Tabletting 1 - Tablet formulation Flashcards
How do you classify tablets
Method of manufacture
1) Compressed tablets
- Uncoated or Conventional
- Sugar coated
- Film coated
- Enteric coated
- Multiple compressed – layer tablets and press coated tablets
2) Moulded tablets
- Compounded triturates
- Lyophilised foam (Zydis®)
According to medical use
- Solution tablets (Solvellae) dissolved & the solution used externally
- Oral tablets - disintegrate after swallowed
- Dispersible or effervescent tablets – disintegrate in water before swallowing
- Orally dispersible tablets – disintegrate in the mouth without water
- Chewable tablets – chewed before swallowing e.g. aluminium hydroxide
- Buccal tablets – placed between cheek & gum where they dissolve and are absorbed
- Implant – eg Testosterone
- Sublingual – dissolve and are absorbed under the tongue eg glyceryl trinitrate
- Pessary - vaginal use
- Lozenge – dissolve slowly in mouth for local effect
What are advantages and disadvantages of tablets?
Advantages
- Accurate Dosage – no patient measurement
- Stability – if stored correctly have long shelf-life
- Easily transported – for manufacturer and patient
- Low cost
- Palatable – coating can disguise flavours and odours
- Versatile – drug release can be varied
- Convenient - easily administered and very portable
Disadvantages
- Psychological difficulty in swallowing
- Fixed dosages – lack of flexibility in dose adjustment
- Physical difficulty in swallowing – some children, elderly patients and some patients with mental illnesses can have difficulty swallowing
- Local irritant effect of some medications to gastrointestinal mucosa
What is the active ingredient are what are their purposes
Local effect: drug delivered into mouth or GI tract for local action (insoluble drugs -antacids and adsorbents). Surface properties and rate of dipersion to produce fine particle size and high SA are important
Systemic effect: – drug must be released from the tablet in the fluids of the mouth, stomach or intestine and absorbed into the systemic circulation to reach site of action
Active ingredient for systemic effect:
- Rapid disintegration is often required (conventional tablets).
- Drug must dissolve before it can be absorbed
- With poorly soluble drugs need to decrease particle size to improve dissolution and absorption
When considering drugs for tablet formulation
- Physical properties of the drug need to be known before formulating – pre-formulation studies
- Choose a salt or crystal form that is more stable, suitable for tableting; more bio- available.
- Some salts may be poorly compressible, and are only suitable for certain types of tablet manufacture
What are excipients (non-therapeutic ingredients) what are some of the types of excipients?
- Almost all tablets require the addition of inactive ingredients (excipients) to:
> Aid manufacture of the tablets
>Achieve suitable physical and mechanical properties of the tablets
>Ensure satisfactory drug release
Excipients have no therapeutic effect of their own but can have significant effects on the performance of the formulation –> not truly ‘inert’
- A single excipient may serve more than one purpose in the same tablet formulation (eg Potato starch may act as binder and disintegrant)
- Some excipients will oppose the function of others.
- Successful formulation is a balancing act.
Examples of excipients:
- Diluents
- Adsorbents
- Binders
- Lubricants, Anti-adherents and Glidants
- Disintegrants
- Wetting agents
- Colouring agents
- Flavouring agents
What are diluents/fillers? What are they made from and what are the advantages and disadvantages?
- Some drugs have very small doses (microgram amounts). To make a tablet that is large enough to compress and handle, an inert bulking agent (diluent) is added.
- Choice of agent should not interfere with the biopharmaceutical, chemical & physical properties of the formulation.
- Diluents should be able to be used over a wide range of production variables (Eg. alteration of compression forces etc.)
Organic materials: usually carbohydrates, may also have binding faction
Most common diluent is lactose
Advantages of Lactose
- Soluble
- Pleasant tasting
- Not hygroscopic (crystalline form)
- Readily compressible
Disadvantages of Lactose
- Patient intolerance
- Polymorphic forms
- Discolours in presence of amines
Another carbohydrate used as a diluent is mannitol
Usually used in chewable tablets for its pleasant taste and negative heat of solution (giving cooling effect)
- Other carbohydrate diluents include: Sorbitol, sucrose, inositol, glucose
- Celluloses can be used as diluents eg: Microcrystalline cellulose (hydrolysed cellulose that has been spray-dried) – used in direct compression.
- Inorganic salts can be used as diluents eg: Dicalcium phosphate, Calcium sulphate, NaCl
What are adsorbents and what are some examples?
Formulations containing liquids may need adsorbent materials
- Substances capable of retaining large amounts of liquid (up to 50% weight) without becoming wet
- These allow oils, fluid extracts and eutectic melts to be incorporated into tablets.
- Adsorbents can cause problems when formulated with small quantities of potent drugs
examples of adsorbents: starch, magnesium carbonate, magnesium silicate, kaolin, silicon dioxide
What are binders? What are some examples?
- Binders (adhesives) are used to promote cohesiveness, so that granules can be formed via the process of granulation
- Helps bonding within the tablet – maintains physical integrity
- In order to minimise powder segregation, improve flow in the tablet press, optimise compressibility and reduce dust, tablet formulations are frequently granulated. (Consider the flow of icing sugar vs granulated sugar)
Binders can be added as:
- Dry powder before wetting
- Solution (most effective method)
- Dry powder before direct compaction
Binders are typically used at 2-10% w/w
Examples
- Sugars eg sucrose
- Natural binders eg Corn starch paste, gelatin solution, pregelatinised starch, cellulose
- Synthetic/semisynthetic polymers
What is the criteria for binder choice? What are some comercially available binders?
- Compatibility with other tablet components
- Providing sufficient cohesion to powders
- No undue hindrance of disintegration and dissolution
- Compressibility of the drug – stronger binders (eg liquid glucose, sucrose) required for drugs that are poorly compressible and weaker binders (cornstarch) can be used for drugs with good compressibility
- Nature of the powder - Fine and porous particles require greater amount of liquid binder compared to coarse particles. Hydrophilic drug/excipients exhibiting absorption characteristics require greater volume
What are some comercially available binders
- Starch Paste - 5-25%w/w
- Pregelatinized Starch (PGS)[Partially and Fully PGS] - 5-20%w/w (Direct Compression) 5-10%w/w (Wet Granulation)
- Polyvinyl Pyrrolidone (PVP)
- Polyethylene Glycol (PEG) 6000
What are disintegrants and provide some examples?
- Oppose the efficiency of a tablet binder & physical forces that act to form tablet.
- Facilitate break-up of the tablet after administration, to produce a larger surface area for dissolution
- Performance of the disintegrant is determined by its position within tablet.
- Disintegrant can be added either prior to granulation (intragranular) or after granulation and prior to compression (extragranular) or at both processing steps.
- Extragranular fraction of disintegrant (20- 50% of total disintegrant) facilitates breakup of tablets to granules and the intragranular addition of disintegrants produces further erosion of the granules to fine particles
Examples of disintegrants
- Starch 5 - 15% (potato or corn)
- Clays: Veegum & Bentonite (better if extragranular)
- Celluloses: Methylcellulose, Sodium Carboxymethylcellulose, Microcrystalline cellulose.
- Pregelatinised Starches
- Cross-linked celluloses, polymers or starches – (2- 4%) superdisintegrants eg sodium starch glycolate
How do disintegrants work?
Capillary Action (Wicking)
Disintegrant facilitates transport of water into pores in the tablet when it is wet.
- Water penetrates into the tablet and replaces the air adsorbed on the particles, which weakens the intermolecular bonds and breaks the tablet into fine particles. Water uptake by tablet depends upon hydrophilicity of the drug/ excipient and on tabletting conditions
Swelling
Swelling of disintegrant particles when wet (eg starch particles) can rupture the tablet.
- Rate, force and extent of swelling may be important factors. Superdisintegrant sodium starch glycolate swells 7-12 fold in all dimensions in 30seconds
Gas Production
- Use of carbonate or bicarbonate salts with tartaric or ascorbic acid in the formulation will produce carbon dioxide when wet, which will rupture the tablet. Used in effervescent tablets.
What are lubricants and what are some examples?
When tablet has been formed in the tablet press it needs to be ejected cleanly. Immediately after compression, tablets tend to expand. Without a lubricant, tablet may bind in the die and crack on ejection.
- Lubricants reduce friction between tablet & die wall and equalise the pressure distribution in the compressed tablet.
- Lubricants increase the density of the particle bed prior to compression by decreasing inter- particulate friction.
- Lubricants are added as fine powder after granulation as they must be between the granules and die.
- Lubricants are hydrophobic and may coat granules which may slow disintegration and dissolution.
- Minimal quantities of lubricants should be used without overblending.
- May interfere with bonding within tablet leading to capping or laminating.
Common lubricants include:
- Magnesium stearate (<1%) –> incompatible with aspirin
- Stearic acid (<1%)
- Talc (<5%)
Some water soluble lubricants available
- Magnesium lauryl sulphate
What are anti-adherents?
- Prevent tablets adhering to punches and dies
- Adhering to punches is known as sticking and picking and gives tablets with rough surfaces as well as damaging the punches
- Lubricants acts as anti-adherents but some formulations may need additional talc
What are glidants?
Improve flow characteristics of the granulation through machinery (reduce friction between particles) – important for evenly sized tablets.
E.g. starch,silicon dioxide, aerosil, talc
What are wetting agents
- Wetting Agents may be added to a formulation if the active ingredient is poorly soluble.
- Added to overcome slow disintegration and dissolution.
- Surfactants are used eg Sodium lauryl sulphate 0.25 % or Tweens.
- Assist penetration of liquids into tablet
- Added in the binding stage –> Wetting agents are mainly added when a hydrophobic drug is to be formulated into tablet.
- Added in the binding stage
- Wetting agents are mainly added when a hydrophobic drug is to be formulated into tablet
What is colouring
- For product identification or aesthetic value.
- Choices limited by regulations that vary in different countries. (Care required if product marketed internationally)
- water-soluble dyes – dissolved in the granulating fluid or adsorbed onto the powders from aqueous or alcoholic solutions for uniform distribution
- water insoluble - lakes (Adsorption of a water soluble dye on a hydrous oxide) - blended with dry excipients) – less prone to colour migration.
