(T1530-11-76) Solubility Enhancement via Amorphous Solid Dispersions: Extended Functionality by Applying a Versatile Polyvinyl Alcohol Platform for Hot Melt Extrusion

Purpose: The limited number of available polymers for hot melt extrusion is a challenge for formulators. Often the development focus is laid only on ASD stability. Novel ASD formulations are also targeting an enhanced functionality by the integration of additional polymers or surfactants [1]. We are proposing a new polymer platform based on polyvinyl alcohol to individually adapt the molecular weight as well as the amphiphilicity of the molecular chain.

Methods: Polymer characterization: Melt rheology Thermo-Fisher Scientific Haake Mars Rheo 60, temperature ramp from 170°C to 230°C ΔT/t = 2°/min, oscillating Controlled Deformation, CD, ɣ₀=0,1 %, f=1,0 Hz, gap=1 mm, plate geometry 25 mm diameter. Solubility in solvents was determined by solvent addition procedure. To a defined weight of powder is pipetted in step-by-step solvent and wait while stirring to see whether there are any residues, and if so, the next pipetting step is carried out. Do this until you get a clear solution. Dissolution tests were performed using a pH-shift method (750 ml 0.1M HCl for 120 Min, add 250 ml PP pH 6.8 final 1000 ml) HME formulation 20% drug load; Paddle; 50rpm; total runtime 300 Min, n=3 via HPLC measurement.

Results: Optimized hydrolysis grade improves hydrophobic interactions for precipitation inhibition. The balance of hydrophilic and hydrophobic groups in our polymer platform ensures optimal stabilization and outstanding release and prolongation performance of the supersaturated state. The dissolution data shows for a low hydrolysis grade outstanding supersaturation performance after shifting the pH from gastric to intestinal fluid conditions which is useful for hydrophobic API´s like itraconazole as model compound (see Fig.3). Even though the platform allows a broad processing window for hot melt extrusion which is shown in the melt rheology data. Melt rheology of both PVA 3-82 and 4-88 showed a significant difference in crossover points as well as the expectable process window (see Fig.1). While the viscosity of PVA 4-88 remains quite high until a temperature of ~200°C and G’ remains the dominant modulus, a crossover of G’ and G’’ can be observed at 203°C within a significant drop in melt viscosity. A second crossover of G’’ and G’ along with a decreasing phase angle δ indicates the begin of polymer degradation at around 235°C. In contrast, G’’ is already the prominent modulus over G’ at 170°C, along with a constant decrease of melt viscosity when increasing the melt temperature. At around 212°C a G’’/G’ crossover as well the drop of phase angle δ indicates a beginning degradation of the polymer melt. The observed rheological behavior of both polymers indicated that extrusion range in terms of barrel temperature as well as torque is lower for 3-82 then for 4-88. Several conducted HME trials both with 3-82 and 4-88 proved that the process range of 3-82 is feasible at 130 - 210°C* and 150 - 250°C* for 4-88, which correlates to the rheological data generated (see Fig.2).

Conclusion: For PVA based polymers the hydrolysis degree is impacting the process temperature range as well as the solubility in relevant media. Higher hydrolyzed PVA shows a superior temperature tolerance, whereas low hydrolyzed PVA can be utilized at lower process temperature and prolongates the supersaturated state of low soluble drug substances.

References: 1. Bhujbal SV, Mitra B, Jain U, Gong Y, Agrawal A, Karki S, et al. Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies. Acta Pharmaceutica Sinica B. 2021;11(8):2505-36.

Figure 1: Melt viscosity data for PVA 3-82 indicating a broad processing range: 130 - 210°C

Figure 2: Melt viscosity data for PVA 4-88 indicating a broad processing range: 150 - 250°C

Figure 3: Dissolution data of drug loaded extruded matrices; assessment via pH shift.