Toward a Better Understanding of the Physical Stability of Amorphous Anti-Inflammatory Agents: The Roles of Molecular Mobility and Molecular Interaction Patterns

Abstract

The aim of this article is to examine the crystallization tendencies of three chemically related amorphous anti-inflammatory agents, etoricoxib, celecoxib, and rofecoxib. Since the molecular mobility is considered as one of the factors affecting the crystallization behavior of a given material, broadband dielectric spectroscopy was used to gain insight into the molecular dynamics of the selected active pharmaceutical ingredients. Interestingly, our experiments did not reveal any significant differences in their relaxation behavior either in the supercooled liquid or in the glassy state. Hence, as a possible explanation for the enhanced physical stability of etoricoxib, its ability to undergo a tautomerization reaction was recognized. The occurrence of intramolecular proton transfer in the disordered etoricoxib was proven experimentally by time-dependent dielectric and infrared (IR) measurements. Additionally, IR spectroscopy combined with density functional theory calculations pointed out that in the etoricoxib drug, being in fact a binary mixture of tautomers, the individual isomers may interact with each other through a hydrogen bonding network. A possible explanation of this issue was achieved by performing dielectric experiments at elevated pressure. Since compression results in etoricoxib recrystallization, the possible influence of pressure on the observed stabilization effect is also carefully discussed.

Distinguishing different classes of secondary relaxations from vapour deposited ultrastable glasses

“…For example, telmisartan and etoricoxib exhibit, apart from the JG relaxation analysed in this work, a faster relaxation which has not been analysed here. 32,35 Also, as commented above, celecoxib exhibits a hidden and low intensity JG relaxation close to the structural relaxation. 38 The further remarkable decrease of the intensity of the secondary process in the USG precludes its analysis in this work.…”

Why is the change of the Johari–Goldstein β-relaxation time by densification in ultrastable glass minor?

“…Black and red closed symbols correspond to the USG and the OG obtained after transformation of the USG and subsequent cooling down, respectively. The red open points and the orange VFT fit to t a in (B and C) are from the literature (etoricoxib, 14,16,17 telmisartan 18,19 ). All the data of toluene are extracted from Yu et al 13 The black and red circles indicate the value of t b at T on .…”

Theoretical Investigation of the Molecular Structure and Molecular Docking of Etoricoxib

“…The recommended dosage prescribed by medical doctors goes from 60 to 120 mg/day coming in 3 presentations (60, 90, 120 mg/tablet). 1,2,5,6 Etoricoxib (ETX) is considered a medium size drug with a molecular weight of 358.84 g/mol. It is synthesized from vinamidinium salts.…”

“…2 In this sense, there are several reports in the literature, which try to synthesize it in an amorphous form to overcome its water solubility issues. 6 In vitro and in vivo studies have shown a rapid absorption and a good bioavailability of ETX when taken orally. 2,10 Here, it is important to mention that ETX is part of the coxib family, which includes other related compounds such as celecoxib, valdecoxib and rofercoxib.…”

“…This type of drugs has arisen a concern in regards to their safety, because a high number of cardiovascular events have been associated with the intake of these drugs. 6,11 However, ETX has shown that is able to inhibit COX-2 but also neurodegeneration, neuroinflammation and memory impairment. Also, is able to reduce neuroinflammation in the hippocampus produced by colchicine.…”