BIOAVAILABILITY

Physicochemical and Dosage

Form Factors
Bioavailabilitas

• Suatu ukuran kecepatan dan

jumlah zat aktif yang berada
dalam sirkulasi sistemik dan
mampu mencapai tempat aksi
Faktor bioavailabilitas

• Physical factors influencing

bioavailability
• Dosage Form Factors
Influencing Bioavailability
 Penggunaan kurva dlm studi BA

Plasma concebtration-time curves for three different formulation of the same

drug administrated in equel sigle doses by the same extravascular route
A. Physical factors
influencing bioavailability
1. Dissolution & Solubility
a) Physiological factors affecting the dissolution
rate of drugs
b) Drug factor affecting dissolution rate
c) Factors affecting the concentration of drug in
the gastrointestinal fluids

2. Drug absorption
Drug dissociation & lipid solubility
• pH-partition hypothesis of drug absorption
• Limitation of the pH-partition hypothesis
• Lipid solubility
 Rate-limiting steps in
drug absorption
Drug in drug Solid drug Drug in Drug in
prodruct particles solution body

Disintregration Dissolution Absorption

release

1. Disintregation
2. Dissolution
3. Absorption across cell membrane
dc DA(Cs  C )

dt h

1.Dissolution& Solubility

• Pers Noyes-Whitney (1897)

dc/dt = (DA (Cs-C))/h
dc DA(Cs  C )
dt

h • dc/dt = kec disolusi
• D = koef difusi (Cairan GI)
• A = luas permukaan efektif obat yg kontak dg
cairan GI
• h = ketebalan lap difusi
• Cs = kelarutan jenuh obat dlm larutan di lap difusi
• C = konsentrasi obat dlm cairan GI
Physicochemical & physiological factors affecting
drug dissolution in the gastrointestinal tract
Factor Physicochemical Physiological
parameter parameter
Effect surface area of Particle size, wettability Surfactants in gastric
drug juice & bile
Solubility in diffusion Hydrophilicity,crystal pH,buffer
layer structure, solubilization capacity,bile,food
component
Amount of drug already Permeability,transit
dissolved
Diffusity layer thickness Viscosity of luminal
Molecular size contents
Boundary layer thickness Motility patterns and flow
rate
Volume of solvent Gastrointestinal
available secretions, co-
administered fluids
physiological factors affecting
the dissolution rate of drugs

Environment of the gastrointestinal tract can affect

the parameters of the Noyes-Whitney equation
dc/dt = (DA (Cs-C))/h
• D (GI fluid) decreased by presense of substance
that increase the viscosity of the fluids
• Food → ↓ dissolution rate of a drug → by
reducing the rate of drug molecules away from
the diffusion layer
• Surfactant in gastric juice &bile salt will affect
both the wettability of the drug, and hence the
effective surface area (A)
Drug factor affecting
dissolution rate

1. Surface area and particle size

2. Solubility in the diffusion layer
3. Crystal form
1.Surface area and particle size

• ↓Particel size → surface area↑→ dissolution

rate↑
• Griseofulvin, nitrofurantoin (steroid, low
solubility) → ↓ particel size (micronized form)
→ ↑oral absorption
• Poorly soluble drug
+ disintegrant,
+ surface-active agents (↑ wetting-solubility)
2. Solubility in the diffusion layer

• Natural pH environment of the gastrointestinal

tract varies from acidic in the stomach to slighty
alkaline in the small intestine
• A basic drug more soluble in an acidic medium
forming a soluble salt
• An acid drug is more soluble in the intestine,
forming a soluble salt at the more alkaline pH
• ↑ solubility→ addition of an acidic or basic
excipient
• Aspirin + alkaline buffer
3. Crystal form
• Polymorphism → the arrangement of a drug
in various crystal form (polymorphs)

• Polymorphs → different physical properties

(solubility, density, hardness, compression
characteristics)

• Metastable polymorph →↑ dissolution rate

• β polymorph (chloramphenicol) → more soluble &
better absorbed
3. Crystal form (2)
• Amorphous form dissolves more rapidly than
the corresponding crystalline forms
• amorphous form of novobiocin was readly
absorbed following oral administration

• Solvates → associate drug with solvent

molecules to produces crystalline forms
anhydrous form of ampicillin → faster
dissolving
Factors affecting the
concentration of drug in the
gastrointestinal fluids
• The rate and extent of absorption of a drug
depend on the effective concentration of drug
(i.e concentration of drug in solution in the
gastrointestinal fluid which is in an
absorbable form

• Physical properties: complexation, micellar

solubilization, adsorption & chemical stability
Complexation

• Mucin + streptomycin →↓ available

concentration of the drug for absorption
→↓bioavailability
• Tetracycline + Ca (dicalciun phospate) →
poorly soluble complex → ↓ bioavailability
• Amphetamine + Na CMC→ ↓ bioavailability
• Phenobarbitone + PEG 4000→↓ bioavailability
Complexation(2)

• Complexation is used to increase drug

solubility, particulary of poorly water-
soluble
• Cyclodextrin (complexing agent)
• Miconazole,piroxicam,
indomethacin,pilocarpine, naproxen,
hydrocortisone, diazepam, digitoxin
Micellar solubilization

• Increase the solubility of drugs in the

gastrointestinal tract
• The ability of bile salts to solubilize
drugs depends mainly on lipophilicity of
the drug
Adsorption
Adsorbent interfering with the absorption
of drugs from the gastrointestinal tract

• Drug + solid adsorbent (kaolin) → ↓ rate and/or

extent of absorption → ↓ effective concentration
of the drug in solution available for absorption
• Kaopectate → ↓ extent of absorption of
promazine, linomycin
• Adsorbent properties of charcoal → an antidote
in drug intoxification
• Talc (in tablets as a glidant) → ↓ absorption of
cyanocobalamin
chemical stability of the drug
in the gastrointestinal fluids
• Drug unstable in the gastrointestinal fluids →↓
amount of drug that is available for absorption → ↓
bioavailability
• Caused by acidic or gastric fluid
• Erythromycin (instable in gastric fluid)
-enteric coating tablet → protect from gastric fluid →
dissolves at the less acid pH range of the small
intestine
-prodrug (erythromycin stearat) → limited solubility
→ liberate the parent drug to be absorbed (free base
erythromycin absorbed in small intestine)
2. DRUG ABSORPTION

Drug dissociation & lipid solubility

• pH-partition hypothesis of drug
absorption
• Limitation of the pH-partition hypothesis
• Lipid solubility
 dissociation constan
lipid solubility of a drug
pH at the absorption site

Influence the absorption

charactersistics of a drug
throughout the GIT
a. pH-partition hypothesis
of drug absorption
• The epithelia gastrointestinal acts as a lipid
barrier towards drugs which are absorbed by
passive diffusion
• Lipid soluble will pass across the barrier
• Unionized weakly acidic or basic drugs will
pass across the gastrointestinal epithelia
• Unionized form at the site of absorption (pH-
partition hypothesis )
 a. pH-partition hypothesis
of drug absorption(2)
• Henderson-Hasselbach equation
weakly acidic drug: log (A-/HA)=pH-pKa
weakly basic drug: log (BH+/B)=pKa-pH

Drug pH=1,2 pH=6,8 More likely to be absorbed

Gastric fluid Intestine fluid from the …
weakly acidic 98,4% 99,98% ionized Stomach
drug (pKa=3,0) unionized
weakly basic 99,98% ionized 98,4% Intestine
drug (pKa=5,0) unionized
b. Limitation of the pH-
partition hypothesis
• Unionized form is not the only factor determining the
rate and extent of absorption of a drug molecule
from the gastrointestinal tract

• The rate of intestinal absorption of a weak acid is

often higher than its rate of absorption in the
stomach
-Surface area that is available for absorption (intestin
> stomach)
-Longer small intestinal resident time
-Microclimate pH

• Mucosal instirred layer  gastrointestinal barrier

diffusion across this layer will also depend on the
relative molecular weight of the drug
c. Lipid solubility
• Partition coefficient (P)
- ability to partition between a lipid-like solvent
(octanol) and water or an aqueous buffer
- a measure of its lipophilicity
• P determined by measuring the drug partitioning
between water and a suitable solvent at constant
temperature
• Thiopentone (greater affinity for GIT membrane →
better absorbed) > barbitone
• P = concentration of drug in organic phase
concentration of drug in aqueous phase
c. Lipid solubility (2)

• Log P < 0 → polar molecules

poorly lipid soluble
example: gentamicin, ceftriaxone,
heparin, streptokinase (by injection)
• Log P > 0 → lipid soluble
absorbed after oral administration
• Log P > 3 → very lipid soluble
c. Lipid solubility (3)
Prodrugs with improved lipid solubility and oral absorption
Parent drug Prodrug Ester
Ampicillin Pivampicillin Pivaloyloxymethyl
Ampicillin Bacampicillin Carbonate
Carbenicillin Indanylcarbenicillin Indanyl
Cefuroxime Cefuroxime axetil Acetylethyl
Enalaprilat Enalapril Ester of 1-carboxylic
acid
Terbutaline Ibuterol Dibutyl
DOSAGE FORM FACTORS
INFLUENCING
BIOAVAILABILITY

1. Influence of the type of dosage

form
2. Influence of excipients for
conventional dosage form
Introduction

• Physiological factors, physicochemical

properties→ bioavailability
• Factors associated with the formulation and
production of the dosage forms are being
designed to affect the release & absorption of
drug
• type of dosage form& the excipient → can
affect the rate and extent of drug absorption
1. Influence of the type of
dosage form
• type of dosage form, method of preparation,
manufacture can influence bioavailability
• Type of oral dosage form will influence
• the number of possible intervening steps between
administration
• the appereance of dissolved drug in the
gastrointestinal fluid
• Drug must be in solution in the
gastrointestinal fluid before absorption can
occur
• Bioavailability aqueous solution > aqueous
suspension > solid dosage form
a. Aqueous solution (1)
• Eliminated the in vivo dissolution step and
present the drug in the most readily available
form for absorption
• Dilution of aqueous solution (poorly water-
soluble drug) had been increased by
formulation techniques
• such as cosolvency, complex formation, or
precipitation of the drug in the gastric fluid
• Bioavailability: a polyethlyene glycol solution
> hydroxypropyl-β-cyclodextrin (precipitation)
a. Aqueous solution (2)
Factors that can influence
bioavilability
• The chemical stability (in aqueous
solution& gastrointestinal fluids)
• Complexation (increase the aqueous
stability)
• Solubilization
• The viscosity of a solution dosage form
b. Aqueous suspension
(1)
• Useful dosage form for administering an
insoluble or poorly water-soluble drug
• Dissolution-rate limited (for absorbtion)
• Result in a large total surface area of
disperse drug (peroral)
b. Aqueous suspension
(2)
Factors that can influence bioavilability

• The particle size & effective surface area of the

dispersed drug
• The crystal form of the drug
• Complexation (suspending agent — non absorbed
complex)
• The inclusion of surfactant as wetting, floculating or
deflocculating agent
• The viscosity of the suspension
c. Uncoated Tablets (1)
• Compression →↓ effective surface area
• Effective surface area of a poorly soluble drug is an
important factor its dissolution rate
• Rate-controlling step of poorly soluble drug → rate of
dissolution of the liberated drug particles in the GI fluids
• Factor (rate of tablet disintegration)
1. concentration & type of drug, diluent, binder,
disintegrant, lubricant, wetting agent
2. compaction pressure
• Tablet → granules → agregated suspension → small
particles
↑ effective surface area of a drug → ↑ dissolution →
↑ absorption
c. Uncoated Tablets (2)
Factors ( dissolution rate & bioavailability)

1. physicochemical properties of the liberated drug

particles in GI fluids (wettability, effective surface
area, chemical stability, crystal form)
2. nature of quantity of the diluent, binder, disintegrant,
lubricant, wetting agent
3. drug-excipient interaction (complexation)
4. size of the granules & their method of manufacture
5. compaction pressure
6. conditions of storage & age of the tablet
d.Coated tablets (1)

• For aesthetic reasons, employed to

mask an unpleasent taste or odour or to
protect an ingredient from
decomposition during storage
Coating
• Physical barrier between the tablets core &
the GI fluids
• Physicochemical nature & thickness →
influence release from a tablet
• Types of film coating materials form barries
which can have a significant influence on the
drug absorption
- HPMC → no significant effect
- ethylcellulose → ↓ rate of drug release
e.Enteric-coated tablet
• Designed to resist the low pH of gastric fluids but to
distrupt or dissolve when the tablet enters the higher
pH of the duodenum
• Enteric coating (polymers: cellulose acetate
phthalate, hydroxypropyl methylcellulose phthalate)
• Enteric coating serves improve the oral bioavailability
• Protects the stomach against drugs which can
produce nause or mucosal irritation (aspirin ,
ibuprofen)
• ↓ onset → dependent on the residence time in the
stomach
Influence of excipient for
conventional dosage form
• Excipient → facilitate preparation, patient
acceptability, drug delivery system
• Influence the rate and/or extent of
absorption of the drug
• Diluent, disintegrating agent, surfactants,
lubricant, viscosity-enhancing agent
Diluents

• Example: phenytoin interaction

• Sodium Phenytoin + calcium sulphate
dyhidrat → ↓ absorption (formed a poorly
absorbable calcium-phenytoin complex)
• Sodium Phenytoin + lactose (without any
alteration: quantity, fequency) → ↑
bioavailability → higher plasma levels →
exceeded the maximum safe concentration →
toxic side-effect
Surfactant (1)
• Emulsifying agent, solubilizing agent,
suspension stabilizers, wetting agent
• To be capable of either increasing, decreasing
or exerting no effect on the transfer of drug
across biological membranes
• To reduce the solid/liquid interaction tension
will permit the GI fluids to wet the solid more
effectively → ↑ total surface area of drug in
contact with the GI fluids → ↑ dissolution &
absorption
Surfactant (2)
• Phenacetin + polysorbate-80 (aqueous
suspension) → surfactant preventing
aggregation, ↑ the effective surface area → ↑
dissolution rate of the drug particles in the
GI fluids
• The ability of a surfactant to influence drug
absorption will also depend on the
physicochemical characteristic &
concentration of the surfactant, nature of the
drug and type of biological membrane
Lubricants

• To reduce friction between the powder &

metal surfaces during their manufacture
• hydrophobic in nature→ retard liquid
penetration into capsule ingredients
• Magnesium stearat →↓dissolution rate
(tablet)
• By simultaneous addition of a wetting agent
Disintegrant
• Required to break up capsule, tablets, and
granules into primary powder particles in
order to increase the surface area of the drug
exposed the GI fluids
• The compactation force → affect
disintegration
• Tolbutamide (two product , the same
formulation with half the amount of
disintegrant)
• both tablets disintegrated in vitro wthin 10
minutes → commercial tablet had a significantly
greater bioavailability → hypoglycaemic response
Viscosity-enhancing
agent
• To control such properties as palability, ease
of pouring, the rate sedimentation of
dispersed particles
• Often a hydrophilic polymers
• Complex (drug & hydrophilic polymers)→↓
the concentration of drug in solution that is
available for absorption
• May produce an increase in viscosity of the GI
contents → ↓ dissolution rate or ↓ the rate of
movement of drug molecules to the
absorbing membrane
 EFFECT OF EXCIPIENT ON THE PHARMACOKINETIC
PARAMETERS OF ORAL DRUG PRODUCTS

EXCIPIENT EXAMPLE KA T MAX AUC

Disintegrant Avicel,explotab ↑ ↓ ↑ / --
Lubricant Talc, hydrogenated ↓ ↑ ↓/--
vegetable oil
Coating agent HPMC -- -- --
Enteric coat Cellulose acetate ↓ ↑ ↓/--
phthalate
Sustained-release Methylcellulose, ↓ ↑ ↓/--
agent ethylcellulose
Sustained-release Castorwax, ↓ ↑ ↓/--
agent (waxy agent) carbowax
Sustained-release agent Veegum, ketrol ↓ ↑ ↓/--
(gum/viscous)
Summary

• Dosage form can play a major rule in

influencing the rate and extent of
absorption (by design)
• Changing the dosage form or excipients
will affect the bioavailability of the drug