Encapsulation processes

SheU material Regulatory status Chemical class Encapsulation process AppHcations... 

Classification of the many different encapsulation processes is usehil. Previous schemes employing the categories chemical or physical are unsatisfactory because many so-called chemical processes involve exclusively physical phenomena, whereas so-called physical processes can utilize chemical phenomena. An alternative approach is to classify all encapsulation processes as either Type A or Type B processes. Type A processes are defined as those in which capsule formation occurs entirely in a Hquid-filled stirred tank or tubular reactor. Emulsion and dispersion stabiUty play a key role in determining the success of such processes. Type B processes are processes in which capsule formation occurs because a coating is sprayed or deposited in some manner onto the surface of a Hquid or soHd core material dispersed in a gas phase or vacuum. This category also includes processes in which Hquid droplets containing core material are sprayed into a gas phase and subsequentiy solidified to produce microcapsules. Emulsion and dispersion stabilization can play a key role in the success of Type B processes also. 

Eig. 2. Elow diagram of a typical encapsulation process based on the complex coacervation of gelatin with gum arabic. 

Fig. 3. Flow diagram of typical encapsulation process based on polymer—polymer iacompatibiHty.

Polymer—polymer iacompatibiHty encapsulation processes can be carried out ia aqueous or nonaqueous media, but thus far have primarily been carried out ia organic media. Core materials encapsulated tend to be polar soHds with a finite degree of water solubiHty. EthylceUulose historically has been the sheU material used. Biodegradable sheU materials such as poly(D,L-lactide) and lactide—glycoHde copolymers have received much attention. In these latter cases, the object has been to produce biodegradable capsules that carry proteias or polypeptides. Such capsules tend to be below 100 p.m ia diameter and are for oral or parenteral administration (9). 

Interfacial Polymerization. Many types of polymerization reactions can be made to occur at interfaces or produce polymers that concentrate at interfaces thereby producing microcapsules. Accordingly, this approach to encapsulation has steadily developed into a versatile family of encapsulation processes. Figure 4 schematically illustrates five types of encapsulation processes that utilize these types of reactions. 

Figure 4a represents interfacial polymerisation encapsulation processes in which shell formation occurs at the core material—continuous phase interface due to reactants in each phase diffusing and rapidly reacting there to produce a capsule shell (10,11). The continuous phase normally contains a dispersing agent in order to faciUtate formation of the dispersion. The dispersed core phase encapsulated can be water, or a water-immiscible solvent. The reactant(s) and coreactant(s) in such processes generally are various multihmctional acid chlorides, isocyanates, amines, and alcohols. For water-immiscible core materials, a multihmctional acid chloride, isocyanate or a combination of these reactants, is dissolved in the core and a multihmctional amine(s) or alcohol(s) is dissolved in the aqueous phase used to disperse the core material. For water or water-miscible core materials, the multihmctional amine(s) or alcohol(s) is dissolved in the core and a multihmctional acid chloride(s) or isocyanate(s) is dissolved in the continuous phase. Both cases have been used to produce capsules. 

Figure 5 illustrates the type of encapsulation process shown in Figure 4a when the core material is a water-immiscible Hquid. Reactant X, a multihmctional acid chloride, isocyanate, or combination of these reactants, is dissolved in the core material. The resulting mixture is emulsified in an aqueous phase that contains an emulsifier such as partially hydroly2ed poly(vinyl alcohol) or a lignosulfonate. Reactant Y, a multihmctional amine or combination of amines such as ethylenediamine, hexamethylenediamine, or triethylenetetramine, is added to the aqueous phase thereby initiating interfacial polymerisation and formation of a capsule shell. If reactant X is an acid chloride, base is added to the aqueous phase in order to act as an acid scavenger. 

Fig. 5. Flow diagram of typical interfacial polymerisation encapsulation process in which reactants X and Y are dissolved in separate mutually immiscible...

A key feature of encapsulation processes (Figs. 4a and 5) is that the reagents for the interfacial polymerisation reaction responsible for shell formation are present in two mutually immiscible Hquids. They must diffuse to the interface in order to react. Once reaction is initiated, the capsule shell that forms becomes a barrier to diffusion and ultimately begins to limit the rate of the interfacial polymerisation reaction. This, in turn, influences morphology and uniformity of thickness of the capsule shell. Kinetic analyses of the process have been pubHshed (12). A drawback to the technology for some apphcations is that aggressive or highly reactive molecules must be dissolved in the core material in order to produce microcapsules. Such molecules can react with sensitive core materials. 

Figure 4c illustrates interfacial polymerisation encapsulation processes in which the reactant(s) that polymerise to form the capsule shell is transported exclusively from the continuous phase of the system to the dispersed phase—continuous phase interface where polymerisation occurs and a capsule shell is produced. This type of encapsulation process has been carried out at Hquid—Hquid and soHd—Hquid interfaces. An example of the Hquid—Hquid case is the spontaneous polymerisation reaction of cyanoacrylate monomers at the water—solvent interface formed by dispersing water in a continuous solvent phase (14). The poly(alkyl cyanoacrylate) produced by this spontaneous reaction encapsulates the dispersed water droplets. An example of the soHd—Hquid process is where a core material is dispersed in aqueous media that contains a water-immiscible surfactant along with a controUed amount of surfactant. A water-immiscible monomer that polymerises by free-radical polymerisation is added to the system and free-radical polymerisation localised at the core material—aqueous phase interface is initiated thereby generating a capsule sheU (15). 

Figure 4c also describes the spontaneous polymerisation ofpara- s.yX en.e diradicals on the surface of soHd particles dispersed in a gas phase that contains this reactive monomer (16) (see XylylenePOLYMERS). The poly -xylylene) polymer produced forms a continuous capsule sheU that is highly impermeable to transport of many penetrants including water. This is an expensive encapsulation process, but it has produced capsules with impressive barrier properties. This process is a Type B encapsulation process, but is included here for the sake of completeness. 

Figure 4d represents in situ encapsulation processes (17,18), an example of which is presented in more detail in Figure 6 (18). The first step is to disperse a water-immiscible Hquid or soHd core material in an aqueous phase that contains urea, melamine, water-soluble urea—formaldehyde condensate, or water-soluble urea—melamine condensate. In many cases, the aqueous phase also contains a system modifier that enhances deposition of the aminoplast capsule sheU (18). This is an anionic polymer or copolymer (Fig. 6). SheU formation occurs once formaldehyde is added and the aqueous phase acidified, eg, pH 2—4.5. The system is heated for several hours at 40—60°C.

Spray Drying. Spray-dry encapsulation processes (Fig. 7) consist of spraying an intimate mixture of core and shell material into a heated chamber where rapid desolvation occurs to thereby produce microcapsules (24,25). The first step in such processes is to form a concentrated solution of the carrier or shell material in the solvent from which spray drying is to be done. Any water- or solvent-soluble film-forming shell material can, in principle, be used. Water-soluble polymers such as gum arable, modified starch, and hydrolyzed gelatin are used most often. Solutions of these shell materials at 50 wt % soHds have sufficiently low viscosities that they stiU can be atomized without difficulty. It is not unusual to blend gum arable and modified starch with maltodextrins, sucrose, or sorbitol. 

Fig. 7. Flow diagram of a typical spray-dry encapsulation process.

Several parenteral microencapsulated products have been commercialized the cote materials ate polypeptides with hormonal activity. Poly(lactide— glycohde) copolymers ate the sheU materials used. The capsules ate produced by solvent evaporation, polymer-polymer phase separation, or spray-dry encapsulation processes. They release their cote material over a 30 day period in vivo, although not at a constant rate. 

Another biomedical appHcation of mictocapsules is the encapsulation of Hve mammalian ceUs for transplantation into humans. The purpose of encapsulation is to protect the transplanted ceUs or organisms from rejection by the host. The capsule sheU must prevent entrance of harmful agents into the capsule, aUow free transport of nutrients necessary for ceU functioning into the capsule, and aUow desirable ceUular products to freely escape from the capsule. This type of encapsulation has been carried out with a number of different types of Hve ceUs, but studies with encapsulated pancreatic islets or islets of Langerhans ate most common. The alginate—poly(L-lysine) encapsulation process originally developed in 1981 (54) catalyzed much of the ceU encapsulation work carried out since. A discussion of the obstacles to the appHcation of microencapsulation in islet transplantation reviewed much of the mote recent work done in this area (55). Animal ceU encapsulation has also been researched (56). 

Low ionic impurity levels are imperative. In order to reduce the coefficient of thermal expansion of the final mol ding, and hence minimise stresses on the encapsulated siHcon chip, the highest possible filler loading is desired. This has to be balanced against the need to maintain as low a melt viscosity as possible to minimise the possibiHty of damage to the device during the encapsulation process. 

Advantages Major advantages of an encapsulation process involve the fact that waste materials never come into contact with water, therefore, soluble materials (such as sodium chloride) can be successfully surface-encapsulated. The impervious jacket also eliminates all leaching into contacting waters as long as the jacket remains intact. 

Another factor influencing contaminant and heat transfer from dirty to clean zones against the stable airflow is a turbulent exchange between these zones. This process should be considered in the design of displacement or natural ventilation systems and evaluation of the emission rate of contaminants from the encapsulated process equipment (Fig. 7.111a). 

The typical TP encapsulation process is an insert injection molding or liquid injection molding operation. The insert, a coil, or an integrated circuit, for example, is placed in a mold equipped with either fixed spider type supports or retractable pins or other features to support it when molten TP is injected. 

The encapsulation process used was the LbL method, employing alternately charged polymers, namely PDA [poly(diallyldimethylammonium chloride)] and PSS... 

Common to all encapsulation methods is the provision for the passage of reagents and products through or past the walls of the compartment. In zeolites and mesoporous materials, this is enabled by their open porous structure. It is not surprising, then, that porous silica has been used as a material for encapsulation processes, which has already been seen in LbL methods [43], Moreover, ship-in-a-bottle approaches have been well documented, whereby the encapsulation of individual molecules, molecular clusters, and small metal particles is achieved within zeolites [67]. There is a wealth of literature on the immobilization of catalysts on silica or other inorganic materials [68-72], but this is beyond the scope of this chapter. However, these methods potentially provide another method to avoid a situation where one catalyst interferes with another, or to allow the use of a catalyst in a system limited by the reaction conditions. For example, the increased stability of a catalyst may allow a reaction to run at a desired higher temperature, or allow for the use of an otherwise insoluble catalyst [73]. 

Adsorption behavior and the effect on colloid stability of water soluble polymers with a lower critical solution temperature(LCST) have been studied using polystyrene latices plus hydroxy propyl cellulose(HPC). Saturated adsorption(As) of HPC depended significantly on the adsorption temperature and the As obtained at the LCST was 1.5 times as large as the value at room temperature. The high As value obtained at the LCST remained for a long time at room temperature, and the dense adsorption layer formed on the latex particles showed strong protective action against salt and temperature. Furthermore, the dense adsorption layer of HPC on silica particles was very effective in the encapsulation process with polystyrene via emulsion polymerization in which the HPC-coated silica particles were used as seed. 

The encapsulation results in a chance collection of molecules that then form an autocatalytic cycle and a primitive metabolism but intrinsically only an isolated system of chemical reactions. There is no requirement for the reactions to reach equilibrium because they are no longer under standard conditions and the extent of reaction, f, will be composition limited (Section 8.2). Suddenly, a protocell looks promising but the encapsulation process poses lots of questions. How many molecules are required to form an organism How big does the micelle or liposome have to be How are molecules transported from outside to inside Can the system replicate Consider a simple spherical protocell of diameter 100 nm with an enclosed volume of a mere 125 fL. There is room within the cell for something like 5 billion molecules, assuming that they all have a density similar to that of water. This is a surprisingly small number and is a reasonable first guess for the number of molecules within a bacterium. 

Sol-gel microencapsulation in silica particles shares the versatility of the sol-gel molecular encapsulation process, with further unique advantages. Sol-gel controlled release formulations are often more stable, potent and tolerable than currently available formulations. The benefits of microencapsulation can be customized to deliver the maximum set of benefits for each active ingredient. Overall, these new and stable combinations of active pharmaceutical ingredients (APIs) result in improved efficacy and usability. 

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