Nano milling involves transforming hydrophobic APIs into a water-soluble form and is achieved by reducing the API down in size to the nanometre range, typically below 200nm, and then stabilising it with biocompatible surfactants. This increase in surface area directly correlates to an increase in the dissolution rate of the final product. An initial micrometre-sized product is processed to reduce its size down into the nano-range using bead milling, which grinds the particles down into a suspension. This process allows for highly concentrated solutions, precise process control, high yield, scalability and reproducibility, making it a valuable tool in various industries.
Sterilisation during nano milling processes is crucial for product quality and safety in many pharmaceutical applications, preventing contamination and ensuring the integrity of the final product. Further, pharmaceutical manufacturing processes are governed by strict requirements set by regulatory bodies, to ensure high-quality, safe and consistent nano-sized pharmaceutical suspensions.
Nano milling in a sterilised environment
Many nano milling processes are conducted in a completely sterile environment. This includes thorough cleaning and sterilisation of machinery, protective containment seals, as well as both safe introduction and recovery of product through sterile ports.
The Nanowitt NW 500 from Frewitt – a leading manufacturer of quality milling equipment – contains specialist features to ensure the sterility of pharma products. Frewitt’s nano milling head includes a mechanical seal that ensures the process is completely sealed but can be easily disassembled for cleaning. The barrier fluid circuit consists of the mechanical seal itself, a sterile tank and recirculation pump, which can be sterilised in place using steam.
The technology also enables the filling of suspension and beads after sterilisation. Importantly, samples can be taken at any time during milling without loss of sterility. After product recovery the entire system can be cleaned automatically via wash-in-place and clean-in-place (WIP & CIP) making it ready for the next batch.
Other key features include autonomous and automated operation functions that enable the machine to run automatically without human intervention, ensuring product quality and operator safety. Its dynamic separator, meanwhile, ensures the system never clogs and provides consistent results, regardless of the bead or product size.
Ergonomic and easy-to-use, the NanoWitt NW 500 also offers real-time size distribution analysis using laser diffraction, or dynamic light scattering, enabling users to monitor the milling process and ensure product quality, as well as a low bead rate and unique configuration that allows for maximum product recovery with minimum loss.
Collectively, these features contribute to the Frewitt Nano Mill’s ability to produce high-quality, nano-sized pharmaceutical suspensions while maintaining a sterilised environment.
Key nano milling challenges
Due to the characteristics of the APIs being milled, a range of issues can affect the quality of a milled product.
One of the most significant challenges is the potential instability of the nanoparticles produced. Nanoparticles can aggregate or precipitate, leading to inconsistent dosing and efficacy. This instability can be exacerbated by environmental factors such as temperature and humidity during storage and transportation.
For efficient size reduction processes, operators need to use a highly performant mill. The patented Nanowitt NW 500 ensures that even the most sensitive pharmaceutical products can be nano milled without an increase in temperature and without degradation of the product.
While reducing particle size is essential for enhancing solubility, excessive action can lead to overmilling, which can degrade the API or alter its desired characteristics. This can result in a product that does not meet regulatory standards or fails to perform as intended in clinical applications.
Continuous monitoring and optimisation of the milling process and adjustments to parameters like milling time, speed, and equipment type, can help address these issues. The Nanowitt NW 500 is controlled entirely by a touch screen panel and a PLC, with dedicated icons permitting the user to control every step of the process and ensure the continuous quality of the product as well as full operator safety.
A major innovation from Frewitt, the dynamic separator ensures uninterrupted processing without clogging or filtering, ensuring repetitive results regardless of beads or product size, enhancing fluid dynamic and suspension homogeneity during milling.
Frewitt’s Nano Mill comes in a modular and flexible design that can accommodate five different milling and micronisation heads, allowing for interchangeable processes like dry milling, wet milling and micronisation.
Frewitt has been a key player in the pharmaceutical, food and fine chemical industries for over 75 years and continues to offer a unique programme for solid material size reduction, ensuring that each material’s unique characteristics are milled to specific results while maintaining active properties.
