Two-piece capsules for Solid Oral Dosage Forms

Q Two-piece capsules for Solid Oral Dosage Forms F4SHIO00_ORAL1V2.indd 1 23/2/06 14:24:15 Solid Oral Dosage Form Applications The most popular m...
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Two-piece capsules for Solid Oral Dosage Forms

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Solid Oral Dosage Form Applications

The most popular medicinal dosage forms

Solid oral dosage forms are the most popular means of taking medicines – the tablet, hard two-piece capsule and soft one-piece capsule – because they are economic, portable, convenient to take without the need for specialist help, deliver a precise dose of medicament and are stable with a reasonable shelf life.

The hard two-piece capsule is the ideal tool for the pharmaceutical formulator because it can: ❚ be used at all stages in product development. ❚ be used for products in all therapeutic classes. ❚ be swallowed easily, which improves patient compliance. ❚ be used as an edible single dose container for materials with a very wide range of physical properties. ❚ be a simple way to reduce the workload during development and speed up the process.


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Qualicaps manufactures a range of hard two-piece capsules with different shell formulations each designed for specific applications:

Qualicaps® Gelatin capsules ❚ High quality gelatin capsules with excellent features: the market standard for many years.

Qualicaps® PEG/Gelatin capsules ❚ Standard gelatin capsules containing 5% w/w Polyethylene Glycol (PEG) 4000 as an additional plasticizer.

Quali-V® capsules ❚ Hypromellose capsules made from plant derived materials that contain nothing of animal origin.

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Solid Oral Dosage Form Applications Hard capsule properties The hard capsule has been in widespread use since the end of 19th century. During this time the material of choice for its manufacture has been gelatin because it is stable and non-reactive, an excellent film former, and solutions form homogeneous films on cooling. It has certain drawbacks associated with its moisture content, which lead to brittleness, and interactions with the contents. Qualicaps in the late 1980s decided to try and make hard capsules that were not so affected by their moisture content. This work resulted in two new capsule shell formulations: Qualicaps® PEG/Gelatin capsules and Quali-V® hypromellose capsules. These have properties similar to standard hard gelatin capsules and also have others that give a superior performance for certain applications.

Capsule shell, physical properties There is a difference in the structure of gelatin and hypromellose capsule shells because of the way in which the walls are formed. Gelatin capsules are formed by a sol-gel transformation induced by cooling: a true gelation process that produces a homogeneous film. Hypromellose solutions do not undergo a sol-gel transformation. To convert them into a gelling-type solution Qualicaps has patented a formulation that contains carrageenan to produce a network and potassium chloride, as a gel promoter, to enable the use of the standard manufacturing machines. Quali-V® capsule shells have a different structure to gelatin shells. Water in gelatin capsules plays an important role as a plasticizer, which helps to make a tough flexible film. This is essential for product performance because, during filling and usage, capsule shells are subjected to many impact forces. These forces are absorbed because the capsule is elastic and can flex. However, gelatin shells lose their flexibility when they lose water: when they are exposed to low humidities or when filled with hygroscopic formulations.


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Brittleness (% broken)

Qualicaps® PEG/Gelatin capsules are an improvement on standard gelatin capsules because they contain 5% w/w Polyethylene Glycol (PEG) 4000 that has been added as an additional plasticizer. These capsules at the same levels of moisture content as gelatin capsules are less brittle, see Figure 1. For example at 10% moisture content Qualicaps® PEG/Gelatin capsules are not brittle whereas gelatin capsules are significantly brittle. This is advantageous when dealing with formulations that are slightly hygroscopic. Quali-V® capsules are made from hypromellose and have a lower moisture specification than both Qualicaps® Gelatin and PEG/Gelatin capsules. Water does not function as a plasticizer in hypromellose shells and thus when these capsules are exposed to low humidities or are filled with hygroscopic formulations they do not become brittle, see Figure 1.

% moisture content

Figure 1. The effect of capsule moisture content on brittleness of empty capsules: a comparison of capsule types. Test conditions: capsules stored in sealed bottles at 45°C, number of replicates = 5. Brittleness determined by dropping 50 g weight from 10 cm on to capsules placed on a flat anvil.

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Solid Oral Dosage Form Applications

% Brittleness

Quali-V® hypromellose capsules are particularly suited for liquid-fill formulations because of the lack of effect of moisture loss on film flexibility. This means that the range of excipients that can be used for manufacturing semi-solid matrices (SSM) and liquid formulations is significantly enlarged. Potential SSM excipients that cause brittleness in gelatin capsules have no effect on Quali-V® hypromellose capsules, see Figure 2.

Time, weeks Figure 2. Qualicaps® Gelatin capsules filled with SSM excipients, the effect of storage on capsule brittleness. Redrawn from information in Nagata, S. and Tochio, S., 2002, CRS poster, Seoul, South Korea.

During this test, both types of capsule shell lost moisture but only the gelatin capsules became brittle, see Figure 3. QUALICAPS® Gelatin capsules

% moisture content

% moisture content

QUALI-V® capsules

Time, weeks

Time, weeks

Figure 3. Hard capsules filled with SSM excipients, the effect of storage on capsule moisture content: a comparison of Qualicaps® Gelatin and Quali-V® capsules. Redrawn from information in Nagata, S. and Tochio, S., 2002, CRS poster, Seoul, South Korea.

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Capsule Shell Solubility and Dissolution Dissolution is the main pharmacopoeial test to ensure the release of the active from a product. This has replaced the imprecise disintegration test, which did not indicate that the active was available. However, the first step in the release of an active from a hard two-piece capsule is the solution and break-up (disintegration) of the capsule shell. How do capsules release their contents? When a capsule is immersed in an aqueous medium at body temperature water will penetrate through the shell. The polymer must first hydrate before it can go into solution. The rate at which water diffuses through hypromellose capsule walls is slower than for gelatin based capsules. The time for the first split in the shell to appear will be longer for Quali-V® capsules. However, after the initial split there is a difference in the way in which Quali-V® capsules dissolve compared to gelatin based capsules because once the carrageenan network has been disrupted the hypromellose shells disperse quicker than the gelatin shells. This has been borne out in dissolution studies that have shown that the dissolution rates of theophylline, a poorly soluble active, from Quali-V®, Qualicaps® Gelatin and PEG/Gelatin capsules were equivalent, see Table 1.

Table 1. Dissolution from hard capsules containing theophylline: a comparison of capsule types, the effect of excipient. Results reported as Mean Dissolution Times. CAPSULE TYPE Formulation

Qualicaps® Gelatin

Qualicaps® PEG/Gelatin


Theophylline (T)*




T + Lactose **




T + Cellulose***




Key: * = theophylline 99.5%, magnesium stearate 0.5% **= theophylline 50%, lactose 49.5%, magnesium stearate 0.5% *** = theophylline 50%, microfine cellulose 49.5%, magnesium stearate 0.5% Size 0 capsules, filled with 425 mg powder made into plugs using an H&K plug tester at 81.9 N of compression force. Redrawn from data in Podczeck, F. and Jones, B.E., 2000, Drug Dev. Ind. Pharm., 28, 1163-1169.

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Solid Oral Dosage Form Applications

Ball bearing release time, seconds

The solubility of Quali-V® hypromellose capsules is less affected by the temperature of liquids than gelatin. Quali-V® capsules are soluble over the range 10° to 55°C but gelatin based capsules are insoluble below about 28°C, see Figure 4. This has implications if medicines are taken with cold drinks. The most significant difference between hypromellose and gelatin capsules is that the solubility properties are different for each manufacturer. The formulation of gelatin capsules is the same for each manufacturer. This is not true for hypromellose capsules because each manufacturer has a patented composition. The excipients, added to make the hypromellose solution into a gelling system, have an influence on their solubility. Quali-V® capsules are the only ones with a good solubility at pH 1.2, see Figure 5.

Temperature, °C Figure 4. The solubility of hard capsules at different water temperature: a comparison of capsule types. Redrawn from data in Chiwele et al, Chem. Pharm. Bull., 2000, 48, 951-956.


1UALI 6¸

% Release



se ello rom p y H



20 Y Hypromellose

0 0





Time, minutes



Quali-V Hypromellose X Hypromellose Y

Figure 5. The dissolution of acetaminophen from hypromellose capsules in acid medium: a comparison of Shionogi Quali-V® capsules with hypromellose capsules from other suppliers. Redrawn from Sakaeda et al, Jpn J. Pharm. Health Care Sci., 2002, 28, 594-598

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Stability Storage at ICH test conditions, 40°C, 75% RH, for 6 months, is an essential part of product development. However, under these storage conditions gelatin undergoes a cross-linking reaction that results in a reduction in the solubility of the shell and a slowing down of the dissolution rate of the contents. The problem received a lot of attention during the 1990s when the FDA organised a working group to study the effect of this problem both in vitro and in vivo. They found that part of this problem was an artefact of the test conditions because in vivo the effects were not as pronounced as in vitro. The result of this work was a change in the USP test conditions for hard and soft gelatin capsules, and for gelatin coated tablets. If the samples tested do not comply with the compendial limits then the tests can be repeated with enzymes, either pepsin or pancreatin, added according to the pH of the test medium. Hypromellose capsules do not undergo cross-linking reactions like gelatin capsules when exposed to ICH conditions. When products filled into Quali-V® capsules are tested any change in dissolution performance is due to the contents and not to the capsule shell. Thus simplifying the task for the formulator. Gelatin capsules when stored at high temperatures and humidities with certain types of compounds, e.g. ascorbic acid that contains aldehyde groups become discoloured because of interactions with the Į-amino groups of the gelatin protein (Figure 6). Quali-V® hypromellose capsules do not contain such reactive groups and the reaction with ascorbic acid does not occur.


Room temperature

40°C, 75% RH

Qualicaps® Gelatin


Figure 6. Comparison of discoloration of Quali-V® Hypromellose and Qualicaps® Gelatin capsules filled with ascorbic acid. Test conditions : capsules stored in polyethylene bottles for 2 months. Redrawn from Ogura et al, Pharm. Tech. Eur., 1998, 10(11), 32.

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Solid Oral Dosage Form Applications The two-piece capsule has undergone significant changes recently and in addition to the traditional gelatin shell there are capsules now available made with different materials. The first significant change to the conventional capsule was the Qualicaps® PEG/Gelatin capsule that gives an improved performance compared to the standard capsule in situations where its moisture content is reduced, i.e., when exposed to low humidities or filled with slightly hygroscopic formulations. Qualicaps was the first to introduce to the market a hypromellose capsule that has all the properties to satisfy the requirements of the pharmaceutical market. Quali-V® hypromellose capsules have some properties that are similar to gelatin, i.e. they can be filled on the same high-speed equipment and others that are very different, i.e. they do not undergo cross-linking when stored at ICH conditions and moisture does not act as a plasticizer for the film. Quali-V® has a patented composition and is different from other available hypromellose capsules. Quali-V® uses carrageenan as a gelling agent that is soluble at acid pH

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