(637f) Growth Phenomena During the Fine Grinding of Active Pharmaceutical Ingredients

A large percentage of active pharmaceutical ingredients (APIs) being identified through combinatorial screening programs are poorly water soluble [1]. Therefore, improvement of dissolution has been a major development focus during the recent years. The reduction of the API´s particle size down to the nanometer scale using media mills or high pressure homogenizers is one approach to overcome the challenge of insufficient bioavailability [2]. By reducing the particle size, the dissolution rate of the API is increased significantly, according to the Noyes-Whitney/Nernst-Brunner equation which leads to an improved biopharmaceutical profile.

In this study the nanogrinding process of three active pharmaceutical ingredients, naproxen, fenofibrate and cinnarizine, was investigated using two different types of media mills: On the one hand a planetary ball mill (PM 400, Retsch GmbH, Germany) was modified according to Juhnke [3] to enable small scale screening of 12 samples of 1 ml volume, simultaneously. On the other hand, a stirred media mill (SL-12 C nano, VMA Getzmann GmbH, Germany) was applied for larger batch sizes with 600 ml volume.

As the fine grinding of particles increases surface free energy, which would lead to an agglomeration of the particles, stabilizers were required to obtain separated primary particles. Naproxen was stabilized using  Kollidon^® 30 (BASF), cinnarizine and fenofibrate using a combination of the cellulose Pharmacoat® 603 (Shin-Etsu) and dioctyl sulfosuccinate sodium salt (DOSS, Sigma-Aldrich). Process parameters were varied and the influence on product quality, particularly particle size and shape, was investigated.

 Some interesting effects were identified for naproxen in the small scale planetary ball mill experiments. Depending on the chosen grinding media size and material, apparent growth of the API particle size was determined via dynamic light scattering (ZetaSizer nano, Malvern Instruments GmbH, Germany) after a certain grinding time. TEM micrographs were taken to identify the changes which  occurred to the samples. When using 100 µm yttrium-stabilized zirconia beads, the product particle shape started to change from spherical to needle-like after about 120 minutes grinding. By increasing grinding time, the needles started to grow into the length direction. By further increasing the grinding time to 16 hours, the particle morphology further changed to platelet-like. However, crystallinity was preserved throughout the comminution process, which was determined via WAXD.

These effects were reproducible but occurred only with a specific process parameter set, regarding bead size, material and number of revolutions of the mill. Obviously (re-)crystallization occurred during the comminution process, depending on the energy transferred to the system. The increase in particle size using 300 µm alumina beads was revealed to have a different origin. On the TEM micrographs really small primary particles (< 100 nm) were observable, which agglomerated strongly and formed a gel network. In contrast to the (re-)crystallization, this effect occurred also in the larger scale inside the stirred media mill. Similar effects (agglomeration and (re-)crystallization, respectively) were observed also for cinnarizine and fenofibrate in the stirred media mill, which will be subject to the presentation.

Thus, during the grinding process three different effects could occur simultaneously: the real grinding of the API, agglomeration and (re-)crystallization.

1. Merisko-Liversidge, E., Liversidge, G.G., Adv. Drug Deliv. Rev. 63, 427-440 (2011)
2. Rabinow, B.E., Nature Reviews, 3, 785–796  (2004)
3. Juhnke, M., Berghausen, J., Timpe, C.: Chem. Eng. Technol. 2010, 33, 1412-1418.