Acoustic and thermal anomalies in a liquid–glass transition of racemic S(+)–R(−) ketoprofen
Graphical abstract
Arrhenius plot of relaxation times of ketoprofen.
Introduction
Glassy pharmaceuticals have attracted much attention from the viewpoint of new pharmaceutical engineering [1], [2]. These materials easily undergo vitrification on cooling from the melts, and they exhibit similar properties as typical structural glasses [3], [4], [5], [6]. However, their fundamental physical properties related to a liquid–glass transition are still unclear. Up to the present, glass forming materials with simple molecular structures were extensively studied by both experimental and theoretical approaches [7], while the understanding of glass formers with complex molecular structures is not enough. Therefore, the study of glassy pharmaceuticals is important to provide basic properties of chemical physics useful to pharmaceutical applications and to understand the dynamical properties of glass transitions on complex molecules.
Ketoprofen is one of non-steroidal anti-inflammatory drugs with good analgesic properties used in the treatment of rheumatoid arthritis and osteoarthritis. A glassy state of ketoprofen can be obtained easily and was studied by thermal [8], [9] and dielectric measurements recently [10]. The temperature dependences of the α-relaxation process and the secondary γ-relaxation process were observed in the previous study [10]. Although previous dielectric measurement investigated wide frequency range from Hz to MHz, the relaxation processes in mHz and GHz ranges were not investigated in detail. Temperature modulated DSC (MDSC) can be then considered as the excellent technique to study very slow relaxation process just above glass transition temperature Tg [5], [11], [12], [13]. Therefore, MDSC can investigate the ‘fragility’ in glass forming materials, which classify the steepness of the temperature dependence of α-relaxation process just above Tg [5], [13]. Fragility is one of the central parameters describing glass transition dynamics near Tg [14], while the determination by the thermal method is not well studied.
Brillouin light scattering has been a powerful tool to characterize acoustic properties of condensed matters in a GHz range [15]. The frequency shift and the linewidth provide the sound velocity and the acoustic attenuation of acoustic waves thermally excited in a material, respectively. Recently, acoustic properties of pharmaceutical materials such as aspirin and ibuprofen were investigated by Brillouin scattering, from which acoustic anomaly across a glass transition was clearly observed [16], [17], [18]. In addition, Brillouin scattering is sensitive to the existence of intramolecular secondary relaxation which couples with acoustic phonon in a GHz range [19], [20], [21].
The purpose of this study is to prove various fundamental properties of the anti-inflammatory drug, racemic ketoprofen, in the glassy, supercooled and equilibrium liquid states by using Brillouin scattering, MDSC and refractive index measurements. The liquid–glass transition, the acoustic behaviors, fragility and thermo-optic properties have been investigated systematically, and the new relaxation map was suggested.
Section snippets
Material
Ketoprofen ((RS)-2-(3-benzoylphenyl) propanoic acid, C16H14O3, a molar mass of 254.28 g/mol) was purchased from Sigma Co. (catalogue No. L1751 (CAS 22071-15-4), 98% GC assay). It is a racemic mixture of S-(+)-ketoprofen and R-(−)-ketoprofen (see Figure 1) and the studied (±)-ketoprofen mixture is referred as ketoprofen. Before staring a measurement, the ketoprofen powder was heated and kept 5 min at 370 K (Tm ∼ 368 K [8], [9]) to get an equilibrium liquid state. And then the liquid ketoprofen was
Brillouin scattering
Figure 1 shows the typical Brillouin scattering spectra of glassy, supercooled liquid, and liquid states ketoprofen collected during heating. For all spectra, the Brillouin doublet corresponding to the longitudinal acoustic mode (LA mode) can be seen and the transverse acoustic mode (TA mode) does not appear from the backward scattering geometry. At a high temperature liquid state, a quasi-elastic scattering so-called central peak can be seen in addition to Brillouin doublet. On heating from 80
Conclusion
Various fundamental properties of the anti-inflammatory drug, racemic ketoprofen, in the glassy, supercooled and equilibrium liquid states were investigated by using Brillouin scattering, MDSC and refractive index measurements. No crystallization was observed in a supercooled liquid state, because of the high polymorphic nature of ketoporfen. Temperature dependences of the sound velocity and acoustic attenuation exhibited clear changes in their slopes at 265 K indicating the occurrence of a
References (33)
- et al.
J. Pharm. Sci.
(1997) Adv. Drug Delivery Rev.
(2001)J. Pharm. Sci.
(2006)- et al.
J. Pharm. Sci.
(2010) J. Cryst. Growth
(2004)Eur. J. Pharm. Sci.
(2013)- et al.
Solid State Ionics
(2008) J. Non-Cryst. Solids
(1991)- et al.
Chem. Phys. Lett.
(2008) - et al.
Chem. Phys. Lett.
(2011)
J. Non-Cryst. Solids
Mater. Sci. Eng. A
Int. J. Pharm.
J. Mol. Struct.
J. Non-Cryst. Solids
Chem. Phys. Lett.
Cited by (10)
The Slow Molecular Mobility in Amorphous Ketoprofen and Ibuprofen
2015, Journal of Pharmaceutical SciencesRelaxation dynamics and fragility during liquid-glass transitions of poly(propylene glycol)s
2015, Current Applied PhysicsCitation Excerpt :This tendency is usual in polymers, for example, poly (ethylene glycol), due to the variation in the density using the Eykman equation [25]. The materials, which have a chirality, often show different properties between the racemic and chiral and their applications have been discussed [28–31]. The difference is attributed to the racemic one having two incompatible stereoisomers, which make it difficult for the racemic PG liquid to be crystallized.
Comparison of thermal and elastic properties of glassy racemic and enantiomorphic ibuprofen studied by Brillouin light scattering and modulated differential scanning calorimetry
2014, Current Applied PhysicsCitation Excerpt :Systematic comparison of many physicochemical properties between the racemic and S-ibuprofens may be great helpful in developing efficient, cost-effective methods for preparing S-ibuprofen. The acoustic properties in the hypersonic region have been investigated for a few representative pharmaceuticals, such as aspirin [15], ibuprofen [12,14], acetaminophen [16] and ketoprofen [17]. The interaction between the density fluctuations caused by the longitudinal acoustic (LA) waves and the intermolecular relaxation processes may have some effect on the acoustic properties in this high-frequency region.
Elastic properties of taurine single crystals studied by brillouin spectroscopy
2021, International Journal of Molecular SciencesSolubility Advantage of Amorphous Ketoprofen. Thermodynamic and Kinetic Aspects by Molecular Dynamics and Free Energy Approaches
2020, Journal of Chemical Theory and ComputationLiquid, glass, and crystalline indomethacin studied by Brillouin scattering
2018, Japanese Journal of Applied Physics