Absorption of drug

ABSORPTION OF DRUG
Asst. Prof. SAGAR A. KASAR,
K.B.H.S.S.T’ INSTITUTE OF PHARAMCY,
MALEGAON(NASHIK)
103/08/17

ABSORPTION
 Drug absorption- is defined as the process of
movement of unchanged drug from the site
administration to systemic circulation.
 Absorption can also be defined as the process
of movement of unchanged drug from site of
administration to the site of measurement.
203/08/17

MECHANISM OF
ABSORPTION
303/08/17

Mechanism of drug absorption
 Passive diffusion
 Carrier mediated transport
 Active transport
 Facilitated diffusion
 Pore transport
 Ionic or electrochemical diffusion
 Ion pair transport
 Endocytosis
403/08/17

Passive diffusion
 Most important Mechanism for most of the Drugs
 Majority of drugs diffuses across the membrane in the
direction of concentration gradient.
 No active role of the membrane
 Proportional to lipid : water partition coefficient
 Lipid soluble drugs diffuse by dissolving in the
lipoidal matrix of the membrane
 Characteristics:-
Not requiring energy
Having no saturation
Having no carriers
Not resisting competitive inhibition
503/08/17

Passive diffusion
 Passive diffusion is best expressed by Fick’s
first law of diffusion – the drug molecules
diffuse from a region of higher concentration
to one of lower concentration until equilibrium
is attained and the rate of diffusion is directly
proportional to the concentration gradient
across the membrane.
603/08/17

Passive diffusion
( )C-C
h
DAK
dt
dQ git
m/w
=
Where ,
dQ/dt – rate of drug diffusion
D- diffusion coefficient of the drug through the membrane
A- surface area of the absorbing membrane for drug diffusion
Km/w- partition coefficient of the drug between the lipoidal
membrane & aqueous GI fluid
(Cgit- C) – conc. Gradient
h- thickness of the membrane.
703/08/17

Passive diffusion
Affecting factors :
 the size of molecule
 lipid solubility
 polarity
 degree of ionization
 the PH of the environment
such as: fluid of body
fluid in cell
blood, urine
803/08/17

Active Transport
ATP 903/08/17

 Uphill transport
 Energy is utilized
 Inhibited by metabolic poisons like fluorides, cyanides
and dinitrophenol and lack of oxygen.
 E.g. Na+,K+.Ca2+,iron, glucose, Amino acids and
vitamins like niacin, pyridoxine and ascorbic acid.
Active transport
1003/08/17

Active Transport
 Drugs having structure similar to such agents are
absorbed & which acts as false nutrients
 E.g. absorption of 5-flurouracil and 5-bromouracil via
pyrimidine transport system.
 Absorption of methyldopa and levodopa via the L-
amino acid transport system.
 Absorption of ACE inhibitor enalapril via small peptide
carrier system.
 Active transport is also important in renal and biliary
excretion of many drugs and their metabolites.
1103/08/17

Facilitated Diffusion
1203/08/17

Facilitated Diffusion
 Downhill transport
 No energy required
 Not inhibited by metabolic poison
E.g. Entry of glucose in RBC
Intestinal absorption of vit B1 and B2
Glycoprotein + vitamin B12 = complex
--carrier
1303/08/17

Carrier Mediated Transport
1403/08/17

Pore (Convective) Transport
 Very small molecules (such as urea, water, and
sugars) are able to cross cell membranes rapidly, as
if the membrane contained channels or pores.
 The model of drug permeation through aqueous
pores is used to explain renal excretion of drugs and
the uptake of drugs into the liver.
 A certain type of protein called a transport protein
may form an open channel across the lipid membrane
of the cell.
 Small molecules including drugs move through the
channel by diffusion more rapidly than at other parts
of the membrane.
1503/08/17

Ion-Pair Transport
 Strong electrolyte drugs maintain their charge at all physiologic
pH values and penetrate membranes poorly.
 When the ionized drug is linked up with an oppositely charged
ion, an ion pair is formed in which the overall charge of the pair
is neutral.
 This neutral drug complex diffuses more easily across the
membrane. For example, the formation of ion pairs to facilitate
drug absorption has been demonstrated for propranolol, a
basic drug that forms an ion pair with oleic acid, and quinine,
which forms ion pair with hexylsalicylate .
 An interesting application of ion pairs is the complexation of
amphotericin B and DSPG (disteroylphosphatidylglycerol) in
some amphotericin B/liposome products.
 Ion pairing may transiently alter distribution, reduce high
plasma free drug concentration, and reduce renal toxicity. 1603/08/17

Vesicular Transport
 Vesicular transport is the process of engulfing
particles or dissolved materials by the cell.
 Two type 1. Exocytosis 2. Endocytosis.
 Endocytosis and exocytosis are the processes
of moving specific macromolecules into and
out of a cell, respectively. 1703/08/17

Vesicular Transport
1803/08/17

Endocytosis
 Pinocytosis (cell drinking) refers to the
engulfment of small solutes or fluid.
 E.g. Orally administered Sabin Polio Vaccine
and large protein molecules.
 whereas phagocytosis (cell eating) refers to
the engulfment of larger particles or
macromolecules, generally by macrophages.
 Cellular uptake of macromolecular nutrients
like fats and starch, oil soluble vitamins like
A,D,E and K and drugs such as insulin.
1903/08/17

Route of administration
 Topical:
 Depends on lipid solubility – only lipid soluble
drugs are penetrate intact skin – only few drugs are
used therapeutically
 Examples – GTN, Hyoscine, Fentanyl, Nicotine,
testosterone and estradiol
 Organophosphorous compounds – systemic
toxicity
 Cornea permeable to lipid soluble drugs
 Mucus membranes of mouth, rectum, vagina etc,
are permeable to lipophillic drugs
2003/08/17

Route of administration
 Subcutaneous and Intramuscular:
Drugs directly reach the vicinity of capillaries –
passes capillary endothelium and reach circulation
Passes through the large paracellular pores
Faster and more predictable than oral absorption
Exercise and heat – increase absorption
Adrenaline – decrease absorption
2103/08/17

Route Of Administration
 Oral Route:- 1st
pass
metabolism
 Before the drug reaches the
systemic circulation, the
drug can be metabolized in
the liver or intestine. As a
Result, the concentration of
drug in the systemic
circulation will be reduced.
2203/08/17

1st
pass Elimination – metabolism
in liver
Buccal cavity
Stomach
Intestine
Rectum
Vena
cava
2303/08/17

Route Of Administration
 Intravenous administration has no absorption
phase
 According to the rate of absorption:
Inhalation→Sublingual→Rectal→intramuscular
→subcutaneous→oral→transdermal
 Example – Nitroglycerine:
 IV effect – immediate, SL – 1 to 3 min and per
rectal – 40 to 60 minute
2403/08/17

FACTORS AFFECTING
ABSORPTION
2503/08/17

Factors Affecting Absorption
Physicochemical
1. Dissolution of drug
2. Chemical form
3. Ionization constant
4. pH
5. Lipophilicity and lipid
partition coefficient
6. Particle size and surface
area
7. Polymorphism and
amorphous
8. Solvates.
Physiological
1. Anatomy of GI tract
2. Surface area GI
absorption sites
3. Gastric emptying rate
gastrointestinal motility
4. GI pH
5. Food and diet
6. Disease state and
physiological disorders
2603/08/17

Factors Affecting Absorption
Dosage Form Related
1. Excipients
2. Solutions
3. Suspension
4. Tablets
5. Capsules
6. Sustained released and controlled
release.
7. Manufacturing process variables
2703/08/17

PHYSICOCHEMICAL
FACTORS
2803/08/17

SOLID
DOSAGE
FORM
SOLID
DRUG
PARTIC
LES
Dissolution
DRUG IN
SOLUTION AT
THE
ABSORPTION
SITE
Permeation
across the
membrane
DRUG IN THE BODY
RDS FOR
LIPOPHILIC
DRUGS
RDS FOR
HYDROPHILIC
DRUGS
2903/08/17

rGIGIa tVSKMAD =
DISSOLUTION AND SOLUBILITY
Where,
Ka- intrinsic absorption rate constant
SGI – the solubility of drug in the GI fluid
VGI – the volume of GI fluid present
.tr- residence of drug in GI.
Class Solubility Permeability Absorption
pattern
Rate limiting
step
examples
I High High Well
absorbed
Gastric
emptying
Diltiazem
II Low High Variable Dissolution Nifidipine
III High Low Variable Permeability Insulin
IV Low Low Poorly
absorbed
Case by case Taxol
3003/08/17

DISSOLUTION AND SOLUBILITY
 ABSOLUTE/ INTRINSIC SOLUBILITY:
is defined as the maximum amount of solute is
dissolved in a given solvent under the standard
conditions of temperature, pressure & pH.
 DISSOLUTION RATE: is defined as the
amount of solid substance that goes into
solution per unit time under standard
conditions of temperature, pH & solvent
composition and constant surface area.
3103/08/17

Dissolution
 DIFFUSION LAYER- MODEL THEORY:
 Modified Noyes-whitey’s equation
D- diffusion coefficient of drug
A- surface area of dissolving solid
Kw/o – water/oil partition coefficient of drug considering
the fact that dissolution body fluid are aqueous.
V- volume of dissolution medium
h – thickness of stagnant layer
(Cs-Cb)- conc. gradient for diffusion of drug
)(
/
/ cCs
Vh
oDAKw
dtdc −=
3203/08/17

Solid drug
particle
Bulk of sol.
With conc.C
Stagnant diffusion
layer of thickness h
& Conc. Cs. Blood
GI Membrane
Film Theory For Drug Dissolution
3303/08/17

Dissolution
 To obtain good in vitro- in vivo dissolution rate correlation the
in vitro dissolution must always performed under sink
conditions. This can be achieved in following ways:
1. Bathing the dissolving solid in fresh solvent from time to time.
2. Increasing the volume of dissolution medium
3. Removing the dissolved drug by partitioning it from the
aqueous phase of dissolution fluid into an organic phase
placed either above or below the dissolution fluid . E.g.
hexane or chloroform.
4. Adding water miscible solvents as ethanol to dissolution fluid
5. Adding selected adsorbents to remove the dissolved drug.
3403/08/17

FACTORS AFFECTING DISSOLUTION AND
DISSOLUTION RATE
 Physicochemical properties of drug : solubility,
particle size, polymorphism, salt formation,
complexation, wet ability.
 Dosage form factors: formulation factors and
excipients.
 R= dc/dt=2.24cs
 Where R= dissolution rate.
 > 1% aq. Solubility avoid b.A. Problems.
3503/08/17

Particle size and S.A. of drug
 Absolute surface area: Total area of solid surface.
 Effective surface area: Area of solid surface exposed.
 Micronisation (<0.1 um) increase energy and
increase interaction, increase surface area and
dissolution rate.
 Micronisation of Non hydrophobic drugs, poorly aq.
Soluble drugs increase dissolution rate. E.g.
griseofulvin, chloramphenicol and tetracyclin.
3603/08/17

 Decrease dose of griseofulvin to half and
spironolactone 20 times.
 Hydrophobic drugs: Micronisation decrease
effective S.A and decrease dissolution rate.
 Adsorb air on surface and inhibit wetability and
float on medium
 Reaggregate to form a larger particle due to
high surface energy, settle or float.
 Production of surface charge prevent wetting
3703/08/17

 Absolute S.A can be converted to effective S.A
by:
 Using wetting agent e.g. tween 80 increase
B.A of phenacetin.
 Adding hydrophilic diluents like PEG, PVP.
Dextrose.
 Micronisation of unstable and degradable
drugs like penicillin G and erythromycin, not
increase dissolution rate and produce
undesirable effects, nitrofurantoin.
3803/08/17

Polymorphism and Amorphism
 Polymorphism: substance in more than one
crystalline form. differ in solubility, M.P, density,
hardness
Internal structure
Crystalline amorphous
Polymorphs
Enantiotropic
Molecular adducts
Monotropic
Non stoichiometric complex
Stoichiometric complex
Organic solvates
hydrates
3903/08/17

Polymorphism and Amorphism
 Stable : low energy, high M.P. least aq. Solubility.
 Metastable: high energy, low M.P. and high Aq.
Solubilities, better B.A.
 E.g. chloramphenicol palmitate B ( A,B,C)
 Riboflavin III (I,II,III)
 Metastable to stable conversion can be prevented ;
by dehydrating the molecular environment, by adding
viscosity building agent like PVP,CMC.
 Amorphous; high Aq. Solubility.
 E.g. amorphous form of novobiocin, chloramphenicol,
cortisone acetate and phenobarbitol.
 Amorphous > metastable > stable.
4003/08/17

Hydrates/Solvates
 Solvates : molecular adduct where the solvent
molecules are incorporated in crystal lattice .
 Hydrates: solvent water.
 Anhydrous form (high energy state): greater aq.
Solubility.
 E.g. Theophylline And Ampicilline.
 Organic Solvate : More Aq. Solubility than non
solvate
 E.g. N-pentanol Solvate Of Fludrocortisone
 Chloroform Solvate Of Griseofulvin.
4103/08/17

Salt Form of the Drug
 Solubility is pH dependent.
 Weak acidic drug: strong base salt prepared
 Solubility in diffusion layer is greater
 Higher pH favors solubility of weak acid.
 pH of diffusion layer (salt form) > bulk solution (free
acid)
 E.g. Na and K salt of barbiturate and sulfonamide.
 Weak basic drug : strong acid salt
 E.g. HCL salt of alkaloids.
 Solubility in diffusion layer is greater
 Lower pH favors solubility of weak base.
 pH of diffusion layer (salt form) < bulk solution (free
acid)
4203/08/17

Salt of
weak
acid
Diffusion
layer with
higher pH
5-6.
Diffusion
of soluble
drug
particles
Soluble form
of drug
Fine precipitate of weak
acid Rapid
dissolution
Absorption
Drug in solution
Absorption
Bulk of the solution with
relative low pH (1-2)
4303/08/17

Salt Form of the Drug
 Increased solubility is due to precipitation of drug as
very fine particles in bulk solution.
 Size of the counter ion of the drug also influence
solubility, small size--- high solubility.
Novobiosine Na > Ca> acid. 50:25:1.
More soluble salt: poor bioavailability.
Na phenobarbital < free phenobarbital.
Due to not disintegration of the tablet.
4403/08/17

Drug Stability
Poor B.A. due to destabilization of drug during its
shelf life is due to Degradation of drug in to inactive
form.
Interaction with one or more different component.
4503/08/17

Drug pKa & Lipophilicity & GI pH
 pKa : pH of fluid at absorption site: function of
unionized drug.
 Strong acid: low pKa; greater proportion of ionized
drug.
 Strong Base: high pKa.
 Lipophilicity:- only the unionized drug if sufficiently lipid
soluble is absorbed into systemic circulation.
 Ideally a perfect hydrophilic- lipophillic balance (HLB)
should be there in the structure of the drug for
optimum bioavailability.
4603/08/17

Drug pKa
 Amount of drug exist in unionized form depends
upon drug pKa & pH at absorption site.
 Unionized form- most suitable for absorption.
 Handerson- Hasselbach equation:
 For weak acids
 For weak bases:
drug)ionizedconc.)/(undrugdlog(ionizepka +=pH
conc.)drugzedconc./ionidrugzedlog(unionipKapH +=
4703/08/17

 Very weak acids (pKa> 8): unionized at all pH values :
absorbed along the entire length of GIT (pH1 to 8).
E.g. Phenytoin, Phenobarbital.
 Moderately weak acids (pka 2.5 to 7.5): unionized in
gastric pH: ionized in intestinal pH: better absorbed
from stomach (pH 1 to 3).e.g. Aspirin. Ibuprofen.
 Stronger acids (pka <2.5): ionized at all pH; poorly
absorbed from GIT.e.g. disodium chromoglycate.
4803/08/17

 Very weak bases (pKa<5 ): unionized at all pH
values : absorbed along the entire length of GIT (pH1
to 8).
 E.g. Theophyline, Caffeine, Diazepam.
 Moderately weak bases (pka 5 to 11.0): ionized in
gastric pH: unionized in intestinal pH: better absorbed
from intestine (pH 5 to 8).
 e.g. Reserpine, Codeine.
 Stronger bases (pka >11): ionized at all pH; poorly
absorbed from GIT. 4903/08/17

pH-partition hypothesis
 Indicates the interrelation ship between pH at
absorption site, dissociation constant & lipid
solubility.
 According to this theory, the GI barrier acts like a lipid
barrier towards weak electrolyte drug.
 This barrier is impermeable to the ionized
drugs(poorly lipid soluble drugs). The greater the
fraction drug in non-ionized form at a given site, the
faster the absorption.
 E.g. a solution of the weak acid aspirin(pKa-3.5) in the
stomach at the pH 1, > 99% of the drug in non-ionized
form. 5003/08/17

Limitations
 A micro climate or virtual pH- determines the
drug ionization and absorption, not the luminal
pH.
 Ionized drug with low lipid solubility & poor
permeability are also absorbed across the
membrane.
 Irrespective of GI pH & degree of ionization,
acidic , basic drugs are absorbed more
rapidally due to long residence time. In GI
tract. 5103/08/17

DOSAGE FORM
FACTORS
5203/08/17

DISINTEGRATION TIME
 Disintegration and Bioavailability
 Coated Tablets: long Disintegration time
 Disintegration time α Amount of binder.
 Hard tablet with high binder: long DT.
 Disintegration time is increases with
disintegrant. 5303/08/17

Manufacturing Variables
 Excipients – Non active contents
 Mfg processes- Method of granulation
Wet granulation: faster dissolution
Limitations :- Formation of crystal bridge
-Liquid may act a medium for chemical rexins.
-Drying may harm thermo labile drugs
 Compression force
Direct compression: faster dissolution
 Intensity of packing of capsule contents
54
03/08/17

Manufacturing Variables
 Agglomerative phase of communition(AOPC):
 The process involves grinding of drug in ball
mill for time long enough to affect
spontaneous agglomeration. The tablets –
rapid dissolution
 Reason- increase in the internal surface area of
granules prepared by AOPC method.
5503/08/17

Mfg/Processing Variables
 High Compression force:
 high density:
 greater hardness
 low porosity:
 low wettability :
 slow dissolution rate. Rateof
dissolution
Compression force
5603/08/17

 High Compression force:
 Deformation :
 Crushing of drug particle
into smaller Spherical shape
to disc shape particle.
 High effective surface Area
 High dissolution rate Rateof
dissolution
Compression force
5703/08/17

Rateof
dissolution
Compression force
Rateof
dissolution
Compression force
5803/08/17

Intensity Of Packing
 Can Inhibit or promote dissolution.
 Diffusion of GI fluids in to tightly packed
capsules creates high pressure within capsule
resulting in rapid burst & dissolution of
contents.
 Capsule with finer particles & intense packing
have poor release & low dissolution rate due to
low pore size & poor penetrability by the GI
fluids.
5903/08/17

Excipients
 Excipients Imparts acceptability,
physicochemical stability, uniformity of
content, and optimum B.A.
1. Vehicle
2. Diluents, colorants
3. Binders and granulating agents
4. Disintegrants, emulsifiers.
5. Lubricants, surfactants
6. Coatings, buffers
7. Suspending agents 6003/08/17

Vehicles
 Aqueous (water, syrup) : Rapid absorption
 Solubilisers (polysorbate 80) promote solubility
of aq. Vehicles.
 Non-aqueous water miscible (propylene glycol,
glyserol sorbital):shows better Bioavailability.
 Non-aqueous water Immiscible (vegetable oils):
absorption depends on partitioning from oil to
water phase. Rate determining step.
 Viscous vehicles : slow absorptions.
6103/08/17

Diluents
 Organic: (Carbohydrates like starch, lactose,
MCC etc)
 Hydrophilic powder promote absorption of
Hydrophobic drug like Spironolactone and
Triamterene by forming hydrophilic coat.
 Inorganic: (DCP)
 Drug diluent Interaction:tetracycline + DCP =
divalent calcium tetracycline complex : poorly
soluble
6203/08/17

Binders
 Aqueous : Acacia, PVP, gelatin and sugar
solution.
 Show better dissolution profile with poorly
wettable drugs like Phenacetin.
 Large amt of binders: high hardness :Long DT/
dissolution.
 PEG 6000 forms poorly soluble complex with
Phenobarbital.
 Non-aqueous like Ethyl cellulose: retard
dissolution. 6303/08/17

Disintegrants
 Disintegrants : hydrophilic
 Small amt of disintegtants : low B.A.
 Adsorbing disintegrants (bentonite, veegum)
avoided with low dose drug (digoxin) since large
amt of drug is permanently adsorbed & only
fraction of it is available for absorption.
 MCC is very good binder & disintegrant but at high
compression force it retards drug dissolution.
6403/08/17

Lubricants
 Commonly used hydrophobic in nature
(metalic stearate and waxes) .
 Inhibit wet-ability, penetration of water into
tablet and their disintegration and dissolution.
 Bcz disintegrants get coated with lubricants.
 Can be prevented by adding lubricants in final
stage.
 Use soluble lubricants like SLS & carbowaxes
which promote drug dissolution.
6503/08/17

Coatings
 Effect of various coatings on drug dissolution:
 Enteric coat > Sugar coat > Non-enteric film
coat.
 Dissolution profile may change on aging.
 Shellac coated tablets, on prolonged storage,
dissolves more slowly in intestine.
 Prevented by adding little PVP in the coating
formulation.
6603/08/17

Suspending agents
 Popular S.A : hydrophilic polymers
 Vegetable gums (acacia, tragacanth, etc)
 Semi-Synthetic gums (CMC, MC)
 Synthetic gums
 Macromolecular gums form unabsorbable
complexes with drugs (CMC with
Amphetamine).
 High Viscosity acts as a mechanical barrier to the
diffusion of the drug by forming a viscid layer on
the GI mucosa. 6703/08/17

SURFACTANTS
 Used as wetting agents, solubilizer, emulsifier.
 Enhance or retard drug absorption by interacting with
drug or membrane or both.
 Increase absorption by:
1. Promoting wettability & dissolution ( polysorbate 80
with phenacetin)
2. Better membrane contact of drug for absorption.
3. Enhance membrane permeability of the drug.
 Increase absorption by:
1. Above CMC form unabsorbable drug-micell complex.
2. Large surfactant conc. induce laxative action.
6803/08/17

Buffers
 Useful in creating right atmosphere for drug
dissolution as for buffered aspirin tablet.
 Buffers containing K+
inhibit absorption. (Vit B12,
Sulphanilamide) by the uptake of fluid by the
intestinal epithelial cells and decrease effective drug
conc in tissue.
 Order of inhibitory effect
K+
> NH+
4 > Li+
> Tris+
.
6903/08/17

Complexing agents
 Complexed drug may alter stability, solubility,
molecular size, partition coefficient, and diffusion
coefficients.
 Complex formation enhance drug B.A. by:
o Enhancing dissolution by forming soluble complex.
(Ergotamine tartarate –caffeine complex, hydroquinone-
digoxin complex)
o Enhancing lipophilicity for better membrane
permeability (Caffeine-PABA complex)
o Enhance membrane permeability (enhance GI
absorption of heparin in the presence of EDTA which
chelates Ca and Mg ions of membrane.
7003/08/17

Complexing agents
 Complexation retard drug absorption by forming poorly
absorbable complex (complexation of tetracycline with
divalent and trivalent cations)
 Complex formation retard drug B.A. by:
1. Failure to dissociate at the absorption site.
2. Large molecular size of the complex that cannot diffuse
through the cell membrane (drug-protein complex)
7103/08/17

Colorants
 Even a very low conc. of water soluble dye can inhibit
dissolution rate of several crystalline drugs by adsorbing
on to the crystal faces.
 E.g. Brilliant blue retards dissolution of sulphathiazole.
 Dyes also inhibit micellar solubilization and impair
absorption of hydrophobic drugs ( steroids)
7203/08/17

Nature and type of dosage form
 Difference in B.A is depends on nature and type of
dosage form.
 It is due to diff in relative rate at which the dosage
form release drugs.
 The release rate depends on complexity of dosage
form.
 More complex dosage form, more number of rate
limiting step.
 B. A of various dosage forms : Solutions >
Emulsions > Suspensions > Capsule > Tablets >
coated tablets > enteric coated > Sustained.
7303/08/17

Solution
 Major rate limiting step: Drug dissolution is
absent.
 Factors:
 The nature of solvent, viscosity, surfactants,
solubilizers, stabilizers.
7403/08/17

Emulsions and Suspensions
 Emulsions :- Are superior than suspension in
administration of poorly soluble lipophilic
drugs.
 E.g. emulsion of Indoxole (anti-inflamatory)
increases 3 fold absorption over suspension.
 Suspension:- Particle size, polymorphism,
wetting agent, viscosity, suspending agents
influence the B.A. of suspensions.
7503/08/17

Powders
 They are superior to tablets and capsules.
 Particle size, polymorphism and wettability affect
the absorption of the drugs.
7603/08/17

Capsules
 Powders and granules: hard gelatin capsule.
 Viscous fluids & oils: soft elastic shells.
 Factors affecting Hard gelatin capsule: particle size,
density, polymorphism, intensity of packing, diluents and
excipients.
 Hydrophilic diluents (lactose) improve wettability,
disaggregation, and dispersion of poorly aq. Soluble drugs.
 Hydrophobic lubricants (Mg. stearate) give inhibitory
effect.
 A hydrophobic drug with fine particle size cause clumping
of particle by decreasing porosity and hence penetrability of
solvent. 7703/08/17

Capsules
 This can be overcome by incorporating hydrophilic diluent
(up to 50 %), small amt of wetting agent/lubricants (SLS, up
to 1 %) and by wet granulation.
 Soft elastic capsules dissolve faster.
 E.g. Indoxole
 Soft gelatin capsules are prepared when the dose is low &
drug is lipophilic.
 Limitations :high water content of the shell (>20 %) migrate
into the shell content & crystallization of the drug occurs
during drying stage.
7803/08/17

Coated Tablets
 Coating act as a barrier.
 Film coat: thin and dissolve rapidly.
 Sugar coat: tough and takes longer time to dissolve.
 Sealing coat of shellac is most deleterious.
 Enteric coat: dissolve only in alkaline pH & thickness of
the coat is determinant factor in drug dissolution.
 Ageing of shellac coated tablets also affect drug release.
E.g. shellac coated tablets of salicylic acid stored for 2
yr showed 60 % decrease in peak plasma level.
7903/08/17

Patient related factors
 Age
 Gastric emptying time
 Intestinal transit time
 Gastrointestinal pH
 Disease state
 Blood flow through GIT
 GI contents
 Pre-systemic metabolism
8203/08/17

AGE
 In Infants gastric pH is high and Intestinal
surface and blood flow is low.
 The cause of Impaired drug absorption in adults:
Altered gastric emptying time, decreased
intestinal surface area and GI blood flow, higher
incidence of achlorhydria.
8303/08/17

Gastric Emptying
 Passage from stomach to small intestine, rate limiting step,
most absorption occur from intestine.
 Gastric emptying is advisable where
 Rapid onset of action desired (sedative)
 Dissolution of drug occur in intestine (enteric coated)
 Drugs are unstable in gastric fluids (penicillin G,
erythromucin).
 Drug is best absorbed from the distal part of small intestine
(Vit. B12).
8403/08/17

Gastric Emptying
 Delay Gastric emptying is advisable where:-
 Food promote dissolution and absorption. (griseofulvin)
 Gastric fluid promote disintegration & dissolution.
 Drug dissolve slowly (griseofulvin).
 The drugs irritate gastric mucosa (Aspirin).
 Drugs absorbed from proximal part of the small intestine.
(Vit C, Vit B12)
8503/08/17

Factors influence Gastric Emptying
 Vol. of meal: : high vol: longer emptying time
 Composition of meal:
carbohydrate > proteins > fats
 Physical state & viscosity of meal
liquid meal <1 hr , solid meal: 6 to 7 hr.
 Temp of meal: high or low temp : longer time
 Gastrointestinal pH :low pH: long time
high pH: low time
HCL> acetic > lacticc> tartaric > citric 8603/08/17

 Electrolyte and osmotic pressure:
Water, isotonic solutions & low salt conc: rapid
emptying
higher electrolyte conc: slow emptying
 Body posture: standing (rapid) >lying on right side>
lying on left side
 Emotional state: stress and anxiety promote gastric
motility while depression retards it
 Exercise : vigorous exercise retards gastric
emptying. 8703/08/17

 Disease state
Gastroenteritis, gastric ulcer, diabetes &
hypothyroidism : retard gastric emptying.
gastrectomy, duodenal ulcer & hyperthyroidism:
promote gastric emptying.
 Drugs
 Poorly soluble antacids, anticholinergis,
narcotic analgesic and tricyclic antidepressants :
retards gastric emptying.
 Metoclopromide, domperidone, cisapride :
promote gastric emptying 8803/08/17

INTESTINAL TRANSIT TIME
 Small intestine is major site for drug absorption
:long intestinal transit time is desired for complete
drug absorption.
 Residence time depends upon intestinal motility or
contraction.
 Peristaltic contraction promote drug absorption by
increasing the drug intestinal membrane contact, by
enhancing drug dissolution.
 Pregnancy retard intestinal transit whereas diarrhea
promotes it
8903/08/17

 Metaclopropamide, laxative, promote intestinal
transit time & enhance absorption of rapidly soluble
drugs.
 Anticholinergics retards gastric and intestinal transit
and promote absorption of poorly soluble drugs.
9003/08/17

 Delayed intestinal transit is desirable for:
 Drugs that release slowly (sustained release)
 When the ratio of dose to solubility is high.
(chlorothiazide)
 Drugs that dissolve only in intestine (enteric coated)
 Drugs which are absorbed from specific site in the
intestine (Li, carbonate, Vit B)
 When drug penetrate the intestinal mucosa very slowly
(e.g. acyclovir)
 When absorption of drug from colon is minimal.
9103/08/17

Gastrointestinal pH
 Disintegration: The disintegration of some dosage forms
is pH sensitive. E.g. enteric coating.
 Dissolution: A large number of drugs either W.A. or
W.B. whose solubility is greatly affected by pH.
 A pH that favors formation of salt of drug enhances the
dissolution of that drug.
 Dissolution is one of the importance rate-determining
steps in drug absorption, GI pH is of great significance
in the oral bioavailability of drugs.
9203/08/17

Gastrointestinal pH
 Absorption: Drug pKa & GI pH influences absorption by
determining amount of drug that exist in the unionized
form.
 Stability: the acidic stomach pH of is known to affect
degradation of penicillin G & Erythromycin.
9303/08/17

Disease state
 GASTROINTESTINAL DISEASES:
 Alerted GI motility-
 Gastrointestinal diseases & infection-
 Achlorhydria- decreased gastric acid secretion, on
gastric emptying & drug absorption especially of
acidic drugs. (aspirin)
 Celiac disease: characterized by destruction of villi &
microvilli. Increased gastric emptying rate & GI
permeability & reduced entro-hepatic cycling of bile
salts- reduced absorption.
9403/08/17

Disease state
 Crohn’s disease:- can alter absorption pattern by
alterering gut wall micro flora, decreased surface area
& intestinal transit time leads for malabsorption of
drug.
 Mal-absorption is also induced by drugs such as
antineoplatics and alcohol which increase
permeability of agents not normally absorbed.
 Gastrointestinal surgery: gastrectomy can result in
dose dumping in the intestine, osmotic diarrhoea and
reduced intestinal transit time.
9503/08/17

Gastrointestinal contents:
 Food-Food interactions:
 Delayed or decreased drug absorption by food could
be due to:
 Delayed gastric emptying, affecting drugs unstable in
the stomach e.g. Penicillins,
 Formation of poorly soluble, unabsorbable complex.
e.g. Tetracyclin-calcium complex.
 Increased viscosity due to food thereby preventing
drug dissolution & or diffusion towards absorption
site.
9603/08/17

 Increased drug absorption following meal could be
due to:
 Increased time for dissolution of poorly soluble drug.
 Enhanced solubility due to GI secretions like bile.
 Prolonged residence time and absorption site contact
of the drug e.g. water soluble vitamins
 Increased lymphatic absorption e.g. acitretin
9703/08/17
Gastrointestinal contents:

 High protein meal : increased oral availability of
Proparanolol:-
 1. protein meal increases hepatic blood flow – bypass
first pass metabolism
 2. it promotes blood flow to GIT thus aiding drug
absorption.
 Interaction of drug with normal GI constituents:
Mucin: streptomycin- retard absorption.
Bile salts- increase solubilisation and absorption of
drugs like Griseofulvin and Vitamins A,D,E & K.
Decreased absorption of neomycin and Kanamycin
9803/08/17

Drug-drug interactions
 Physicochemical drug-drug interactions:
 Absorption : antidiarrhoeal preparations containing
adsorbents like attapulgite or kaolin-pectin retard
absorption of no. of drugs.
E.g. promazine, lincomycin
 Complexation: antacids & minerals containing
aluminium, calcium, iron, magnesium retard
absorption of tetracyclines.
Anion exchange resins cholestyramine & colestipol
bind cholesterol metabolites, bile salts a number of
drugs in the intestine & prevent their absorption.
9903/08/17

Drug-drug interactions
 Physiological drug-drug interactions can be due to:
 Decreased GI transit : Anticholinergic such as
propenthalin retard GI motility & promote GI
absorption of drugs like Ranitidine, Digoxin
 Increased gastric emptying: Metoclopramide
promotes GI motility & enhances absorption of
Tetracycline, Pivampacillin & Levodopa.
 Altered GI metabolism: antibiotics inhibits GI
metabolism of drugs eg. Erythromycin enhances
efficiency of Digoxin
10003/08/17

Presystemic metabolism
 The loss of drug through bio-transformation by
eliminating organs during its passage to systemic
circulation is called as first-pass or presystemic
metabolism.
 Digestive enzymes: Hydrolyses- cloramphenicol
palmitate - choramphenicol
 Bacterial enzymes:
 Gut-wall enzymes: Alcohol dehydrogenase (ADH)
 Hepatic enzymes: Isoprenalin, propranolol,
alprenolol, diltiazem, nifedipine.
10103/08/17

Absorption of drug

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