No abstract

The production of nanosuspensions via stirred‐media milling has proved to be an effective method to overcome bioavailability challenges of poorly water‐soluble active pharmaceutical ingredients (APIs). The fine‐grinding of the APIs cinnarizine and fenofibrate was investigated. Important process parameters were varied and the influence on product quality was studied. Different challenges were identified prior to and during milling: Foaming inside the milling equipment and agglomeration of fenofibrate occurred, and a long‐term grinding experiment for cinnarizine revealed an increase in particle size, caused by ripening of the drug crystals during milling. Thus, the stability against ripening during the process is a newly identified challenge for the fine‐grinding of APIs.

It was demonstrated that in vitro flux measurements using lipophilic artificial membranes could correctly reproduce the rank order of PK results for ITZ formulations. The drop in flux over time for solid dispersions could be backed by experimental indications of crystallization.

In-die compression analysis is an effective method for the characterization of powder compressibility. However, physically unreasonable apparent solid fractions above one or apparent in-die porosities below zero are often calculated for higher compression stresses. One important reason for this is the neglect of solid compressibility and hence the assumption of a constant solid density. In this work, the solid compressibility of four pharmaceutical powders with different deformation behaviour is characterized using mercury porosimetry. The derived bulk moduli are applied for the calculation of in-die porosities. The change of in-die porosity due to the consideration of solid compressibility is for instance up to 4% for microcrystalline cellulose at a compression stress of 400 MPa and thus cannot be neglected for the calculation of in-die porosities. However, solid compressibility and further uncertainties from, for example the measured solid density and from the displacement sensors, are difficult or only partially accessible. Therefore, a mathematic term for the calculation of physically reasonable in-die porosities is introduced. This term can be used for the extension of common mathematical models, such as the models of Heckel and of Cooper & Eaton. Additionally, an extended in-die compression function is introduced to precisely describe the entire range of in-die porosity curves and to enable the successful differentiation and quantification of the compression behaviour of the investigated pharmaceutical powders.

In order to enable the accelerated preclinical and clinical pharmaceutical development of formulations based on nanomilling, a screening media mill was developed and evaluated for the production of nanoparticulate active pharmaceutical ingredients (API). The screening media mill is based on the principle of a conventional planetary mill, equipped with up to 24 milling beakers of 0.05-1.0 mL individual milling chamber volume. The applicability of the screening media mill was evaluated by 0.7-12.8 mg naproxen (2 wt %) per batch with a nanomilling formulation known from the literature. A case study for the preclinical formulation development is presented, applying 42 screening experiments by one operator within 5 working days, using in total 110 mg API. Promising nanomilling formulations with median particle sizes below 200 nm could be identified, suitable for preclinical in vivo studies. A second case study for the early clinical development of another proprietary API showed the successful formulation development within 12 working days. Up-scaling to a miniaturized stirred media mill of 10 mL milling chamber volume resulted in a satisfying comparability of the selected formulations, with varying performance. Further up-scaling of the most promising formulation to a laboratory-scale stirred-media mill showed the successful production of 250 g API with a median particle size of 140 nm.