Terahertz Pulsed Spectroscopy to Monitor Polymorphic Conversion Processes

Table of Contents

Introduction
Terahertz Pulsed Spectroscopy
Results and Discussion
Conclusions

Introduction

Carbamazepine (CBZ) is a dibenzapine derivative and is primarily used in the treatment of epilepsy and other neurological disorders. CBZ is polymorphic and is said to be present in four anhydrous forms, as a dehydrate and also as other solvates. Of the anhydrous forms, the polymorph with a basic monoclinic crystal structure is most frequently referred to as Form III.

The triclinic polymorph is typically called form I. Forms I and III form dimers by cyclic hydrogen bonding between the CONH2 groups. Forms I and III are enantiotropic, with form III being the stable form at room temperature and form I being stable at elevated temperatures. The solid-state conversion from form III to form I that happens below the melting temperature of form III has been suggested to occur via a solid-vapor solid mechanism.

Terahertz Pulsed Spectroscopy (TPS) is particularly sensitive to the intermolecular bonding of materials and thus is perfectly suited to the study of polymorphism. In this research, the temperature induced transition between CBZ forms I and III is tested using TPS. The spectral changes asociated with the polymorphic transitions are tested to expose information about the conversion mechanism.

Figure 1. Terahertz absorption spectra (ambient temperature - 293 K terahertz spectra for CBZ form I and III.

Terahertz Pulsed Spectroscopy

Transmission spectra from 2 cm-1 to 95 cm-1 at 0.1 cm-1 spectral resolution were gathered using a TeraView TPS spectra 1000 terahertz spectrometer. To eliminate spectral contribution linked with atmospheric moisture the sample chamber was purged with dry nitrogen (10 l/min) before and during the experiment. Each sample spectrum was referenced against a spectrum of an empty sample holder, with nitrogen purging. For each rapid-scan spectrum within one minute, an average of 1800 co-added scans was recorded.

The sample pellets were held in a brass ring with an 8 mm circular aperture and inserted into a heatable transmission cell which did not have any windows. Temperature was calibrated using compounds of established melting point. The sample pellet temperature was modified at a rate of approximately 2 K•min-1.

Results and Discussion

Room temperature (293 K) terahertz spectra for CBZ form I and III can be seen in Figure 1. Theterahertz absorption spectrum for CBZ form III exhibits distinct spectral features with peaks at 29 cm-1, 42 cm-1 and 61 cm-1. CBZ form I shows a sharp peak at 32 cm-1 with a weak shoulder at 24 cm-1 and two additional peaks at 45 cm-1 and 52 cm-1. CBZ form I seems to exhibit none of the features of form III in the range between 2 cm-1 and 70 cm-1.

At least two transfomation processes have been reported for CBZ form III conversion to form I upon heating. One of the processes is a melt of form III at 445 K followed by crystallization of the melt to form I at higher temperatures. The second process is a solid-solid transformation below the melting point of form III. This process occurs in temperatures between 403 K and 433 K.

Upon heating CBZ form III in the TPS temperature dependent measurements, between 293 K to 433 K all the spectral features display a red-shift, peak widening and decrease in intensity, illustrated in figure 2.

Figure 2. Terahertz absorption spectra of CBZ form III during the temperature dependent measurements. The plots are offset in absorbance for clarity. (a) Heating from 293 K to 453 K, transformation of form III to I takes place. (b) Cooling the transformed sample of CBZ form I from 453 K to 303 K.

Additional heating up to 453 K leads to melting of CBZ form III followed by recrystallization to form I. At 443 K, an intermediate spectrum with peaks corresponding to both form III and form I is observed. The spectral features of form III at 39 cm-1 and 57 cm-1 lose substantial intensity at this temperature and the spectral feature of form I primarily at 32 cm-1 red-shifts towards 31 cm-1. At 453 K, the conversion from CBZ form III to form I is complete and only form I spectral features are recorded as illustrated in Figure 2a. In this figure, the baseline is subtracted for more clarity. Cooling form I from 453 K to 303 K generates a blue-shift, the peaks sharpen, and increase in intensity as shown in Figure 2b.

Figure 3. Terahertz absorption spectra of the conversion process of CBZ form III to I at different temperatures. 433 K solid line, 443 K dotted line, 453 K dashed line.

Figure 4. TPS spectra of the isothermal solid-solid transformation from CBZ form III (black) to form I (light grey) at 438 K. The spectra were taken in 5 minutes intervals until complete conversion.

The data from the isothermal experiment at 438 K gives more information regarding the solid-solid conversion process. It shows that the feature of form I at 31 cm-1 progressively increases in intensity as the transformation progresses (refer Figure 4). Firstly, the peak shifts position to a lower wavenumber. After 40 minutes, at 438 K the red-shift stops and the peak position is unaffected for the rest of the conversion process.

In contrast, the form III peak primarily at 39 cm-1 is blue-shifted and diminishes in intensity, disappearing after 65 minutes. The spectral feature of form I at 52 cm-1 appears after 100 minutes at 438 K red-shifted at 50 cm-1. Until completion of the conversion process after 150 minutes a slight red-shift can be noticed. Again in comparison to the form I peak shifting behavior, the form III peak at 57 cm-1 blue-shifts until it vanishes after 40 minutes.

The sequence in the appearance and disappearance of the spectral features of forms III and I during the conversion process shows that the mechanism requires more than one step. Both form III spectral features reduce from the beginning of the process onwards. One of the form I features only appears very late in the process whereas the other feature appears at the start of the transformation.

Additionally, it is interesting to note that the decaying peaks of form III both blue-shift at varying rates whereas the emerging peaks of form I both red-shift during the conversion. The dynamics of these shifts may offer clues to the processes under the conversion once the spectral features can be assigned to particular structural information.

It has been reported, CBZ form III and I both exhibit an asymmetric unit cell of hydrogen-bonded anti-carboxamide dimers. In form III, four molecules form the unit cell with one in its asymmetric unit whereas in form I the cell comprises of eight molecules with four in the asymmetric unit. The molecular conformation and the strong hydrogen bonding scheme in CBZ stay the same for all its polymorphic forms.

All variances in the crystal polymorphs occur only due to the varied packing structure of the carboxamide dimer units. This indicates that the spectral alterations noticed during the isothermal conversion process directly denote shifting phonon modes. As the dimers alter their relative arrangement during the transformation the lattice structure gets displaced causing a realignment of the unit cell from P-monoclinic in form III to triclinic in form I.

The red-shifts and blue-shifts that happen in the terahertz spectra at different points during the conversion are most probably directly related to the contraction and expansion of the unit cell as the CBZ dimers realign.

Conclusions

It is possible to examine the mechanism of a polymorphic transition using TPS. TPS has the potential to follow quick changes in the crystalline forms of organic materials. To assign the recorded phonon modes and hydrogen-bond-stretching vibrations to particular molecular structures or lattice systems requires extra understanding about the nature of the phonon modes.

This information has been sourced, reviewed and adapted from materials provided by TeraView Ltd.

For more information on this source, please visit TeraView Ltd.

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