Extraordinary Long-Term-Stability in Kinetically Stabilized Amorphous Solid Dispersions of Fenofibrate

Abstract

Inhibition of recrystallization of the drug substance in kinetically stabilized amorphous solid dispersions (ASDs) within and beyond shelf life is still a matter of debate. Generally, these ASD systems are considered to be prone to recrystallization, but examples of their long-term stability are emerging in the literature. Since, in some cases, the formation of crystals may impact bioavailability, recrystallization may present a relevant risk for patients as it potentially lowers the effective dose of the formulation. This study shows that such metastable formulations may indeed remain amorphous even after 15 years of storage under ambient conditions. A formulation of fenofibrate stored for 15 years was compared to a freshly prepared batch. A complete physicochemical characterization regarding content, purity, water content and glass transition was conducted. The emphasis of this physicochemical characterization was on crystallinity as a critical quality attribute: polarized light microscopy (PLM) was used as the standard qualitative method and X-ray powder diffraction (XRPD) as the standard quantitative method. An investigation of the crystal growth kinetics by transmission Raman spectroscopy (TRS) was conducted to build a predictive model. The model was applied successfully to predict the observed physical state of the 15-year-old samples. The observations presented here demonstrate that kinetic stabilization alone is able to prevent crystallization in ASDs over prolonged storage periods, suggesting the need for a reassessment of the risk perception for this kind of ASD formulations.

Crystallization Risk Assessment of Amorphous Solid Dispersions by Physical Shelf-Life Modeling: A Practical Approach

“…ASD extrudate and placebo extrudate milled particles (Alpine, Höchst im Odenwald, Germany), as well as the API, had a D50 of 252, 271, and 213 μm, respectively, determined using a Mastersizer 3000 (Malvern Instruments, Malvern, U.K.). More details are reported in an earlier study . Two types of tablets were manually compressed: sample tablets and reference tablets.…”

“…In addition, reference tablets, in which part of the amorphous API content (up to 15 wt %) was replaced with crystalline API (cAPI) and the placebo extrudate to keep the ratio of API and excipients constant, were prepared with identical shape, weight, and pressure. A detailed description of the calibration series and data evaluation, including figures of merit, can be found in our previous studies. , …”

“…A PLS model was used in this study to quantify the crystalline content of fenofibrate sample tablets in each crystal growth experiment. It was established based on spectral data of reference tablets as previously reported . In both model-building and regression, a data preprocessing routine was used to remove the spectral impact of physicochemical aspects as variable optical path lengths or particle size effects (spectral background).…”

“…In this publication, a strategy for crystallization risk assessment of ASD products, based on our previously presented methodology to monitor crystal growth in ASDs using TRS, is introduced . As discussed in our prior study, it is possible to monitor the crystal growth in ASDs even at elevated environmental stress using TRS .…”

“…In this publication, a strategy for crystallization risk assessment of ASD products, based on our previously presented methodology to monitor crystal growth in ASDs using TRS, is introduced . As discussed in our prior study, it is possible to monitor the crystal growth in ASDs even at elevated environmental stress using TRS . A first attempt to extrapolate the crystal growth kinetics using the augmentation of the approach by Genton and Kesselring introduced by Zhang et al, which links the natural logarithm of the rate constant for crystal growth to the water content in the ASD, has been presented in our previous study .…”