Multiple orifices in customized microsystem high-pressure emulsification: The impact of design and counter pressure on homogenization efficiency
Graphical abstract
Introduction
The processing of nanodisperse systems, either emulsions or suspensions, is a demanding challenge for manufacturing devices. Nevertheless, these processes have continuously been developed and well been characterized to provide high quality products. These nanodisperse products are of high interest in many fields of research and manufacturing because the nanoscale dimensions may provide advantageous and innovative properties to materials well known from macroscale.
Many efforts are carried out in the field of dairy processing (e.g. milk, yoghurt, butter). Development in this field is primarily focusing on high throughput and energy efficiency. With the manufacturing of pharmaceutical formulations, however, the production volume is likely to be smaller while the product properties are more critical and have to be met in a narrow range. In pharmaceutical applications, nanoemulsions and solid nanoparticles (especially solid lipid nanoparticles, SLN) are promising vehicles for drug delivery. Nanoemulsions and nanoparticles may facilitate the application of hardly soluble drugs, enhance their bioavailability and permeation through biological barriers, enable drug targeting, sustain drug release, and protect drugs against degradation [1]. Furthermore, these particulate systems allow many ways of administration such as by parenteral [2], peroral [1], [3], dermal [4], [5], [6], [7], ocular [8], [9] or respiratory [10], [11] route. Regarding the tolerance of nanodisperse lipid systems in vivo, nanoemulsions are routinely used for parenteral nutrition since the 1950s [12]. Since many years, nanoemulsions have also been used as commercial drug delivery systems e.g. for diazepam [13].
However, pharmaceutical application poses special requirements towards product quality concerning defined, small particle sizes, narrow particle size distributions, and high stability.
As the most common production technique, the top-down manufacturing method of high-pressure homogenization has extensively been developed and characterized for the production of nanosized particles [14], [15]. Different principles in homogenization devices are applied: radial diffusers, axial flow nozzles (or orifices) and counter jet dispersers [16], [17]. The latter two principles are commonly implemented without movable parts, yielding advantages towards human error, mechanical failure, and wear.
In this study, the intensified development and characterization of customized microsystems is described, which provide several advantages: a high surface-to-volume ratio, a defined residence time distribution, and a defined input of stresses to the product stream (by customizing microchannel design). Additionally, the application of small educt batches and a good product recovery, due to small dead volumes, are facilitated. This is of special interest for applications in early pharmaceutical development if just small amounts of active pharmaceutical ingredients (APIs) are available for formulation screening. The use of such microsystems offers cost reduction and simultaneously decreases process times and hazardous potentials.
With regard to an integrated overall microsystem that comprises further process steps – both prior (e.g. the dispersion of solid APIs in the oil phase and the initial junction of the oil phase and the aqueous phase) and subsequent ones (e.g. defined cooling and crystallization of solid lipid nanoparticles) to the high-pressure homogenization – a continuously operating system is required. Thus, the homogenization must yield small particle sizes with a narrow size distribution by the application of a single passage through the microsystem. According to that, the homogenization efficiency of the microchannel design is of special interest.
In previous work, we showed that microsystems are generally able to meet these requirements [18], [19], [20]. The results rose questions about the underlying mechanisms and influences on droplet disruption and stabilization that needed further investigation of the microsystem design as well as the process parameters. Most promising candidates were orifice microchannels due to their simple structure in combination with high homogenization efficiency. Especially the application of multiple orifices showed interesting results and perspectives [19] which are investigated in detail in this study. The number of orifices, the distance between orifices, and the combination of different orifice widths are evaluated over a wide pressure range.
In the literature, the addition of a second consecutive homogenization stage or structure has been described to lead to an enhanced reduction in droplet size [21], [22], [23], [24]. This is most likely explained by the application of counter pressure towards the first orifice, fostering the cavitation intensity which is understood to contribute to droplet disruption [23], [25]. The applicability of this counter pressure theory to explain the effects in the present microsystems was studied with regard to design modifications and the application of external counter pressure.
In addition, the effects of formulation variations regarding the emulsifier (faster adsorption to interfaces) and the viscosities of continuous and disperse phases were examined. These experiments furthermore provide insight regarding the differentiation of the breakup efficiency and the stabilization efficiency of the microsystems.
Section snippets
Materials
Medium chain triglycerides (MCT; Miglyol® 812, Caelo, Hilden, Germany) were used as liquid oil for emulsion preparations. Macrogol-15-hydroxystearate (MHS; Solutol® HS 15, BASF, Ludwigshafen, Germany) was used in aqueous solution as nonionic emulsifier/stabilizer. It consists of polyethylene glycol mono- and diesters of 12-hydroxystrearic acid and approx. 30% free polyethylene glycol. Sodium dodecyl sulfate (SDS; Texapon® L100, Henkel & Cie, Düsseldorf, Germany) was used as anionic emulsifier in
Characterization of flow parameters
Characteristic diagrams of the emulsion (stabilized with MHS) flow rate, the maximum mean fluid velocity (Eq. (2)) and the Reynolds number (Eq. (3)) at 1500 bar were compiled (Fig. 3) to facilitate the interpretation of the efficiency of droplet break-up within the microsystems. The single orifice microsystem displays the highest flow rates while the triple orifice microsystem displays the lowest flow rates (Fig. 3A) due to the increased flow resistance. All double orifice microsystems show flow
Conclusion
The knowledge of common homogenization devices and the implications of previous work on microsystems were successfully pursued towards the application of multiple orifice microsystems in continuous nanoemulsion production. Therefore, an especially efficient microsystem was designed and design aspects were systematically evaluated.
Both, the droplet breakup efficiency and the efficiency of the prevention of coalescence of newly formed droplets were identified crucial. The droplet breakup is most
Acknowledgements
The present study was performed in the context of the Research Group 856 “Mikrosysteme für partikuläre Life-Science-Produkte” (mikroPART). The authors would like to kindly thank the German Research Foundation (DFG) for funding this research group. Furthermore, the authors would like to thank BASF for the kind support with materials. One of the authors (S.B.) gratefully acknowledges the financial support of the Volkswagen Foundation.
References (58)
- et al.
Solid lipid nanoparticles for drug delivery
J. Drug Deliv. Sci. Technol.
(2011) - et al.
Lipid nanoparticles for parenteral delivery of actives
Eur. J. Pharm. Biopharm.
(2009) - et al.
Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products
Int. J. Pharm.
(2009) - et al.
Sun protection enhancement of titanium dioxide crystals by the use of carnauba wax nanoparticles: the synergistic interaction between organic and inorganic sunscreens at nanoscale
Int. J. Pharm.
(2006) - et al.
In vitro erythemal UV-A protection factors of inorganic sunscreens distributed in aqueous media using carnauba wax-decyl oleate nanoparticles
Eur. J. Pharm. Biopharm.
(2007) - et al.
Characterization of solidified reverse micellar solutions (SRMS) and production development of SRMS-based nanosuspensions
Eur. J. Pharm. Biopharm.
(2003) - et al.
Drug release and permeation studies of nanosuspensions based on solidified reverse micellar solutions (SRMS)
Int. J. Pharm.
(2005) - et al.
A toxicological evaluation of inhaled solid lipid nanoparticles used as a potential drug delivery system for the lung
Eur. J. Pharm. Biopharm.
(2010) - et al.
Solid lipid nanoparticles production, characterization and applications
Adv. Drug Deliv. Rev.
(2001) - et al.
Design and characterization of a submicronized o/w emulsion of diazepam for parenteral use
Int. J. Pharm.
(1989)
Preparation, characterization and biocompatibility studies on risperidone-loaded solid lipid nanoparticles (SLN): high pressure homogenization versus ultrasound
Colloids Surf. B
The production of parenteral feeding emulsions by Microfluidizer
Int. J. Pharm.
The influence of customized geometries and process parameters on nanoemulsion and solid lipid nanoparticle production in microsystems
Chem. Eng. J.
Innovative process chain for the development of wear resistant 3D metal microsystems
Microelectron. Eng.
The influence of alkali fatty acids on the properties and the stability of parenteral O/W emulsions modified with Solutol HS 15®
Eur. J. Pharm. Biopharm.
Re-coalescence of emulsion droplets during high-energy emulsification
Food Hydrocolloids
Formation of nanoemulsions stabilized by model food-grade emulsifiers using high-pressure homogenization: factors affecting particle size
Food Hydrocolloids
Incorporating emulsion drop coalescence into population balance equation models of high pressure homogenization
Colloids Surf. A
Development of the new gaulin micro-gap™ homogenizing valve
J. Dairy Sci.
Studying the effects of adsorption, recoalescence and fragmentation in a high pressure homogenizer using a dynamic simulation model
Food Hydrocolloids
Emulsion processing—from single-drop deformation to design of complex processes and products
Chem. Eng. Sci.
Influence of increasing viscosity of the aqueous phase on the short-term stability of protein stabilized emulsions
J. Food Eng.
Stability of emulsions under equilibrium and dynamic conditions
Colloids Surf. A
Visual observations and acoustic measurements of cavitation in an experimental model of a high-pressure homogenizer
J. Food Eng.
Effect of dynamic interfacial tension on the emulsification process using microporous, ceramic membranes
J. Colloid Interface Sci.
Solid lipid nanoparticles: an oral bioavailability enhancer vehicle
Exp. Opin. Drug Deliv.
Lipid nanoparticles (SLN®, NLC®) for cutaneous drug delivery: structure, protection and skin effects
J. Biomed. Nanotechnol.
Low cytotoxicity of solid lipid nanoparticles in in vitro and ex vivo lung models
Inhalation Toxicol.
Emulsification: more than just comminution: Emulgieren: Mehr als nur zerkleinern
Chem. Ing. Tech.
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