Soft gelatin capsules are capsules in which the mechanical properties of gelatin have been manipulated by the addition of a plasticizer (most notably glycerol or other polyhydric alcohols, e.g. sorbitol), resulting in a more flexible capsule.
The popularity of soft gelatin capsules has increased in recent years due to the ability to formulate liquid-based formulations that provide a greater Cmax than tablet formulations.
This has particular applications in the treatment of acute conditions, e.g. pain.
A wide range of shapes of soft gelatin capsule is available, including round, oval, oblong, tubular and various other miscellaneous shapes.
The various components of the soft gelatin capsule shell are as follows:
Typically type B (alkali-processed) gelatin is used; however, type A (acid-processed) may also be employed for the manufacture of soft gelatin capsules.
Plasticizing agents
As detailed previously, the mechanical properties of the soft gelatin capsule are controlled by the inclusion (and concentration) of plasticizers.
For this purpose polyhydric alcohols, principally glycerol or sorbitol or mixtures of these, are used.
The concentration of plasticizer is generally 20–30% w/w of the wet mass.
This concentration range is an important determinant of the mechanical properties of the soft gelatin capsule.
Concentrations in excess of 30% w/w will result in the capsule being too flexible and tacky whereas capsules in which the concentration of plasticizer is below 20% w/w will be too brittle.
In both scenarios splitting of the capsule shell may occur either during storage or during use.
The hardness of the finished (dried) soft gelatin capsule is specifically defined by the ratio of the plasticizer to gelatin, with ratios of 0.4:1.0 and 0.8:1.0 offering extremes of the typically mechanical properties (hard and soft, respectively).
Water
Water is required both during the manufacturing process (to facilitate manufacture) and in the finished product to ensure that the capsule is flexible.
Initially during manufacture of the soft gelatin capsules, the concentration of water is between 30 and 40% w/w of the wet mass; however, following formation, of the capsule, the product is exposed to controlled drying, resulting in a final capsule water content of 5–8% w/w.
If the capsule is overdried a brittle product will result.
Miscellaneous excipients
As is the case for hard gelatin capsules, soft gelatin capsules may be colored or opaque, the chosen color(s)/opacifiers being added during the manufacturing process.
Titanium dioxide is primarily used as an opacifier for capsules.
In addition, if required, flavoring agents may be added to the capsule shell.
Manufacture of soft gelatin capsules
The original manufacturing method for soft gelatin capsules was originally patented by RP Scherer in 1933.
Whilst variations of this patent have been published, the main principles of the original Scherer method are still employed for the manufacture of soft gelatin capsules
In this method, the wet mass formulation is initially prepared containing gelatin, plasticizer(s), water and other excipients, as required.
Following this, the gelatin solution is fed onto two drums via a spreader box, at which stage ribbons of gelatin are produced.
The two sets of ribbons are then fed between two rotary dies (generally lubricated with mineral oil) to form pockets whilst, simultaneously, a metered volume of the capsule fill material is dispensed into the forming pocket.
The two halves of the capsule (containing the fill material) are sealed by the application of heat (37–40°C) and pressure, detached from the gelatin ribbon and collected.
Following collection, the capsules are washed to remove any lubricant (mineral oil) from the surface of the capsule, dried to remove circa 60–70% w/w water before being allowed to equilibrate under defined conditions of humidity (20–30% relative humidity) and temperature (21–24°C).
Following equilibration, the water content within the capsule shell will be at the required level.
It should be noted that other related methods (e.g. the reciprocating die process) are available for the production of soft gelatin capsules; however, a full description of these is beyond the scope of this note.
Formulation of the fill of soft gelatin capsules
As YOU will have observed from the description of the manufacture of soft gelatin capsules, the fill material for soft gelatin capsules is primarily liquid-based (although powder filling equipment is available).
The therapeutic agent may be dissolved or dispersed within the fill material.
There are several categories of fill material: (1) lipophilic liquids; (2) self-emulsifying systems; and (3) water-miscible liquids.
Lipophilic liquids
Lipophilic liquids are commonly used as fill materials for soft gelatin capsules and incorporate both vegetable oils (e.g. soyabean oil) and fatty acid esters.
Only a limited number of therapeutic agents are soluble in these materials and therefore, when used as a fill material, the formulation will either require the inclusion of co-solvents and/or surface-active agents or, alternatively, the fill may be formulated as a suspension (requiring the inclusion of viscosity-modifying agents and/or surfactants).
Self-emulsifying systems
Self-emulsifying systems are lipophilic liquids that contain a nonionic emulsifying agent (e.g. the Tween series).
Following release into the gastrointestinal tract, the fill material rapidly emulsifies into small droplets (with high surface area) and, in so doing, enhances the dissolution and hence absorption of the therapeutic agent.
Water-miscible liquids Liquids
In this category include high-molecular-weight alcohols, e.g. PEG 400, PEG 600, non-ionic surface-active agents (e.g. Tweens) and Pluronics (polyoxyethylenepolyoxypropylene block co-polymers).
Small concentrations of ethanol and water (generally less than 10%) may be tolerated within soft gelatin capsules.
As before, the selected therapeutic agent may be dissolved or, if the solubility is exceeded, dispersed within the solvent, the latter necessitating the addition of surface-active or viscosity modifying agents to stabilize the formulation.
As required, additional formulation excipients will be required in the above liquid systems: the details of these have been outlined in previous note.
