Comparison of Ceolus™ Grades in Continuous Manufacturing of Tablets using Direct Compression

1. Introduction

The introduction of continuous manufacturing of tablets has been gaining momentum, because it offers reductions in development and manufacturing costs and time and improved reliability of quality assurance.
In this study, grades of Ceolus™, microcrystalline cellulose (MCC) in formulations containing 40% fine powder-type drug, were compared using the CRA-RIS SYSTEM (Figs. 1, 2), a direct compression, continuous manufacturing system produced by Kikusui Seisakusho Ltd. The feasibility of stable continuous manufacturing and the MCC grades that could produce tablets with the best physical properties were investigated.

2. Experiment

2-1. Materials

API: Acetaminophen (APAP) fine powder
Excipients: MCC, Ceolus™ KG-1000, KG-802, UF-711, PH-102, Asahi Kasei Corporation
Excipients: Spray dried lactose (SD lactose)
Disintegrant: Croscarmellose Sodium (CCS), Kiccolate™ ND-2HS, Nichirin Chemical Industries, Ltd.
Fluidizer: Fine silicon dioxide (SiO2)
Lubricant: Magnesium stearate (Mg-St)

Table 1 shows the powder properties of the Ceolus™ grades, Table 2 shows the powder properties of APAP, and Table 3 shows the test formulations and blend powder properties. The Ceolus™ grades selected for the study were direct compression standard grade PH-102, and the high compactable grades KG-1000, KG-802, and UF-711.

Table 1 Powder properties of the Ceolus™ grades

Table 2 Powder properties of APAP

Table 3 Test formulations and blend powder properties

1 KG-1000, which has the highest compactability, achieved good hardness even when added in small amounts, so the added volume was decreased to 5% lower than the other formulations. The added volume of CCS was increased by 1% because slow dissolution was expected. 2 Powder properties were measured in powder samples taken from the force feeder after the end of the continuous manufacturing test.

2-2. Procedures for the experiment

1) Preparation
Trial tableting: Trial tableting was carried out for several minutes with each formulation to produce tablets of the target weight. As a result, the CRATER granulating screen diameter for KG-1000 was adjusted from φ2.0 mm to φ3.0 mm.
2) Continuous manufacturing
Direct compression, continuous manufacturing system: CRA-RIS SYSTEM (Kikusui Seisakusho Ltd.) Tablet press conditions: 45 punches, turntable rotation speed 41.2 rpm, force feeder rotation speed 45 rpm CRATER granulating screen diameter: φ3.0 mm (KG-1000), φ2.0 mm (KG-802, UF-711, PH-102)
Tablet weight, diameter: 180 mg, φ8.0 mm–12R
Pressure: 12 kN (main pressure), 6 kN (pre-pressure)
Continuous manufacturing time: 60 min
Sampling time: 0, 2, 4, 6, 8, 10, 15, 30, 45, 60 min (AP content RSD and dissolution evaluated at 0,4,15, 30, 45, 60 min)

3. Evaluation of properties

Tablet weight RSD (%): Ten tablets were weighed using an electronic balance. Tablet weight RSD (%) was then obtained from the mean and standard deviation (SD) using the following formula. Tablet weight RSD (%) = SD/mean × 100 (target ≤2%)
API content RSD (%): The content of ten tablets was measured in a dissolution tester (NT-60, JASCO Corporation) using Japanese Pharmacopoeia Solution 1, with paddle rotation speed of 50 rpm. API content RSD (%) was then obtained from the mean and SD using the following formula. API content RSD (%) = SD/mean × 100 (target ≤2%)
Tablet hardness (N): The hardness of 10 tablets was measured using a hardness meter (Tablet Tester
8M, Dr. Schleuniger). The mean value was used. (target ≥50 N).
Friability (%): This was measured using a friability tester (PTF 30ERA, Pharma Test) with 37 tablets,
25 rpm, for 4 minutes. (target ≤0.20%)
Disintegration time (min): The disintegration time for 6 tablets was measured using a disintegration
tester (NT-40HS, Toyama Sangyo Co., Ltd.) with purified water at 37 °C and no disc, and the mean time was used. (target: ≤30 min)
Dissolution test: The change in dissolution rate in 60 minutes was measured using a dissolution tester (NT-60, JASCO Corporation) with Japanese Pharmacopoeia Solution 1 and paddle rotation speed of 50 rpm. The dissolution rate was measured in 2 tablets, and the mean value was used. (target: dissolution rate ≥85% at 15 min from start)

2-3 Results

Fig. 4 shows the changes in feed volume from the POLARIS 4 loss-in-weight feeder. Apart from a non-steady state lasting about 1 minute after start-up, it was confirmed that all of the four evaluated grades were supplied in a stable manner in line with the set values.

Comparison of Ceolus™ Grades in Continuous Manufacturing of Tablets using Direct Compression_Fig. 4 MCC feed volume data — Fig. 4 MCC feed volume data

Fig. 5 shows tablet weight and weight RSD for each formulation at each sampling time, and Fig. 6 shows the mean weight RSD for each formulation at each sampling time. Tablet weight RSD results were good, meeting the target of ≤2% in all formulations.