Mix and match: milling options for inhalation products

To ensure proper delivery, inhalation products require APIs and carriers to be sized precisely and mixed carefully. Hosokawa Micron reviews the mixing and size reduction technologies available

315 UPZ Fine Impact Mill

In formulations for inhalation, the importance of achieving the correct particle sizes, both for the API and the carrier (which are each required at different sizes), cannot be underestimated and with a number of equipment options it is essential to consider all aspects of the materials involved and the final product requirements.

Dry-powder inhaler formulations typically comprise a carrier substance and active pharmaceutical ingredient (API). Additives are often required to enhance product properties, such as flowability or to support the mechanical bonding of carrier with API.

The carrier material, typically lactose, represents a high proportion of the final product and is often required to be of coarser particle size in the range of 40–200μm. The API is only a tiny percentage of the inhalable formulation and needs to be of finer particle size, usually in the single micron range. API powders are often cohesive with poor flow properties and are sometimes required in a tight particle size distribution. Consideration must be given to the amorphous content of the API.

A high shear blender – the 5 litre Cyclomix

The actual manufacturing process, including crystallisation and drying, cannot be sufficiently controlled and influenced to achieve the required particle size, which necessitates additional steps – for example de-agglomeration after the dryer or real grinding, to achieve the right particle size for inhalation.

Particle size is considered to be the single most important design variable of a DPI formulation, making it especially important to characterise the different powders to be processed when choosing milling equipment. Product properties such as hygroscopicity, flow properties and bulk density, among others, influence which types of mill are suitable.

The spiral jet mill is the most common jet mill used for micronisation of fine particles in pharmaceutical industry. The particles fed to the grinding chamber are crushed by collision with each other and the walls of the grinding chamber. With no movable parts or drives the mills are easy to inspect and clean. In addition, they generally do not create heat during grinding, which makes them ideal for use with heat sensitive pharmaceutical powders. Spiral jet mills are available in many sizes, depending on required capacities or batch sizes.

Opposed-jet mills

Alternatively, the opposed-jet mill can be used. In this case, product is fed to the mill gravimetrically and falls into the grinding chamber where the particles are accelerated by the fast gas stream and grinding takes place by particle to particle collision.

The ground particles are offered to the integrated air classifier. The air/gas flow has to go through the lamellae. The particles are subject to two forces. The drag force of the air – and the centrifugal force of the classifier wheel. Fine particles rise with the air whereas coarse particles are rejected by the classifier and drop back into the mill. High classifier speed means fine end product and low speed means coarser product. These classifiers are typically most suitable for particle sizes in the range 5–150µm.

Flowability of the carrier

The carrier material is often lactose. To achieve the required properties such as the optimum flowability, the particle size distribution (for the carrier as well as for the API) is crucial. Depending on the type of applicator, the optimum fineness might be in the range of 40μm or can be up to 200μm. High fine dust content is normally not allowed and therefore the production of the carrier is often a combination of milling, classifying and sometimes blending steps. The fact that the carrier material is mostly coarser than the API requires typically a different mill type.

The difference with the various fluid energy impact mills used for the API compared with those used for the carrier is that the speed to which the carrier particles are accelerated is much lower, therefore the achieved particle size is coarser. Those mills are suitable for medium range finenesses and the advantage is that they can be equipped with a number of different grinding tools suitable for different products and requirements.

As an example, pin mills are used for fine grinding of lactose. Typical finenesses are around 300μm and the typical maximum fineness with lactose is around 90% <75μm.

The 200ZPS Classifier Mill

When steeper particle size distribution or higher-end fineness is required, an impact mill with an integrated air classifier might have advantages. Inhalers should not contain high levels of fine dust and this very often necessitates a second classifying step to remove the very fine end of the particle size distribution. The principle is more or less the same. The material is gravimetrically fed to the classifier from the side or from the top. There is an airflow created by a blower. The feed material will be dispersed in air/gas and then offered to the classifier. Coarse material will be rejected and will drop to the bottom where the coarse fraction (in this case the final product) is collected. The fine fraction will leave the classifier and is separated by a filter.

Stable formulations

The finely ground API is blended with carrier particles (excipients) which are prepared with a defined surface area and surface energy. To achieve an even layering of API particles, an appropriate blender with the correct operational parameters needs to be selected. This allows for the proper handling (transportation, storage and dosing) of the API, which is typically a cohesive powder and normally fairly difficult to work with, especially in the small quantities needed. Phenomena related to the interaction between the carrier particles and the API play an important role in the final quality of the product.

The blending properties and surface characteristics of the carrier particles will affect the bonding between API and the carrier

The blending properties and surface characteristics of the carrier particles will affect the bonding between API and the carrier. The flowability of the formulated material, as well as the fluidisation properties together with the entrainment and separation characteristics determine the physical behaviour of the formulation in the inhaler device.

To obtain the right formulation a balance has to be found that creates sufficient mixing energy to disperse the API, as single particles within the bulk carrier particles yet, on the other hand, not too high to lead to possible damage of the carrier particles creating undesirable variations in the product characteristics. Similarly, the bonding of the API particles onto the surface of the carrier particles has to be sufficiently strong to form a stable formulation. Just as with the mixing, the bonding strength has to be such that while providing the proper handling characteristics it also is capable of releasing the API while being inhaled, so that the API is delivered as required.

Hence, this will necessitate a dedicated mixing process as well as a proper selection and manipulation of the powder properties associated with the DPI formulation. The overall mixing mechanism takes care of the distribution of one component within the other. The ability to transport particles throughout the mixture is key. Optimal mixing is achieved when the different components can randomly be distributed.

In summary, the advantages of a high intensity impact and shear mixer include the following:

  • Perfect dispersion of fines due to the combination of impact and shear mixing
  • Accurate temperature control with jacketed vessels
  • Rounding-off or densification of particles possible
  • Single layer coating achievable
  • Create homogeneous mixture without lumps
  • Reproducible processes
  • With the conical design vessel, filling rates between 30-100%
  • Full discharge through the central bottom discharge valve
  • CIP and SIP able designs.
A high shear blender – the 5 litre Cyclomix 315 UPZ Fine Impact Mill The 200ZPS Classifier Mill

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