System-agnostic prediction of pharmaceutical excipient miscibility via computing-as-a-service and experimental validation.

We applied computing-as-a-service to the unattended system-agnostic miscibility prediction of the pharmaceutical surfactants, Vitamin E TPGS and Tween 80, with Copovidone VA64 polymer at temperature relevant for the pharmaceutical hot melt extrusion process. The computations were performed in lieu of running exhaustive hot melt extrusion experiments to identify surfactant-polymer miscibility limits. The computing scheme involved a massively parallelized architecture for molecular dynamics and free energy perturbation from which binodal, spinodal, and mechanical mixture critical points were detected on molar Gibbs free energy profiles at 180 °C. We established tight agreement between the computed stability (miscibility) limits of 9.0 and 10.0 wt% vs. the experimental 7 and 9 wt% for the Vitamin E TPGS and Tween 80 systems, respectively, and identified different destabilizing mechanisms applicable to each system. This paradigm supports that computational stability prediction may serve as a physically meaningful, resource-efficient, and operationally sensible digital twin to experimental screening tests of pharmaceutical systems. This approach is also relevant to amorphous solid dispersion drug delivery systems, as it can identify critical stability points of active pharmaceutical ingredient/excipient mixtures.

Kinetics of Water-Induced Amorphous Phase Separation in Amorphous Solid Dispersions via Raman Mapping.

The poor bioavailability of an active pharmaceutical ingredient (API) can be enhanced by dissolving it in a polymeric matrix. This formulation strategy is commonly known as amorphous solid dispersion (ASD). API crystallization and/or amorphous phase separation can be detrimental to the bioavailability. Our previous work (Pharmaceutics 2022, 14(9), 1904) provided analysis of the thermodynamics underpinning the collapse of ritonavir (RIT) release from RIT/poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) ASDs due to water-induced amorphous phase separation. This work aimed for the first time to quantify the kinetics of water-induced amorphous phase separation in ASDs and the compositions of the two evolving amorphous phases. Investigations were performed via confocal Raman spectroscopy, and spectra were evaluated using so-called Indirect Hard Modeling. The kinetics of amorphous phase separation were quantified for 20 wt% and 25 wt% drug load (DL) RIT/PVPVA ASDs at 25 °C and 94% relative humidity (RH). The in situ measured compositions of the evolving phases showed excellent agreement with the ternary phase diagram of the RIT/PVPVA/water system predicted by PC-SAFT in our previous study (Pharmaceutics 2022, 14(9), 1904).

Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions.

In amorphous solid dispersions (ASDs), an active pharmaceutical ingredient (API) is dissolved on a molecular level in a polymeric matrix. The API is expected to be released from the ASD upon dissolution in aqueous media. However, a series of earlier works observed a drastic collapse of the API release for ASDs with high drug loads (DLs) compared to those with low DLs. This work provides a thermodynamic analysis of the release mechanism of ASDs composed of ritonavir (RIT) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). The observed release behavior is, for the first time, explained based on the quantitative thermodynamic phase diagram predicted by PC-SAFT. Both liquid-liquid phase separation in the dissolution medium, as well as amorphous phase separation in the ASD, could be linked back to the same thermodynamic origin, whereas they had been understood as different phenomena so far in the literature. Furthermore, it is illustrated that upon release, independent of DL, both phenomena occur simultaneously for the investigated system. It could be shown that the non-congruent release of the drug and polymer is observed when amorphous phase separation within the ASD has taken place to some degree prior to dissolution. Nanodroplet formation in the dissolution medium could be explained as the liquid-liquid phase separation, as predicted by PC-SAFT.

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.