(M1530-12-80) A New and Sustainable Twin Screw Wet Granulation Method Making Subsequent Drying Obsolete

Purpose: Direct compression has become the preferred route for manufacturing tablets. The process is effective, cost efficient and can be integrated into continuous production concepts. However, the properties of the active ingredient (e.g., compressibility, flowability) or the targeted dose (very low or very high) often limit the eligibility of a formulation for direct compression and trigger the need for a granulation step. Today, wet granulation, with the addition and removal of a granulation liquid is still the most widely used processing approach to produce granules. In contrast to dry granulation, wet granulation requires a drying step (e.g., fluid-bed drying) which is energy and labor intensive, comes with a large inventory footprint and is often the bottleneck manufacturing lines. Particularly in continuous manufacturing drying provides challenges, and often requires a semi-continuous approach [1,2]. It was the aim of this study to demonstrate that wet granulation in a continuous twin-screw granulation process can be conducted without requiring a subsequent drying step. Certain excipients having the capability to release and bind water during the process are the enabler of this approach making the drying step obsolete.

Methods: Potassium sodium tartrate (KNaC4H4O6 · 4 H2O, “PST”) which has a precedence of use as food additive and as pharmaceutical excipient, was identified to be particularly suitable: it has a melting point between 70 and 80°C, its crystal water is released with increasing temperatures and decomposition occurs only at temperatures of ~250°C [3]. Figure 1 shows how these thermal material properties, and the release of crystal water can be used in extruder granulation without addition of additional granulation liquid and drying step. For proof-of-concept trials, a formulation of paracetamol fine powder (Atabay) (74.25% w/w), Aerosil® (Evonik) (0.75% w/w), potassium sodium tartrate (Spectrum Chemical) (20% w/w), povidone K 30 (Kolldion^® 30, BASF SE) (5% w/w) were used. Granulation experiments were performed in a „Consigma 1“(C1) extruder (25 mm; L/D-ratio 20/1) from GEA Group (barrel temperature: 105°C). The particle size distribution of the granules was measured by laser diffraction (Malvern Mastersizer 2000 from Malvern Panalytical). The granules were sieved (1000 µm), mixed with 5 %(w/w) croscarmellose sodium (VIVASOL^® JRS Pharma), 1% (w/w) sodium stearyl fumarate (PRUV^®, JRS Pharma) and were then compressed into tablets (flat, 12 mm, Romaco Styl’One EVO from Korsch). Dissolution experiments were performed in a USP (United States Pharmacopeia) Type II apparatus (paddle) with 900 mL phosphate buffer solution pH 5,8.

Results: Paracetamol powder with 0.75% fumed silica was successfully granulated with 20% PST and 5% povidone K30. Particle size, bulk and tapped density as well as flowability increased significantly. The tabletability plot (compression pressure/tensile strength of tablets) of the formulation showed excellent compressibility (Figure 2). The tensile strength of a 500 mg paracetamol tablet was 1.9 MPa at a low compression pressure of 140 MPa. Dissolution test results showed a quick and complete dissolution: 80% drug release were obtained after 14 minutes, well in-line with USP requirements (80% after 30 minutes) (Figure 3).

Conclusion: We propose a new innovative wet granulation process that uses water of crystallization of potassium sodium tartrate for wet granulation in a twin-screw extruder. The granulation liquid is released in-situ at elevated temperatures. Water re-constitution is triggered during the cooling-down phase after granulation. The concept study with paracetamol proved that wet granulation can be conducted, and the granules processed in tableting, without employing a drying step. The resulting tablets had a high tensile strength at low compression pressures and presented compendial dissolution behavior. The proposed new process can help to reduce energy consumption and improve CO₂ footprint and is very suitable for implementation in continuous manufacturing lines.

References: [1] B. Liu et al., 2021,
[2] Nieuwmeyer et al., 2007
[3] Glatz et al., 1970 and Shyju et al., 2012

Twin screw granulation making use of in-situ released crystal water from PST as granulation liquid​

Figure 2: PST granulation results and tablet formulation​

Figure 3 Tabletability of paracetamol granules and dissolution of tablets with a tensile strength of 2.2 MPa