(M0930-12-82) Interaction of Thermal and Rheological Parameters Critical for the Processability of Polyvinyl Alcohol-Based Systems during Hot Melt Extrusion

Purpose: Hot melt extrusion is a common process used in the pharmaceutical industry to make poorly soluble active pharmaceutical ingredients available for oral dosage forms. The development of new formulations is time- and material consuming, especially in the search for suitable plasticizers for the final composition. To simplify the formulation work, a deep understanding of the interrelationships of the different polymer properties is required. For the processability of a polymer by hot melt extrusion (HME), the upper limit for the melt viscosity is 10,000 Pas. This upper limit is often a bottleneck that must be overcome to keep the torque within the appropriate range [1]. This study investigates the influence of different plasticizers on the viscosity of different PVA grades in the melt and examines the correlations from thermal analysis by DSC with the rheological key parameters.

Methods: Materials: Polyvinyl alcohol (PVA, Parteck^® MXP 3-82 and 4-88), glycerol (GLY), triacetin (TRI), triethylcitrate (TEC), polyethylene glycol (PEG 300), mannitol (MAN, Parteck^® M200) and sorbitol (SOR, Parteck^® Si150), from Millipore Sigma (Darmstadt Germany). The plasticizer content was 10wt% for all blends. The blends were mixed in a mortar with a pestle. Melt rheology: Haake™ Mars™ plate rheometer (Thermofisher Scientific 8, USA). Plate diameter=20 mm, gap between plates=1 mm, sample mass ≈ 550 mg, heated up to 200°C, temperature of 200°C was maintained for 5 minutes and then lowered to 170°C. Viscosity and phase angle delta, were determined in a range from 170°C to 250°C for the PVA 4-88 blends, and from 150°C to 230°C for the PVA 3-82 blends, with a heating rate of 2 K/min, constant strain rate (0.1 %) and constant frequency (6.28 rad/s), n=3. Differential scanning calorimetry (DSC): DSC 3+ (Mettler Toledo, USA) sample mass ≈ 5 mg, n=3, 1st heating cycle -80°C to 210°C, cooling cycle 210°C to -80°C, 2nd heating cycle -80°C to 250°C with a heating rate of 10 K/min, purge gas: N₂ with a flow rate of 50 ml/min, data evaluated with STARe-Excellence Software (Mettler Toledo, USA).

Results: The rheograms (Figure 1.) show different melt viscosity curves for the two PVA grades. PVA 3-82 reached the processable limit at about 182 °C, PVA 4-88 at 192 °C. The plasticizers also showed different influences on the different PVA grades. For both polymers triacetin and glycerol presented the strongest impacts on viscosity reduction in relation to temperature. Triacetin lowered the viscosity below the limit for hot melt extrusion over the entire measuring range. Glycerol provided a greater effect on PVA 4-88 compared to PVA 3-82. Mannitol, sorbitol and PEG300 showed a similar influence on the viscosity of PVA. TEC could not be processed with PVA 4-88 it showed signs of decomposition (Figure 1. B). With PVA 3-82, TEC displayed no signs of decomposition, but it increased the viscosity of the pure PVA from 190°C onwards. Besides viscosity, a second important parameter in preliminary rheological testing is the phase angle delta. It indicates the ratio of storage modulus and loss modulus, and thus the elastic and viscous behavior of the melt [2]. For hot melt extrusion, a predominantly viscous behavior is desired which is indicated by a phase angle over 45°. The drop in the phase angle after reaching the maximum indicates another change in the viscoelastic behavior which is possible linked to beginning of decomposition. The polyols seem to have a temperature stabilizing effect on the PVA 3-82. Triacetin and glycerol increased the ideal viscoelastic range the most. TEC showed a reversed rheological behavior for both polymers, predominantly elastic properties were observed. Considering the data of thermal analysis, differences in the shifts of glass transition temperature and melting point are revealed (Table 1.). The plasticizers lowered the melting point compared to pure PVA, which explains the changed and, in some cases, enlarged process window. An exception is TEC, which showed a significant lowering of the melting point but indicated signs of decomposition at high temperatures.

Conclusion: Suitable plasticizers for melt extrusion with PVA were identified and ranked in terms of their influence on viscosity of the melt. Combinations could be identified that increase the temperature range at which the polymers can be processed or shift it to a lower temperature. This may be a new approach for formulating temperature sensitive active pharmaceutical ingredients. Moreover, a correlation between the preliminary thermal analysis and the viscous behavior of the binary systems in the melt was observed.

References: 1. Kolter, K., et al. Hot-Melt Extrusion with BASF Pharma Polymers. 2012.
2. Gupta, S.S., et al., Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion-I: Polyvinylpyrrolidone and related polymers. Journal of Excipients and Food Chemicals, 2016. 5(1): p. 1001.

Figure 1. Complex viscosity against temperature: A: PVA 3-82 and PVA 3-82 /plasticizer systems; B: PVA 4-88 and PVA 4-88/ plasticizer systems, mean, n=3.

Figure 2. Phase angle δ against temperature A: PVA 3-82 and PVA 3-82 /plasticizer systems; B: PVA 4-88 and PVA 4-88/ plasticizer systems, mean, n=3.

Table 1. Thermal evaluation of binary systems; DSC measurements (n=3), second heating cycle.