Tablets Flashcards
1
Q
What is the most popular dosage form and why?
A
- Tablets are the most popular dosage forms
- Oral route is convenient and a safe way of drug administration
- Better physical and chemical stability than liquid dosage forms
- Accurate dosing of the drug (fixed dose per tablet)
- Convenient to handle and use (patient’s preference)
- Production procedures can be quality-controlled
- Mass production, low cost(manufacturer’s consideration)
2
Q
Tablets are mainly used for which drug delivery
A
Systemic drug delivery
3
Q
Before being absorbed what must happen to the drug
A
Drug must dissolve first before being absorbed – Need to break down to small pieces (disintegration)
– Need to dissolve (dissolution)
– Formulation strongly influences these processes
4
Q
Administration of tablets
A
– swallowing whole
– after being chewed
– retaining in the mouth (can avoid the acidic environment of the stomach
– Buccal - designed to release the drug slowly
– Sublingual - designed for fast action
– dissolve or disperse first in water before administration
5
Q
Disadvantages of tablets as a dosage form
A
– Poor bioavailability of poorly water-soluble drugs or poorly
absorbable drugs
– Difficult to swallow for some patients, e.g. children.
– Irritation to the G.I tract (some drugs)
6
Q
Good tablets – some general attributes
A
- Correct dose
- Elegant; weight and size are consistent
- Drug should be released in a controlled and reproducible way
- Biocompatible – not toxic excipients, contaminants, microorganisms
- Sufficient mechanical strength to survive transport and handling
- Physically, chemically and biologically stable
- Acceptable by the patient for the intended use (e.g. excipients for chewable tablets? Need to consider taste?)
- Properly packed
7
Q
How are tablets normally formed?
A
Normally tablets are formed by forcing particles into close proximity to each other by powder compaction, so that the particles cohere into a POROUS solid of defined shape
8
Q
Powder compression
A
reduction of volume of a powder due to the application of a force
9
Q
Powder compaction
A
the formation of a porous specimen of defined geometry by powder compression (remains in a certain shape)
10
Q
Three stages in tablet formation
A
– The filling stage–powder fills the die by gravity or centrifugal force
– The compression stage–the upper punch lowers into the die and the powder is compressed; then upper punch moves up
– The ejection stage–lower punch moves up to reject the tablet
11
Q
Single punch tablet press
A
- One die and one pair of punches
- The hopper shoe moves to and from the die by translational or rotational movement
- Tablet weight (amount of material filled into the die) is controlled by the position of the lower punch
- Lower punch remains stationary during compaction
- About 200 tablets per minute
12
Q
Rotary tablet presses
A
- Many dies on the die table and many pairs of punches
- Die table and punches rotate together,
- The same punches always works with the same die
- 10000 tablets per min can be achieved. Suitable for mass production
13
Q
Instrumentation of tablet press – in research & development
A
• Forces during compression are recorded – Forces from the upper and lower punches – Forces transmitted to the die
• Displacement (position of punches) is recorded
• Used in research. Normally instrumented single-punch hydraulic presses (also called compaction simulator) are used in this case
– Useful to investigate the relation between applied force and the properties of tablets produced
– To describe and analyse compression properties of powders by recording punch forces and punch displacement
14
Q
Instrumentation of tablet press - in production
A
• Normally only forces are recorded on production machines.
– Variation in force is an indication of variation of tablet weight.
- Each time the punch goes down, force can be recorded
15
Q
Reasons for granulation for tableting
A
– To improve flowability of the powder
– To improve mixing homogeneity and reduce segregation
– To improve the compactability of the powder (e.g. by adding a binder)
– To improve the density of the powder
– To ensure a homogeneous colour of the tablets
– To improve dissolution of poorly soluble drugs by dispersing fine powders of the drug in hydrophilic diluent
16
Q
Tableting via wet granulation
A
Dry powder (Disintegrants can also be included in this stage) -> Wet mixing granulation -> Dry granules -> Dry granules of controlled particle sizes -> Tableting
17
Q
Disadvantages of tablet production via wet granulation
A
• Production time is long
• Consumes energy in the drying process in wet granulation
• Stability problems
– Some drugs are not stable in wet conditions
– Some drugs are not stable when heated in the drying process
• High cost
18
Q
Tablet production by direct compaction - Advantages
A
– Simplified production procedure. There are only two steps in
operation : powder mixing and tableting
– Reduced production time
– Reduced consumption of energy
– Low cost due to the reduction in production time and energy
– Less stability issue (no solvent and heat involved)
– Potential faster dissolution due to quick disintegration into primary particles
19
Q
Tablet production by direct compaction - Disadvantages
A
– Need special grades of excipients (tend to be more expensive! - designed for direct compaction)
– Higher risk of powder segregation
– Powders of high drug content is difficult to form into tablets, if the drug has poor compactability
20
Q
Direct compaction has been used mainly for two types of drugs
A
– Drugs that have good flowability (e.g. powders with large size)
– Potent drugs that are of low content (e.g. a few mg) in the tablet. In this case, the powder properties are mainly controlled by the excipients.
21
Q
Type of tablet excipients
A
• Diluent (filler, or bulking agent) • Disintegrant • Binding agent (binder) • Glidant (improves the flow of powders) • Lubricant (reduces the friction between powder and die • Other – Anti-adherent – Sorbent – Taste adjusting agent
22
Q
Tablet excipients – diluent
A
• Low dose drugs need diluent (filler) so that tablets of certain weight (normally > 50 mg) can be produced
23
Q
Desired feature of an ideal diluent
A
– Biocompatible (non-toxic, non irritant etc) – Chemically inert
– Non-hygroscopic
– Low cost
– Good compressibility and compactibility – Acceptable taste
– Low cost
• All these requirements cannot be met by a single excipient. There are many different excipients to choose from
24
Q
Tablet excipients – diluent examples
A
- Lactose
- Cellulose powders
- Microcrystalline cellulose (one of the cellulose group)
- Dextrose, glucose
- Sucrose
- Mannitol
- Inorganic salts, e.g. calcium carbonates and calcium phosphates
25
Tablet excipients – diluent (Lactose)
– The most common filler in tablets
– Dissolves readily in water
– Pleasant taste
– Available as anhydrous and crystalline
– Anhydrous lactose dissolves faster than crystalline
– Anhydrous lactose possesses excellent compaction properties, so used for direct compression
– Disadvantage:
• intolerant to some people
• Anhydrous lactose may spontaneously convert to the more stable crystalline form, in suitable conditions, e.g. high temp and humidity.
26
Tablet excipients – diluent (Cellulose powders)
```
– Biocompatible
– Inert
– Good disintegrating property
– Good compatibility (can be used as dry binders)
– Disadvantage: hygroscopic
```
27
Tablet excipients – diluent (Microcrystalline cellulose)
– Are prepared by hydrolysis of cellulose followed by spray drying
– Particles formed are aggregates of smaller cellulose fibres
– The particles have crystalline and amorphous regions
– The crystallinity may vary depending on the source of the cellulose and preparation procedure
– The crystallinity will affect the properties of the particles, inc hygroscopicity and powder compactability
28
Tablet excipients – diluent (Dextrose, glucose)
Often used in chewable tablets
29
Tablet excipients – diluent (Sucrose)
– Less popular nowadays due to cardiogenicity
| – Was widely used as a sweetener/diluent in effervescent tablets and chewable tablets
30
Tablet excipients – diluent (Mannitol)
– Good taste and produces cooling sensation when sucked or chewed
31
Tablet excipients – diluent (Inorganic salts)
– Insoluble in water,
| – Hydrophilic (easily wetted by water)
32
Tablet excipients – disintegrant
• Added to a formulation to ensure that tablets breakup to small particles when in contact with liquid
33
Mechanisms by which a disintegrant works
– Facilitate water uptake, i.e. helps to transport water into the pores of the tablets.
• Wetting of surface, by surfactants
• Capillary forces to suck water into tablets (remember capillary
rise?)
– Rupture the tablets by swelling of the disintegrant.
– Deformed particles restore to their original shape upon contact with water
– Particle repulsion upon contact with water
– Producing CO2 (effervescent tablets, not normal tablets)
34
Tablet excipients – disintegrant type
• Starch (potato,corn and maize)
– The most common one in traditional tablets – Swell upon in contact with water
– Up to 10%
• Cellulose
• Modified starch or modified cellulose
– Very effective even in low quantities (1-5%)
• Gas generating disintegrant
– Bicarbonate or carbonate salts together with weak acid, e.g. citric acid and tartaric acid
– CO2 is generated when in contact with water
– Used in effervescent tablets
35
Tablet excipients - binder
• Binder is added to ensure that tablets can be formed with required mechanical strength. It can be added:
– as dry powder before wet granulation
– as a solution to produce wet granules (solution binder)
– as a dry powder which is mixed with other powder before compaction (dry binder)
• Solution binders are the best
• Up to 2-10% by weight
• Examples of solution binders
– Sucrose, starch, polyvinylpyrrolidone, cellulose derivatives
(especially HPMC)
• Examples of dry binders
– Microcrystalline cellulose and cross linked polyvinylpyrrolidone
36
• Examples of solution binders
– Sucrose, starch, polyvinylpyrrolidone, cellulose derivatives
(especially HPMC)
37
• Examples of dry binders
– Microcrystalline cellulose and cross linked polyvinylpyrrolidone
38
Tablet excipients – glidant
• To improve the flowability of the powders/granules
• Colloidal silica (very small particle size)
– Most widely used
– Used in low quantity (about 0.2%)
– Improve flow by adhering to the surface of other particles and reducing interparticulate friction
– Magnesium stearate can also improve powder flow
• Talc 1-2%
– Hydrophobic
– Large quantity can reduce dissolution rate
39
Tablet excipients – lubricant
• To ensure low friction between tablets and die wall. High friction may result in:
– vertical scratches on tablet edges
– capping or fragmentation of tablets during ejection
process
• Mechanisms of lubrication
– Fluid lubrication – rarely used (e.g. liquid paraffin in effervescent tablets)
– Boundary lubrication – fine particulate solid, e.g. magnesium stearate (most widely used). It is used in low quantity, <1%)
40
Lubricant and strength of tablets
• May reduce tablet strength as lubricants reduce bonding between particles, which are affected by
– Coverage of the granules/particles by fine Lubricant particles
• Partial coverage
• Full coverage
– Cracking of granules/particles during compression creating fresh surfaces without lubricant particles
41
Lubricant and dissolution of tablets
* Dissolution of tablets may be retarded by lubricants as most of lubricants are hydrophobic
* The more lubricant, the stronger the retardation effect
* The sequence and manner that the lubricant is mixed with the powders may also affect the dissolution of drugs
* Hydrophilic lubricants can be used to avoid these problems. E.g. polyethylene glycol
42
Other tablet excipients
• Anti-adherent–reduce the adhesion between the powder and the punches
– Anti-adherent is added to avoid sticking or picking (powders adhere to the surface of the punches)
– Magnesium stearate, talc and starch
• Sorbent–substances that are capable of absorbing some quantities of liquid and appears to be “dry powder”.
– Liquid drugs can be added to tablets – Microcrystalline cellulose, silica
• Flavour - Patient compliance. Coating?
• Colourant. Identification and patient compliance. Coating?
43
Technical problems during tableting
• Common problems
– High dose and weight variation of the tablets – Low mechanical strength of the tablets
– Capping and lamination of the tablets
– Adhesion or sticking of powder to punches
– High friction during tablet ejection
• Powder properties must be controlled to avoid these problems, including:
– Homogeneity and segregation tendency
– Flowability
– Compression properties and compactability
– Friction and adhesion properties
44
Mechanisms of compression of particles
• Particles in the die are rearranged so that they are closer to each other
• After the interparticle spaces are reduced to the minimum, any further
increase of pressure will result in the deformation of particles
– Elastic deformation
• Temporary deformation
• Due to small movement of the cluster of molecules or ions
– Plastic deformation
• Permanentdeformation
• Sliding of molecules along sliding planes within the particle • Big particles will break into smaller ones if pressure is further
increased
• The smaller particles can be rearranged, deformed and the same cycle of events may repeat several times during one compression
• Eventually particle surface will be at proximity and the particles will stick to each other
45
Mechanisms of compression of particles -
| Elastic and plastic deformation can be
– time-independent
– or time-dependent (Viscoelastic or viscous deformation).
• If the stress is applied for a prolonged period of time, elastic deformation can become plastic
• Punch displacement-time profile needs to be considered.
• In other words, stress rate needs to be considered
46
Compression mechanisms of primary particles and granules
```
- Dense particles
Repositioning of particles
Particle deformation
-elastic -plastic -viscoelastic
Particle fragmentation
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- Granules
Repositioning of granules Granule deformation (permanent)
Granule densification
Granule fragmentation / attrition
Deformation of primary particles
```
47
Die-wall friction during compression
* When pressing, upper punch descend while the lower punch remains stable (upper punch force = Fa)
* While ejecting the tablets, lower punch push the tablet out (lower punch force = Fb)
* The transmission of force from the upper punch to the lower punch depends on the die-wall friction
48
• Friction can be indicated in several ways
– The difference between the Fa and Fb (Fa-Fb)
– The ratio between the Fb and Fa (R=Fb/Fa)
– Maximum ejection force from the lower punch (Fe)
49
Friction equation
* Fa = Fbe KL/D (power of)
* Fa/Fb = e KL/D (power of)
– Where K is a function of friction coefficient between particles and die wall
– L is the length of the powder column
– D is the diameter of the powder column
50
Structural changes of tablet during compression
• Scanning microscopy
– Fragmentation into smaller particles
– Permanent deformation of particles – Formation of cracks in particles
• Size and size distribution of particles after disintegration
• Pore structure and specific surface area of tablets
– There are pores in tablets which increases the total surface area of a tablet
Maximum upper punch pressure (MPa)
– Total surface area can be obtained by air permeability or gas adsorption
– It is one of the means to indicate fragmentation during compression
51
Force-displacement profiles
• The relationship between upper punch force and displacement is called force- displacement profiles
Compression
• The AUC represents the work of energy involved.
• It has been suggested that E1 and E3 should be as small as possible to form tablets with good mechanical strength
52
E2: Force-displacement profiles
E2: Work of compaction
53
E3: Force-displacement profiles
E3: Work recovered during decompression
54
Mechanisms of bonding in tablets
• Bonding by intermolecular forces (also known as adsorption bonding)
– Bonds are formed between particles when they were brought into intimate contact
– The forces involved operate between 10-100nm
• The formation of solid bridge (also known as diffusion theory of bonding)
– Molecules at solid surfaces ‘mixed’ due to compression. This requires that the molecules in the solid state are movable, at least temporarily during compression
– An increased mobility of molecules can occur due to melting or glass- rubber transition of solid (remember Tg?)
• Mechanical interlocking (works well when particles have irregular shapes)
• Binder bridges (where binder is added to the tablet formulation). This may also be classified as solid bridge.
55
Question 1. Compression pressure v.s. melting, any link?
work can be converted to heat, hence an increase
| in pressure will result in an increase of temperature
56
Question 2. For solids of low melting point, which mechanism is likely to come into play during compression?
Due to the potential increase of temperature during compression, the solid may melt and solidify after cooled, forming solid bridges
57
Question 3. For amorphous solids which tend to have glass- rubber transition, what is likely to be one the bonding mechanisms during compression?
Glass-rubber transition may result in increased mobility of molecules, promoting the formation of solid bridges
58
Compression pressure and tablet strength
• A lower threshold below which tablets cannot be formed
• A upper threshold above which the strength of the tablet will
– Level off (line A in Fig)
– Reduce (line B in Fig), where lamination or capping tend to occur
• Tablets generally fail by breakage of interparticle bonds
Compaction pressure
• Can also fail by intraparticle breakage
59
Factors causing lamination and capping
• Formulation factors
– Granules are too elastic in nature. Add necessary
excipients to make it more plastic
– Bonding failure. Add components to enhance bonding
```
• Compaction factors
– The force of compression too large
– Rate of force application too fast
– The ratio of initial compression to main compression force too large
– The condition of die cavity poor
– The condition of punches poor
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60
Tablet strength during storage may decrease due to..
– Reduced bonding due to water condensation
– Change of microstructure due to dissolution of materials in condensed water
– Softening of amorphous materials due to the moisture
61
Tablet strength during storage may increase due to..
– Crystallisation of materials dissolved
– Crystallisation of amorphous materials in rubbery state
– Restructure of amorphous materials due to moisture uptake
– Change of tablet microstructure due to polymorphic transformations
62
Tablet types
* Immediate release tablets
* Extended release tablets
* Delayed release tablets
* Chewable tablets
* Effervescent tablets
* Lozenges
* Sublingual tab
* Buccal tab
63
```
EXPAND
• Chewable tablets
• Effervescent tablets
• Lozenges
• Sublingual tab
```
• Chewable tablets
– Disintegrated in the mouth by chewing
– Normally used to achieve quick action, e.g. antacid tablets
– Or facilitate the intake of the tablets, e.g. tablets for the elderly and children
– Can be taken without water
• Effervescent tablets
– Effervescent tablets are dropped into a glass of water before administration
– CO2 is produced by the reaction of carbonate with weak acid in water
– Quick action, e.g. analgesic drugs
– Facilitate the intake of the drug
• Lozenges
– Dissolves slowly in mouth and drug release in the saliva
– Intended for local action, e.g. to treat throat infection
– Disintegrants are not used
– Excipients should have good taste, e.g. glucose, mannitol and sorbitol
– High pressure is used to produce tablets of low porosity so that dissolution is slow
• Sublingual tablets
– Placed under the tongue
– Drug released in the mouth but absorbed to systematic blood circulation
– Rapid on set of action without first pass effect of the liver
– Small and porous for fast drug release
64
Tablet testing
• Tablet weight
• Dose uniformity
• Disintegration
• Dissolution
• Mechanical strength
– Attrition-resistance method - friability testing
– Fracture resistance methods
• Determine the force needed to break the tablet along its diameter
• The pressure must be applied under defined and reproducible conditions
• It records tensile failure although it is achieved by compressive forces
• The term“hardness” is also used but is not accurate here. Hardness
refers to the deformation property of a solid
65
Coating of tablets
* Sugar coating
* Film coating
* Press coating
66
Reasons for tablet coating
• Protects the ingredients from light and moisture
• Masks bitter taste of drugs
• Coloured coating hides batch-to-batch differences due to the different colours of raw materials
• Appearance and sales appeal
• Coloured coating for quick identification
• Coating increases the physical strength of the tablet, and
– makes it easier for automatic packing – avoids ‘dust’ during handling
• Functional films for enteric or controlled-release properties
67
Sugar-coating
• Sealing of tablet cores by a polymer layer to prevent the moisture from getting into the tablets
– Shellac
– cellulose acetate phthalate
– polyvinyl acetate phthalate
• Subcoating
– Many layers of subcoating are needed to give the tables the required shape (corners need to be round up)
– Bulking agents are usually added to the sucrose solution used,e.g. calcium carbonate or talc
• Smoothing: A few more coats of syrup solution is need to smooth the tablets
• Colouring: Nearly all sugar-coated tablets are coloured. Appearance is important!
• Polishing: Normally beewax or carnauba wax are used.
• Printing: Manufactures logo or code can be printed for identification purpose
68
Film coating
• Film coating is achieved by the spray of coating liquid on to tablets. A thin film of polymer is formed when the solvent is removed
• The film is thin enough to
– preserve the original shape of the tablets
– reveal the monograms embossed in the tablets during the compression
• Relatively a modern technique and can be automatically controlled
69
The coating liquid of film coating
• Coating liquid usually contains
• A polymer which forms the main structure of the film
– Cellulosederivatives,e.g.HPMC (hydroxypropyl methylcellulose), ethyl cellulose
– Methacrylate amino ester copolymers. These are insoluble in water below pH 4 but when pH is increased to neutral or alkaline, they become soluble
• A plasticizer, which reduces the brittleness of the film – Polyols, e.g. polyethylene glycol 400
– Esters, e.g. diethyl phthalate
– Oils/glycerides, e.g. fractional coconut oil
• Colourants, pigments (water insoluble). E.g. iron oxide, titanium dioxide
• Solvents. Old days, organic solvents; nowadays, water
70
Sugar coating v.s. film coating
Sugar coating
• Appearance - Rounded, polished
• Weight increase due to coating materials -
• Embossed logo or break line - Not possible
• Coating stages - Multistage process, require special skills
• Typical batch coating time - 8 hours or longer
• Functional coating - Not usually possible, apart from EC
```
Film coating
• Retains contour of the original core
• 2-3%
• Possible
• Usually single stage
• 1.5-2 hours
• Easily adaptable for controlled release
```
71
Press coating
* Compaction of granular materials around an already preformed core
* Mainly to separate chemically incompatible materials
* A inert middle layer can be put in place to separate the layers that are not compatible
* Very complex and special equipment is needed
72
Enteric coating
– Protect the drug (some drugs are not stable at low pH)
– Protect the stomach (some drugs are irritant to the stomach)
• Materials often used for EC normally have carboxylic acid groups on the polymer and their solubilities are pH-sensitive
– Cellulose acetate phthalate
– Polyvinyl acetate phthalate
– Suitable acrylic derivatives
