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 4b represents the case where a reactant dissolved in the dispersed phase reacts with the continuous phase to produce a co-reactant. The co-reactant and any remaining unreacted original reactant left in the dispersed phase then proceed to react with each other at the dispersed phase side of the interface and produce a capsule shell. Capsule shell formation occurs entirely because of reaction of reactants present in the droplets of dispersed phase. No reactant is added to the aqueous phase. As in the case of the process described by Figure 4a, a reactive species must be dissolved in the core material in order to produce a capsule shell. 

A specific example of the process represented by Figure 4b occurs when a multihmctional isocyanate is dissolved in a Hquid, water-immiscible core material and the mixture produced is dispersed in an aqueous phase that contains a dispersing agent. The aqueous phase reacts with some of the isocyanate groups to produce primary amine functionaHties. These amino groups react with unreacted isocyanate groups to produce a polyurea capsule shell (13). 

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 system developed by personnel at Sanofl uses the Formulogic shell with specific preformulation data on the drug. The system recommends one first-pass clinical capsule formulation with as many subsequent formulations as desired to accommodate an experimental design [24]. An example of a formulation proposed for naproxen at a dose of 500 mg is shown in Table 28.2. In addition to the formulation the system provides advice on the milling of the drug, the process to be used for blending, and details of the capsule shell. 

A degree of compactibility is important to prevent loss of material from the end of the plug during transport to the capsule shell. 

FS Horn, SA Veresh, WR Ebert. Soft gelatin capsules II. Oxygen permeability study of capsule shells. J Pharm Sci 64 851-857, 1975. 

NA Armstrong, KC James, WKL Pugh. Drug migration into soft gelatin capsule shells and its effect on the in-vitro availability. J Pharm Pharmacol 36 361— 365, 1984. 

Asymmetrical membrane capsules were prepared, for example, by dip coating mandrels with solutions containing 15 wt% CA and 33 wt% ethanol in acetone. After the mandrels were withdrawn from the coating solution they were immersed in water to precipitate the polymer and create the asymmetrical membrane capsule shell. This process was used to create both the body and the cap for the capsules. The capsules were sealed at the juncture between the cap and body by banding with a solution of CA in acetone. 

Figure 12 Release of doxazosin from asymmetrical capsule shells versus the osmotic pressure of the receptor solution (gastric buffer, 7.5 atm, and dextrose solutions, 21 and 34 atm). (From Ref. 28.)...

In the preparation of capsules, various colored empty gelatin capsule shells may be used to hold the powdered drug mixture. Many commercial capsules are prepared with capsule bodies of one color and a different colored capsule cap, resulting in a two-colored capsule. This makes certain commercial products even more readily identifiable than solid colored capsules. For powdered drugs, dispensed as such or compressed into tablets, a generally larger proportion of dye is required (about 0.1%) to achieve the desired hue than with liquid preparations. 

Fluorescence from pharmaceutical capsule shells and tablet coatings has hindered measurement of their composition by Raman spectroscopy. By switching from the conventional backscattering mode to a transmission mode, Matousek et al. demonstrated that fluorescence could be eliminated in many instances [8]. Backscattering- and transmission-mode Raman spectra of several samples are shown in Figure 7.5. Each spectrum was acquired in 10s with 80mW 830-mn laser power. Matousek et al. also speculate that signal acquisition times could be relatively easily shortened to well below 0.1 s when the transmission mode is combined with optimized optics [8]. 

Figure 7.5 Raman spectra of a series of tablets with different coatings to illustrate improvements in spectral quality using transmission-mode instead of conventional backscatter geometry. Bands from the capsule shell are marked with a symbol. Reprinted from Matousek et al. (2007) [8] with permission from John Wiley Sons, Ltd.

Coating materials with degradable bonds including capsule shells Hydrogels and matrices consisting of cross-linked, degradable polymers... 

Further examples of enzymatically degradable drug formulation wrappings are capsule shells made of the polysaccharides chitosan [65,66] or cross-linked dextran [67]. 

Gelatin is produced by partial acid or partial alkaline hydrolysis of animal collagen. It has a wide variety of therapeutic and pharmaceutical uses. It is often used in the manufacture of hard and soft capsule shells, suppositories and tablets, and is sometimes used as a sponge during surgical procedures, as it can absorb many times its own weight of blood. 

A new variation of interfacial polymerization was developed by Russell and Emrick in which functionalized nanoparticles or premade oligomers self-assemble at the interface of droplets, stabilizing them against coalescence. The functional groups are then crosslinked, forming permanent capsule shells around the droplets to make water-in-oil (Lin et al. 2003 Skaff et al. 2005) and oil-in-water (Breitenkamp and Emrick 2003 Glogowski et al. 2007) microcapsules with elastic membranes. 

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