Solid amorphous dispersions are frequently used to improve the solubility and, thus, the bioavailability of poorly soluble active pharmaceutical ingredients (APIs). Spray-drying, a well-characterized pharmaceutical unit operation is ideally suited to producing solid amorphous dispersions due to its rapid drying kinetics. This paper describes a novel flowchart methodology based on fundamental engineering models and state-of-the-art process characterization techniques that ensure that spray-drying process development and scale-up are efficient and require minimal time and API. This methodology offers substantive advantages over traditional process-development methods, which are often empirical and require large quantities of API and long development times. The methodology is used from early formulation-screening activities (involving milligrams of API) through process development and scale-up for early clinical supplies (involving kilograms of API) to commercial manufacturing (involving metric tons of API). It has been used to progress numerous spray-dried dispersion formulations, increasing bioavailability of formulations at preclinical through commercial scales.
Spray-drying is a widely used unit operation for pharmaceutical applications. In addition to its use in preparing solid amorphous spray-dried dispersions (SDDs), spray-drying is used in excipient manufacture, pulmonary and bio therapeutic particle engineering, the drying of crystalline active pharmaceutical ingredients (APIs), and encapsulation.
In common practice, spray-drying process development is often empirical and is experimentally driven. Traditional methods often use an iterative design of experiments (DOE) or statistical treatment of the process parameters and resulting product attributes. This is often a time-intensive exercise, requiring large quantities of API, and the resulting process is often not well understood or sufficiently robust.
The spray-drying process is a well-established unit operation in the pharmaceutical industry. To manufacture an SDD, a spray solution—which consists of API and polymer dissolved in a common solvent—is delivered to an atomizer inside a spray-drying chamber concurrently with a hot drying gas. Organic solvents are typically used to produce SDDs because the API tends to be poorly water-soluble. Nitrogen drying gas is employed to provide an inert processing atmosphere when processing organic solvents. The spray solution is atomized into droplets using a spray nozzle. Many different types of spray nozzles can be used including two-fluid, ultrasonic, rotary, and pressure (or hydraulic) nozzles. Pressure nozzles are often preferred due to their simplicity, scalability, and ease of droplet-size tuning. When the spray-solution droplets contact the hot drying gas, the solvent in the droplets evaporates, leaving dried SDD particles entrained in the drying gas that exits the drying chamber. These particles are collected and then separated from the gas stream, usually by a cyclone separator.
Based upon an evaluation of the physicochemical properties of the API, several initial formulations (generally, two to four) are selected and screened in this step. A screening-scale spray dryer designed for maximizing yields from SDD batches of <100 mg is used. This dryer is not designed to replicate optimized bulk powder properties (e.g., particle size, density) of larger-scale spray dryers, but rather is used to match physicochemical properties for fast, efficient formulation-screening studies. Analogous to the process-development flowchart methodology, a formulation selection flowchart, comprising predictive physical-stability models, rapid chemical-stability screens, and bio relevant in vitro performance tests is key to selecting a lead SDD polymer and drug-to-polymer ratio. For the sake of brevity, these will not be addressed in this paper.
After a robust formulation has been identified, equipment-related and formulation-related process constraints are identified, resulting in definition of the drying-gas flow rate (M gas) and drying-gas inlet temperature (T in).
The thermodynamic operating space described above defines the process based upon near-equilibrium assumptions and does not account for kinetic limitations such as the drying of large droplets or increased drying resistance due to film formation at the droplet surface. Drying kinetics of single droplets can be studied experimentally, but the information provided—while useful—does not account for the actual conditions in the spray dryer such as droplet velocity and momentum exchange between the droplets and the drying gas.
Many aspects of this approach can be directly translated to other atomization/evaporative processes, such tablet-coating and fluid-bed processes. A similar strategy can also be applied to many other pharmaceutical-processing unit operations.
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