Poor water solubility is an increasingly common issue in pharmaceutical development. About 40% of marketed drugs and as many as 90% of active pharmaceutical ingredients (APIs) in the discovery pipeline are poorly water-soluble. When these APIs are introduced without modification or enhancement, they fail to dissolve and have limited bioavailability. As a result, there are multiple techniques available to increase the solubility of APIs and improve their delivery:
- Particle Size Reduction: nanomilling, micronization
- Amorphous Solid Dispersions: hot melt extrusion, spray drying
- Encapsulation Techniques: lipid- and polymer-based particles
- Other Solubilization Techniques: pH modification, salt forms, co-solvent systems, surfactants, complexation (cyclodextrin)
Nanomilling: A proven approach to improving the rate of dissolution and bioavailability
In our experience at Particle Sciences, we’ve found nanomilling to be a particularly efficient, reproducible process that is very scalable. The basic principle behind nanomilling is increasing the surface area-to-volume ratio of an API by reducing the particle size below 1000 nm, typically in the 100s of nm range. This conversion of drug particles into nanocrystals allows for greater interaction with water, which increases dissolution rate. In general terms, smaller particles dissolve more quickly.
The technology behind nanomilling was developed in the 1980s and the first FDA-approved nanocrystal drug came to market in 2000. Since then, numerous BCS class II and IV APIs have benefitted from nanomilling and gained FDA approval (see table below). Nanomilling has been used to increase bioavailability and minimize fed/fasted variability in both liquid and solid dosage forms.
Advantages of nanomilling
One of the greatest advantages of nanomilling when compared to other formulation approaches for poorly water-soluble APIs is its universality. While nanomilling is most useful for APIs with solubility below 200 µg/mL, it can be applied to just about any insoluble API in a relatively easy manner, making it an appealing first-line approach to solubilization. Other advantages include:
- NO harsh organic solvents or pH extremes: Most nanomilled suspensions are aqueous-based
- High API concentrations: 5-40+% API (w/w)
- Easy Scale-Up: Commercial nanomilling equipment utilizes a recirculation process that allows batch sizes to increase without changing process variables
- Reproducibility: Once a nanomilling process is optimized, there is minimal variation in particle size from batch-to-batch
The nanomilling process
Nanomilling is a “top-down” approach to turning large, coarse particles into smaller, finer particles. It entails the application of mechanical energy to physically break down crystalline API structures. The main technique used for nanomilling API is high energy media milling. This technique relies on milling media—0.2-1 µm beads that are made from ceramics or highly crosslinked polystyrene. The beads shear and collide with the API particles during the milling process, reducing their particle size.
During nanomilling, the API is suspended in a solution containing water and at least one stabilizer to prevent reaggregation of particles over time. The nanomilling process generates an intermediate consisting of nanoparticles suspended in an aqueous vehicle. This is often referred to as a nanoparticulate suspension (or nanosuspension). Nanosuspensions have been converted into a wide range of dosage forms, including oral liquids, capsules, tablets, films, injectables, aerosols, and more.
The opinions expressed in this blog post are the author’s only and do not necessarily reflect those of MedicalDesignandOutsourcing.com or its employees.