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.

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.

This manuscript represents the view of the Dissolution Working Group of the IQ Consortium on the challenges of and recommendations on solubility measurements and development of dissolution methods for immediate release (IR) solid oral dosage forms formulated with amorphous solid dispersions. Nowadays, numerous compounds populate the industrial pipeline as promising drug candidates yet suffer from low aqueous solubility. In the oral drug product development process, solubility along with permeability is a key determinant to assure sufficient drug absorption along the intestinal tract. Formulating the drug candidate as an amorphous solid dispersion (ASD) is one potential option to address this issue. These formulations demonstrate the rapid onset of drug dissolution and can achieve supersaturated concentrations, which poses significant challenges to appropriately characterize solubility and develop quality control dissolution methods. This review strives to categorize the different dissolution and solubility challenges for ASD associated with 3 different topics: (i) definition of solubility and sink conditions for ASD dissolution, (ii) applications and development of non-sink dissolution (according to conventional definition) for ASD formulation screening and QC method development, and (iii) the advantages and disadvantages of using dissolution in detecting crystallinity in ASD formulations. Related to these challenges, successful examples of dissolution experiments in the context of control strategies are shared and may lead as an example for scientific consensus concerning dissolution testing of ASD.

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