(M1530-07-40) Mannitol vs Lactose in Twin Screw Continuous Wet Granulation Using New Binder

Purpose: In recent years, continuous manufacturing processes received growing attention due to their potential to produce flexible batch sizes, allowing producers to adapt to market demands, storage space requirements, minimize handling errors, etc. This requires a reevaluation of available excipients. Using twin screw continuous wet granulation, a new binder and acetaminophen as a model drug, we compared the performance of two water-soluble fillers lactose and mannitol on a tablet simulator.

Methods: In order to get robust granules, the binder played a critical role in wet granulation. Two different formulation blends were made with different water-soluble fillers. Formulation blend 1 consisted of 20.00 % of acetaminophen, 36.00 % lactose (Granulac® 80, Meggle Pharma) as water-soluble filler, 36.00 % microcrystalline cellulose (Microcel® 101 SD, Roquette) as water-insoluble filler and 5.00 % pregelatinized hydroxypropyl pea starch – medium viscosity (Lycoat® RS 720, Roquette) as water-soluble binder with 3.00 % of croscarmellose sodium (Solutab^® A, Roquette). Blend 2 consisted of 20.00 % of acetaminophen, 36.00 % of crystalline mannitol (PEARLITOL® 50 C, Roquette) as water-soluble filler, 36.00 % of Microcel® 101 SD as water-insoluble filler and 5.00 % of LYCOAT® RS 720 as water-soluble binder with 3.00 % of Solutab^® A. Continuous twin screw wet granulation (MODCOS XS-Line) was used to make granules of blends. Three Liquid/Solid ratio (L/S ratio) for granulation were kept same for both blends (0.1492, 0.2647, and 0.4353 L/S) with two different screw speed (SS) of 150 RPM and 325 RPM. Granules were dried in fluid bed dryer connected at the end of twin screw granulator with inlet temperature of 70 °C to get final product temperature of 48 °C. Granule particle size was analyzed before and after milling using Malvern laser particle size diffractor. Granules were milled using Quadro Co-Mill from Mesh 18 (Round) at speed of 4,000 RPM to get uniform size granules for compression. Mannitol- and lactose-based milled granules were blended with 1.00 % of MgSt for 2 min at speed of 49 rpm using TURBULA^® mixer. Hausner ratio of milled granules were checked using tapped density tester (TD1). Granules were compressed using 10.00 mm standard concave punch (Natoli Engineering) using STYL’One Evo compaction simulator (MedelPharm) simulating Korsch XL 100 tablet press at 5, 10, and 15 kN compression force at 25 RPM with a target tablet weight of 300 mg. Breaking force of tablets was checked using hardness tester.

Results: The best tablet performance (tablet mechanical strength) was reached for mannitol-based granules at L/S ratio of 0.4353 with a screw speed of 150 RPM (Figure 1). At L/S ratio of 0.1492 with a screw speed of 150 RPM and 325 RPM, no granules forming. 2.The best tablet performance (tablet mechanical strength) was reached for lactose-based granules at L/S ratio of 0.2647 with a screw speed of 150 RPM (Figure 2). At L/S ratio of 0.1492 with a screw speed of 150 RPM and 325 RPM, no granules formed. 3. Mannitol-based granules displayed better performance at all L/S ratio with different screw speed compared to lactose-based granules in resulting tablets as evaluated by tablet simulator.

Conclusion: Mannitol in combination with pregelatinized hydroxypropyl pea starch in continuous twin screw granulation are a good combination of excipients leading to robust granules and tablets. 2. Crystalline mannitol can be an option when the formulator is encountering issues with lactose based twin screw wet continuous granulation tablet manufacturing.

Figure 1: A. Tabletability, B. Compactibility, and C. Compressibility profile evaluated by compaction simulation. Blend 1: Lactose-based granules. Run 1: 0.2647 L/S ratio with SS of 150 RPM. Run 2: 0.2647 L/S ratio with SS of 300 RPM. Run 3: 0.1492 L/S ratio with SS of 150 RPM. Run 4: 0.1492 L/S ratio with SS of 300 RPM. Run 5: 0.4353 L/S ratio with SS of 150 RPM. Run 6: 0.4353 L/S ratio with SS of 300 RPM.

Figure 2: A. Tabletability, B. Compactibility, and C. Compressibility profile evaluated by compaction simulation. Blend 2: Mannitol-based granules. Run 1: 0.2647 L/S ratio with SS of 150 RPM. Run 2: 0.2647 L/S ratio with SS of 300 RPM. Run 3: 0.1492 L/S ratio with SS of 150 RPM. Run 4: 0.1492 L/S ratio with SS of 300 RPM. Run 5: 0.4353 L/S ratio with SS of 150 RPM. Run 6: 0.4353 L/S ratio with SS of 300 RPM.