dosage form factors

Question 1

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

Question 2

Factors associated with the formulation of aqueous solutions that can influence drug bioavailability include:

Answer 2

• 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.

Question 3

remember

Answer 3

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

Question 4

what is a suspension

Answer 4

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.

Question 5

whats the difference between gelatin capsule and suspension

Answer 5

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)

Question 6

Factors associated with the formulation of aqueous
suspension dosage forms that can influence the
bioavailabilities of drugs from the gastrointestinal tract
include:

Answer 6

• 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.

Question 7

what kind of vehicles do we use for liquid-filled capsules

Answer 7

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

Question 8

what happens after the release of the drug from the capsule

Answer 8

• 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.

Question 9

• If the lipophilic vehicle is a digestible oil and the drug is
highly soluble in the oil:
s.

Answer 9

• 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

Question 10

For a drug that is less lipophilic or is dissolved in a nondigestible oil:

Answer 10

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

Question 11

Factors associated with the formulation of liquid filled
gelatin capsules which can influence the bioavailabilities
of drugs from this type of dosage form include:

Answer 11

• 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.

Question 12

what is better: powder filled capsules or tablets and why

Answer 12

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

Question 13

the rate of drug dissolution from a hard capsule gets affected by

Answer 13

• 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.

Question 14

whats the relation between packing density and dissolution rate in powder filled capsules

Answer 14

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.

Question 15

Formulation factors that can influence the
bioavailabilities of drugs from hard gelatin capsules
include:

Answer 15

• 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

Question 16

• 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

Answer 16

• 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

Question 17

The overall rate of tablet disintegration is influenced by
several interdependent factors which include

Answer 17

• 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

Question 18

Poor disintegration will lead to poor dissolution.

Question 19

what is thw rate limiting step for poorly soluble drugs tablets

Answer 19

the rate-controlling
step is usually the overall rate of dissolution of the
liberated drug particles in the gastrointestinal fluids (not
the disintegration) .

Question 20

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:

Answer 20

• 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

Question 21

Tablet coatings may be used simply for aesthetic reasons to:

Answer 21

• Improve the appearance of a tablet
• Add a company logo
• Mask an unpleasant taste or odor
• Protect an ingredient from decomposition during storage.

Question 22

why do coated tablets have more problems

Answer 22

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.

Question 23

The physicochemical nature and thickness of the coating can
thus influence how quickly a drug is released from a tablet.

Question 24

The physicochemical nature and thickness of the coating can
thus influence how quickly a drug is released from a tablet.

Question 25

why do sugar coated drugs release slowly

Answer 25

• 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.

Question 26

how do we solve the slow release of sugar coated drugs

Answer 26

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

Question 27

does film coating influnce bioavalibility

Answer 27

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.

Question 28

give an example on enteric coating polymers

Answer 28

• 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.

Question 29

• 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

Answer 29

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.

Question 30

give an example on the influnce of diluents on bioavability

Answer 30

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.

Question 31

what are the uses of surfactants

Answer 31

• Emulsifying agents • Solubilizing agents • Suspension stabilizers • Wetting agents

Question 32

The ability of a surfactant to influence drug absorption will also depend on:

Answer 32

• The physicochemical characteristics of the surfactant • The concentration of the surfactant • The nature of the drug • The type of biological membrane involved.

Question 33

surfactants can act as?

Answer 33

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

Question 34

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

Answer 34

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

Question 35

what are lubricants

Answer 35

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

Question 35

what are lubricants

Answer 35

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

Question 36

what are disintegrants

Answer 36

• 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.