Micronization of Active Pharmaceutical Ingredients (API) From R&D to the production scale

Introduction
The comminution or de-agglomeration of active pharmaceutical ingredients (API) is called micronization and brings about several advantages. With almost half of new chemical entities (NCEs) impaired by poor water solubility, nanoparticles are the solution. Reducing drug particles to nano size increases their surface area and subsequent solubility dramatically. The increase of the particle surface caused by the comminution results in a considerably better dissolution rate and bioavailability of the agents and therefore the APIs act faster. Due to the increased bioavailability a lower amount of APIs is required which in turn leads to a more cost-efficient product with less risks and side effects for the patient.

DELTAVITA Technology
The NETZSCH line of DELTAVITA mill, based on proven ZETA Mill technology stands out in the world of ultrafine nanoparticle applications. Through the use of a high-energy, high flowrate, multiple-pass grinding strategy, DELTAVITA mills achieve excellent repeatability as well as homogeneous dispersion. DELTAVITA mills are fast, extremely versatile and designed to produce a very narrow range of nano-sized particles (200 nm and below) in a homogeneous solution. In the time it takes for an ordinary mill to complete one pass, DELTAVITA mills cycle through as many as 10 passes. They are time, cost and energy efficient, saving about 30 percent more energy than other mills. The DELTAVITA process eliminates excessive heat buildup and output blockage that plagues screen separation systems in other fine-bead mills. The DELTAVITA mills unique media separation technology demonstrates NETZSCHs superior technical capabilities.

Figure 4

Circulation processing with single vessel

Figure 5

Results of scale up from laboratory to production scale bead mill

Figure 1

NETZSCH ZETA Mill Technology with yttria stabilized zirconia wetted parts DELTAVITA 10.000 with yttria stabilized zirconia wetted parts and a grinding chamber volume of 10 liters

Conclusions
Figure 2

Real comminution vs. dispersing

Real comminution - the primary particles are ground within a liquid phase by high shear, pressure and impact forces. De-agglomeration or dispersing - Agglomerates and aggregates are dispersed by shear, pressure and impact forces. The surface air is removed and the surface of the particles is wetted.

Besides the machine design there are other essential conditions for the successful comminution or dispersion of solids. These are the right formulation of the product suspension as well as the selection of the best grinding media and the optimal operating parameters of the mill. The development of the formulation and the optimization of the operating parameters can be conducted in laboratory mills. In particular when it comes to the selection of the operating parameters of the mill NETZSCH can revert to a pool of experience of more than 6 decades. Figure 3 shows the development of the particles size distribution of APIs during a grinding test on a laboratory bead mill. The customer aimed at a close particle size distribution with x99,3 < 400 nm. Moreover, the parameters had to be optimized to ensure that the product suspension would not exceed a defined maximal temperature during the comminution process. Once the operating parameters have been optimized the results can be transferred to production-size mills. An essential parameter for the scale-up is the specific energy input, which states the energy input with reference to the product quantity produced. Figure 5 shows the results of the scale-up from a laboratory agitator bead mill to a production-size mill.

Figure 3

Development of PSD during a grinding test in a laboratory agitator bead mill

Among other impressive qualities, DELTAVITA advantages for pharmaceutical applications are a single-tank process to reduce contamination, precise temperature control, ease of use and easy-to-clean design.

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NETZSCH Premier Technologies, LLC. Exton, PA

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