Capsules can be classified as two main types based on the physical characteristics of the shell: soft capsules and hard capsules. For the purpose of this chapter, soft-shell capsules and hard-shell capsules are referred to as softgels and hardgels, respectively. Softgels have a thicker shell and typically exhibit a higher degree of elasticity because of the added plasticizer and have slightly longer rupture time when compared with hardgels. By comparison, hardgel capsules have a thinner and more rigid shell than do softgel capsules. Both softgels and hardgels are composed of a polymer, e.g., gelatin, starch, or a cellulose derivative such as hypromellose (HPMC) or other polymers, a plasticizer, and water. For hardgels, water acts as the plasticizer, whereas softgels contain high-boiling-point polyols such as glycerol or sorbitol as plasticizer, and also contain water. Although many parameters affect the physical and chemical properties of the shell, the ratio of polymer to plasticizer primarily determines the rigidity, brittleness, and dissolution performance of the shell.

Capsules can also be characterized by the chemical properties of the fill material (hydrophobic-based versus hydrophilic-based fill materials) or by the physical properties of the fill material (solution versus dispersion versus solid). Hydrophobic solutions include neat oils, combinations of miscible oils, or active ingredients dissolved in oil vehicles. Hydrophobic dispersions include active ingredients dispersed or suspended in oil or in oil-wax mixtures. The latter often are termed semisolids. Hydrophilic solutions can be neat liquids, combinations of water-miscible liquids, or active ingredients dissolved in water-miscible vehicles. Hydrophilic dispersions or suspensions include active ingredients dispersed or suspended in hydrophilic vehicles such as polyethylene glycol. Solid fill materials consist of mixtures of excipients and active ingredients whose properties like hydrophilicity/hydrophobicity, polymorphism, particle size, etc., drive the dissolution behavior.

A number of issues affect the development of a dissolution procedure and the dissolution behavior for capsules, including:

Gelatin is a hygroscopic material, and its moisture content affects the properties of hard and soft gelatin capsules. Since certain excipients are known hygroscopic agents, it is particularly important to monitor the mechanical properties of gelatin capsules stored under various conditions of temperature and relative humidity. The factors that can affect the capsule properties include: moisture exchange between the shell and the fill material, which potentially can create brittleness in the gelatin shell; and chemical interactions between the fill material and gelatin, which can result in gelatin cross-linking.

The potential for aldehydic impurities and formation of degradants and degradation of the active ingredients or excipients in the formulation should be investigated during product development by means of stability studies (aldehydes contribute to cross-linking; see section 2. Cross-Linking in Gelatin Capsules). Understanding the possible routes of aldehyde or ketone formation, and possible sources of aldehyde, helps to predict capsule behavior. The rate of cooling and drying may modify the characteristics of the active ingredient release from the matrix. The possibility of migration of the active ingredient into the capsule shell, particularly when the softgel is made of gelatin, should be investigated for its impact on dissolution testing.

Capsule shells can become reactive depending on the storage conditions. Product packaging and storage conditions are chosen to prevent adverse effects on capsule quality. The ingress of moisture and/or oxygen into the packaging and through the capsule shell, as well as the rate of ingress, can affect the final shelf life for the product. In some cases, an increase in water content of the capsule shell may produce a measurable reduction in the dissolution time because a moistened product may facilitate polymer hydration.

Due to the water content of gelatin shell (usually between 13% and 16%), this type of capsule behaves as a moisture reservoir which may affect the stability of humidity-sensitive active ingredients.

When a capsule is immersed in an aqueous medium, the water permeates the walls, the polymer becomes hydrated, and swells. When fully hydrated, the shell starts to dissolve. The amount of time it takes for water to penetrate capsule shells varies, depending on the nature of the capsules shell and other factors. This time has been reported to be approximately 40 s for gelatin capsules and about 3 min for HPMC capsules. This delay may be significant only for dissolution testing of immediate-release dosage forms, while it should have minor or no impact on dissolution testing of modified-release formulations.

As is the case with other oral solid dosage forms, USP Apparatus 1 (basket), USP Apparatus 2 (paddles), USP Apparatus 3 (reciprocating cylinder), and USP Apparatus 4 (flow-through cell) are most often chosen as the dissolution apparatus for capsules (see 711 and 2040). However, several specific benefits and drawbacks must be considered in selecting and using the dissolution apparatus for capsules:

The capsule dissolution process involves three stages: (1) rupture of the capsule shell, (2) release and dispersion of the capsule fill material, and (3) dissolution of the active ingredient(s) in the medium. Each dissolution apparatus referred to previously can achieve these three stages, but they may cause different hydrodynamic effect upon capsules as on any other dosage form as well.

Other apparatus may be considered with proper justification, with each candidate apparatus evaluated for variations in media composition, media volume, agitation or flow rate, and other test parameters to determine what effect each has on the dissolution performance of the product.

General recommendations for the selection of appropriate dissolution media can be found in chapters 1092 and 2040, FDA Guidance for Industry—Dissolution Testing of Immediate-Release Solid Oral Dosage Forms and FDA Guidance for Industry—Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In vitro/In vivo Correlations.

Characteristics of the dissolution medium that may affect the opening or rupture of the capsule shell, the release and dispersion of the capsule fill material, and the dissolution of the active ingredient(s) are discussed in the following sections.

During product and dissolution method development, forced formation of cross-linking in the gelatin capsule may be useful to establish the type and amount of enzyme that will be used in the test, and to better understand the behavior of the formulation in the dissolution medium. This can be achieved by spiking excipients with known amounts of formaldehyde or other cross-linking agents, or exposing the capsules to high humidity.

Establishing the proper sampling technique and location for capsules follows the procedures described in chapters 711 and 1092. In the case of hydrophobic liquid filled capsules, the fill material typically forms a film on the surface of the dissolution medium during the course of the test, sampling must be performed in such a way that the cannula penetrates the oily layer without being clogged. In addition to standard validation and compatibility studies, care must be taken when a filter is used to ensure that it does not become clogged with oil or undissolved capsule shell material when the sample is taken. Similar considerations apply to automated sampling equipment because filters and transfer lines may become obstructed during sampling. To address this issue, the use of surfactants and/or enzymes in dissolution media may be needed to better solubilize the capsule shell and fill. Another point to be considered in the case of automated sampling equipment is the probe. If it remains inside the medium during the test, it could perturb the oily layer and possibly influence the hydrodynamics and change the dissolution profile. An alternative approach is to remove the probe and to introduce it just at the time of the sampling. The sampling method should be validated for each product.

Evaluate the solubility of the active ingredient(s) in aqueous media within a pH range of 1.0 to 7.2–7.5.

Enzymes such as pepsin (at pH <4.0) or pancreatin (at pH 6.8) may be used if the product shows evidence of cross-linking in the gelatin capsule. If the product is a formulation such as 2 or 3 above, evaluate the use of surfactants and possible interaction with enzymes.

USP Apparatus 1 or 2. If the capsule is filled with low-specific-gravity liquid and has a tendency to float, sinkers should be used. If the product is a formulation such as 2 or 4 above, consider Apparatus 3 as an option.

Agitation speed typically is 50–100 rpm for baskets and 50–75 rpm for paddles. Higher speeds should be justified.

A dissolution profile should be established during the development phase to identify when the rate of active ingredient release has leveled off.

Knowledge of the composition of the shell (polymer, plasticizers, water content, etc.), as discussed at the beginning of this chapter, is an important aspect and helps determine critical quality attributes. Other important aspects of understanding the critical quality attributes are the composition and properties of the gel mass and finished shell. In its simplest form, the shell of a capsule is prepared from a molten gel mass, which in the case of hardgels comprises gelatin or other polymers and water and in the case of softgels the shell is comprised of gelatin and a plasticizer dissolved in an aqueous vehicle. The ratio of polymer to plasticizer varies depending on the desired performance traits of the shell, the size of the shell, and the composition of the fill material. Other minor components added to the gel mass may include colorants, flavors, stabilizers, buffers, and opacifiers. The physical characteristics and quality of these minor components are central to the design of high-quality and robust formulations. The composition of hardgels usually does not vary with capsule size.

Processing aids include gelatin ribbon lubricants in the softgel manufacturing process. Commonly used ribbon lubricants include mineral oil and medium chain triglyceride. Since ribbon lubricants are applied to both the inner and outer surfaces of the capsule shell, the evaluation of their potential adverse effects is focused on the capsule itself and primarily on gelatin cross-linkage.

Knowledge of the stability and reactivity of gelatin or other polymers is essential to anticipate their influence on final product quality. At room temperature, the capsule shells as supplied are relatively effective in protecting the fill from oxygen and its effects, and when an opacifier such as titanium dioxide is added to the shell, it can prevent photodegradation of the fill. In addition, the low water activity of the shell does not promote microbial growth. For bacteria, yeasts, and molds to grow a higher water activity of at least 80 aw is required; the water activity of capsule shells typically is less than 0.40 aw.

Storage conditions of the final product range from refrigeration to standard room temperature. Products should be stored according to the label directions. Brief excursions outside of these conditions should be evaluated to determine their influence on the final product quality. Storage conditions and duration for the empty capsule shells should also be considered.

It is important to understand the properties of the active ingredient(s) during formulation development.

Formulations developed using liquid-filling technology may be applicable when the active ingredients (1) display poor solubility in aqueous systems, (2) short half-life requiring frequent dosing, (3) low melting point, (4) low dose/high potency where containment is important, (5) requirement for taste or odor masking and (6) critical chemical or physical stability as in the case of highly hygroscopic active ingredients. Other factors to consider during formulation development include:

Important factors to consider during a liquid-filling operation are temperature and viscosity of the fill material and, in the case of a dispersion or suspension, the particle size of the dispersed active ingredient(s). In principle, any excipient found to be compatible with the shell can be used, but in a manufacturing environment the viscosity of the fill material is important. Excipients that are solid at room temperature but melt at temperatures up to 70 may be suitable (depending on the shell polymer) for formulating active ingredient(s) provided those excipients yield the desired in vivo performance.

Both shell and fill excipients should be controlled for levels of known cross-linking agents such as formaldehyde and reducing sugars.

Imperfections in the shell and/or in the seam may affect dissolution. They may also give rise to leaking of the capsules contents.

The appropriate in-process controls should be in place to monitor and reduce the lot-to-lot variability.