Soft Gelatin Capsules

• Soft gelatin capsules, often called "softgels", are hermetically sealed, one-piece capsules with a flexible, plasticized gelatin film that encapsulates a pre-determined dose of liquid, suspension, or semi-solid fill.

Rationale for Softgel Selection

• Softgels address formulation challenges not possible with tablets.
• They may be costlier than tablets and require specialized equipment.
• Softgels improve drug absorption, increase bioavailability, and reduce plasma variability, especially for poorly water-soluble drugs.
• Patient compliance is enhanced due to ease of swallowing and absence of poor taste.
• Convenient for liquid drug administration.
• Softgels ensure better operator safety and environmental control, overcoming issues of compressed or hard-shell capsules.
• Liquid flow in softgel manufacturing is more precise than powder flow.
• Drug solutions offer better homogeneity compared to powder mixtures.
• Drugs are protected against oxidative degradation by lipid vehicles and softgel capsule shells.

Types of Soft Capsules

• Orally administered softgels contain solutions or suspensions, releasing contents in the stomach.
• Chewable softgels have a flavored shell for releasing the liquid fill matrix.
• Suckable softgels feature a gelatin shell with flavored medicament or air inside for sucking.
• Twist-off softgels have a tag for twisting or snipping, allowing access to the fill material.
• Meltable softgels are designed for use as pessaries or suppositories.

Capsule Shape and Size

• Standard softgel shapes are oval, oblong, and round.
• Capsule size indicates nominal capacity in minims (1cc=16.23 m).
• Maximum capsule sizes for oral use are 20 minims oblong, 16 minims oval, or 9 minims round.

Comparison of Hard and Soft Gelatin Capsules

• Hard gelatin capsules consist of two pieces, while softgels are single-piece.
• Hard gelatin capsules usually contain solids, semi-solids, and liquids, whereas softgels typically contain semi-solids and liquids.
• It is possible to encapsulate a tablet in a softgel (Gel-Tab).
• Hard gelatin capsules have limited shapes; softgels have many.
• Hard gelatin capsules are not plasticized and more brittle, while softgels are plasticized and highly elastic.
• Closure involves friction fit in hard gelatin capsules, whereas softgels are hermetically sealed through heat and pressure.
• Manufacturing involves separate shell production and filling for hard capsules, whereas softgels have one-process manufacture and filling.
• Fill accuracy is 2-5% with modern machines for hard capsules but 1-3% for softgels.

Soft Gelatin Capsule Manufacture

• Softgel formulation should be viewed as a biphasic dosage form, including the gelatin shell (outer shell) and fill matrix (inner fill).

Shell Composition (Gelatin Shell Formulation)

• Softgel shells are typically gelatin, plasticizer, colorants, and flavors.
• Up to 50% of the gelatin mass is lost during processing.
• Gelatin can be Type A or Type B, with 40-50% of the wet gel formulation.
• Gelatin selection depends on compatibility with other ingredients and physicochemical properties.
• Plasticizers, such as glycerol, sorbitol or propylene glycol, constitute 20-30% of the formulation and make the shell elastic.
• To ensure minimal interaction between the liquid fill matrix and the softgel shell is crucial.
• Plasticizers are used in greater concentrations compared to hard gelatin capsules.
• Plasticizer content affects shell flexibility, dissolution, and disintegration.

Gelatin Shell

• The ratio of plasticizer to dry gelatin determines shell hardness.
• 0.4/1 Ratio glycerin/gelatin means hard.
• 0.6/1 Ratio glycerin/gelatin means medium.
• 0.8/1 Ratio glycerin/gelatin means soft.
• Water makes up 30-40% of the wet gel formulation.
• Water ensures proper softgel processing and encapsulation.
• Dry softgels have equilibrium water content of 4-10% w/w.
• Colorants, such as soluble dyes or pigments, are used at low concentrations (up to 0.5%).
• Colorants provide product identification.
• The capsule shell should never be lighter in hue than the capsulated material.
• It is important to test for compound reactions and avoid iron compounds and unclear fill.
• Titanium dioxide, may be added to produce an opaque shell.
• Preservatives, when required, prevent microbiological contamination during manufacture.
• Approximately 0.2% concentration of total drug medicament of methyl and propylparaben is used as a preservative.
• Flavoring agents, such as ethyl vanillin, are used for taste masking.

Properties of Soft Gelatin Shells

• Capsule shells protect against oxygen diffusion.
• Softgels contain residual water and protect compounds susceptible to hydrolysis.

Fill Material Composition

• Soft gelatin capsules hold liquid, suspension, or semi-solid matrices.
• Solids can be encapsulated as solutions, suspensions, powders, granules, pellets, or tablets.
• The drug can be in solution or suspension in the fill matrix.

Liquid-Phase Fill Matrix Criteria

• Must have the capacity to dissolve the drug if a solution fill is desired.
• Must have the ability to disperse in the GI tract to release the fill matrix.
• Must have the capacity to retain the drug in solution.
• Must have to compatibility with the softgel shell.
• Must have the ability to optimize drug absorption.
• The fill matrix can be hydrophilic (e.g., polyethylene glycols), lipophilic (e.g., triglyceride vegetable oils), or a combination.

Softgel Fill Matrices

• Lipophilic solutions, often made with liquid vehicles like soy or castor oil, are frequently used.
• These solutions have limited drug dissolving capacity.
• Viscosifying agents like hydrogenated oils or waxes can be added.
• Polar liquids with high molecular weight are common in the fill matrix to dissolve or suspend the drug.
• Polyethylene glycol (PEG) is the most used, with PEG 400 having a molecular weight of ~400 Da.
• Small hydrophilic molecules, like ethanol or water, can be incorporated but should remain below 10% by weight.
• Self-emulsifying drug delivery systems (SEDDS) consist of lipophilic and hydrophilic components along with surfactants.
• Drugs insoluble in softgel matrices are formulated as suspensions.
• Suspension formulations offer advantages for certain low-solubility drugs.
• High concentrations of water cannot be incorporated.
• It is not recommended to fill emulsions, which are also unstable.
• Extremes of pH must be avoided as pHs below 2.5 cause hydrolysis and pHs above 7.5 cause tanning.
• Liquids easily migrating through the shell are unsuitable.

Soft Capsule Manufacture Steps

• Preparation of gel mass and liquid fill material> Encapsulation > Drying > Inspection > Packaging

Gel Mass Preparation

• Performed in a 300-litre stainless steel vessel.
• Gelatin is dissolved in water at ~80°C under vacuum.
• The process includes plasticizer addition, for example, glycerol.
• Once dissolved, it is decanted into 200-kg mobile vessels, then components like colors are added.
• The mass must be kept at a constant temperature.

Process of Fill Material Preparations:

• An active(API) ingredient and non-active ingredients must be mixed by dispersion to create a dispensation.
• Use a non-aqueous liquid vehicle.
• Utilize mixer homogenizers to mix.
• Product must be stored in tanks until encapsulated.
• Protect oxygen sensitive drugs by mixing under vacuum and/or inert gas or add antioxidants.
• Ensure particle measures below 200 µm if the drug is a suspension to avoid particles getting trapped within the capsule.

Encapsulation

• Two materials of gelatin capsule -fill and outer shell are taken to the encapsulation bay.
• Machines are segregated to compress the gelatin into separate ribbons.
• Can be plate process, rotary, or die process.
• Oldest method
• A sheet of plain or coloured, warm gelatin is placed over a die plate.
• Fill the pockets containing API and cover the medication with a gelatin sheet.
• Remove capsules and wash with solvent.
• Limited use because of high production loss.

Rotary Die

• This is a continuous process, in which soft gelatin capsules are prepared and then immediately medicated with a liquid.
• 2 hoppers and 2 rotating dies.
• Fluid mixture is placed into the medicated hoppers to go in opposite directions.
• Halves of the capsule are formed, measured, then sealed from heat& pressure.
• Bicolored capsules can be made using this method.

Reciprocating Die and Accogel Processes

• Ribbons of gelatin are used to encapsulate the fill, differentiating from encapsulation.
• Pockets are made with medication, then cut out from the film using tanks containing a cooled solvent bath to prevent capsules from adhering to one another.
• In rotary process: Die and sealing rolls transfer doses into pockets for pressure and capsules.

Seamless Process

• Process uses one piece capsule without use of dies.
• Utilizes molten gelatin through outer nozzle through concentric tube and uses medicated liquid to dispense inner orifice.
• Then creates pulsation leading to gelatin.
• This is cooled and quickly removed.

Drying

• Capsules are excessively soft and flexible due to high-water content in the shell of 30-40%w/w.
• Finished product will be handled in microbiological terms as equilibrium reaches 4-10% w/w.
• There are two steps: Primary is the low-intensity drying with a rotary (dynamic) process to the dryer for 1-3 hours at 35 degrees Celsius.
• Secondary is the static dryer, where trays are stacks in a tunnel and dried at a controlled temperature of 21-24 degrees Celsius and approximately 20-30% humidity.

Inspection

• The created capsules are sorted, polished, and printed before they are sent to the inspection station.
• Special quality control test will determine the Seal Thickness measured from microscope.
• Total or Shell Moisture test: determined by toluene distillation
• Capsule fragility or Rupture test: Force required to rupture the capsule is determined

Packaging

• To prevent contamination.
• Desiccants are used to absorb excessive moisture in plastic/glass containers.
• Blister packaging is available.
• Lastly, capsules are stored in aluminium or plastic film by stripping.