting point. With
362.4 0.5 K (onset) with an enthalpy change of 141 2.4 J g1 (see
expression (6), the melting point of solid A can be found by setting
Table S2 in the supporting information for the measurement values
AL G(T) equal to zero, because that is implied by an equilibrium
obtained by DSC). In addition, an exothermic solidsolid transition
between the phases liquid and solid A. The temperature of fusion of
was observed on cooling from room temperature to 200 K. This
A (if AL G(T) = 0, T = TAL ) can subsequently be found by numeri-
transition reverts endothermically on reheating at 265.3 0.5 K
cal methods. A similar approach can also be found in a publication
(onset) with an enthalpy change of 3.0 1.0 J g1 (Table S2) and
by Bennema et al. (2008).
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 3.3. Powder diffraction and specic volume
as such, after preliminary X-ray diffraction showed that the powder
consisted of the orthorhombic form P21 21 21 (form II). The lattice parameters of benzocaine have been determined as
Differential scanning calorimetry (DSC) experiments were per- a function of temperature from 200 K up to the melting point. They
formed on a Q100 analyzer from TA Instruments (New Castle, have been compiled in Tables 3 and 4. On heating, a phase change
DE, USA). Different quantities (210 mg) of benzocaine and dif- was observed between 260 and 270 K (Fig. 3); by comparing the
ferent heating rates from 0.2 up to 10 K min1 were used. The diffraction patterns available in the CSD, the low and high temper-
measurements were carried out on samples sealed in aluminum ature phases were found to be form III and form II, respectively. The
pans. diffraction pattern at 265 K possesses Bragg peaks of both phases,
High-resolution X-ray powder diffraction patterns were an observation that matches the transition temperature obtained
obtained as a function of temperature from 200 K up to the liquid by DSC.
state with a CPS120 diffractometer from INEL (France) equipped The lattice parameters lead to the following two expressions for
with a liquid nitrogen 700 series Cryostream Cooler from Oxford the specic volume, vspec , as a function of temperature obtained by
Cryosystems (Oxford, UK). Data were collected for at least 1 h per tting the data in Tables 3 and 4, respectively
diffraction pattern. The heating rate between the measurements
Form III : vIII /cm3 g1 = 0.766(3) + 2.2(2) 104 T/K (7)
was 1.3 K min1 and before data collection the sample tempera-
ture was left to stabilize for at least 15 min. The lattice parameters
as a function of temperature have been determined with Paw- Form II : vII /cm3 g1 = 0.762(2) + 2.53(8) 104 T/K (8)
ley 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 Table 4
Lattice parameters and specic volume of form II (high temperature, orthorhombic
constructed HP-DTA, similar to the apparatus previously built by
P21 21 21 ) of benzocaine as a function of temperature.
Wringer (1975) with temperature and pressure ranges from 203
to 473 K and 0 to 300 MPa, respectively, was used. Samples were T/K a/ b/ c/ Vcell /3 vspec /cm3 g1
sealed in cylindrical tin pans and to ensure that in-pan volumes 270 8.2430 5.3057 20.853 911.99 0.83116
were free from residual air, specimens were mixed with an inert 280 8.2458 5.3039 20.885 913.41 0.83246
peruorinated liquid (Galden from Bioblock Scientics, Illkirch, 300 8.2592 5.3187 20.928 919.31 0.83784
310 8.2598 5.3246 20.940 920.93 0.83932
France) before sealing. HP-DTA scans were carried out with a heat- 320 8.2652 5.3304 20.966 923.69 0.84183
ing rate of 2 K min1 . In addition, DSC runs at ordinary pressure 330 8.2736 5.3375 20.997 927.20 0.84503
(i.e., in standard aluminum pans) with mixtures of benzocaine and 345 8.2813 5.3462 21.049 931.91 0.84932
peruorinated liquid were carried out to verify that the latter was 355 8.2867 5.3522 21.082 935.02 0.85216
360 8.2873 5.3548 21.099 936.31 0.85333
inert.
484 I. Gana et al. / International Journal of Pharmaceutics 456 (2013) 480488
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 pres-
sure increases. They intersect at the III-II-L triple point, which is
according to these results located at high pressure and high temper-
ature. 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
The various data obtained by measurement in relation to the
observed transitions have been summarized in Table 5.
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.
4. Discussion
4.1. Consistency of the obtained data
The temperature of the III II transition under ordinary con-
ditions 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 tran-
sition 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 exper-
imental 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 consis-
tency 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 experimen-
tal 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
(9) 1.076 0.0036, which is in agreement with previous ndings for
other active pharmaceutical ingredients. The average ratio of vL /vII
(10) at Tfus is 1.10 based on data from several APIs (active pharmaceu-
tical 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
 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 265.3 0.5 3.0 1.0 0.0030 0.0010 2.70 0.06

II L (fusion) 362.4 0.5 141.0 2.4 5.99 0.13

slope of 4.56 MPa K1 would be found. Although the latter value is because if one scrutinizes Eq. (6), it can be seen that the effect
smaller than the slope obtained by the PT measurements, it is still of the heat capacity only depends on the distance of the melting
much larger than the slope for the solidsolid transition III II temperature of form III from the melting point of form II, which
(Table 5). Hence topologically speaking, the conclusion on the appears to be very small. The difference between the two solid heat
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 corre-
sponds 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 intersec-
tion 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 speak-
ing, 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 equilib-
rium curves and the triple point can be found in the topological
pressuretemperature phase diagram of forms II and III of benzo-
caine (Fig. 5).

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 melt-
ing 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 thermody-
namic 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 tran- Fig. 5. Topological pressuretemperature phase diagram of the stability hierarchy
sition temperatures as given in Table 5 are used. This leads to a of the benzocaine polymorphs III and II. (a) Measured curves, solid line: equilibrium
temperature of fusion for form III, TIIIII , of 359.6 K, just below the 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
temperature of fusion for form II (362.4 K).
phases are indicated in their respective phase domains (III, II, and L). (b) Entire topo-
The heat capacities for the solid phase of benzocaine and its logical diagram not to scale with all equilibrium curves and triple points between
liquid can be found in Table S1 and the resulting expressions for phases III, II, L, and V (vapor phase). Black solid lines: most stable phase equilibria,
their temperature dependence are Eqs. (1) and (2). As indicated gray broken lines: metastable phase equilibria, and dotted lines: supermetastable
below Eq. (6) in the introduction, it is the difference Cp,L Cp,III that 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
is used; hence Eq. (1) is subtracted from Eq. (2) resulting in:
triple points by III-II-V, III-II-L, III-L-V, and II-L-V. If a two-phase equilibrium (line)
Cp,L Cp,III (T )/J g1 K1 = 0.0019T/K + 1.0 (11) 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
Employing Eq. (6), leads to a temperature of fusion for form
(gray broken line), then it passes through the stable triple point III-II-V (solid black
III of 359.6 K, which is identical to the value found without tak- circle) and it turns stable (solid black line), the stable sublimation curve of the solid
ing into account the heat capacities. It is not surprising however, 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 posi-
tion 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 temper-
ature plane at a given temperature. This slope can be extrapolated
to nd the coordinates of a given equilibrium at a different pres-
sure 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 transi-
tion. 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 transi-
tion 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 experi-
mental dP/dT slope. It resulted in vL = 0.9185 cm3 g1 . Moreover
the specic volume of form III can be obtained by extrapola-
tion 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 ordi-
nary 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 coin-
ciding 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 equi-
librium 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 melt-
ing 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: III-
II-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 rel-
atively 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 pres-
sure 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 pres-
sure 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 pres-
sure of the liquid can be described as a function of temperature:
vap H
General expression : ln P = + Bvap (14)
RT
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 deter-
mined 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 con-
stant 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 follow-
ing 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 Pressure III II L

/K /Pa P/Pa P/Pa P/Pa

III-II-V 265 0.007 0.007 0.007 0.12

III-L-V 360 84 84 79 84
II-L-V 362 96 102 96 96
III-II-L 439 463 106 463 106 463 106 463 106

therefore estimates in the absolute sense, but completely accept- 6. Conclusion

able for comparison in the relative sense.
For liquid benzocaine, the expression for the vapor pressure as The benzocaine phase transition between the previously
a function of temperature becomes: reported monoclinic P21 (form III) and the orthorhombic form
P21 21 21 (form II) has been located for the rst time. The transi-
55160 tion temperature is 265.3 0.5 K and the enthalpy change equals
Vapor pressure : ln(Pvap /Pa) = + 22.88 (15)
RT 3.0 1.0 J g1 .
At triple point II-L-V, solid form II, the liquid, and the vapor The equilibrium curves of the III-II and the II-L equilibria in the
are in equilibrium, which means that the vapor pressure of form pressuretemperature phase diagram have been obtained by high-
II equals that of the liquid. With Eq. (15), the vapor pressure pressure differential thermal analysis. They intersect at 439 K and
of the liquid at TIIL (362.4 K = TII-L-V ) can be calculated result- 463 MPa, which are the coordinates where form III, form II, and the
ing in 96 Pa. This pressure provides a value for the sublimation liquid are in equilibrium with each other, i.e. the triple point III-II-L.
pressure of form II, the sublimation enthalpy being equal to With the triple point coordinates, the position of the equilibrium
the sum of the vapor pressure enthalpy and that of the melt- between form III and the liquid has been determined followed by
ing transition: sub,II H = vap H + fus,II H = 78445 J mol1 . Using the the complete topological phase diagram with respect to phases III,
sublimation enthalpy, the sublimation constant Bsub,II can be calcu- II, liquid, and vapor.
lated (Bsub,II = 30.60). It results in the following expression for the Surprisingly, form I has not been obtained during the inves-
sublimation pressure of form II: tigation despite repeated efforts reminiscent of what Dunitz
and Bernstein named disappearing polymorphs (Dunitz and
78445 Bernstein, 1995). Its disappearance is surprising, because the sparse
Sublimation pressure form II : ln(Psub,II /Pa) = + 30.60
RT calorimetric data on this form appear to indicate that it may be the
(16) most stable phase of the three known solid phases under ambi-
ent conditions. Nonetheless, even if form I would turn out to be
the most stable phase, the phase relationships between the other
The same can be done for the sublimation pressure phases presented in Fig. 5 will remain valid.
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 sublima-
Acknowledgments
tion constant Bsub,III becomes 30.83. It results in the following
expression for the sublimation pressure of form III:
M.B. and J.-Ll. T. were supported by the Spanish Ministry of
78946 Science and Innovation (Grant FIS2011-24439) and the Catalan
Form III : ln(Psub,III /Pa) = + 30.83 (17) Government (Grant 2009SGR-1251).
RT

Either Eq. (16) or (17) can be used to calculate the sublima-

tion 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 includ-
ing 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 spec-
ulation, form I has not been incorporated in the present phase
diagram.
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.
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