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.
Spray-dried formulations of a hydrophobic, crystalline drug, GDC-A, were prepared using the suspension-PulmoSphere™ technology. Increases in drug loading resulted in decreases in the primary particle ...size distribution and increases in tapped density. This enabled fine particle doses of up to 25 mg to be achieved with a portable dry powder inhaler from a size three capsule. The powders were physically and chemically stable, with no changes in physical form or degradants observed during processing or on storage in an open configuration at 40°C for 1 month. The potential benefits of the suspension-based spray drying process relative to solution-based spray drying in terms of stability, lung targeting, and safety/tolerability are discussed.
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Continuous tablet manufacturing has been investigated for its potential advantages (e.g., cost, efficiency, and controllability) over more conventional batch processes. One avenue for tablet ...manufacturing involves roller compaction followed by milling to form compactible granules. A better understanding of these powder processes is needed to implement Quality by Design in pharmaceutical manufacturing. In this study, ribbons of microcrystalline cellulose were produced by roller compaction and milled in a conical screen mill. A full factorial experiment was performed to evaluate the effects of ribbon density, screen size, and impeller speed on the product size distribution and steady-state mass holdup of the mill. A population balance model was developed to simulate the milling process, and a parameter estimation technique was used to calibrate the model with a subset of experimental data. The calibrated model was then simulated at other processing conditions and compared with additional unused experimental data. Statistical analyses of the results showed good agreement, demonstrating the model’s predictive capability in quantifying milled product critical quality attributes within the experimental design space. This approach can be used to optimize the design space of the process, enabling Quality by Design.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A method of spray modeling and measurements for pharmaceutical pan tablet coating applications is proposed. It consists of (1) spatially resolved spray characterization and (2) computational ...predictions of subsequent spray evolution using CFD. Both (1) and (2) are in line with PAT guidelines that emphasize process understanding and analytical process design. (1) utilizes a dual-mode Phase Doppler Anemometry (PDA) system. Data are obtained at multiple points covering the entire spray cross-sectional area. Measurements are validated by ensuring that PDA-measured mass flowrate matches measured mass flowrate and by comparing PDA-calculated absorptances to the optical patternator measured ones. Experimental data show that drop size, velocity, and volume flux vary spatially throughout a spray cross-sectional area. Spatial variation in size and velocity do not significantly change with variations in spraying parameters. Drop size decreases with an increase in atomizing/shaping air pressure, a decrease in liquid supply rate, and a decrease in formulation concentration (viscosity). Drop velocities increase with an increase in atomizing air pressure, a decrease in liquid supply rate, a decrease in formulation concentration, and a decrease in gun-to-target distance. In contrast to size and velocity distribution, spatial variation in volume flux is sensitive to changes in operating conditions. For elliptical sprays, an increase in shaping air pressure and an increase in liquid viscosity lead to the development of a dumbbell-shaped pattern. Increasing atomizing air pressure narrows the spray whereas increasing liquid supply rate produces a more elliptical spray. On the contrary, volume flux distributions for round sprays are significantly less sensitive to changes in either operating conditions or liquid viscosity. (2) utilizes a commercially-available CFD package to predict how sprays evolve under drum coater conditions. Results show that drum rotation induces gas swirling that transports small drops away from the spray zone. It also lengthens the spray. Drying air promotes spray evaporation, therefore reducing local drop number density. Furthermore, since drying air enters from the top of the drum, it pushes the spray downward, leading to spray patterns that resemble the letter ‘C’. Drying air flow also helps reduce the effects of drum rotation on spray evolution by providing droplets with additional axial momentum. The additional momentum in turn increases droplet velocities. Computed drop sizes and drop velocities generally agree well with measured data, but ∼46% difference is observed when comparing measured and computed volume flux magnitude. Measured volume flux data, however, are likely less accurate due to the systematic limitations of the standard (Fiber) PDA system. Results from (1) provide a comprehensive understanding on how changes in atomizer operational parameters influence spray characteristics and patterns, and on how drum coater parameters (drying air flow and drum rotational speed) influence the spray evolution process. Results from (2) provide a means to model spray evolution in the drum coater and to reinforce process understanding, particularly for the influence of drum rotation on drying air flow, and for the influence of process variables on spray pattern.
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