(T0930-02-11) Formulation and Process Variables that Affect Tableting of Carbamazepine Dihydrate

Purpose: Tablet manufacturing is affected by several formulation and process variables, such as particle size, drug loading in the formulation, mechanical properties of individual components, compaction pressure, and dwell time. Interactions between these variables can also play a significant role in the mechanical properties of tablets.¹ A problem observed during the tableting of carbamazepine dihydrate is punch sticking. Such sticking can lead to quality concerns related to weight variation, content uniformity, tablet appearance, and patient compliance. Additionally, the requirement of periodic cleaning of punch tooling reduces manufacturing efficiency.² While there is a qualitative understanding of how different cohesive and adhesive forces among drugs, excipients, and punch surfaces affect punch sticking, relatively limited knowledge of the effects of different formulation and process variables is available.^3–6Also, interactions between different variables and their impact on mechanical properties of carbamazepine dihydrate tablet is unclear. Therefore, the purpose of this work was to provide a comprehensive assessment of the effect of formulation and process parameters on the tableting of carbamazepine dihydrate using a design of experiments (DoE) approach.

Methods: Formulations with different drug loadings were prepared by mixing carbamazepine dihydrate, 0.25% magnesium stearate, and a sufficient quantity of MCC PH102 in a Turbula mixer operated at 50 rpm for 8 min. The powders were compressed using a Styl’One compaction simulator (simulating a Korsch XL100 and 25 ms dwell time) using 12.7 mm round flat-faced removable tooling. The tip was removed after a predetermined number of compressions and weighed to obtain the sticking mass. The tablet tensile strength (TS) and tablet brittleness index (TBI) were obtained using appropriate equations applied to the diametrical breaking profiles of tablets. To understand the impact of various formulation and processing parameters on the tableting of carbamazepine dihydrate, a DoE-based approach was used. The sticking mass, TS, and TBI were chosen as the response variables. The drug loading (10, 20, and 30% w/w), compaction pressure (100, 150, and 200 MPa), and particle size (D₅₀: 53.5, 156.6, and 319.3 µm) were input as the independent variables in the Box-Behnken design. Small dihydrate crystals were obtained by slurrying carbamazepine in water, while large carbamazepine dihydrate crystals were obtained by slow evaporation from water–ethanol (60:40 v/v) solution. The response variables were measured after 5, 10, 20, 30, 40, and 50 tablets. Further, the statistical model was built using a forward stepwise regression method. A result with a p-value less than 0.05 was considered to be statistically significant.

Results: Figure 1a indicates a positive correlation between drug loading and the sticking mass, whereas compaction pressure and particle size show a significantly negative effect on it. Additionally, the particle size and drug loading interaction significantly affect sticking mass. For example, an increase in sticking mass at 30% drug loading, could be reduced to nearly zero if larger particles with ~150 µm D₅₀ are used. Figure 1b indicates that particle size has a negative correlation with TS, with a significant square effect. Contrastingly, compaction pressure positively affects TS. However, the stepwise regression model indicates that the interactive terms between particle size, drug loading, and compaction pressure are not statistically significant. Additionally, Pearson’s correlation analysis indicates no significant association between sticking mass and TS. TBI also has a positive correlation with both particle size and drug loading (Figure 1c), with a significant square effect by particle size. This is attributed to the fact that a larger particle size results in a lower surface area available for bonding, thereby causing weaker interactions between neighboring particles, resulting in higher TBI.

Conclusion: The current study showed that punch sticking, tablet brittleness, and tablet tensile strength of carbamazepine dihydrate formulation are influenced by a number of factors, such as particle size, drug loading, and compaction pressure. Thus, these variables can be targeted in commercial tablet formulations to ensure the manufacturing of high-quality carbamazepine tablets.

References: 1. Sun CC. Decoding powder tabletability: roles of particle adhesion and plasticity. J Adhes Sci Technol. 2011;25(4-5):483-499.
2. Yamashita H, Sun CC. Material-sparing and expedited development of a tablet formulation of carbamazepine glutaric acid cocrystal–a QbD approach. Pharm Res. 2020;37:1-10.
3. Paul S, Taylor LJ, Murphy B, et al. Toward a molecular understanding of the impact of crystal size and shape on punch sticking. Mol Pharm. 2020;17(4):1148-1158.
4. Paul S, Taylor LJ, Murphy B, et al. Mechanism and kinetics of punch sticking of pharmaceuticals. J Pharm Sci. 2017;106(1):151-158.
5. Mullarney MP, MacDonald BC, Hutchins A. Assessing tablet-sticking propensity. Pharm Technol. 2012;36(1):57-62.
6. Paul S, Taylor LJ, Murphy B, et al. Powder properties and compaction parameters that influence punch sticking propensity of pharmaceuticals. Int J Pharm. 2017;521(1-2):374-383.

Acknowledgements: We thank the National Science Foundation for support through the Industry-University Collaborative Research Center grant (IIP-2137264), Center for Integrated Materials Science and Engineering for Pharmaceutical Products (CIMSEPP).

Figure 1. Surface plots for the effect of (a) particle size and drug loading on sticking mass after 5 tablets, (b) particle size and compaction pressure on TS after 5 tablets, and (c) particle size and drug loading on TBI after 5 tablets; TS: tensile strength, TBI: tablet brittleness index.