A Hot-Melt Extrusion Risk Assessment Classification System for Amorphous Solid Dispersion Formulation Development.

Several literature publications have described the potential application of active pharmaceutical ingredient (API)-polymer phase diagrams to identify appropriate temperature ranges for processing amorphous solid dispersion (ASD) formulations via the hot-melt extrusion (HME) technique. However, systematic investigations and reliable applications of the phase diagram as a risk assessment tool for HME are non-existent. Accordingly, within AbbVie, an HME risk classification system (HCS) based on API-polymer phase diagrams has been developed as a material-sparing tool for the early risk assessment of especially high melting temperature APIs, which are typically considered unsuitable for HME. The essence of the HCS is to provide an API risk categorization framework for the development of ASDs via the HME process. The proposed classification system is based on the recognition that the manufacture of crystal-free ASD using the HME process fundamentally depends on the ability of the melt temperature to reach the API's thermodynamic solubility temperature or above. Furthermore, we explored the API-polymer phase diagram as a simple tool for process design space selection pertaining to API or polymer thermal degradation regions and glass transition temperature-related dissolution kinetics limitations. Application of the HCS was demonstrated via HME experiments with two high melting temperature APIs, sulfamerazine and telmisartan, with the polymers Copovidone and Soluplus. Analysis of the resulting ASDs in terms of the residual crystallinity and degradation showed excellent agreement with the preassigned HCS class. Within AbbVie, the HCS concept has been successfully applied to more than 60 different APIs over the last 8 years as a robust validated risk assessment and quality-by-design (QbD) tool for the development of HME ASDs.

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

Amorphous solid dispersions (ASDs) of a poorly water-soluble active pharmaceutical ingredient (API) in a polymer matrix can enhance the water solubility and therefore generally improve the bioavailability of the API. Although examples of long-term stability are emerging in the literature, many ASD products are kinetically stabilized, and inhibition of crystallization of a drug substance within and beyond shelf life is still a matter of debate, since, in some cases, the formation of crystals may impact bioavailability. In this study, a risk assessment of API crystallization in packaged ASD drug products and a mitigation strategy are outlined. The risk of shelf-life crystallization and the respective mitigation steps are assigned for different drug product development scenarios and the scientific principles of each step are discussed. Ultimately, the physical stability of ASD drug products during shelf-life storage is modeled. The methodology is based on the quantification of crystal growth kinetics by transmission Raman spectroscopy (TRS), modeling the impact of water sorption on the glass-transition temperature of the ASD, and the prediction of moisture uptake by the packaged ASD drug product during storage. This approach is applied to an ASD of fenofibrate that features both fast API crystallization under accelerated storage conditions and long-term stability in a suitable protective packaging under conventional storage conditions.

Assessment of the amorphous solid dispersion erosion behavior following a novel small-scale predictive approach.

In general, the erosion rate of copovidone-based amorphous solid dispersions (ASDs) in contact with water diminishes with increasing drug load, causing poor drug release from the final drug product. A new easy-to-use tool with low material- and time-consumption, the microscopic erosion time test (METT), was established to allow prediction of the API-specific drug load threshold between an eroding and a non-eroding ASD. This API-specific drug load value is further described as the drug load dispersibility limit (DDL) and is the highest drug load at which an eroding ASD was still observed. A minor increase of 2.5% in drug load above the DDL already led to a non-eroding ASD and it was subsequently connected to the drug load-associated drop in API in vitro dissolution of ASD tablets and an impeded tablet disintegration. In total, 19 APIs in copovidone-based ASDs were characterized via the METT while a subset of these was investigated in more detail, namely indomethacin, celecoxib, dipyridamole, fenofibrate, naproxen and ritonavir. Furthermore, indomethacin- and celecoxib-containing ASDs with various drug loads were prepared and characterized to link the METT outcome with ASD tablet in vitro dissolution and disintegration performance.