(126a) Enabling Novel Drug Delivery Therapies by Nanomilling of APIs: Acceleration of Preclinical and Clinical Pharmaceutical Development Using a Screening Approach

Nanomilling refers to the reduction of the active pharmaceutical ingredient (API) particle size down to the sub-micron range. Recent advances have been achieved in stirred media milling for the production of such colloidal systems with API particle sizes of 100 to 300 nm. These nanosuspensions can be further processed into standard dosage forms, such as capsules and tablets, suitable for oral administration, especially for difficult to develop poorly soluble APIs. Oral dosage forms including nanomilled APIs has been shown to dramatically increase the rate of dissolution in vitro, improve bioavailability, reduce variability and alleviate positive food effects.

At the early stage in preclinical pharmaceutical development, the API is usually in tight supply, e.g., often less than 100 mg. With such small amounts a rational based preclinical formulation development will become difficult. Clinical development is characterized by short development time lines and up to now by limited scientific knowledge for the selection and understanding of appropriate nanomilling formulations with respect to API content, stabilizer type(s) and stabilizer content(s).

In order to enable the preclinical and clinical pharmaceutical development a screening approach was investiagted using a planetary mill equipped with miniaturized milling beaker. The screening tool offers batch sizes down to a few mg API and the processing of up to 24 batches in parallel. The first case study presented shows the feasibility assessment of an API in the early stage of pharmaceutical development by 42 screening experiments with in total 110 mg API from one person within five working days. Upscaling experiments using a miniaturized stirred media mill of 200 mg API batch sizes demonstrated a superior comparability for several nanomilling formulations of varying performance. The second case study presented is related to the early clinical development using about 100 screening experiments performed by one person within 12 working days. Promising nanomilling formulations were identified and characterized by particle size, morphology, API content and crystallinity/polymorphism. The upscaling of a promising nanomilling formulation to 250 g API batch size will be shown for the support of early clinical development using a lab scale stirred media mill. The presented results highlight the valuable screening approach to enable an accelerated preclinical and clinical pharmaceutical development.