(T1030-03-16) Research of Powder Properties of Microcrystalline Cellulose Grades Desirable for Direct Continuous Compression System

Purpose: The continuous production system of tablets has a potential to eliminate the scale-up process of development and consequently reduce the production cost. Furthermore, the direct compression process for tablets is considered more beneficial from economical viewpoint since it primary involves powder mixing and tableting processes only. Therefore, the continuous direct compression process is considered the most economical process for tablet production. The key point for the continuous direct compression system is the uniform mixing of the API and excipients in the mixing process. If the mixing state of the API and excipients is not uniform and segregation occurs, the API content RSD and tablet hardness may not achieve the target values, which could result in the failure to meet the drug quality standard. In this study, we compared four types of microcrystalline cellulose (MCC) with different particle shapes and bulk densities, and investigated which powder properties could be more desirable to produce tablets with low API content RSD and stable hardness in the continuous direct compression process.

Methods: We used CRA-RIS SYSTEM as a continuous direct compression system. The CRA-RIS SYSTEM consists of four loss-in-weight feeders, continuous mixer, and a rotary tableting machine. In this study, we used Acetaminophen as a model API. We used four MCC grades, CEOLUS^TMKG-1000, KG-802, UF-711 and PH-102, which differ in bulk density, particle shape and particle size. The tablet formulation consisted of 40% acetaminophen pre-mixed with 1% silicon dioxide, 37-41% spray-dried lactose pre-mixed with 1-2% croscarmellose sodium, 15-20% MCC, and 1% magnesium stearate. The amount of MCC KG-1000 was 5% lower than other grades because tablets with high hardness can be produced even with relatively low concentration than other grades. Tablet diameter, tablet weight and API content were 8 mm, 180 mg, 72 mg, respectively. Continuous production was performed using RA-RIS SYSTEM for 60 minutes andtablets were sampled at regular intervals to evaluate API content RSD, tablet hardness, and hardness RSD.

Results: The API content RSD of the KG-1000, KG-802, UF-711 and PH-102 formulation was 0.81%, 1.36%, 1.29%, and 1.87%. Tablet hardness and RSD of hardness of the KG-1000, KG-802, UF-711 and PH-102 formulation were 100 N and 7%, 91 N and 8%, 93 N and 7%, and 81 N and 10%. Among the four grades evaluated for comparison, the tablets with KG-1000, which had the lowest bulk density and fiber shape, showed the lowest API content RSD. The tablets with KG-1000 also had high hardness and low RSD of hardness. Although KG-1000 shows the worst flowability in the evaluation of repose angle, the basic flowability energy (BFE) per volume, one of the indicators of dynamic flowability measured with a powder rheometer, is shown to be the lowest among the four grades evaluated in this comparison. BFE of the KG-1000, KG-802, UF-711 and PH-102 powder was 863 mJ, 1116 mJ, 1026 mJ, and 1374 mJ. This indicates that KG-1000 flows with the lowest force of the four grades. Therefore, it is assumed that KG-1000 was mixed with API more uniformly than other grades during the screw mixing process in continuous production, resulting in lower RSD of API content in tablets and stable hardness in production. On the other hand, among the four grades, PH-102 had a higher API content RSD and lower hardness stability. PH-102 has a high flowability energy per volume, and it is assumed that the mixing state of PH-102 with the main drug is worse than that of other grades. In addition, grades with lower bulk density and BFE than PH-102, such as KG-802 and UF-711, also resulted in lower API content RSD and more stable tablet hardness than PH-102. The results showed that the use of CEOLUS^TM KG-1000 with low bulk density and good dynamic flowability, can produce tablets with low API content RSD and excellent hardness stability in a direct continuous compression process.

Conclusion: It was suggested that the use of MCC with good dynamic flowability, will allow for uniform mixing conditions with the API and resulted in tablet with low API content RSD and excellent hardness stability in a direct continuous compression process

Fig.1 Powder Properties of MCC CEOLUS Grades



Fig.2 Experimental procedures



Fig.3 Results：API Content RSD and Tablet hardness