How Micronization Services Help Pharmaceutical Manufacturers Innovate and Optimize

Justin Klinger, Feb 17, 2022 9:45:00 AM

Micronization Techniques for Pharmaceuticals

It’s hard to overstate the importance of particle size in pharmaceutical preparations. 

Achieving the optimal particle size can make materials easier to handle and process, improve delivery of active pharmaceutical ingredients (APIs), and enhance various qualities or characteristics of raw materials.

Milling processes can also be an important step in separating entrapped components from a material before it’s incorporated into a blend.

Because particle size is so critical to pharmaceutical formulations, particle size reduction processes, including micronization services, play a key role in the drug manufacturing process.

It may sound like a simple task to reduce a large, solid unit into fine particles that measure in the micrometer range.

In fact, micronization technology includes a wide range of equipment and processes to account for the range of material properties, size and shape requirements, and other specifications needed for pharma products.

In this article, we’ll take a closer look at milling methods used in the micronization process, and the importance of particle size in pharmaceutical formulations.

Why Bigger Isn’t Always Better

Micronization refers to particle size reduction processes that result in particles less than 10 microns in diameter. Micronized powders are used in catalysts, pigments, biopolymers, and more. Demand in pharmaceutical materials — finely ground active substances and excipients — is growing.

But why so small?

In an ideal world, all oral formulation drugs would have good solubility and permeability, making it easy to formulate tablets or powders in capsules. But that’s not always the case. Many small-molecule drugs have good permeability, but poor solubility (with a limited dissolution rate). For these drugs, micronization is particularly effective, making it possible to develop formulations that dissolve completely in the small intestine.

Next, consider the many other means of drug delivery besides oral dosing for the administration of pharmaceutical products:

  • Injection
  • Parenteral
  • Topical
  • Transdermal
  • Inhalation
  • And more

Particle size range and distribution have an impact on sedimentation rate, absorption, bioavailability, and more. Several of these delivery methods require extremely fine particle sizes in order for the API to be delivered and have the desired effect on the patient.

Sometimes, an extremely small particle size is needed to achieve the desired efficacy while maintaining product safety and minimizing adverse reactions or side effects. Depending on the material, some injectable and inhaled drugs require particle sizes in the range of 2–20 microns, and with a very tight size distribution. Particle size reduction is particularly critical in inhaled formulations, the preferred delivery method for drugs that treat respiratory conditions. 

These products need to be developed to target precise areas of the respiratory tract and lungs, where they have the most therapeutic effect. Too large, and the particles tend to remain in the throat; too small, and they can be exhaled before they reach the airway or lungs.

Similarly, particle size can affect depth and speed of absorption of a topical product, such as a medicine delivered in a cream, gel, or transdermal patch. When fine powders need to be blended in a formulation, the closer the particle sizes, and the narrower their size distribution ranges, the easier it is to achieve a homogenous blend. Micronization can also enhance formulation attributes including:

  • Texture
  • Viscosity
  • Mouthfeel
  • Blending time
  • Stability in suspension
  • Color

Micronization Technology, Processes, and Methods

Creating a new surface area requires the use of energy proportional to the bonds that hold the particles together, and that requires the use of specialized size reduction equipment. Selection of the mill type, energy input, time, and other variables are based on materials’ initial properties, with hardness being the most important characteristic to consider.

Size reduction processes often involve accelerating particles so that impact, either particle-to-particle or particle-to-milling surface, does the grinding. Commonly used micronization equipment include mechanical impact mills, spiral jet mills, and fluidized bed jet mills. 

Different mill types apply mechanical impact or fluid energy to reduce particle size. Together, the two jet milling processes allow for steep particle size distribution and sharp top-size control.

Spiral Jet Mills

A 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 end product’s fineness: feed particle size, feed and air flow rates, nozzle pressure and angle, chamber diameter and width, and product outlet diameter.

An optimal raw feed material for a spiral jet mill micronization project would have these characteristics:

  • Final specification of fine or ultra-fine particle size
  • Moh’s hardness of 3
  • Brittle crystalline grinding characteristics

Fluidized Bed Jet Mills

Fluid bed jet milling allows for high-velocity particle impacts 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 milling chamber can be combined with an integral forced vortex air classifier. This separates the particles by size during milling, allowing for tight control over the maximum particle size.

Fluid bed jet mills are known for less energy consumption, reduced wear and build-up inside the grinding chamber, and low noise emission.

An optimal raw feed material for a fluid bed jet mill micronization project would have these characteristics:

  • Final specification of fine or ultra-fine particle size
  • Moh’s hardness of 10+
  • Material capable of fluidization by expanded compressed gas in the grinding chamber

The fluidized bed jet mill is able to produce an infinitely adjustable particle size distribution.

Pharmaceutical Innovation Relies On Micronization Technology

As highly potent APIs become increasingly advanced, the pharmaceutical industry requires smaller and smaller particle sizes. The capability to tightly control and monitor size is vital in developing, formulating, and manufacturing pharmaceuticals in wide dosage ranges and varying administration methods.

Changes in particle size can also alter other properties, such as particle shape/morphology, surface area, and porosity. These changes can affect the end product’s performance, processability, stability, and appearance. Manufacturers depend on micronization to achieve content uniformity, uniform flow, and blendability.

As a formulation moves through the R&D process from initial concept to commercialized, shelf-ready product, many steps are needed to achieve a new API’s final dosage form, including determining the right excipients, blending, final processing, and testing. Of all these variables, API particle size is often the most important determination. 

Working closely with your toll processing partner’s technical team of experienced material scientists, engineers, and equipment operators can help optimize process efficiencies, and it can even shorten the time required to transform your new formulation into a shelf-ready product.

Particle size reduction is just the beginning of processing needs for many pharmaceutical products. Learn more about the next step when you download our Guide to Blending for Pharmaceuticals. Just click below to claim your copy today.

Evaluating toll processors for pharma blending. A cGMP manufacturers guide.

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