Mastering Micronization for the Effective Delivery of Semi-Solid Drugs

Micronization is a process for reducing the diameter of a solid material’s particles to enable the solubility of Active Pharmaceutical Ingredients (APIs). Whether administered orally or topically,  this solubility is a key factor in bioavailability, and ultimately, the effectiveness of a drug.

The micronization of APIs is increasingly becoming a key capability for Contract Development and Manufacturing Organizations (CDMOs) as demand for semi-solid drugs, creams and gels continues to grow, as well as the use of APIs in foodstuff ingredients.  All of these chemicals need to be micronized in order to increase their strength.

The traditional techniques for micronization have been based on friction to reduce the particle size, and this is accomplished by milling or grinding particles. Modern techniques, also use supercritical fluids, which make the API soluble.

Micronization Requires Expertise – How We Do It

While micronization is fast becoming a key requirement for API manufacturing, there is a shortage of CDMOs that can provide this capability, given the costly and complex instruments and machinery, as well as the specialized expertise that is required.

A good example of a micronization project we successfully completed was the development of the world’s first synthetic form of medical-grade azelaic acid. Azelaic acid often is used to treat human skin conditions including acne, rosacea, melasma and hyperpigmentation.

The API’s bacteriostatic and bactericidal properties work against a variety of aerobic and anaerobic micro-organisms that infect skin pores on acne-bearing skin. It also reduces the production of keratin, a natural substance that promotes the growth of acne bacteria. In addition, azelaic acid has the ability to reduce inflammation, making it useful as a treatment for rosacea. It’s used as an active ingredient in topical gels to clear bumps and swelling associated with rosacea’s characteristic facial redness.

Azelaic acid has become more popular as an ingredient in topical drugs than other dicarboxylic acids due to its greater solubility. As a result, in the last decade we have received numerous requests for the ingredient.

When we first started synthesizing azelaic acid 10 years ago, we were getting our raw material from China, then recrystallizing it and, on occasion, changing the particle size as requested by sponsors for their various applications. While that process met all regulations then, the times – and regulations – have changed. Generally, medications derived from animal products have met with more resistance because of changes in regulatory requirements, animal welfare concerns, religious beliefs and other reasons. To address these concerns, PCI Synthesis has developed a completely synthetic process, along with associated analytics, that have been scaled and validated.

We developed this azelaic acid using advanced micronization techniques that enabled us to deliver small particles, evenly distributed throughout gels, creams and other semi-solid drug products, safely and effectively.

Complex Machinery, Instrumentation Required

In order to perform micronization on an API, very specific, complex and expensive equipment is required.  Here at PCI Synthesis we have invested in the equipment and analytical instrumentation infrastructure and expertise to conduct it quite effectively and ensure that the finished products can be scaled up and manufactured time and time again

Below are some of the equipment in use here at PCI Synthesis:

• Fitzpatrick Fitzmill Model: DASO-6 – which provide a quick, efficient milling method to size- reduce raw materials and achieve a uniformed processed product
• Quadro Engineering Comil Models 194-S, U20: Which is another screen-milling/conical milling technology
• Sturtevant Micronizer Models M2, M4: A unique fluid energy grinding system to generate particle-on-particle impact and produce sub-micron particle sizes
• Sweco Sifter Models S18, S30: A separation solution to maximize productivity, providing maximum vibration control to enable recovery of clean, acceptable product.
• The Malvern Mastersizer 2000: A particle-size analyzer used by the quality control lab to approve finished dosage products and determine the particle size and distribution

Different Micronization Techniques

Micronization reduces particles down to the micrometer or, in some cases, nanometer size, by using fluid energy, such as a jet mill, rather than by mechanical means.  Mechanical particle-size reduction using a bead mill, however, can also be used to obtain micrometer- and nanometer-sized particles.

Jet milling uses pressurized gas to create high particle velocity and high-energy impact between particles. Compared with mechanical milling, jet milling reduces metal contamination and, because process temperature is relatively constant, can be used for heat-sensitive products. Jet milling, however, requires a deep understanding of the process and equipment.

Bead milling. A bead mill uses wet mechanical milling to obtain nanoscale particles. In an agitator bead mill, grinding beads and agitating elements are used to reduce the API particle size through impact, and because bead milling is a wet process, it avoids any problems related to dust.

Micronization is just one of the new techniques for ensuring the safe and effective delivery of APIs in new formats, such as creams, gels and other ointments. Through careful investment in micronization tools and equipment, and experts who know how to perform the required techniques, CDMOs can be well equipped to meet growing demand.

If you have any questions about our micronization capabilities, please call us at (978) 462-5555 or email us at info@pcisynthesis.com.