Article pubs.acs.org/molecularpharmaceutics
Correlation between Molecular Mobility and Physical Stability in Pharmaceutical Glasses Mehak Mehta,† Vishard Ragoonanan,†,§ Gregory B. McKenna,‡ and Raj Suryanarayanan*,† †
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States Department of Chemical Engineering, Texas Tech University, Lubbock, Texas 79409, United States
‡
S Supporting Information *
ABSTRACT: We investigated a possible correlation between molecular mobility and physical stability in glassy celecoxib and indomethacin and identified the specific mobility mode responsible for physical instability (crystallization). In the glassy state, because the structural relaxation times are very long, the measurement was enabled by time domain dielectric spectroscopy. However, the local motions in the glassy state were characterized by frequency domain dielectric spectroscopy. Isothermal crystallization was monitored by powder Xray diffractometry using either a laboratory source (supercooled state) or synchrotron source (glassy state). Structural (α) relaxation time correlated well with characteristic crystallization time in the supercooled state. On the other hand, a stronger correlation was observed between the Johari− Goldstein (β) relaxation time and physical instability in the glassy state but not with structural relaxation time. These results suggest that Johari−Goldstein relaxation is a potential predictor of physical instability in the glassy state of these model systems. KEYWORDS: celecoxib, indomethacin, amorphous, glassy, Johari−Goldstein, crystallization, dielectric spectroscopy, structural relaxation
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INTRODUCTION A large fraction of the new drugs under development are characterized by poor aqueous solubility.1 As a result, their absorption following oral administration can be a challenge. Drug amorphization is an effective and popular strategy to enhance solubility.2 However, a major challenge with this approach is the risk of crystallization due to physical instability. This can negate the bioavailability advantage brought about by the solubility enhancement. Hence, current research efforts are directed toward understanding the factors influencing crystallization. Molecular mobility has been extensively investigated in light of its possible role in governing physical stability.3−7 Molecular mobility comprises both global and local motions. Global motion is cooperative in nature and responsible for bringing about the glass transition. It is also referred as α or structural relaxation. On the other hand, local motions (or secondary relaxations) are noncooperative in nature and arise from either a part or an entire molecule.8,9 In several compounds, structural relaxation time has been linked to physical stability in the supercooled state (T > Tg).10−12 Interestingly, β relaxation (also referred to as Johari−Goldstein relaxation13) has been implicated in physical instability of glasses (T < Tg).14−17 Because amorphous pharmaceuticals are typically stored as glasses, evaluation of such correlations in this state is of immense practical value. The structural relaxation time in the supercooled state is typically 100) was directly linked to β relaxation processes. A similar result was observed in naproxen glass wherein the Johari−Goldstein relaxation was shown to be responsible for the physical instability.30 Crystallization in glassy fulvene and indomethacin has also been circumstantially linked to β relaxation.14,17 On the other hand, in several pharmaceutical glasses including nifedipine, griseofulvin, phenobarbital, and sucrose, the structural relaxation time below Tg was shown to be coupled to crystallization.3,5,18,19 However, in these cases, the relaxation time was either an estimate obtained using the Adam−Gibbs model or was obtained using DSC. Although both α and β relaxations have been shown to influence physical stability in the glassy state, very few studies have systematically and comprehensively characterized all of the mobility modes that may influence crystallization in the temperature range of interest. We had two specific objectives to accomplish this goal: (i) comprehensively characterize the molecular mobility, i.e., both global and local motions, in supercooled and glassy states of two model compounds (celecoxib and indomethacin), and (ii) investigate the potential correlation between crystallization and the specific mobility mode in the glassy state. The model compounds were chosen because they can be readily rendered amorphous by melt quenching14,31 and tend to crystallize rapidly in the glassy state.6,32 This enabled the development of correlation models to predict crystallization in systems of interest. The ultimate aim is to enable the development of stabilization approaches by modulating the specific mobility correlated with the observed physical instability.
detector (LynxEye; Bruker AXS) was used. The isothermal crystallization kinetics, in the supercooled state, was evaluated at several temperatures. The powder samples were periodically exposed to Cu Kα radiation (40 kV and 40 mA), and the diffraction patterns were obtained under dry nitrogen purge by scanning over an angular range of 5−40° 2θ with a step size of 0.05° and a dwell time of 0.5 s. Synchrotron XRD (SXRD; Transmission Mode). The enhanced sensitivity of this technique enabled us to monitor low levels of crystallization. Powdered samples, stored at several temperatures in the glassy state, were hermetically crimped in DSC pans and exposed to synchrotron radiation. Experiments were performed in the transmission mode in the 17-BM-B beamline at Argonne National Laboratory (Argonne, IL, USA). A monochromatic X-ray beam [wavelength of 0.75009 Å; beam size of 250 μm (horizontal) × 160 μm (vertical)] and a twodimensional area detector (XRD-1621, PerkinElmer) were used. Calibration was performed using an Al2O3 standard (SRM 674a, NIST). Using a stepper motor, the sample was oscillated (±1 mm from the center along the horizontal axis) during data collection. Each sample was scanned at 30 points with an exposure time of 1 s for each scan (2 mm/30 s), and the results were averaged. The raw images were integrated to yield onedimensional d-spacing (Å) or 2θ (deg) scans using the GSAS II software developed by Brian H. Toby and Robert B. Von Dreele at Argonne National Laboratories.33 Quantification of XRD Data. At each time point, the crystallinity index was calculated using eq 1. The crystallinity index can be considered equivalent to the % crystallinity if the total integrated intensity (amorphous + crystalline) remains constant throughout the isothermal crystallization experiment.34
EXPERIMENTAL SECTION Preparation of Amorphous Materials. Celecoxib (C 1 7 H 1 4 F 3 N 3 O 2 S, purity >98%) and indomethacin (C19H16ClNO4, purity >98%; γ form) were used as received. Amorphous samples were prepared by melting the crystalline powder followed by quench cooling on aluminum blocks precooled to −20 °C. The melt was lightly crushed using a mortar and pestle in a glovebox at room temperature (
