Milling is one of the most common pharmaceutical unit operations, which reduces particle size and increases its surface area. Nanomilling refers to the reduction of the particle size below 1000 nm by wet media milling, and the intermediate product is a nanoparticle suspension, conveniently referred to as a nanosuspension. Nanosuspensions allow higher mass packing (and thus higher dose) per liquid volume, and a better bioavailability.
EXAMPLES - PRODUCTS IN MARKET
In general, the production of nanosuspensions via is an effective method to overcome bioavailability challenges of several poorly water-soluble drugs. Examples include Rapamune® (Pfizer (Wyeth), Emend® (Merck), Tricor® Lipanthyl® (Abbott Laboratories), Megace® ES (PAR Pharmaceuticals), and Invega® Sustenna® Xeplion® (Janssen).
TECHNICAL DISCUSSION
The resulting particle size of a milling process depends on (i) process-equipment parameters; (ii) mechanical and physico-chemical properties of drug particles; and (iii) physical stability of the milled suspension. Thus, the key(s) for achieving a stable drug nanosuspension with desired particle size rely on a proper stabilizer formulation and effective process-equipment parameters. A poorly formulated drug nanosuspension may undergo aggregation, Ostwald ripening, fast sedimentation of particles, and cake formation during milling/storage, leading to unexpectedly slow dissolution and other issues.
WET MEDIA MILLING PROCESS
Among different types of the wet media milling process, the wet-stirred media milling is probably the most popular one. In the article, we are going to discuss its working principle as well as its key process parameters to achieve the desired particle size ranges. Below is a schematic of a wet stirred media mill with recirculation mode of operation:
(Credit: Meng Li et al, Pharmaceutics. 2016 Jun; 8(2): 17. )
You first pre-mix the suspension, then pass the suspension through a tube into the milling chamber (via the inlet). The milling chamber contains beads. You then turn on the rotor at high speeds. The grinding process occurs.
Formulation
When we say a physically stable suspension, it means no significant aggregration of the particles found in the suspension. To achieve a physically stable suspension, surfactants and/or water-soluble polymers are often added to the suspension before the milling process. Surfactants and water-soluble polymers may be absorbed to the particle surface forming a barrier for the aggregation, charged stabilizers can further alter the zeta potential of the particle after the absorption, thus, selection of proper stabilizers and their optimum concentration are very important for the suspension stabilization.
Meng Li et al (Pharmaceutics. 2016 Jun; 8(2): 17) has listed out the ranges and types of stabilizers in various suspension. One may find the information useful. Application of matrix or DOE will speed up the formulation development.
Process
Key process parameters are stirrer speed (rpm), suspension flow rate (mL/min), milling time (h), bead type, size and load (%).
Meng Li et al also list out the ranges of these parameters based on various reference articles. Though it is a good reference, one may perform IQOQPQ, and consult manufacturer for the initial sets for the ranges of each parameters. During the development process, one may optimize the manufacturing process / parameters.
