Accelerated Formulation Development for Nanomilled Active Pharmaceutical Ingredients Using a Screening Approach

Abstract

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.

Surfactant choice and the physical stability of nanosuspensions as a function of pH

“…An examination of the literature however shows that nanosuspensions are formulated in a largely empirical manner (Van Eerdenbrugh et al, 2009;Lee et al, 2008;Juhnke et al, 2010;Bodmeier and Chen, 1990). One popular formulation method involves the use of a polymer in combination with a charged surfactant.…”

Systematic Screening of Different Surface Modifiers for the Production of Physically Stable Nanosuspensions

“…In most cases, it seems that the stabilizer selection is carried out empirically. Very often, surface modifiers that have been documented for the same particle size reduction technique and the same route of administration but for different APIs are used as default for the next formulation development process . One of the rare examples for a more systematic surfactant screening to obtain stable nanosuspensions has been reported by Eerdenbrugh et al In this study, nine different APIs have been tested with 11 different polymeric stabilizers and two surfactants.…”

“…Nowadays, novel apparatus such as planetary mill enables fast screening processes as different nanosuspension compositions can be screened in parallel . However, up to now, only a few reports are available in the literature that describe the systematic selection of different types of surfactants/stabilizers and their concentration levels for formulating stable nanosuspensions.…”

Scaling Wet Fine Grinding Processes of Organic Particles Using Stirred Media Mills

“…The establishment of grinding processes is often linked to extensive research and development effort. First steps are marked by screening experiments with very small sample amounts, usually these are covered by batch grinding experiments , . A disadvantage of batch grinding is the limited control of process parameters like temperature and pH‐value as well as the limited possibility of successive additive dosage.…”