The molecular integration of poorly water soluble active pharmaceutical ingredients (APIs) in a suitable polymeric matrix is a possible approach to enhance the dissolution behavior and solubility of these APIs. Like all newly developed pharmaceutical formulations, these formulations (often denoted as amorphous solid dispersions (ASDs)) need to undergo storage stability tests at defined relative humidity (RH) and temperature conditions. In a previous work ( Int. J. Pharm. 2017 ; 532 , 635 - 646 ), it was shown that thermodynamic modeling can be successfully used to predict the long-term stability of ASDs against API crystallization and moisture-induced amorphous-amorphous phase separation (MIAPS). This work in turn demonstrates the prediction of water sorption in ASDs accounting for the potential occurrence of API crystallization and MIAPS. The water sorption and phase behavior of ASDs containing the APIs felodipine and ibuprofen incorporated in three different hydrophilic polymers poly(vinylpyrrolidone), poly(vinyl acetate), and poly(vinylpyrrolidone-co-vinyl acetate) at the conditions 25 °C/60% RH and 40 °C/75% RH were predicted using the perturbed-chain statistical-associating fluid theory (PC-SAFT). The predictions were successfully validated via two-year-lasting water sorption experiments. It was shown that crystallization of the API and MIAPS on the one hand and water sorption in the ASDs on the other hand dramatically influence each other and that this behavior can even be quantitatively predicted by PC-SAFT, which already provides valuable insights at early stages of formulation development.

Bottom-up approaches to producing aqueous crystal suspensions of active pharmaceutical ingredients (APIs), such as anti-solvent crystallisation, are gaining interest as they offer better control over surface properties compared to top-down approaches. However, one of the major challenges that needs to be addressed is the removal of organic solvents after the crystallisation step due to strict limitations regarding human exposure. Within this work, we investigated a process concept for the removal of solvent (i.e., ethanol) from the API crystal suspension using membrane-based diafiltration. A four-stage diafiltration process successfully reduced the ethanol concentration in the API (here, naproxen) crystal suspension below 0.5 wt% (the residual solvent limit as per ICH guidelines) with a water consumption of 1.5 g of added water per g of feed. The solvent exchange process had no negative influence on the stability of the crystals in suspension, as their size and polymorphic form remained unchanged. This work is a step towards the bottom-up production of API crystal suspension by applying solvent/anti-solvent crystallisation. It provides the proof of concept for establishing a process of organic solvent removal and offers an experimental framework to serve as the foundation for the design of experiments implementing a solvent exchange in API production processes.

Several studies have shown that aqueous two-phase extraction using an aqueous two-phase system (ATPS) is a promising purification technology for biomolecules (e.g., monoclonal antibodies). To beneficially influence the partitioning of the target biomolecule, a displacement agent can be added to the ATPS. Within this work, the influence of the displacement agents, sodium chloride (NaCl) and lithium bromide (LiBr), on the phase behavior of two ATPSs containing triammonium citrate and polyethylene glycol 2000 (PEG2000) and tripotassium citrate and PEG2000 was determined and compared to previous measurements for trisodium citrate−PEG2000 ATPS. Therefore, the tieline length (TLL), tie-line slope (TLS), and the size of the biphasic region of the ATPS were investigated at 298.15 K, 101.3 kPa, and pH 7. The results show that the addition of NaCl to the ATPS increases the TLL up to 47.4%, while the TLS stays constant. In contrast, the addition of LiBr causes a decrease in the TLS up to 34.5%, while the TLL remains constant. These results are in agreement with previous measurements performed for trisodium citrate−PEG2000 ATPS. Prospectively, the investigations enable a mechanistic understanding of the displacement agent effect on the phase behavior and transfer of this information to other organic salt−polymer ATPSs to improve their extraction performance.

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