Hard Gelatin Capsules: Formulation and Manufacturing Considerations

Formulation considerations for powder-filled hard gelatin capsules

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

a. Flow

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

b. Density

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

c. Lubricity:

Magnesium stearate is typically added to most powder formulations. When mixed with other particles, magnesium stearate 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 machine, and adequate flow of the formulation. Other lubricants commonly used are stearic acid and sodium stearyl fumarate.

d. 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.

e. 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 interactions between the components can lead to bioavailability or stability problems. For example, the use of polyethylene glycol (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; thus, making it insoluble. Similar problems have been observed due to the presence of residual peroxides in excipients.

f. Dose

Dose and drug loading (i.e., %w/w of the formulation, that is the drug substance) 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 Active Pharmaceutical Ingredient (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).

g. 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.

h. Moisture sorption–desorption isotherm

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

i. 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 considerations for liquid-filled hard gelatin capsule

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

a. Noninteraction with capsule shell

Physicochemical compatibility between the drug/formulation excipients and the capsule shell are required for any capsule formulation. As described earlier in formulation considerations for powder-filled hard gelatin capsules, 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.

b. Dose

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

c. 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 suitable 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.

Storage, packaging and stability considerations

Finished hard gelatin capsules normally contain an equilibrium moisture content of 13 to 16%. This moisture is critical to the physical properties of the shells since at lower moisture contents (<12%), shells become too brittle and may crack when exposed to the appropriate stress. At higher moisture contents (>18%) they become too soft and may lose shape. It is therefore important to avoid extremes of temperature and to maintain a relative humidity of 40 to 60% when handling and storing capsules.

The bulk of the moisture in capsule shells is physically bound, and it can readily transfer between the shell and its contents, depending on their relative hygroscopicity. The removal of moisture from the shell could be sufficient to cause splitting or cracking, as has been reported for the deliquescent materials potassium acetate and sodium cromoglycate. Conditions that favour the transfer of moisture to powder contents may lead to caking and retarded disintegration or other stability problems. It may be useful to first equilibrate the shell and its contents to the same relative humidity within the acceptable range before filling.

Another problem that has received substantial attention in recent years is the loss of water solubility of shells, apparently because of sufficient exposure to high humidity and temperature or to exposure to trace aldehydes. Such capsules develop a “skin” or pellicle, during dissolution testing, exhibit retarded dissolution, and may fail to meet the USP drug dissolution specifications. This decrease in solubility of gelatin capsules is presumed to be the result of gelatin cross-linking caused by impurities such as formaldehyde.

Hard gelatin capsules can be individually protected by enclosure in strip or blister packs. In the former, the units are hermetically sealed in strips of aluminium foil or plastic film. In the latter one of the films enclosing the units is formed into blisters. An ideal foil or film for these packs should be:

1. Heat stable
2. Impermeable to moisture, water vapour, air, and odours
3. Strong enough for machine handling
4. Reasonably easy for patients to tear and open

Examples of hard gelatin capsules

Examples of solid-filled hard gelatin capsules

• Cinobac – Cinoxacin (Eli Lilly and Co.)
• Amphetamine and dextroamphetamine – Adderal XL (Shire Pharmaceuticals)
• Methylphenidate hydrochloride – Ritalin LA (Novartis)
• Didanosine – Videx EC (Bristol Myers)

Examples of liquid- or semi-solid-filled hard gelatin capsules

• Vancomycin – Vancodin (Lilly)
• Captopril – Captopril-R (Sankyo)
• Ibuprofen – Solufen (SMB Ivax)
• Piroxicam – Solicam (SMB)

References

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