Nanomilling of Drugs for Bioavailability Enhancement: A Holistic Formulation-Process Perspective

Abstract

Preparation of drug nanoparticles via wet media milling (nanomilling) is a very versatile drug delivery platform and is suitable for oral, injectable, inhalable, and buccal applications. Wet media milling followed by various drying processes has become a well-established and proven formulation approach especially for bioavailability enhancement of poorly water-soluble drugs. It has several advantages such as organic solvent-free processing, tunable and relatively high drug loading, and applicability to a multitude of poorly water-soluble drugs. Although the physical stability of the wet-milled suspensions (nanosuspensions) has attracted a lot of attention, fundamental understanding of the process has been lacking until recently. The objective of this review paper is to present fundamental insights from available published literature while summarizing the recent advances and highlighting the gap areas that have not received adequate attention. First, stabilization by conventionally used polymers/surfactants and novel stabilizers is reviewed. Then, a fundamental understanding of the process parameters, with a focus on wet stirred media milling, is revealed based on microhydrodynamic models. This review is expected to bring a holistic formulation-process perspective to the nanomilling process and pave the way for robust process development scale-up. Finally, challenges are indicated with a view to shedding light on future opportunities.

Keywords: drug nanoparticles; process modeling; process parameters; stabilization; wet stirred media milling.

Figure 1

The number of published scientific papers in the period from 2006 to 2015 which reported the use of wet milling for poorly soluble drugs (source: Scopus database, key words: “poorly soluble drug” or “BCS Class II” or “insoluble drug” or “slightly soluble drug” or “drug nanoparticle” or “drug nanocrystal” and “wet milling”).

Figure 2

Schematic of possible mechanisms operating during the wet media milling of drugs.

Figure 3

Schematic of a wet stirred media mill with recirculation mode of operation [45] (reprinted with permission. Copyright Elsevier 2014).

Figure 4

Schematic of physical stabilization mechanisms in drug nanosuspensions: (a) steric stabilization imparted by nonionic polymers or nonionic surfactants; (b) electrostatic stabilization imparted by anionic surfactants; and (c) electrosteric stabilization imparted by both nonionic polymers and anionic surfactants.

Figure 5

Effects of the stirrer speed (u) on the time-wise variation of the characteristic sizes of griseofulvin particles during wet stirred media milling (WSMM). Drug loading: 10% w/w, bead loading: 50 mL with a volumetric concentration of 0.388, bead size: 400 µm, and flow rate: 126 mL/min. Adapted from [45] with permission. Copyright Elsevier 2014.

Figure 6

Effects of the bead concentration (c) on the time-wise variation of the characteristic sizes of griseofulvin particles during wet stirred media milling (WSMM). Drug loading: 10% w/w, bead size: 400 µm, flow rate: 126 mL/min, and stirrer speed: 11.7 m/s. Adapted from [45] with permission. Copyright Elsevier 2014.

Figure 7

Effects of the drug loading on the time-wise variation of the characteristic sizes of griseofulvin particles during wet stirred media milling (WSMM). Bead loading: 50 mL with a volumetric concentration of 0.388, bead size: 400 µm, flow rate: 126 mL/min, and stirrer speed: 11.7 m/s. Adapted from [45] with permission. Copyright Elsevier 2014.