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Particle engineering using jet milling or spray drying can be used to obtain appropriate particle characteristics for inhalation drug products.
For pulmonary drug delivery, particle size (specifically the aerodynamic diameter) has a significant impact on lung deposition and retention in the different airway regions. Jet milling and spray drying are two particle engineering methods used to optimize particle properties. Pharmaceutical Technology spoke with Herbert Chiou, PhD, product development lead (inhalation & novel therapeutics), and Salvatore Mercuri, R&D Manager, both at Lonza Pharma & Biotech, about optimizing and scaling up micronization processes.
PharmTech: Jet milling is the conventional approach commonly used for mechanical micronization of drug particles for pulmonary delivery. Can you provide an overview of the different types of jet mills used?
Chiou and Mercuri (Lonza): Jet milling is the most common method used to produce particles in the 1–20 µm range, characterized by a narrow particle size distribution. Jet mills differ in configuration of the milling chamber (i.e., where the comminution takes place) and in particle classification system. Spiral or opposed jet mills are typical milling approaches, with both using fluid energy to achieve comminution through an impact breakage mechanism.
In spiral jet mills, the material, accelerated by a Venturi pipe, is fed into the milling chamber. High pressure gas (e.g., 2–10 bar) enters the low cylindrical milling chamber through many nozzles (e.g., 5–12) tangentially distributed around the peripheral walls. The gas expansion generates a spiral vortex in which the comminution takes place, due to particle-on-particle collisions. Particles in this flow field are subject to centrifugal and drag forces. Larger particles are dragged to the outer zone of the milling chamber, while small particles are exhausted from the central outlet with the gas stream.
The spiral jet mill gives a ‘static’ classification of the powder. The cut-off of the powder exhausted from the jet mill is related to the geometrical characteristic of the classification tubes and to the operating parameters applied (i.e., material feeding rate, feeding and grinding pressures).
In opposed jet mills, the grinding gas enters the mill via three or more coplanar nozzles situated at the bottom of the milling chamber. Subsequently, the powder particles entering the milling chamber via a double valve system are accelerated to high velocity and start to collide with each other. The milling gas is also responsible for a fluidizing effect that transports the particles to the upper part of the milling chamber where the classification takes place. In this case, a ‘dynamic classifier’ (i.e., classifier wheel) is used. Particles that are larger than the cut-off will be returned to the milling zone, whereas particles that are sufficiently small can be exhausted with the gas stream. The higher the speed of the classifier wheel, the lower the cut-off of the particles that can leave the jet mill.
The physical characteristics of the drug substance and the particle size to be achieved determine the choice of the most suitable jet mill configuration and the appropriate operating parameters.
PharmTech: What types of drugs are suitable for the jet milling approach?
Chiou and Mercuri (Lonza): Considering that, in jet milling, the comminution occurs due to particle-on-particle collisions, no specific requirements in terms of material hardness are needed. Jet milling is a suitable technique even for very hard materials. Despite this, the efficiency of the process and, consequently, the extent of the particle size reduction are correlated to the physico-chemical characteristics of the material. Plastic materials (e.g., thermoplastic polymers) are more difficult to micronize, compared to brittle and highly crystalline materials. Particle morphology also plays a crucial role in micronization applications; a needle or plate crystal can be fractioned more easily than an equant or prismatic crystal.
Thermolabile compounds can also be jet milled because the particles are accelerated by a gas stream under expansion. Therefore, no overheating of the material occurs, per the Joule–Thomson effect.
PharmTech: What considerations would lead to an alternative particle engineering approach, such as spray drying?
Chiou and Mercuri (Lonza): For product development of respiratory products, there isn’t a one-size-fits-all approach, but spray drying may be a tool to use when any of the following questions is applicable to the API:
Would the API have any interactions with the lactose carrier if it is blended? APIs containing amino groups could react with lactose, because it is a reducing sugar. Use of non-reducing sugars as carriers are being investigated and require rounds of studies to optimize the formulation with respect to release. With the spray drying approach, non-reducing sugars can be used as bulking agents in the formulation to dilute the API concentration and maintain uniformity.
Are there any concerns in mixing two APIs together uniformly through a blending process, especially if there is a significant difference in concentrations between the APIs? While uniform dry powder blends can be produced, the spray drying approach uses uniform solutions or suspensions and can typically achieve better content uniformity.
Does the API have physical stability concerns? With spray drying, it is possible to include excipients with high glass transition temperatures (i.e., glass formers) to limit long-range diffusional mobility.
Is there a flowability issue with a smaller particle size of the API? Would the issue be compounded if there is a high dose requirement? Sub-micron particles, which can be generated by processes like crystallization or jet milling, may be spray dried as a suspension to form slightly larger agglomerates (still in the respirable range), which have improved flowability but maintain a high surface area for improved solubility. Alternatively, particles may be engineered to be porous to achieve a certain aerodynamic particle size. There has also been work done with respect to using excipients, such as magnesium stearate, to act as a lubricant, but if the process of adding surface energy modifying agents does not provide the desired effect, physical shape would be the next option to consider.
PharmTech: What are the key considerations for a jet milling process? How do you determine optimal conditions?
Chiou and Mercuri (Lonza): The development of the jet milling process starts with the characterization of the unmilled material’s bulk properties (e.g., morphology, tap density, flowability) and with defining the milling behavior of the material. For this assessment, the operating parameters that can be varied are three-fold: material feeding rate, feeding pressure, and grinding pressures. In cases where the specifications are not achieved by adjusting the standard process parameters, the modification/assessment of the jet mill geometry (e.g., nozzle angle, shape of the milling chamber, size and length of the static classification system) is also taken into consideration.
This approach is particularly helpful in identifying the solution for achieving the required particle size distribution (PSD) while reducing/avoiding solid-state changes of the material. In fact, the impact of the micronization process on the solid state of the material has to be carefully assessed given the higher specific energy for comminution to reach the required PSD for pulmonary drug delivery, which is generally characterized by a Dv50 [median for a volume distribution] between 2–5µm.
The best approach to determine the optimal working conditions is to conduct a risk assessment with the customer to identify all the possible critical process parameters, such as the variability of the raw material size, the water content specifications, and the knowledge about the solid-state changes.
Following this step, a stress test and a short stability study (e.g., one week) can be performed to determine the impact of the specific energy on the solid state of the API and the impact of the contingent solid-state changes on the post-micronization stability of the API (e.g., particle size increase).
A screening design of experiments (DoE) potentially followed by an response surface methodology is generally used to properly define the design space and the normal operating range (NOR) for a particular API.
The last step of the development is usually to execute one or more confirmation runs to endorse the development results and also to evaluate the process variability by means of an intensive sampling protocol throughout the trial duration.
PharmTech: What are some of the considerations in scaling up a jet milling process?
Chiou and Mercuri (Lonza): The calculation of the scale-up factor for the main jet milling operating parameters (i.e., material feeding rate, feeding pressure, and grinding pressure) is performed, keeping constant the specific energy applied to the powder among the different jet mill sizes.
To scale up a micronization process developed through DoE approach, the best working condition defined from the design space analysis will be scaled up and tested on the commercial-scale jet mill. If PSD results (i.e., DoE responses or critical quality attributes) are included in the calculated confidence intervals, other working conditions need to be verified to confirm that the mathematical model used to describe the design space during development could be applied on the industrial-size jet mill.
To scale up a process developed applying a trial-and-error approach, the best working condition defined during the developmental work is scaled up and tested on the commercial-scale jet mill. If PSD results comply with the customer specifications, the ‘edges of failure’ of the process are assessed by varying the main operating parameters around the defined working point.
The size of the jet mill is usually defined, taking into consideration the volumes needed to be micronized at commercial scale and keeping in mind that it is not feasible to micronize under the critical pressure (i.e., related to the nozzle diameter and needed to achieve a sonic effect at the grinding nozzle outlet).
PharmTech: What are the key considerations in spray drying for dry powder inhaler (DPI) applications?
Chiou and Mercuri (Lonza): With spray drying for DPI applications, one has to evaluate the goal of the produced powder. For example, is the spray-dried powder the ‘complete’ formulation to fill or does the customer only need engineering of the API, which would later be mixed with a carrier? The answers to these questions help determine the loading of the active material in the final powder and which excipients (if any) to use. Another question to consider: is the material susceptible to moisture? In addition to packaging configuration, spray drying could incorporate excipients to help with moisture protection.
For most small molecules, a crystalline API is generally preferable to minimize any stability issues. However, in some cases, it may be preferable to have an amorphous API to increase the dissolution kinetics. Regardless of the particle engineering approach, particle size control is crucial for DPI applications.
PharmTech: What are some of the key considerations for scaling up a spray drying process for DPI applications?
Chiou and Mercuri (Lonza): At the feasibility stage of product development, it is recommended that a small-scale dryer is used to evaluate initial formulation screening to conserve API. Once the formulation selection has been made, larger quantities are required for toxicological studies, which require scaling. Is the feedstock composition aqueous or organic? Water-based feedstock has a lower throughput than feedstock containing mainly organic solvent. When scaling up, the atomization pressure, nozzle geometry, and feed rates would need to be evaluated in concert to generate approximately the same droplet size to ensure the product is as close to those formulated in the feasibility study.
For collection, cyclone separation is commonly used for both jet milling and spray drying, which separates particles based on aerodynamic diameter. As the particles are engineered to be entrained in the airways for pulmonary delivery, separation of the particles from the airstream for collection requires special attention to the cyclone geometries, internal velocities, and pressure drops to ensure high collection yields. High-efficiency cyclones need to be designed accordingly to be compatible with larger spray dryers during scale up, such that it does not impact the drying process.
PharmTech: What analytical testing tools are used to characterize the physicochemical properties of spray-dried or jet-milled micronized particles?
Chiou and Mercuri (Lonza): Standard physicochemical characterization techniques for drug substances still applies to engineered particles, and additional characterization techniques help guide product development. This understanding may also predict product performance and stability. Impurities, typically characterized by chromatographic methods, have to be evaluated to determine if the selected particle engineering approach is appropriate to the API and if it generates any degradants. As aerodynamic PSD significantly impacts lung deposition, understanding morphology and geometric PSD is crucial. Scanning electron microscopy, as well as optical microscopy coupled with particle imaging, can provide particle morphology information, while laser diffraction techniques provide the geometric particle size. Moreover, the aerodynamic assessment of inhalable powders is performed through the use of impactors.
Additional characterization includes techniques that allow researchers to study the impact of the process on the solid state of micronized/spray-dried materials. The energy involved in the process may induce amorphous formation and/or favor polymorphic transitions. Such solid-state modifications can be detected by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). In addition, isothermal microcalorimetry or dynamic vapor sorption (DVS) are used to determine amorphous content as well as susceptibility to moisture. Moisture content and residual solvents are also evaluated as the different processes can impact the final content.
PharmTech: What advances have you seen in particle engineering techniques and what areas are still lacking?
Chiou and Mercuri (Lonza): Jet milling and spray drying are well-established particle engineering techniques. Additional improvement in process control and optimization has occurred in the past few years.
From the equipment point of view, some advances in the application of computational fluid dynamics (CFD) and discrete element method (DEM) tools are allowing geometric optimization of jet mills and spray dryers to achieve either higher throughput or improved particle size classification.
We are also seeing advances in co-micronization of APIs and excipients that allow for advanced formulation properties with regards to the starting powder blends. Going forward, we see additional work towards combining jet-milling and spray-drying techniques to achieve beneficial formulation characteristics.
PharmTech: What do you see as needs or areas of research in the inhalation delivery space?
Chiou and Mercuri (Lonza): Due to the cost and time of human clinical studies, there is a drive to reduce risk; the pharmaceutical development team needs high confidence prior to committing to the API and subsequent human clinical study. There is ongoing research and advances in developing more clinically relevant techniques, such as using the Alberta Idealized Throat and human breath profiles; improved animal studies for understanding pharmacokinetics through improved delivery techniques with appropriate animal model selection; and in vivo-relevant dissolution models that could be used for screening formulations.
The next challenge is to find better ways to minimize patient errors and improve compliance. Human factors are being recommended by FDA for combination products, which includes inhalers. Particles for inhaled drug products may need to be engineered for delivery at low inspiratory flowrate for patients with compromised breathing, for example.
Vol. 42, No. 4
When referring to this article, please cite it as J. Markarian, "Optimizing Particle Engineering Methods for Inhalation Drug Products," Pharmaceutical Technology 42 (4) 2018.
Jennifer Markarian is manufacturing editor for Pharmaceutical Technology.