Capsules Flashcards
What are capsules?
- A very common unit dosage form.
- Solid dosage form in which the active agent plus other inactive ingredients are enclosed in a shell of (usually) gelatin.
- The ingredients may be in solid, liquid or paste-like form.
- Two types of capsules available: Hard Gelatin Capsules + Soft Gelatin Capsules
What are the advantages and disadvantages of capsules?
Advantage of capsules:
- Attractive appearance + colour and other coding for identification
- More stable than liquid dosage forms
- Shells can be opacified for protection from light (Titanium Dioxide)
- Tasteles
- Accurate dosage
- Slippery when moist
- ease of swallowing
- Less complicated formulation than tablets
- Gelatin shells are inert and digestible
- Release characteristics can be controlled
- Suitable for clinical trial drugs
- Can be prepared on small compounding scale
Disadvantages of Capsules
- Some patients may find them difficult to swallow
- Not suitable for small children
- Strict vegetarains object to gelatin –> need alternative
- Unsuitable for aqueous solutions or substances that are miscible with gelatin
What is gelatin and what types of gelatin are they?
Gelatin – prepared by the partial hydrolysis of skin, white connective tissue and bones of animals.
Two types of gelatin available:
- Type A – produced by acid hydrolysis and is manufactured from pork skin –> contributes to plasticity and clarity
- Type B – produced by alkaline hydrolysis and is manufactured mainly from animal bones –> contributes to the firmness
What are hard gelatin capsules?
Describe their mositure content, manufacturing method, formulation, excipients
Hard gelatin capsules = more common type, suitable for small scale use
> Shells made from gelatin and water (+/- low concentration of sodium lauryl sulfate - processing aid)
>Shells that manufactures as two pieces (cap and body) that join together
> Clear, colourless, and esentially tasteless
Moisture content
- Normally contain 13-16% moisture
- High humidity
- Distortion and loss of rigidity
- Very dry conditions
- Brittleness
- Storage conditions need to be controlled
- Dessicant pouches (drying agent) are often included
Manufacture
- Caps and bodies prepared separately
- Pegs of the desired size (larger diameter pegs used for cap than body) are dipped in molten gelatin and then removed and dried in controlled air flow.
- When dry, the shells are trimmed to length and the caps and bodies are joined.
- Eight different sizes of capsule shells are available – 000 (largest) to 5 (smallest)
Formulation
- Particle size of different ingredients should be similar to avoid segregation of components. Milling of one or all components may be required.
- Active ingredient and inactive excipients are blended together to ensure uniformity in each capsule (cf individual powders).
- Fewer excipients used than for tablets.
- Method of filling (large or small scale) dictates need for excipients. Compressed plug of powder in capsule formed by industrial filling machines –> neeed for extra excipients.
Excipients
- Diluent (filler) will be required for potent drugs to ensure adequate fill for each capsule. If the filling process involves creation of a plug of powder, then the diluent needs some cohesive properties. E.g. Lactose, Starch, Microcrystalline cellulose
- Disintegrant used to assist breakup of the capsule’s contents in the stomach. Used in commercial scale manufacture when the filling process has produced a plug of powder. Encourages access of water to separate particles. E.g. pregelatinized starch, croscarmellose and sodium starch glycolate
- Glidant – on an industrial scale, powder or particles must flow freely through the filling equipment. Low concentrations of glidants improve flow and ensure even filling. eg Magnesium stearate, colloidal silica, talc.
- Lubricant - reduces friction and eases ejection of powder plugs from filling machines. eg Mg Stearate
> Small quantities of lubricants may be beneficial by preventing aggregation of particles
>Lubricants tend to to be hydrophobic esp Mg Stearate, so excessive quantities may make the formulation powders harder to wet and slow dissolution
- Wetting agent – may be added to counter the “water-proofing” effect of lubricants and enhance dissolution. eg Sodium Lauryl Sulfate
- Release control agents – some capsules are intended for extended release of contents and may include coatings on pellets to cause delayed or sequential release of active ingredients. Methylcellulose may be used to achieve sustained release of powdered ingredients.
- Compounded capsules typically have a simple formulation: Drug +/- diluent.
What is the impact of formulation on drug release?
What is some of the factors that determine the rate at which the drug is released?
When a hard gelatin capsule is immersed in a dissolution fluid at 37°C, the capsule ruptures.
Rate at which the drug is released depends on:
- How readily the powder mass is wetted
- How rapidly the dissolution fluid can penetrate the powder
- How rapidly the powder contents disintegrate and de-aggregate when the filling process has formed a solid plug of the contents
- The nature of the actual drug itself
- Ingredients deliberately added to slow or delay release
- The inclusion of fillers, lubricants, surfactants disintegrants and the amount of compaction of the contents affect the drug release.
What is the process of filling hard capsules?
- Capsules are filled by volume
- Weight of powder will fit into each capsule size varies depending on bulk density of the powder
Four step process
- Rectifying (orients all the capsule shells in same direction) –> sorting mechanism guides capsules bodies into a holding ring
- Separation (caps are seprated from bodies) –> - a similar apparatus holds the caps and the caps and bodies are separated from each other by vacuum
- Filling (capsule bodies are filled with contents) –> – the holding ring with the capsule bodies is rotated under a hopper containing the formulation. The formulation is forced into the capsule bo
- Closing (caps are replaced on bodies) –> when the capsule bodies have been filled the cap-holding ring is secured over the body-holding ring and pins push the two halves back together.
> The joined capsules are ejected into a receiver box
> Final step is cleaning and polishing the finished capsule, dust is removed from the outside of the capsules by shaking with sodium chloride and then rolling on a cloth covered surface
How to seal hard capsules?
Many capsule shells are designed to be self-locking eg Coni-Snap®, Snap-fit®. These have grooves in the body and cap that lock together.
- “Spot-welded” with a heated pin to fuse the cap to the body.
- A band of molten gelatin may be applied around the join eg Kapseal®
- On a small scale the neck of the body may be moistened with water before replacing the cap.
How to compound hard capsules?
Test capsules are separately filled with drug source and diluent to determine weight of each required to fill the capsule – packing statistics. The volume of the capsule occupied by the desired amount of drug is then used to calculate the amount of diluent it will displace.
- For a small number of capsules a trituration of drug and diluent (if required) is prepared as for an individual powder. Enough for 2 extra capsules is prepared.
- Capsule caps and bodies are separated and the bodies held in a capsule block.
- The required weight for each capsule is weighed and transferred into the capsule body via a small funnel.
- The outside of the opening of the capsule body is moistened and the cap replaced firmly, OR cap is replaced on body and depressed until locking mechanism engages.
What are some formulation considerations?
- Aqueous solutions cannot be included inside gelatin capsules due to softening and distortion.
- Fixed or volatile oils can be used in hard capsules provided the capsule is well sealed.
- Eutectic mixtures of drugs should be mixed with an inert adsorbent.
- Capsules containing hygroscopic substances (absorb moisture from air) need dessicant (drying agent) in packaging.
What are soft gelatin cpasules?
- Made of gelatin to which plasticizer eg. glycerol or a polyhydric alcohol has been added. (Moisture content 5-10%)
- May contain a preservative eg methyl or propyl hydroxybenzoate, but often do not.
- Typically ovoid or oblong in shape. Seam is visible.
- Can be opacified or coloured (even two tone) and printed for ID.
- Suitable for liquid, suspension or paste.
- Completely sealed – cannot be opened without destroying the capsule.
- Industrial scale.
- Rapid release of contents in stomach.
- Contents are usually liquid and designed for rapid dispersion or dissolution on release
- rapid absorption and increased bioavailability
- Useful for poorly soluble drugs as they can be presented dissolved or suspended in lipophilic or hydrophilic solvent with possible addition of surfactant.
- After administration the drug is rapidly dispersed
- rapid and more complete absorption.
- Having a drug in solution can also improve dose uniformity for potent drug formulations
How do you prepare soft gelatin capsules
Clue: Plate method, rotary die/reciprocating die process
Filling and sealing takes places in one process
Plate Method
- Warm sheet of gelatin is laid over a mould.
- The liquid filling is poured into each mould.
- Another sheet of gelatin is laid on top.
- The top mould plate is placed on top and pressure is applied to form capsules.
Rotary Die/Reciprocating Die Process
- Liquid gelatin is formed in two 2 ribbons that flow into a rotating/ opening and closing die roll
- As the ribbons converge in the die, the filling is injected between them
- The movement of the die closes off the capsule and seals them by pressure and heat
- Using two different coloured ribbons produces two-tone capsules
What are some fomulation considerations for soft gelatin capsules?
- Unsuitable for aqueous liquids and low MW weight water-soluble substances
- Suitable for non-volatile water soluble compounds eg polyethylene glycol
- Suitable for water insoluble liquids eg oils (eg soya bean oil), aromatic oils
- May use combination of oil and surfactant –> self-emulsifying system
Describe the BP Test For capsule (test for content) –> content for active ingredient
20 capsules (or smaller allowable sample ≥5) are combined and assayed to determine the amount of drug present. Limits are given in the monograph for each capsule (eg 90-110%)
Describe the BP Test For capsule (test for content) –> B.P. Test for Uniformity of Mass
Tests to see if capsules are of even weight. Contents of 20 capsules are weighed and mass of each capsule content is compared to the average mass of the sample.
> Less than 300 mg = 10 % permitted % deviation for different capsule size
> More than 300 mg or more = 7.5 % permitted % deviation for different capsule size
not more than 2 out of 20 capsules can be outside mean weight of those percentages
Describe the BP Test For capsule (test for content) –> B.P. Test for Uniformity of Content
Required for capsules which contain active ingredient less than 2mg or 2% of total mass.
- Sample of 10 individual capsules are assayed for drug content to ensure each tablet has correct amount of drug.
- Effects of inadequate mixing are very significant if drug is only small proportion of mix
