(T1030-09-58) Comparing the Performance of Wet and Dry Polymer Binders in High Shear Wet Granulation and Twin-Screw Granulation Processes

Purpose: The purpose of this study is to identify the critical process attributes needed to switch from a high shear wet granulation batch process to a twin screw wet granulation continuous process.

Methods: A full factorial design of experiments (DoE) was constructed to study the effect of binder choice, liquid to solid (L/S) ratio, binder addition method, and granulator type. A formulation of 52.1% micronized acetaminophen, 39.6% microcrystalline cellulose, 2.6% croscarmellose sodium, and 5.2% binder (HPMC, HPC, PVP) was used for all trials on the high shear wet granulator (HSWG) and twin screw (TS) granulator. For the HSWG the L/S ratio ranged from 0.3 to 0.5 g/g. For the TS granulation the L/S ratio ranged from 0.4 to 0.6 g/g. For both granulators, some of the trials used dry binder addition and some used pre-dissolved binder addition. The HSWG trials were conducted in a GMXB-Pilot with the 10 L bowl attachment. The granulated material was wet milled using a Quadro^® Comil^® U10 and then dried using a VFC-Lab 3 fluid bed dryer. The dried material was then milled to final particle size using a Quadro^® Comil^® 194S. The TS granulation trials were conducted in a GF-215 twin screw wet granulation unit. The dry material blend was fed into the twin screw barrel using a Coperion K-Tron powder feeder. The granulated material was discharged into a conical mill before entering the spiral dryer. The material collected from the dryer did not require any further milling. Moisture, particle size, and tablet hardness were measured for each sample generated from all trials.

Results: While the granule size can be explained quantitively with the nucleation regime map, the size is mostly related to the flowability of the granules. Once the granules have adequate flowability to produce acceptable tablet %RSD, then the sizes might not be a critical process attribute anymore. Tablet hardness is the next important quality attribute to consider because low tablet hardness will increase the risk of tablet fracture during tablet coating or shipping. Comparing wet and dry binder solvation methods, in the TS granulator, the entire process of the granulation is completed in the scale of seconds. For binders with slow dissolution, dry binder addition method may not have enough time to dissolve and form bridges between the particles, hence giving weaker tablets. In contrast, in the high shear wet granulation process takes approximately five minutes to complete the water addition and granulation steps. That gives enough time for slow dissolution binder in dissolution and granule growth.

Conclusion: Although both granulators can produce granulations suitable for tableting, they require different process parameters and formulations for optimization. The TS granulator is optimized with PVP as the binder, wet binder addition, and a lower L/S ratio. The HSWG is optimized with HPC as the binder and dry binder addition.

Acknowledgements: This project was a joint effort between Freund-Vector and Eli Lilly. Eli Lilly provided the materials, and analyzed the samples. F-V provided the granulation equipment and conducted the DoE.

Granuformer continuous twin screw granulation and drying equipment

Twin screw granulator screw configuration

Physical properties for all trials