(T1030-11-64) Mechanistic Prediction of Tablet Breaking Force for Binary Blends Based on Individual Component Properties

Purpose: Traditionally, tablet formulation has relied on a trial-and-error approach to enhance tabletability. However, the complexity of modern pharmaceutical formulations now necessitates the development of predictive models to guide excipient and formulation design, thereby optimizing tablet performance and quality. The primary objective of this study is to develop a mechanistic tablet breaking force or tensile strength prediction model based on the concept of inter-particle bonding strength and the number of particle bonds, hereafter called the bonding number. A particle adhesion force model is used for calculating bonding strength and a particle coordination number approach is used to calculate bonding number. The prediction model is developed first for single-component systems and then extended to binary-component systems.

Methods: Microcrystalline Cellulose Pharmacel 101 (PhC101) from DFE Pharma Corporation, USA, served as the binder. PhC101 underwent particle size adjustment using a Fluid Energy Milling (FEM) unit from Sturtevant Inc., MA, USA. Avicel PH-101 (Av101), Avicel PH-102 (Av102), and Avicel PH-105 (Av105) from FMC Corporation (USA) were also used as binder. Micronized Paracetamol (mAPAP) and coarse Paracetamol (cAPAP) were sourced from Mallinckrodt Pharmaceuticals (USA) and Changshu Huagang Pharmaceutical CO., Ltd (China), respectively, while Ibuprofen 50 (IBU) was obtained from BASF (USA). Binary blends, comprising one of the three APIs and corresponding excipients, were mixed in a V-blender (Patterson-Kelley, USA) at 25 rpm for 12 mins with total 100g materials. Tablets were fabricated using a Carver platen press (Carver, Inc., USA) equipped with a stainless-steel die featuring a 0.5-inch inner diameter, containing 500mg of powder or blend. Additionally, tablets were prepared using a Gamlen D1000 compactor (Gamlen, Inc., UK) with a 6 mm punch die, incorporating 100mg of powder or blend. The tablet breaking force was assessed using either a Texture analyzer (Texture Technologies Corp., USA) or a Gamlen TTA (tablet tensile analyzer).

Results: Theoretically, the breaking force of a compact can be determined by summing the forces acting on all particles within the compact's plane, as illustrated in Fig. 1[1]. Bonding strength can be viewed as the function of the modified Rumpf adhesion force with increasing contact area between two particles[2, 3]. Bonding number is the summation of the number of interparticle bonding per cross-sectional area, which is based on coordination number and the number of particles across the cross-section [4]. Fig. 2 demonstrates the robust predictive accuracy achieved, affirming the successful extension of the prediction model from single to binary components. In a single component tablet, there are two fitting parameters: plastic parameter k and corrected contact number. The value of k represents the level of local shape change at the contact point. The value of k for MCC and IBU is 0, affirming that ductile materials tend to undergo particle-level deformation rather than asperity-level deformation during compaction. Being a ductile material, the corrected contact number, representing the contact point between two particles, is higher than brittle material in magnitude level. Another interesting finding is that the corrected contact number strongly correlates with particle size. Based on the properties of individual components, tablet breaking force of binary blend could be predicted without having to prepare blends for parameter fitting. Fig. 3 illustrates the theoretical and experimental tensile strength of binary blend tablets at various drug loadings and tablet porosity. The breaking force, converted to TS, is determined based on formulations comprising Avicel 101 and IBU50. The nonlinear relationship between drug loading and tensile strength is observed. The model can design high drug loaded formulations because it can evaluate the highest possible drug loading, ensuring the tablets meet specified breaking force or tensile strength requirements.

Conclusion: With particle properties provided and the desired tablet thickness specified, this model can offer theoretical predictions of tablet breaking force or tensile strength, thereby offering valuable guidance for tablet formulation design.

References: 1. Rankell, A.S. and T. Higuchi, Physics of tablet compression XV. Thermodynamic and kinetic aspects of adhesion under pressure. Journal of Pharmaceutical Sciences, 1968. 57(4): p. 574-577.
2. Rumpf, H., Packing of granular solids, in Powder technology 1990, Chapman and Hall: London. p. 43-54.
3. Li, Q., et al., Interparticle van der Waals force in powder flowability and compactibility. International Journal of Pharmaceutics, 2004. 280(1-2): p. 77-93.
4. Rumpf, H., The strength of granules and agglomerates. Agglomeration, 1962: p. 379-418.


Figure 1. Illustration of bonding number and bonding strength.


Figure 2. Tabletability of single component material: a) Avicel 101 and b) 60%cAPAP+40%25um PhC101.


Figure 3. Predicted tablet tensile strength with varying drug loading and different tablet porosity. Tablet contains IBU50 and Avicel 101 only.