Combined Effect of the Preparation Method and Compression on the Physical Stability and Dissolution Behavior of Melt-Quenched Amorphous Celecoxib

Abstract

In an earlier investigation, amorphous celecoxib was shown to be sensitive to compression-induced destabilization. This was established by evaluating the physical stability of uncompressed/ compressed phases in the supercooled state (Be ̅ rzinş̌et al.. Mol. Pharmaceutics, 2019, 16(8), 3678−3686). In this study, we investigated the ramifications of compression-induced destabilization in the glassy state as well as the impact of compression on the dissolution behavior. Slow and fast melt-quenched celecoxib disks were compressed with a range of compression pressures (125−500 MPa) and dwell times (0−60 s). These were then monitored for crystallization using lowfrequency Raman spectroscopy when kept under dry (∼20 °C; <5% RH) and humid (∼20 °C; 97% RH) storage conditions. Faster crystallization was observed from the samples, which were compressed using more severe compression parameters. Furthermore, crystallization was also affected by the cooling rate used to form the amorphous phases; slow melt-quenched samples exhibited higher sensitivity to compression-induced destabilization. The behavior of the melt-quench disks, subjected to different compression conditions, was continuously monitored during dissolution using low-frequency Raman and UV/vis for the solid-state form and dissolution properties, respectively. Surprisingly the compressed samples exhibited higher apparent dissolution (i.e., higher area under the dissolution curve and initial celecoxib concentration in solution) than the uncompressed samples; however, this is attributed to biaxial fracturing throughout the compressed compacts yielding a greater effective surface area. Differences between the slow and fast melt quenched samples showed some trends similar to those observed for their storage stability.

Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time–Temperature Transformation

“…Even if there is accidental nucleation, for example, due to unintended excursion of product temperature, there may not be adequate growth during product storage. From the point of solid dosage form manufacture, one other stress factor that can induce nucleation is compression. ,, The effect of this unit operation on the stability of ASD stability was outside the scope of this investigation and warrants careful consideration. Likewise, the role of residual moisture on nucleation, while recognized to be important, is outside the scope of this investigation .…”

Low- versus Mid-frequency Raman Spectroscopy for in Situ Analysis of Crystallization in Slurries

“…In situ and off-line analysis was carried out with a purpose-built Raman setup 4 , 9 , 23 , 28 equipped with a 785 nm excitation laser (Ondax, Monrovia, CA, USA). Before the sample was irradiated with a backscattering geometry, amplified spontaneous emission was removed by using BragGrate bandpass filters (OptiGrate, Oviedo, FL, USA).…”