Soft gelatin capsules as defined in our previous “Soft Gelatin Capsules: Formulation and Manufacturing Considerations”, are hermetically sealed one-piece capsules containing a liquid or a semisolid fill without a bubble of air or gas. They are made from a more flexible, plasticized gelatin film than hard gelatin capsules.
Soft gelatin capsules have gained popularity in the pharmaceutical industry for human and veterinary use due to the many advantages it possesses over other commonly used solid dosage forms such as tablets, hard gelatin capsules etc. The bioavailability of hydrophobic drugs can be significantly increased when formulated into soft gelatin capsules.
Many problems associated with tabletting, including poor compaction and lack of content or weight uniformity, can be eliminated when a drug is incorporated into a soft gelatin capsule. Also, improved stability of drugs that are highly susceptible to oxidation can be achieved with soft gelatin capsule.
This article, therefore, provides an overview of the basic components of soft gelatin capsule shell as well as the various methods used in the manufacture of soft gelatin capsules.
Contents
The various components of the soft gelatin capsule shell are as follows:
Similar to hard gelatin capsule shells, the basic component of soft gelatin capsule shell is gelatin. A large number of different gelatin shell formulations are available depending on the nature of the liquid fill matrix. Most commonly, the gelatin is alkali- (or base-) processed (type B) gelatin and it normally constitutes 40% of the wet molten gel mass. Type A acid-processed gelatin can also be used. The properties of gelatin shells are controlled by the choice of gelatin grade and by adjusting the concentration of plasticizer in the shell. The physicochemical properties of gelatin are controlled to allow
Physicochemical properties of gelatin important to capsule formation include gel strength, viscosity, change in viscosity with temperature and shear, melting point, settling point (temperature), settling time, particle size (affects time to dissolve), and molecular weight distribution (affects viscosity and strength).
Plasticizing agents are added in a soft gelatin capsule formulation to ensure adequate flexibility. They interact with gelatin chains to reduce the glass transition temperature (Tg) of the gelatin shell and/or promotes the retention of moisture (hygroscopicity). The most common plasticizer used for soft gelatin capsules is glycerol. Sorbitol, maltitol, and polypropylene glycol can also be used in combination with glycerol.
Glycerol derives its plasticizing ability primarily from its direct interactions with gelatin. In contrast, sorbitol is an indirect plasticizer because it primarily acts as a moisture retentive agent. Compared to hard gelatin capsules and tablet film coatings, a relatively large amount (20 -30% w/w) of plasticizers are added in a soft gelatin capsule formulation to ensure adequate flexibility. The amount and choice of the plasticizer contribute to the hardness of the final product and may even affect its dissolution or disintegration characteristics, as well as its physical and chemical stability.
Read Also: Manufacture of Hard Gelatin Capsule
Water usually accounts for 30-40 % of the wet gel formulation and its presence is important both during the manufacturing process (to facilitate manufacture) and in the finished product to ensure that the capsule is flexible. The desirable water content of the gelatin solution used to produce a soft gelatin capsule shell depends on the viscosity of the specific grade of gelatin used. It usually ranges between 0.7 and 1.3 parts of water to each part of dry gelatin.
After the capsule is formed, most of the water is removed from the soft gelatin capsules through controlled drying. The finished soft gelatin capsules contain 13–16 % w/w water, which represents the proportion of water that is bound to the gelatin in the soft gel shell. This level of water is important for good physical stability, because in harsh storage conditions softgels will become either too soft and fuse together, or too hard and embrittled.
Preservatives are often added to prevent the growth of bacteria and mould in the gelatin solution during storage. Examples of commonly used as preservatives include potassium sorbate, and methyl, ethyl, and propyl hydroxybenzoate.
A colourant (soluble dyes, or insoluble pigments or lakes) and/or opacifier (e.g., titanium dioxide) may be added to the shell for visual appeal and/or reducing the penetration of light for the encapsulation of a photosensitive drug. The colour of the capsule shell is generally chosen to be darker than that of its contents.
Other, infrequently, used excipients can include flavouring agents and sweeteners to improve palatability. Acid-resistant polymers are used to impart enteric release characteristics. They can also be used to formulate chewable soft gelatin capsules. A chelating agent, such as ethylene diamine tetracetic acid (EDTA), can be added to prevent chemical degradation of oxidation sensitive drugs catalysed by free metals in gelatin, such as iron.
Softgels are manufactured using the following methods
This is the oldest commercial process used in the manufacture of soft gelatin capsules. In this process, a warmed sheet of plain or coloured plasticized gelatin is placed over a die plate having a number of depression or moulds or numerous die pockets. By applying vacuum, the sheet is drawn into these depressions or pockets to form capsule wells. The capsule wells are then filled with medication-containing liquid. A second sheet of gelatin is carefully placed on top of the filled wells followed by the top plate of the mould. Pressure is then applied to the combined plate to form, seal and cut the capsules into individual units. This method is used for small scale preparation of soft gelatin capsules and capsules formed generally, had one flat side.
The major problems with this method of manufacturing softgels were the lack of dosage uniformity, high manufacturing losses, and its labour-/cost-intensiveness. This equipment is no longer available.
Most soft gelatin capsules are prepared by the rotary die process, a method developed and perfected in 1933 by Robert P. Scherer. This process almost eliminated all the problems associated with the plate process and produced soft gelatin capsules with improved uniformity and high standards of accuracy.
In this process, two plasticized gelatin ribbons (prepared in the rotary-die machine) are continuously and simultaneously fed with the liquid, semiliquid or paste fill between the rollers of the rotary die mechanism. The forced injection of the feed material between the two ribbons causes the gelatin to swell into the left- and right-hand die pockets which govern the size and shape of the softgels as they converge. As the die rolls rotate, the convergence of the matching dies pockets hermetically seals and cuts out the filled capsules.
Softgel formation mechanism (rotary die mechanism)
The precise and extremely low clearance of the rotating parts demands continuous lubrication of the machine to avoid even a slight build-up. The lubrication oil should, therefore, be a GRAS (generally recognized as safe) material. Immediately after manufacture, the formed capsules automatically undergo volatile solvent washing to remove any traces of lubricating oil from the exterior of the capsules. The capsules are then conveyed to a drying station and dried on trays, either in air or under vacuum, to equilibrium moisture content to about 6 – 10 % with forced conditioned air of 20% – 30% relative humidity at 21°C–24°C. The drying technique may proceed with an infrared drying step to speed up the process.
After drying is complete, capsules are then be transferred to the inspection station and sampled for release, after performing the required quality control tests for sizes sorting, colour sorting, and packaging. Depending on the manufacturer, additional finishing operations such as off-line print can be performed.
Schematic drawing of a rotary-die soft gelatin capsule filler
This continuous soft gelatin capsule processing technology was developed by Norton Company in 1949. This process is similar to rotary process in that ribbons of gelatin are formed and used to encapsulate the fill, but it differs in the actual encapsulating process. The gelatin ribbons are fed between a set of vertical dies that continually open and close to form rows of pockets in the gelatin ribbons. These pockets are filled with the medication and are sealed, shaped, and cut out of the film as they progress through the machinery. As the capsules are cut from the ribbons, they fall into a cooled solvent bath that prevents the capsules from adhering to one another.
Although the rotary die process and reciprocating die process were capable of producing soft gelatin capsules containing oily liquids and pastes, Lederle Laboratories in 1949 developed accogel process, a continuous process that produces soft gelatin capsules containing powders and granules.
The process involves a measuring roll that holds the fill formulation in its cavities under the vacuum and rotates directly above the elasticized sheet of the gelatin ribbon. The ribbon is drawn into the capsule cavities of the capsule die roll by vacuum. The measuring rolls empty the fill material into the capsule-shaped gelatin cavities on the die roll. The die roll then
converges with the rotating sealing roll covered with another sheet of elasticized gelatin. The convergence of two rotary rolls creates pressure to seal and cut the formed capsules
The seamless technique produces one-piece soft gelatin capsules without the use of dies. The process is often referred to as a bubble method that creates seamless, spherical soft gelatin capsules called pearl.
In this process, a molten gelatin stream flows though the outer nozzle of a concentric tube at a constant rate, and the medicated liquid formulation is dispensed through the inner orifice by means of a precision metering pump. The emerging stream is broken up into an intermittent but steady flow of uniform-sized by a pulsating mechanism, leading to the formation of droplets enveloped in molten gelatin. The formed capsules are quickly removed from the nozzle, slowly congealed, and automatically ejected from the system.
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