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PMY2006 > Capsules > Flashcards

Capsules Flashcards

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
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2
Q

What are the two types of pharmaceutical capsules

A
  • Hard gelatin capsules (HGCs)
  • Soft gelatin capsules
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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

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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
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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
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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
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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
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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
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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

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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
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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

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12
Q

What are the types of HGC closures

A
  • Coni-Snap
  • Dbcaps
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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
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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
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15
Q

What are the HGC sealing methods

A
  • Gelatin band sealing
  • Hydroalcoholic solvent seal
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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
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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.
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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
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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
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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
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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
Q

Dosator

A
  • 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
Q

Dosing disc and tamping finger

A
  • 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
Q

Why use liquids or semi-solids to fill HGCs?

A
  • 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
Q

Filling of HGCs: Semi-solids

A
  • 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
Q

Filling of HGCs: semi-soilds

A
  • Non-aqueous liquids
30
Q

Method’s for Filling of HGCs: liquids/semi-solids

A
  • 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
Q

Filling of HGCs: liquids/semi-solids: Viscosity

A
  • 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
Q

Liquid-filled HGCs – Excipient selection

A

-Water-miscible liquids (some PEGs/poloxamers)
-Water-immiscible liquids (lipophilic liquids, castor, olive &
sunflower oil)

33
Q

Water-miscible liquids (some PEGs/poloxamers)

A

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
Q

Water-immiscible liquids (lipophilic liquids, castor, olive &
sunflower oil)

A

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
Q

Liquid-filled HGCs – Equilibrium moisture content

A
  • 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
Q

What are Soft gelatin capsules (SoftGels)

A
  • 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
Q

Advantages of SoftGels

A
  • 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
Q

Why do softgels have Improved drug absorption and bioavailability

A
  • 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
Q

Composition of SoftGels

A
  • 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
Q

Composition of SoftGels: Gelatin properties

A
  • 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
Q

Composition of SoftGels Plasticisers

A
  • 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
Q

Methods of Manufacture of SoftGels

A
  • Rotary die Methods
  • ## Globex Methods
43
Q

Rotary die method

A
  • 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
Q

Globex method

A
  • 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
Q

Colourants: HGCs and SoftGels

A
  • Dyes
  • Pigments
  • Opacifiers
46
Q

Dyes

A
  • 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
Q

Pigments

A
  • 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
Q

Opacifiers

A
  • Titanium dioxide is used extensively as an opacifying agent. Protects from light and conceals the capsule contents.
49
Q

Preservatives: HGCs and SoftGels

A

-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
Q

Preservatives: HGCs and SoftGels: Esters of p-hydroxybenzoic acid

A
  • 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
Q

Preservatives: HGCs and SoftGels: Sulphur dioxide (~1000 ppm)

A

Can affect colourants, eg at 60 ppm it can cause colour loss with amaranth (red), sunset yellow and others.

PMY2006 (12 decks)

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