Micronization as a Bioavailability Enhancement Tool

Published on: 

Pharmaceutical Technology Europe spoke with Piero Iamartino, R&D director at Micro-Macinazione, about the role of micronization in pharmaceutical manufacturing.

Poor bioavailability is often a result of poor solubility. One way to enhance the solubility of a drug and increase its dissolution rate in the gastrointestinal tract is to reduce the particle size, which consequently increase the total surface area. There are several methods to reduce particle size.

Pharmaceutical Technology Europe spoke with Piero Iamartino, R&D director at Micro-Macinazione, about the role of micronization in pharmaceutical manufacturing.

“In spite of its status as an ‘old technology,’ introduced more than 50 years ago, micronization is still recognized as a valuable approach for increasing bioavailability of oral dosage forms when particle size of the synthesized API is among the solubility-limiting factors,” explains Iamartino. “In particular, micronization can be considered a viable option when the API is required to be kept in its crystalline form for an effective formulation process. In fact, the amorphization process is negligible when normal operating conditions are applied.” The decision to use micronization is based on whether or not the increase in surface area produces the desired level of bioavailability, Iamartino points out.

PTE: What are the advantages of micronization compared to other solubility/bioavailability enhancement techniques?

Iamartino: Micronization is an extremely versatile process, which can be easily applied to drug substances showing different chemical characteristics, because it acts only on their physical profile, reducing their particle size by applying a jet of fluid (nitrogen) without using any mechanical tool. Drug substances exhibiting poor thermal stability may benefit from micronization. The use of nitrogen (at a controlled temperature) and the short processing time do not expose drug substances to any significant heat.

Micronization is a straightforward process requiring rather simple equipment (jet mills), which allows an easy industrial scale up and offers a cost-effective manufacturing process.

PTE: Can you talk us through the different micronization techniques?

Iamartino: Fluid jet mills are used for running a micronization process. Two techniques are currently applied based on the different configurations of the milling chamber, the fluid-dynamic conditions applied, and the particle classification system in place.

In spiral jet mills, a supersonic vortex of powder is generated by the fluid entering through many nozzles distributed around a low cylinder chamber. Particle size reduction occurs mainly by collision between particles, as a function of fluid pressure, powder feeding rate, and the shape of the chamber. A certain degree of particle size selection can be achieved through the configuration of the outlet device.

In opposite jet mills, a fluidized powder bed is generated by the fluid entering through three nozzles installed in opposite positions at the bottom of a high cylinder chamber. Particle size reduction always occurs by collision between particles, as a function of the key operating parameters. In this case, a dynamic classifier (rotating basket) is installed at the outlet of the chamber, allowing a certain degree of particle size selection based on the rotating speed applied.


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.

PTE: What recent advances in micronization have you observed over the past five years?

Iamartino: Although micronization can be considered a rather consolidated technology, the interest in improving process control and optimization has increased in the past few years.

Special devices for on-line control of particle size have been developed and are proposed to be installed for continuous process monitoring, allowing adjustment of the operating parameters to keep the process with the target specifications. Though these systems represent a significant advancement in micronization process control, they are still expensive and require careful adaptation to each drug substance to be micronized.

From the equipment point of view, some advances in the application of fluid-dynamics would allow optimization of the jet mill configuration with the aim of reducing micronization fluid consumption and achieving either a higher yield and a better control of the particle size, especially in terms of distribution range.

Another advancement is the development of jet mill equipment suitable for installation within a high containment system for the micronization of highly potent active ingredients.

PTE: Do you see a demand for micronization technologies? What area of innovation is lacking or what advances do you hope to see in the near future with regards to micronization?

Iamartino: There is a significant increase in new drug substances showing poor water solubility, especially belonging to BCS Class II, for which appropriate technologies are required for improving the pharmacokinetic profile. Micronization represents one of the most effective and straightforward approaches for meeting this objective by acting on a key physical parameter.

The importance of using a well-defined particle size range of a drug substance, especially for the development of solid dosage forms, is becoming more and more apparent. Next to traditional mechanical mills, fluid jet mills are now recognized as alternative equipment for achieving the required particle size, with a more reliable distribution range. In this respect, jet milling is a good candidate for continuous manufacturing, also considering the fact that it would perfectly fit in a continuous process line.

Based on recent advancement, micronization would offer a new opportunity for dosage form development, as it can be applied as a preformulation step for improving technological and biopharmaceutical properties. For instance, the co-micronization of a blend of a drug substance and an excipient would allow a micronized powder to be created with advanced properties with regard to the starting powder blend. This recent approach would also require the development of innovative engineering solutions to be adopted in the use of the jet milling process and this is a challenge my team is working on.