(W0930-03-15) Understanding the Stabilization Mechanism of Polyvinyl Alcohols (Parteck® MXP) in ASDs by Structure-Related Properties and PC-SAFT Modeling

Purpose: For the development of amorphous solid dispersions (ASDs), the physical stability of the formulation is a key challenge determining their performance additional to dissolution and active pharmaceutical ingredient (API) solubility. Since physical stability studies are time-consuming and the analytical effort can become significant, selecting the right polymer/API combination early on is crucial for proper CMC development. Within the scope of industrial digitalization, statistical learning and physics-based modelling approaches leverage the pharmaceutical development process by reducing experimental effort and time. The perturbed chain statistical associated fluid theory (PC-SAFT) has become a state-of-the-art approach to understand thermodynamic properties of ASDs within the last years. In this work, the PC-SAFT approach was applied to calculate ASD phase diagrams containing the semi-crystalline polymer polyvinyl alcohol (PVA – Parteck® MXP) and various model APIs (indomethacin, naproxen and itraconazole). In addition, PC-SAFT activity calculations enabled API/PVA compatibility predictions, thus providing an intermolecular interaction-based assessment of beneficial API/PVA combinations.

Methods: PC-SAFT, DVS, DSC, PXRD, physical stability, hot-melt extrusion, in-silico predictions

Results: The PC-SAFT approach, which has been broadly applied to amorphous solid dispersions in literature (1-3), is successfully extended to hot-melt extruded solid dispersions containing the semi-crystalline polymer PVA (Parteck® MXP) as carrier matrix. It is assumed that the API solely dissolves in the amorphous parts of the polymer, whereas the crystalline polymer fractions are considered unavailable for API interactions. For one GFA I (low glass forming ability) and two GFA III (good glass forming ability) APIs, the phase diagrams have been predicted via PC-SAFT (crystalline API solubility and amorphous phase separation) and Kwei (glass-transition temperature, cf. Figure 1). The phase diagrams of indomethacin/PVA and naproxen/PVA appear very similar and show a maximum for the glass transition temperature indicating API/polymer interactions. In case of naproxen, the glass transition temperature is significantly decreased at higher API loadings reflecting the lower glass forming ability and low kinetic stabilization potential of pure amorphous naproxen. Immiscibility is predicted for itraconazole loads above 12w%, the new evolving amorphous phase contains 99.9w% itraconazole. Experimentally, such de-mixing zones are often hard to analyze and maybe overseen with classical analysis techniques especially in the early development phase. The relative stability of metastable ASDs is reflected by the investigation of the crystallization driving force increasing in the order indomethacin ≤ naproxen < itraconazole (cf. Figure 2). The theoretical findings were confirmed by experimental data regarding the GFA, highest drug loading yielded with Parteck® MXP and physical stability data. The lower maximum stable API loading of naproxen (10w%) compared to indomethacin (30w%) is explained by the lower naproxen glass forming ability while the crystallization driving force is similar. In addition, PC-SAFT has been utilized to predict interactions in various API/PVA mixtures. These calculations are full predictions and require no additional experimental data, they thus serve as screening tool for early formulation development (cf. Figure 3). Evidently, compounds exhibiting aromatic nitrogen acceptor functional groups show stronger interactions with PVA, likely due to the formation of the strong OH^…N hetero synthon (4).

Conclusion: The PC-SAFT approach has been successfully extended to the semi-crystalline polymer PVA (Parteck® MXP). Parteck® MXP shows stabilizing properties most likely due to interactions of the hydroxyl groups with hydrogen bonding acceptor moieties of the APIs. The phase behavior of the semi-crystalline polymer ASDs and also the interactions between API and polymer were described accurately by PC-SAFT. In addition, the phase diagrams indicate that Parteck® MXP has a stabilizing effect on indomethacin and naproxen, rendering it a promising carrier matrix for solid dispersions. The modeled phase diagrams very well explain the observed results of the long-term stability tests.

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Figure 1: Modeled API/PVA4-88 phase diagrams of (a) IND/PVA4-88, (b) NAP/PVA4-88 and (c) ITR/PVA4-88. The via PC-SAFT modeled solubility in amorphous PVA4-88 is the orange line, the via Kwei modeled glass-transition temperature is the green line. The black line in c is the with PC-SAFT predicted miscibility gap between PVA4-88 and ITR. Symbols are experimental data points obtained from DSC measurements.


Figure 2: Relative crystallization driving force of metastable ASDs.


Figure 3: Via PC-SAFT predicted API/PVA4-88 activities in 20wt% ASDs at 25°C. Low values represent strong interactions and high ASD stabilization potential, high values represent weak interactions and low ASD stabilization potential.