(155f) A Mechanistic Powder Tabletability Equation: Formulating Hot Melt Extrusion Amorphous Solid Dispersion Tablets

A mechanistic powder tabletability equation is applied to showcase its ability to guide the development of Hot Melt Extrusion Amorphous Solid Dispersions by incorporating physical particle properties into the prediction of tablet tensile strength based on the bonding strength and bonding number. This investigation aims to establish insights between the interplay of particle and material properties including primary particle size, Sauter mean diameter, surface energy, Young’s modulus, and poison ratio to calculate the bonding strength and bonding number with tablet porosity and compaction pressure. Amorphous Solid Dispersions (ASD) are a promising path forward to increase the bioavailability of active pharmaceutical ingredients, yet fundamental understanding lacks for the creation of its high-performance solid dosage forms. The primary objective of this study is to quantitatively assess and validate the concept of bonding strength and bonding number based mechanistic powder tabletability equation. To achieve this, the study will adapt a particle adhesion force model for calculating bonding strength and employ a particle coordination number approach to calculate bonding number of a single component. There are two fitting parameters, plastic parameter k and corrected contact number c are related to powder ductility tendency and contact area after compression, respectively. By leveraging the properties of the particles and specific tablet dimensions, the study aims to establish formulation guidelines. The proposed model is expected to serve as a valuable resource, offering guidance for rational excipient design, rational formulation design, and in subsequent work, estimates of the highest possible drug loading.

Griseofulvin (GF; Letco Medical, Decatur, AL, USA) was used as the model Biopharmaceutics Classification System (BCS) class II drug and processed with PVPVA (Kollidon VA 64, a vinylyrrolidone-vinyl acetate copolymer, BASF, New York, NY) at 0%, 10%, and 50% GF loadings (w/w). Moreover, formulated tablets were prepared with 3 grades of Microcrystalline Cellulose Avicel: PH-105, PH-101, and PH-102 (FMC Corporation, St. Louis, MO) as a binder, Sodium Chloride (Sigma Aldrich St. Louis, MO), to reduce gelling, and Kollidon CL (BASF, New York, NY) as a disintegrant.

HME was performed with a 11 mm diameter co-rotating twin-screw extruder (Thermo Fisher Scientific, Waltham, MA). A temperature profile of 210C was selected.

Extrudates were milled: 1) electric burr grinder (DBM-8P1, Cuisinart, Stamford, CT) at the finest grinding setting and 2) Fluid Energy Mill with a feed rate of 1 g/min, feed pressure of 75 psi, and grind pressure of 70 psi. Sieve cuts were taken: < 45, 45 – 75, 75 – 125 μm.

Solid state characterization was performed on the milled extrudates after both milling steps via X-Ray Powder Diffraction (XRPD) (PANalytical, Westborough, MA).

The 100 mg tablets were prepared with a Gamlen D1000-series tablet press (Gamlen Tableting) with a 6mm single punch die set with five replicates each. The tablet breaking force was measured with Gamlen TTA.

The milled extrudates were characterized with XRPD after both milling steps to verify lack of crystalline content for all drug loadings of GF/PVPVA extrudates.

The tabletability behavior of three particle size sieve cuts of neat milled extrudates, < 45, 45 – 75, 75 – 125 μm for GF/PVPVA system with drug loadings of 0%, 10%, and 50% shown. A novelty of this model is demonstrated by the ability to vary system parameters such as particle size distribution for a given material and develop a mechanistic understanding of the tabletability profile. Thus, this can aid in determining the optimal particle size for the desired tablet mechanical properties. Each MCC grade resulted in increased tensile strength with rising compaction pressure and closely aligned with the experimental tensile strength after c was determined. A mechanistic mixing rule was implemented to determine the corrected contact number for the blend solely based on the individual component’s corrected contact number and its particle properties. Thus, the predicted tabletability curve can be predicted for a range of ASD loadings, particle size, and tablet porosities.

The particle size of milled extrudates and MCC grades were systematically evaluated to determine the optimal particle size for sufficient tablet tensile strength without excessive particle size reduction for a given drug loading.