Science of Medicine Week 26 Flashcards
What are the advantages of solutions as oral pharmaceutical products?
- easy to swallow e.g. children
- faster therapeutic response as no dissolving
- homogeneous system with no phase separation
- reduced irritation and immediate dilution by gastric contents
- taste-masking
How do solutions have reduced irritation?
tablets can irritate gastric mucosa if a tablet is in one area - solutions are diluted
What are the disadvantages of oral solutions?
- problems with manufacture, transport, administration
- growth of microorganisms
- poorer stability of ingredient in aqueous solution than if in solid form
- shorter shelf life than solid dosage forms
- dose accuracy issues
- taste issues
- unsuitable for drugs chemically unstable in water
- bulk for patients to carry
What are the 2 main challenges with the manufacture of oral solutions?
- getting homogeneity of the drug throughout the solution
- the will be variation in the aqueous solubilities of different drugs
If solubility is HIGH at the selected pH of the oral solution…
the drug can be readily incorporated into the vehicle (water)
If drug solubility is MODERATE at the selected pH of the oral solution…
solubility of the drug in the formulation must be enhanced using cosolvents and related methods
If drug solubility is LOW at the selected pH of the oral solution….
we need to use an alternative dosage form e.g. suspension
What is the vehicle used in oral solutions?
purified water USP (United States Pharmacopoeia)
Why can’t we use tap water for oral solutions?
there will be chemical impurities
What does preparation of purified water include?
distillation, ion exchange methods, or reverse osmosis
What is the maximum solid residue that is allowed to be obtained after evaporating the sample?
1mg / 100mL
How can we increase the solubility of the drug in a solution?
using cosolvents, surface active agents and complexation
What are 4 examples of cosolvents used in oral solutions?
- glycerol
- alcohol USP
- propylene glycol
- poly(ethylene) glycol
What are the excipients often seen in oral solutions?
- buffers
- sweetening agents
- viscosity-enhancing agents
- antioxidants
- preservatives
- the vehicle
- flavouring agents
- colouring agents
Why do oral solutions need buffers?
to control the pH of the solution
What are examples of buffers in solutions?
citrates, acetates, phosphates
Why do solutions need sweetening agents?
increase palatability of the drug
What are examples of sweetening agents in solutions?
sucrose, liquid glucose, sorbitol (use aspartame for diabetes and children)
Why do we need viscosity-enhancing agents?
to thicken the solution as if it is too runny, it will spill off the spoon - losing some dose
What type of substance do we use to make the solution more viscous?
polymers
What are examples of non-ionic polymers used as viscosity-enhancing agents?
cellulose derivatives (methylcellulose)
What are examples of ionic hydrophilic polymers used as viscosity-enhancing agents?
sodium carboxymethylcellulose and sodium alginate
Why may a syrup not need viscosity-enhancing agents?
the sugar gives it a viscous nature already
Why do we need antioxidants in oral solutions?
to increase the stability of the API or other excipients if they are susceptible to degradation by oxidation
How do antioxidants work?
they are essentially redox systems that exhibit an increase in oxidative potential compared to the drug, or compounds in the drug that inhibit radical-induced drug decomposition - so the antioxidant is degraded in preference to the drug
Around what % w/w of antioxidant is needed in a solution?
usually lower than 0.2%
What are examples of antioxidants?
ascorbic acid, sodium sulphite, sodium metabisulfite, sodium ascorbate
Why do we need preservatives?
they control microbial growth in the solution
What are the 3 properties needed for a good preservative?
- broad spectrum of antimicrobial activity
- chemically, physically stable over the shelf-life of the product
- low toxicity
What are examples of preservatives?
- benzoic acid and its salts
- sorbic acid and its salts
- alkyl esters of parahydroxybenzoic acid
however, using a combination is always beneficial to widen antimicrobial activity
define the ‘minimum inhibitory concentration’ (MIC)
the minimum concentration of preservative needed to inhibit microbial growth
What may the MIC be affected by?
other excipients and the pH of the solution
What are the 3 factors that directly affect the efficacy of preservatives in oral solutions?
- the pH of the solution
- the presence of micelles
- the presence of hydrophilic polymers
How does pH affect the preservative efficacy?
- the unionised form of the preservative is the one with antimicrobial properties
- the fraction of the acidic preservative at a particular pH is given by the Henderson-Hasselbalch equation
Why is the unionised form of the preservative the one with antimicrobial properties?
the unionised form of the acid:
1. diffuses across the outer membrane of the microorganism and eventually into the cytoplasm
2. the neutral conditions in the cytoplasm allow the preservative to dissociate causing acidification of the cytoplasm and inhibition of growth of the microorganism
How does the presence of micelles affect the efficacy of the preservative?
- micelles aid the solubilisation of lipophilic drugs, so may be used in oral solutions
- the preservative (unionised form) will have lipophilic properties, so partition into the micelle
- decreased availability of the preservative
What do we need to do if there are micelles in the oral solution?
we need to increase the concentration of preservative - the concentration of preservative in the formulation must be equal to or greater than the MIC of the preservative
How does the presence of hydrophilic polymers affect the efficacy of preservatives?
the free concentration of preservative may decrease with hydrophilic polymers due to chemical interactions between the polymer and preservative
How do we solve this?
by increasing the concentration of preservative in the formulation
What are the 4 basic taste sensations used in oral solutions?
- salty - apricot, butterscotch
- sweet - vanilla, fruit, berry
- bitter - cherry, mint
- sour - citrus
What do flavour adjuncts do?
add flavour whilst desensitizing the taste receptors
What are the 3 main steps involved in the manufacturing of oral solutions?
- dissolving the solutes in the solvent or solvent mixture
- filtration system
- at the industrial scale, we use large mixing vessels that are temperature controlled and add the components in a fixed order
What are the 3 main types of solutions administered orally?
solutions, syrups, elixirs
define oral syrup
a highly concentrated, aqueous solution of sugar or sugar substitute with a flavouring agent - often cherry syrup
When will we not add a flavour to a syrup?
if the solution has a high sucrose concentration - over 85%
How are drug incorporated into syrups?
the drugs are directly incorporated into the syrups or added as the syrup is being prepared
What is the choice of syrup determined by?
the physicochemical properties of the drug - think about the solubility of the drug in the vehicle
What excipient may be able to be left out of an oral syrup?
preservatives - the sugar concentration is so high that water concentration is low, preventing growth of microorganisms
What are the 4 main components of oral syrups?
- purified water
- sugar or substitutes
- flavours
- colours
What excipients do we NOT need in oral syrups?
- sweetening agents
- viscosity-enhancing agents
- preservatives
define oral elixir
a clear, hydroalcoholic solution formulated for oral use
What must the concentration of alcohol used in an elixir be sufficient for?
ensuring all of the other components remain in solution - we may also use other polyol cosolvents
What is the main issue with oral elixirs?
they contain alcohol - so not suitable for children or adults avoiding alcohol
Which excipient is not required for most oral elixirs?
preservatives, but alcohol concentration must be greater than 12% v/v - alcohol has antimicrobial properties
define suspension
a formulation in which the drug is not fully soluble and exists as fine solid particles dispersed in a liquid
Why is the drug dispersed in the external phase (the vehicle)?
because the solubility of the drug in the vehicle is low - if the drug was solubilised, it would be a solution
Because suspensions are unstable, what does this lead to?
- sedimentation
- particle-particle interactions
- caking (compaction)
To understand the physical stability of a suspension, which 2 main properties must be consider?
- the electrical properties of the dispersed particles
- the effect of distance of separation between particles on their interaction
When dispersed into an aqueous medium, why may particles gain a charge?
- ionisation of functional groups on the drug molecule
- and/or adsorption of ions to the surface of the drug particles
What is formed after adsorption of ions onto the surface of drug particles?
the electrical double layer
What is the zeta potential?
the electrical potential (voltage) measured at the boundary between the electrical double layer and the bulk medium the particles are suspended in
How can you compress the electrical double layer to stabilise suspensions?
increasing the concentration of electrolyte
What does a high zeta potential result in?
strong repulsion between particles resulting in a stable suspension
What does a low zeta potential result in?
weak repulsion between particles resulting in aggregation or flocculation
Which 3 states of interaction between particles in a suspension are possible?
- no interaction
- coagulation (agglomeration)
- loose aggregation (flocculation)
What happens in coagulation (agglomeration)?
- the particles form an intimate contact with each other
- cannot be used for pharmaceutical formulations
- the particles cannot be redispersed when shaking
What happens in loose aggregation (flocculation)?
- this is loose reversible interaction between the particles
- the particles can be redispersed when shaking
What does the DLVO theory describe?
how particles dispersed in a liquid medium experience electrical repulsive and attractive (VDW) forces
What is the equation for the overall energy of interaction between particles in a suspension?
Vt = Va + Vr
overall energy of interaction = energy of the attraction + energy of repulsion
At short inter-particle distances, which forces dominate?
attractive
What is the primary minimum?
- particles are close together
- energy of interaction is low
- strong attraction occurs
- coagulation occurs (agglomeration)
What is the primary maximum?
- the interparticles distance increases
- energy of interaction is high
- repulsive forces dominate
- particles can remain in suspension
What is the secondary minimum?
- inter-particle distance is increased further
- repulsive forces decrease
- particles are WEAKLY attracted
- this causes flocculation
Which of these is key to determining the stability of a suspension system?
the depth of the secondary minimum as it determines how loosely or tightly particles will flocculate
define sedimentation
when the particles in a suspension settle at the bottom of a container due to gravity
define caking
when particles at the bottom of the container are gradually compressed by the weight of the particles above and by doing this, sufficient energy is available to overcome the primary maximum (repulsive forces) and the particles become close enough to form an irreversible interaction at the primary minimum (coagulation)
What are the factors considered in the Stokes equation?
- particle radius
- density of particles
- density of suspension medium
- viscosity of the suspension medium
- gravitational constant
What does Stokes equation tell you about?
the velocity of sedimentation in a suspension
What the assumptions of the Stokes equation?
- there are spherical particles of uniform size
- the suspension is dilute
- there are no physical-chemical interactions between particles and the suspension medium
How can we decrease the rate of sedimentation?
- decreasing the average particle diameter
- increasing the viscosity of the vehicle
Which 2 factors need to be measured to assess the sedimentation of drug suspensions?
- sedimentation volume
- and/or the degree of flocculation
What is the equation for sedimentation volume?
sedimentation volume = the volume of sediment / the initial volume of the suspension
F = Vs / Vi
When does flocculation occur?
at the secondary minimum
What happens during flocculation?
there is random arrangement of particles and sediment is not closely packed, and caking does NOT occur
What is the aim of a suspension formulation?
to achieve a partial or controlled flocculation
How is the sedimentation of drug suspensions assessed?
measuring the degree of flocculation
define degree of flocculation
the ratio of the ultimate sedimentation volume of the flocculated suspension to the ultimate sedimentation volume of the deflocculated suspension
How can we try to get flocculation to occur instead of caking?
to add space between particles
What do we need to do to particles with a high zeta potential? Why?
we need to modify the magnitude of the secondary medium by controlled flocculation so that we can prevent the risk of hard cakes forming during slow sedimentation - we can modify the secondary minimum to encourage controlled, reversible flocculation
How is controlled flocculation done?
adding electrolyte or charged surfactants to reduce the zeta potential and electrostatic repulsion at the primary maximum to give a lowered energy barrier and allow a secondary minimum in which flocs can be formed
What are the 4 features of an acceptable suspension formulation?
- low rate of sedimentation
- a disperse phase that can be easily redispersed with gentle shaking
- flow properties that allow the formulation to be easily removed from the container
- aesthetically pleasing
What are the advantages of oral suspensions?
- delivery of low solubility drugs
- avoids large volumes of solvent being needed to make a solution
- taste masking
- easy swallowing
- controlled drug delivery
- cosolvents avoid precipitation upon storage
What are the disadvantages of oral suspensions?
- stability issues
- hard to make aesthetic
- bulky and difficult to carry for a patient
- difficult to get homogeneous dose due to sedimentation
Why do oral suspensions have an earlier onset time than oral capsules?
the step of dissolving and disintegration is not needed for suspensions, but is for capsules
What is the main challenge with suspensions?
stability - due to sedimentation
What is sedimentation caused by?
particle-particle interactions that lead to caking
What can impact sedimentation velocities in suspensions?
the different excipients used as they impact particle size
What are the 3 main parameters we must control in oral suspensions?
- the electrical properties of the dispersed particles - the zeta potential affects how particles interact
- the effect of distance of particles on their interaction
- viscosity
What are the 2 physical properties of suspensions we must consider?
- particle size
- wetting of particles
How can particle size be minimised?
- chemical methods e.g. controlled precipitation
- physical method e.g. milling
Why are the wetting properties of the drug important?
if particles are poorly wetted, this leads to aggregation
Why are drug particles in suspension not easily wetted?
particles in suspension will be hydrophobic and insoluble, therefore not easily wetted
How do surface active agents help with wetting?
they help water to spread over the drug particles
How do surface active agents help with wetting of drug particles?
- they reduce the interfacial tension between particles
- the high interfacial tension between particles leads to aggregation due to attractive forces
- they are DIFFERENT to hydrophilic polymers used to control crystal growth
define crystal growth
when previously dissolved particles in a vehicle crystallise on the surface of larger particles, increasing particles diameter
How does crystal growth occur?
- small particles have a higher aqueous solubility than larger ones when dispersed
- if you increased storage temperature, smaller particles dissolve in the vehicle
- when temperature falls again, crystallisation of previously dissolved drug may occur on surface of larger particles
- particle size is no longer controlled
How can we decrease crystal growth?
by using hydrophilic polymers
How do hydrophilic polymers decrease crystal growth?
one end of the chain undergoes adsorption to the drug particles and the other end is free to create distance between particles, giving them protection
What are the components of oral suspensions?
- the vehicle
- buffers
- electrolytes
- surface active agents
- hydrophilic polymers
- preservatives
- antioxidants
- sweetening agents/flavours
What is the vehicle used in oral suspensions?
purified water USP
Which buffer is commonly used for suspensions?
citrate - prevents certain degradation reactions due to pH (hydrolysis)
What are the 3 major excipient differences for suspensions compared to solutions?
- hydrophilic polymers
- electrolytes
- surface active agents
What do electrolytes do in a suspension?
control flocculation by decreasing the zeta potential by compressing the electrical double layer
What do surface active agents do?
to allow wetting of drug particles and facilitate flocculation
What is the concentration of surface active agents used?
less than 0.5% w/w
Why are non-ionic surfactants preferred over ionic ones?
ionic ones can cause greater toxicity due to interactions with cell membranes in the body
What are examples of surface active agents used?
- polyoxyethylene fatty acid sorbitan esters
- lecithin
Why are hydrophilic polymers added?
to prevent crystal growth and therefore aid physical stability
What is an added bonus of hydrophilic polymers?
- they increase the viscosity of suspensions
- therefore decrease the rate of sedimentation - Stokes equation
What is the issue with hydrophilic polymers?
they may bind to preservatives, trapping them and reducing their effectiveness
Why are preservatives ALWAYS needed?
because the external phase is water
What are examples of hydrophilic polymers used in suspensions?
- cellulose derivatives
- polyvinylpyrrolidone
- sodium alginate (ionic)
- natural polymers such as xanthan gum
- hydrated silicates
What are the 2 methods used for manufacture of suspensions?
- direct incorportation
- preciptation method
define direct incorporation
the process of adding a drug or excipient directly into the suspension vehicle without pre-treatment
What is the most important determinant in the direct incorporation method?
the mixing rate - proper mixing prevents sedimentation issues
How can we reduce the particle size of the suspended drug?
using a ball mill
What are the steps of the precipitation method?
- the drug is dissolved in the vehicle
- a counterion is added to cause the precipitation of the drug as an insoluble salt
- excipients are then dissolved in the vehicle before precipitation to aid in the uniform dispersion of the precipitated drug
- high shearing rates (intense mixing) is used to ensure a homogeneous suspension is got
- after precipitation and mixing the volume is adjusted by adding a diluent to achieved the required final concentration of suspensions for dose accuracy
What is the main issue with the precipitation method for manufacturing oral suspensions?
- precipitation interactions can lead to ionic byproducts which may interfere with suspension stability
- if the concentration of ionic byproducts is too high, they may cause impurities and alter the pH of the suspension and affect bioavailability
How can we remove excess ionic byproducts?
by washing the precipitated drug with an aqueous solvent
