Mutual Impact of Phase Separation/Crystallization and Water Sorption in Amorphous Solid Dispersions

Abstract

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.

The Investigation of Flory–Huggins Interaction Parameters for Amorphous Solid Dispersion Across the Entire Temperature and Composition Range

“…Six hours were selected for all the ASD samples where most of the systems have reached steady state after five hours at 90% RH (steady state, Supplementary Materials C). Compared with a moisture-induced system, Luebbert et al suggested that more water molecules are absorbed into the sample when the AAPS occurs, whilst less moisture will be absorbed by the sample when drug crystallization occurs [52]. This suggests that the equilibrium can be reached for ASD when a constant mass was obtained during high humidity AAPS state.…”

Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch

“…Despite certain assumptions and limitations, these models can provide working thermal-phase diagrams of a given drug and polymer that are equally important for the processing temperature selection in HME. For example, the group of Sadowski has shown the applicability of PC-SAFT-derived thermal-phase diagrams to determining the drug-polymer solubility curves and miscibility gaps, even in the presence of moisture, and verified it using the experimental stability data for the ASDs containing physico-chemically diverse APIs and polymers (55)(56)(57)(58)(59)(60).…”

Predicting process design spaces for spray drying amorphous solid dispersions

“…( Prudic et al, 2014a ; Burnett et al, 2006 ; Kyeremateng et al, 2014 ; Lehmkemper et al, 2017a ; Lehmkemper et al, 2017b ) Solvent-induced phase separation and unwanted API crystallization were successfully described using thermodynamic models like Flory-Huggins( Duarte et al, 2015 ) and the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). ( Luebbert et al, 2018b ; Gross and Sadowski, 2001 ) Although the solvent is not present in the final ASD anymore after drying, it might affect the ASD during the manufacturing processes and therewith also the final product quality, e.g. by affecting API solubility and glass transition ( T g ), or by inducing liquid-liquid phase separation.…”