(M1130-11-70) A DoE Approach to Study the Influence of TSWG Process Parameters on the Characteristics of Granules and Tablets

Purpose: The Twin Screw Wet Granulation (TSWG) is a manufacturing process gaining increased attention in the pharmaceutical industry for its advantages with respect to other batch-wise granulation approaches, especially the versatility, straightforward scale-up and the integration in a continuous manufacturing line [1-3]. At an early stage of a pharmaceutical development program, the available quantity of API is limited and, a twin-screw granulator can accommodate relatively small batch size. Moreover, larger campaigns, that are typically requested at later stages, can be conducted using the same equipment. A DoE study was conducted in order to assess the influence of the main process parameters on the characteristics of granules and tablets. A leading formulation containing a soluble drug, namely niacin was used, and the factors evaluated in the DoE were the Liquid/Solid ratio (L/S), the screw design, the feed rate, the screw speed and the screen type to calibrate the size of the granules. The responses evaluated were referring to the process (e.g. torque and barrel temperature), the granules (e.g. particle size distribution-PSD, density and flowability) and the tablets (e.g. tensile strength, friability and disintegration time).

Methods: The blends (10.5% niacin) were sieved and mixed in a blender (MB015, Pharmatech^®) for 15min at 17rpm. Powders and demineralized water were added to a twin-screw granulator (Process 11, Thermofisher^®) by using a volumetric feeder and a peristaltic pump, respectively. A fractional factorial DoE (2^5-1, six center points, resolution V, statistical power >80%), was executed and analyzed using Design-Expert^®. Twenty-two runs were randomly conducted (Fig.1) and the main factors and the two-way interactions were estimated independently. The granules were dried in a fluid bed (Strea1, GEA) at LOD < 3% and passed through a conical mill (Comil^®U5, Quadro) equipped with sieves (300/457/991µm openings). The granules were characterized for PSD (sieve analysis), density, angle of repose and Hausner ratio using Ph.Eur. methods, and friability [3]. After mixing with extragranular excipients, the blends were compacted with a single-punch press (EK0, Korsch) equipped with an 11.28mm-diameter flat punch (weight=450mg). The tablets were characterized for hardness, tensile strength, thickness, friability and disintegration time, by compendial methods.

Results: The statistical model was significant with p < 0.05 (Fig.2). A high-shear screw design (factor-A) and a low L/S ratio (factor-C) increased the values of torque and temperature. At blocks 6-8, a higher temperature was observed at high screw speed (factor-B) and powder feed rate (factor-D). The sieve type (factor-E) influenced the PSD of the granules. By setting the largest sieve opening, the fraction >500µm increased for a low-shear screw configuration and high screw speed. Generally, the quantity of coarse particles increased with the L/S ratio and low powder feed rate. Conversely, it reduced at high feed rate (Fig.3). The friability was acceptable ( < 30% w/w) and impacted by factor-E and factor-A. The flowability was between passable and excellent according to the values of angle of repose and Hausner ratio. The latter was mainly affected by the milling type. The density (bulk and tapped) was higher for a small opening sieve and high-shear screw design. The tablet hardness (and tensile strength) was affected by the interactions AE, AC, AB and DE. For a low-shear screw design, higher hardness could be observed with small sieve opening, high L/S ratio and low screw speed. For a high-shear screw design, the relevant impacts were reduced. The main interaction influencing the time of disintegration and friability was BC and BD, respectively. Longer disintegration time could be observed at low L/S ratio and low screw speed whereas, at high L/S ratio the disintegration time was faster regardless of the screw speed (BC). Lastly, low friability was obtained at low-shear screw configuration.

Conclusion: A DoE study was successfully carried out, and the influence of the main process variables on the process outcomes and the quality attributes of granules and tablets were identified. The high-shear screw configuration affected the barrel temperature and the torque, probably due to the higher energy imparted by the two mixing zones. Moreover, the granules presented higher density likely ascribed to higher compaction forces. Similarly, lower L/S ratio led to higher torque and temperature values. The presence of water could dissipate the heat and affect the viscosity of the formulation. The screen type influenced the granule PSD, friability and density also as an interaction with other factors. Therefore, the selection of the sieve was critical for the downstream. All the tablets showed adequate hardness and friability, although the disintegration time range was 4-21min. To obtain faster disintegration a low-shear configuration and high L/S was effective. In conclusion, the results proved the viability of the TSWG technology for the preparation of granules suitable for tableting and, in future, for capsule filling. It is envisaged to evaluate the analytical and physical properties of the prototypes (e.g. content uniformity, impurities, porosity), the process parameters and formulation composition (e.g. screw design and drug loading).

References: [1] Portier et al, Pharmaceutics 2021, 13, 668
[2] Keleb et al, Int J Pharm, 2002, 69
[3] Portier et al, Int J Pharm, 2020, 119004

DoE factors, levels and runs

DoE responses and statistical models

Factors impacting coarse particles