R.D. Oparin, Y.A. Vaksler, M.A. Krestyaninov et al.
Journal of Molecular Liquids xxx (xxxx) xxx
CBZ is the only one used in pharmaceutics nowadays as the most stable
at room temperature. However, polymorph I that is less stable at room
temperature [30], could be more interesting pharmacologically, e.g. in
composites with polymers, where it can be stabilized by polymer
matrix.
• To analyze the polymorphic composition of the solid CBZ phase ob-
tained by CBZ crystallization from the SCF solution, using micro-
Raman spectroscopy.
In our work [18], we showed that metastable polymorphic form I can
be obtained from polymorphic form III by recrystallization through the
solution in scCO2 at a temperature of 110°C. This process can be formally
separated into two principal stages. At the first stage, CBZ form III was
dissolved in scCO2. This led to the conformational equilibrium of the
CBZ molecules in the scCO2 phase due to the thermodynamic factor.
The second stage consisted of crystallization of the CBZ polymorphic
form I that is the most stable in the given conditions from the SCF solu-
tion. We also showed that the temperature and density of the CO2 phase
significantly affect the solubility of CBZ in scCO2, and the temperature
has an influence on the dissolution kinetics. Thus, the yield of poly-
morph I directly depends on the fluid phase density and temperature.
Despite the fact that the use of the considered approach makes it possi-
ble to produce polymorph I, it is always possible to obtain the initial
form as a side product. This situation will remain so while there is con-
formational equilibrium in the SCF solution. It is possible to completely
shift this equilibrium towards the conformer being present in poly-
morph I by increasing the temperature. For example, in our previous
study [17] of the conformational equilibria of mefenamic acid (MA) in
a scCO2 medium, we showed that there is only one conformer in the so-
lution phase at a temperature above the MA melting point. This con-
former determines the formation of MA metastable form II through
crystallization from its SCF solution. In the present study, we will also at-
tempt to create the same conditions that will allow us to obtain a similar
result for CBZ.
2. Materials
The CO2 gas (99.99% purity) was purchased from “The Linde Group”.
The powder of the CBZ form III (5H-Dibenz[b,f]azepine-5-carboxamide)
was purchased from “Sigma-Aldrich” (CAS Number 298‐46-4). Accord-
ing to the DSC results presented in Ref. [30], the first endothermic peak
appears at 174.8°С and immediately followed by an exothermic peak,
the second endothermic peak appears at 193.2°С (see Fig. 1). The results
of the thermomicroscopy also presented in this work showed that form
III melts and subsequently crystallizes to form I from 162 to 175°С
(endo-exo melting-recrystallization). In turn form I melts between 189
and 193°С. Thus, the first endothermic peak on the DSC curve corre-
sponds to the melting of form III, whereas the exothermic peak is attrib-
uted to the crystallization of form I, which melting gives the second
endothermic peak on DSC curve. Though, there is a certain discrepancy
between hot-stage and DSC measurements, which might have arisen
from various heating rates and/or other experimental parameters
being used in this work, nevertheless these data give us a useful initial
information on high-temperature conversion of CBZ from form III to
form I under atmospheric pressure.
3. Experimental part
3.1. 3.1. Visual analysis of the structural changes in the CBZ sample
Assuming that the increase in the temperature of the CBZ–scCO2 bi-
nary mixture will shift the equilibrium in the scCO2 phase towards the
conformer corresponding to polymorph I, we can expect that CBZ crys-
tallization from the scCO2 phase (for example, via Rapid Expansion of
Supercritical Solution RESS) will produce «pure» polymorph I. More-
over, one can expect that at high temperatures the time required for
reaching the CBZ equilibrium concentration in scCO2 will be signifi-
cantly less compared with the low-temperature process (at 110°C), as
it was described in work [18]. As a consequence, the total process time
can be also significantly reduced.
Thus, the main aim of this study was to evaluate the possibility of pre-
paring CBZ polymorph I from CBZ saturated solution in scCO2 at the tem-
peratures above the CBZ melting point. Consequently, in order to study
the high-temperature conformational equilibria of CBZ in scCO2, we ex-
panded the temperature range studied in work [18] to 200°C.
To achieve this aim we set out to do the following tasks:
The thermal changes in the CBZ surface permanently contacting
with CBZ saturated solution in scCO2 were visually observed with the
help of the system specially designed by us. It is based on a digital
long-focus optical microscope. This microscope is united with a univer-
sal High-Pressure-High-Temperature (HPHT) optical cell via a precise
positioning system. Moreover, the microscope is also equipped with co-
axial brightening that allows making a bright image of a target placed
deep inside the optical cell. The HPHT cell is equipped with an optically
transparent sapphire window enabling to take a photo of the CBZ sur-
face inside the cell. Its thickness of 9 mm in combination with a small di-
ameter (the external diameter is 12 mm and the effective working
diameter is 8 mm) allows to work at pressures of up to 1 kbar inside
the cell. A detailed description of the optical cell and window sealing
system is presented in our previous publication [17]. To control the tem-
perature and pressure of the reaction medium inside the cell, we used
the experimental setup that was successfully applied in a number of
our works [15,17,19]. The photos of the CBZ surface permanently
contacting with CBZ saturated solution in scCO2 were made with an op-
tical resolution of 2 megapixels. The images were obtained for a number
of temperatures along the chosen isochore. These photos are presented
in Fig. 2.
• To study in details the conformational equilibria of the CBZ molecules
in the scCO2 medium in a two-phase CBZ–scCO2 mixture under
isochoric heating (at a constant CO2 density equal to 1.3 of its critical
value) in the temperature range from 110 to 200°C, including the re-
gion of the CBZ phase transition associated with its melting.
Fig. 1. DSC profile of CBZ polymorph III measured at atmospheric pressure [30].
2