Micronizing – and particularly nanosizing – active pharmaceutical ingredients (APIs) has become an integral part of the drug development & manufacturing process. And with a variety of techniques available to improve the delivery or bioavailability of drug compounds, precise control over particle size has become all the rage.

Why micronize (or nanosize) an API or drug compound? There are a number of reasons to precisely control API particle size, and much of it is driven by the nature of the compound in development.

Why Particle Size Matters
The primary reason precise control over particle size matters? Solubility. Though more than 50% of the drugs on the market today have poor solubility, the future is looking insoluble (but not insolvable!) indeed. Estimates place the number of new chemical entities with low solubility as high as a stunning 90%!

Low Solubility Drug Compound Challenges
Low solubility is a considerable challenge during drug formulation, and it can impact a potential drug in a number of ways two of which:

Surface Area and Dissolution
One issue in the drug development process is the bioavailability of a compound, and one of the key factors affecting bioavailability is solubility. Reducing the size of the particle increases the surface area. This improves the drug’s dissolution properties …and can have a positive impact on the drug’s bioavailability.

Particle Size Distribution
Yes – ‘going small’ can have a huge impact on a drug’s performance. But while size matters, so does uniformity…all of the particles need to be as close to the target size as possible. Creating a narrow, homogenous average particle size distribution improves API uniformity, which can also enhance oral bioavailability.

The two key pharma particle reduction techniques used today are micronization and nanosizing:

Micronization
The reduction of particle sizes to the low micron range – “micronization” – typically involves physically milling the compound. Different types of mills offer different benefits. Jet mills, for example, use pressurized gases to reduce particle sizes instead of mechanical mills. Benefits of micronization using jet mills include reducing metal contaminants and an ambient temperature process…ideal for heat-sensitive compounds where molecular degradation or modification is possible. Disadvantages include inefficiency and infrastructure requirements, since systems tend to be large and require a hefty supply of gas.

Mechanical – or impact – mills (examples include pin mills and hammer mills) are typically more compact and much more efficient. The key disadvantages are heat generation and difficulty producing narrow distributions in the extreme low-micron range.

Nanosizing
The term ‘nanosizing’ is used to reference particle sizes in the sub-micron range, typically 100-200 nm (nanometers, or 1/1000th of a micrometer) in size. Nanosizing is typically accomplished by milling the compound in a stabilized solution to the targeted size, which can be further processed into the final dosage form.

If micronizing drug compounds improves solubility and bioavailability, nanosizing reduces particle sizes even more in an effort to further improve the dissolution rates and bioavailability. The advantages of nanosizing are numerous, and include: improving or altering a compound’s pharmacokinetic properties, producing lower systemic toxicity, increasing solubility, and improving bioavailability.

A Smaller Drug May Be a Different Drug
Altering the physical particle size can change a compound’s traits, and it is important for drug development teams to build a thorough understanding of API resizing effects on absorption, distribution, metabolism, toxicity and elimination.

How important is particle size in your drug development program?