(T1230-09-59) A Continuous Twin Screw Melt Granulation Process for High Drug Loading Oral Dosage Formulation

Purpose: Continuous manufacturing (CM) in the pharmaceutical industry is a method for manufacturing pharmaceutical products by combining more than one unit operation in manufacturing. The advantages of CM are not only increasing the speed of production, but also monitoring in real time to ensure product quality. The current manufacturing procedure for a commercial “drug A” utilizes the solvent-based complex wet granulation procedure. This manufacturing step is a batch manufacturing process and time consuming because of the size limitation of the granulator. Therefore, we tried to develop a new drug formulation using a melt granulation process to continuously manufacture granules for tablet compression of drug A. The new formulation combined with the continuous twin screw melt granulation process could significantly save manufacturing time and provides high quality granules for tablet compression.

Methods: “API A” was supplied from Teva. Copovidone and Stearic acid 50 were from BASF Corp. Melt granules of API with excipients were generated by Thermo Fisher Process 11 Parallel Twin Screw Extruder System. Tablets of API/melt granules were manufactured and analyzed by STYL’One tablet press simulator. The hardness of tablets was tested using an ERWEKA EasyCheck B Tablet tester.

Results: A commercial product with “API A” having a >85% drug loading. Hence, the API was characterized for the particle size, flow property and tabletability profile to understand the manufacturing step. The API showed very poor flow (1, 2) based on the Hausner Ratio (1.87), Carr’s Index (46.5) and Angle of Repose (66.5°). Tensile strength results indicated that even at high compression pressure (~260 MPa), the tensile strength (~0.33 Mpa) of the tablet with only API is not close to the minimum product handling value (~1.70 Mpa) (Figure 1), suggesting the requirement of binder. The resultant parameters (particle size, flow parameters and tablet strength) were also entered in a virtual pharma online assistant ZoomLab^TM tool to predict the potential applicable manufacturing process of this API (3). The tool predicted that the overall processability of API was insufficient to formulate tablets by direct compression (Figure 2). This virtual pharma assistant recommended wet granulation to improve processibility of API, which is the current commercial manufacturing method. However, the process was found to be complex due to the limited capacity of the granulator. Melt granulation is a technique using meltable binders that melt or soften at relatively low temperature (50 to 100 °C) to help form an agglomeration of powder (4). As a continuous manufacturing process, twin screw melt granulation was utilized to generate the granules for tablet compression. Two excipients, Copovidone (Kollidon® VA 64) and Stearic acid 50 (Kolliwax® S) were evaluated as binders in the melt granulation process. Copovidone has a relatively low T_g value, ~101°C. However, even with a high percentage of copovidone in the formulation (20%), there are no melt granules formed. On the other hand, the formulation can form melt granules with as low as 5% of stearic acid 50, which has a melting temperature T_m ~64°C. This observation suggested that melting of the binder leads to a stronger molecular interaction with API in contrast to the interaction at the polymer glass temperature (T_g). Therefore, melt granules were formed by using plasticizers, polyethylene glycol (PEG) 3350 or 1450, to reduce the melting temperature of copovidone (~140°C). Formulation #1 with stearic acid 50 (Table 1) has 90% API amount comparable to the commercial drug product and exhibits an improved tabletability property as compared to pure API (Figure 1). Granules generated by waxy lipids normally have poor compressibility and mechanical strength (5). Hence, the tensile strength of tablets for product handling and film coating ( >2.0 MPa) is only achieved at a very high compression pressure ( >240 MPa) based on formulation #1. Additionally, a longer disintegration time ( >30 min) was observed due to the hydrophobic property of stearic acid 50. The melt granules containing 20% copovidone and 10% PEG 1450 showed “good granule properties” (round shape, adequate hardness, narrow particle size distribution) (4) with ~68-70% drug loading (Table 1, Formulation #2). The melt granules showed a fair flow property (Angle of Repose 38.7°), which is significantly better than the pure API. The tablets compressed with Formulation #2 melt granules show a high tensile strength ( >2.0 MPa) at a lower compression pressure ( >108 MPa) suggesting good tabletability. Additionally, the tablet showed faster disintegration time ( < 20 min). Hence, formulation #2 is a better choice for future research.

Conclusion: Twin screw melt granulation procedure was applied to study the potential continuous manufacturing possibility of a commercially available “drug A”. Melt binder stearic acid 50 and copovidone were evaluated to understand the role of glass transition or melting temperature in the formation of melt granules. The new formulation combined with the twin screw melt granulation process could significantly save manufacturing time and provides high quality granules for tablet compression.

References: [1] C. Turchiuli, M. Fuchs, M. Bohin, M.E. Cuvelier, C. Ordonnaud, M.N. Peyrat-Maillard, E. Dumoulin, Innovative Food Sci. Emerg. Technol. 2005, 6: 29–35.
[2] A. Mehta, G. C. Barker, Reports on Progress in Physics, 1994, 57: 383.
[3] https://www.basf.com/global/en/who-we-are/innovation/our-innovations/health_and_nutrition/zoomlab.html
[4] S. Shanmugam, Bioimpacts, 2015, 5: 55-63
[5] S. P. Forster, E. Dippold, T. Chiang, Pharmaceuticals, 2021, 13:665-686

Table 1 Melt granulation formulations

Figure 1. Tensile strength under different compression pressure

Figure 2. ZoomLabTM predicted the possible manufacturing routes of API A