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.     

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.     

Population Balance Model Validation and Predictionof CQAs for Continuous Milling Processes: toward QbDin Pharmaceutical Drug Product Manufacturing

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.