liquid oral dosage forms Flashcards
why do oral solutions provide a faster therapeutic response?
the drug is immediately available for absorption as there is no dissolution process
how does bioavailability differ for oral solutions compared to solid dosage forms?
usually oral solutions have higher bioavailability as long as it does not precipitate in the gi tract. although sometimes the bioavailability may be the same just the rate of absorption would be quicker for solutions.
solutions are a homogenous system - what does this mean?
there is uniform distribution throughout the preparation, this means there will be no issues with dose variations due to phase separation on storage.
why do solutions generally cause less irritation?
solutions are immediately diluted by gastric contents hence there is reduced irritation where as excipients of solid dosage forms may cause irritation.
why do solutions have lower shelf life?
once solutions are opened they get exposed to microorganisms hence they will then have a lower shelf life.
what are some of the downsides of solutions?
drugs have poorer stability in aqueous solutions, can be difficult for patients to accurately dose, taste palatability issues, unsuitable for drugs that are chemicallly unstable in water, expensive to ship and bulky for patients to transport.
what happens if the aqueosu solubility of the drug is high at the selected ph of the formulation?
the drug can be readily incorporated into the vehicle
what if the aqueous solubility of the drug is moderate at the selected ph of the drug?
the solubility of the drug must be enhanced using cosolvents etc.
what if the aquous solubility of the drug is low at the selected ph of the formulation?
an alternative formulation should be used e.g. you could use a suspension rather than a solution.
what is used as the vehicle in solutions?
purified water (USP) as it is low cost and low toxicity however it would not be used for parenteral solutions
how is purified water prepared?
purified water can be prepared through distillation, ion exchange methods or reverse osmosis.
different entities can be added to improve the solubility of a drug within a formultion like cosolvents surfactants and complexation. what are some examples of cosolvents that may be used?
glycerol, alcohol usp, propylene glycol usp or polyethylene glycol.
why is a buffer added to solutions?
a buffer can be added to maintain a constant ph. the buffer used depends on the required ph, examples include acetates, citrates and phosphates - there is a limit of how much buffer can safely be added.
sweetening agents are used to increase palatability of solutions - what are some examples of these?
sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium and aspartame.
what would be a low sugar sweetener and why would it be used?
we dont want to give high amounts of sugar to children or patients with diabetes mellitus hence we can use aspartame as the sweetener.
why are viscosity enhancing agents used?
viscosity enhancing agents can be added to solutions to increase the viscosity of the solution so that its easier to pour and get an accurate dose. drugs are also solubilised better is more viscous solutions.
what are some viscosity enhancing agents used in formulations?
cellulose derivaties like methyl cellulose (nonionic), sodium carboxymethylcellulose (anionic), sodium alginate (anion).
some formulations may not require viscosity enhancing agents, why is this?
certain liquid formulations dont need viscosity enhancers e.g. syrups as these have inherent viscosity due to the presence of sugar.
why are antioxidants added?
antioxidants are added to solution to increase the stability of drugs as they can be susceptible to chemical degradation by oxidation. you can get both water soluble and insoluble antioxidants that are only required in small concentrations.
how do antioxidants work?
antioxidants will get oxidiesd in preference to the drug, protecting the drug from decomposition.
the antioxidants are ether redox systems that exhibit more oxidative potential than the drugs - they inhibit free radical induced drug decomposition.
why are preservatives added?
preservatives are used to control microbial activity, they must cover a broad spectrum of antimicrobial activity (a few preservatives can be used in combination to acheive this), they must also be physically and chemically stable over the shelf life and have low toxicity.
what are some preservatives used in solutions?
benzoic acid and its salts, sorbic acid and its salts, alkyl esters of parahydroxybenzoic acid.
the correct form of preservative is required at a specific concentration to inhibit microbial growth - whats this called?
minimum inhibitory concentration
what might affect the concentration of preservative?
the presence of other excipients and the ph of the formulation.
factors that directly affect the efficacy of preservatives are the ph of the formulation, the presence of micelles and the presence of hydrophilic polymers.
how will changing the ph of formulation affect the preservative?
changing the ph will affect the fraction of unionised form of preservative which will affect its strength of action.
how dos preservatives work?
the unionised form of the preservative has antimicrobial properties - this diffuses across the outer membrane of the microorganism and into the cytoplasm. here the neural conditions allow the preservative to dissociate, the acidification of the cytoplasm therefore inhibits growth.
how can the fraction of acidic preservative at a particular ph be calculates?
using the henderson hasselbach equation, the fraction = 1/1+10^ph-pka
micelles improve the solubilisation of lipophilic drugs - how do they effect preservaties?
if the preservative is lipophilic it may enter the micelle hence it will be unaiavalable for antimicrobial action. this means the available concentration of preservative in solution decreases. the concentration of preservative must therefore be increased to obtain the correct free concentration so that its greater than the minimum inhibitory concentration.
how do hydrophilic polymers affect preservatives?
preservaties can chemically interact with the dissolved polymer hence decreasing the free concentration of the preservative, the concentration of preservative must therefore be increased.
why cant you use cationic hydrophilic polymers with acidic preservatives?
sometimes there is incompatibility with the preservative with hydrophilic polymers due to electrostatic interaction.
what are flavour adjuncts?
flavour adjuncts both add flavour and desensitise the taste receptors.
how are solutions prepared?
the solutes are dissolved into the solvent in a particular order and then filtered - in industry the vessels are thermostatically controlled so its done at an appropriate fixed temperature.
what are the 3 principal oral solutions?
solutions, syrups and elixirs
all components of the solution should be soluble - no signs of precipitation
why are oral solutions formulated over a broad ph?
they are developed over a broad ph range for resilience of the gi environment although the usual ph is 7
what are oral syrups?
oral syrups are aqueous solutions of sugar or sugar substitute. the drugs are directly incorporated into these systems or added as the syrup is being prepared.
how must the vehicle of syrups be chosen?
the syrup vehicle must be chosen appropriately based on physicochemical properties of the drug. e.g. using an acidic syrup may reduce the solubility of acidic drugs and they will therefore precipitate.
what are the components of syrups?
purified water and sugar - no viscosity agents or sweeteners are required and increasing the concentration of sucrose will mean theres lower water activity so no addition of preservative is required.
sugar free syrups can use glycogenetic for children and diabetic patients
flavours can be added - sometimes these may have therapeutic activity e.g. antacids contain mint due to the carminative properties of the ingredient.
what are oral elixirs?
oral elixirs are clear hydroalcoholic solutions, they have sufficient alcohol concentration to ensure all components remain in solution - its therefore unsuitable for children. if the alcohol concentration is greater than 12% preservatives are not required sue to its antimicrobial properties.
what are linctuses?
linctuses are viscous preparations in which the drug is dissolved in a vehicle composed of high sucrose, primarily used for treatment of a cough as it has soothing actions on the inflamed mucous membranes.
what are mouthwashes/ gargles used for?
mouthwashes and gargles may be usedfor treatment of infection and inflammation of the oral cavity.
what are suspensions?
a suspension is a dispersion in which the drug is dispersed in the system/vehicle not solubilised - this is used for drugs with low solubility.
the diameter of the disperse phase ranges from 0.5um to 100um - when the particle size is less than 0.5um it is colloidal.
whats the main issue with suspensions?
suspensions have low stability leading to sedimentation, particle particle interactions and caking (compaction)
what must we understand to understand the physical stability of suspensions?
the electrical properties of dispersed particles and the effect of distance of separation between particles on their subsequent interaction.
following dispersion within an aqueosu medium oarticles may aquire a charge, what may cause this?
ionisation of functional groups on the drug molecule or adsorption of ions to the surface of the particle may cause particles to aquire a charge following dispersion.
what happens when ions adsorb onto the surface of a particle?
an electrical double layer will be established - the boundary of this second layer will possess zeta potential - this measures the degree of electric charge on particles relative to the bulk medium in which they are suspended.
what could electrical properties of the drug particles lead to?
the electrical properties of disprsed particles could mean they attract or repek hence its essential we control these forces.
how can we control the electrical forces of particles?
addition of electrolytes will compress the electrical double layer to improve solubility.
what are the 3 states of interaction possible in a suspension?
- no interaction - particles are sufficiently distant from one another, this is thermodynamically stable as long as theres no sedimentation
- coagulation/agglomeration - particles form an intimate contact with each other - this is a pharmaceutically unacceptable formulation - once agglomeration occurs we are unable to redisperse the particles as its irreversible
- loose aggregation/flocculation - loose reversible interaction between the particles enabling the particles to be redispersed upon shaking.
whats the dlvo theory?
when dispersed in a liquid medium particles will experience both electrical repulsive forces and attractive van der waals forces.
how can we calculate the overall energy of interaction between particles (Vt)?
Vt = Va + Vr
where va is the energy of attraction and vr is energy or repulsion.
what does the potential energy curve for particles show?
by drawing a graph of energy of interaction against inter particle distance you will see there are two minimums and 1 maximum.
- at short inter particle distance the attractive forces predominate and particles tend to agglomerate
- as inter particle distance increases, sufficient energy is added to separate the particles hence repulsive forces predominate and particles remain in suspension
- if inter particle distance increases further, the repulsice force will decrease and particles will be weakly attracted - this is the secondary minimum - the depth of this is key to determining the stability of the system.
what is sedimentation of a suspension/why does it occur?
particles in a suspension will sediment due to gravity and settle at the bottom of the container, larger particles will reach the bottom initially and smaller particles will occupy the space between the larger particles. particles at the bottom are gradually compressed by those above - this produces sufficient energy to overcome the primary maximum (repulsive forces) and the particles become sufficiently close to form an irreversible interaction at the primary minumum, this is reffered to as caking.
what is stokes equations used for?
stokes equation can be used to calculate the velocity of sedimentation - using this we can see what factors affect sedimentation
what does the stokes equation assume?
stokes equation assumes particles are spherical and uniform size, dilute suspension and no physical/chemical interactions between the particles and suspension medium.
the stokes equation can only be applied to dilute pharmaceutical suspensions (less than 2%) that has no interactions and particles settle freely.
controlling particle sedimentation may enhance the physical stability of pharmaceutical suspensions. how can rate of sedimentation be reduced?
rate of sedimentation can be practically reduced by reducing average particle size and increasing the viscosity of the vehicle.
how can we assess sedimentation of drug suspensions?
the degree of flocculation and by calculating the sedimentation volume.
how does flocculation affect sedimentation?
in a deflocculated system particles are not associated so when sedimentation occurs the particles settle. however in flocculated systems particles form floccules in a random arrangement, this means when sedimentation occurs it is not closely packed and sedimentation does not occur.
clearing of the supernatant is too rapid for acceptable formulation - the aim of a suspension is therefore to achieve partial/controlled flocculation.
what does measuring the degree of flocculation involve?
measuring the degree of flocculation involves measuring the ratio of the ultimate sedimentation volume of the flocculated suspension to the ultimate sedimentation volume of the deflocculated system.
what must be done if particles have a high zeta potential?
particles in which the zeta potential is high (hence the primary maximum) we must manipulate the magnitude of the secondary minimum - controlled flocculation.
how can flocculation be controlled?
flocculation can be controlled by addition of electrolytes or charged surfactants that reduce zeta potential and hence Vr to give a satisfactory secondary minimum in which flocs can be formed.
what should an acceptable suspension have?
an acceptable suspension should have a low rate of sedimentation, be easily redispersed with gentle shaking, have flow properties that allow it to be easily removed from the container and be aesthetically pleasing.
what are the advantages of oral suspensions?
good for low soluble drugs, good for taste masking, good for patients with dysphagia can administer controlled drug delivery by covering particles on polymers.
what are some disadvantages of suspensions?
problems with dosing if sedimentation occurs, need to ensure stability over shelf life, difficult co create an aesthetic suspension, bulky and inconvenient to transport.
what physical properties of the drug must be considered when preparing a suspension?
- particle size - according to stokes law you can increase the stability of a suspension by modifying rate of particle sedimentation - this is done by minimising particle size either through chemical methods (controlled precipitation) or through physical methods like milling.
- the wetting properties of the drug - insoluble drug particles are hydrophobic and therefore not easily wettable - particles that are poorly wetted will lead to aggregation, surfactants can be added to reduce the interfacial tension.
smaller particles have a higher solubility when dispersed in an aqueosu vehicle compared to larger particles. smaller particles will also dissolve at increased temperature. how can crystals grow in suspensions?
smaller particles may dissolve in the vehicle then form crystals on larger particles which will increase the diameter of suspended drug particles.
what can be done to reduce crystal growth?
- hydrophilic polymers reduce crystal growth by adsorption onto the drug particles for protection.
- we can control crystal growth through temperature cycling, monitoring particle diameter and physical stability.
the same excipients used for solutions are generally used for suspensions too, however we also want the excipients to physically stabilise the suspension by controlling the rate of floccule/particle sedimentation. what excipients are added for this?
- electrolytse control flocculation by reducing zeta potential
- surfactants help with wetting of hydrophobic molecules to facilitate flocculation - non ionic surfactants are preferred like sorbitan esters and lecithin. - ionic surfactants have greater toxicity.
- hydrophilic polymers are added to improve stability by affecting flow properties.
how do hydrophilic polymers work?
hydrophilic polymers adsorb onto the surface of suspended drug particles - due to the large mw one section of the polymer chain will adsorb onto the particleswhilst the remainder of the chain is in aqueous solution. the hydrophilic polymers prevent particles from coming into close contact, their ability to stabilise suspensions depends on the concentration and the type of polymer, they increase viscosity which will decrease the rate of sedimentation hence increasing the physical stability according to stokes equation.
what are some of the hydrophilic polymers used in oral suspensions?
cellulose derivatives like methylcellulose, polyvinylpyrrolidone, sodium alginate, acacia.
why are preservatives added to suspensions?
to keep pathogenic microorganism absent. examples are parabens and organic acids like benzoic acid. the preservatives do interact with hydrophilic polymers but an appropriate free concentration of the preservative must always be available.
what are the two methods of manufacturing suspensions?
- direct incorporation - everything is directly added to the vehicle
- precipitation method - excipients in the vsicle is mixed with the drug in vesicle.
for direct incorporation, mixing rate is an important determinant. what mixing rate would be used for different suspensions?
- if the suspension is flocculated high speed mixing is used
- if flocculation properties are poor high speed mixing would result in increased viscosity making it difficult to mix homogenously
- the suspended drug particle can be reduced in size using a ball mill or it can be optimised through particle size reduction techniques priot to incorporation into the vehicle.
whats the precipitation method of producing suspensions?
in the precipitation method the drug is dissolved in the vehicle prior to precipitation following the addition of a counter ion - the salt formed is insoluble. as its often deflocculated its mixed at low shear rates.
the excipients are also dissolved in a portion of the vehicle which is then added to the suspension of drug. at this stage the drug may be exposed to high shearing rayesto ensure homogeneity.
the volume of formulation is then corrected using a diluent.
whats a potential issue with the preparation of suspensions using the precipitation method?
ionic byproducts may be produced from the precipitation interaction. if the concentration of these is too high the precipitated therapeutic agent must be washed with an aqueosu solvent
what is an emulsion?
an emulsion is a disperse system in which an insoluble liquid is dispersed within a second liquid phase e.g. oil and water phases. the drug would then be in one of these phases
what are the two phases of an emulsion?
- disperse phase - this is the phase that is subdivided
- continuous phase - this is the phase in which the disperse phase is distributed.
why are emulsions useful?
emulsions are good as some drugs may have better solubility in lipids hence they can be dispersed in an oil phase.
emulsions are not just used orally , what else are they used for?
- parenteral nutrition
- rectal administration of antiepileptic drugs
- cream formulations - emulsions offer greater viscosity which is good for topical administration.
what are the advantages of emulsions?
allows low slouble drugs to be administered, taste masking as the drug can be absorbed into the internal phase whilst the external phase contains sweeteners/flavourings, can use oils that add additional therapeutic effect, less irritation topically if the drug is in the internal phase, good for patients who cant take solid dosage forms.
what are some of the disadvantages of emulsions?
thermodynamically unstable hence must add something to stabilise the emulsion from separation of the two phases, can be difficult to manufacture.
what types of emulsions are there?
oil in water, water in oil or multiple emulsions - this is an emulsion in which the disperse phase contains droplets of another phase e.g.o/w/o
what properties would an ideal emulsion have?
physically stable so no phase separation occurs
flow properties allow easy use
formulation can be easily spread for topical administartion
how is the type of emulsion defined?
the type of emulsiom is defined by the stability of the two phases - the phase with lower stability forms the external phase.
other determinants are the phase volume of the internak phase (usually 50% for stability), chemical properties of the film surrounding the intenal phase, viscosity of the internal and external phase.
what tests can be used to identify the type of emulsion?
miscibility tests - the emulsion will be miscible with addition of the external phase so if it is miscible with water it must be an oil in water emulsion
staining tests - you can add an oil soluble dye and it will dye the oil phase not the water phase. for oil in water emulsions a pale colour will be reached as the internal phase is dyed, under the microscope you will see coloured droplets on a colourless background. whereas for a water in oil emulsion the external phase will be died so a more intense colour will be reached, under the microscope you will see colourless globules with a coloured background.
conductivity tests - water can conduct electricity hence if the external phase is water the emulsion will conduct electricity. you can connect 2 electrodes in the emulsion with a battery and light source if the light lights up it must be an oil in water emulsion.
what types of instability can emulsions have?
flocculation, creaming, coalescence, cracking and phase inversion.
what is cracking of an emulsion?
this is complete coalescence of the internal phase resulting in separation of the two emulsion layers due to destruction of the mon/multi layer film at the interface between the droplet and external phase. if an emulsion cracks it cannot be recovered as it causes irreversible instability.
why might cracking of an emulsion occur?
incorrect selection of an emulsifying agent, incompatible excipients, temperature or microbial spoilage.
what is flocculation of an emulsion?
in the flocculated state secondary van der waals forces maintain droplets at a defined distance of separation within the secondary minimum., shaking will redisperse the droplets to form a homogenous formulation.
flocculation of the emulsion may stabilise the formulation however it may also have negative effects what is this?
the close location of the droplets might enable droplet coalescence to occur if the mechanical properties of the interfacial film are compromised.
what is creaming of an emulsion?
creaming is a result of the density difference between the oil and water phases, it involves sedimentation or elevation of the droplets of the internal phase, producing a layer of concentrated emulsion either at the top or bottom of the container.
the rate of creaming of an emulsion can be calculated using the stokes equation, how can the rate be reduced?
you can reduce the rate of creaming by reducing the average particle size of the disperse phase and increasing the viscosity of the emulsion. creaming can be prevented if the density difference of the two phases is zero although this is not easily achieved in practice.
what can be done once creaming occurs?
creaming is unsightly but upon shaking the emulsionit can be rendered homogenous.
what is coalescence of an emulsion?
coalescence is when particles merge to form large droplets - this can lead to cracking.
what is phase inversion of an emulsion?
phase inversion is when the external and internal phases of an emulsion switch hence an O/W would become W/O
why does phase inversion of an emulsion occur?
when the critical value of the phase volume is exceeded phase inversion may occur.
what are the frequent phase volume ratios of an emulsion?
o/w is 74/26
w/o is 40/60
why can hydrophilic polymers be added to emulsions?
hydrophilic polymers improve stability of emulsions - they adsorb at the interface between the internal and external face producing gel like multilayers - surfactants are monomolecular films.
how can adsorbed particles be used to improve stability?
finely divided particles can be added as they get sufficiently wetted by both phases but are preferentially wetted by one of the phases. if particles are preferentially wetted by aqueous phase they will be used for o/w emulsions.
what are some of the particles used for adsoprtion of emulsions to improve stability
o/w emulsion use aluminium hydroxide, magnesium hydroxide and kaolin
w/o emulsions use talc and carbon black
what emulsions are used for oral and parenteral administration?
oil in water emulsions are used - we never want to use water in oil emulsions parenterally
what emulsions are used for topical administration?
o/w is good for water soluble drugs for local effect and is non greasy
w/o is used for a more moisturising effect this is more greasy
why would you reduce droplet size of an emulsion?
you can reduce droplet size using a colloid mil to reduce the rate of creaming.
for emulsions we need to add an emulsifying agent to help the two phases mix. what affects the agent used?
the type of emulsion - often 2 emulsifying agents are used, 1 for the internal phase and one for the external phase
clinical use and toxicity - anionic surfactants are restricted for external application
the hlb requirements of the internal phase - if hlb is unknown we will use an unknown agents to cover many hlb values - a weighted mean approach. although it could be proplematic to use a surfactant with a high hlb and one with a low hlb so add an intermediate one as well to balance the overall hlb.
lanolin is a surfactant used in cream formulations, what is it?
lanolin is a natural surfactant found in sheeps wool fat, its a wax like material thats a mixture of fatty alcohols fattu acid esters of cholesterol and sterols. it can absorb twice itsweight of water - this is god for formulating ointments
what are lanolin alcohols?
lanolin alcohols are natural wool alcohols containing a mixture of steroid alcohols and triterpene alcohols like cholesterol.these have exceelent water absorptive properties and are used in water in oil emulsions. also as theyre prone to oxidation they provide the emulsion with antioxidant properties.
whats anionic emulsifying wax?
anionic emulsifying wax has a mixture of cetostearyl alcohol, water and sls, it can be used for o/w emulsions at low concs or in topical formulations at higher concs.
whats non ionic emulsifying wax?
this contains cetostearyl alcohol and cetomacragol 1000. using a higher concentration will increase rhological structure and therefore stability.
how beeswax used in emulsions?
beeswax is a mixture of esters of monohydric alcohols and straight chain acids and long chain hydroxyacids. the principal component is myricyl palmitate. beeswax improves the consistency of creams.
what is the aquous phase formed from?
the vehicle used for the aquoes phase is purified water (sterile water for parenteral use), buffers may also be added.
how is the oil phase developed?
vegetable oils like cottonseed oil and arachis oil and almond oil is used for the oil phase.
how ar emulsions manufactured?
dissolutiojn of the oil soluble components in the oil phase and dissolution of the water soluble componenets in the aquoes phase, there is then turbulent mixing of the two phases. in manufacture mechanical stirrers, homogenisers, ultrasonifiers and colloid mills may be used.
why can it be good to dissolve drugs in oils?
if drugs are hydrophobic they can be dissolved in oils, our body then naturally breaks down lipids for absorpion of facts hence when the body breaks down the oil the drug molecules will be released.
