Formulation factors affecting oral absorption

By: Tsegaye N.(B. Pharm., MSc)

06/06/2024 Biopharmaceutics 1
Formulation…

 The rate and/or extent of absorption of a drug from the gastrointestinal tract have
been shown to be influenced by many physiological factors and physicochemical
properties associated with the drug itself.
 The bioavailability of a drug can also be influenced by changing:
 Dosage form or
 Excipients/manufacturing techniques
 Increasingly many dosage forms are being designed to affect the release and
absorption of drugs.

06/06/2024 Biopharmaceutics 2
Influence of the type of dosage form

 The type of dosage form can influence bioavailability of drugs.

 Thus, whether a particular drug is incorporated and administered in the form of a
solution, suspension or solid dosage form can influence its rate and/or extent of
absorption from the gastrointestinal tract.
 The type of oral dosage form will influence the number of possible intervening
steps between administration and the appearance of dissolved drug in the
gastrointestinal fluids.
 In general, drugs must be in solution in the gastrointestinal fluids before
absorption can occur.

06/06/2024 Biopharmaceutics 3
Cont…

 Hence 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 (hard gelatin
capsules or tablets).
 Drug stability, patient acceptability can also influence the type of dosage form in
which a drug is administered via the gastrointestinal route.

06/06/2024 Biopharmaceutics 4
Schematic outline of the influence of the dosage form on the appearance of drug in solution in the
gastrointestinal tract

06/06/2024 Biopharmaceutics 5
Aqueous solutions

 For drugs that are water soluble and chemically stable in aqueous solution,
formulation as a solution
 Normally eliminates the in vivo dissolution step and
 Presents the drug in the most readily available form for absorption.
 However, dilution of an aqueous solution of a poorly water-soluble drug whose
aqueous solubility had been increased by formulation techniques such as:
 Cosolvency,
 Complex formation or salt
 Solubilizing agents

06/06/2024 Biopharmaceutics 6
Cont…

 Aqueous solution of a salt of a weak acidic drugs to gastric pH can also result in
precipitation of the free acid form of the drug.
 In most cases the extremely fine nature of the resulting precipitate
 Permits a more rapid rate of dissolution than if the drug had been administered in
other types of oral dosage forms, such as: Aqueous suspension, Hard gelatin capsule
or Tablet
 However, for some drugs this precipitation can have a major effect on
bioavailability.

06/06/2024 Biopharmaceutics 7
Cont…

 Factors associated with the formulation of aqueous solutions that can influence
drug bioavailability
 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 and chemical stability of the drug or the
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.

06/06/2024 Biopharmaceutics 8
Aqueous suspensions
 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.
 The oral administration of an aqueous suspension results in a large total surface
area of dispersed drug being immediately presented to the gastrointestinal fluids.
 This facilitates dissolution and hence absorption of the drug.
 In contrast to powder-filled hard gelatin capsule and tablet dosage forms,
 Dissolution of all drug particles commences(to start/begin) immediately on
dilution of the suspension in the gastrointestinal fluids .

06/06/2024 Biopharmaceutics 9
Cont…
 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.
 Well formulated, finely subdivided aqueous suspension is regarded as being an
efficient oral drug delivery system.
 Factors associated with the formulation of aqueous suspensions that can influence
drug bioavailability
 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, flocculating or deflocculating agent;
 The viscosity of the suspension.
06/06/2024 Biopharmaceutics 10
Powder filled capsules

 Generally the bioavailability of a drug from a well formulated powder-filled hard

gelatin capsule will be better than or at least equal to that from the same drug in a
compressed tablet.
 Provided the hard gelatin shell dissolves rapidly in the gastrointestinal fluids and
the encapsulated mass disperses rapidly and efficiently,
 Relatively large effective surface area of drug will be exposed to the
gastrointestinal fluids, thereby facilitating dissolution.

06/06/2024 Biopharmaceutics 11
Cont…

 The overall rate of dissolution of drugs from capsules appears to be a complex

function of the rates of different processes:
 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,
and
 The rate of dissolution of the dispersed drug particles.
 The inclusion of excipients (e.g. diluents, lubricants and surfactants) in a capsule
formulation:-
 Significant effect on the rate of dissolution of drugs, particularly those that are poorly
soluble and hydrophobic.

06/06/2024 Biopharmaceutics 12
Cont…

 For example a 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.

06/06/2024 Biopharmaceutics 13
Cont…

 Both the formulation and the type and conditions of the capsule-filling process
can affects
 Packing density and liquid permeability of the capsule contents.
 In general, an increase in packing density (i.e. a decrease in porosity) of the
encapsulated mass will probably result
 Decrease in liquid permeability and dissolution rate, particularly if the drug is
hydrophobic

06/06/2024 Biopharmaceutics 14
Cont…
 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.
06/06/2024 Biopharmaceutics 15
Tablet
Uncoated tablets
 Tablets are the most widely used dosage form.
 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 .
 These processes necessitate the addition of excipients, which serve to return the
surface area of the drug back to its original pre-compressed state.
 Bioavailability problems can arise if a fine, well dispersed suspension of drug
particles in the gastrointestinal fluids is not generated following the administration
of a tablet

06/06/2024 Biopharmaceutics 16
Cont…

 Because the effective surface area of a poorly soluble drug is an important factor
influencing its dissolution rate,
 It is especially important that tablets containing such drugs should
 Disintegrate rapidly and completely in the gastrointestinal fluids if rapid release,
 Dissolution and absorption are required.
 The overall rate of tablet disintegration is influenced by several interdependent
factors, which include:
 Concentration and type of drug (API)
 Excipients: diluent, binder, disintegrant, lubricant and wetting agent
 Compaction pressure (Tablet hardness)
06/06/2024 Biopharmaceutics 17
Cont…

 Disintegration of a tablet into primary particles is thus important, as it ensures that

a large effective surface area of a drug is generated in order to facilitate
dissolution and subsequent absorption.
 However, simply because a tablet disintegrates rapidly this does not necessarily
guarantee
 The dissolution of liberated primary drug particles in GI fluids and
 The rate and extent of absorption are adequate.

 Note: in the case of poorly soluble drugs the rate-controlling step is usually the
overall rate of dissolution of the liberated drug particles in the gastrointestinal
fluids.

06/06/2024 Biopharmaceutics 18
Cont…
 Factors influencing the dissolution and bioavailabilities of poorly soluble drug
from uncoated conventional tablet
 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.

06/06/2024 Biopharmaceutics 19
Tablets
Coated Tablets
 Tablet coatings may be used simply for:
 Aesthetic reasons to improve the appearance of a tablet or to add a company logo,
 Masking an unpleasant taste or odor
 Protect an ingredient from decomposition during storage (Environmental factor)
 Protect GI irritation
 Bypassing gastric environment
 Currently the most common type of tablet coat is film; however, several older
preparations, such as vitamins and ibuprofen, still have sugar coats.

06/06/2024 Biopharmaceutics 20
Cont…

 Coated tablets are subject to additional potential problem of being surrounded by

a physical barrier.
 Due to presence of a coating (physical barrier) between the tablet core and the
gastrointestinal fluids
 In the process of sugar coating the tablet core is usually sealed with a thick,
multiple layers of a sugar-based solution or suspension to the tablet core.
 The sugar coating typically consists of sucrose, gum arabic, and other excipients,
rather than a polymeric film
 Composition and thickness sugar coating potentially retard (slow down) drug release or
dissolution rate

06/06/2024 Biopharmaceutics 21
Cont…

 The coating of a tablet core by a thin film of a water-soluble polymer, such as

hydroxypropyl methylcellulose(HPMC),
 Have no significant effect on the rate of disintegration of the tablet core and
subsequent drug dissolution,
 Provided that 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.

06/06/2024 Biopharmaceutics 22
Enteric Coated Tablets
 The following Polymers can be used as enteric coatings.
 Cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, the copolymers
of methacrylic acid and their esters and polyvinyl acetate phthalate
 These materials do not dissolve over the gastric pH range but dissolve rapidly at
the less acid pH (about 5) values associated with the small intestine.
 Enteric coating thus provides a means of delaying the release of a drug until the
dosage form reaches the small intestine.

06/06/2024 Biopharmaceutics 23
Cont…

 Such delayed release provides a means of protecting drugs which would otherwise
be destroyed if released into gastric fluid.
 Hence, enteric coating serves to improve the oral bioavailability exhibited by such
drugs from uncoated conventional tablets.
 Enteric coating also protects the stomach against drugs which can produce
nausea or mucosal irritation (e.g. aspirin, ibuprofen) if released at this site.
 The onset of the therapeutic response is largely dependent on the residence time of
the enteric-coated tablet in the stomach.

06/06/2024 Biopharmaceutics 24
Cont…

 The residence time of an intact enteric-coated tablet in the stomach can vary from
about 5 minutes to several hours.
 Hence there is considerable intra- and inter subject variation in the onset of
therapeutic action exhibited by drugs administered as enteric-coated tablets.
 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.

06/06/2024 Biopharmaceutics 25
Influence of Formulation Components of Dosage Forms

 Drugs are almost never administered alone but rather in the form of dosage forms
that generally consist of a drug (or drugs) together with a varying number of other
substances (called excipients).
 Excipients are added to the formulation in order to
 Facilitate the preparation
 Improve patient acceptability
 Functioning of the dosage form as a drug delivery system

06/06/2024 Biopharmaceutics 26
Cont…
Excipients include:
 Disintegrating agents, diluents/fillers, lubricants, suspending agents, emulsifying
agents, organoleptic agents, chemical stabilizers, granulating agents, etc.
 They exert no therapeutic or biological action, or modify the biological action
of the drug present in the dosage form
 They have the ability to influence the rate and/or extent of absorption of the
drug.
 For instance, it has been illustrated by virtue of the formation of poorly soluble,
non-absorbable drug-excipient complexes between:
 Tetracyclines and dicalcium phosphate,
 Amphetamine and sodium carboxymethylcellulose, and
 Phenobarbitone and polyethylene glycol 4000.
06/06/2024 Biopharmaceutics 27
Diluents

 Inorganic filler like 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.
 Hence, although the size of dose and frequency of administration of the sodium
phenytoin capsules containing calcium sulphate dihydrate gave therapeutic blood
levels of phenytoin in epileptic patients (require optimization of dosage regimen)
 Since, the efficiency of absorption of phenytoin had been lowered by the
incorporation of this excipient in the hard gelatin capsules .

06/06/2024 Biopharmaceutics 28
Cont…

 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.

06/06/2024 Biopharmaceutics 29
Surfactants

 Surfactants are often used in dosage forms as emulsifying agents, solubilizing

agents, suspension stabilizers or wetting agents.
 Surfactants in general cannot be assumed to be 'inert' excipients as they have been
shown to be capable of either increasing, decreasing or exerting no effect on the
transfer of drugs across biological membranes.
 Surfactant monomers can potentially disrupt the integrity and function of a
biological membrane that would tend to enhance drug penetration and hence
absorption across the gastrointestinal barrier, but may also result in toxic side-effects.
 Inhibition of absorption may occur as a consequence of a drug being incorporated
into surfactant micelles.

06/06/2024 Biopharmaceutics 30
Cont…

 The release of poorly soluble drugs from tablets and hard gelatin capsules may be
increased by the inclusion of surfactants in their formulations.
 The ability of a surfactant to reduce the solid/liquid interfacial tension 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.
 The resulting increase in the total effective surface area of drug in contact with
the gastrointestinal fluids would tend to increase the dissolution and absorption
rates of the drug.

06/06/2024 Biopharmaceutics 31
Cont…

 It is interesting to note that the enhanced gastrointestinal absorption of

phenacetin in humans resulting from the addition of polysorbate-80 to an
aqueous suspension
 Surfactant preventing aggregation and thus increasing the effective surface area and
dissolution rate of the drug particles in the gastrointestinal fluids.
 The ability of a surfactant to influence drug absorption will also depend on the
 Physicochemical characteristics and concentration of the surfactant, the nature of the
drug and the type of biological membrane involved .

06/06/2024 Biopharmaceutics 32
Lubricants- usually quite hydrophobic

 Both tablets and capsules require lubricants in their formulation to reduce friction
between the powder and metal surfaces during their manufacture.
 For instance, 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
and thus reduce dissolution rate
 These effects can usually be overcome by simultaneous addition of a wetting agent
(water-soluble surfactant) and use of a hydrophilic diluent.

06/06/2024 Biopharmaceutics 33
Disintegrants- helps to break up

 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.

06/06/2024 Biopharmaceutics 34
Viscosity Enhancing Agents-often Hydrophilic Polymers

 Viscosity-enhancing agents are often employed in the formulation of liquid

dosage forms for oral use in order to control such properties as palatability, ease
of pouring and, in the case of suspensions, the rate of sedimentation of the
dispersed particles.
 There are a number of mechanisms by which a viscosity-enhancing agent may
produce a change in the gastrointestinal absorption of a drug.
 Complex formation between a drug and a hydrophilic polymer could reduce the
concentration of drug in solution that is available for absorption.
 The administration of viscous solutions or suspensions may produce an increase in
viscosity of the gastrointestinal contents.

06/06/2024 Biopharmaceutics 35
Cont…

 This could lead to a decrease in dissolution rate and/or a decrease in the rate of
movement of drug molecules to the absorbing membrane.
 Normally, a decrease in the rate of dissolution would not be applicable to
solution dosage forms unless dilution of the administered solution in the
gastrointestinal fluids caused precipitation of the drug.
 In the case of suspensions containing drugs with bioavailabilities that are
dissolution-rate dependent, an increase in viscosity could also lead to a decrease in
the rate of dissolution of the drug in the gastrointestinal tract.

06/06/2024 Biopharmaceutics 36
Reading assignment

 Excipients like Binder,

 Process variables (Compression force, Method of granulation…..)

06/06/2024 Biopharmaceutics 37
Thank you
Q?
Quiz-1 (5%)

1. How do the physicochemical properties of drugs, such as molecular weight,

partition coefficients, and ionization state (pKa), affect their permeability across
the intestinal epithelium?(3pt)
2. What is the significance of dosage form design (e.g., immediate-release,
modified-release) on the rate and extent of drug absorption from the GI tract?
(2pt)