Small Matters: A Review of Micronization Techniques for Pharmaceuticals

Justin Klinger, May 7, 2020 7:45:00 AM

Micronization Techniques for Pharmaceuticals

Pharmaceutical manufacturing leans heavily on size reduction as a vital operation to make handling easier, increase surface area per unit volume, and separate entrapped components.

Although reducing large solid unit masses into coarse or fine particles may sound simple, how it’s done varies. Many types of size reduction equipment are used to process specific materials, based on the material’s properties (hardness being the most important characteristic).

Creating a new surface area means adding energy that’s proportional to the bonds holding the particles together. Size reduction produces particles in a narrow size distribution range, and it’s easier to mix powders with narrow size ranges.

Pharmaceutical suspensions require finer particle size, which reduces the rate of sedimentation (particles in suspension settling out and coming to rest). Plus, the smaller the particle size, the quicker the rate of absorption of a drug.

Why does “small” matter?

“Micronization” describes size reduction during which the resulting particle size is less than 10 microns. The size reduction process may involve accelerating particles so either particle-to-particle impact or impact against a surface does the grinding.

Micronized powders are used in catalysts, pigments, biopolymers, and more. Demand in pharmaceutical materials — finely ground active substances and excipients — is growing. Some materials, injectable drugs and dry powder inhalants for instance, require particle sizes of 2-20 microns, with a minimum of fine and oversized particles.

As a product moves from concept stage to on shelf, many steps are needed to get that new active pharmaceutical ingredient (API) into dosage form (typically mixed with excipients), which also requires patient testing. Of all physical characteristics that determine an API’s properties, particle size distribution may be the most important of all variables.

How does micronization affect a pharmaceutical product?

Pharmaceutical size reduction is complex: particle size distribution may vary widely pre-milling; formulation variables (mixing speed and blending time) need to be considered; particle size in powders for inhalation must be tightly controlled.

It’s so complex that discussing product design here is simply an overview. The one essential factor, however, is knowing the material properties of the raw materials to be processed.

Another key to micronization for pharmaceuticals is the delivery method.

In a perfect world, all oral formulation drugs would have good solubility and permeability, so the delivery method could be tablets or powders in capsules. Unfortunately, a significant proportion of small molecule drugs have good permeability and poor solubility (with a limited dissolution rate). Micronization is particularly effective for these drugs, enabling for formulations that dissolve completely during their time in the small intestine.

Particle size reduction is critical in inhaled formulations, the preferred method of drugs that treat respiratory conditions. These drugs can be targeted where they have the most therapeutic effect: parts of the respiratory tract and lungs. If the particle size is too large, the drug ends up in the throat. Too small, and the particles are exhaled before they reach the airway or lungs.

What are the techniques used for micronization?

Commonly used micronization equipment include mechanical impact mills (spiral jet mills) and fluid energy (fluid bed) impact mills.

The spiral jet mill consists of a flat cylindrical grinding chamber with nozzles arranged around the peripheral wall. A pneumatic feed injector accelerates feed into the grinding chamber where the material is subjected to two forces: centrifugal force provided by the nozzles and drag force by the spiraling airflow.

Several factors affect the product’s fineness: feed particle size, feed and air flow rates,  nozzle pressure and angle, chamber diameter and width, and product outlet diameter.

Optimum spiral jet mill project:

  • Fine and ultra-fine size reduction of materials
  • Moh’s hardness of 3
  • Brittle crystalline grinding characteristics

Fluid bed jet milling allows for high impact velocities of 300-500 meters per second, compared to 50-150 meters per second in a mechanical impact mill. A fluid bed jet mill’s high-energy micronization lower chamber can be combined with an integral forced vortex air classifier, allowing for greater control of the maximum particle size.

The two processes together allow for steep particle size distribution and sharp top-size control. Fluid bed mills are also known for less energy consumption, reduced wear and buildup grinding chamber, and low noise emission.

Optimum fluid bed mill project:

  • Fine and ultra-fine size reduction of materials
  • Moh’s hardness of 10+
  • Material can be fluidized by the expanded compressed gas in the grinding chamber
  • Able to produce an infinitely adjustable particle size distribution

The pharmaceutical industry relies on micronization

Today’s APIs are increasingly more intricate, with the pharmaceutical industry requiring smaller and smaller particle sizes. The link between particle size and product performance is well-known, so being able to monitor size is integral in formulating and manufacturing pharmaceutical dosage forms.

Particle size changes can alter properties (shape, surface area, porosity), which can affect the end product in many ways: product performance, processability, stability, and appearance. Look to micronization’s content uniformity, uniform flow, and mixing capabilities.

You’re invited to learn more about micronization techniques for pharmaceuticals by reaching out to Custom Processing Services.

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