dosage form factors Flashcards
The bioavailability of a given drug tends to decrease in the
following order of types of dosage form: aqueous
solutions > aqueous suspensions > solid dosage forms
Factors associated with the formulation of aqueous solutions that can influence drug bioavailability include:
• The chemical stability exhibited by the drug in aqueous
solution and the gastrointestinal fluids.
• Complexation, i.e. the formation of a complex between the
drug and an excipient included to increase
• The aqueous solubility of the drug
• The chemical stability of the drug
• Viscosity of the dosage form
• Solubilization, i.e. the incorporation of the drug into
micelles in order to increase its aqueous solubility
• The viscosity of a solution dosage form, particularly if a
viscosity-enhancing agent has been included.
remember
aqueous solution= no dissolution
the aquoues solution might precipitate into a fine powder that is ready to be re absorbed just like weak acid salts
what is a suspension
An aqueous suspension is a useful dosage form for administering an
insoluble or poorly water-soluble drug.
• Usually the absorption of a drug from this type of dosage form is
dissolution-rate limited.
whats the difference between gelatin capsule and suspension
In contrast to powder-filled hard gelatin capsule and
tablet dosage forms, dissolution of all drug particles starts
immediately upon dilution of the suspension in the
gastrointestinal fluids.
• A drug contained in a tablet or hard gelatin capsule may
ultimately achieve the same state of dispersion in the
gastrointestinal fluids, but only after a delay
(disintegration)
Factors associated with the formulation of aqueous
suspension dosage forms that can influence the
bioavailabilities of drugs from the gastrointestinal tract
include:
• The particle size and effective surface area of the
dispersed drug
• The crystal form of the drug
• Any resulting complexation, i.e. the formation of a
non-absorbable complex between the drug and an
excipient such as the suspending agent
• The inclusion of a surfactant as a wetting or
flocculating agent
• The viscosity of the suspension.
what kind of vehicles do we use for liquid-filled capsules
Drugs encapsulated in liquid-filled capsules for peroral administration are dissolved or dispersed
in non-toxic, non-aqueous vehicles.
• Such vehicles may be water immiscible (i.e. lipophilic) or water miscible (i.e. hydrophilic).
• Vegetable oils are popular water-immiscible vehicles
• Polyethylene glycols and certain non-ionic surfactants (e.g. polysorbate-80) are water miscible.
• Sometimes the vehicles have thermal properties such that they can be filled into capsules while
hot, but are solids at room temperatur
what happens after the release of the drug from the capsule
• A water-miscible vehicle disperses and/or dissolves readily
in the gastrointestinal fluids liberating the drug
(depending on its aqueous solubility) as either a solution or
a fine suspension rapid absorption.
• Gelatin capsules containing drugs in solution or suspension
in water-immiscible vehicles release of the contents will
almost certainly be followed by dispersion in the
gastrointestinal fluids.
• Dispersion is facilitated by emulsifiers included in the vehicle, and
also by bile.
• Once dispersed the drug may end up as an emulsion, a solution,
a fine suspension or a microemulsion.
• Well formulated liquid-filled capsules aimed at improving
the absorption of poorly soluble drugs will ensure that no
precipitation of drug occurs from the microemulsion in
the gastrointestinal fluids.
• If the lipophilic vehicle is a digestible oil and the drug is
highly soluble in the oil:
s.
• It is possible that the drug will remain in solution in
the dispersed oil phase and be absorbed (along
with the oil) by fat absorption processes
For a drug that is less lipophilic or is dissolved in a nondigestible oil:
Absorption probably occurs following partitioning of the
drug from the oily vehicle into the aqueous gastrointestinal
fluids.
• In this case, the rate of drug absorption appears to depend
on the rate at which drug partitions from the dispersed oil
phase.
• The increase in interfacial area of contact resulting from
dispersion of the oily vehicle in the gastrointestinal fluids
will facilitate partition of the drug across the oil/aqueous
interface.
• For drugs suspended in an oily vehicle, release may involve
dissolution in the vehicle, diffusion to the oil/aqueous
interface and partition across the interface
Factors associated with the formulation of liquid filled
gelatin capsules which can influence the bioavailabilities
of drugs from this type of dosage form include:
• The solubility of the drug in the vehicle
• The solubility of the drug in gastrointestinal fluids
• The particle size of the drug (if suspended in the
vehicle)
• The nature of the vehicle, i.e. hydrophilic or lipophilic
• If lipophilic vehicle is used: is it a digestible or a
non-digestible oil.
• The inclusion of a surfactant as a wetting/emulsifying
agent in a lipophilic vehicle or as the vehicle itself
• The inclusion of a suspending agent (viscosity
enhancing agent) in the vehicle
• The complexation, i.e. formation, of a nonabsorbable
complex between the drug and any excipient.
what is better: powder filled capsules or tablets and why
powder filled capsules due to
the hard gelatin shell dissolves rapidly in the
gastrointestinal fluids
• The encapsulated mass disperses rapidly and efficiently a relatively
large effective surface area of drug will be exposed to the
gastrointestinal fluids, thereby facilitating dissolution
the rate of drug dissolution from a hard capsule gets affected by
• The dissolution rate of the gelatin shell
• The rate of penetration of the gastrointestinal fluids into
the encapsulated mass
• The rate at which the mass deaggregates (i.e. disperses) in
the gastrointestinal fluids
• The rate of dissolution of the dispersed drug particles
• The inclusion of excipients (e.g. diluents, lubricants and
surfactants) in a capsule formulation can have a significant
effect on the rate of dissolution of drugs, particularly those
that are poorly soluble and hydrophobic.
• The hydrophilic diluent (e.g. sorbitol, lactose) often serves to
increase the rate of penetration of the aqueous
gastrointestinal fluids into the contents of the capsule and
to aid the dispersion and subsequent dissolution of the drug in
these fluids.
• However, the diluent should exhibit no tendency to adsorb or
complex with the drug, as either can impair absorption from
the gastrointestinal tract.
whats the relation between packing density and dissolution rate in powder filled capsules
In general, an increase in packing density (i.e. a
decrease in porosity) of the encapsulated mass will
probably result in a decrease in liquid permeability
and dissolution rate
• Particularly if the drug is hydrophobic, or if a
hydrophilic drug is mixed with a hydrophobic
lubricant such as magnesium stearate.
Formulation factors that can influence the
bioavailabilities of drugs from hard gelatin capsules
include:
• The surface area and particle size of the drug
• The use of the salt form of a drug in preference to the
parent weak acid or base
• The crystal form of the drug
• The chemical stability of the drug (in the dosage form and
in gastrointestinal fluids)
• The nature and quantity of the diluent, lubricant and
wetting agent
• Drug-excipient interactions (e.g. adsorption, complexation)
• The type and conditions of the filling process
• The packing density of the capsule contents
• The composition and properties of the capsule shell
(including enteric capsules)
• Interactions between the capsule shell and its contents
• When a drug is formulated as a compressed tablet there is an
enormous reduction in the effective surface area of the drug, owing to
the granulation and compression processes involved in tablet making. how can we solve this
• These processes necessitate the addition of excipients, which serve to
return the surface area of the drug back to its original precompressed
state.
• If a fine, well dispersed suspension of drug particles in the
gastrointestinal fluids is not generated following the administration of a
tablet Bioavailability problems can arise
The overall rate of tablet disintegration is influenced by
several interdependent factors which include
• The concentration and type of drug
• The concentration and type of diluent
• The concentration and type of binder
• The concentration and type of disintegrant
• The concentration and type of lubricant
• The concentration and type of wetting agent
• The compaction pressure
Poor disintegration will lead to poor dissolution.
what is thw rate limiting step for poorly soluble drugs tablets
the rate-controlling
step is usually the overall rate of dissolution of the
liberated drug particles in the gastrointestinal fluids (not
the disintegration) .
The overall dissolution rate and bioavailability of a
poorly soluble drug from an uncoated conventional
tablet is influenced by many factors associated with
the formulation and manufacture of this type of
dosage form. These include:
• The physicochemical properties of the liberated drug
particles in the gastrointestinal fluids, e.g. wettability,
effective surface area, crystal form, chemical stability
• The nature and quantity of the diluent, binder, disintegrant,
lubricant and any wetting agent
• Drug-excipient interactions (e.g. complexation),
• The size of the granules and their method of manufacture
• The compaction pressure and speed of compression used
in tableting
• The conditions of storage and age of the tablet
Tablet coatings may be used simply for aesthetic reasons to:
• Improve the appearance of a tablet
• Add a company logo
• Mask an unpleasant taste or odor
• Protect an ingredient from decomposition during storage.
why do coated tablets have more problems
The presence of a coating presents a physical barrier between
the tablet core and the gastrointestinal fluids:
• coated tablets therefore not only possess all the potential
bioavailability problems associated with uncoated
conventional tablets but are subject to the additional
potential problem of being surrounded by a physical
barrier.
The physicochemical nature and thickness of the coating can
thus influence how quickly a drug is released from a tablet.
The physicochemical nature and thickness of the coating can
thus influence how quickly a drug is released from a tablet.
why do sugar coated drugs release slowly
• In the process of sugar coating the tablet core is usually
sealed with a thin continuous film of a poorly watersoluble polymer such as
• shellac or
• Cellulose acetate phthalate.
• This sealing coat serves to protect the tablet core and its
contents from the aqueous fluids used in the subsequent
steps of the sugar-coating process.
Hence the presence of this water-impermeable sealing
coat can potentially retard drug release from sugarcoated tablets.
how do we solve the slow release of sugar coated drugs
annealing agents
such as polyethylene glycols or calcium carbonate
may be added to the sealer coat in order to reduce
the barrier effect to rapid drug release
• They do not substantially reduce the water impermeability
of the sealing coat during sugar coating they dissolve
readily in gastric fluid
does film coating influnce bioavalibility
The coating of a tablet core by a thin film of a watersoluble polymer, such as hydroxypropyl methycellulose
should have no significant effect on the rate of
disintegration of the tablet core and subsequent drug
dissolution
The film coat dissolves rapidly and independently
of the pH of the gastrointestinal fluids
• However, if hydrophobic water-insoluble film-coating
materials, such as ethylcellulose or certain acrylic resins,
are used the resulting film coat acts as a barrier which
delays and/or reduces the rate of drug release.
give an example on enteric coating polymers
• Cellulose acetate phthalate
• Hydroxypropyl methylcellulose phthalate
• Copolymers of methacrylic acid and their esters
• Polyvinyl acetate phthalate
• These materials do not dissolve over the gastric pH range
but dissolve rapidly at the less acid pH (> 5) values
associated with the small intestine.
• Gastric emptying of enteric coated tablets is an all-or-nothing
process:
• The tablet is either in the stomach or in the
duodenum.
• Consequently, drug is either not being released or
being released
this causes a problem where the drug might stay for hours or mins in the stomach , how do we solve it
the product can be formulated as
small individually enteric-coated granules or pellets
(multiparticulates) contained in a rapidly dissolving hard
gelatin capsule or a rapidly disintegrating tablet
• This largely eliminates the dependency of this type of
dosage form on the all-or-nothing gastric emptying
process associated with intact enteric coated tablets
For coated granules or pellets that are sufficiently small
(less than 1 mm diameter) they will be able to empty
from the stomach with liquids.
Hence enteric-coated granules and pellets exhibit a
gradual but continual release from the stomach into the
duodenum.
• This type of release also avoids the complete dose of drug
being released into the duodenum, as occurs with an
enteric-coated tablet.
• The intestinal mucosa is thus not exposed locally to a
potentially toxic concentration of drug.
give an example on the influnce of diluents on bioavability
The classic example of the influence that excipients
employed as diluents can have on drug bioavailability is
provided by the Australian outbreak of phenytoin
intoxication which occurred in epileptic patients as a
consequence of the diluent in sodium phenytoin capsules
being changed.
• Many epileptic patients had been previously stabilized with sodium
phenytoin capsules containing calcium sulphate dihydrate as the
diluent
• These patients developed clinical features of phenytoin over-dosage
when given sodium phenytoin capsules containing lactose as the
diluent even though the quantity of drug in each capsule
formulation was identical.
It was later shown that the excipient calcium sulphate
dihydrate had been responsible for decreasing the
gastrointestinal absorption of phenytoin
• Possibly because part of the administered dose of drug
formed a poorly absorbable calcium-phenytoin
complex.
when the calcium sulphate dihydrate was
replaced by lactose without any alteration in the
quantity of drug in each capsule, or in the frequency
of administration:
• An increased bioavailability of phenytoin was achieved.
• In many patients the higher plasma levels exceeded the
maximum safe concentration for phenytoin and produced
toxic side-effects.
what are the uses of surfactants
• Emulsifying agents
• Solubilizing agents
• Suspension stabilizers
• Wetting agents
The ability of a surfactant to influence drug absorption will also
depend on:
• The physicochemical characteristics of the surfactant
• The concentration of the surfactant
• The nature of the drug
• The type of biological membrane involved.
surfactants can act as?
1-Surfactants can act as penetration enhancers
• They can potentially disrupt the integrity and function of a
biological membrane.
• Such an effect would tend to enhance drug penetration and
hence absorption across the gastrointestinal barrier
• But may also result in toxic side-effects.
2-• Inhibition of absorption may occur as a consequence of a drug
being incorporated into surfactant micelles.
• If such surfactant micelles are not absorbed, then
solubilization of a drug in micelles may result in a
reduction of the concentration of ‘free’ drug in solution in
the gastrointestinal fluids that is available for absorption
• Inhibition of absorption may occur as a consequence of a drug
being incorporated into surfactant micelles.
• If such surfactant micelles are not absorbed, then
solubilization of a drug in micelles may result in a
reduction of the concentration of ‘free’ drug in solution in
the gastrointestinal fluids that is available for absorption
The release of poorly soluble drugs from tablets and hard
gelatin capsules may be increased by the inclusion of
surfactants in their formulations. how so
Surfactant will reduce the solid/liquid interfacial tension
this will permit the gastrointestinal fluids to wet the
solid more effectively and thus enable it to come into
more intimate contact with the solid dosage forms.
(wetting effect)
• This wetting effect may thus aid the penetration of
gastrointestinal fluids into the mass of capsule contents
that often remains when the hard gelatin shell has
dissolved reduce the tendency of poorly soluble drug
particles to aggregate in the gastrointestinal fluids.
In either case increased dissolution and absorption rates of the
drug
what are lubricants
Lubricants
• Both tablets and capsules require lubricants in their formulation
to reduce friction between the powder and metal surfaces
during their manufacture.
• Lubricants are often hydrophobic in nature.
• Magnesium stearate is commonly included as a lubricant during
tablet compression and capsule-filling operations.
• Its hydrophobic nature often retards liquid penetration into
capsule ingredients.
• Similar reductions in dissolution rate may be observed when
magnesium stearate is included in tablets.
• However, these effects can usually be overcome by the
simultaneous addition of a wetting agent (i.e. a water-soluble
surfactant) and the use of a hydrophilic diluent
what are lubricants
Lubricants
• Both tablets and capsules require lubricants in their formulation
to reduce friction between the powder and metal surfaces
during their manufacture.
• Lubricants are often hydrophobic in nature.
• Magnesium stearate is commonly included as a lubricant during
tablet compression and capsule-filling operations.
• Its hydrophobic nature often retards liquid penetration into
capsule ingredients.
• Similar reductions in dissolution rate may be observed when
magnesium stearate is included in tablets.
• However, these effects can usually be overcome by the
simultaneous addition of a wetting agent (i.e. a water-soluble
surfactant) and the use of a hydrophilic diluent
what are disintegrants
• Disintegrants are required to break up capsules, tablets
and granules into primary powder particles in order to
increase the surface area of the drug exposed to the
gastrointestinal fluids.
• A tablet that fails to disintegrate or disintegrates slowly
may result in incomplete absorption or a delay in the
onset of action of the drug.
• The compaction force used in tablet manufacture can
affect disintegration:
• In general, the higher the force the slower the
disintegration time.
• Even small changes in formulation may result in
significant effects on dissolution and bioavailability.
