Soft Gelatin Capsules: Formulation and Manufacturing Considerations

Soft gelatin capsules, also known as softgels or soft elastic capsules, 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, gelatin film plasticized by the addition of glycerine, sorbitol, or a similar polyol.

As with hard gelatin capsules, soft gelatin capsules are predominantly administered orally. Some can be formulated and manufactured to produce a number of different drug delivery systems such as

1. 1. Chewable softgels where a highly-flavoured shell is chewed to release the drug liquid fill matrix
   2. Suckable softgels which consist of a gelatin shell containing the flavoured medicament to be sucked and a liquid matrix (or just air inside the capsule)
   3. Twist-off softgels which are designed with a tag to be twisted or snipped off, thereby allowing access to the fill material and
   4. Meltable softgels designed for use as pessaries or suppositories.

Soft gelatin capsules have grown in popularity in recent years because they enable administration of liquids in a solid dosage form with a bioavailability advantage over other commonly used solid dosage forms (e.g., tablets). They are available in a variety of sizes, shapes, and colours that may be specific to the manufacturer.

In this article, we will discuss the following:

1. The rationale for the selection of soft gelatin capsules as a dosage form.
2. Composition of the soft gelatin capsule shell
3. Formulation considerations during manufacture of softgels
4. Liquids that may be encapsulated into soft gelatin capsules
5. Manufacture of soft gelatin capsules
6. Quality control of soft gelatin capsules
7. Advantages and disadvantages of soft gelatin capsules

Rationale for the selection of soft gelatin capsules as a dosage form

Soft gelatin capsules may be selected as the preferred formulation approach for one or more of the following reasons:

a. Improved oral bioavailability

Presenting a drug substance to the gastrointestinal tract in a solubilized form overcomes the processes of disintegration and dissolution that are required from solid dosage forms (such as tablets and hard gelatin capsules) before the active pharmaceutical ingredient (API) is available for absorption. This has been utilized to improve the bioavailability of drugs with a range of solubilities.

Also, the use of certain lipid vehicles can be associated with increased oral bioavailability and reduced intra- and inter- patient variability by modification of gastrointestinal digestive processes.

b. Improved Content Uniformity

Presentation of drug substances in a solution form can overcome the challenges of achieving dosage unit homogeneity compared to other solid oral dosage forms. Because soft gelatin capsules are filled with liquids or suspensions, excellent content uniformity can be achieved with even the most potent of drugs. The accuracy of the filling mechanism enables the dose to be filled to a tolerance of ± 1% for solutions and ± 3% for pastes.

c. Technological advantage for formulation of oils and low melting point drugs

When the API is an oily liquid, has a melting point lower than about 75 °C or proves difficult to compress, liquid filling of softgels (with or without other diluents) can provide a successful approach to presenting it in a solid oral dosage form.

d. Safety reasons during manufacturing, dispensing, and usage of potent and cytotoxic drugs

Most of the unit operations involved in the manufacture of tablets and hard gelatin capsules can generate a significant quantity of airborne powders. This can be a cause of concern for the manufacture of highly potent or cytotoxic compounds because of safety considerations for the operator and environment.

In the case of soft gelatin capsules, the powder handling is restricted to drug dissolution or dispersion in a liquid medium. Therefore, soft gelatin capsules provide greater operator safety during manufacturing. In addition, as the drug formulation is hermetically sealed in a shell, the exposure to the medication is minimized during dispensing as well as use.

e. Improved Stability

Preparations of liquid-filled soft gelatin capsules have proven beneficial to oxidative degradable drugs. Varying the level of glycerol in the shell formulation will alter the permeability of the shell to oxygen. The filling process can be performed under nitrogen, so by appropriate selection of shell composition, this technology can provide excellent protection for oxygen-sensitive drugs.

f. Line extension products for strategic marketing advantage in a therapeutic area with intense competition.

Drugs available as soft gelatin capsules can offer patient benefit, such as ingestion without water and portability a good example of such drugs are cough and cold medicines.

Composition of soft gelatin capsule shell

The major components of soft gelatin capsule shell are gelatin, plasticizer and water. Besides these three components, soft gelatin capsule shell may contain other ingredients such as colourants and/ or opacifiers for visual appeal and/or reducing the penetration of light for the encapsulation of photosensitive drug substances.

Flavours and sweeteners may be added to improve palatability. Preservatives e.g., potassium sorbate, and methyl, ethyl, and propyl hydroxybenzoate are added to prevent the growth of bacteria and mould in the gelatin solution during storage.

Acid-resistant polymers when present in the capsule shell formulation are used to impart enteric release characteristics. They can also be used to formulate chewable soft gelatin capsules e.g., ChildLife’s Pure DHA chewable 250 mg softgel capsule.

 

Component	Function	Typical content (% w/w)
Gelatin	Polymeric base	66.3
Glycerine	Plasticizer	33.0
Methylparaben + propylparaben (80/20 ratio)	Preservative	0.1
Colour	Colourant	0.1
Titanium dioxide	Opacifier	0.5
Water	Solvent/process aid	q.s. (0.7–1.3 × of gelatin)

Typical composition of a soft gelatin capsule shell

Types of vehicles used in soft gelatin capsules

Soft gelatin capsules are prepared to contain a variety of liquid, paste, and dry fills. Liquids that may be encapsulated into soft gelatin capsules include the following:

1. Water-immiscible volatile and non-volatile liquids such as vegetable and aromatic oils, aromatic and aliphatic hydrocarbons, chlorinated hydrocarbons, ethers, esters, alcohols, and organic acids.
2. Water-miscible non-volatile liquids, such as polyethylene glycols, and nonionic surface-active agents, such as polysorbate 80.
3. Water-miscible and relatively non-volatile compounds such as propylene glycol and isopropyl alcohol, depending on factors such as concentration used and packaging conditions

Note: Liquids that can easily migrate through the capsule shell are not suitable for soft gelatin capsules. These materials include water above 5% and low molecular weight water-soluble and volatile organic compounds such as alcohols, ketones, acids, amines, and esters.

Manufacture of soft gelatin capsules

Soft gelatin capsules (softgels) are manufactured using the following methods

1. Plate process
2. Rotary die process
3. Reciprocating die process
4. Accogel process
5. Seamless gelatin capsules

Read more on manufacture of soft gelatin capsules

Formulation considerations during manufacture of softgels

Manufacturers should keep the followings in mind when producing soft gelatin capsules

a. Compatibility of the drug with gelatin (and shell components)

The contents of soft gelatin capsules vary from solids, solid in liquid, solution or suspension, a combination of miscible liquid, or a simple liquid formulation. Fill materials are limited to
those that do not interact with the gelatin shell and/or other components of the shell.

b. Stability of the drug with moisture

The moisture content of soft gelatin capsules plasticized with glycerol is considerably higher than that of hard gelatin capsules. Therefore, to ensure chemical stability of the drug, moisture-sensitive drugs should not be formulated in soft gelatin capsules.

c. Stability of the drug at temperature 35°C to 40°C

This is another important consideration in the development of soft gelatin capsules.  During encapsulation, fill materials may be heated up to 35°C. Hence, highly thermolabile drugs may not be encapsulated in soft gelatin capsules.

d. pH of the fill material

Extreme acidic and basic pH should be avoided because a pH below 2.5 would tend to hydrolyse gelatin (leading to leakage). Also, fill materials with pH greater than 9 and aldehydes has a tanning effect on the gelatin. Tanning process involves crosslinking of gelatin, which results in hardening of the shell. The shell becomes insoluble in water and resistant to digestion by gastrointestinal enzymes: trypsin and chymotrypsin.

e. Migration of drug substances into the shell

One of the most important aspects of soft gelatin capsule formulation is to ensure that there is minimum interaction or migration between the liquid fill matrix and the softgel shell. Drug substances can migrate from an oily vehicle into the shell, and this has been related to their water solubility and the partition coefficient between water and the nonpolar solvent. The possible migration of a drug into the shell must be considered in the packaging of topical products in soft gelatin tube-like capsules, as this could affect drug concentration in the ointment, as applied. For other products, such as oral capsules or suppository capsules, both the shell and the contents must be considered in judging drug content when migration occurs.

Quality control of soft gelatin capsules

Quality control and inspection for soft capsules are almost the same as for other solid dosage forms and must follow good manufacturing practices. To read more on quality control of soft gelatin capsules click the link: Quality Control of Soft Gelatin Capsules

Examples of commercially available drugs prepared as soft gelatin capsules

• Aquasol A – Retinol (Vitamin A)
• Depakene – Valproic acid
• VePesid – Etoposide
• Lanoxicap – Digoxin
• Zantac – Ranitidine HCl
• Adalat – Nifedipine
• Unison SleepGel – Diphenhydramine HCl
• Vesanoid – Tretinoin
• Correctol Stool Softner – Docusate sodium
• One-A-Day Antioxidant Plus – Antioxidant vitamins and mineral supplement
• Phayzyme-125 – Simethicone
• Robitussin Severe – Guaifenesin and pseudoephedrine HCl
• Gas-X – Simethicone
• Unique E – Mixed tocopherol
• SuperEPA – Omega-3
• Avodart – Dutasteride
• Fortovase – Saquinavir

Advantages of Soft Gelatin Capsules

The advantages of soft gelatin capsules include:

1. Soft gelatin capsules provide a patient-friendly dosage form for peroral administration of nonpalatable and/or oily liquids.
2. Solutions or suspensions with an unpleasant odour or taste can be easily ingested in a soft gelatin capsule dosage form, which offers tidy appearance and convenient ingestion.
3. The proper choice of vehicle may promote rapid dispersion of capsule contents and drug dissolution.
4. Higher degree of reproducibility is achieved during the manufacture of soft gelatin capsules than is possible with powders or granules feed in the manufacture of tablets or hard gelatin capsules since the liquid fill is metered into individual capsules via positive displacement pump.
5. Soft gelatin capsule can be particularly advantageous for low dose drugs that are lipid-soluble because it can allow greater uniformity of content between dosage units than the conventional tablet dosage form.
6. It can also be more suitable than a tablet dosage form for the encapsulation of liquid, water-insoluble drugs.
7. The capsules can be formulated to be immediate-release (IR), slow or sustained-release (SR), or enteric-coated.
8. Soft gelatin capsules are hermetically sealed as a natural consequence of the manufacturing process. Thus, this dosage form is uniquely suited for liquids and volatile drugs. Many drugs subject to atmospheric oxidation may also be formulated satisfactorily in this dosage form.

Disadvantages of Soft Gelatin Capsules

The disadvantages of soft gelatin capsules include:

1. Moisture-sensitive drugs may not be stable in soft gelatin capsules due to the relatively higher water content in soft gelatin shell (20–30% w/w).
2. The use of soft gelatin capsule shell imposes significant limitations on the drug formulations that can be encapsulated in this dosage form, that is, restricted to liquids and semisolids.
3. Soft gelatin capsules are not an inexpensive dosage form, particularly when compared with direct compression tablets.
4. The manufacturing process is relatively tedious and difficult to optimize (e.g., ribbon thickness, fill weight, and weight variation). In addition, the breakage of even one capsule during the manufacturing can lead to the coating of drug formulation on the outer surface of several other capsules. This can also happen during storage in multiple-use containers, such as high-density polyethylene (HDPE) bottles.
5. There is more intimate contact between the shell and its liquid contents than exists with dry-filled hard gelatin capsules, which increases the possibility of interactions. For instance, chloral hydrate formulated with an oily vehicle exerts a proteolytic effect on the gelatin shell; however, the effect is greatly reduced when the oily vehicle is replaced with polyethylene glycol.

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