09/03/2020

NATURE OF DRUGS AND

FORMULATION FACTORS
INFLUENCING DRUG ABSORPTION

FAKULTAS FARMASI UNIVERSITAS

JEMBER

Biopharmaceutic Consideration in Dosage

Form Design
• To achieve the desired therapeutic objective, the
drug product must deliver the active drug at an
optimal rate and amount.
• By proper biopharmaceutic design, the rate and
extent of drug absorption can be varied from rapid
and complete absorption to slow and sustained
absorption.

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Sequence of events in the absorption of drugs

from orally administered solid dosage form
• Disintegration
• Deaggregation and subsequent release of drug
• Dissolution
• Movement of the dissolved drug through the GI
membran into the systemic circulation.

• In a series of kinetic or rate processes, the rate at

which the drug reaches the
determined by the slowest
involved in the sequence.
• Such a step is called as the
(RDS) or rate limiting step.
systemic circulation is
of the various steps
rate determining step

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Physicochemical Factors Affecting Drug

Absorption
• Drug solubility and dissolution rate
– Two critical slower rate determining processes in
the absorption of orally administered drug are:
• Rate of dissolution
• Rate of drug permeation through biomembran

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Theories of drug dissolution

1. Diffusion layer model/film theory

– Solution of the solid to form a thin film or layer
at the solid/liquid interface called as the stagnant
film or diffusion layer which is saturated with the
drug, this step is usually rapid.

• Noyes whitney equation:

𝑑𝐶
𝑑𝑡
= k (Cs-Cb)
𝑑𝐶
=dissolution rate
𝑑𝑡
K=dissoltion rate constant
Cs=concentration in stagnant layer
Cb=concentration in the bulk (time t)

• Brunner incorporated Fick’s first law of diffusion+Noyes

whitney+Surface area:
𝑑𝐶 𝐷𝐴𝐾(𝐶𝑠 − 𝐶𝑏)
=
𝑑𝑡 𝑉ℎ
𝑑𝐶
=dissolutionrate
𝑑𝑡
D=diffusion coefficient of drug
A=surface area of dissolving solid
V=volume of dissolution
h=thickness of stagnant layer
K=dissoltion rate constant
Cs=concentration in stagnant layer
Cb=concentration in the bulk (time t)

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• Non sink conditions :-

Modified noyes-whitney’s equation represents the first order
dissolution process, the driving force which the concentration
gradient (Cs- Cb), and this condition is said as non sink
condition , done only for in-vitro
•
Sink conditions :-
The in-vivo dissolution is always rapid than in-vitro dissolution
because the moment the drugs dissolves , it is absorbed in the
systemic circulation , as a result Cb= 0 and the dissolution is at
maximum.

Dissolution rate under non-sink and

sink conditions.

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Theories of drug dissolution

2. Danckwert’s Model (penetration or surface renewal

theory)
– Did not approve of the existence of stagnant
layer and suggested the existence of turbulence
in the dissolution medium.
– Solvent exposed to new solid surface each time.

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Theories of drug dissolution

3. Interfacial barrier model (double barrier or limited

solvation theory)
– In this model it is assumed that the reaction at
solid surface is not instantaneous i.e. the
reaction at solid surface and its diffusion across
the interface is slower than diffusion across
liquid film.
– therefore the rate of solubility of solid in liquid
film becomes the rate limiting than the diffusion
of dissolved molecules

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Factors affecting drug dissolution and

dissolution rate
• Physicochemical properties of the drug
– Particle size and effective surface area
– Polymorphism and amorphism
– Hydrates/solvates (pseudopolymorphism)
– Salt form
– Drug pKa (pH partition hypothesis)
– Drug stability
• Dosage form factors
– Disintegration time
– Manufacturing process
– excipient
– Nature and type of dosage form
– Product age and storage condition

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Paticle size and effective surface area

• From modified Noyes whitney equation:larger the
surface area, higher the dissolution rate.
• The surface area increase with decreasing particle size
(micronization).
• Size reduction in some hydrophobic drugs are decreased
the effective surface area (fall in dissolution rate)
because:
– Adsorb air, inhibit wettability
– Particles aggregation
– Impart surface charge that prevent wetting
• Particle reduction not always advisable for:
– Unstabble drug (penicillin G and erythromycin)
– Produce undesirable effect (irritation )
– Sustained effect is desired

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Polymorphism and Amorphism

• Polymorphs : when a substance exist in more than one
crystalline form.
– Stable polymorph : lowest energy state, highest melting
point, least aqueous solubility.
– Metastable polymorph : higher energy state, lower melting
point, higher aqueous solubilities better
bioavailability.
• Amorphous form : having no internal crystal structure
• Ex: chloramphenicol palmitate – A,B,C of which ‘B’ form
shows best bioavailability and ‘A’ form is inactively
biologically.
• Amorphous: high Aq. Solubility.
• E.g. amorphous form of chloramphenicol, cortisone acetate
and phenobarbitol.

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Hydrates/solvates (Pseudopolymorphism)

• Solvates : the solvent molecules are incorporated in

the crystal lattice of the solid.
• The solvates can exist in different crystalline forms
called as pseudopolymorphs.
• When the solvent in association with the drug is
water the solvate is known as hydrate.
• Anhydrous form of a drug has greater aqueous
solubility than the hydrates.
• Solvates have greater aqueous solubility than the
nonsolvates.

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Salt Form of The Drug

• One of the easy approach to enhance the solubility

and dissolution rate of such drugs is to convert them
into their salt forms.

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Drug pKa, Lipophilicity and pH Partition Hypothesis

• Most of drugs are weak acids or weak bases.

• The ionization of drugs may markedly reduce their ability to permeate
membranes
• The deree of ionization of drugs is determined by the surrounding pH and
their pKa
For drug compounds of molecular weight greater than 100, which are
primarily transported across the biomembrane by passive diffusion, the
process of absorption is governed by:
– The dissociation constant (pKa) of the drug
– The lipid solubility of the unionized drug (a function of drug Ko/w)
– The pH at the absorption site
• Degree of ionization depends upon the pH of the biological fluid.
• Unionized fraction of drug can permeate membrane passively.

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• Percent of drug ionized at particular pH can be determined by

Handerson-Hasselbach equations:

• If there is a membrane barrier that separates the aqueous

solution of different pH such as the GIT and the plasma, ratio
R of drug concentration on either side of the membrane
derived by Shore et al:

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Influence of pH on Ionization of Drug

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Limitation of pH Partition Theory

• Presence of virtual membrane pH (determines

extent ionization of drugs & absorption)
• Absorption of ionized drugs (passive absorption)
• Influence of GI surface area and residence time of
drug
• Presence of aqueous unstirred diffusion layer

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• The GI membrane act like simple lipid barrier.

• Larger the fraction of unionized drug , faster
the absorption.
• Greater the lipophilicity (Ko/w o/w )of the
unionized drug,better the absorption

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Then certain generalization about ionization and

absorption of drug can be made, as predicted from the
pH-partition hypothesis

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Lipophilicity and Drug Absorption

• Ideally for optimum absorption, a drug should have

sufficient aqueous solubility to dissolve in the fluids
at the absorption site and lipid solubility (Ko/w) high
enough to facilitate the partitioning of the drug in
the lipoidal biomembrane and the systemic
circulation.

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Drug stability

• Major stability problem resulting poor bioavailability

are:
– Degradation into inactive form
– Interaction with different component in the dosage form
and GIT, forming unabsorbable/poorly soluble complex.

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Dosage Form Factors Affecting Drug Absorption

1. Disintegration time
– Disintegration time is important for the therapeutic
success.
– In vitro disintegration test isn’t guarantee the
bioavailability of the drugs
– If the disintegration drugs do not dissolve, absorption is
not possible.
– If disintegration time to slow, dissolution will be much
slower and absorption may be insufficient.

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Manufacturing/Processing variables

1. Method of granulation
– Duration of blending, time and temperature of drying
– Formation of crystal bridge by the presence of liquid
– The liquid act as chemical reactions such as hydrolysis
– The drying step may harm the thermolabile drugs
2. Compression force
– Influence density, porosity, hardness, disintegration time,
and dissolution of tablets

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Factors Affecting Bioavailability

The nature of the excipients in the drug product
1) Excipients are pharmacodynamically inactive
substances that are added to a formulation to provide
certain functional properties to the drug and dosage
form.
2) it should be inert, inactive, neither enhances nor
diminishes the therapeutic effect of the drug
3) Role/effects of excipient
a. may affect drug absorption
b. may increase solubility
c. may increase retention time of drug in the GIT
d. may act as carriers to increase diffusion across intestinal wall

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Different Excipients used in Tablets

1. Diluents – added to increase the bulk/mass of the

dosage form
➢ ex. Lactose, Dibasic Ca Phosphate, starch,
microcrystalline cellulose
2. Binder – makes the diluent adhere to the tablet to
form a compact mass. Pressure is applied to make
the tablets contact.
➢ Ex. Acacia, alginic acid, gelatin, povidone, etc.

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Different Excipients used in Tablets

• 3. Lubricant
– helps to have an easier transfer from one stage of
manufacture to another
– assist the smooth tableting process.
❖Ex. Mag. Stearate, stearic acid, talc, hydrogenated
vegetable oil
✓ excessive magnesium stearate (a hydrophobic lubricant) in
the formulation may retard drug dissolution and cause
slower drug absorption.

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Different Excipients used in Tablets

4. Disintegrants
• a decrease in the amount of disintegrant can
significantly lower bioavailability.
• Adsorbent disintegrants like bentonite and veegum
should be avoided with low dose.
• MCC (disintegrants and binder) at high compression
forces may retard drug dissolution.

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Different Excipients used in Tablets

5. Tablet Coating
✓ protection
✓ uneven coating can cause uneven release of active
ingredient

• Example:
an enteric coatings – employed to permit safe passage of
tablet through the acid environment of the stomach
where certain drugs may be destroyed, to the more
suitable juices of the intestines where tablet dissolution
safely takes place. ( shellac, cellulose acetate phthalate)

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• b. film-coatings
employed to protect the drug substance from the
destructive influences of moisture, light and air
throughout their period of storage or to conceal a
bad or bitter taste from the taste buds of the patient.
(hydroxypropylmethylcellulose).
c. sugar-coatings – conceal bitter taste (liquid glucose,
sucrose)

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Excipient Used in Liquid Dosage Form

1. Vehicle (solvent)
❖ bioavailability of a drug from vehicles depend to a
large extent on its miscibility with biolgical fluids.
❖Viscosity is another factor
– Aqueous vehicles
– Non aqueous water miscible vehicles
– Non aqueous water immiscible vehicles

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Excipient Used in Liquid Dosage Form

2. Suspending agents/viscosity imparters

❖ Na-CMC forms a poorly soluble complex with
amphetamine.
❖ an increase in viscosity act as mechanical barrier to
the diffusion
❖ retard GI transit

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Excipient Used in Liquid Dosage Form

3. Surfactants
❖ mechanism of surfactant increase an absorption:
✓ Promotion of wetting
✓ Better membrane contact
✓ Enhanced membrane permeability
❖Decreased absorption by surfactant due to:
✓ Formation of unabsorbable complex
✓ Laxative action

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Excipient Used in Liquid Dosage Form

4. Buffers
❖ useful in creating the right atmosphere for drug
dissolution

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Excipient Used in Liquid Dosage Form

5. Complexing agent
❖ alter stability, solubility, molecular size, partition
coefficient, diffusion coefficient.
❖ complexation used to enhance drug bioavailability:
✓ Enhanced dissolution
✓ Enhanced lipophilicity
✓ Enhanced membran permeability
❖ complexation reduce drug availability:
✓ formation of poorly soluble or poorly absorbable complex

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Excipient Used in Liquid Dosage Form

6. Colorants
✓ inhibit dissolution (ex:brillian blue-sulfathiazole)
✓ Inhibit miscellar solubilization
✓ Cationic dyes more reactive due to greater power for
adsorption

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Excipient Used in Liquid Dosage Form

7. Crystal Growth Inhibitors

✓ PVP and PEG inhibit conversion of a high energy
metastable polymorph into stable.

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Effect of excipients on the pharmacokinetic

parameters of oral drug producta
Excipients Example ka tmax AUC
Disintegrants Avicel, Explotab ↑ ← ↑/—
Lubricants Talc, hydrogenated ← ↑ ←/—
vegetable oil
Coating agent Hydroxypropylmethyl — — —
cellulose
Enteric coat Cellulose acetate phthalate ← ↑ ←/—
Sustained-release agents Methylcellulose, ← ↑ ←/—
ethylcellulose
Sustained-release agents (waxy Castorwax, Carbowax ← ↑ ←/—
agents)
Sustained-release agents Veegum, Keltrol ← ↑ ←/—
(gum/viscous)

↑ = Increase; ← = decrease; — = no effect. ka = absorption rate constant; tmax = time

for peak drug concentration in plasma; AUC = area under the plasma drug
concentration time curve.

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Nature and Type of Dosage Form

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• As a general rule, the bioavailability of a drugs :

Solutions > Emulsions > Suspension > Capsules > tablets

> coated Tablets > Enteric Coat Tablets > Sustained
Release Products.

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• Product age and storage conditions

– Solution dosage form precipitation
– Changes in particle size distribution (suspension)
– Changes in dissolution and disintegration (tablet)

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