Manufacturing Amorphous Solid Dispersions with a Tailored Amount of Crystallized API for Biopharmaceutical Testing.

The preparation of an amorphous solid dispersion (ASD) by dissolving a poorly water-soluble active pharmaceutical ingredient (API) in a polymer matrix can improve the bioavailability by orders of magnitude. Crystallization of the API in the ASD, though, is an inherent threat for bioavailability. Commonly, the impact of crystalline API on the drug release of the dosage form is studied with samples containing spiked crystallinity. These spiked samples possess implicit differences compared to native crystalline samples, regarding size and spatial distribution of the crystals as well as their molecular environment. In this study, we demonstrate that it is possible to grow defined amounts of crystalline API in solid dosage forms, which enables us to study the biopharmaceutical impact of actual crystallization. For this purpose, we studied the crystal growth in fenofibrate tablets over time under an elevated moisture using transmission Raman spectroscopy (TRS). As a nondestructive method to assess API crystallinity in ASD formulations, TRS enables the monitoring of crystal growth in individual dosage forms. Once the kinetic trace of the crystal growth for a certain environmental condition is determined, this method can be used to produce samples with defined amounts of crystallized API. To investigate the biopharmaceutical impact of crystallized API, non-QC dissolution methods were used, designed to identify differences between the various amounts of crystalline materials present. The drug release in the samples manufactured in this fashion was compared to that of samples with spiked crystallinity. In this study, we present for the first time a method for targeted crystallization of amorphous tablets to simulate crystallized ASDs. This methodology is a valuable tool to generate model systems for biopharmaceutical studies on the impact of crystallinity on the bioavailability.

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

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.

Frozen in Time: Kinetically Stabilized Amorphous Solid Dispersions of Nifedipine Stable after a Quarter Century of Storage.

Kinetically stabilized amorphous solid dispersions are inherently metastable systems. Therefore, such systems are generally considered prone to recrystallization. In some cases, the formation of crystals will impact the bioavailability of the active pharmaceutical ingredient in these formulations. Recrystallization therefore may present a significant risk for patients as it potentially lowers the effective dose of the pharmaceutical formulation. This study indicates that such metastable formulations may indeed remain fully amorphous even after more than two decades of storage under ambient conditions. Different formulations of nifedipine stored for 25 years were compared with freshly prepared samples. A thorough physicochemical characterization including polarized light microscopy, differential scanning calorimetry, X-ray powder diffraction, and transmission Raman spectroscopy was undertaken. This in-depth characterization indicates no signs of recrystallization in the stored samples. The observations presented here prove that long-term stability of amorphous solid dispersions much beyond the typical shelf life for pharmaceutical formulations is indeed possible by kinetic stabilization alone. These findings implicate a reevaluation of the propensity to recrystallize for kinetically stabilized amorphous solid dispersions.

Gold catalysis: in situ EXAFS study of homogeneous oxidative esterification.

Gold complexes were prepared and investigated as catalysts for the oxidative esterification of aldehydes. Stabilisation by pyridine ligands gave good conversions and the in situ extended X-ray absorption fine structure (EXAFS) study of the reactions indicated that the reaction mixtures contained only mononuclear gold species. Thus, this is the first proof for a homogeneous gold-catalysed oxidation reaction; the presence of nanoparticles could be excluded experimentally.