(W1130-09-57) Modelling Twin Screw Wet Granulation Process: Impact of L-HPC on Granules and Tablet Properties

Purpose: Twin Screw Wet Granulation (TSWG) has become popular due to its flexibility for continuous manufacturing in the pharmaceutical industry. (1, 2) Low-substituted hydroxypropyl cellulose (L-HPC) is a multifunctional excipient with disintegration properties that has high water absorption and swelling capability, and its excellent water retention property enables a stable wet granulation process. In the present study, the effect of various grades of L-HPC and process parameters on the material attributes for granules and tablet properties in TSWG application were evaluated, optimal formulation has been investigated by non-linear response surface method.

Methods: Acetaminophen (Yamamoto Chemical) was used as a model drug, L-HPC (Shin-Etsu Chemical) and PHARMACOAT^® 603 (Hypromellose 2910, 3 mPas viscosity in water) (Shin-Etsu Chemical) were used as a disintegrant and binder, respectively. All ingredients were mixed and passed through 500 µm sieve before processing. All granulation experiments were performed using HAAKE Process 11 (Thermofisher Scientific) and powder feed rate was fixed at 10 g/min. Purified water was used as a granulation solution. Water absorption amount of L-HPC was measured by Peneto Analyzer (PNT-N, Hosokawamicron: 14.7, 16.0, 17.3 g/ 2 g). The L-HPC levels in the formulation (5, 10, 15wt%) were selected as formulation factors. The screw speed (200, 300, 400 rpm) and L/S (liquid/solid) feeding ratio (0.05, 0.10, 0.15) were selected as process parameters. Based on Box-Behnken design, a total of 27 experiments were generated. After TSWG process, particle size (d₅₀), bulk density (BD) and angle of repose (AoR) of granules were measured. Granules were lubricated with 1% magnesium stearate (MgSt) and tablets (8 mm in diameter, 200 mg per tablet) were prepared using a rotary tablet press (Virgo, Kikusui). As tablet properties, tensile strength (TS), disintegration time (DT) and tablet weight variation were measured. The effect of the independent factors on granule properties and tablet properties were evaluated using multiple linear regression analysis (MLR) and response surface method incorporating thin-plate spline interpolation (RSM-S) as modelling tools. The optimal formulation and process parameters for desirable tablet properties were estimated.

Results: Effect of formulation factors and process parameters on the granules and tablets properties evaluated using MLR were shown in Table. The particle size of granules was significantly affected by the amount of L-HPC and L/S feeding ratio. It is suggested that L-HPC absorbs water and swells, leading to the consolidation of material during the granulation. The binder was well dissolved by increased L/S ratio which contributed to the growth of granule size. The properties of L-HPC highly affected BD and AoR of the granules. The compressed granules showed good flowability during the tableting process leading to a low tablet weight variation: less than 1.0% in all formulations. The impact of each parameter on tablet weight variation and tensile strength was not significant, while the disintegration time was highly affected by them. It is suggested that the higher water absorption grade of L-HPC (LH-21 and B1), lower screw speed and higher L/S ratio are able to produce faster disintegration property of the tablet in this study. Figure 1 shows the response surface of disintegration time from the tablets estimated by RSM-S. Similar trend of the relationships between the disintegration time and input factors analyzed by MLR can be seen. The correlation coefficient was evaluated in each analytical model to confirm the accuracy. A better correlation between the input factors and the properties of granules and tablets was seen with RSM-S modelling tool compared to MLR. The tensile strength and the disintegration time of the tablets were estimated by RSM-S, and 3D diagrams based on three factors with higher contribution to the tablet properties were shown in Figure 2. Model target properties in the design space are set as 1.4 MPa or more for the tensile strength and 10 min or below for the disintegration time. The design space for both parameters was successfully estimated. Tensile strength of tablets is decreased under higher screw speed using high water absorption grade of L-HPC. On the other hand, disintegration time is delayed under low L/S ratio and high screw speed with low water absorption grade of L-HPC. It is important to properly understand the causal relationships of the factors to ensure the desired target properties. The formulation and process factors were optimized based on the original data using RSM-S. The targets were high tensile strength and short disintegration time. To evaluate the accuracy of the prediction model, a tablet was prepared by TSWG according to the optimal parameters and tested. The tablet properties correlated very well with the predictions.

Conclusion: Effect of formulation and process parameters in TSWG were investigated. Causal relationships among formulation, process parameters and tablet properties were explained by MLR. However, for more accurate estimation, the RSM-S modelling tool is preferred. In this study LH-21 was the most suitable grade of L-HPC to produce robust and excellent tablet properties.

References: 1. Dhenge RM.; Cartwright JJ.; Hounslow MJ.; Salman AD. Int J. Pharm. 2012, 438, 20-32
2. Kytta, KM.; Lakio, S.; Wikstrom, H.; Sulemanji, A.; Fransson, M.; Ketolainen, J.; Tajarobi, P. Powder Technol. 2020, 376, 187–198

Table. Effect of factors on the granules and tablets estimated by MLR


Figure 1. Response surface of disintegration time

Figure 2. 3D diagrams for tablet properties