The past: Micronization and milling for particle reduction

Particle size reduction is frequently the first choice to improve an existing active ingredient. For inhalation, micronization is often employed. These techniques are often classified as ‘top-down’ methods as they involve the comminution of larger particles into smaller ones. Historically, jet-milling has been used extensively in the pharmaceutical industry to provide acceptable particles for different inhaler types. Despite the wealth of knowledge and numerous applications of ‘top-down’ techniques, several important issues, such as crystallinity, solid-state and batch-to-batch consistency regarding particle size and distribution are still a major concern.
 

Generation of nanoparticles is commonly attempted through extended ball milling or emulsion techniques. Milling as a typical ‘top-down’ technique usually results in highly energetic particles which necessitate a high surfactant and stabilizer loading to prevent irreversible aggregation or recrystallization of amorphous domains. Similarly, emulsion processes, although ‘bottom-up’ techniques, use large quantities of surfactants to produce the emulsion and are largely unable to generate a dry powder advantageous for long term storage.
 

Challenges in particle size reduction

Providing suitable microparticles with the right particle size and distribution for inhalation is still a major challenge. Jet-milling frequently generates a substantial amount of fines in the powder, while simultaneously a fraction of the powder is only incompletely milled, leading to lower fine particle fractions (FPF) making larger doses necessary. Further, milling often introduces static electricity onto the powder making them cohesive leading to handling problems and potentially to lower emitted doses (ED) from the device.