(M1330-12-82) Unlocking the Potential of Co-processed Excipient and algorithm-based tool for Direct Compression Tablet Manufacturing

Purpose: A new “all-in-one” co-processed excipient was developed to produce tablet faster through Direct Compression (DC). This co-processed excipient contains lactose (filler), Kollicoat® IR (binder), Kollidon® CL-F (disintegrant) and sodium stearyl fumarate (lubricant) for a blend with good flowability, compressibility, and lubrication effect. In this study, different particle size of a model drug (caffeine) was used to understand physiochemical properties of blend prepared by the co-processed excipient in DC tablet manufacturing. Additionally, algorithm-based tool (ZoomLab^TM, BASF) was utilized to understand the impact of the particle in achieving content uniformity with various dose.

Methods: Caffeine powder /granule and the co-processed excipient (Kollitab^TM DC 87L) were passed through a #40 mesh sieve then blended by V-blender (10% caffeine with 90% co-processed excipient). The flow properties of the blend were determined by Hausner Ratio and Carr’s Index (1). The 300 mg tablets were compressed by using a Korsch XL100 Tablet Press. The hardness was tested using a ERWEKA EasyCheck B Tablet tester. The friability was tested by using a Vonderkamp/10801 friability tester (2). The content uniformity was tested via UV absorption at 273 nm. Tablet disintegration was determined utilizing Pharma Test/PTZ-Auto disintegration tester at 37 °C.

Results: Caffeine granule, caffeine powder and the co-processed excipient have a particle size D50 ~300 µm, ~ 40 µm and ~180 µm, respectively. The co-processed excipient blend containing caffeine powder (10% w/w) or caffeine granules (up to 50% w/w) demonstrated a good flowability (1) with a Hausner Ratio < ~1.19, Carr’s Index < 15.0 (Table 1). Furthermore, the co-processed excipient blend demonstrated the passable flowability with up to 40% caffeine powder. This indicates the co-processed excipient can provide the direct compression blend with good flowability even at high percentage of caffeine powder. The decreased flowability of the powder/ the co-processed excipient (from 10% to 40% w/w drug loading) should be caused by the smaller particle size and irregular shape of the caffeine powder which brings in the larger cohesion and mechanical interlocking (3). A Virtual Pharma Assistant tool ZoomLab^TM (4) was used to predict the proper caffeine dose strength for study based on the probability of passing content uniformity (CU) test. As per prediction, a dosage range 40 to 60 mg of caffeine granules per tablet has higher than 93% of the probability of passing the CU test. However, the probability of passing the CU test in Stage I decreases to 77.4% with a 30 mg dose strength per tablet. In contrast, caffeine powder in tablet at all dosage condition (30 mg to 60 mg) have 100% of probability of passing the CU test. Therefore, 300 mg caffeine tablet with 30 mg dose strength was utilized as the model tablet to validate the prediction. With 10% caffeine, tablets with the co-processed excipient showed excellent friability (0.00%) even at low compression force ~6 kN. Additionally, the difference in the API particle size had a relatively small effect on the tablet hardness, as well as the tablet disintegration time (Figure 1). This is due to the low ratio of API in the formulations where the co-processed excipient controlls the overall tablet physical properties. The tablets with caffeine powder show a mean assay value 98.34 ± 0.93 (%RSD; n= 10) (tablet weight variation ~0.64% RSD), while the tablets with caffeine granules have mean assay value 96.43 ± 6.69 (%RSD; n= 10) (tablet weight variation ~0.88% RSD). Both assay %RSD values are consistent with results predicted by ZoomLab^TM for 95% confidence internal using a modified version of the Yalkowsky-Bolton equation (4), which are 0.6% for caffeine powder (0.93% based on experiments) and 5.1% for caffeine granules (6.69% based on experiments). The CU data of the caffeine powder tablet passed the acceptance value (AV) test and presented a CU in accordance with US pharmacopeia (±15% from label claim). Meanwhile, the caffeine granules failed the stage I test. This is because caffeine powder has a better content uniformity in the blend as compared to the granules form due to the particle size distribution for the blend at 10% drug loading (5). Notably, no extra lubricant is required during the tablet compression, which helps to simplify the manufacturing steps and the regulatory process.

Conclusion: The co-processed excipient (Kollitab^TM DC 87L) can provide the caffeine (10%) blend with excellent flowability. The blend still has passable flowability with up to 40% caffeine powder. Meanwhile, 10% caffeine powder tablet with the co-processed excipient has excellent friability and hardness even at low compression force. The tablets containing caffeine powder had the better content uniformity than granular counterparts at 10% drug loading proving the effectiveness and accuracy of ZoomLab^TM tool in predicting the proper dose strength of a drug using particle size and its distribution which help to reduce time for formulation development. Hence, combining ZoomLab^TM tool and the co-processing excipient can help to reduces processing time and labor cost during tablet manufacturing.

References: [1] C. Turchiuli, M. Fuchs, M. Bohin, M.E. Cuvelier, C. Ordonnaud, M.N. Peyrat-Maillard, E. Dumoulin, Innovative Food Sci. Emerg. Technol. 2005, 6: 29–35.
[2] https://www.usp.org/sites/default/files/usp/document/harmonization/gen-chapter/g06_pf_ira_32_2_2006.pdf
[3] Liu, L. X.; Marziano, I.; Bentham, A. C.; Litster J. D.; White, E. T.; Howes, T, Int. J. Pharm., 2008, 362:109-117
[4] https://myapps.basf.com/zoomlab/
[5] Huang, C.; Ku, M. S., Int. J. Pharm., 2010, 383:70-80

Table 1 Tapped density testing results of caffeine/ the co-processed excipient blend

Figure 1. Tablet hardness and disintegration time under different compression forces

Figure 2. Caffeine tablet content uniformity