Hard gelatin capsules also known as hard-shell gelatin capsules or two-piece capsules are solid dosage forms in which one or more medicinal agents and/or inert materials are enclosed within a small shell. They are a well-established dosage form that provides solutions to many of today’s drug delivery and nutraceutical formulation challenges.
A hard gelatin capsule shell consists of two prefabricated, cylindrical sections (a cap and a body) each of which has one rounded, closed-end and one open end. The body has a slightly lower diameter than the cap and fits inside the cap.
Hard gelatin capsule shells are fabricated and supplied empty to the pharmaceutical industry by shell suppliers and are then filled in a separate operation. During the capsule filling unit operation, the body is filled with the drug substances and the shell is closed by bringing the body and the cap together.
- 1 Components of hard gelatin capsules
- 2 Capsule sizes and shapes
- 3 Manufacture of empty hard gelatin capsules
- 4 Filling of hard gelatin capsules
- 5 Formulation considerations for powder-filled hard gelatin capsules
- 6 Formulation considerations for liquid-filled hard gelatin capsule
- 7 Storage, packaging and stability considerations
- 8 Examples of hard gelatin capsules
- 9 Advantages of Hard Gelatin Capsules
- 10 Disadvantages of Hard Gelatin Capsules
- 11 References
Components of hard gelatin capsules
Hard gelatin capsule shell is composed largely of gelatin. Other than gelatin, it may contain materials such as plasticizer, colourants, opacifying agents, and preservatives which either enable capsule formation or improve their performance. Hard gelatin capsules also contain 12–16% water, but the water content can vary, depending on the storage conditions.
Capsule sizes and shapes
Empty hard gelatin capsule shells come in a variety of sizes ranging from an arbitrary numbering of 000 to 5 with 000 being the largest size and 5 being the smallest. The shape has remained virtually unchanged since its invention except for the development of the self-locking capsule during the 1960s when automatic filling and packaging machines were introduced.
The size of hard gelatin capsule selected for use is determined by requirements of the formulation, including the dose of the active ingredient and the density and compaction characteristics of the drug and other components. The first step to estimating the optimal capsule size for a given product is to determine the density of the formulation using tapped density for powders and bulk density for pellets, minitablets, and granules. The appropriate capsule size may then be calculated using the measured density of the formulation, the target fill weight, and capsule volume. The fill weight for liquids is calculated by multiplying the specific gravity of the liquid by the capsule body volume multiplied by 0.9.
To accommodate special needs, some intermediate sizes (‘elongated sizes’) are produced. These capsule sizes typically have an extra 10% of fill volume compared to the standard sizes e.g. elongated size 00 capsules (00el), elongated size 0 capsules (0el), elongated size 1 capsules (1el), elongated size 2 capsules (2el) etc. The table below shows capsule volumes and typical fill weights for formulations with different tapped densities.
Manufacture of empty hard gelatin capsules
Hard gelatin capsules are manufactured using a dip-coating method and the various stages involved are as follows:
Step 1: Preparation of the gelatin solution (dipping solution)
Step 2: Dip-coating the gelatin solution on to metal pins (moulds)
Step 3: Rotation of the Dip-coated pins
Step 4: Drying of the gelatin-coated pins
Step 5: Stripping and trimming
Step 6: Joining of the trimmed capsule shell
Step 7: Printing
Filling of hard gelatin capsules
The filling of hard gelatin capsules is an established technology, with equipment available ranging from that for very small-scale manual filling (e.g., Feton capsule filling machine), through intermediate-scale semi-automatic filling to large-scale fully automatic filling. Hard gelatin capsules can also be hand-filled one at a time, as done in a compounding pharmacy. The difference between the many methods available is the way in which the dose of material is measured into the capsule body.
The basic steps in filling hard gelatin capsules include:
- Rectification of capsules (placing empty gelatin capsules on the removable plate with bodies facing downward).
- Separation of caps from bodies.
- Dosing of fill material (The body is filled with the formulation manually using a plastic spatula, and the excess powder is removed).
- Replacement of caps/ closing capsule shells and
- Ejection of filled capsules
Filling of powder formulations into hard gelatin capsules
Hard gelatin capsules can be filled by hand for research or experimental purposes or when filling a small number of capsules in the pharmacy. This is done by placing the powder to be filled on a sheet of clean paper or on a pill tile or porcelain plate and pressing the open end of the capsule downward until it is filled. The cap is then placed to close the capsule.
On a small-scale manufacture, hard gelatin capsules can be filled manually using a manual or a hand-operated capsule machine. This is done by directly filling the powder into the capsule shell and relying on the bulk/tapped density of the powder to get the correct dose for the volume of the capsule shell used. The various types of hand-operated capsule machines have capacities ranging from 24 to 300 capsules and, when efficiently operated, are capable of producing about 200 to 2,000 capsules per hour.
Large scale production involves the use of machines that come in great variety of shapes and sizes, varying from semi- to fully automatic and ranging in output from 3000 to 150 000 per hour. Powder filling is accomplished by either of the two dosing devices: dosator device or dosing disk/tamping device.
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.
The tamping device operates by filling the cavities bored into the dosing disk, similar to the die-filling operation during tabletting. A tamping punch slightly compresses the filled powder by repeated action, which is followed by the ejection of the plug into the capsule body.
Large scale filling of hard gelatin capsules follow the same basic steps of filling two-piece capsules 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 depending 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 tabletting.
A more detailed discussion of capsule filling machines can be found in the article “Capsule Filling Machines (Encapsulators)”.
Filling of tablets into hard gelatin capsules
Tablets are placed in hoppers and allowed to fall down tubes, at the bottom of which is a gate device that will allow a set number of tablets to pass. These fall by gravity into the capsule bodies as they pass underneath the hopper. Most encapsulators used for this purpose have a mechanical probe that is inserted into the capsule to check that the correct number of tablets has been transferred.
Tablets for capsule filling are normally film-coated to prevent dust generation and are sized so that they can fall freely into the capsule body but without turning on their sides.
A recent innovation is the filling of coated minitablets, which have a significantly smaller surface area than the equivalent quantity of pellets, thus, reducing the amount of coating required and improving its uniformity.
Filling of multiparticulates and mini-tablets into hard gelatin capsules
Capsules formulated to give modified-release patterns are often filled with granules or coated pellets using machines adapted from powder use. These materials can be filled via volumetric filling and dosator filling using aspirational air ﬂow.
Volumetric filling can be achieved in a number of ways. The dosing disk method can be adapted in a way that the filled dosing chambers are not tamped and the filled dosing chamber is transferred above the capsule body, where a sliding plate opens the chamber to release the multiparticulates. Similarly, the dosator filling principle is adapted, whereby the dosator strikes in the multiparticuate bed to vacuum transfer the multiparticulates by air and transfer them to the capsule body.
In the double-slide method, a chamber is opened and closed by a moving plate. A second plate then opens and closes at the bottom of the chamber to fill the metered pellet dose into the capsule.
The piston dosing systems are based on the gravimetric principle where a dosing piston is underneath the multiparticulate bed. The dose is adjusted by the moving piston and a mechanical closure before the piston moves further down to reach to open a channel through which the multiparticulates ﬂow into the capsule body. This principle is also used for the filling of two diﬀerent multiparticulates whereby the first filling and closing of the piston is followed by lowering of the piston to collect second filling before moving to the release stage of the multiparticulates into the capsule body in the dosing disk principle the dosing chamber is closed at the bottom and gravimetrically filled with the pellets.
When the dosing disk moves the upper end closes und the dosing chamber moves directly above the capsule body to release the pellets. Filling of multiparticulates by dosator-type machines is achieved by the dosator driving into the pellet bed and sucking in the pellets by vacuum.
Because pellets are not compressed during the filling process, it is necessary to make an allowance for their size when calculating the weight of particles that can be filled into a capsule. Unlike powders, which have a much smaller size, pallets cannot fill as much of the available space within the capsule because of packing restrictions. The degree of this effect will be greater the smaller the capsule size and the larger the particle diameter.
Filling of liquids/semisolid formulations into hard gelatin capsules
As drug discovery continues to yield poorly water-soluble molecules, there is an increasing need for formulation techniques that can improve drug solubility. One such approach is the use of liquid-based formulations containing lipids, solvents, or surfactants, usually in combination, to improve drug solubility and bioavailability. The final formulation may be filled through piston pump systems into hard gelatin capsules as a room temperature liquid, or as a molten semisolid.
The filling of a liquid or semi-solid formulation is dependent on the viscoelastic properties of the formulation and the need to fulfil certain characteristics at the filling temperature. As a general rule, the formulation should have a viscosity of between 50 and 1000 Centipoise (cP) (although formulations of much higher viscosity can be suitable for manufacturing) and should not exceed 70 °C.
The particle size in suspension should ideally be less than 20 µm and formulations should be such that no stringing, dripping, splashes or solidification of the formulation should occur at the dosing nozzle. Unless a hot-melt is filled that completely solidifies below 40 °C, hard capsules are recommended to be band or fusion sealed using separate band sealing or Liquid Encapsulation Microspray Sealing (LEMS®) sealing equipment. For research purposes, a machine that is capable of filling and sealing 1500 capsules an hour (e.g. CFS® 1500) has been developed.
Note: If hard gelatin capsules cannot be used because of any formulation, preference, or cultural reason, alternative materials such as polymer-based shells or hypromellose may be used.
Liquid Excipients Compatible with Hard Gelatin Capsule Shells
|Lipophilic excipients||Vegetable oils e.g., Peanut oil, Castor oil, Olive oil, Fractionated coconut oil, Corn oil, Sesame oil, Hydrogenated vegetable oil, Soybean oil|
|Esters e.g., Glycerol Stearate, Glycol Stearate, Isopropyl myristate, Ethyl oleate|
|Fatty Acids e.g., Stearic acid, Laurie acid, Palmitic acid, Oleic acid, Oleic acid|
|Fatty Alcohols e.g., Cetyl alcohol, Stearyl alcohol|
|Hydrophilic excipients||PEG 3000–6000 MW|
|Amphiphilic excipients||Poloxamers, Lecithin, PEG esters (e.g., Gelucir 44/14; 50/13; Labrafil)|
|Abbreviations: PEG, polyethylene glycol; MW, molecular weight.|
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:
Adequate ﬂow through the hopper and into the dosing device (dosator) for reproducible filling of the capsules.
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.
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.
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.
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.
The capsule size imposes a limit on the maximum amount of formulation that can be filled into a hard gelatin capsule.
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:
- Heat stable
- Impermeable to moisture, water vapour, air, and odours
- Strong enough for machine handling
- 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)
Advantages of Hard Gelatin Capsules
Some of the advantages of hard gelatin capsules as a dosage form include:
- Hard gelatin capsules often have been assumed to have better bioavailability than tablets. Most likely, this assumption is derived from the fact that the gelatin shell rapidly dissolves and ruptures, which affords at least the potential for rapid release of the drug.
- Hards gelatin capsules allow a degree of flexibility of formulation not obtainable with tablets. Often, they are easier to formulate because there is no requirement that the powders be formed into a coherent compact that will stand up to handling. However, the problems of powder blending and homogeneity, powder fluidity, and lubrication in hard capsule filling are similar to those encountered in tablet manufacture.
- Modern capsule filling equipment makes possible the multiple filling of diverse systems such as beads, granules, small tablets, powders, and even semisolids.
- Capsules make possible the filling of bead-type modified-release products since they are filled without a compression process that could rupture the particles.
- Hard gelatin capsules are ideally suited for clinical trials and are widely used in preliminary drug studies. For comparative bioequivalence studies tablets can even be hidden in capsules to ensure the test being blinded.
Disadvantages of Hard Gelatin Capsules
- From a manufacturer’s point of view, there is perhaps some disadvantage in the fact that the number of suppliers of shells is limited.
- Filling equipment is slower than tabletting, although that gap has narrowed in recent years with the advent of high-speed automatic-filling machines.
- Generally, hard gelatin capsule products tend to be more costly to produce than tablets; however, the relative cost-effectiveness of capsules and tablets must be judged on a case-by-case basis.
- This cost disadvantage diminishes as the cost of the active ingredient increases or when tablets must be coated. Furthermore, it may be possible to avoid the cost of a granulation step by choosing encapsulation in lieu of tabletting.
- Highly soluble salts (e.g., bromides, chlorides, and iodides) generally should not be dispensed in hard gelatin capsules. Their rapid release may cause gastric irritation owing to the formation of a high drug concentration in localized areas.
- Both hard gelatin capsules and tablets may become lodged in the oesophagus, where the resulting localized high concentration of certain drugs (e.g., doxycycline, potassium chloride, indomethacin) may cause damage.
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