Tuning the Kinetic Stability of the Amorphous Phase of the Chloramphenicol Antibiotic

Abstract

We employ broadband dielectric spectroscopy to study the relaxation dynamics and crystallization kinetics of a broad-spectrum antibiotic, chloramphenicol, in its supercooled liquid form. Two dynamic processes are observed: the structural α relaxation, which becomes kinetically frozen at T g = 302 ± 1 K, and an intramolecular secondary relaxation. Under isothermal conditions, the supercooled drug displays interconversion between different isomers, followed by recrystallization. Recrystallization follows the Avrami law with Avrami exponent n = 1.3 ± 0.1, consistent with a one dimensional growth of crystalline platelets, as observed by electron microscopy. Exposure to humid atmosphere and subsequent heating to high temperature is found to degrade the compound. The partially degraded sample displays a much lower tendency to crystallize, likely because the presence of the degradation products results in spatial frustration. This sample exhibits enhanced conductivity and an additional relaxation, intermediate to the ones observed in the pure sample, which likely corresponds to the noncooperative dynamics of the main degradation product. We find that dispersing the antibiotic in polylactic acid results in an amorphous sample which does not crystallize at room temperature for relatively long times.

Amorphous binary dispersions of chloramphenicol in enantiomeric pure and racemic poly-lactic acid: Morphology, molecular relaxations, and controlled drug release

“…In some cases, the secondary relaxation corresponds to "intramolecular" motions involving a relative motion of polar sidegroups of a polymer chain (as in polyvynilpirrolidone (Romanini et al, 2018)) or of a subpart of a molecule (as it is the case for the chloramphenicol molecule (Rivas et al, 2018) and other drugs (Tripathi et al, 2015)). In other cases, the secondary relaxation involves the rigid reorientation of the whole molecule or chain segment, as the cooperative α relaxation but involving only local degrees of freedom (Ngai and Paluch, 2004).…”

“…In other cases, the secondary relaxation involves the rigid reorientation of the whole molecule or chain segment, as the cooperative α relaxation but involving only local degrees of freedom (Ngai and Paluch, 2004). The latter secondary relaxations are termed Johari-Goldstein relaxations (Johari and Goldstein, 1970), and they are observed for example in fully rigid molecules (Romanini et al, 2012) and in polymers with monoatomic or methyl sidegroups such as polybutadiene (Schroeder et al, 2007) and 1,4polyisoprene (Roland et al, 2004), but they are also observed together with intramolecular modes in other polymers (Romanini et al, 2018;Cerveny et al, 2008).…”

“…(Rivas et al, 2018;Tian et al, 2016;Kostopoulou et al, 2014) We have shown in a recent article that CAP is prone to degradation at high temperatures. (Valenti et al, 2018) In particular, we found that exposure of the drug to humid atmosphere and subsequent heating to its melting point (Tm = 423 K) (O'Neil, 2013;Ford, 1987) degrades the compound, something that should be avoided due to the possible toxicity of degradation products. The motivation for the present work is twofold: on one hand, devising an optimum temperature range for obtaining ASDs of active pharmaceutical ingredients, which should favor the dispersion's homogeneity while not compromising the chemical stability of the drug; on the other hand, investigating possible benefits of using an intrinsically amorphous polymer, rather than a semicrystalline one, for ASDs.…”

“…One of the ways to improve the stability of an amorphous drug is by dispersing it in a biopolymer excipient. (Romanini et al, 2018) There are various methods available to obtain amorphous solid dispersions (ASDs), and in all of them an energy input in the form of heat proves to be beneficial to increase the homogeneity of the dispersion and thus its kinetic stability against recyrstallization. (Dedroog et al, 2019) However, heating can also have drawbacks, especially for drugs that are not thermally stable.…”

Segmental relaxation and partial crystallization of chain‐extended Poly(l‐lactic acid) reinforced with carboxylated carbon nanotube

“…Dielectric spectroscopy is a versatile tool that provides useful information on the intensity (dielectric strength) and relaxation time of the macromolecular dynamic processes . In addition, the dielectric analysis of heterogeneous materials allows studying interfacial effects such as Maxwell–Wagner–Sillars (MWS) relaxations .…”