(M1330-10-56) Comparative Study of Suitability for Wet Continuous Manufacturing Process Using MCC with Different Characteristics - Part 2

Purpose: The continuous manufacturing systems are becoming popular as a manufacturing method that eliminates the scale-up process of development and reduces production costs. In the continuous wet granulation method, raw material supply, hydration, granulation, drying processes, and tableting are all performed in the system. During the granulation process, it is crucial to avoid any stagnation, such as clogging of raw materials in the system. Additionally, the physical properties of granules obtained through granulation, particularly for their size and distribution, must be properly controlled as they affect tablet properties like API dissolution and weight relative standard deviation (RSD). Therefore, formulation design to meet these demands is very important. Last year, we reported the results of a comparison of Microcrystalline Cellulose (MCC) grades using the continuous wet granulation system Granuformer® Gf-2050 (Freund Corp., Japan). In this study, we report the results of continuous wet granulation using another continuous manufacturing system, the CTS-MiGRA SYSTEM (Powrex Corp., Japan) for further investigation.

Methods: We used four types of MCC: Ceolus™ PH-101, KG-802, UF-702, and UF-711. Ethenzamide (ETZ) was used as the API. Mannitol, corn starch (CS), hydroxypropyl cellulose HPC-L were used as other excipients. The water absorption properties for each MCC are as follows. PH-101: 200%, KG-802: 230%, UF-702: 240%, UF-711: 240%. These powders were mixed using a high shear granulator VG-100 (Powrex Corp., Japan) under the following conditions: Blade - 190 rpm, Cross screw - 3000 rpm, and Time - 3 minutes. After mixing, all formulations were fed into the CTS-MiGRA SYSTEM and granulated using water. The granulation conditions were as follows: Granulation rate - 250 g/min, Tilt angle - 0 degrees, Water content - 10~30%. The drying conditions were Input temperature - 85 degrees Celsius, Airflow - 1.0 m³/min, Product temperature - 43 degrees Celsius. The amount of water added during the granulation process was varied to investigate its effect on blockage in the system, and the granule properties were evaluated. Tableting was carried out as follows: 0.5 parts of magnesium stearate were added to 99.5 parts of the obtained dry granules and mixed for 30 seconds in a PE bag. The mixed granules were then put into a rotary tablet press 102i (Fette Compacting GmBH) through a force feeder (10 rpm) to obtain tablets (180 mg, φ8 mm-12R). The settings of the rotary tablet press were as follows: 30 punches and a rotation speed of 30 rpm for the turntable. All granule formulations are shown in Table 1. We conducted granulation operations for each formulation, varying the water addition during granulation to assess process robustness.

Results: The maximum water addition (MWA) for formulations A, C, and D was 25%, while formulation B had the highest MWA at 30% (see Figure 1). This is attributed to the properties of UF-702 included in formulation B. UF-702 in this case is characterized by its porous nature and larger particle size, suggesting it excels as a water-retaining buffer. Formulation E had the lowest maximum water addition at 17.5% as it doesn’t contain MCC. The significantly lower water absorption capacity of CS at 60% compared to MCC is considered an influencing factor. The size distributions of each granule at the highest water content for each formulation are shown in Figure 1. Granule E contained many small particles that passed through a 75um opening suggesting that the granulation process may not have been sufficient. On the other hand, the granule A to D which contained MCC showed fewer small particles, suggested improved granulation compared to the formulation containing CS instead of MCC. Particularly, formulations A and B had the lowest amount of small particle. Next, the ETZ content in size-sieved granules is shown in Figure 2. It was found that the content of ETZ in the small particles was the lowest for all formulations. Based on the results so far, the maximum permissible water addition is highest for sample B, indicating its excellent robustness in the granulation process. Additionally, sample B also showed suppressed generation of small particles. Considering these results, sample B (UF-702) is recommended in this system. Upon examination of the tablet manufacturing process, formulations containing MCC required lower compression pressures (5~7 kN) compared to CS formulation ( >10 kN) to achieve a tablet hardness of 60 N. Additionally, formulations containing MCC showed superior tablet friability and disintegration time compared to the CS formulation, although no significant differences were observed between MCC grades.

Conclusion: We conducted a comparison of MCC grades called Ceolus™, focusing specifically on the granulation process in continuous wet granulation system called the CTS-MiGRA system. UF-702 was found to be optimal in this system, while KG grade was identified as optimal in the other system we reported on last year. It was confirmed that selecting suitable excipients, such as MCC grades according to the specific continuous wet granulation system, can significantly impact the robustness of pharmaceuticals quality.

References: M. Higuchi, K. Tsuru, Comparative Study of Suitability for Wet Continuous Production Process Using MCC with Different Characteristics, Poster M1130-08-51, AAPS PharmSci 360, Orlando, October 2023.

Table 1. Formulations

Figure 1. Particle size distribution of all granules

Figure 2. ETZ content in size-sieved granules