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Pharmaceutical Manufacturing: Comparing Particle Reduction Techniques

While there are a number of particle size reduction technologies in use in the pharmaceutical industry today, from our vantage point as an API manufacturer we typically see requests for either jet milling or multi milling. Each has distinct advantages – and also some disadvantages.

But before we turn to a discussion on milling and mechanical reduction, it is important to mention that among the best ways to achieve a particular particle size distribution (PSD) is in-process crystallization. Crystallization offers the potential for extended product shelf life and stability, and should be evaluated with a number of particle size distribution (PSD) techniques using PAT tools (FBRM & PVM) and QbD-DOE (solubility studies – MSZW).

Jet Milling Versus Multi Milling: Determining Which Type of API Particle Reduction Milling Technology to Use

The choice between these two particle reduction milling techniques is driven by the API’s properties, the desired particle size, the API batch sizes and – to some degree – the manufacturing infrastructure & processing costs.

Here are some pros and cons of these two particle reduction techniques:

Jet Milling
Fluid energy – or jet – mills are excellent at reducing particle sizes. For size reduction up to a D90 of less than 10 microns, losses will be minimal – typically 2-3% at bulk scales. Beyond size, jet milling has another benefit: it increases bioavailability for APIs with solubility issues (BCS class 2 or 4).

One downside to jet milling, however, is static. Products produced with jet mills often have high static charges and tend to agglomerate. This can cause poor flow properties, and can lead to problems with blend uniformity.

At larger commercial scales, issues can arise with potential dust explosion hazards (especially with APIs that have low Minimum Ignition Energy – MIE < 3 MJ). Because of this, nitrogen can be used as a fluid with oxygen sensors and in combination with other procedures to safeguard personnel and infrastructure from hazards. 

Multi Milling
A multi mill uses variable-speed beaters with different-shaped edges and screens to achieve particle reduction.

Using different screen mesh sizes (e.g., 0.3, 0.5, 1, 2, 3 mm), multi mills are a common choice for de-lumping operations, granulation, or to obtain a coarser PSD of particles. Granulation can be either wet or dry. Among the disadvantages, shear-sensitive products cannot be handled. Its low operation cost, however, and minimal space constraints make it both effective and efficient.

How Each Type of Mill Is Typically Used in API Manufacturing
We’ve found that we most frequently use jet milling with air & nitrogen, yielding a D90 of less than 5 microns, while using multi milling for de-lumping processes. While both are popular techniques, jet milling is best at delivering accuracy and a tight particle size distribution while multi milling remains the most cost-efficient technique.

So Which Reduction Technique Should You Use?
As mentioned above, whichever technique is used – whether it be jet milling, multi milling or in-process crystallization – there may be an impact on chemical properties or stability issues. It is crucial to generate impurity profile data during the API development phase, and monitor for real time or accelerated conditions of the stability data.

In some cases, an alternate methodology or milling fluid (nitrogen or air) may be selected, or packaging conditions may be modified to avoid an impact on chemical properties or polymorph.

Multi milling and fluid energy jet mills are two common techniques used in pharmaceutical API development and manufacturing. Whichever method you choose to control the particle sizes of a drug intermediate, generating data to measure the impact of each method on the API is absolutely essential.

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