Collective relaxation dynamics and crystallization kinetics of the amorphous Biclotymol antiseptic

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Abstract

We employ dielectric spectroscopy to monitor the relaxation dynamics and crystallization kinetics of the Biclotymol antiseptic in its amorphous phase. The glass transition temperature of the material as determined by dielectric spectroscopy is Tg = 290 ± 1 K. The primary (α) relaxation dynamics is observed to follow a Vogel–Fulcher–Tammann temperature dependence, with a kinetic fragility index m = 86 ± 13, which classifies Biclotymol as a relatively fragile glass former. A secondary relaxation is also observed, corresponding to an intramolecular dynamic process of the non-rigid Biclotymol molecule. The crystallization kinetics, measured at four different temperatures above the glass transition temperature, follows an Avrami behavior with exponent virtually equal to n = 2, indicating one-dimensional crystallization into needle-like crystallites, as experimentally observed, with a time-constant nucleation rate. The activation barrier for crystallization is found to be Ea = 115 ± 22 kJ mol−1.

Introduction

Pharmaceutically active molecules and active pharmaceutical ingredients (API’s) are generally stored in solid form, either as crystalline or amorphous (glassy) powders. Compared to the crystalline form, the amorphous form of API’s offers the advantage of a higher solubility (Gupta et al., 2004) and bioavailability (Serajuddin, 1999). The amorphous glass state has however the disadvantage of being thermodynamically unstable against the nucleation of crystalline phases (Bhardwaj et al., 2013, Zhou et al., 2002). The microscopic mechanisms governing the kinetic stability of amorphous API remains unclear, and the crystallization kinetics appears to be determined by a large number of factors such as preparation method, thermal and mechanical treatments employed during formulation (Patterson et al., 2005), storage temperature, application of pressure or exposure to humidity (Yu, 2001). It is generally found that storage well below the glass transition temperature Tg (e.g., at Tg  50 K) prevents crystallization of the amorphous state and thus ensures a physically stable drug during its shelf-life (Capen et al., 2012, Pogna et al., 2015). In general, the thermal energy and the molecular mobility below Tg are considered to be too low to produce the rearrangements necessary for the nucleation of the crystalline phase, although some authors have proposed that the secondary Johari–Goldstein relaxation (considered as the primitive relaxation) can provide enough mobility to activate the crystallization process. (Adrjanowicz et al., 2012a) A recent study (Schammé et al., 2015) on Biclotymol, 2,2′′-methylenebis(4-chloro-3methylisopropylphenol), an antiseptic used for mouth, throat and pulmonary infections, has shown that it can be stored in its amorphous form during months also several degrees above the Tg of the material, i.e., at temperatures at which the material is in the supercooled liquid state and the molecular mobility is slow but not negligible. Motivated by this finding, we present here an experimental study of the recrystallization of Biclotymol from its supercooled state at four different temperatures, by means of broadband dielectric spectroscopy, a well-established technique to investigate crystallization kinetics in API’s (Adrjanowicz et al., 2010, Adrjanowicz et al., 2012b, Kaminski et al., 2011). We find in particular that crystallization takes place on the timescale of hours even at moderate temperatures (Tg + 14K), and that therefore temperature control is critical to preserve the amorphous state. Moreover, we study in detail the fragility of this glass-forming API and the crystallization mechanism. Crystallization can be well described by the Avrami law with integer exponent n equal to 2, corresponding to one-dimensional growth of needle-like crystallites, as experimentally observed, with a time-independent nucleation rate.

Section snippets

Material and methods

Biclotymol powder of medicinal grade was provided by Bouchara–Recordati (France) and used as received. The sample batch was the same as in our previous work (Céolin et al., 2008). Differential scanning calorimetry measurements were carried out in the temperature range between 250 and 450 K with heating or cooling rates 10 K min−1, using a Q100 calorimeter from TA-Instruments. The value of the melting temperature determined by calorimetry was used as a check that the quality of the sample had not

Results and discussion

Fig. 1 shows the real (a) and imaginary (b) part of the complex relative dielectric permittivity of Biclotymol in its supercooled liquid (amorphous) state, as measured upon heating from low temperature (only the data between Tg and Tg + 32 K are shown; the molecular structure of Biclotymol is shown as an inset to Fig. 1(a)). A clear primary relaxation is observed, visible as a peak in the imaginary permittivity (b) and as a corresponding decrease in the real permittivity (a). The primary

Conclusions

We have presented a dielectric spectroscopy study of the relaxation dynamics and crystallization kinetics in the supercooled amorphous phase of the pulmonary antiseptic Biclotymol. This pharmaceutically active molecule is found to be a relatively fragile glass-former with fragility index m = 86 ± 13. The primary relaxation process is characterized by an asymmetric spectral lineshape and non-simply-activated temperature dependence. This collective relaxation freezes out at the glass transition

Acknowledgments

This work has been partially supported by the Spanish Ministry of Science and Innovation through project FIS2014-54734-P and by the Generalitat de Catalunya under project 2014 SGR-581.

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