Micronization and Milling: A Strategic Tool to Enhance Drug Development and Manufacturing

Particle size distribution (PSD) has a profound impact not only on dissolution rate and bioavailability, but also on the processability of the material – affecting flowability, static charge, stickiness and other bulk properties essential for efficient manufacturing.

A scientific approach to PSD must be applied as early as possible, ideally starting during preclinical development. Defining the most suitable PSD from the beginning ensures both therapeutic efficacy and formulation robustness, while avoiding the risk of costly rework or regulatory complications down the line. In most cases, once clinical trials have started, the opportunity to revisit these foundational aspects becomes limited, and improvements may only be considered much later – if at all – often after a product becomes generic, when such changes are far more difficult to implement.

Benefit Achieved from the Micronization/Milling Step

We can identify two major categories of benefits from micronization and milling processes. First, reducing particle size can significantly improve bioavailability, particularly for poorly soluble APIs. This is a well-established principle supported by numerous studies and extensive scientific data^{1, 2}. Second, micronization contributes to the consistency and performance of the drug during the formulation phase, by improving powder behavior, flow properties, and dosing uniformity.

While formulators often request very fine PSDs to improve dissolution rate, they also worry about resulting poor flowability. Indeed, smaller PSD often means lower bulk density (BD) and higher specific surface area (SSA), which can negatively affect powder flow. However, this is not universally true. For substances that form needle-shaped crystals, reducing the particle size can actually improve flowability due to changes in particle shape and interaction.

In the case of high-potency APIs, where the active is only a small fraction of the formulation, flowability is determined more by the excipients than the API itself. Thus, even a fine PSD in the API won’t hinder processing, since the bulk properties are governed by the blend.

Even when bioavailability is already high, milling may still be essential for achieving controlled and reproducible PSD, which in turn ensures formulation consistency and manufacturing robustness. Key processing steps parameters – such as blending, granulation, tableting and capsule filling – are all influenced by PSD and particle morphology.

Inconsistent PSD can lead to significant production challenges, such as OOS (Out Of Specifications) in quantity uniformity results, variability between batches, or even regulatory issues requiring time-consuming change control processes. These outcomes come with real financial risks, from delays in product registration to out-of-stock situations. Therefore, opting for micronization or milling processes potentially reduces future cost and risk.

For example, in injectable formulations designed for local delivery (such as intra-articular injections in the shoulder or knee), even a few coarse particles can clog the needle and prevent the full dose from being administered. In such cases, bioavailability is not the issue; instead, it's a physical requirement to ensure that the product can be administered safely and reliably. This is another illustration of how micronization can contribute to a robust drug product and a resilient supply chain.

Ultimately, the micronization or milling step helps formulators achieve the required performance, whether the goal is better dissolution, content uniformity or processability.

Select the Most Appropriate Technology

We typically refer to “micronization” when the target PSD has a D90 below 40–50 µm, “fine milling” for D90 between 50–100 µm, and simply “milling” when D90 exceeds 100 µm. These distinctions help guide the choice of technology, as different equipment types are suited to different PSD targets and product characteristics. A summary of available technologies and their typical PSD capabilities is shown in Figure 1.

Fig-1

In general, low-potency APIs are used at high doses, which means large volumes of powder and greater sensitivity to flowability during manufacturing. In such cases, a medium-coarse PSD is preferred to ensure robust powder flow. Mechanical mills such as pin mills are often ideal for this purpose, producing a tight and consistent PSD. In contrast, using a spiral jet mill in such a case might lead to a broader, less homogeneous distribution and reduced flowability.

Conversely, for high-potency APIs, the required dosage is often very small, and the API needs to be evenly distributed throughout the excipients. In this context, a fine PSD improves uniformity. Since flowability depends mostly on excipients in these cases, a spiral jet mill is well-suited to deliver a fine and narrow PSD that blends easily, even in small quantities.

While the selection of technology depends on the desired PSD, it must also consider the API’s physical and chemical properties, such as moisture sensitivity, hardness, crystal habit, and heat sensitivity. Other available comminution technologies can be considered depending on equipment availability and product-specific requirements (see Table 1).

Table 1: advantages and disadvantages of different technologies.

Mitigation of the Possible Disadvantage

Despite their many advantages, milling and micronization can introduce challenges. These include reduced flowability, increased surface energy, static charge buildup, higher amorphous content or even increased levels of impurities.

These risks are usually associated with high-energy processes – such as high-pressure jet milling or high-speed mechanical milling – which can generate heat and disrupt the solid-state structure.

To mitigate these effects, various process control strategies can be employed:

• Use of nitrogen as process gas to avoid oxidation and control thermal effects

• Cryogenic milling or controlled low-temperature operation to prevent heat-related degradation

• Environmental control, especially RH%, to manage electrostatics and cohesion

• Post-milling conditioning, at defined temperature, time, and humidity, to stabilize the material

• Co-micronization with suitable excipients to improve the solid-state stability

• Packaging under nitrogen, especially for oxygen- or moisture-sensitive APIs 

These strategies require both the technical capability and pharmaceutical experience of the milling partner. Selecting the right supplier – who is both competent in technology and experienced with pharmaceutical APIs – is critical. Competence means having a robust, GMP-compliant system. Experience means having worked with a wide range of substances across multiple projects. For instance, having 10-20 years of experience with just one compound, does not qualify a company as an expert in pharmaceutical micronization across the board.

Conclusion

The micronization or milling step is far more than a mechanical operation – it is a strategic component of modern drug development and manufacturing. While it is often recognized for its role in enhancing bioavailability, its broader value lies in ensuring consistent product quality, formulation robustness and supply chain reliability.

The benefits of this step – if planned correctly – will pay back many times its cost by avoiding delays, preventing rework, and minimizing regulatory risks.

Three key decisions are critical:

1. Select the right supplier, one who combines technical knowledge with proven pharmaceutical experience.

2. Design an intelligent development strategy, based on structured experimentation and early-stage data collection. A flexible and knowledgeable partner can support all development phases and help you avoid costly surprises later.

3. Protect your IP but share the necessary product knowledge to enable proper experimental design and ensure meaningful, supportive results.

Choosing a low-cost supplier may appear financially attractive in the short term, but without flexibility, competence and availability, it may become a costly strategic mistake. The right partner offers long-term value, not just low price.

References:

1. Katharina Brodka-Pfeiffer, Peter Langguth, Peter Graβ, Heribert Häusler. Influence of mechanical activation on the physical stability of salbutamol sulphate. European Journal of Pharmaceutics and Biopharmaceutics, August 2003.

2. Gordon T. McInnes, Michael J. Asbury, Lawrence E. Ramsay, John R. Shelton. Effect of Micronization on the Bioavailability and Pharmacological Activity of Spironolactone. J Clin Pharmacol. 1982; 22; 410-417

Giovanni Frigerio, MS

CSO

Munit SA

Giovanni Frigerio, MS

CSO
Munit SA

Giovanni Frigerio has more than 25 years of experience in the powder engineering process for pharmaceutical industry. It started to work at Jetpharma from 2000 to 2003 as Head of Quality control Laboratory. From 2003 to 2016 was the technical director and Qualified Person at Jetpharma. From 2017 to now is the Chief Scientific Officer at Munit SA, supporting technical and scientific operations for Jetpharma SA in Switzerland and for Microchem Srl in Italy.