Preparation of Nanosized Pharmaceutical Formulations by Dual Centrifugation

Abstract

Dual centrifugation (DC) is an innovative in-vial homogenization and in-vial nanomilling technique that has been in use for the preparation of liposomes for more than one decade. Since then, DC has continuously been developed for preparing various liposomes and other lipid nanoparticles including emulsions and solid lipid nanoparticles (SLNs) as well as polymersomes and nanocrystals. Improvements in equipment technology have been achieved over the past decade, so that DC is now on its way to becoming the quasi-standard for the simple, fast, and aseptic production of lipid nanoparticles and nanocrystals in small and medium batch sizes, including the possibility of simple and fast formulation screening or bedside preparations of therapeutic nanoparticles. More than 68 publications in which DC was used to produce nanoparticles have appeared since then, justifying an initial review of the use of DC for pharmaceutical nanotechnology.

Basic Principles of Dual Centrifugation (DC) and Focus of the Review

DC is a unique process in which a sample vial in a fast-running centrifuge (primary rotation) is additionally turned around a second axis (secondary rotation) [1]. As a result, the direction of the high centrifugal acceleration continuously changes in relation to the (turning) sample vial, which results in highly frequent and, at the same time, strong movements of the sample material inside the vial, which typically contains heavy ZrO-beads to support the process [2]. The very intense sample movements can principally be used for mixing, shaking, milling, or homogenizing. This review focuses on the preparation of lipid and polymer nanoparticles such as liposomes, emulsions, solid lipid nanoparticles, or polymersomes using DC as a tool for in-vial homogenization and of nanocrystals using DC as a tool for in-vial nanomilling.

In addition to the high centrifugal acceleration of the samples due to a fast primary rotation and an optimal turning frequency of the sample vial around the second rotational axis, the use of lengthy vials that are placed into the dual rotor at a 90° angle to the axis of the second rotation (horizontal vial positioning, compare Figure 1) is ideal for introducing the maximal energy into the sample material. Due to the very high in-vial homogenization and milling performance, this review is restricted to DC using lengthy vials and the horizontal vial positioning, which, however, includes virtually all previous publications on lipid and polymer nanoparticles prepared with DC.

One important aspect explaining the impressive homogenization or milling results is the fact that the horizontal vial orientation gives the sample inside the vial the maximal way to accelerate (Figure 1 and Figure 2), resulting in the strongest impact when the sample containing heavy ZrO-beads reaches the end of the vial. This sample movement is in a certain way comparable to that of a horizontal laboratory shaker, with the important difference that the sample acceleration during DC is more than two orders of magnitude higher and therefore strong enough for efficient homogenization or nanomilling [2].

Figure 3. Comparison of DC-devices used for the preparation of nanosized pharmaceutical formulations using the horizontal vial positioning. (A) ZentriMix 380 R from Hettich with the corresponding DC-rotor (C) and adapter for horizontal positioning of ten 2 mL vials on one level (in total 40 vials in one run possible) (E). The ZentriMix-rotor is removeable and can be replaced by a normal centrifugal rotor for using the device as normal centrifuge. The DV1 device from Netzsch is identical in construction. (B) DAC 150 from Hauschild with corresponding DAC-rotor (D) and customized adapter for horizontal orientation of 2 mL vials (F).

The second important aspect explaining the good homogenization efficacy using lengthy vials in combination with a horizontal vial positioning is that the sample does not “fly” directly from top to bottom. Instead, the sample including the ZrO-beads glides along one side of the inner vial wall from top to bottom and vice versa. Since the axes of the secondary rotation have an approx. 40° angle related to the main (primary) rotational axis (compare Figure 2), the sample gliding takes place on a defined path inside the vials. The explanation for this is that the vector of centrifugal acceleration hits the vessel at this 40° angle and thus acts on the sample in two directions. One vector of the parallelogram of forces pushes the sample from top to bottom of the vial, and the other vector presses the sample on the gliding path (Figure 2). This results in additional “high-performance friction” of the sample by the heavy ZrO-beads.

Download the full article as PDF here Preparation of Nanosized Pharmaceutical Formulations by Dual Centrifugation

or read it here

Koehler, J.K.; Schmager, S.; Bender, V.; Steiner, D.; Massing, U. Preparation of Nanosized Pharmaceutical Formulations by Dual Centrifugation. Pharmaceuticals 2023, 16, 1519. https://doi.org/10.3390/ph16111519