(M1130-10-59) Prediction of Maximum Drug Loading in a Tablet Using Percolation Theory

Purpose: This study explores the application of the percolation threshold theory in pharmaceutical formulation development. Specifically, it seeks to determine the maximum concentration of an Active Pharmaceutical Ingredient (API) that can be introduced into a formulation before the API's properties dominate. The influence of the API's particle size distribution (PSD), morphology, and the size ratio between API and excipients on this threshold is assessed. The study focuses on binary blends of Compound-X or its spray-dried dispersion (SDD), which exhibit poor flow and compressibility, with microcrystalline cellulose (MCC), known for its superior compressibility and flowability. Blends containing 2.5 to 30% w/w of API or SDD were analyzed for various properties to determine percolation thresholds. This approach aims to streamline the formulation development process by predicting maximum acceptable drug loading.

Methods: Binary blends of Compound-X or its SDD with MCC (Avicel® PH-102) were prepared with 2.5, 5, 10, 15, 20, and 30% w/w API or SDD. Particle size and morphology were evaluated using a laser diffraction particle size analyzer and scanning electron microscopy (SEM). True density was analyzed using an Accupyc gas displacement pycnometer. Flow properties were assessed using an FT4 powder rheometer and shear cell analysis at 3 kPa for the flow function coefficient (FFc), cohesion, and effective angle of internal friction (AIF(E)). Heckel analyses were performed using a compaction simulator (Medelpharm Styl’One™ Evolution), with material compacted to theoretical zero porosity using an 11.28 mm diameter flat-faced punch. Compression profiles at slow and fast rates (5 mm/sec and 300 mm/sec) were used to determine strain rate sensitivity. Tablets were evaluated for weight, thickness, and breaking force to calculate tensile strength.

Results: The morphology of the API and SDD is shown in Figure 1. The API exhibited irregular particles of varied sizes (D50 = 17.4 µm), while the SDD showed aggregates of spherical particles (D50 = 6.7 µm). Density, flowability, and compression parameters are summarized in Figure 2. The API had a low bulk density of 0.27 g/mL and was classified as cohesive, with FFc < 4 and AIF(E) > 41º. Avicel® PH-102 had a higher bulk density of 0.33 g/mL and was free-flowing, with FFc > 10 and low AIF(E) < 41º. Increased drug content in the blends led to decreased bulk density and poorer flow properties. A critical percolation threshold around 20% drug load was identified, demonstrating a sudden shift in flowability from easy-flowing to cohesive. Heckel analysis revealed the API had a strain rate sensitivity of 17%, yield pressure around 60 MPa, and low bonding capacity, with a high risk of lamination during fast compression. Conversely, Avicel® PH-102 showed harder particles with a yield pressure of 70 MPa, high bonding capacity, and no risk of lamination. Increasing drug content decreased bonding capacity and increased lamination risk, with a noticeable tensile strength drop at 20% drug load, confirming the percolation threshold (Figure 3). Further studies on SDD and its binary blends with MCC will provide more comprehensive insights into the influence of the API’s PSD, morphology, and size ratio on the percolation threshold.

Conclusion: This study identified a critical percolation threshold around 20% drug load for Compound-X API in binary blends with Avicel® PH-102, where significant shifts in flowability and compression properties were observed. Understanding this threshold is crucial for optimizing drug loading in pharmaceutical formulations, ensuring desirable flow and compression characteristics while minimizing risks such as lamination. Further examination of the SDD properties and its interactions with MCC will enrich these findings and will further refine the application of the percolation threshold concept in formulation development.

Morphology of API and SDD Particles.

Summary of density, flowability, and compression parameters for API, Avicel® PH-102, and their binary blends, illustrating the effects of increasing API content.

Effect of drug loading on the tensile strength of tablets.