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.

Phase-appropriate Application of Process Analytical Technology for Early Pharmaceutical Development of Oral Solid Dosage Forms-the Case Study of Uniformity Screening of Dosage Units and Blends.

Process analytical technology (PAT) in late-stage drug product development is typically used for real-time process monitoring, in-process control, and real-time release testing. In early research and development (R&D), PAT usage is limited as the manufacturing scale is relatively small with frequent changes and only a few batches are produced on an annual basis. However, process understanding is critical at early R&D in order to identify process and formulation boundaries, so PAT applications could be particularly useful in early-stage R&D. For oral solid dosage form, conventional HPLC-based content uniformity (CU) methods with sampling of 3 tablets per stratified sampling location in early R&D are typically not sufficient to identify these manufacturing process boundaries and temporal profile. Here, we report a screening CU method based on a multivariate model using transmission Raman spectroscopy (TRS) data on a phase-appropriate calibration set of only 16 tablets. This initial model was used for multiple pre-GMP development batches to provide critical information about blend uniformity and content uniformity (CU). In this work, the precision of the TRS method was evaluated; multiple spectral preprocessing approaches were compared regarding their effects on measurement precision as well as their ability to mitigate the photo bleaching effects during precision experiments. Overall, the TRS-based CU method was much faster than a traditional HPLC-based method allowing a much larger number of tablets to be screened. This larger number of analyzed tablets enabled the processes boundaries and temporal changes in CU to be identified while providing proper statistical assurance on product quality.

Numerical analysis of die filling with a forced feeder using GPU-enhanced discrete element methods.

Understanding die filling behaviour of powders is critical in developing optimal formulation and processes in various industries, such as pharmaceuticals and fine chemicals. In this paper, forced die filling is analysed using a graphics processing unit (GPU) based discrete element method (DEM), for which a powder feeder equipped with a wired stirrer is considered. The influences of operating parameters, such as the initial powder bed height, the filling speed, and the stirrer speed, on the die filling performance are systematically explored. It is shown that a larger initial powder bed height leads to a higher filling ratio, which can be attributed to a higher filling intensity; while the deposited particle mass in the die is almost independent of the powder bed height, when the initial fill level is larger than a critical bed height. Additionally, the filling ratio slightly increases with the increase of stirrer speed for cases with a stirrer, while the filling ratios are lower than that without a stirrer, which is attributed to the stirrer occupying some space above the die and reducing the effective discharge area. The obtained results can provide useful information for optimising the feeder system design and the operating condition.

Capsule-Based dry powder inhaler evaluation using CFD-DEM simulations and next generation impactor data.

Capsule-based, single-dose dry powder inhalers (DPIs) are commonly-used devices to deliver medications to the lungs. This work evaluates the effect of the drug/excipient adhesive bonding and the DPI resistances on the aerosol performance using a combination of empirical multi-stage impactor data and a fully-coupled computational fluid dynamics (CFD) and discrete element method (DEM) model. Model-predicted quantities show that the primary modes of powder dispersion are a function of the device resistance. Lowering the device resistance increases its capacity to transport a wider range of particle size classes toward the outlet and generate more intense turbulence upstream therein. On the other hand, a higher device resistance increases the velocity of the tangential airflow along the device walls, which in turn increases the intensity of particle/device impaction. Correlating model data and experimental results shows that these differing powder dispersion mechanisms affect different formulations differently, with finer aerosols tending to result when pairing a lower resistance device with formulations that exhibit low API/excipient adhesion, or when pairing a high resistance device with more cohesive formulations.

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.

Simplifying Johanson's roller compaction model to build a "Virtual Roller Compactor" as a predictive tool - Theory and practical application.

The purpose of the study is to build a "virtual roller compactor" as a predictive tool to assess the roll force (RF)-maximum pressure (Pmax) and RF-ribbon density relationship for pharmaceutical roller compaction. We provided a theoretical basis to demonstrate that, there exists a critical nip angle for a pharmaceutical powder, beyond which the RF-Pmax relationship is insensitive to wall friction angle or effective angle of internal friction. We showed that for most pharmaceutical roller compaction, the critical nip angle is lower than 17 degree, and can be exceeded via wall friction elevation, using rolls with non-smooth surface. Under this condition, the original Johanson model can be substantially simplified to a single equation requiring only one material property (compressibility). By performing manufacturing-scale roller compaction using materials with diverse compressibility, we showed that the simplified, friction angle-free model performed similar to the original Johanson model. It can predict the RF-Pmax and RF-ribbon density relationship well after applying a correction factor. The predictive tool, in the form of a user-friendly graphical user interface, was created based on the simplified model. The tool was adopted for in-house, bench-scale formulation development and scale-up because of its ease-of-use, good predicting capability, and very low material demand.

Impact of Method of Preparation of Amorphous Solid Dispersions on Mechanical Properties: Comparison of Coprecipitation and Spray Drying.

Usage of the amorphous phase of compounds has become the method of choice to overcome oral bioavailability problems related to poor solubility. Due to the unstable nature of glasses, it is clear that the method of preparation of the amorphous glass will have an impact on physical/chemical stability and in turn in vivo performance. The method of preparation can also have a profound impact on the mechanical properties of the amorphous phase. We have explored the impact of preparation method on the mechanical properties of an amorphous solid dispersion using a development compound, GDC-0810. Three methods were used to generate amorphous solid dispersions (ASDs) of 50% GDC-0810 with hydroxypropyl methylcellulose acetate succinate: (1) spray drying, (2) coprecipitation using overhead mixing, and (3) coprecipitation using resonant acoustic mixing. All 3 methods were found to generate ASDs with good phase mixing and similar glass transition temperatures. Coprecipitated ASD powders (overhead mixing and resonant acoustic mixing) demonstrated superior tabletability and flow properties when compared to the spray drying powder. Careful choice of manufacturing process can be used to tune material properties of ASDs to make them more amenable for downstream operations like tableting. Acoustic mixing has been demonstrated as a scalable new method to make ASDs through coprecipitation.

Evaluation of three approaches for real-time monitoring of roller compaction with near-infrared spectroscopy.

Three different approaches have been evaluated for monitoring ribbon density through real-time near-infrared spectroscopy measurements. The roll compactor was operated to produce microcrystalline cellulose (MCC) ribbons of varying densities. The first approach used the slope of the spectra which showed a variation through the ribbon that could be attributed to density. A second qualitative approach was also developed with a principal component analysis (PCA) model with spectra taken in-line during the production of ribbons in an ideal roll pressure range. The PCA (i.e., real-time) density scans show that the model was able to qualitatively capture the density responses resulting from variation in process parameters. The third approach involved multivariate partial least squares (PLS) calibration models developed at wavelength regions of 1,120-1,310 and 1,305-2,205 nm. Also, various PLS models were developed using three reference methods: caliper, pycnometer, and in-line laser. The third approach shows a quantitative difference between the model-predicted and the measured densities. Models developed at high-wavelength region showed highest accuracy compared with models at low-wavelength region. All the PLS models showed a high accuracy along the spectra collected throughout the production of the ribbons. The three methods showed applicability to process control monitoring by describing the changes in density during in-line sampling.

Nondimensional scaling laws for controlling pharmaceutical spray uniformity: understanding and scale-up.

Spatially resolved drop size, drop velocity, and spray volume flux measurements for sprays produced by a commonly used pharmaceutical coating nozzle were performed in this study. Results showed three distinctive spray patterns: Gaussian, homogeneous, and dumbbell shaped. We found that transition from a dumbbell-shaped to a homogeneous pattern is related to the shaping air-induced breakup of already formed drops: depending on the drop size upstream of the location where the shaping air flows meet (i.e., the "junction" point), the drop viscosity, and the magnitude of the shaping air velocity, the shaping air can either pinch the spray or cause additional drop breakup. When the former outweighs the latter, the dumbbell-shaped pattern occurs; the homogeneous pattern is present when the opposite occurs. A corollary to this experimental interpretation is that whether additional drop breakup homogenizes the sprays or pinches, it is related to a Weber number (We) that is calculated using drop sizes upstream of the junction point, drop viscosity and surface tension, and the shaping air velocity at the junction point. With this idea in mind, we propose a We-based scaling method for optimizing the uniformity of air-assist spray patterns.