Development of a Nanocrystal Formulation of a Low Melting Point API Following a Quality by Design Approach

Abstract

Preparation of nanocrystal formulations by wet media milling and spray-drying is a reliable technique to enhance dissolution and ameliorate absorption limitations of poorly soluble BCS II drugs. However, when thermosensitive compositions are dried at high temperatures, the risks of particle aggregation and thermal degradation must be considered. The present study investigates the effects of nanosuspension formulation variables when performing the spray drying process at equidistant temperatures above and below the melting point. Towards this purpose, Fenofibrate is exploited as a model drug of unfavorable pharmacokinetic profile and low melting point (79–82 °C), properties that render thermal processing a nontrivial task. Rationalizing the system’s behavior by combining molecular simulations with QbD methodology, the preparation of stable nanocrystals can be “steered” in order to avoid undesirable melting. The statistically resolved operational conditions showed that Fenofibrate Critical Quality Attribute–compliant nanosuspensions i.e., bearing hydrodynamic diameter and ζ-potential of 887 nm and −16.49 mV, respectively, were obtained by wet milling drug to Pharmacoat and mannitol weighted optimum ratios of 4.075% and 0.75%, after spray drying at the desired temperature of 77 °C. In conclusion, we present a quality assurance methodology of nano-comminution generally applicable for thermo-labile BCS II drugs.