Assessing the Interrelationship of Microstructure, Properties, Drug Release Performance, and Preparation Process for Amorphous Solid Dispersions Via Noninvasive Imaging Analytics and Material Characterization.

PURPOSE: The purpose of this work is to evaluate the interrelationship of microstructure, properties, and dissolution performance for amorphous solid dispersions (ASDs) prepared using different methods. METHODS: ASD of GDC-0810 (50% w/w) with HPMC-AS was prepared using methods of spray drying and co-precipitation via resonant acoustic mixing. Microstructure, particulate and bulk powder properties, and dissolution performance were characterized for GDC-0810 ASDs. In addition to application of typical physical characterization tools, we have applied X-Ray Microscopy (XRM) to assess the contribution of microstructure to the characteristics of ASDs and obtain additional quantification and understanding of the drug product intermediates and tablets. RESULTS: Both methods of spray drying and co-precipitation produced single-phase ASDs. Distinct differences in microstructure, particle size distribution, specific surface area, bulk and tapped density, were observed between GDC-0810 spray dried dispersion (SDD) and co-precipitated amorphous dispersion (cPAD) materials. The cPAD powders prepared by the resonant acoustic mixing process demonstrated superior compactibility compared to the SDD, while the compressibility of the ASDs were comparable. Both SDD powder and tablets showed higher in vitro dissolution than those of cPAD powders. XRM calculated total solid external surface area (SA) normalized by calculated total solid volume (SV) shows a strong correlation with micro dissolution data. CONCLUSION: Strong interrelationship of microstructure, physical properties, and dissolution performance was observed for GDC-0810 ASDs. XRM image-based analysis is a powerful tool to assess the contribution of microstructure to the characteristics of ASDs and provide mechanistic understanding of the interrelationship.

The effect of unloading and ejection conditions on the properties of pharmaceutical tablets.

This study investigates decompression and ejection conditions on tablet characteristics by comparing compact densities and tensile strengths made using regular rigid dies and custom-built die systems that enable triaxial decompression. Die-wall pressure evolution during decompression and ejection stresses did not meaningfully impact the density and tensile strength of the materials tested: microcrystalline cellulose, crystalline lactose monohydrate, and mannitol. Furthermore, the apparent differences in tensile strength between rectangular cuboids and cylindrical compacts are unrelated to decompression and ejection conditions, but rather a consequence of their shapes and of the test configurations. This suggests that elastic and plastic deformations that may occur during decompression and ejection are not significantly influenced by die-wall pressure evolution. We thus conclude that while triaxial decompression and constraint-free ejection may allow the production of defect-free compacts for materials that otherwise are defect prone using a rigid die, they seem to pose no benefits when the materials already produce defect-free compacts using a rigid die.

Beyond Brittle/Ductile Classification: Applying Proper Constitutive Mechanical Metrics to Understand the Compression Characteristics of Pharmaceutical Materials.

Active pharmaceutical ingredients (API) and excipients are often classified as 'brittle' or 'ductile' based on their yield pressure determined through the Heckel analysis. Such a brittle/ductile classification is often correlated to some measure of elasticity, die-wall stresses, and brittle fracture propensities from studies performed with a handful of model excipients. This subsequently gives rise to the presumption that all ductile materials behave similarly to microcrystalline cellulose (MCC) and that all brittle materials to lactose, mannitol, or dicalcium phosphate. Such a 'one-size-fits-all' approach can subsequently lead to inaccurate classification of APIs, which often behave very differently than these model excipients. This study compares the commonly reported mechanical metrics of two proprietary APIs and two classical model excipients. We demonstrate that materials classified as 'ductile' by Heckel's 'standards' may behave very differently than MCC and in some cases may even have a propensity for brittle failure. Our data highlight the complexity of APIs and the need to evaluate a set of mechanical metrics, instead of binary assignments of ductility or brittleness based on quantities that do not fully capture the tableting process, to truly optimize a tablet formulation as part of the overall target product profile.

Impact of drug loading on the compaction properties of itraconazole-PVPVA amorphous solid dispersions.

The impact of drug loading on the compaction properties of itraconazole (ITZ)- poly(vinylpyrrolidone-co-vinyl-acetate) (PVPVA) amorphous solid dispersions (ASDs) was studied. Neat amorphous ITZ, amorphous PVPVA, and their ASDs from 20% to 80% ITZ loadings were prepared by spray drying. Physical characterization showed that all powders have comparable particle size and morphology. All samples were equilibrated under 33% RH prior to compaction studies using a compaction simulator. Tabletability and compactability profiles of the ASD powders differed significantly, while their compressibility was similar. At compaction pressures from 50 to 150 MPa, tensile strength of ASD compacts increased with the increase of ITZ loading, reaching to the maximum at 40-60% ITZ loadings and then decreased as ITZ loading further increased. However, at the compaction pressure of 200 MPa, a monotonic decrease of tensile strength with the increase of ITZ loading was observed. In addition, except for the ASD with 20% ITZ loading, the detrimental effect of compaction pressure on tensile strength was observed at pressures at or above 150 MPa. Overall, this work highlights the importance of evaluating the compaction properties of ASD intermediates prior to downstream tablet development, especially if a high drug loading ASD is desired.