(271) Start a Hard Capsule Making Unit

In the manufacture of pharmaceuticals, encapsulation refers to a range of techniques used to enclose medicines in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally or be used as suppositories. The two main types of capsules are:

Hard-shelled capsules, which are normally used for dry, powdered ingredients or miniature pellets (also called beads that are made by the process of Extrusion and Spheronization) - or mini tablets;
Soft-shelled capsules, primarily used for oils and for active ingredients that are dissolved or suspended in oil.

Both of these classes of capsules are made from aqueous solutions of gelling agents like:

Animal protein mainly gelatin;
Plant polysaccharides or their derivatives like carrageenans and modified forms of starch and cellulose.
Single-piece gel encapsulation

In 1834, Mothes and Dublanc were granted a patent for a method to produce a single-piece gelatin capsule that was sealed with a drop of gelatin solution. They used individual iron moulds for their process, filling the capsules individually with a medicine dropper. Later on, methods were developed that used sets of plates with pockets to form the capsules. Although some companies still use this method, the equipment is not produced commercially any more. All modern soft-gel encapsulation uses variations of a process developed by R.P. Scherer in 1933. His innovation was to use a rotary die to produce the capsules, with the filling taking place by blow molding. This method reduced wastage, and was the first process to yield capsules with highly repeatable dosage.

The current owner of the RPScherer technology is Catalent Pharma Solutions, the world's largest manufacturer of prescription pharmaceutical softgels.

Softgels can be an effective delivery system for oral drugs, especially poorly soluble drugs. This is because the fill can contain liquid ingredients that help increase solubility or permeability of the drug across the membranes in the body. Liquid ingredients are difficult to include in any other solid dosage form such as a tablet. Softgels are also highly suited to potent drugs (for example, where the dose is <100 ug), where the highly reproducible filling process helps ensure each softgel has the same drug content, and because the operators are not exposed to any drug dust during the manufacturing process.

In 1949, the Lederle Laboratories division of the American Cyanamid Company developed the "Accogel" process, allowing powders to be accurately filled into soft gelatin capsules.

Two-piece gel encapsulation

James Murdock of London patented the two-piece telescoping gelatin capsule in 1847.^[2] The capsules are made in two parts by dipping metal pins in the gelling agent solution. Two-piece gelatin capsule machinery is manufactured by R&J Engineering Corporation of Canada. The capsules are supplied as closed units to the pharmaceutical manufacturer. Before use, the two halves are separated, the capsule is filled with powder or more normally pellets made by the process of Extrusion & Spheronization (either by placing a compressed slug of powder into one half of the capsule, or by filling one half of the capsule with loose powder) and the other half of the capsule is pressed on. With the compressed slug method, weight varies less between capsules. However, the machinery required to manufacture them is more complex.^[3]

The powder or spheroids inside the capsule contains the active ingredient(s) and any excipients, such as binders, disintegrants, fillers, glidant, and preservatives.

Manufacturing equipment

The process of encapsulation of hard gelatin capsules could be done on manual, semi-automatic and automatic machines. Softgels are filled at the same time as they are produced and sealed on the rotary die of fully automatic machine.

Standard sizes of two-piece capsules

Size	Volume (ml)^[A]	Locked length (mm)^[A]	External diameter (mm)^[A]
5	0.13	11.1	4.91
4	0.21	14.3	5.31
3	0.3	15.9	5.82
2	0.37	18	6.35
1	0.5	19.4	6.91
0	0.68	21.7	7.65
0E	0.7	23.1	7.65
00	0.95	23.3	8.53
000	1.37	26.14	9.91
13	3.2	30	15.3
12	5	40.5	15.3
12el	7.5	57	15.5
11	10	47.5	20.9
10	18	64	23.4
7	24	78	23.4
Su07	28	88.5	23.4

Soft Gelatin Capsules - A Review

Soft gelatin encapsulation, a new concept in the presentation of drug and food ingredients offers many benefits including segment control, elimination of taint problems during manufacture, extended shelf-life of product, and convenience of use. Soft gelatin capsules (SGC) is the current buzzword in the Pharma industry in recent years. The purpose of this review was to compile the recent literature with special focus on the advances of soft gelatin capsule and recent developments of SGC. This review also summarizes the in vitro and in vivo studies to evaluate the performance and applications of these systems. Soft gelatin capsule formulations are becoming more popular in recent years. These formulations can mask odor and unpleasant taste, and are easy to swallow. They are suitable for encapsulation of lipid solutions, suspensions, or paste-like formulations, making them a useful option when formulating poorly water-soluble drugs. The commercial pharmaceutical and nutraceutical markets have driven the development of alternative shell forming materials for the traditional capsule shell material gelatin. The on-going establishment and further development of the manufacturing technology for liquid fill capsules have provided a base for certain new applications for oral drug delivery, especially for lipid-based systems. A review of the US patent activity over the past decades reveals an improved sign of patent activity distinctively related to the softgel technology.

Introduction

Soft gelatin capsules1 (referred to as soft elastic gelatin capsules, liquid gels or softgels) are a unique drug delivery system that can provide distinct advantages over traditional dosage forms such as tablets, hard gelatin capsules and liquids. However due to economic, technical and patent constraints there are relatively a few manufacturers of softgels in the world. Softgel is a hermetically sealed, one-piece capsule with a liquid or semisolid fill. The softgel consists of two major components, the gelatin shell and the fill. In the finished product gelatin shell is primarily composed of gelatin, plasticizer and water. The fill material can include a wide variety of vehicles and can either be a solution or a suspension. Softgels may be coated with suitable exterior coating agents such as Cellulose acetate phthalate (CAP) to obtain enteric release of encapsulated material. The standard softgel shape of oral pharmaceutical products is oval, oblong and round, though softgels can be manufactured in many shapes.

Soft gelatin capsules generally contain the drug in a non aqueous solution or suspension. The vehicle may be water immiscible liquid, such as PEG, and non ionic surface active agent, such as Polysorbate 80. Hydrophobic drugs dissolved in a lipophilic solvent such as vegetable oil would generally demonstrate poor bioavailability compared to the same drug given as a powdered solid, suspension or hard gelatin capsules. However, a drug dissolved or dispersed in a water miscible solvent may have better bioavailability than a compressed tablet of the same drug.

The merits of filling hard gelatin capsules with liquids is usually compared to soft gelatin capsules (softgels) There are significant differences between the dosage forms but they should be viewed as complementary rather than competing technologies. It is perfectly possible to switch between the two formats as well. The formulation usually dictates the most appropriate capsule type, but in cases where the formulation allows a choice, hard capsules have several advantages over softgels:

Water Content - The softgel shell has a far higher water content than the hard capsule shell which may not be acceptable for moisture sensitive products.
Placticisers - Softgels contain placticisers (usually glycerol or sorbitol) which can migrate into the capsule content or can aid migration of the fill into the shell. The gelatin used in hard capsule shells contains no plasticiser.
Fill Vehicles - Thermo softening vehicles (melting at above 35 degrees C) are not acceptable for softgel filling. Hard capsules can be filled at up to 75 degrees C offering a wider range of suitable excipients, particularly for controlled release formulations.
Microbial Growth - Softgels are more susceptible to microbial growth due to higher moisture content.
Shell permeability - Softgels are more susceptible to moisture and gas transmission and can be an issue to oxidation sensitive products. This is caused mainly by the presence of plasticisers in softgels which create channels in the shell that are larger than those found in hard capsules.
Cost - Softgel filling speeds are slow (30k/hour) and tray drying can take from days to weeks. For hard capsules the separate cost of purchasing the capsule shell must be factored in, but is off-set by processing efficiencies and higher filling speeds (40-50k/hour). In general, the costs of softgels and hard capsules are comparable.
Coating - Hard capsules are generally regarded as being easier to coat (eg. enteric coating) than softgels.
Manufacturing Capacity - Softgel manufacturing capacity is limited to a relatively small number of manufacturers, mainly due to the expensive cost of the equipment. Hard Shell technology is widely available with contract manufacturers and it is a relatively straight forward process to transfer the technology inhouse.
Intellectual property of shell - Liquid formulations may require a formulation of the softgel shell itself. If this is contracted out to a softgel manufacturer, intellectual property rights to the shell typically remain with the contract manufacturer, therefore limiting the possibility of changing manufacturers. This is not applicable for hard capsules which do not require reformulation of the shell.

Materials and development timelines - Less materials are required to develop a hard capsule product (under 1kg of drug substance) This is particularly important for early clinical development, where the availability of the drug is usually restricted. Development timelines are generally much shorter as well.


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