(M1130-08-51) Comparative Study of Suitability for Wet Continuous Production Process Using MCC with Different Characteristics

Purpose: The continuous production systems are becoming popular as a manufacturing method that eliminates the scale-up process of development and reduces production costs. In the wet continuous production method, the raw material supply, hydration, granulation (kneading), and drying processes are all performed in the system. Therefore, the point is that there is no stagnation such as clogging of raw materials during the process. In addition, physical properties of granules obtained by granulation, particularly the size of granules, must be properly controlled because they affect tablet properties such as API dissolution and weight RSD.Therefore, prescription design to meet these demands is very important. In this study, we investigated the process compatibility of prescription design focusing on microcrystalline cellulose (MCC), which is used as a pharmaceutical excipient, in a continuous production system. We compared different types of MCC grade called CEOLUS^TM to investigate what powder properties contribute to process compatibility and which grade is suitable for the wet continuous production system.

Methods: The powder formulation consisted of 1 part of acetaminophen (APAP) as the API, 62 parts of lactose, 27 parts of corn starch, 10 parts of Microcrystalline cellulose(MCC), and 3.5 parts of HPC-L powder as a binder. APAP was pulverized to a size of 1 to 20 um using a Comil. As MCCs, Asahi Kasei’s Ceolus^TM PH-101, UF-702, UF-711, KG-802, and KG-1000 were used as they possess different powder properties such as bulk density, particle shape, particle size, and water absorption property. All ingredients were added in the Granuformer® Gf-2050 system (Freund Corporation, Japan) thorough the input slot with loss-in feeder. After all ingredient were mixed, water was added and granulation was carried out by twin-screw kneader (puddle spin-speed :100rpm). The amount of water added during the granulation process was varied between 30 and 40% to investigate the effect on the blockage in the system and the size variation of granules. After sizing of wet granule through φ=3mm screen, drying was carried out 120℃ air at the flow rate of 8.5m3/min to obtained dry granules. We measured the size of dry granules, and tableting was carried out as follow. To 99.5 parts of the obtained dry granules 0.5 part of magnesium stearate was added then was mixed for 30 seconds in a PE bag followed by mixed granules were put in the rotary tableting machine LIBRA2 (Kikusui Seisakusho, Japan) thorough open feeder to obtain tablets (200mg, φ8mm-12R). The setting of the rotary tableting machine was as follow ; 12 punches, 30rpm of spin-speed of the turntable.

Results: When the amount of water adding was increased, formulation powders showed clogging tendency at the sizing screen, The tendency was differed by MCCs. Among all MCCs, KG-1000 showed less clogging tendency compared to the other MCCs. At the range of water amount 37~40%, while KG-1000 showed clogging at the rate stage of granulation, other MCCs showed clogging at the early stage of granulation process. We also measured the increment of the size of dry granules according to the amount of water added. Comparing at the range of water amount from 30～35%, diameter of the dry granules was increased 12.8mm by 1% of water amount for PH-101. For KG-802, UF-702, UF-711,and KG-1000 were ９mm, 7.4mm, 8.4mm,11.2mm, and 5.6mm of increment of dry granule by 1% of water amount respectively. There seemed to be correlation between water absorption properties of MCCs (R2=0.87). Tablet hardness, friability, disintegration time, dissolution time were evaluated. As results, KG-1000 showed the best in tablet hardness among all, while keeping good disintegration time and dissolution.

Conclusion: We compared different types of MCC grades called CEOLUS^TM to investigate what powder properties contribute to process compatibility using the continuous production system "Granuformer® Gf-2050. We observed correlation between water absorption properties of MCCs and the degree of growth of granules with amount of water added. Among all MCC, KG-1000 which posses highest water absorption property showed less clogging and the most moderate particle growth by the amount of water added during granulation process.