1
Q
Why are capsules used?
A
- Tablets are not easily formulated/manufactured:
Change polymorphic form on compression
Degrade on compression
Water sensitive (wet granulation)
Not easily dry granulated - Some people find capsules easier to swallow: elongated shape
- Suitable for drugs that need gastric protection
- Suitable for taste-masking
2
Q
What are the two types of pharmaceutical capsules
A
- Hard gelatin capsules (HGCs)
- Soft gelatin capsules
3
Q
What are hard gelatine capsules
A
Two-piece system consisting of a cap and a body, with a locking device via indentations on the outside of the body and/or the inside of the cap
Used in most commercial medicated capsules and also commonly used in clinical drug trials
4
Q
Describe the Pulsincap system
A
- Pulsincap Includes an insoluble capsule body and a swellable/degradable plug, typically made of a hydrophilic polymer or lipid.
- The lag time is controlled by the plug, which is pushed away by swelling or erosion, allowing cap® system –a pulse of drug release from the insoluble capsule.
- These include dual-drug loaded systems
5
Q
What are the steps in a dual-drug loaded Pulsatile drug release capsule
A
- Release of drug A granules
- swelling of eroded tablet and swelling bed
- removal of eroded tablet
- release of drug B tablet
6
Q
Describe the Pulsatile drug release capsules Osmotic system
A
- Includes a capsule that is coated with a semipermeable membrane.
- The capsule contains a layer of osmotically active agent and the drug
formulation(s). - Following ingestion, water is drawn into the osmotically active layer.
This expands gradually, pushing drug out of the capsule
7
Q
Capsule shell materials – Gelatin facts
A
- This is the most common capsule material
- Natural origin; prepared by hydrolysis of collagen (animal skin,
white connective tissue, and bone) - Heterogeneous mixture of single or multistranded polypeptides
- Stable in air when dry, but subject to microbial decomposition when moist
- Naturally contains 13-16% moisture
-Alternatives available including hydroxypropyl methylcellulose (HPMC) and starch hydrolysate (vegetarian gelatin), suitable for patients who wish to avoid animal-derived components
8
Q
Why is gelatin used
A
- Non-toxic & widely used in foodstuffs
- Readily soluble in biological fluids at body temperature
- Good film former (strong & flexible)
- Concentrated (40%, w/w) aqueous solutions of gelatin are mobile liquids above 45oC
- This is extremely important duringmanufacture - Undergoes a solution-to-gel transition when cooled down
9
Q
What is the grade of gelatin characterised by
A
The grade of gelatin is characterised by its bloom strength
High bloom strength = harder material and more viscous in solution
10
Q
What is bloom strength
A
- A measure of gel rigidity – cohesive strength of cross-linkage between molecules
- Defined as: The load/weight in grams required to push a plunger with a set bottom diameter (12.7 mm) a set distance (4 mm) into a 6.67% w/w gelatin gel that is prepared in water and allowed to mature at 10oC for 16-18 h.
- Proportional to the molecular weight of gelatin
11
Q
What can HGC’s be filled with
A
-Dry Solids
- Powders, Pellets, Granules , Tablets , Combinations
- HGCs can also be filled with semi-solids or liquids
12
Q
What are the types of HGC closures
A
- Coni-Snap
- Dbcaps
13
Q
Coni-Snap®
A
- Tapered rim to aid closure
- Air vents allow air to escape
- Six dimples to provide pre-lock Closely-matched locking rings
14
Q
Dbcaps
A
- Larger diameter, shorter length
- The cap covers most of the body; impossible to hold the body and open without crushing it
- Provides increased security of the contents
15
Q
What are the HGC sealing methods
A
- Gelatin band sealing
- Hydroalcoholic solvent seal
16
Q
HGC sealing methods
A
- In HGCs containing semi-solid thermo-softening or thixotropic mixtures, their solidification after filling is beneficial and prevents leakage.
- HGCs containing liquids need
additional sealing to prevent leakage - Liquid filled HGC are sealed using two well-accepted methods
17
Q
Hydroalcoholic solvent seal
A
- 50:50 water/ethanol mixture is sprayed onto the joint between the
cap and the body; excess is removed by suction - Capillary action draws the fluid into the joint and the presence of water softens the gelatin.
- Gentle heating (45°C) fuses the two layers fuse together, forming a seal.
18
Q
What are the methods for filling HGC powder
A
- “Punch” filling by hand
- Feton hand-operated device
- Auger filling
- Vibration and/or compression-assisted
- Dosator
- Dosing disc and tamping finger
19
Q
Filling of HGCs
A
- Each ingredient, including the API, should have a closely matching particle size distribution to ensure homogeneity and avoid segregation during filling
- If the size distribution is narrow and mono-modal, powder flow will be easy to characterise and predict
- If distribution is wide and bimodal, there will be a tendency to segregate. This can cause imbalanced filling of API versus excipient(s) over time
- Use of > 20% fine powder (< 50 μm) will lead to poor flow properties and an increased variability in fill mass
- Powders containing particles > 150 μm have excellent flow properties
20
Q
“Punch” filling by hand
A
- Often used at the pharmacy counter for extemporaneous preparations
- The ingredients are triturated to the same particle size and then mixed by geometric dilution
- The powder is placed on a powder paper or ointment slab and smoothed with a spatula to a height approximately half the length of the capsule body
- The base of the capsule is held vertically and the open end is repeatedly pushed or “punched” into the powder until the capsule is filled
- The cap is then replaced to close the capsule
21
Q
Feton hand-operated device
A
- Empty capsules are placed on the loading tray. This is placed on top of the filler unit.
- The capsules rotate in the correct orientation to place the capsule body into the filler unit.
- The loading tray is then removed.
- The top plate is lifted to remove the caps from the capsules.
- The bodies are then filled, and top plate is returned to cap them.
22
Q
Auger filling
A
- Powder is placed in a hopper containing a rotating auger that continuously feeds material to capsule bodies.
- The amount of powder fed into each capsule is dependent on the time that the capsule spends below the hopper, the rotation speed of the auger, and the screw design.
- Important: Powder bulk density may change over time in this set up. This change in bulk density can affect the fill volume, unless auger speed and rotation are adjusted accordingly.
23
Q
Vibration-assisted filling
A
- Vibration: Powder container (above the capsule body) has a mesh floor and is connected to a vibrating device so that powder passes through the mesh to fill the capsule body.
- Fill mass depends on: Rotation speed of turntable and strength of vibration
- Capsule body is placed in a rotating turntable and passes underneath powder bowl
24
Q
compression-assisted filling
A
- Compression: Capsule body is overfilled and compressed by a plunger before a scraper removes excess prior to capping.
- Fill mass depends on: Compression setting of the plunger and the final plug length, defined by the scraper height.
25
Dosator
- A powder bed is fed by a hopper.
- A dosing tube (dosator) is plunged into the powder bed by a spring- loaded piston.
- The powder enters the tube to form a plug.
- The tube rises out of the powder bed and moves to the capsule body. The plunger moves down and deposits powder into the capsule body.
- Dose is determined by the plug volume, and is adjusted by moving the piston position.
- For this method, the powder must form a plug and have moderate flow properties
26
Dosing disc and tamping finger
- A revolving powder hopper is above a dosing plate with drilled holes.
- At each tamping station, a steel rod (tamping finger) presses a set mass
of powder onto the tamping plate, forming a plug.
- The plug builds sequentially at each of the stations, which are often arranged in a circle.
- At the transfer station, the powder plug is pushed into the capsule body.
27
Why use liquids or semi-solids to fill HGCs?
- Powder flow problems avoided
- Avoidance of airborne particles
- Improved fill weight accuracy
- Convenient for formulations with a low melting point (oils, etc.)
- Can improve solubility and absorption
- Low dose/high potency drugs
28
Filling of HGCs: Semi-solids
- Thermo-softening mixtures – Filled in the molten state, when they can be pumped and filled, and subsequently solidify. e.g. PEG 4000, solid fats.
- Thixotropic mixtures – Thin (low viscosity) upon shearing by mixing; these form hard masses (high viscosity) upon standing when shearing ceases. Filled as fluids, and semisolid during storage. Pastes
29
Filling of HGCs: semi-soilds
- Non-aqueous liquids
30
Method’s for Filling of HGCs: liquids/semi-solids
- Piston filling
- Volumetric dosing device
- Prevention of leakage
- Semi-solids are filled in the liquid state, where possible, either by heating (for thermo-softening mixtures) or by stirring (for thixotropic mixtures)
- After filling, these revert to the solid state
31
Filling of HGCs: liquids/semi-solids: Viscosity
- The viscosity of the fluid affects the variability of the fill volume
-Low viscosity: loss of liquid due to splashing from capsule during filling
- High viscosity: difficult to pump and problems in transfer from nozzle to capsule body
- Viscosities of 0.1-20 Pa.s are acceptable for liquid filling of HGCs (coefficient of variation [CoV] ~1%)
32
Liquid-filled HGCs – Excipient selection
-Water-miscible liquids (some PEGs/poloxamers)
-Water-immiscible liquids (lipophilic liquids, castor, olive &
sunflower oil)
33
Water-miscible liquids (some PEGs/poloxamers)
Vehicle dissolves/disperses readily in the GI fluids, liberating the drug either as a solution or fine dispersion, depending upon aqueous solubility; this aids rapid absorption
34
Water-immiscible liquids (lipophilic liquids, castor, olive &
sunflower oil)
Release is followed by dispersion in the GI fluids.
Drug may be present as an emulsion, fine suspension or nano-
emulsion
Well formulated systems to improve drug solubility will ensure that the drug does not precipitate in GI fluids.
35
Liquid-filled HGCs – Equilibrium moisture content
- HGC shells contain 13-16% moisture.
- Necessary to assess whether excipients change the EMC of the HGC to an unacceptable value.
- Significant capsule brittleness should not be detected in capsules stored at 30% and 50% relative humidity for four weeks.
**Note: Capsules made from different materials will have different EMC values**
36
What are Soft gelatin capsules (SoftGels)
- Single units consisting of a continuous pliable gelatin shell containing either a liquid, paste, semi-solid or dry material. Solids at room temperature that melt at approx 45°C may be used.
- New drug entities tend to be less water-soluble and hence difficult to formulate
- Soft gelatin capsules can provide the improved dissolution associated with liquids, whilst retaining the convenience of a solid dosage form
- Most commonly used for oral administration
- Includes chewable/suckable versions, or meltable forms used for suppositories
- Can be used as containers for topical formulations
37
Advantages of SoftGels
- **improved drug absorption:** Reduction in variability for poorly soluble drugs
- **Patient compliance:** Easy to swallow, convenient, taste-free
- **Safety of potent and cytotoxic drugs:** Avoids dust
- **Oils & low mp drugs:** Overcomes problems with manufacture of these as tablets
- **Dose uniformity for potent drugs:** Liquid flow – higher precision than powder flow
- **Product stability:** Protected from water and oxygen
38
Why do softgels have Improved drug absorption and bioavailability
- Drug is delivered to the GI tract in solution form.
- This means that drug absorption is faster, compared to delivery in the solid form.
- SoftGels may also increase the extent of absorption; ie increased bioavailability.
- This is particularly true for hydrophobic drugs with a high molecular weight, which can be delivered as emulsions
39
Composition of SoftGels
- Shell is composed of:
- 40-50% w/w low bloom-strength gelatin
- 20-30% w/w plasticiser
- Water (eg 30-40%)
- Plus lower levels of:
- Preservatives
- Flavours
- Colourants
- Opacifiers
40
Composition of SoftGels: Gelatin properties
- The gelatin type and grade used must be able to produce films with sufficient mechanical strength and elasticity to allow manipulation during the encapsulation process.
- Gel strength: 150-200 bloom
- Viscosity (60°C/6.67% w/w in water): 2.8-4.5 mPa.s
- Controlled viscosity breakdown
- Well-defined particle size to allow fast dissolution and deaeration of the molten mass
- A broad molecular weight distribution to provide an appropriate melting temperature and rapid setting.
41
Composition of SoftGels Plasticisers
- Soft gel capsules contain an appreciable quantity of plasticiser, in addition to water.
- Typically 20-30% by weight
- Plasticiser makes the gelatin pliable, which is important for moulding.
- Glycerol and sorbitol are the most commonly used plasticisers.
- Propylene glycol is also used.
- ** Plasticiser allows the polymer chains to slide, making the polymer more flexible**
42
Methods of Manufacture of SoftGels
- Rotary die Methods
- Globex Methods
-
43
Rotary die method
- The capsule shell formulation is melted
- Ribbons are produced with a defined width and thickness.
- The ribbons are brought together between two twin rotating dies
- Metered filling is injected between the ribbons at the moment that the dies form a pocket of ribbon material.
- Capsules are sealed by pressure and heat, collected, washed and dried.
44
Globex method
- Filling is pumped through the inner capillary of a concentric double capillary.
- Melted shell formulation is pumped through the outer capillary.
- The capsules are immersed in a cooling bath at 4°C: usually liquid paraffin.
- Cooling bath ensures immediate sol- gel transformation and formation of a flexible yet robust film.
- Seam-free capsules are collected, washed and dried.
45
Colourants: HGCs and SoftGels
- Dyes
- Pigments
- Opacifiers
46
Dyes
- Dyes are defined as intensely coloured organic substances that impart colour to a substrate by selective absorption of light.
- Dyes are used in their water soluble form
- Azo dyes are characterised by their azo linkage (-N=N-) eg benzene or naphthalene joined by azo linkages
- Allura red, amarant, azorubine (reds), sunset yellow (orange), tartrazine (yellow)
- Indigo dyes – two isatin molecules joined by a double bond
Indigo carmine (blue)
47
Pigments
- Pigments are defined as coloured particulate organic or inorganic solids which are usually insoluble in the substrate. They alter appearance by selective absorption and/or scattering of light.
- Iron oxides are commonly used pigments that can be black, yellow or red, depending on the oxidation state.
48
Opacifiers
- Titanium dioxide is used extensively as an opacifying agent. Protects from light and conceals the capsule contents.
49
Preservatives: HGCs and SoftGels
-Gelatin is a good medium for bacterial and fungal growth.
-During manufacture, warmth and the presence of water provide
ideal growth conditions for microbes.
-To prevent this, preservatives are typically added during manufacturing.
- These can affect the physical integrity of the capsule shell.
50
Preservatives: HGCs and SoftGels: Esters of p-hydroxybenzoic acid
- Methylhydroxybenzoate (methylparaben) and propylhydroxybenzoate (propylparaben)
- Effective against a spectrum of organisms
- Combinations are generally used, ranging from 0.015-0.2% (w/w) for methylparaben and 0.02-0.06% (w/w) for propylparaben (approximately 4:1; methyl to propyl)
51
Preservatives: HGCs and SoftGels: Sulphur dioxide (~1000 ppm)
Can affect colourants, eg at 60 ppm it can cause colour loss with amaranth (red), sunset yellow and others.
PMY2006
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