Hard gelatin capsules

Hard gelatin capsules

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 col-loid 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 respon-sible 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, fol-lowed by the insertion of the cap over the body.

The shapes and interlocking arrangement of the body and the cap have evolved to meet the manufacturing and use requirements of hard gelatin capsules as shown in Figure 21.2.

Figure 21.2 Schematic diagrams (a–c) of hard gelatin capsules illustrating their design features. The larger, narrower part of the capsules is the body and the smaller, wider part is the cap.

·           Conventionally, the body and the cap had smooth edges with a diam-eter of the cap being slightly higher than that of the body. The two components could slide over each other (Figure 21.2a).

·           To minimize defects during the production process, the design of the edge of the body was tapered to allow smooth penetration into the cap with minimum defects during high-speed production operation (Figure 21.2b).

·           The capsules were modified to have an encircling groove each on the cap and the body (Figure 21.2c) and/or a notch to allow firm locking of the cap on the body (Figure 21.2b and c).

·           To accommodate the need for a firm seal in the case of liquid and semisolid-filled hard gelatin capsules, raised circular bands (dimples) were introduced on the body and the cap along the sealing zone (Figure 21.2c).

·           For the use of hard gelatin capsules in double-blind clinical trials, it was necessary to have hard gelatin capsules that could not be reopened after closing. To meet this objective, capsules with the cap that covers most of the body were developed.

For human use, empty gelatin capsules are manufactured in eight sizes, ranging from 000 (the largest, fill volume 1.37ml) to 5 (the smallest, fill volume 0.13ml), as shown in Table 21.1. The powder-filling capacity of these capsules varies depending on the packed density of the formulation. Modern high-speed capsule-filling machines are capable of filling up to 200,000 capsules per hour, matching the production capacity of tablets. The formulation filled weight in the capsules can range from 30 to 1400 mg, depending on the powder’s bulk and compact densities.

Table 21.1 Typical sizes of hard gelatin capsules

Hard gelatin capsules can be filled with powders, granules, pellets, microtablets, tablets, capsules, liquids, or semisolids. Most of the marketed products contain powders or granules. Recently, the liquid- or semisolid-filled hard gelatin capsules have gained popularity.

After ingestion, the gelatin shell imbibes water, softens, swells, and dissolves in the GI tract. Encapsulated drugs are released rapidly and dis-persed easily, leading to rapid absorption.

Advantages and disadvantages of hard gelatin capsules

Comparison with tablets

Hard gelatin capsules often provide formulation capability for uniquely challenging drug molecules. For example, a drug candidate with a low melt-ing point or that is liquid at room temperature usually has poor manufac-turability 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.

In addition, very low-dose drugs (in μg) can have content uniformity chal-lenges when formulated as a tablet. The distribution of these drugs can be significantly better when encapsulated as a solution in a liquid or semisolid matrix in a hard gelatin capsule.

Hard gelatin capsules generally require less formulation components and place less stringent requirement on the powder properties of the formula-tion. 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 blind-ing 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 formu-lated 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).

Comparison with soft gelatin capsules

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 premanufactured 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 degrada-tion (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.

Solid-filled hard gelatin capsules

Main applications

Hard gelatin capsules are often preferred over tablets as the dosage form for initial (Phase I and Phase IIA) clinical studies of new molecular enti-ties (NMEs). This is because the effect of limited availability of the active pharmaceutical ingredient (API) to conduct necessary screening for the development of tablets. Many initial clinical studies simply use a drug-in-capsule (DIC) product, which is the only drug manually encapsulated in the hard gelatin or HPMC capsules.

Hard capsules are also preferred for the comparator and blinded clinical studies. These clinical studies require that the patient and/or the doctor should not be able to identify the actual drug product being administered to the patient. In these studies, two or more drug products are administered after encapsulating them in hard gelatin capsules of the same specifications and such that the capsules cannot be opened.

Formulation considerations

Hard gelatin capsule-manufacturing process places a relatively less strin-gent requirement on the powder properties of the fill formulation than tab-lets. The important formulation considerations include the following:

1.        Flow: Adequate flow through the hopper and into the dosing device (dosator) for reproducible filling of the capsules.

2.        Density: Reproducible density of the powder is important for fill weight uniformity of capsules because the dosing devices in high-speed capsule-filling machines are filled based on the volume of the powder for a target weight.

3.        Lubricity: Magnesium stearate is typically added to most powder formulations. When mixed with other particles, magnesium stea-rate coats their surface and acts as a lubricant. Lubricants facilitate the lack of adhesion to metallic machine parts, especially the dosing device used to form a plug in high-speed machines, and adequate flow of the formulation. Other lubricants commonly used are stearic acid and sodium stearyl fumarate.

4.        Compactibility: Some high-speed capsule-filling machines form a plug of the powder before filling into the capsule. In cases where plug formation is required for encapsulation, some level of compactibility of the powder is needed.

5.        Noninteraction with capsule shell: Lack of interaction between the drug substance and/or formulation components with the capsule shell, either gelatin or HPMC. This interaction could be in the form of solubilization or changing the water content of the shell. Hygroscopic and volatile components are usually unsuitable. The fill should not contain more than 5% w/w of water. In addition, chemical interac-tions between the components can lead to bioavailability or stability problems. For example, the use of PEG in drug formulation can lead to cross-linking of gelatin on storage due to the unintended presence of formaldehyde in PEG, which can diffuse into the shell and react with gelatin. Similar problems have been observed due to the presence of residual peroxides in excipients.

6.        Dose: Dose and drug loading (i.e., %w/w of the formulation, that is the API) influences drug content uniformity between the capsules, the extent to which the powder properties of the formulation are affected by the physicochemical characteristics of the drug substance, and manufacturability of the capsule dosage form. For example, it may be difficult to assure adequate uniformity of the content of the API for drugs with extremely low doses (e.g., in μg), and it may not be possible to fill a capsule of acceptable size for extremely high-dose drugs (e.g., more than 600 mg). For intermediate doses, the percent drug loading in the formulation can range widely. Drug properties predominantly govern the powder properties of the formulation for high drug-loading formulations (e.g., more than 60% w/w).

7.        Particle size, shape, and density: Particle size and shape influence the flow, uniformity, and thus content of the active in a formulation. A drug substance with irregular or spherical-like crystals is more likely to flow well than the needle-shaped crystals. Drug content uniformity is also affected by particle density, if it is significantly different than the density of the excipients.

8.        Moisture sorption–desorption isotherm: Moisture sorption and retention properties of the drug and excipients, indicated by a hys-teresis in the sorption–desorption isotherm, can affect the physical stability of gelatin during storage and the chemical stability.

9.        Solubility and wettability: Solubility and wettability of the drug substance affect its dissolution characteristics. A low-solubility drug substance might require the addition of a wetting agent (e.g., surfactant such as polysorbate 80) in the formulation.

Formulation components

The powder formulations for encapsulation into hard gelatin capsules require a careful consideration of the filling process requirements, such as lubricity, compactibility, and flow. Additives present in capsule formula-tions, such as the amount and choice of fillers, lubricant, disintegrant, and surfactant, and the degree of plug compaction, can influence drug release from the capsule. The functional categories of formulation components are as follows:

1. Fillers (or diluents): Active ingredient is mixed with a sufficient vol-ume of a diluent, usually microcrystalline cellulose, lactose, man-nitol, starch, or dicalcium phosphate, to increase the bulk of the formulation.

2. Glidants: Glidants are finely divided dry powders added to the formu-lation in small quantities to improve their flow rate from the hopper and into the body of the capsule during the filling process. Glidants, such as colloidal silicon dioxide, powdered silica gel, starch, talc, and magnesium stearate, improve flow by

a. Reducing the roughness by filling surface irregularities.

b. Reducing attractive forces.

c. Reducing electrostatic repulsion.

The optimal concentration of the glidant used to improve the flow of a powder mixture is generally less than 1% w/w.

3. Lubricants: Capsule formulations usually require a lubricant just as the tablet formulations to reduce powder adhesion to the machine parts, especially during plug formation. Lubricants ease the ejection of plugs by reducing the adhesion of powder to metal surfaces and fric-tion between the sliding surfaces in contact with the powder. The most common lubricants for capsule formulations are hydrophobic stearates, such as magnesium stearate, calcium stearate, and stearic acid.

4. Surfactants and wetting agents: Surfactants may be included in cap-sule formulations of poorly water-soluble drugs to reduce the contact angle, increase the wettability of drug particles, and enhance drug dissolution. The most commonly used surfactants in capsule formula-tions are sodium lauryl sulfate and sodium docusate (sodium dioctyl sulfosuccinate).

In addition, a hydrophilic polymer, such as HPMC, is sometimes used as a wetting agent in the formulations of poorly soluble drugs. Powder wettability and dissolution rate of several drugs, such as hexo-barbital and phenytoin, were enhanced with the inclusion of methyl-cellulose or hydroxyethylcellulose in their capsule formulations.

5. Disintegrants: A disintegrant is frequently included to aid rapid disin-tegration and dissolution of the contents. Common disintegrants used in hard gelatin capsule formulations include croscarmellose sodium, crospovidone, and sodium starch glycolate.

Controlled-release beads and minitablets are often filled into gelatin capsules for convenient administration of an oral controlled-release (CR) dosage form. For example, SR antihistamines, antitussives, and analgesics are first manufactured into extended-release (XR) micro-capsules or microspheres, and then placed inside a gelatin capsule. Another example is enteric-coated lipase minitablets that are placed in a gelatin capsule for more effective protection of these enzymes from the acidic environment.

Manufacturing process

Very small-scale and experimental filling of the hard gelatin capsules can simply be carried out manually, that is, by removing the cap from the body of an empty capsule shell, filling the body with a preweighed amount of API or formulation, and attaching the cap. This can be carried out in early clinical studies by the sponsor or by the pharmacist. Compounding by

Figure 21.3 Hand-filling machine used to fill hard gelatin capsules.

the pharmacist is preferred when the stability of the drug in the capsule is unknown and is called on-site compounding.

Small-scale manufacture (several hundred capsules) can be done by using a manual capsule-filling machine. As illustrated in Figure 21.3, the manual-filling operation involves the following steps:

1. Placing empty gelatin capsules on the removable plate with bodies facing downward. This removable plate is then placed on the base plate and the bodies of the capsules are locked in position with the base plate using a lever.

2. The removable plate is removed with the caps on it. The body is filled with the formulation manually using a plastic spetula, and the excess powder is removed.

3. The removable plate is placed back on the base plate and pressing the flat plate seals the capsule caps. The sealed capsules are removed from the base plate by opening the lock on the body using the lever and inverting the base plate.

Large-scale filling of hard gelatin capsules follows the same principles using a high-speed capsule-filling machine, with two significant improvements:

·           Capsule alignment and separation are driven by vacuum, instead of mechanical interlocking.

·           Powder filling may require a soft compact (plug) formation depend-ing on the formulation weight and capsule fill volume. This compact is usually much softer than a typical tablet. The compaction force  used for plug formation is typically 20–30 N, compared to 10–30 kN typically used for tableting.

·           The high-speed powder filling is accomplished by either of the two dosing devices: (a) dosator device or (b) dosing disk/tamping device.

1. The dosator device uses an empty tube that dips into powder bed, which is maintained at a height approximately two-fold greater than the desired length of the plug. The dosator piston’s forward movement helps form the plug, which is then transferred to the body of the capsule, and released.

2. The tamping device operates by filling the cavities bored into the dosing disk, similar to the die-filling operation during tableting. A tamping punch slightly compresses the filled powder by repeated action, which is followed by the ejection of the plug into the capsule body.

Liquid- and semisolid-filled hard gelatin capsules

Main applications

Liquid- and semisolid-filled hard gelatin capsules are sometimes used to improve the bioavailability of drug substances with low solubility and wet-tability. Lipids in the formulation tend to increase the bile flow in vivo and promote drug absorption. For example, mixtures of mono-, di-, and tri-glycerides of mono- or dicarboxylate esters of PEGs, commercially available as Gelucire®, are available in various melting point and hydrophilic–lipophilic balance (HLB) ranges. Oral availability of drug solution in Gelucire® or in PEG is frequently higher than that of powder drug formulation. In addition, self-emulsifying and self-microemulsifying drug delivery systems (SEDDS and SMEDDS, respectively) can significantly improve drug’s bioavailability, for example, in the case of cyclosporine A and fenofibrate.

Liquid filling of hard gelatin capsules may also be indicated in the case of drugs with extremely low dose (e.g., in μg) and drug loading (e.g., less than 5% w/w) in the formulation to assure uniformity of content. Uniformity of drug distribution between different dosage units can be higher with a drug solution in a liquid or semisolid base than a blended powder.

Drugs with manufacturability issues in a tablet dosage form may also be for-mulated as a liquid-filled hard gelatin capsules. For example, drugs with low melting points can show significant sticking issues in both tablet- and powder-filled capsule dosage forms. Certain drugs with significant instability to light or moisture can show better stability in liquid or semisolid filled, compared to a powder-filled, hard gelatin capsule. The presence of an opaque waxy base and a molecular mixture of the antioxidant with the drug can increase the effectiveness of environmental protection in the capsule dosage form.

Examples of drug substances formulated as liquid-filled hard gelatin capsules are listed in Table 21.2.

Table 21.2 Examples of commonly used capsule dosage forms

Formulation considerations

The main formulation considerations for liquid-filled hard gelatin capsule are similar to those for soft gelatin capsules:

1. Noninteraction with capsule shell: Physicochemical compatibility between the drug/formulation excipients and the capsule shell are required for any capsule formulation. As described earlier, known drug–gelatin interactions include pH effect on gelatin hydrolysis or tanning, hygroscopicity or water effect on shell integrity, and the role of diffusible aldehydes in cross-linking gelatin shell.

2. Dose: The capsule size imposes a limit on the maximum amount of formulation that can be filled into a hard gelatin capsule.

3. Hygroscopicity: The formulation components should not significantly affect the moisture level of the shell. For example, highly hygroscopic excipients such as glycerol, sorbitol, and propylene glycol are not suit-able for liquid-filled hard gelatin capsules in high concentrations, although they may be used for soft gelatin capsules. This is because of the lower inherent moisture content of the hard gelatin shell.

Formulation components

Drug solution in an appropriate base formulation can be filled into hard gelatin capsules at room or slightly higher temperature. The functional cat-egories of formulation components are as follows:

1. Triglycerides for solubilization of the drug substance. These include either the medium chain triglycerides, such as Miglyol® 810 and 812, or the long chain triglycerides, such as soybean oil, olive oil, and corn oil.

2. Surfactants can be included in the formulation as solubility, dissolu-tion, and/or absorption enhancers, such as Cremophor®, Gelucire®, Labrafil®, and Tween®.

3. Cosolvents can be used in low concentrations, especially for SEDDS and SMEDDS, such as ethanol, propylene glycol, and PEG.

Manufacturing process

The main consideration and process risk in the manufacture of liquid-filled hard gelatin capsules is their tendency to leak at the joint between the body and the cap. This concern has been addressed in one of the two ways:

1. Applying a zone of gelatin film on the joining region of the body and the cap. This is known as banding, because a band of gelatin is formed on the outside of the capsule.

2. Spraying a solution of ethanol and water on the overlapping areas of the body and the cap along with the application of heat (e.g., 40°C–60°C for several seconds). This process is known as sealing. The low surface tension of the solvent mixture allows it to diffuse into and dissolve gelatin, which also melts during heating, to allow the fusion of gelatin from the cap with that from the body.