Purpose: Ensuring content uniformity of low dose tablet formulations in the traditional batch direct compression (DC) process can be challenging. For example, segregation can occur when emptying the container to the tablet press. Continuous direct compression (CDC) can provide benefits over the batch DC since no containers are emptied to the tablet press but the materials are fed individually to the blender and after that they move straight to the tablet press. However, especially active pharmaceutical ingredients (APIs) can be difficult to steadily feed to the continuous process due to for instance their cohesive nature.
In this study two different APIs were individually incorporated to the same tablet formulation and corresponding process performance and tablet properties were studied. The aim of this study was to investigate how robust, regarding final product quality, the CDC process is when manufacturing low dose formulations.
Methods: Model APIs were Paracetamol (para) and Spironolactone (spiro) (3% w/w). The formulation contained also Microcrystalline cellulose (MCC, Avicel PH-101, 14% w/w), Lactose monohydrate (LMH, Tablettose 80, 82% w/w) as fillers, and Magnesium stearate (MgSt, 1% w/w) as lubricant.
Three level full factorial Design of Experiments (DoE) was used as two APIs as categorical factors and blender paddle speed (300, 700 and 1100 rpm) and total powder throughput (12, 20 and 28 kg/h) as continuous factors. This concluded altogether in 22 experiments (N1 – N22) (Table 1).
The CDC line consisted of three twin screw loss-in-weight (LIW) feeders (K-ML-D5-KT20, Coperion K-Tron) (API, MCC, LMH, the first blender inlet), a twin screw LIW microfeeder (K-CL-SFS-MT12, Coperion K-Tron) (MgSt, the second blender inlet) a continuous blender (Modulomix, Hosokawa Micron) and a rotary tablet press (PTK-PR1000, PTK CO, Ltd). Tablet weight was 400 mg and the turret speed of the tablet press was adjusted according to the total powder feed rate.
Particle size distribution of APIs were measured using laser diffraction (Malvern Mastersizer) and average particle size (d50) was calculated. Flowability (basic flow energy, BFI) of APIs was measured using FT4 powder rheometer (Freeman Technology). Tablet weight, weight variation, friability, disintegration and dissolution were measured from the samples collected after 20 min of tableting i.e. during steady state. In addition compactibility of tablets was measured from center point experiments (total powder throughput 20 kg/h, blending speed 700 rpm) N1 (spiro) and N12 (para).
Results: d50 of para was 15 µm and spiro 4 µm. BFI of para was 750 mJ and 430 mJ for spiro suggesting poor flowability of Spiro. Both materials seemed to be cohesive and spiro was aggregated.
Compactibility of the spiro tablets was better compared to the para tablets. For spiro it required approximately 9.5 kN compression force to produce 100 N breaking force and for para 12.5 kN. However due to the low API content in the formulation, the compactibility was very good for both of the formulations.
Tablet weight variation (rsd%) between the experiments was generally larger with spiro. On the other hand, tablet weight variation within the experiments was larger with para. Thus, the spiro experiments were more different with each other compared to para experiments but the weight variation within each spiro experiment was smaller which suggest more steady process when process parameters were kept the same.
All tablets fulfilled Ph. Eur. requirements for friability. Para tablets had slightly lower friability (0.42 – 0.58%, average 0.49%) than spiro tablets (0.43 – 0.88%, average 0.67%).
Disintegration of the tablets was very fast (para average 48 s, spiro average 46 s), so no significant difference was noticed between APIs.
All of the tablets also passed the USP dissolution test for IR tablets. As expected para tablets dissolved faster due to physico-chemical properties of the APIs. 85% of the label claim was reached less than 4 min wit para and less than 10 min with spiro.
As conclusion, it can be stated that no clear differences were seen in tablet properties between APIs. Some differences were seen on how APIs behaved in the process, but these differences might be more significant if the API dose would have been higher.
Interestingly even though full factorial DoE was used to uncover the interactions between blending speed and total powder throughput, it seemed that these process parameters did not have much effect on the tablet properties. It was only noted that when total powder throughput was low, the tablet weight was higher, probably due to slower tableting speed and thus more efficient die filling. Blending speed was not a statistically significant factor in relation to tablet properties.
Based on the results it can be stated that CDC process was stable and robust with this model formulation despite the API.
Conclusion: Studied low dose formulations and CDC process were very robust even though different APIs were incorporated to the formulation. All measured parameters fulfilled specification regardless of API.
Hannes Niinikoski– University of Eastern Finland
Tuomas Ervasti– University of Eastern Finland
Eero Mäki-Lohiluoma– Orion Pharma
Heidi Mikkonen– Orion Pharma
Ossi Korhonen– University of Eastern Finland