Excipients Flashcards
What does the appearance and palatability have to do with drug design
Most drugs taste bad in their natural form. Improving their look and taste increases compliance
When is the taste of a drug important
When the medicine will come into direct contact with the taste buds (oral liquid/chewable tables)
Does the addition of flavours and colours impact the behaviour of the formulation
Not usually as the concentrations of them is limited
What are the sweeteners we can use
Sucrose - not usually used due to health implications
Saccharin - can be used in much lower concs than sugar
Aspartame - degradation product = phenylalanine. Cant be used in patients with phenylketonuria
What makes organic compounds sweet
An increase of -oh groups. Hence, in general, organic esters, alcohols and aldehyde taste present as they are volatile (which gives them an odor)
What other ways can be used to mask the taste of a drug
Coating. This is used for capsules and coated tablets to prevent contact between the drug and the tastebuds
How does a coating affect drug release
The coatings thickness and composition will determine drug release. It will inhibit (and decrease) dissolution to some extent
How does a sugar coating work
The tablet core is sealed with a think film of poorly water soluble polymer (shellac or cellulose acetate pthalate) this retards drug release
Give an example of a hydrophobic, water insoluble film (used as an alternative to a sugar coating)
Ethylcellulose - will delay or reduce drug release influencing absorption
What is an enteric coating (give examples)
A barrier which prevents the drug from coming into contact with the stomach acid but is disrupted by the higher pH of the duodenum. Example - cellulose acetate phthalate and polyvinyl acetate which dissolve at pH5
What is a diluent
A substance that makes up the major proportion of the dosage form to enable the drug to be handled and seen
Should be inert, non-hygroscopic (don’t absorb water from the environment), biocompatible, cheap, have good compatibility and dilution capacity, good water solubility and acceptable taste
Give some examples of drug diluents
Lactose, sucrose, mannitol, sorbitol, calcium phosphate, calcium carbonate, cellulose
Can changing the diluent affect the absorption of the dosage form
Yes - see lecture for case study
Hydophilic diluents ….. the rate of dissolution.
Explain
Increase
The particles of hydrophilic diluent dissolve in the gastrointestinal fluids leaving gaps in the capsule mass. These gaps can be penetrated by the GI fluids leading to an increased dissolution rate (as the surface area is increased)
What is a disintegrant and how do they work
Natural, synthetic or chemically modified polymers. They are used to promote the breakdown of solid dosage forms.
When they come into contact with intestinal fluid they absorb liquid and start to swell, dissolve or form gels. This causes the tablet to rupture, increasing surfactants area and enhancing the dissolution.
What are the 4 mechanisms by which disintegrants work
- Capillary action (wicking) - water is pulled into pores by the disintegrant and reduce the physical bonding forces between particles
- Swelling - particles swell and break up the matrix from within, swelling sets up localised stress spreads throughout the matrix
- Deformation - particles swell to precompression size and break up the matrix
- Repulsion - water is drawn into the pores and particles repel each other because of the resulting electrical force (water is ionic and gives the drug molecules a charge)
Give examples or non-ionic and anionic polymers
Non-ionic- natural or physically modified polysaccharides such as starches, cellulose or cross-linked pvp
Anionic - chemically- modified cellulose products or low crosslinked polyacrylates
Disintigrants can …. bioavailibility
Regulate. Case study - toldutamide see lecture
What is a drug lubricant
A substance which reduces frictional forces between particles and between particles and the metal contact surfaces of manufacturing equipment. They assist smooth tablet formation and promote powder flow
They can be solids or liquids
How do boundary lubricants work
By adhering to solid surfaces (granules and machine parts) ro reduce friction
Give some examples of lubricants
Salts of long chain fatty acids (magnesium strearate) or fatty acid esters (sodium steady fumarate)
What is a fluid film lubricant
Melt under pressure and create a thin fluid film around particles, but resolidify after the pressure is removed (hydrogenated vegetable oil, glyceryl distearate or stearic acid)
What is a liquid lubricant
A lubricant which is released from the granules under pressure and create a fluid film. They do not resolidify when the pressure is removed but are reabsorbed or redistributed through the tablet matrix
What is the issue around adding lubricant
They are often hydrophobic (lipid based) and retard liquid penetrative into a solid dosage form in the gi tract - can be overcome by inclusion of a wetting agent and hydrophilic diluent
What is a binder
Binders to cause adhesion of the powdered drug to other excipients. Cause agglomeration of powder into granules during mixing with a granulation fluid by altering inter-particle adhesion. They ensure the tablets can be formed with the required mechanical strength
How is the binder incorperated into the dosage form
The binder may be either dissolved or dispersed in the granulation liquid or blended in a dry state
Give some examples of binders
Binders may be natural polymers, synthetic polymers or sugars
Examples: polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), sucrose, starch
What do chemical stabilisers do
Promote longevity of formulations. Drug formulations may be subject to oxidation. Oxidation usually causes a colour change and may also cause precipitation or a change in odour
How do we minimise the likelihood of the drug becoming oxidised
Oxidation is minimised by incorperatingantioxidants, which delay the onset and/or significantly reduce the rate of complex oxidative reactions
Which type of antioxidants do we use for each type of preparation (Aqueous preparations of variable pHs an lipid preparations)
Sodium sulfite is used in aqueous preparations with high pH
sodium bisulfite is used in aqueous preparations with neutral pH
Sodium metabisulfite and ascorbic acid are used in aqueous preparations with low pH
Alpha-tocopherol and ascorbyl palmitate (lipid soluble) are used in lipid-based preparations
What is a chelator
Chelators such as EDTA are used to form soluble, stable complexes with certain metal ions e.g. copper, iron and calcium
This removes the ions from solution to prevent them reacting with other elements and/or precipitating preventing them from oxidising.
Chelators are used in oral, parenteral and topical formulations and are also referred to as chelants or sequestering agents
What is a buffer
A buffer is defined as a mixture of a weak acid or base and one of its salts
It is designed to maintain the pH of an aqueous system within very narrow limits
Why might we want to keep formulations within a particular defined pH range?
In suspension formulations, if a particular pH is required due to the route of administration
if the solubility of the drug is significantly affected by changes in pH
Why might a buffer be a hinderance to the dosage form
Due to its ionic nature (buffers arer usually WA/WB), a buffer system will contribute charges to the formulation, which may affect
flocculation behaviour
the ionization state of other components
When would we include antimicrobial preservatives
If water is present in a non-sterile formulation, an antimicrobial preservative is required to prevent microbial contamination
(solutions, suspensions, topical products)
Give some examples of preservatives and what theyre used for
sorbic acid, benzoic acid - often used in oral formulations and they are most effective when they are unionized as they will not interfere with the flocculation
parabens - included in topical or parental preparations
benzalkonium chloride -used in aqueous eye drop formulations
What are sorbic and benzoic acid’s pKas
The pKa of sorbic acid is 4.8 and the pKa of benzoic acid is 4.2.
So as you might expect, they will be partially ionized at the pH conditions likes to be found in an oral formulation
Is benzalkonium chloride cationic or anionic. How does it ellicit its antimicrobial effects?
It is a cationic surfactant
Benzalkonium chloride’s hydrophilic, cationic region destabilises the pathogen’s cell membrane by forming electrostatic interactions with negatively charged components.
Once in close contact with the pathogen, benzalkonium chloride’s hydrophobic tail region penetrates the hydrophobic bilayer to cause cell leakage and lysis.
Why do we use viscocity enhansing agents
To stabilise colloidal disperse systems
They control palatability (can improve mouth feel),
ease of pouring and the
rate of sedimentation of dispersed particles
How can viscocity enhansing agents negatively impact the drugs percormance
Complex formation between a drug and a hydrophilic viscosity enhancing agent could reduce the concentration of drug in solution that is available for absorption
These agents may also increase the viscosity of the gastrointestinal contents, decreasing dissolution and/or uptake rates of the drug
Give some example of viscocity-enhancing agents
hydrophilic polymers (e.g. tragacanth, gum arabic) or insoluble inorganic materials (e.g. clays - bentonite)
How is viscocity enhansed
Entrapment of the solvent by the flocculated colloidal particles, which disrupts laminar flow
What is the difference when using natural vs synthetic viscocity enhansing agents
Clays and gums are natural materials and are subject to much greater batch to batch variation than synthetic materials
Cellulose is a very commonly used viscocity enhanser. Give examples of some chemically altered versions of it
Cellulose ethers are obtained from native cellulose by chemical treatment, replacing the hydrogen of the –OH group on the glucose residues with a different functional group
Methyl (–CH3) group substitution gives methylcellulose (MC)
Ethyl (–CH2CH3) group substitution gives ethylcellulose
2-hydroxypropyl (–CH2CH(OH)CH3) substitution gives hydroxypropylcellulose (HPC)
Mixed substitution of (–CH3) and (–CH2CH(OH)CH3) gives hydroxypropyl methylcellulose (HPMC)
Carboxymethyl group (–CH2COOH) substitution gives carboxymethylcellulose (CMC)
What is a key benefit of using cellulose based polymers
These polymers do not interfere with the flocculation behaviour of the system
Why do we use surfactants
Surfactants are used as emulsifying agents, wetting agents and suspension stabilisers
What are the benefits of using surfactants
Release of poorly soluble drugs can be increased by inclusion of a surfactant, as it reduces the solid/liquid interfacial tension.
This allows gastrointestinal fluids to wet the tablet more easily, promoting dissolution and therefore absorption
What are the drawbacks of using polymers
Poorly soluble drugs may get incorporated into surfactant micelles, reducing absorption as micelles are excreted not absorbed => this reduces the concentration of free drug available
Surfactant monomers can potentially disrupt the integrity and function of a biological membrane enhancing absorption, but may also have toxic side effects
What are wetting agents
Wetting agents are typically surfactants below their critical micelle concentration
They improve the flow of the liquid vehicle across the particle surface
They reduce the interfacial tension between the solid particle and liquid medium, promoting dissolution
Give examples of wetting agents used in oral liquid dosage forms
sodium lauryl sulfat, lecithin and polysorbate (Tween)
How do wetting agents aid drug delivery
They reduce the interfacial tension between the solid particle and liquid medium, promoting dissolution
The wetting effect aids penetration of GI fluids into the mass of a solid capsule
Wetting agent are also used to increase the ease of skin spread for topical lotions and sprays
What is a flocculation modifier
Flocculation modifiers are ionic materials which ionize once in solution in the suspension medium e.g. sodium chloride
Flocculation modifiers can either promote or prevent flocculation; we are usually trying to prevent it. It depends on the relative extent of the attractive and repulsive energies
Which parts of the drug are moslt likely to flocculate
Materials which ionize in solution, such as preservatives and buffers, will contribute charges to individual drug particles which generally leads to increased flocculation behaviour
Excipients can directly interact with drugs via physical and chemical interactions.
Explain how each works and what impact this will have on the drug
Physical: adsorption of drug molecules onto the surface of excipients can make the drug unavailable for dissolution and reduce bioavailability
Chemical: a chemical reaction between drug and excipient alters bioavailability or stability
