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).

Strategy for Fast Decision on Material System Suitability for Continuous Crystallization Inside a Slug Flow Crystallizer.

There is an increasing focus on two-phase flow in micro- or mini-structured apparatuses for various manufacturing and measurement instrumentation applications, including the field of crystallization as a separation technique. The slug flow pattern offers salient features for producing high-quality products, since narrow residence time distribution of liquid and solid phases, intensified mixing and heat exchange, and an enhanced particle suspension are achieved despite laminar flow conditions. Due to its unique features, the slug flow crystallizer (SFC) represents a promising concept for small-scale continuous crystallization achieving high-quality active pharmaceutical ingredients (API). Therefore, a time-efficient strategy is presented in this study to enable crystallization of a desired solid product in the SFC as quickly as possible and without much experimental effort. This strategy includes pre-selection of the solvent/solvent mixture using heuristics, verifying the slug flow stability in the apparatus by considering the static contact angle and dynamic flow behavior, and modeling the temperature-dependent solubility in the supposed material system using perturbed-chain statistical associating fluid theory (PC-SAFT). This strategy was successfully verified for the amino acids l-alanine and l-arginine and the API paracetamol for binary and ternary systems and, thus, represents a general approach for using different material systems in the SFC.

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.