100 Years of Vitamins: The Science of Formulation is the Key to Functionality †

Micronutrients and nutraceuticals such as vitamins, carotenoids, polyunsaturated fatty acids and polyphenols are classes of food ingredients that are essential for human health and well-being. These compounds are rarely added purely to the targeted food application but rather in encapsulated, solid, dry product forms with added functionalities such as improved stability, bioavailability or handling. This review presents some of the industrially most relevant particle technologies, as well as emerging ones, for synthesis and formulation of micronutrients and nutraceuticals. The influence of technological process parameters on product particle physicochemical properties such as size, morphology and structure are highlighted as well as their importance for end-use applications.


The Histor y of Vitamins
In 1912, the Polish biochemist Casimir Funk (1884Funk ( -1967 coined the term vitamins. The discovery of vitamins as essential factors in the diet was a scientific breakthrough that changed the world! Already in 1906, Frederick Gowland Hopkins indicated that "no animal can live on a mixture of pure protein, fat and carbohydrate" -this started the search for "growth factors" in food. The Dutch physician Christian Eijkman found that a constituent of rice bran can prevent a beriberi-like disease in chickens and Gerret Gryns was the first scientist to adopt the deficiency theory for the etiology of this disease. He stated that the disease breaks out when a substance necessary for the metabolism is lacking in the food. In 1912, Casimir Funk isolated a bioactive substance from rice bran which was at first given the name "vita-amine". Funk realized that this substance could cure chickens and human patients from beriberi. He published a landmark paper "The etiology of the deficiency diseases" and stated that all "deficiency diseases can be prevented and cured by the addition of certain preventive substances, the deficient substances", for which he proposed the name "vitamines" 1) . Two years later in 1916, the American biochemist Elmer V. McCollum introduced capital letters to differentiate between vitamin A, vitamin B, vitamin C and vitamin D. Later, vitamin E and vitamin K were added and it was realized that a food containing vitamin B can contain more than one factor and a further differentiation into vitamin B 1 , vitamin B 2 and so on was applied.
These obser vations and findings facilitated the experimental research in the following years enormously. The next three decades were full of scientific breakthroughs in the understanding of the role of vitamins and by 1941, all 13 vitamins had been discovered and characterized. These are now classified as either water-(e.g. vitamin C) or fat-soluble (e.g. vitamin A), as listed in Table 1. The scientific breakthroughs were honored with twelve Nobel Awards to 20 Nobel Prize winners. The Nobel Award in Chemistry 1928 was given to Adolf Windaus for his studies on the constitutions of the sterols and their connection with the vitamins. This was followed by the Nobel Prize in Medicine and Physiology in 1929 jointly to Christiaan Eijkman for the discovery of the anti-neuritic vitamin and to Sir Frederick Gowland Hopkins for the discovery of the growth-stimulating vitamins.
Already in the 1940s, authorities had started to establish dietary standards and nutrient requirements (recommended daily allowance) for the optimal intake of vitamins depending on age, gender and risk groups. In order to secure a sufficient intake of vitamins for the full population, a number of countries implemented fortification programs of staple food; today food fortification is established in more than 60 countries. Examples are the fortification of flour or sugar with vitamin A especially in low-income countries, the fortification of flour with folic acid in the US, Canada and Latin American countries, the fortification of margarine with vitamin A and D or the fortification of milk and juices with vitamin D. The World Bank s assessment of fortification was: "probably no other technology available today offers as large an opportunity to improve lives and accelerate development at such low cost and in such a short time" . Today, there is a wide consensus amongst scientists about adequate vitamin intake and the relation to health and healthy aging. Science continues to provide new approaches and insights on the role of vitamins and to demonstrate that "the identification of the role of vitamins was one of the most important contributions of science to mankind".

Micronutrients and Nutraceuticals: A Formulation Challenge
The understanding that micronutrients are essential for human and animal growth and health 7) and that they have to be part of the diet was a major stimulus for nutrition science. Research was extended also to nutraceuticals and health ingredients such as polyunsaturated fatty acids, oily plant extracts and fruit powders that provide certain health benefits (but are not essential) 8) . Subsequent to the recognition of the vitamins and the discovery of their function it became clear that breakthroughs in the production, formulation and application would have to be achieved in order to allow them to be used by humans and animals. This inspired scientists in pharmaceutical companies in Europe and the US to develop synthetic routes and formulation technologies. The first production of a vitamin on a technical scale was achieved by Hoffmann-La Roche in 1934 for vitamin C based on a combined fermentation and chemical process developed by Tadeus Reichstein. In the following years all vitamins became available via chemical synthesis, fermentation or extraction from natural materials. Industrial production was not the complete solution yet, and new challenges arose with the incorporation of micronutrient and nutraceuticals in end-user applications such as tablets, vitamin waters, beverages, yoghurts and other foodstuffs.
Especially lipids and fat-soluble vitamins 2) are difficult to add to food products (e.g. to a hydrophilic environment such as a beverage), and are often chemically unstable to, e.g. oxidation, hydrolysis, light and heat 9,10) . New technologies had to be explored and again know-how and formulation competencies of pharmaceutical companies gave the basis for the development of vitamin forms. This offered opportunities to provide vitamins for humans and animals for optimal growth and health. Therefore, micronutrients and nutraceuticals are nowadays rarely sold in pure form and are mostly delivered in microencapsulated product forms to protect the active ingredient from the surrounding environment [11][12][13][14] . Thereby the stability and shelf-life of the compounds are prolonged and they can be released in a controlled and tailored manner. Further benefits of microencapsulation processes include easier handling, improved sensor y properties with respect to appearance and taste and uniform dispersion of low-concentrated actives 15) . Innovation in colloid and nanosciences facilitates the development of product forms for different applications. Progress in formulation results from close  (smell, taste) cooperation between basic science carried out at universities and applied science in industr y. However, the knowledge of formulation is often a special expertise of companies, protected by patents and not available in textbooks.
Particle properties in these dry product forms are of the utmost importance to achieve the desired performance in target applications and have to be carefully controlled during their synthesis. For example, particle size can govern the optical appearance and sensory perception of the product as well as the dissolution rate and bioavailability of the active. Particle morphology and shape influence flowability, ease of handling and processing of the powders. For example, during the preparation of multivitamin-multimineral tablets, several nutraceutical components and excipients are blended. The mixture must be uniform (no segregation) and free-flowing for accurate dosing in the tabletting equipment. Encapsulates are traditionally classified as reservoir (core-shell) or matrixtype spherical particles 16) , however, other shapes and morphologies such as rods or irregular shapes as well as aggregates and agglomerates also have to be considered. The internal structure and composition such as porosity, cr ystallinity and glass transition temperature would affect the stability and shelf-life of the products. Controlled release and stability of encapsulated active compounds can be achieved by the proper selection of the matrix material and its concentration [17][18][19][20] . Common encapsulation materials in the food industry are listed in Table 2. One of the central issues in the design of an optimal encapsulation material is the molecular mobility through the matrix as this affects the stability of the active ingredient. It has been shown that small quantities of low-molecular-weight compounds such as glycerol, sucrose or maltodextrin, in combination with highmolecular-weight carbohydrates improve storage stability 21) . The molecular mobility can be understood with the concepts of glass transition of amorphous biopolymers as well as the molecular free volume present in their disordered matrix. The oxygen diffusivity in a glassy carbohydrate matrix depends exponentially on the radius of the free volume element 22) . Therefore, already small differences in free volume can have a substantial impact on degradation of the encapsulated bioactive substance via chemical reactions, e.g. fish-oil lipid oxidation.
Here, the synthesis and formulation technologies (not solely limited to microencapsulation) of micronutrients and nutraceuticals are reviewed that result in solid physical morphology. Emphasis is placed on resulting particle properties such as size and shape and their influence on performance in target applications. Industrially most relevant microencapsulation technologies such as spray drying and extrusion will be covered. Novel technologies that are not yet applied on an industrial scale and mostly yield nanoscale particles will also be highlighted. Although the application of nano-sized delivery systems in foods is still under some debate, the worldwide sales of nanofood products has grown and nanotechnologies are applied by several major food companies 25) . Emulsion technologies that are often part of encapsulation processes in the liquid state especially of lipophilic compounds will not be described here, and the reader is kindly referred to recent reviews focused on this topic [26][27][28][29] . However, emulsions are often converted from the liquid state to dry powders 3) by technologies such as spray-or freeze-drying that are covered in the following text. Encapsulation technologies such as inclusion complexation 30,31) and liposomes [32][33][34] will also not be discussed as their use in foods is limited due to regulatory, cost or performance issues 16) . Finally, a focus is placed on recent advances, and therefore primarily literature published within the past 5 years is reviewed.

Particle Technologies from Nano to Macro Sizes
Par ticle technologies applied for the synthesis and formulation of nutraceuticals in industr y or academia span several length scales from nano to macro sizes ( Table 3). Product properties are to a large extent governed by the particle size. Therefore, performance in the final application can be modulated by the proper choice of particle synthesis and formulation technology ( Table 3), which are typically classified as either top-down or bottom-up approaches 8) . The former involves the break-up of larger particles or droplets to smaller ones using mechanical energy in classic processes such as milling 35) or emulsification [26][27][28] . In the case of emulsions, the smaller droplets formed are then typically stabilized by surface-active compounds, so-called emulsifiers, such as low-molecular-weight surfactants, proteins or polysaccharides. These emulsifiers adsorb at the droplet surface thereby reducing the interfacial energy and facilitate droplet disruption during processing and/or prevent droplet coalescence 28) . The final microencapsulated product particle is then formed during the dr ying step, e.g. by spray dr ying 36) , or by directly cooling the emulsion to form solid lipid nanoparticles 26) . In the bottom-up approach, individual components such as molecules, monomers or ions are assembled into larger structures or particles using a physical or chemical process 8) such as flame spray pyrolysis or precipitation/crystallization. These processes mostly yield particles of the pure compounds in the nanometer size range. On the other hand, e.g. extrusion technology can produce macrosized particles with incorporated nutraceuticals that can be directly applied in the final food application.
Industrially most relevant as well as emerging novel technologies for the synthesis and formulation of nutraceuticals will be described in the order of the resulting particle sizes from nano to macro, though a certain overlap between the various technologies exists ( Table 3).

Flame spray pyrolysis
Flame spray pyrolysis (FSP) is a bottom-up approach for the synthesis of nanostructured materials 37) . Traditionally and on an industrial scale, vaporfed flame reactors have been utilized for the synthesis of metal oxide nanoparticles such as SiO 2 or TiO 2 . The emergence of FSP technology, where a liquid precursor solution, emulsion or slurry is sprayed and ignited, enabled the development of functional nanostructured materials with a first break-through in the synthesis of highly active supported noble metal catalysts 38) . In recent years, this has been followed up by research on bio-related compounds for dental, orthopedic and even nutritional applications.
Rohner et al. 39) produced amorphous FePO 4 by FSP with closely controlled particle characteristics ( Fig.  1). Water-soluble, highly bioavailable Fe compounds such as FeSO 4 often cause unacceptable changes in the color or taste of foods, whereas poorly watersoluble Fe compounds such as FePO 4 , although more stable in foods, tend to have a low bioavailability. The absorption of the latter in the human body can be improved by decreasing their size to the nanoscale 40) , e.g. by a bottom-up approach such as FSP. An organic Fe-containing precursor solution is atomized through conventional air-assist or ultrasonic nozzles during FSP synthesis 37) . The thus formed spray is ignited by rather small pilot flames and the organic solution is combusted. Particles are formed by nucleation from the gas phase and grow by surface reaction and/or coagulation and subsequent coalescence into larger particles 37) . The size of the as-produced FePO 4 nanoparticles ( Fig. 1) can be precisely controlled by FSP process parameters such as precursor composition or precursor feed rate to the reactor. The chemical composition of FSP-made particles can also be tailored to produce multicomponent compounds 37) . Combined Fe/Zn-containing nanoparticles 41) as well as Mg-or Ca-doped Fe 2 O 3 42) have been produced by FSP for iron food fortification in foodstuffs such as rice, flour or dairy products. The nano-sized particles have high specific surface areas (SSA; up to 200 m 2 /g) 41) that ensure their high solubility and bioavailability 41,43) . Each primary, single, constituent particle is dense and spherical 39) . However, during synthesis, multiple particles can assemble into larger  37) . The presence of agglomerates can actually facilitate the powder handling and they can also easily be broken up to their constituent aggregates and/or primary particles, e.g. by ultrasonication or high-pressure dispersion 44) .
The in vivo bioavailability of these FSP-made Fe and Fe/Zn compounds in rats was comparable to the golden standard FeSO 4, and no tissue accumulation could be detected 43) . Thus the nanosizing of such poorly water-soluble Fe compounds is a promising approach to increase their absorption in the human body and their nutritional value, though further toxicological studies also in humans are required before this technology can be applied industrially 40) . From a technological point of view, the scale-up of FSP reactors from laboratory to pilot scale is feasible and has already been realized in industrial-oriented settings 45) .

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC)
An emerging type of encapsulation system are lipid nanopar ticles. The first and second generations are termed solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), respectively [46][47][48][49][50] . Lipid nanopar ticles have been widely studied for pharmaceutical and cosmetic applications where nanotechnologies can be implemented more readily. Their potential in food and agricultural industries has recently also been highlighted 51,52) . In general, lipid nanoparticles can be compared with conventional liquid emulsions in the sense that lipid droplets stabilized by a surfactant are dispersed in an aqueous continuous phase. However, in the case of SLN or NLC, the lipid phase is either fully or partially solidified 26,50) . The lipids used to prepare both SLN and NLC are typically triglycerides, fatty acids, waxes and partial glycerides 50) . Some of the main advantages associated with SLN are high encapsulation efficiencies, good physical stability, no organic solvents required during synthesis, easy large-scale production with cheap raw materials and a controlled release profile of the active substance due to the solid matrix 50,52) . SLN typcially crystallize with imperfections in their crystal lattice after preparation, which also allows the incorporation of active substances. However, during storage, a polymorphic transition to lower-energy crystal lattice arrangements can occur resulting in the expulsion of the incorporated active substance. In order to overcome this drawback of SLN, NLC were developed that exhibit a less ordered cr ystal lattice arrangement by blending solid and liquid lipids. The imperfections in NLC also allow for a higher loading of active substances compared to SLN 50,53) .
Lipid nanopar ticles are commonly prepared by forming an oil-in-water emulsion (at a temperature above the melting point of the lipid phase) and then cooling the emulsion so that the dispersed lipid phase completely or partially solidifies 50) . The preparation of a fine emulsion is crucial in order to obtain particle sizes in the nano range with preferably narrow polydispersity for the product SLN or NLC. Production techniques include, e.g. melt homogenization, melt microencapsulation and cold homogenization, which have all been reviewed elsewhere 51) .
Mainly lipophilic nutraceuticals have been incor- The FSP-made FePO 4 particles were dense and spherical, while the commercial ones exhibited an irregular and highly porous structure. The particle size calculated from specific surface area measurements corresponds to 11 nm for the small, FSP-made particles (c). The SAED (selected area electron diffraction) patterns in the insets are characteristic of an amorphous substance for all three compounds 39) .
porated into lipid nanoparticles, as they can enhance the chemical stability of these active substances that are sensitive to light, oxidation and hydrolysis 50) . Several studies have demonstrated the incorporation of carotenoids such as lutein 53,54) or -carotene [55][56][57] into NLC. Liu et al. 53) developed lutein-loaded NLC by optimizing the concentration of lipophilic and hydrophilic surfactants during their preparation. The lutein-loaded NLC had an imperfect crystalline lattice and a spherical morphology with particle sizes as small as 130 nm. However, the particle size increased with increasing lutein load due to entrapment of the active substance in the matrix of the nanoparticles. The encapsulated lutein was effectively protected in the presence of a simulated gastric fluid, and slowly released lutein in vitro into simulated intestinal fluid 53) . The particle sizes of NLC loaded with -carotene were stable and did not exhibit polymorphic transitions after 7 months of storage at 4-8 , which could make them feasible in beverage applications 57) . Thrandur et al. 56) emphasized the proper choice of surfactants during NLC manufacture to improve the protection of -carotene against chemical degradation. The role of the surfactant is dual, as it controls the formation of the crystal lattice structure during synthesis and stabilizes it during storage.
Lipophilic α-tocopherol 55) , vitamins K 1 58) and A [59][60][61] have also been incorporated into NLC. The reported concentration of encapsulated active substance is typically quite low, e.g. 2% for vitamin A palmitate 59) and <5% for vitamin K 1 58) . Similarly to lutein-loaded NLC 53) , the SLN size increased with increasing vitamin K 1 content (132 and 212 nm for 0.25 and 5.0% vitamin K 1 , respectively) and furthermore the entrapment efficiency decreased (Fig. 2) 58) . Vitamin-K 1loaded SLN were stable after 4 months with respect to particle size and vitamin content if stored at temperatures < 25 . The stability of NLC loaded with vitamin A palmitate was improved by freeze-drying 61) . Cr yoprotectants such as glucose or mannitol were added during freeze-drying in order to prevent particle aggregation resulting in the sizes 200 -250 nm in the dry product form 61) .

Precipitation
Precipitation or crystallization is a bottom-up approach for the synthesis of nano-to micron-sized particles. It was mainly developed in the pharmaceutical industries to increase the aqueous solubility and oral bioavailability of poorly water-soluble drugs 62,63) . Product properties such as particle size, morphology and surface properties can be more closely controlled by precipitation methods compared to classic top-down approaches such as milling 64) . The nucleation and growth kinetics dictate the final particle size and are controlled via supersaturation 63) . However, the precipitation process is more challenging compared to a relatively simple milling method. The high surface area formed by precipitation needs to be rapidly stabilized to avoid aggregation/agglomeration, recrystallization and Ostwald ripening 62,63) . For example, the Ostwald ripening of -carotene nanoparticles has been investigated both numerically and experimentally 65) . It was shown that the particle dispersions are more stable the narrower the initial size distribution, as the difference in solubility between small and large particles decreases 65) .
Precipitation approaches have mainly been applied to carotenoids [66][67][68][69][70][71][72][73] and polyphenols 3) amongst the micronutrient and nutraceutical compounds, and are mostly carried out with supercritical fluid technologies. In the supercritical gas phase, carbon dioxide is most commonly used as it is inert, non-toxic and has a low supercritical temperature ideal for heatsensitive materials 64) . Carotenoids have a low solubility in supercritical CO 2 and therefore the CO 2 is used as an antisolvent in such precipitation processes 70) . Particle size and morphology can be controlled by The incorporation of more vitamin K 1 into the SLN increased the particle size due to incorporation of the vitamin into the matrix of the lipid nanoparticles 58) .
antisolvent precipitation process parameters such as temperature and pressure, generally resulting in mean sizes between 1 and 200 µm or even smaller 70) . For example, the mean particle size of trans-resveratrol was reduced from 560 to 230 nm by decreasing the precipitation temperature from 25 to 5 74) . The trans-resveratrol particles were stabilized by adsorption of hydroxypropyl methylcellulose (HPMC) on the particle surface (Fig. 3). The commercial transresveratrol particles were needle-shaped and had particle sizes ranging between 20 and 100 µm (Fig. 3a).
Precipitation without HPMC resulted in irregularly shaped particles several microns in size (Fig. 3b), while aggregates of almost spherical particles ~240 nm in size were formed in the presence of HPMC (Fig. 3c) 74) . The saturation solubility and dissolution rate of precipitate trans-resveratrol nanopar ticles were significantly higher compared to the commercial starting material and could be attributed both to the decrease in particle size as well as to crystallinity 74) . Active compounds can also be directly encapsulated by co-precipitating them simultaneously with a second component such as a biopolymer or a sugar, forming either a polymer coating around the active compound, polymer particles with the active compound incorporated or co-crystals with the individual components connected by non-covalent interactions 3,69,70,73,75) . For example, the solubility of pterostilbene can be dramatically increased by forming co-crystals with compounds of a significant aqueous solubility 75,76) . The concentration ratio between the active compound and the biopolymer during co-precipitation has a great influence on the final particle morphology, encapsulation efficiency and yield 69,70) . Green-tea polyphenols have been co-precipitated and encapsulated with a biodegradable polymer poly--caprolactone 77) . The product particles were rather spherical, 3 -5 µm in size with a narrow particle size distribution but a high degree of agglomeration. A high fraction of the polyphenols was entrapped in the crystalline domains of the polymer and can thus only be released by matrix degradation, a process that may take months 77) .

Spray dr ying
Spray dr ying as an encapsulation process was introduced in the 1930s 9, 10) and is still the most frequently used technology in the food industry 4) . The process is relatively cheap, straightforward and flexible, and produces stable particles of high quality 9,18,36,78) . It has been used to encapsulate and protect a range of lipophilic micronutrient and nutraceutical compounds such as fish oil, vitamins and polyphenols 15,19,[79][80][81][82] . For many years, the spray dr ying of heat-sensitive active compounds was a challenge due to high process inlet temperatures. However, process optimization and control of the temperature has now also enabled the spray drying of sensitive active compounds such as lycopene, anthocyanins and -carotene 36,81,83,84) .
In a spray drying process, a liquid product is atomized in a hot gas current to instantaneously evaporate water and obtain a dry powder. The initial liquid feed can be a solution, an emulsion or a suspension 3,15) . The three main steps of microencapsulation by spray dr ying are preparation of the dispersion or emulsion, homogenization, and finally atomization of the  mass into the dr ying chamber 9) . The particle size and shape of spray-dried products depend to a large extent on the initial feed properties (e.g. solution viscosity, matrix materials and their concentration in the solution) as well as on the process parameters (e.g. nozzle geometry, tower height, inlet temperature). Typically, spray-dried products are rather fine powders of spherical particles 10 -100 µm in size. However, with an adequate set of process parameters available, large-sized particles (2 -3 mm) can also be obtained 3,9) . Wide size distributions are not uncommon due to the droplet size distribution in the liquid spray.
The influence of process parameters on product particle properties has been investigated in several studies 9,78,85,86) . The oil droplet size in the emulsion should be rather small and the viscosity should be low enough to prevent air inclusion and the formation of elongated, large particles 78) . Furthermore, a low emulsion droplet size results in a lower amount of unprotected (fish) oil on the surface of the particles that is essential for the shelf-life of the product 87) . A low inlet temperature facilitates the formation of dense particles with a spherical shape (Fig. 4), smooth surfaces and a uniform particle size distribution 78,86) . At higher temperatures, the water evaporation rates increase and yield irregular particle shapes due to cycles of rapid wall solidification, inflation and collapse 78) . However, the choice of too low an inlet temperature results in inefficient drying and powder agglomeration 78,86,88) .
Matrix materials used for spray dr ying must be soluble in water at an acceptable level and available for food applications, this narrows down the available choices 15) . Maltodextrins were the most widely applied matrix materials for spray drying in the past 3) . Nowadays, research focuses on combinations of mainly plant-based materials to obtain particles with improved protective barriers. Jafari et al. 87) spraydried fish oil with either whey protein concentrate (WPC) or modified food starch as surface-active biopolymers. The particles produced with modified food starch had more surface dents and shrinkage compared to WPC (Fig. 5) that could be attributed to a slower skin formation during dr ying 87) . Therefore,

Fig. 6
Scanning electron micrographs of fish oil microcapsules produced by spray granulation (SG; a), spray drying (SD; b,c) or freeze drying (FD; d). The lowest surface oil content (SOC) was found for the spray-granulated product 93) .
the fish oil was better entrapped in the modified food starch formulation. Similarly, Drusch et al. 89) found that a higher protein (caseinate) content in fish oil microcapsules leads to an increase of lipid oxidation during storage. Furthermore, an excess of protein increased the free volume which could negatively affect oxygen diffusion into the capsules 89) . Alginate, a marine carbohydrate, has been combined with starch as wall materials for the spray drying of fish oil microcapsules 90) . The addition of alginate resulted in a higher oil load capacity and in quite spherical particles with a high protection of the fish oil against oxidation. Microcapsules with up to 50% fish oil loading and > 90% encapsulation efficiency have been produced with sugar beet pectin 17,88) . Nevertheless, residual metal ions in sugar beet pectin accelerate the fish oil oxidation, resulting in poor storage stability. Blends of maltodextrin and apple pectin have also been investigated as encapsulation materials for polyphenols 91) . The combination of pectin with maltodextrin improved the storage stability and sensory properties of the product microcapsules compared to maltodextrin alone.

Freeze dr ying
Freeze drying is considered an alternative technology to encapsulate heat-sensitive compounds, as the active compound does not experience high temperatures during processing 92) . Although spray dr ying is considered an energy-intensive process due to its poor heat utilization, freeze drying remains a considerably more expensive technology 9) . Therefore, at least on an industrial level, freeze drying cannot yet be considered an alternative to spray drying and requires further research. Anwar et al. 93) made a comparative study of spray drying, spray granulation and freeze drying for the encapsulation of fish oil (Fig.  6). The microcapsule product stability decreased in the order spray granulation > spray drying > freeze drying. This could be attributed to the process drying temperature: a longer residence time at a lower temperature was found favorable for a lower oxidation of the fish oil. Although the temperature during freeze drying is very low, the resulting particle morphology is porous, irregular and flake-like, which allows oxygen diffusion 93) .

Spray chilling
A similar process to spray drying is spray chilling or spray cooling where a molten liquid is atomized into cooled or chilled air. The resulting droplets solidify and form prills or powders that are solid at room temperature. The same processing equipment as for spray drying can be used 94) . Common spraychilled carriers for encapsulation are fats, waxes, polyethylene glycols, fatty acids and fatty alcohols ( Table 2) 16) . Unlike spray dr ying, spray chilling does not involve the evaporation of water around the core 15) . However, the resulting products are not water-soluble and therefore their application should not require this function. An advantage of spray cooling is the possibility to produce different particle sizes, ranging from about 10 to 1000 µm ( Table 3) 11) . Wegmüller et al. 95) investigated the triple fortification of salt by spray cooling a mixture of vitamin A, iron and iodine in a hydrogenated palm fat matrix. The active compounds were quite stable during storage but high losses were found during processing. This process is nevertheless not as common for the microencapsulation of nutraceuticals as spray drying.

Complex coacer vation
Coacervation is a liquid-liquid phase separation of an initial solution of one or more hydrocolloids into two aqueous phases: a hydrocolloid-rich phase (coacervate) and a hydrocolloid-lean phase 16,96) . It is one of the oldest techniques of encapsulation and only a few studies have been published on this technology in the past years for micronutrients and nutraceuticals. Nevertheless, the production cost of particles by complex coacervation is still very high, and this technology is therefore only suitable for the microencapsulation of high-value active or for unstable compounds, e.g. polyphenols 4) . Fish oil coacer vates are added to a number of food products including bread, yoghurt, milk and infant formulae, and it has been shown that they are as bioavailable and bioequivalent as standard fish oil soft-gel capsules 97) . Complex coacervates are typically made from an oil-in-water emulsion with oppositely charged proteins and polysaccharides, e.g. gelatin and gum arabic 98) , and the process is carried out in five steps involving polymer dissolution and hydration, emulsification (formation of the core), coacervation (formation of the shell), hardening and washing/separation 96) . Coacervate particles are often not perfectly spherical but have rather an oval shape 4,16) . The slurry containing the coacervates can also be spray-dried or fluid-bed-dried to convert it into a dry powder, however, this might result in a loss of the initial structure 16,97,98) . Important process parameters include pH, ionic strength, temperature, molecular weight and concentration of the polymers that also determine the solubility of the resulting coacervates 4,96,98,99) . Gum arabic can be replaced by other negatively charged molecules such as pectin, carrageenan or alginate and gelatin by whey proteins 16,[100][101][102] . Recently, hydrophobic nutraceuticals such as vitamin D 2 or fish oil have been entrapped in electrostatically stable nanoparticles < 100 nm in size. The small nanocomplexes yield transparent solutions and can be used in clear acid beverages 101,103) .

Gel-particle technologies
Gel-particle technologies produce microparticles (or microbeads) composed of a biopolymer network that entraps the active compound 16) . The par ticle morphology can be either a homogeneous matrix or a core-shell structure ( Table 3). The gel microparticles are typically produced in the presence of the active compound, but post-loading especially of coreshell structures is also possible. Sodium alginate -CaCl 2 is the most commonly used gelling system (ionic gelation), and has been applied to a range of nutraceuticals, e.g. vitamin A palmitate 104) or -carotene 66) . Gel particles are typically produced by either so-called extrusion (dropping) or emulsion processes 105) . In the extrusion process, the size of the particles can be controlled by the droplet generation tool, e.g. vibrating nozzles or piezo effects, as well as by the viscoelasticity of the polymer solution. The generated droplets fall into a gelling bath containing, e.g. a CaCl 2 solution and react into gel particles. This process has the advantage of producing rather spherical and monodisperse particles. The use of concentric nozzles (co-extrusion) allows the synthesis of coreshell microcapsules. In the emulsion process, particle formation occurs by the addition of either CaCl 2 or an acid to an emulsion of alginate solution and the active compound in an oil, although several variations of the process exist 16,105) . Smaller microparticles can be produced by this method compared to the extrusion process and the particle size can be adjusted by common emulsification process parameters.
Novel material systems have been exploited for the generation of microbeads. Ca-pectinate beads have been investigated for the site-specific and sustainedrelease delivery of resveratrol 106) . Dropping solutions of water-soluble cellulose ethers such as methyl cellulose (MCE) or hydroxyl propyl methylcellulose (HPMC) into an aqueous solution of polyphenol (EGCG) results in the formation of spherical milky white beads with average diameters 600 -2500 µm (Fig. 7) 107) . The beads have a core-shell structure with a porous shell (thickness 200 -350 µm) and a hollow core with some unreacted polymer, and is formed due to the strong interactions of polymer and EGCG on the bead surface. The shell actually consists of a network of colloidal aggregates 200 -500 nm in size 107) .
Additional coating layers are often applied to particles in order to improve the stability of the active compound. Vitamin A palmitate has been formulated  Fig. 7 Cross-section of hollow core-shell beads synthesized from MCE and EGCG solutions (left) 107) and chitosan beads with vitamin A palmitate embedded in the core matrix and surrounded by double chitosan-alginate and calciumalginate shells 104) .
into double-layer capsules: the vitamin A palmitate/ chitosan core was surrounded by a chitosan-alginate membrane and an additional calcium-alginate outer shell (Fig. 7) 104) . The resulting capsules were 1000 -1200 µm in size and exhibited a high vitamin A palmitate encapsulation ef ficiency (>90%) and loading (42.5%). This resulted in a significantly improved long-term stability of vitamin A palmitate at both refrigerator and ambient conditions 104) . EGCGloaded gelatin nanoparticles about 200 -300 nm in size have been coated layer by layer with shells of polyelectrolytes 5 -20 nm thick 108) . This resulted in the sustained release of EGCG from the coated nanoparticles with a maximum EGCG concentration in solution after 8 h compared to 15 min from uncoated gelatin nanoparticles 108) . A novel class of gel-like materials is constituted by the so-called aerogels that are highly porous ( 90 -99%), lightweight ( 0.07-0.46 g/cm 3 ) and with a high surface area (S a 70 -680 m 2 /g) resulting in enhanced active bioavailability and loading capacity 109) . Aerogels are obtained from wet gels (e.g. hydrogels) by using a suitable dr ying technology, usually a supercritical dr ying process, in order to preserve the porous texture. However, a drawback in the processing is the replacement of water present in the gel structure by a solvent (solvent exchange), forming an alcogel prior to the drying step.
Traditionally, this method focused on the synthesis of silica and carbon aerogels, however, recent research has led to the development of biodegradable and biocompatible polysaccharide-based aerogels that could also be of interest for food applications [109][110][111] . Aerogels have been produced from polysaccharides such as starch, pectin, alginate, -carrageenan, agar, chitosan and cellulose 109) . Alginate aerogel microspherical particles possess a high surface area of up to 680 m 2 /g, a pore volume of up to 4.0 cm 3 /g and mean particle diameters ranging from 25 µm to few hundred microns 112) . The structural properties of polysaccharide aerogels depend on their preparation method and the chemical nature of the gel phase 109,111) . For example, an increase in temperature during gelation leads to densification of the nanoporous structure in starch aerogels (Fig. 8) 109,111) . The loading of such aerogel structures still has to be demonstrated with micronutrients or nutraceuticals as research has so far focused on pharmaceutical actives.

Extrusion
The extrusion process has mostly been used to encapsulate active compounds in a carbohydrate melt (melt extrusion) 16) . Most commonly, the carbohydrate melts are processed and mixed with active compounds in twin-screw extruders and are pressed downstream through a die to shape the product particles. Cutters can be mounted directly at the die to obtain pellets, or post-processing shaping equipment such as mills or spheronizers can be used 12,16) . The particles produced by extrusion techniques are typically dense, spherical and 0.5 to 2 mm in size 12) .
Most studies on melt extrusion have focused on the encapsulation of flavor or pharmaceutical compounds rather than micronutrients or nutraceuticals. Chang et al. encapsulated ascorbic acid in an amorphous maltodextrin matrix by extrusion 113) . Control of the water content was the most important process parameter to assure that the product extrudates had glass transition temperatures above room temperature 113) . Vitamin K 1 and vitamin D 3 have been encapsulated in matrices consisting of mannitol, sorbitol, gluconolactone and maltodextrin by melt extrusion 114) . The encapsulation of oil in a starch matrix in the presence of low-molecular-weight emulsifiers by extrusion has also been demonstrated 115) . Li et al. developed a coldforming extrusion process for the agglomeration and microencapsulation of ferrous fumarate in dough matrices 116) . The extruded particles were 300 -700 µm in size and had a higher density, lower porosity and smoother surface texture compared to particles made by fluidized-bed agglomeration. It was possible to apply a coating to the extruded particles and they were then suitable for fortification of iodized salt 117) .

Per formance in Application: Influence of Particle Properties
In the preceding sections, particle technologies for the synthesis and formulation of micronutrients and nutraceuticals have been briefly presented. A thorough characterization of the as-obtained micronutrient-or nutraceutical-loaded particles is essential, including physicochemical properties such as particle size, size distribution, morphology, density, porosity, surface charge, shell thickness, mechanical strength, glass transition temperature, degree of crystallinity, flowability and compressibility 16) . Luykx et al. recently published a comprehensive review on analytical methods including separation (e.g. chromatography), imaging (e.g. TEM, SEM, atomic force microscopy) and characterization (e.g. photo correlation spectroscopy, NMR spectroscopy, X-ray diffraction, smallangle X-ray scattering) techniques for nano delivery systems in food 118) . The particle s physicochemical characteristics will in turn govern its interaction with other molecular species and determine the bulk physicochemical properties of the overall food system (e.g. appearance, texture and stability) 119) . The choice of technology, control and understanding of the resulting particle properties is therefore crucial to achieve the desired performance in target enduse applications; several examples have already been cited in the preceding paragraphs. Readers are also kindly referred to the reviews on colloidal delivery systems for micronutrients and nutraceuticals by Velikov and Pelan 8) as well as on properties of biopolymer particles by McClements and coworkers 119,120) .
Particle size is probably the most important prop-erty in the design of micronutrient or nutraceutical deliver y systems. The recent trend has been a down-sizing from micro-to nano-sized deliver y systems 25) . Nanoparticles provide a greater surface area compared to micro-sized particles and can therefore increase solubility and bioavailability 3,8) . This has been demonstrated, e.g. for flame-made Fe and Fe/Zn compounds 43) and precipitated resveratrol 74) . However, although the primary particle size might be small, aggregation during post-processing steps such as freeze dr ying can reduce the effective surface area exposed to the dissolution medium and thereby reduce the dissolution rate 74) . The particle cr ystal structure also has an influence on solubility 42,74) . It has been demonstrated that the surface area has a limited influence on the solubility of amorphous compounds (as it is mostly high already), while a high specific surface area is required to ensure a high solubility of crystalline compounds 41) .
Particle size also has a pronounced effect on optical properties. This is exploited in the development of carotenoids as natural colorants turning from yellow through orange to red by changing the particle size 121) . Particles ideally < 50 nm that do not scatter light are required in transparent, low-turbidity beverages enriched with nutraceuticals ( Fig. 9) 101,103,119) . In contrast, large particles (> 500 nm) are used in opaque products. Alternatively, the particle refractive index or the concentration can also be modulated to alter the optical properties 119) . The particle composition itself can play a role as for example iron, which can be delivered in dif ferent molecular forms to avoid color and sensory changes when used to fortify food 41) . Small particle sizes (< 400 nm) are also favorable for product stability to avoid creaming or sedimentation in food applications 8,57) . Particle shape and morphology affects flowability, miscibility with other

Fig. 9
Colloidally stable nanocomplexes of DHA-loaded -lactoglobulin and increasing concentration of low methoxyl pectin. A precipitate is visible in the first four vials while the dispersions in the other vials are transparent. The visual observation correlates well with the mean particle size of the complexes as a function of the pectin concentration. Transparent, stable solutions had average particle sizes of ~100 nm 103) .
food ingredients, appearance, rheology, mouth feel and release characteristics 120) . Probably one of the most challenging tasks in the formulation of micronutrients and nutraceuticals is to control the release rate while still assuring protection of the active compound during processing, transport and storage. In general, the release of an entrapped compound from a dense particle is slower than from a highly porous structure which also inversely impacts the stability of the active compound 78,120) . Release of active ingredients from particles dispersed in a liquid medium is often measured to determine the release kinetics and effective diffusion coefficients. These will depend on, e.g. diffusion of the active compound through the matrix, the size and morphology of the particles, composition, transfer from the matrix to the environment and degradation or dissolution of the matrix material 16) . Four release mechanisms are typically distinguished for the dissolution of a particle: diffusion, erosion, fragmentation and swelling/ shrinking 119) . The difference in lutein release profiles shown for SLN and NLC in Fig. 10 can be related to the particle matrix composition and internal structure. This on the other hand can also be used as means to improve the stability of active compounds, e.g. as in the case of compounds entrapped in extruded hydrophilic glassy matrices that provide an almost impermeable barrier against oxygen 11,113,122) .

Concluding Remarks
One hundred years of vitamins -the "histor y of vitamins" has still not come to an end! Triggered by new technologies and building on new science, a renaissance in vitamin research started. We see a constantly increasing number of publications and studies which open up new and improved applications. We learn about nutrient-gene interactions and with the discover y of polymorphism, specific requirements for vitamins are identified. In addition we still have to assure that everyone all over the globe has access to vitamins according to recommendations. This can only be achieved by industrial production providing vitamins in the desired quality and bioavailability delivered via product forms tailored to the targeted application (e.g. acceptable sensory characteristics, storage stability, ease of handling). Table 3 summarizes the synthesis and formulation technologies for the dry powder delivery systems of micronutrients and nutraceuticals described in this review. A broad choice of technologies exist covering particles from nano-through micro-to macro-sizes with morphologies ranging from core-shell to matrix-type. The industrially most relevant particle formation technology is spray dr ying. The influence of process parameters on the resulting particle characteristics such as size and morphology is quite well understood. Nevertheless, only a few studies discuss the importance of particle shape for processing in the food industry, e.g. the influence of surface irregularities and particle morphology on flowability and coating 123) . Novel techniques can quantify and classify the particle shape (e.g. elongation, circularity, compactness and convexity) with advanced image analysis techniques and software algorithms 124) . Novel developments are mostly made in the field of nanotechnology, as the nanostructures can provide unprecedented properties. However, the scalability of these upcoming nanotechnologies still has to be proven in many cases. Another challenge is the compatibility of some technologies with legislatively approved, food-grade raw materials without the use of solvents during processing. Furthermore, technologies developed in other industries, e.g. the pharmaceutical industry, might be too costly for processing food ingredients and need to be adapted to reduce cost.
The thorough characterization of particulate deliver y systems described in this review is of great importance to understand and design their behavior in end-use applications. Physical, mechanical, structural and mass transfer properties need to be considered 16) . Often a compromise has to be made to ensure the protection of the active compound during processing and storage while still controlling the release at the desired location and time. Analysis of the systems is often complicated by their multicomponent nature including bio-polymers whose properties might even vary from batch to batch. A range of powerful characterization techniques are nowadays available for the delivery systems of micronutrients and nutraceuticals. For example, the mechanical stability of microcapsules can be studied with a combination of fluorescence and atomic force microscopy to help understand the release behavior and deformation properties 125,126) . The observed mechanical properties have to be explained by and related to the structural properties on a molecular level inside the microcapsules. Current research therefore tries to identify the complex relationship between these properties by advanced analysis methods often combining several techniques and modeling. Innovative methods that are in development include, e.g. moisture sorption isotherms 127) , positron annihilation lifetime spectros-copy to determine free volume 21,128) , coupled with exact measurements of the glass transition temperature of the product as a function of water activity and composition.
Consumer awareness towards a healthy and wellbalanced diet and therefore the demand for functional, high-quality food products and nutritional supplements steadily increases. Formulation scientists in industr y and academia will therefore continue to enhance the delivery systems of micronutrients and nutraceuticals to provide the best performance and quality for the costumers needs.