2.1.2. MM (NanoCrystals®)

In this technique, NC are obtained by subjecting API to a media-milling process. The media mill consists of a milling chamber, milling shaft, and recirculation chamber [16]. The generation of high energy and shear forces as a result of milling media and API collisions provide the requisite energy to disintegrate microparticulate drugs into nanosized particles. The milling media may be glass, zirconium oxide, or highly cross-linked polystyrene resin. During this process, the milling chamber is initially charged with milling media, water or buffer, API and stabiliser. The system is then rotated at a very high shear rate, and the milling process is performed under controlled temperature conditions in either batch or recirculation mode. When using the batch mode, dispersions with unimodal size distribution profiles and mean diameters <200 nm are produced in approximately 30–60 min. The media milling process can successfully process micronized and unmicronized drug crystals. Following the optimization of formulation and the process parameters, minimal batch-to-batch variability is observed when evaluating the quality of resultant dispersion(s).

However, the generation and introduction of milling media residue into the final product due to media erosion is of major concern. This phenomenon could be problematic during the production of nanosuspensions intended for chronic administration. However, the advent of polystyrene resin-based milling media has led to the reduced occurrence of the aforementioned issue, for which residual polymeric monomers are typically 50 ppb and the residuals generated during the milling process of not more than (NMT) 0.005 % *w*/*w* of the final product or resulting solid dosage form [50,51].

MM has been used with considerable success to yield NCC containing furosemide and caffeine, acetamide, urea and nicotinamide as co-formers, carbamazepine, and separately indomethacin with the co-former saccharin [52]. Initially, the manufacture of micronized co-crystals of each was performed using liquid assisted grinding (LAG) with methanol, acetonitrile, or acetone, or using a slurry technique [52]. Subsequently, the resultant cocrystals were dispersed in a solution containing 0.5 % *w*/*v* HPMC and 0.02 % *w*/*v* sodium dodecyl sulphate (SDS) in distilled water and wet-milled using zirconia beads. Wet-milling was conducted three times at 2000 rpm for 2 min and then 500 rpm for 2 min cycles. The milling chamber was maintained at –10 ◦C during the process. Lastly, the resulting suspension and zirconia bead mixture was transferred to a centrifuge filter-mesh chamber to separate and collect the suspensions at 400 rpm for 1 min [52].

Itraconazole nanosuspensions have also been manufactured using wet-milling with Tween® 80 dissolved in a 20 mL vial containing 5 mL demineralised water, followed by the dispersion of 250 mg itraconazole in this aqueous phase. Different concentrations of dicarboxylic acid co-formers (maleic, adipic, glutaric, and succinic acid) were dissolved in the suspension. Zirconium oxide milling pearls (30 g) of 0.5 mm diameter were added to the suspension. The vials were placed on a roller-mill and grinding performed at 150 rpm for 60 h after which the nanoparticles were separated from the pearls by sieving [53].

Witika et al. demonstrated the use of (MM) to produce NCC of lamivudine and zidovudine. The initial step involved the use of solution co-crystallisation to produce co-crystals. During the second step, NCC were manufactured using a top-down method, specifically, wet media milling using an in-house modified jigsaw as the milling chamber. A 115 mg aliquot of the harvested or dried co-crystal was placed in a 1.5 mL stainless steel milling chamber. The milling liquid comprised of different % *w*/*v* TPGS 1000 and SLS concentrations as defined by experimental design software. Stainless-steel balls were used as milling media with milling times of 10, 20, or 30 min at a constant milling speed of 65 Hz [54].
