Common oral solid dosage forms
- Tablets
- Capsules
- Powders/Granules
- Pastilles, lozenges
- Gums
- Oral lyophilisates (i.e. MAXALT MELT (rizatriptan benzoate))
• As before, the key aim is to determine when to use aparticular dosage form
Capsules
Capsule – Capsula – small box
Hard and soft gelatin capsules
Capsules
• Manufacture:
• Manufacture:
– Avoids certain processes (i.e. compaction, possibly granulation, drying – if wet granulation was required)
– Difficult to counterfeit
• Manufacture:
– Specialist filling equipment is normally required
Capsules
• Bioavailability:
• Bioavailability
– May be used to increase oral bioavailability of poorly watersoluble drugs (especially liquid-filled capsules)
– An easy method by which to deliver liquids
• Bioavailability
– Homogeneity of fill
Capsules
• Formulation:
• Formulation:
– A range of formulation types means a range of ways to deliver drugs
• Formulation:
– Physical and chemical stability, particularly for liquid-filled capsules, may be an issue
Hard Gelatin Capsules
- Edible package composed of gelatin (or
occasionally polymers / starch) - Gelatin is derived from animal tissue (type A from the acid treatment of pig skin, type B from an alkaline treatment of demineralised bones – may be used individually or in blends)
- Consist of a cap and body
- Usually filled with powders, but increasingly used for liquid-filled systems
- Capsule has locking device via indentations on outside of body and/or inside of cap
Powder filling of hard gelatin capsules
- Equipment consists of a powder hopper which feeds powder into a reservoir
- Usually dosator used to fill capsules
•dosing tube in which there is a spring loaded piston
•tube plunged into powder bed - powder rises in tube to form ‘plug’
•tube rises out of powder bed, moves over capsule body and plunger moves down, depositing powder in shell - Dose therefore determined by volume of plug in dosator - adjusted by moving position of piston
Powder filling of hard gelatin capsules - industrial scale
• Industrial scale – may be ‘dependent’ or ‘independent’
- Dependent – uses the capsule body directly to measure the powder
- Still used in many countries but slow, can be very dependent on operator skill and uniformity of dosing clearly dependent on powder flow and uniformity of filling
- Independent – most commonly used for large pharma
- ‘Plug’ of material formed from powder which is then transferred to body
- Force used in 10-100N, compared to 10-100kN used for tabletting
- Most common approach is to use a dosator
- The piston may compress powder to form a coherent plug
- The tube rises out of powder bed, moves over capsule body and plunger moves down, depositing powder in shell
- The dose therefore determined by volume of plug in dosator - adjusted by moving position of piston
What is a dosator
– This is a tube containing variable volume chamber at bottom and piston at top
Types of gelatin
• Type A
– From the acid treatment of pig skin, using HCl, H2SO4 or H3PO4 for ca. 1 day, followed by processing, purification, etc.
• Type B
– Alkaline treatment of demineralised bones, by placement in a slurry of calcium hydroxide for 1 – 3 months
– Following this, gelatin is extracted by a series of hot water washes, with water temperature increasing in each subsequent wash
– Solutions form a gel and evaporation of water results in production of solid gelatin
• Replacements / alternatives: HPMC, starch
Difference in types of gelatin
• Type A and Type B gelatin have different properties:
– Different isoelectic points;
– Therefore solubility varies as a function of pH
• Different range of molecular weights
The use of gelatin
• MW – 15,000 – 250,000
• Grade / quality is defined by the bloom strength
– The weight, in grams, required to depress a plunger (of defined 12.7mm diameter) to a defined depth of 4mm within an aged gelatin gel (6.66% w/w) in water.
• Physical / physicochemical properties:
– Non-toxic, widely used in foods
– However, bovine spongiform encephalopathy (BSE) has been an issue (now uses grade 1 – highly unlikely source of BSE, or grade 2 – unlikely but not absolutely excluded)
– Soluble in biological fluids; below 30 degrees gelatin capsules swell but do not dissolve in aqueous solution
– Excellent film-former, so easy to make capsules from it
– Rheological properties enable it to be easily processed, even at high temperatures
– Sol-gel transition means it readily forms a solid when cooled
Composition of hard gelatin capsule shells
Process aids
- Small amount (<0.15% w/v) of sodium lauryl sulphate (SLS) as a wetting agent to ensure that the metal moulds are uniformly covered when dipped into the gelatin solution.
- No longer contain preservatives.
- Moisture levels in the finished capsules are 13.0-16.0% w/v to prevent bacterial growth. (This amount of moisture is strongly bonded to the gelatin molecules, so the water activity / availability is substantially reduced)
Hard Gelatin Capsules
• Filled with:
– Powder (or granules)
– Similar to aspects of tablet manufacture:
• Particle size should be uniform and consistent, to ensure even flow and dosing during filling
• May be granulated – reduces problems of filling with irregular shapes in capsules
– Filling is bench-scale (hospitals, research, clinical trials) or industrial scale (manufacture)
• Filled with:
– Liquid or semisolid formulation (i.e. gel)
• …into which the drug is dispersed or dissolved (i.e. a solution or a suspension)
• Uses a metered volumetric system
• Sensitive to temp
• Prone to leakage, sealing at the join between the capsule cap and the body is vital
Capsule Sizes
Capsules available in 8 sizes with different fill volumes: 5 - 0.13ml 4 - 0.20ml 3 - 0.27ml 2 - 0.37ml 1 - 0.48ml 0 - 0.67ml 00 - 0.95ml 000 - 1.36ml
Size 000 is approx 2cm in height, size 5 about 1cm.
As an example, Size 0 used for 500mg doses of antibiotic
Why use HGCs?
- Industry will generally use tablets if it can
- Capsules used for materials that can not be easily formulated as a tablet due to e.g.
•change polymorphic form on compression
•degrade on compression
•sensitivity to water and not easily dry granulated
•advantages associated with delivering liquids / dispersed systems (i.e. solubility issues)
Composition of hard gelatin capsule shells
- Colourants
Either soluble dyes or insoluble pigments - Pigments
• titanium dioxide most widely used (white, opacifying agent)
• also iron oxides which may be black, red or yellow
-Dyes
• azo (-N=N-) or (more common) non-azo
• erythrosine, indigo carmine and quinoline - yellow most common
Manufacture of HGCs
- A concentrated gelatin solution is prepared in hot demineralised water
- Moulds (‘pins’) mounted on metal bars and are dipped into gelatin solution
- Removed with film of gelatin, rotated to ensure uniform thickness then passed through series of drying kilns, stripped off pins and cut to size and two halves joined together
Typical excipients used for HGCs
• diluents (e.g. starch, lactose) - particularly for low dose drugs, helps make dose manageable and aids flow and
compression
• glidants (e.g. Fumed Silicon Dioxide (Aerosil)) - reduced interparticulate adhesion
• lubricants (e.g. magnesium stearate) - reduces adhesion to metals
Dissolution
• Must consider dissolution of capsule shell itself as part of the overall dissolution process; followed by disintegration of granules / dispersal of powder; dissolution
• Gelatin capsules readily soluble at 37oC but this decreases dramatically as temp drops – virtually insoluble at 30oC
– stability
Noyes Whitney equation:
Noyes Whitney equation:
dm/dt = DA(Cs-C)/h
Particle size
Drugs with a large surface area/g (i.e. small particle size) will theoretically dissolve quickly
But be careful – this only works because you get MORE particles when you reduce the size
As capsule particles dissolve, they get smaller but the number of particles stays the same – i.e. comparative lack of disintegration when compared to tablets
Also need to be careful because if aggregation occurs, effective surface area will decrease.
Need to consider packing of bed within capsule - tightly packed small particles will hinder water penetration
Care required is re: hydrophobicity of powder contents –
lubricants and glidants tend to reduce wetting
Alternative approaches
Granulation
- Several studies have indicated beneficial filling/ dissolution properties
- However this introduces a further unit operation into the manufacturing process
- Controlled release formulations
- Pellets may also be filled into capsules, particularly in the context of controlled release oral formulations
Liquid filled hard gelatin capsules
Interest in filling capsules either
a) with a liquid and then ‘banding’ to prevent leakage
b) with a molten liquid which then sets
Second possibility (b) known as ‘solid dispersions’
Used for drugs with very poor solubilities and bioavailability
Drug mixed with a polymer such a polyethylene glycol (PEG) which melts at 60 oC
Drug release is often found to be significantly
enhanced by a number of possible mechanisms.
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Particle size29
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Drying24
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Powder Flow31
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Solid State29
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Granulation27
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Tablets72
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Med Chem 126
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Med Chem 223
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Med Chem 319
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QSAR35
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Capsules40
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Drug Delivery To The Lung42
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Case Study 1 - ACE inhibitors44
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Injections34
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Case Study 2 - Benzodiazepines and Combinatorial Chemistry60
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Oral Controlled Delivery32
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Aseptic Production 114
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Aseptic Production 233
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Aseptic Production 318
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Aseptic Production 430
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Radiopharmacy35
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Chromatography And Analysis56
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Mass Spectrometry Intro20
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Mass Spectrometry 124
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Mass Spectrometry 230
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Mass Spectrometry 333
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BP Testing (Solid Dosage Forms)12
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Dissolution34
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Suspensions34
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Use of MS and NMR in Drug Discovery12
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Workshop on Suspensions20
