Low-Frequency Raman Spectroscopy as an Avenue to Determine the Transition Temperature of β- and γ-Relaxation in Pharmaceutical Glasses

Abstract

In an earlier investigation, low-frequency Raman (LFR) spectroscopy was shown to detect the transition temperature of the β-relaxation (T β) in both amorphous celecoxib and various celecoxib amorphous solid dispersions [Be̅rziņšK. Be̅rziņš, K. Mol. Pharmaceutics20211838823893]. In this study, we further investigated the application of this technique to determine T β, an important parameter for estimating crystallization potency of amorphous drugs. Alongside commercially available amorphous drugs (zafirlukast and valsartan disodium salt), differently melt-quenched samples of cimetidine were also analyzed. Overall, the variable-temperature LFR measurements allowed for an easy access to the desired information, including the even lesser transition of the tertiary relaxation motions (T γ). Thus, the obtained results not only highlighted the sensitivity, but also the practical usefulness of this technique to elucidate (subtle) changes in molecular dynamics within amorphous pharmaceutical systems.

The Influence of Gastrointestinal Biomolecules on Solid-State Transformations in Pharmaceutical Particulates

“…Notably, Koskela et al have recently characterized primary indomethacin polymorphs (α, γ, δ, and ε) using LFR spectroscopy (Figure ), each of them exhibiting unique spectral features (phonon modes) that enable clear distinction between them. Furthermore, they are also distinguishable from the amorphous form of the API that is characterized by a broad vibrational density of states (VDOS) feature encompassing multiplex information. , In addition, the available MFR information on ζ, η, and θ forms in the literature , can be utilized to relate the specific MFR spectral features of these polymorphs to the simultaneously probed LFR domain (if encountered) using Raman configurations encompassing a broad spectral range such as the one utilized in this study. These aspects make LFR spectroscopy the perfect analytical method for probing indomethacin solid-state transformations of different complexity.…”

Application of Low-Frequency Raman Spectroscopy to Probe Dynamics of Lipid Mesophase Transformations upon Hydration

“…9 Similarly, this technique can be successfully applied for the analysis of amorphous pharmaceutical materials, where even critical information about their global and local molecular mobility governing their physical stability can be obtained. 10 Our previous work has further highlighted the structural sensitivity of this technique by enabling direct monitoring of drug solubilization in complex media such as milk or infant formula, which showed comparable results to synchrotron SAXS. 11,12 However, to the best of our knowledge, LFR spectroscopy has not yet been explored for the dynamic analysis of self-assembled lipid systems.…”

“…Static Mesophase Hydration. For ex situ hydration measurements of equilibrated systems measured both by SAXS and Raman spectroscopy for the determination of lipid bulk phase behavior at ambient temperature (∼20 °C), different lipid and tris buffer solution (TBS; prepared using 50 mM tris(hydroxymethyl)aminomethane maleate salt, 150 mM sodium chloride and 5 mM calcium chloride in water adjusted to pH 7.4 with 1 M sodium hydroxide) ratios (10,20,30,40,50, and 60% TBS w/w) were weighted into 5 mL glass vials, sealed, vortexed, and heated (∼70 °C) with an air gun (3cycles). After 24 h of equilibration at ambient temperature (∼20 °C), small amounts of bulk lipids were transferred into 1.5 mm thick borosilicate glass capillaries (Hilgenberg, Kassel, Malsfeld, Germany), flame sealed, and further secured with a glue gun.…”

“…The recent advances in holographic volume Bragg Gratings necessary to access the LFR region for dispersive Raman systems have allowed further experimental exploitation. , For example, the LFR region has shown advantages for both polytypic discrimination and quantification, which possess unique crystalline substances that differ only in one of the dimensions of the cell unit . Similarly, this technique can be successfully applied for the analysis of amorphous pharmaceutical materials, where even critical information about their global and local molecular mobility governing their physical stability can be obtained . Our previous work has further highlighted the structural sensitivity of this technique by enabling direct monitoring of drug solubilization in complex media such as milk or infant formula, which showed comparable results to synchrotron SAXS. , However, to the best of our knowledge, LFR spectroscopy has not yet been explored for the dynamic analysis of self-assembled lipid systems.…”

In Situ Monitoring of Drug Precipitation from Digesting Lipid Formulations Using Low-Frequency Raman Scattering Spectroscopy

“…The analogous format was utilised (on the same pH-STAT system with the same capillary and pump) using LFRS as the analytical technique. Unlike the conventional mid to high-frequency Raman spectroscopy (typically 400–4000 cm −1 ) that primarily probes the intramolecular bond vibrations of the molecules, LFRS (<200 cm −1 ) provides signatures from both the intramolecular and intermolecular (lattice or phonon) vibrations [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. As such, distinctive sharp phonon peaks from crystalline solids can be observed in LFRS, which can be used to study the bulk [ 26 , 27 , 28 ] and/or spatial components [ 29 , 30 , 31 ] in pharmaceutical systems.…”