Capsules are the dosage forms in which the drug formulation in a powder, semisolid, or liquid form is enclosed in a shell. This shell is generally made from gelatin, but can be made from other polymers such as hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), seaweed, or starch. Depending on the composition of the gelatin shell, the capsules can be hard or soft gelatin capsules.
Soft gelatin capsules (also known as softgels) are made from a relatively more flexible, plasticized gelatin film than hard gelatin capsules.
Hard capsules, such as hard gelatin or HPMC capsules, are typically used for powder or solid fills, whereas soft gelatin capsules are used for semisolid or liquid fills. Lately, hard capsules have also been used for liquid or semisolid fills.
Most soft and hard capsules are intended to be swallowed as a whole. Some soft gelatin capsules are intended for rectal or vaginal insertion as suppositories. Some soft gelatin capsules are intended to be cut open by the patient to remove and externally apply the contained medicament, for example, ophthalmically.
The capsule shell dissolves rapidly on contact with gastrointestinal (GI) fluids, thus releasing the capsule’s contents. Drug’s bioavailability from capsules is usually high and similar to those of immediate-release (IR) tablets. Coating of capsule shell or drug particles (within the capsule) with sustained-release (SR) polymers can prolong drug release and affect bioavailability.
Hard gelatin capsules have a significant amount of bound water. These capsules are generally not physically stable in low humidity conditions, such as in the presence of desiccant in the packaged drug product. They tend to become fragile and crack at low humidity. On the other hand, HPMC capsules have lower equilibrium moisture contents than gelatin capsules and have better physical stability (i.e., do not become fragile and crack) on exposure to low humidity. The majority of capsule products manufactured today are hard gelatin capsules.
Hard gelatin capsule
Gelatin is a colorless, almost tasteless, translucent proteinaceous substance that is brittle when dry and elastic when mixed with controlled amount of moisture. It is produced by irreversible, partial hydrolysis of collagen, which is obtained from animal skin and bones. It forms a semisolid colloid gel in the presence of water, which displays a temperature-dependent gel–sol transformation and viscoelastic flow.
It has crystallites (microscopic crystals formed during the cooling phase of manufacture of capsule shells) that stabilize the three-dimensional gel network structure and are responsible for streaming birefringence in gelatin solutions. A hard gelatin capsule shell consists of two pieces: a cap and a body.
The body has slightly lower diameter than the cap and fits inside the cap. They are produced empty and are then filled in a separate operation. During the capsule filling unit operation, the body is filled with the medicament, followed by the insertion of the cap over the body.
Advantages and disadvantages of hard gelatin capsules
Hard gelatin capsules often provide formulation capability for uniquely challenging drug molecules. For example, a drug candidate with a low melting point or that is liquid at room temperature usually has poor manufacturability as a tablet, especially if it requires a high dose. Such a compound can be encapsulated in a liquid- or semisolid-filled hard gelatin capsule.
Hard gelatin capsules generally require less formulation components and place less stringent requirement on the powder properties of the formulation. They can also allow flexibility in formulation with the possibility of filling one or more of diverse systems including powders, granules, pellets, and small tablets. In addition, hard gelatin capsules can be used for blinding in clinical studies.
The disadvantages of hard gelatin capsules are owed to the inherent high moisture content requirement of gelatin. For example, highly soluble salts, such as iodides, bromides, and chlorides, of drugs are generally not formulated in hard gelatin capsules because these can draw moisture from the shell, thus making the shell brittle
Storage under low humidity conditions, such as with the use of desiccant in packaging, can also make the shell brittle. In addition, gelatin is prone to cross-linking in the presence of very low (in parts per million range) concentrations of formaldehyde, which may be present in certain pharmaceutical excipients such as polyethylene glycol (PEG).
In comparison to soft gelatin capsules, the manufacturing process of hard gelatin capsules is less demanding, tedious, and costly. This is because the soft gelatin capsule manufacture requires the formation of gelatin ribbons during the encapsulation process itself, whereas the hard gelatin capsules use pre-manufactured capsule shells. The hard gelatin capsule manufacture also does not require a curing or moisture-loss step after encapsulation of the drug formulation.
The residual water in the capsule shells is lower (~10–16% w/w) for hard gelatin capsules than for soft gelatin capsules (~30% w/w). This can affect the stability of the encapsulated formulation directly by chemical degradation (e.g., hydrolysis) of water-sensitive compounds or plasticization of the reaction medium with water, thus increasing the rate of degradation. In addition, soft gelatin capsule shells have a high oxygen permeation rate, which can contribute to the oxidation of sensitive drugs.
Soft gelatin capsules
Soft gelatin capsules consist of a hermetically sealed outer shell of gelatin that encloses a liquid or semisolid medicament in the unit dosage. Soft gelatin capsules are a completely sealed dosage form and cannot be opened without destroying the capsules. Drugs that are commercially prepared in soft capsules include cyclosporine, declomycin, chlorotrianisene, digoxin, vitamin A, vitamin E, and chloral hydrate.
Advantages and disadvantages of soft gelatin capsules
Soft gelatin capsules provide a patient-friendly dosage form for per oral administration of non-palatable and/or oily liquids. Solutions or suspensions with an unpleasant odor or taste can be easily ingested in a soft gelatin capsule dosage form, which offers tidy appearance and convenient ingestion.
This dosage form can be particularly advantageous for low dose drugs that are lipid soluble because it can allow greater uniformity of content between dosage units than the conventional tablet dosage form. It can also be more suitable than a tablet dosage form for the encapsulation of liquid, water-insoluble drugs. The capsules can be formulated to be immediate release (IR), slow or sustained release (SR), or enteric coated
The use of soft gelatin capsule shell imposes significant limitations on the drug formulations that can be encapsulated in this dosage form, that is, restricted to liquids and semisolids. The manufacturing process is relatively tedious and difficult to optimize (e.g., ribbon thickness, fill weight, and weight variation). In addition, the breakage of even one capsule during the manufacturing can lead to the coating of drug formulation on the outer surface of several other capsules. This can also happen during storage in multiple use containers, such as high-density polyethylene (HDPE) bottles.
Soft gelatin capsules have certain disadvantages compared to liquid-filled hard gelatin capsules. Due to the relatively higher water content in soft gelatin shell (20–30% w/w) compared to hard gelatin capsules (13–16% w/w) moisture-sensitive drugs may not be stable in soft gelatin capsules.
Non-gelatin soft capsules
The use of alternate polymers for the formation of soft capsules is driven by marketing or formulation requirements. For example, Vegicaps® are animal-free. Their shell is made from seaweed extract and gluten-free starch. For moisture sensitive drugs, HPMC capsules may be preferred, which generally have lower equilibrium moisture content than gelatin capsules. HPMC capsules also have better physical stability on exposure to low humidity.