(M1030-07-39) Comparative Analysis of Co-Processed AVICEL DG® vs Individual Microcrystalline Cellulose and Anhydrous Dicalcium Phosphate in Tablet Formulation

Purpose: The principal objective of this study was to execute a comparative analysis between co-processed AVICEL DG® and the individual components, Microcrystalline Cellulose (MCC) and Anhydrous Dicalcium Phosphate (ADCP), in tablet formulation using a dry granulation process. This study focused on various physical characteristics including ribbon density, particle size distribution (PSD), compressibility, and dissolution of the resultant tablets to evaluate if co-processed AVICEL DG® and individual excipients were interchangeable and to show potential advantages of either selection in the formulation.

Methods: Three separate studies were performed for this analysis of AVICEL DG® versus MCC and ADCP in a tablet formulation. The first compared intragranular (IG) and extragranular (EG) ADCP placement. The second compared use of different grades of MCC. The third compared the effect of different ratios of ADCP:MCC. Each formulation was maintained with consistent composition and processing conditions to ensure reliable comparability. Tablets for all formulations were compressed using a standardized tablet press to ensure uniform compression forces and production of tablets with consistent dimensions and weights. The process included dispensing, screening, mixing (using milling device), and dry rinsing the active pharmaceutical ingredient (API) container to create a pre-blend. The pre-blend was dry granulated (roller compaction), milled, and lubricated to create a final blend for compression. Process parameters such as blend times and speeds were kept constant. Roller compaction was used to prepare the granules. Target ribbon densities were estimated for each batch. Actual ribbon densities were monitored and controlled throughout the process, given the particle size distribution from the milling process is dependent on the density measurements. The roller compaction process was repeated until the desired PSD was obtained. Finally, dissolution profiles were compared to evaluate the release rate of the API in dissolution media.

Results: Comparison of IG and EG placement of ADCP in formulation versus AVICEL DG®: Ribbon density results demonstrate increased ribbon densities for both IG and EG placement of ADCP compared to AVICEL DG® (Figure 1). PSD results demonstrate larger particle formation and larger granule formation with AVICEL DG® compared to the MCC and ADCP formulations (Figure 2). Dissolution results demonstrate a better dissolution profile with IG ADCP compared to EG placement and AVICEL DG® (Figure 3). Comparison of different grades of MCC, specifically MCC101 and MCC102, in formulation versus AVICEL DG®: Ribbon density results demonstrate increased ribbon densities for both MCC101 and MCC102 compared to AVICEL DG® (Figure 1). PSD results demonstrate the most consistent spread across sieve openings for MCC102 compared to MCC101 and AVICEL DG® (Figure 2). Dissolution results demonstrate an overall faster release profile for both MCC formulations compared to AVICEL DG®, with MCC102 demonstrating the fastest release (Figure 3). Comparison of different ratios of ADCP:MCC102, specifically 1:2, 1:3, and 1:4, in formulation versus AVICEL DG®: Ribbon density results demonstrate increased ribbon densities for IG ADCP:MCC102 (1:3) and (1:2) compared to (1:4) and AVICEL DG® (Figure 1). PSD results demonstrate the most consistent spread across sieve openings for IG ADCP:MCC102 (1:3) compared to both other ratios and AVICEL DG® (Figure 2). Dissolution results demonstrate the fastest release profile for IG ADCP:MCC102 ratio of 1:3 compared to both other ratios and AVICEL DG® (Figure 3). The density and PSD results indicated better resistance to abrasion and mechanical stress in the MCC and ADCP blend formulations. MCC, as a ductile excipient, deforms under compression and provides hydrogen bonding between aggregates during compaction which helps maintain uniform particle size during milling and compaction¹. ADCP, as a brittle excipient, is likely to break into smaller fragments, leading to variability in PSD². In addition, faster dissolution release profiles in the MCC and ADCP formulations likely contributed to quicker tablet breakdown and onset of action for the immediate release API formulation. ADCP is relatively insoluble and can hinder the penetration of dissolution media into the granule when added extra-granularly, therefore slowing drug release from the matrix². Furthermore, the dissolution profiles of ADCP:MCC tablets proved optimal at a 1:3 ratio. When testing at an increased ratio, a slower dissolution profile was observed due to the hydrophobic properties of ADCP. Comparatively, a decreased ratio negatively impacted ribbon formation causing visible splitting and sticking of material.

Conclusion: In conclusion, this study demonstrated the interchangeability of co-processed AVICEL DG® with the individual excipients MCC and ADCP for this tablet formulation. Furthermore, it demonstrated the ideal formulation to be IG ADCP:MCC102 (1:3). The 1:3 ratio, intragranular placement of ADCP, and MCC102 demonstrated the best dissolution profile, PSD, and ribbon density results. The MCC and ADCP formulation enhances particle quality, improves ribbon density, shortens disintegration time, and improves dissolution profiles. Utilizing these individual excipients can lead to better manufacturing outcomes, improved patient compliance, and more effective therapeutic interventions. Future research should continue to explore and optimize the applications of co-processed excipients in drug formulation to further capitalize on their benefits.

References: 1. Janssen PH, Jaspers M, Meier R, Roelofs TP, Dickhoff BH. The effect of excipient particle size on the reduction of compactibility after roller compaction. Int J Pharm. 2022;4(10):100117. doi: 10.1016/j.ijpx.2022.100117
2. Wilms A, Kleinebudde P. Towards better understanding of the influence of process parameters in roll compaction/dry granulation on throughput, ribbon microhardness and granule failure load. Int J Pharm. 2020;2(10):100059. doi:10.1016/j.ijpx.2020.100059

Figure 1. Ribbon density results for all three studies.

Figure 2. PSD results for all three studies.

Figure 3. Dissolution profile results for all three studies.