Micronization has been used for decades in the pharmaceutical industry. It is the standard that formulators turn to when making inhalable drug particles. The process is not mechanisatically understood, but sufficient information and experience has been gleaned over the years to make industry comfortable with it as a unit operation. There are drawbacks, however. One is, as mentioned, that the operation is not fully understood. This can lead to trial-and-error ways of running the process. Also, the process is wasteful. A certain amount of material is lost during the process, resulting in a reduced yield. The process generates particles with a wide particle size distribution. Also, a significant amount of dust is generated during the process. This means that cumbersome containment systems are required to protect operators and the product. However, there are alternatives.
Learning from the computer industry
In 2005, researchers at the University of North Carolina (UNC) developed a technology called Particle Replication in Nonwetting Templates (PRINT). The project, led by Professor Joseph DeSimone, takes from the computer industry's procedure for making transistors. The process consists making etched silicon wafers that serve as templates for the drug particles. These particles have a set of pre determined characteristics and the particles are producing by, essentially, rolling them out. The advantage of a template allows formulators to design the size and shape of the drug particles, to target specific areas of the lungs. The PRINT process has a significant advantage over micronization in that is consistently produces uniform particles. However, throughput using PRINT is lower than traditional micronization, which could be a disadvantage.
Could decafinated coffee have the answer?
Another technique that shows promise is supercritical fluid (SCF) technology. This is further advanced than PRINT and could be used to manufacture an FDA-approved drug. SCF technology has been around for a number of years and is used routinely to make decaffinated coffee. For the pharmaceutical industry, the hope is that this process can produce uniform particles quickly and without the need for a crystallisation solvent. Supercritical Anitsolvent Precipitation (SAS), using carbon dioxide as the supercritical fluid, is one way of using SCF to make inhalable drug particles.
The process consists of introducing a solution of the drug and solvent into a flow of supercritical CO2. The solvent is rapidly extracted, leaving behind the supersaturated drug substance. The particles are formed in milliseconds.They are uniform in shape and have a narrow particle size distribution. Compare this with a crystallization process that takes hours, after which the drug substance needs to be micronized to achieve the optimum particle size distribution for an inhalable drug product. The advantages are clear. Why perform two or three unit operations to achieve your goal, when it can be done in one? Also, SAS is less energy intensive, from the particles perspective, than micronization. During the micronization process, particles are smashed against the walls of the mill. This kind of high-energy operation can induce changes in the particle properties; for example, the morphology of the particles could change, becoming amphorphous, which could impact the bioavailability and stability of the drug.
There are a number of techniques that are available that could replace micronization in the future. Companies need to be less risk-averse and take on these new technologies and the advantages they offer.
Further information can be found in Pharmaceutical Technology, Vol 35, Issue 5: Beyond Micronization by Erik Greb, May 2011.