(M1130-12-82) PVA as Binder in Continuous Twin-Screw Granulation

Purpose: Granulation of powder blends is a commonly applied technique for pharmaceutical formulations which have no suitable flowability or compactability or are inhomogeneous with regards to the API content. Mainly wet granulation is applied [1] and here, especially continuous twin-screw granulation (TSG) is a technique that offers several benefits. TSG is more efficient, requires less water compared to batchwise techniques such as high shear granulation [2, 3] and granules have more favorable properties (more porous, less spherical). In a continuous line, the components are gravimetrically fed into a blender and then the blend is gravimetrically fed into the granulator. Most preferably, the binder – often HPMC, HPC or PVP based - is included in the dry blend and granules are formed by the addition of pure water. Lower viscous grades of PVA are already used, however, not systematically evaluated. Therefore, this work assesses the applicability and suitability of different grades of PVA as binder in twin-screw granulation. Different formulation compositions are tested representing hydrophilic and hydrophobic nature.

Methods: Dicalcium phosphate (DCP, Calipharm A , Innophos,USA) was used as hydrophobic excipient, Mannitol (D(-)-Mannitol fine powder EMPROVE® ESSENTIAL, MilliporeSigma, Germany) as hydrophilic filler. Different grades of PVA (4-88, 18-88, 40-88, MilliporeSigma, Germany) were used as binder, 5 % w/w was added to the filler. Additionally, formulations with model compounds were assessed, therefore, Paracetamol Semi-Fine (Mallinckrodt, USA) is used (50 % w/w), 45 % w/w Mannitol (D(-)-Mannitol fine powder EMPROVE® ESSENTIAL, MilliporeSigma, Germany) and 5 % w/w PVA (4-88, 18-88, 40-88, MilliporeSigma, Germany). The granulation process set-up is represented graphically, a ConsiGma^TM-25 system is used (GEA, Belgium). Granules are characterized with respect to size (QicPic, Sympatec, Germany), friability (PTF 300, Pharma Test, Germany) and compactability (STYL’One, Kilian, France). Before compaction, granules were milled (ConsiGma^TM-25 system, GEA, Belgium) with grater screen of 1500 µm on 900 rpm, 2 % Magnesium stearate is added, and 400 mg tablets are produced (different forces).

Results: In Figure 1, the particle size of the placebo granules is shown. For both fillers PVA 18-88 and 40-88, the d50 decreases at higher L/S-ratios due to plastic deformation, more malleable granules. Low amounts of fines are seen for all formulations on the highest L/S-ratios (not shown). The steep increase of size for PVA 18-88 and mannitol is also reflected in higher torque values (not shown). All tested PVA grades are effective binders demonstrated by low friability values at low L/S ratios. In the mannitol formulation, PVA 40-88 is the most effective binder since it produces granules with friabilities below 30% (i.e. considered as good friability values) at the lowest L/S-ratio. Nevertheless, high torque values are obtained at the highest L/S-ratios, limiting the advantage of this binder. PVA 18-88 produces granules with the lowest absolute friability, but also resulted in high torque values. PVA 4-88 is considered the best PVA grade for granulation of the highly soluble mannitol formulation as it yields granules with good friability (i.e. below 30%) an does not result in too high torque values. PVA 4-88 is the most effective binder at lowest L/S-ratios for the DCP formulation. No significant differences are seen for the lowest absolute friability between the PVA binders for the DCP formulation. In the formulation with paracetamol as model drug and mannitol as filler, the following results are achieved. PVA 4-88 is the most effective filler in this formulation as it produces the strongest granules at the lowest L/S-ratios (Figure 7). However, with all PVA grades very low granule friability can be achieved ( < 5%), consequently all PVA grades are suitable binders in this formulation. Overall, the hardness is very similar for all granules which finally leads to comparable tablet hardnesses (Fig. 3). Good tablets are produced at a compaction pressure of 127 MPa since the tensile strength is higher than 1.7 MPa (dotted horizontal line).

Conclusion: The use of PVA as binder in TSG is comprehensively evaluated by using different grades and excipients differing in hydrophilicity / hydrophobicity. Generally, PVA is an efficient binder for various formulations as it produces strong granules on low L/S-ratios which are favorable since these enable short drying times during downstream processing. Low amounts of fines are obtained and the granules show superior tableting performance.

References: [1] Pharmaceutics. 2021 May; 13(5): 668, Continuous Twin Screw Granulation: A Review of Recent Progress and Opportunities in Formulation and Equipment Design, Christoph Portier, Chris Vervaet, and Valérie Vanhoorne
[2] Beer, P.; Wilson, D.; Huang, Z.; De Matas, M. Transfer from high-shear batch to continuous twin screw wet granulation: A case study in understanding the relationship between process parameters and product quality attributes. J. Pharm. Sci. 2014, 103, 3075–3082
[3] Megarry, A.; Taylor, A.; Gholami, A.; Wikström, H.; Tajarobi, P. Twin-screw granulation and high-shear granulation: The influence of mannitol grade on granule and tablet properties. Int. J. Pharm. 2020, 590, 119890

Figure 1: Granule size and friability dependent on L/S ratio; 95 % of mannitol or DCP are included, 5 % PVA (w/w).

Figure 2: Particle size (d50) and friability of granules as a function of L/S ratio. Granules contain 50 % Paracetamol, 45 % Mannitol, 5 % PVA (all w/w).

Figure 3: Tablet hardness for tablets of granules with 50 % Paracetamol, 45 % Mannitol and 5 % PVA (all w/w).