Microencapsulation : fundamentals, applications and technologies

Professor Denis Poncelet , Professor, ENITIAA ( Food Engineering School ), President of the Bioencapsulation Research Group, Chairman COST865, Cofounder and Scientific Adviser Capsulae , France  

Abstract : Life really starts when "God" decides to immobilise biochemistry inside small capsules, the biological cells. This entrapment provides material immobilisation, protection, mass transfer control, structure determination and functionality. During the last half century, engineers developed many processes of encapsulation to approach the incredible power of cells. Microencapsulation, even not directly visible for customers, is involved in plenty of products that we use every days.

Regarding the spreading of encapsulation technologies over many fields, to reach specific targets, it is generally difficult to analyse, classify and select the right technology for a specific industrial application. The presentation will make an overview of the potentialities of microencapsulation, will classify and organize technologies, point out advantages and disadvantages of the different approaches to developing industrial processes.

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BioSwitch: Release on command of active ingredients

Dr Ted Slaghek, Johan Timmermans, Sjaak van Veen, Roy Montijn and Rik Thijssen,

TNO Quality of Life, PO Box 360 , 3700 AJ, Zeist , The Netherlands

Abstract: This paper describes the development of a new delivery system whereby it is possible to deliver an active ingredient on demand. The technology uses (modified) natural polymers and/or charged such as polysaccharides and proteins which are cross linked into a three dimensional network (matrix). Due to the charge, present in the three dimensional network, it is possible to contain an active ingredient until through the action of an outside stimulus the network's integrity is dismantled. An obvious outside stimulus is e.g. enzyme activity hydrolyzing the polymers, used to create the three dimensional network.

The object of the research is to develop a new technology which is able to release an active ingredient only when it is needed and should stay dormant when it is not needed. In order to develop such a system a matrix has to be developed which is able to contain an active ingredient and only release the ingredient through the action of an outside stimulus as depicted in figure 1. In such a way it is possible to use active ingredients in a more efficient way resulting in a higher efficiency of the use of active ingredients. Also depending on the active ingredient a longer stability can be achieved. In order to develop the above described matrix it turned out that the use of biopolymers or modified biopolymers is crucial. Examples are carboxymethyl cellulose (CMC), oxidized starches, cationised starches, pectins, (hydrolysed) proteins such as gelatin and gums like guar gum and also blends of polymers may be used. These polymers have to be crosslinked in order to form the matrix in which the active ingredient is incorporated. Typical cross linkers used are sodium trimetaphosphate, epichlorohydrin, and di-epoxides.

Figure 1:

The research on this topic started about two and a half years ago at TNO. During the lecture the newest developments will be discussed.

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Power Ultrasound, Crystals and Particle Engineering

Dr Graham Ruecroft
Chief Technical Officer, Prosonix Ltd

The Magdelen Centre, Robert Robinson Avenue , Oxford Science Park
Oxford , OX4 4GA , UK
Tel: +44 (0) 1865 784244; Switchboard: +44 (0) 1865 784251
Mobile : +44 (0) 7968 707682; Fax: +44 (0) 1865 784251 graham.ruecroft@prosonix.co.uk ; W: www.prosonix.co.uk

Biography: Graham Ruecroft received BSc (1983), MSc (1986) and PhD (1989) degrees in chemistry from the Teesside Polytechnic, North London Polytechnic and the Open University (all UK ) respectively. He has spent over 20 years in the UK pharmaceutical and fine chemical industries including Wellcome Foundation, Ferring Research, Enzymatix, Chiroscience, Chirotech, Dowpharma and Ultrafine; principally in Process R & D, synthetic  chemistry and crystallization. He joined Accentus C3 Technology (UK) as Head of Process Research & Development in 2003. He is a co-founder and director of Oxford based Prosonix, which bought the C3 Technology business in 2006, where he is the Chief Technical Officer

Abstract: Power ultrasound within chemical processing has particular importance in crystallisation control including nucleation, size distribution down to micron-size, and morphology. Typically mesoscopic particles for drug inhalation are manufactured by primitive pharmaceutical technologies such as micronization to turn large, regular crystals into irregular 1 – 5 ?m particles that can undergo morphological change and surface polymorph transformations leading to amorphicity and decreased stability. Microcrystalline drug particles for inhalation can be prepared using new power ultrasound assisted technologies such as the Solution Atomisation and sonoXtallization (SAX) technology being developed by Prosonix in conjunction with the University of Bath, UK. This allows the production of spherical drug particles with superior geometrical, surface and performance properties, and aims to have a high level of control of the surface characteristics and surface geometry of micron and sub-micron sized particles.

Power ultrasound (20 and 100 kHz) techniques can include antisolvent precipitation in the production of microcrystalline particles when a drug solute solution makes contact with an antisolvent, which may include water. Ultrasound can assist crystallisation through cavitation and acoustic streaming. Prosonitron ultrasonic flow-cell equipment can be used to prepare micron and sub-micron particles of single APIs and combination particles, whereby two drug substances are incorporated into a single particle. By varying flow-rates and insonation conditions, the particle size can be controlled quite effectively from sub 5 micron down to hundreds of nanometres.

SAX is a sonocrystallization technique for production of particles with optimum size and morphology suitable for formulation where microcrystallinity is essential. There are benefits in the production of particles for inhaled therapeutics, and also see potential in the production of nanosuspensions, pharmaceutical co-crystals and combination-based products. SAX allows production of spherical particles within a well-defined size range and with control of the macroscopic morphology, including polymorphism and surface topology: Important characteristics in defining the performance of such particles, in turn defined by aerodynamic properties of particles, shelf life, stability, bioavailability and efficacy. It is particle geometry that is the central design principle in controlling surface forces and hence interfacial interactions. For SAX, cavitation is particularly effective in promoting nucleation. It is also very effective in conventional batch crystallization, including polymorphic systems, by helping to reliably form seed crystals enabling control of crystal size distribution, morphological control, elimination of impurities in the crystal, and improved solid-liquid separation behaviour.

It is now possible to use power ultrasound at industrial scale required for fine chemical and pharmaceutical manufacture. Industrial equipment to allow effective and focussed distribution of acoustic energy into a liquid by using a number of low-power transducers bonded to the outside of a cylindrical duct is now available. The scale-out feature of the technology ensures that success in the lab can be replicated across scale. The in-line continuous flow or batch mode process can be applied to intermediates, excipients, APIs, binders and sugars, and importantly can be validated across scale in cGMP environments.

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Microencapsulation and Controlled Release of Flavours

Fabio Campanile , Head Flavour Delivery Systems R&D, Givaudan

Huizerstraatweg 28, 1411 GP Naarden, The Netherlands
Tel. +31356992141
Fax +31356950304

e-mail fabio.campanile@givaudan.com

Abstract: Encapsulation in the foods business has been the focus of relevant activities in the past decade. Particularly in the area of flavours, various encapsulation techniques have been successfully applied in order to enhance flavour functionality and performance in applications where long shelf life stability is required or heavy thermal processing is applied. Another important emerging aspect of flavour encapsulation involves the use of controlled release as a new tool for the design of consumer's products.

The present work reviews some of the more relevant techniques in the area of microencapsulation and controlled release of flavours focusing on relevant processes and recent innovation in the field. Specific examples will be mentioned with reference to end use applications.

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Lipid nanoparticles (SLN, NLC) for improved formulation of cosmetic and pharmaceutical actives

Prof. Rainer H. Müller, PhD

Free University of Berlin , Department of Pharmaceutical Technology, Biopharmaceutics & Cosmetics, Kelchstr. 31, 12169 Berlin, Germany

www.mueller-berlin.com , mpharma@zedat.fu-berlin.de

Abstract: The lipid nanoparticles are a particulate carrier system with a particle matrix composed of lipids being solid at body temperature. They are derived from o/w emulsions by replacing the liquid lipid (oil) by a solid lipid (so-called solid lipid nanoparticles – SLN). Alternatively a blend of a solid lipid with a liquid lipid (oil) can be used which is also solid at body temperature (nanostructured lipid carriers – NLC). The NLC as a second generation of lipid nanoparticles were developed in 1999/2000, the first cosmetic products based on NLC are meanwhile on the market.

The special features of the lipid nanoparticles will be discussed for improved formulation of actives. Due to the solid character of the particle matrix, labile actives can be protected against degradation increasing their shelf life. Incorporation of molecular sunscreens leads to an increased protection against UV radiation. Applying active-loaded lipid nanoparticles to the skin leads to an increased “bioactivity” of the actives in the skin. The localisation of drugs in the skin can be modulated depending on the composition of the lipid nanoparticles. After oral administration the lipid nanoparticles enhance the bioavailability of actives. This is of interest not only for pharmaceutical actives, but also for nutrition supplements and nutraceutical products. Basically the controlled release properties can be applied in various areas.

From the technical point it is of interest that the lipid nanoparticles are made from accepted excipients. Large scale production is easily possible using established high pressure homogenisation lines. Various market applications will be discussed, e. g. the cosmetic products on the market in Europe and Asia . Potential for products in other areas such as pharmaceuticals will be highlighted.

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Vesicular Delivery Systems: Options to Target Cosmetic Actives to Different Locations in Skin

Dr Joanna Newton, Dow Corning Corporation, Belgium

Abstract: Currently, there are many different carrier systems available to deliver cosmetic actives into and onto the skin and hair surface. These range from relatively simple systems such as conventional emulsions through to more technically complex nanoparticles and micro / millicapsules systems.

Vesicular systems possess a structure like “hollow particles” with water at the exterior and interior of the particles, with bilayer forming the particles. Vesicular systems are of particular interesting as carrier systems for their ability to encapsulate lipophilic actives within the bilayer and to encapsulate hydrophilic actives at the interior of vesicles.

Recent Dow Corning developments of novel silicone technologies have led to innovative delivery systems suitable for a broad range of personal care applications bases on silicone vesicles. Silicone vesicles are microstructures formed via the assembly of individual surface-active silicone polymers. They can be viewed as analogs to liposomes, except their wall material is composed of polyether-modified dimethicone (dimethicone copolyols). They rearrange into a bilayer structure (lamellae), where the hydrophobic moiety is folded to form the inside of the bilayer while the hydrophilic moieties are facing the outside.

However, to further establish a diversified solution set for delivery systems, Dow Corning took a decision to complement the offering and capabilities of these silicone chemistries with additional organic vesicular technologies.

Phospholipid-based vesicular systems are a class of carrier systems which consist of microscopic vesicles composed of one or multi lipid bilayers surrounded by a watery core. Such systems were first commercially exploited in the 1980's, but their widespread exploitation was somewhat limited by issues surrounding their physical and chemical stability. However, recent studies have led to a significantly increased understanding of liposomes as carrier systems eliminating some of these stability issues.

Dow Corning, working in collaboration with an external partner, has developed 2 new ranges of liposome materials, which utilizes high purity, unsaturated flexible phospholipid raw materials. The penetrating liposome system allows penetration of the liposome into the upper layers of the epidermis, delivering a variety of cosmetic actives into the skin. The second non-penetrating range is stabilized by a sterically-hindered polymeric group, which deliberately prevents penetration and deposits the cosmetic actives on to the surface of the skin or hair.

These two distinctive classes of vesicular systems provide innovative materials for the creative formulator which are particularly effective at delivering a wide range of desirable features and benefits.

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Using Microencapsulation to Achieve Controlled Release

Ronald J. Versic, Ronald T. Dodge Co., USA

Abstract: The purpose of this presentation is to p rovide each attendee an introduction to the basic concepts of controlled release and microencapsulation in particular. Then there will be an explanation of the significant/important technologies in commercial use.

Finally, there will be a description of representative products in commercial use. Each of these products will then be related back to the technology used in their production.

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Encapsulation by Melt Extrusion Technology

Dr Gülden Yilmaz, Agrotechnology & Food Sciences Grou, Wageningen University , The Netherlands

Abstract: Industrial applications of the extrusion process can be dated back to 1930. Emergence of extrusion technology was mainly in the plastics processing area and during the following years of development and application, extrusion technology has become a well-elaborated tool with technical solutions available for different fields.

One of those growing applications is the utilization of extrusion for the production of controlled release formulations. The basic idea behind encapsulation using extrusion is to create a molten mass in which the active agents, i.e. either liquids or solids, are dispersed or dissolved. Upon cooling, this mass will solidify, thereby entrapping the active components. Extrusion is an efficient and cost effective production technology to obtain matrices encapsulating a wide range of encapsulants. Usually the required release-kinetics of the encapsulant may also be achieved by the right formulation of the matrices. A wide variety of compounds can be encapsulated, such as flavors, essential oils, agrochemicals, nutraceuticals, pharmaceutically/biologically/chemically active compounds and even live cells.

To encapsulate the compound of interest efficiently and effectively, utilizing this technology, co-rotating, double screw extruders equipped with sinusoidal screws (self-wiping) are preferred. The reason for this is that firstly, self-wiping screws ensure a narrow and well-defined residence time. Secondly, the mixing performance of double, co-rotating screws appears to be the optimal configuration, since the surfaces of the screws move toward each other. Thirdly, distinctive properties, such as short residence time, and maximal flexibility, make double screw extruders a preferred choice for encapsulation processes.

Optionally modification of the matrix properties can be achieved chemically, enzymatically or physically such as cross-linking, modification of the crystallinity or the Mw of the matrix during the course of the process. Schematic representation of an extruder used for encapsulation is shown in Figure 1.

Figure 1. Schematic representation of an extruder for encapsulation.

The main prerequisite for the polymer or the mixture of materials to be used as the matrix formulation in an extrusion encapsulation process is the thermoplasticity. This gives a wide range of options although not each of those options is explored. Depending on the polymer or the product properties that are required additives are often used such as plasticizers, lubricants, emulsifiers.

The variety of applications is due to the extrusion process that is so flexible, continuous process, excessive use of solvent is not required, making a drying step abundant, and that it can, if necessary, be employed at relatively low temperatures. Furthermore, it has been shown that the modification of the product characteristics can easily be done by means of small modifications to the processing technology. Both hydrophilic and hydrophobic components can be encapsulated either in hydrophilic pr hydrophobic matrix materials. In case of two phase formulations very fine dispersions of the encapsulant (down to nanometer scale) can be obtained. Throughout the last years it has been also demonstrated that also the release rate and kinetics of the encapsulants can be controlled and modulated by the composition of the formulations and the processing conditions.

In this lecture, encapsulation via extrusion technology is discussed with a focus on the technological aspects, possible applications and recent developments in this field.

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Controlled Delivery of Agrochemicals

Dr Ian Shirley, Syngenta , UK

Abstract: Many technologies for diverse applications have been developed and applied to the controlled delivery of agrochemicals, which are taken here to include products for use in crop protection and in other professional markets such as public health and materials protection. As in other industries, such as pharmaceuticals, the aim is to deliver the right amount of active compound to the right place at the right time. Methods are thus evolving for targeted and timed delivery.

The talk will give an overview of technologies ranging from micro- to macro-delivery vehicles highlighting progress over the past 15 years. A more detailed discussion will be given on microcapsule technology where many crop protection active ingredients are applied by spraying.

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Extrusion Granulation: An Alternative Biocide Delivery System

James Robson, Exwold Technology Ltd., UK

Abstract: This talk will discuss both the process involved in “low pressure wet” extrusion, looking at the important part that formulation chemistry plays in achieving the desired end product specification, and the applications which granules using this process can be used for.

Low pressure extrusion granulation began back in the 1950's when pharmaceutical companies were looking for a consistent method of feeding a mixed powder matrix into a tablet pressing machine.  Simple powder blends had such a low bulk density that the compression ratio needed in tabletting gave very poor quality tablets.  The solution was an extruded granule which increased the bulk density between 2 and 3 times.

In the mid 1960's the Agrochemical industry was also looking for new delivery techniques for pesticide formulations. Granules we considered a significant advance over powdered products for a variety of reasons, including improved handling/flow properties, elimination of dust hazards, more accurate measurement for dosage purposes.

By combining formulation chemistry and processing variations it is now possible to produce granules with specific properties, eg: dissolution speed, particle size, bulk density, strength, colour, geometry, etc…

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Delivery of Biocides from Antifouling Coatings

Paul Kappock , Technical Manager for the Marine Anti-fouling Business, Arch Chemicals Inc., USA

Abstract: The growth of organisms on the bottom of ships dramatically increases the fuel consumption and decreases the speed of the ship. The application of antifouling coatings to ships can have a dramatic effect on both fuel consumption and speed. Historically, the release of biocide from the paint film has been and continues to be the predominant mechanism for prevention of fouling. Antifouling technology has evolved from the solubilization and leaching of biocide from an insoluble matrix to ablative and self polishing polymers that release biocide at a more controlled and efficient rate. The toxicity and environmental persistence of many of the biocides has led to regulations that ban or restrict their use. Today, in many countries, there is a short list of products that are allowed to be use in antifoulant coatings. Newer technologies are constantly being evaluated to minimize, optimize, or eliminate the need for biocides.

Release of biocides from the paint film is dependent on the properties of the polymer and the biocide. Acrylates are the most common of the self polishing polymers. The polymer polishing mechanism depends on using hydrolysable monomers. Zinc, copper, and silyl acrylates erode at different rates, allowing for flexibility in formulating coatings for ships with varying requirements. Biocides that are low in water solubility and immiscible in the binder will be released at the same rate that polymer erodes, while biocides miscible in the binder will be released at a faster and less controlled rate. The ideal release rate will provide just enough biocide at a predictable and steady rate to prevent fouling of the paint film. Details of polymer erosion and biocide release in model systems are presented in this paper.

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