Ariel R. Muliadi

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.

A Comparison of Phase Doppler Analyzer (Dual-PDA) and Optical Patternator Data for Twin-Fluid and Pressure-Swirl Atomizer Sprays

The goal of this study was to determine when patternation information derived from Phase Doppler Analyzer (Dantec Dynamics, Skovlunde, Denmark, dual-PDA) measurements of volume flux, drop velocity, and mean size agreed with corresponding values measured using an optical patternator (Enurga, Inc., West Lafayette, IN, SetScan OP-600). To achieve this, data from each instrument were transformed into spatially resolved absorptances (equivalent to drop surface area per unit spray volume) and compared. Key conclusion is absorptance agreement to within 20% in many cases. However, discrepancies between phase Doppler analyzer (PDA)-calculated and optical patternator-measured absorptances become larger as the drop arrival rate increases, as the mean drop size decreases, and when a significant drop size-velocity correlation is present. These discrepancies are attributed to an underestimation of the volume flux (which becomes more important with increasing droplet arrival rate), an over-reporting of the mean drop diameter (which is the result of the restrictive data acquisition scheme applied when ensuring mass closure for the PDA measurements), the limited PDA dynamic range (which can preclude simultaneously accounting for both the largest and smallest drops in the spray), and by the optical patternators number-density based measurement scheme (which will not yield the same results as the flux-based PDA when a drop size-velocity correlation is present).

Comparison of Particle Dynamics Analyzer (PDA) and SetScan Optical Patternator Results

The primary goal of this study was to determine when patternation information derived from Particle Dynamics Analyzer (Dantec Dynamics dual-PDA) measurements of volume flux, velocity and mean drop size agreed with corresponding values measured using an optical patternator (En’Urga, Inc SetScan OP-600). To achieve this, data from each instrument was transformed into spatially resolved absorptances (equivalent to drop surface area per unit volume) and compared. The secondary goal of this study was to explain the cause of any discrepancies in comparison of the two absorptance sets when they occurred. Key conclusions drawn from this study are: absorptance agreement to within 20% can be achieved in many cases; however, the difference between the PDA-calculated and optical patternator-measured absorptances becomes larger as the drop arrival rate increases, as the drop size decreases, and when a significant drop size-velocity correlation is present. These discrepancies are attributed to an underestimation of the volume flux (which becomes more important with increasing droplet arrival rate), an over-reporting of the mean drop diameter (which is the result of the restrictive data acquisition scheme applied when ensuring mass closure), the limited PDA dynamic range (which can preclude simultaneously accounting for both the largest and smallest drops in the spray), and by the optical patternator’s number-density based measurement scheme (which will not yield the same results as the flux-based PDA when a drop size-velocity correlation is present).Copyright

Evaluation of Spray Characteristics in Pharmaceutical Tablet Coating Processes: The Influences of Drum Rotational Speed and Drying Air Flow Rate

In this study, drop size, velocity, and volume flux for sprays produced by a pharmaceutical nozzle (Spraying Systems 1/4-JAU-SUE15A-PA67288–45°-SS) were characterized using a Fiber-PDA system (Dantec). Spraying was performed in a 120 cm (24 in) diameter tablet pan-coater (Accela-Cota Model 10, Thomas Engineering, UK). The separate influences of drum rotational speed and drying air flow rate were studied by making measurements at four different pan-coater operating conditions: stationary drum with drying air turned on/off, and 8 rpm rotating drum with drying air turned on/off. For each case, four different spraying conditions (liquid supply rate and atomizing air pressure) were used. PDA scans were performed along the spray semi-major and semi-minor axes at two different axial distances (7.5 and 10 cm) from the atomizer tip. Results were as follows. When both the drying air and drum rotation were absent, increasing liquid supply rate while operating the atomizer at the lower of two atomizing air pressures decreased drop size. The opposite occurred when operating at the higher of the two atomizing air pressures. This suggests that the nozzle operated as a simplex pressure-swirl atomizer at lower levels of atomizing air pressure, but as an air-assist atomizer at higher levels of atomizing air pressure. Regardless, liquid supply rate had no significant effect on drop velocity. In contrast, a decrease in atomizing air pressure or an increase in axial distance always led to an increase in drop size and a decrease in drop velocity. Supplying drying air to the pan-coater resulted in up to a 6 m/s increase in drop velocity, but had mixed effects on drop size. When the spray gun was operated as an air assist atomizer, supplying drying air to the drum led to an increase in D32 . The reverse was observed when the gun operated as a simplex pressure-swirl atomizer. These two observations are most evident when operating at the lower liquid supply rate (70 g/min), suggesting that they may have arisen from drop evaporation. Increasing the drying air supply rate also reduced spray extent and volume flux magnitude. Adding drum rotation to the process generally led to (i) increased drop size and (ii) increased drop velocity. (i) likely arose from the transport of small drops away from the spray zone, while (ii) likely resulted from changes in droplet trajectories. Both are the result of the gas-phase swirling motion that is due to the drum rotation. (i) was most noticeable when the nozzle was operated as an air-assist atomizer. In addition, drum rotation decreased spray volume flux magnitude at the spray center, but increased it at other locations, essentially making the spray more dumbbell-shaped. Finally, the influence of drum rotation on drop velocity diminished when drying air flow was included. This was because the drying air momentum helped the drops oppose the effects of the swirling flow induced by the drum rotations.Copyright