Encapsulation capsule shells

Table 1 Hsts representative examples of capsule shell materials used to produce commercial microcapsules along with preferred appHcations. The gelatin—gum arabic complex coacervate treated with glutaraldehyde is specified as nonedible for the intended appHcation, ie, carbonless copy paper, but it has been approved for limited consumption as a shell material for the encapsulation of selected food flavors. Shell material costs vary greatly. The cheapest acceptable shell materials capable of providing desired performance are favored, however, defining the optimal shell material for a given appHcation is not an easy task.

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. 

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). 

A unique feature of in situ encapsulation technology is that polymerization occurs ia the aqueous phase thereby produciag a condensation product that deposits on the surface of the dispersed core material where polymerization continues. This ultimately produces a water-iasoluble, highly cross-linked polymer capsule shell. The polymerization chemistry occurs entirely on the aqueous phase side of the iaterface, so reactive agents do not have to be dissolved ia the core material. The process has been commercialized and produces a range of commercial capsules. 

The drug dissolution profiles from capsules have been documented to change with time due to changes in the gelatin capsule shell properties, interaction between gelatin and an encapsulated ingredient such as anionic compounds (e.g., substituted benzoic and sulfonic acid dyes), and compounds with keto groups. The... 

Capsule shell sizes are generally standardized with Lnite volumes [12,13] available for dispensing the API or powder blend. The capsule size selection would depend on the dose and the bulk density of the NCE. Historically, if the doses were within a reasonable range, it was feasible to dispense API directly into the capsule body utilizing manual, semiautomatic, or automatic high-speed encapsulators available for manufacturing. 

Figures 23.3 through 23.5 illustrate the stepwise process low typically utilized in wet and dry granulation techniques for the manufacture of tablet dosage forms. For capsules, the process tends to be simpler with utilization of Lrst three steps from dry granulation followed by encapsulation in appropriate-size capsule shells. Depending on the batch size, a manual LHer (e.g., Bonapace), semiautomatic encapsulator (e.g., Capsugel Ultra 8), or automated encapsulator (Zanasi, Macofar, etc.) could be utilized for manufacturing.

There are many advantages for choosing to develop and scale-up a capsule formulation over a tablet. As there is no need to form a compact that must withstand rigorous handling, development timelines can be reduced. Encapsulated products allow for easier blinding of clinical supplies and the ability to manufacture unique fills such as tablets in capsules, sustained release pellets, liquids, or semisolids. However, the costs of the capsule shells add an additional expense above the costs of tablet manufacture. 

Fluorescent dyes as markers can also be used to follow particle-cell interactions, via LSM and FACS measurements. Hence, polyure thane/urea capsules were created in inverse miniemulsion that could encapsulate a fluorescent dye with 90% efficiency [129]. In this case, carboxymethylation was carried out on the particle surface, followed by the physical adsorption of poly(2-aminoethylmethacrylate) or polyethylene imine polycations. As expected, the rate of uptake of capsules modified by the polycation was higher than for non-modified capsules. Rosenbauer et al. applied the same synthetic procedure, but in the presence of a surfactant that crosslinked the shell [130]. The commercially available surfactant containing several amine groups reacted with the diioscyanate monomer subsequently, the capsule shell wall was found to be less permeable than capsules synthesized with a non-crosslinkable surfactant. Baier el al. used the above-described synthesis to perform a polymerase chain reaction (PCR) in crosslinked starch nanocapsules [131]. The permeability of the shell was also evaluated using fluorescence spectroscopy. The combination of a cleavable polyurethane [132] with the interfacial polyaddition described above [126] afforded polymer shells that could be opened by ultraviolet (UV) irradiation, or by modifying the temperature or pH [133], In order to determine the release of encapsulated sulforhodamine dye, polyurethanes with... 

Microcapsules containing liquid pesticide have certain drawbacks. One example is when the pesticide is itself both volatile and toxic and has a high vapor pressure. A second example is when the capsule shell is strong and thick. In the first case, the pesticide diffuses very rapidly from the capsules and its odor initially repels the pest. Diffusion from the capsules is rapid, however, and when they are empty the pests return to the site (e.g., crops). In the second case, the capsules do not release the pesticide to produce a minimum effective level at the application site, and so pestiddal action is not achieved. In order to overcome these problems, a WO patent disclosed the preparation of microcapsules of pesticides containing pest attractant using a capsule-in-capsule approach [50]. As shown in Figure 5.18, the outer capsule contains pest attractant or food, in which the iruier capsule containing the pesticide, is encapsulated. 

Capsules disintegrate when the capsule shell dissolves and the powder mixmre is wetted. Hydrophilic excipients promote the wetting of the powder bed (Fig. 4.1). Due to the low compaction of the encapsulated powder, and the easy dissolution of most diluents for capsules, the addition of a disintegrating agent is often not needed for pharmacy preparations. However, when excipients compact easily (e.g. calcium monohydrogen phosphate dihydrate) a disintegrant is recommended. 

When encapsulating tablets for blind studies, the tablet containing the active substance is concealed in a capsule designed for clinical trials. Tablet as a whole may, or may not be embedded in powder that has been placed previously into a capsule shell. 

Figure 4a represents interfacial polymerization encapsulation processes in which shell formation occurs at the core material-continuous phase interface due to reactants in each phase diflfiising and rapidly reacting there to produce a capsule shell (1,8). The continuous phase normally contains a dispersing agent in order... 

A key feature of encapsulation processes (Figs. 4a and 5) is that the reagents for the interfacial polymerization reaction responsible for shell formation are present in two mutually immiscible liquids. They must diffuse to the interface in order to react. Once reaction is initiated, the capsule shell that forms becomes... 

Figure 4c also describes the spontaneous polymerization of para-xylylene diradicals on the surface of solid particles dispersed in a gas phase that contains this reactive monomer (12) (see Xylylene Polymers). The poly(p-xylylene) polymer produced forms a continuous capsule shell that is highly impermeable to the transport of many penetrants, including water. This is an expensive encapsulation process, but it has produced capsules with impressive barrier properties. It is a type B encapsulation process, but is included here for the sake of completeness. 

Figure 4d represents in situ encapsulation processes (13,14), an example of which is presented in more detail in Figure 6 (14). The first step is to disperse a water-immiscible liquid or solid 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 shell (14). This is an anionic polymer or copoljuner (Fig. 6). Shell 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.

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