absorption of drugs.ppt

ABSORPTION OF DRUGS
NIVYA.P
M.PHARM I YEAR,
DEPARTMENT OF PHARMACEUTICS,
COLLEGE OF PHARMACY,
MADRAS MEDICAL COLLEGE,
CHENNAI-03.
1

CONTENTS
 DEFINITION
 INTRODUCTION
 STRUCTURE OF CELL MEMBRANE
 MECHANISM OF DRUG ABSORPTION
 FACTORS AFFECTING ABSORPTION
 PHYSIO-CHEMICAL FACTORS
 PHARMACEUTICAL FACTORS
 DOSAGE FORMS
 REFERENCES
2

INTRODUCTION OF ABSORPTION
Definition:
 Absorption can also be defined as the process of movement
of unchanged drug from the site of administration into the
systemic circulation.
 Concentration can be measured more accurately in plasma.
In drug absorption two parameters are frequently used.
 Magnitude of drug that reaches the systemic circulation
 Rate at which the drug is absorbed.
3

CELL MEMBRANE STRUCTURE
 Also called the plasma membrane, plasmalemma or
phospholipid bilayer.
 The plasma membrane is a flexible barrier that surrounds &
contains the cytoplasm of a cell.
 Cell membrane mainly consists of:
1.Lipid bilayer -phospholipid
-Cholesterol
-Glycolipids.
2. Proteins - Integral membrane proteins
- Lipid anchored proteins
- Peripheral Proteins
Hydrophobic core of the membrane is responsible for the
relative impermeability of polar molecules.
4

 GI lining constituting the absorption barrier allows most nutrients
like glucose, amino acids ,fatty acids, vitamins, etc.
 The basic structural framework of the plasma membrane is the
lipid bilayer.
 This forms a continuous, spherical lipid bilayer app. 7nm thick.
5

GASTRO INTESTINAL TRACT
STOMACH :
 The surface area for absorption of drugs is relatively small
in the stomach due to the absence of macrovilli &
microvilli.
 Stomach emptying applies more to the solid dosage forms
because the drug has to dissolve in the GI fluid before it is
available for absorption.
 Since solubility & dissolution rate of most drugs is a
function of pH.
6

SMALL INTESTINE :
 It is the major site for absorption of most drugs due to
large surface area.
 The blood flow to the small intestine is 6 to 10 times that
of stomach.
 Peristaltic movements of intestine is slow, transit time is
long, permeability is high.
 The transit time in small intestine for most healthy adults
is between 3 to 4 hours, a drug may take about 4 to 8
hours to pass through the stomach & small intestine
during fasting state.
 During the fed state, the small intestine transit time may
take about 8 to 12 hours.
7

LARGE INTESTINE :
 The length and mucosal surface area is very small
compared to small intestine so absorption of drug
from this region is insignificant.
 The main role is absorption of water and
electrolytes.
 Because of long residence time (6 to 12 hours)
colonic transit may be important in the absorption
of some poorly soluble drugs and sustained release
dosage forms.
8

MECHANISM OF DRUG ABSORPTION
There are three main mechanisms of drug transport across the
gastrointestinal epithelium.
 Trans cellular, i.e., Across the cells
 Passive transport
 Active transport
 Para cellular, i.e., Between the cells Pore transport
 Permeation through tight junctions of epithelial cells
 Persorption
 Vesicular i.e., Within the vesicles into cells.
 Pinocytosis
 Phagocytosis
9

TRANSCELULAR /INTRACELLULAR
The passage of the drugs across the GI epithelium is the
common pathway for the drug transport.
3 steps:
 Permeation of GI epithelial cell membrane, a lipoidal
barrier is the major obstacle to drug absorption.
 Movement across the intracellular space (cytosol).
 Permeation of the lateral or baso lateral membrane .
Passive transport process
 Passive diffusion
 Carrier mediated transport
 Facilitated diffusion
 Ionic electrochemical diffusion
 Ion pair transport
10

Passive Diffusion
 It is defined as the
difference in the drug
concentration on either
side of the membrane.
 Also called nonionic
diffusion
 It is the major process for
absorption of more than
90% of the drugs.
 The driving force for this
process is the
‘concentration or
electrochemical gradient’.
11

 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 & the
rate of diffusion is directly proportional to the
concentration gradient across the membrane”.
dQ = D A Km/v (CGIT – C)
dt h
12

Cntd…
Where,
dQ/dt = Rate of diffusion (Amount/time)
D = Diffusion co efficient of the drug
through the membrane( Area/time)
A = Surface area of the absorbing membrane
for drug diffusion(Area)
Km/w = Partition co efficient
Cgit - C = Concentration gradient
h = Thickness of the membrane
13

PORE TRANSPORT
 It is also called as Convective transport, Bulk flow
or filtration.
 Mechanism – Protein channels present in the cell
membrane.
 The driving force for this process is the ‘hydrostatic
pressure or the osmotic differences across the
membrane’.
 The process is important in the absorption of low
molecular weight (less than 100), low molecular
size drugs.
 Example: Urea, Water, Sugar
14

 The rate of absorption via pore transport depends on the
number & size of the pores, & given as follows:
dc = N R 2
A ∆C
dt (η) (h)
where,
dc /dt = rate of the absorption.
N = number of pores
R = radius of pores
∆C = concentration gradient
η = viscosity of fluid in the pores
15

Two types
Facilitated diffusion
Active transport
Facilitated diffusion
 This mechanism involves the driving force is
concentration gradient.
 In this system, no expenditure of energy is involved
(down-hill transport), therefore the process is not
inhibited by metabolic poisons that interfere with
energy production.
 Eg. Vitamin B12.
16

Active transport
 Transport process
require energy from
ATP to move drug
molecules from
extracellular to
intracellular fluid.
 It is process where the
materials are transported
across membranes
against a concentration
gradient.
17

 The drug is transported from a region of lower to
one of higher concentration i.e.. against the
concentration gradient or ‘uphill transport’.
 Examples : Sodium, potassium, iron, glucose and
vitamins like niacin, pyridoxine and ascorbic acid.
Types
 Primary active transport –Uniport
 Ion transporters
 ABC (ATP – binding cassette ) transporters -
Eg: p Glycoprotein. MDR.( Multi drug resistance)
 Secondary active transport
 Symport (co -transport)
 Antiport (counter -transport)
18

Paracellular/IntercellularTransport
 It is defined as the transport of drugs through the junctions
between the GI epithelial cells. This pathway is of minor
importance in drug absorption. The two paracellular
transport mechanisms involved in drug absorption are –
 Permeation through tight junctions of epithelial cells –
this process basically occurs through openings which are
little bigger than the aqueous pores. Compounds such as
insulin and cardiac glycosides are taken up this
mechanism.
 Persorption – is permeation of drug through temporary
openings formed by shedding of two neighbouring
epithelial cells into the lumen.
19

Endocytosis
 Also called Corpuscular or Vesicular transport
 It involves engulfing extracellular materials within a
segment of the cell membrane to form a saccule or a
vesicle which is then pinched-off intra cellularly.
 Includes two type of process:
 Phagocytosis (cell eating): adsorptive uptake of solid
particulates, and
 Pinocytosis (cell drinking): uptake of fluid solute.
Fats, starch, vitamins like A, D, E, K
20

FACTORS AFFECTING DRUG ABSORPTION
(a)PHARMACEUTICAL FACTORS
 Physicochemical Factors
 Dosage form characteristics
(b)PATIENT RELATED FACTORS
21

PHYSICOCHEMICAL FACTORS
 Lipid solubility ,dissociation constant and pH
 Dissolution
 Salt form
 Particle size and Effective surface area
 Polymorphism and Amorphism
 Solvates and hydrates(Pseudopolymorphism)
 Drug permeability and absorption
 Viscosity
22

Lipid solubility dissociation constant and pH
More the drug in non ionized form , more is it lipid soluble and
better is the absorption.
pH partition hypothesis
The interrelationship of dissociation constant, lipid
solubility, pH at the absorption site and absorption
characteristics of various drugs throughout the GIT.
23

 The pH partition theory is the process of drug absorption
from the GIT and its distribution across all biological
membrane.
 The theory states “ That for the drug compound of
molecular weight greater than 100 , which are primarily
transported across the bio membrane by passive diffusion ,
the process of absorption is governed by
 Dissociation constant
 Lipid solubility
 pH at the absorption site
24

The rate of loss of drug in solution form from the absorption
site is given by:
-DCt/dt = KaCu
Ct
Where,
Dct/dt= rate of drug loss from absorption site
Ka = absorption rate constant
Ct =Total drug concentration
Cu = concentration of unionized drug.
25

The dissociation constant is expressed for both acids and
bases as a pKa value:
 FOR ACID
pH= pKa +log conc.(ionized)/conc.(unionized)
 FOR BASE
pH= pKa +log conc.(unionized)/conc.(ionized)
Weakly acidic drugs (Eg :Aspirin) dissolve faster in gastric
fluids.
Weakly basic drugs (Eg :Quinine) dissolve faster in intestinal
fluids.
Acidification or basification of both stomach and intestine will
produce converse effects.
26

Dissolution
Drug gets absorbed in the biological system, when it gets
dissolved in the physiological fluid at the absorption site.
Solid dosage form(tablet or capsule)
Disintegration(coarse particles of drug)
Dissolution
Drug in solution(very fine particles)
Drug in systemic circulation
27

Theories of drug dissolution
 Diffusion layer model / film theory
 Danckwert’s model / surface renewal theory
 Interfacial model / double barrier model theory
29

Salt form
 Conversion of a weakly acidic or basic drug in its salt
form enhances the solubility and dissolution rate of the
drug.
 Weakly acidic drug- strong base salt
Eg. Na, K salts of barbiturates, sulphonamides
 Weakly basic drug- strong acid salt
Eg. Hcl,SO4 salts of alkaloidal drugs.
Particle size and surface area
 Particle size and surface area share an inverse
relationship.
 Surface area can be classified as
(1)Absolute surface area
(2)Effective surface area
30

 Greater the effective surface area, better the dissolution and so the
absorption.
 Absolute surface area can be converted to effective surface area
by :
(1)Use of surfactants like Polysorbate 80.
(2)Adding hydrophillic diluents like PEG,PVP etc.
Polymorphism and amorphism
 POLYMORPHISM
-Substances exist in more than one crystalline form
-Definite structural arrangements
-Different physical properties :
Density, Melting point, Boiling point, solubility.
c

Two types
Enantiotropic - reversible-altering temp & pressure.
Eg. Sulphur
Monotropic - unstable at all temp & pressure.
Eg. Glyceryl stearates
 STABLE - ↑Melting point ↓energy ↓solubility
 METASTABLE - ↓Melting point ↑energy ↑ solubility
↑ bioavailability
 AMORPHISM
No internal crystal structure ↑ aqueous solubility
Eg. Novobiocin- amorphous form 10 times more soluble than
crystalline form.
Dissolution: Amorphous>meta stable >Stable
32

33
CRYSTALLINE
AMORPHOUS
POLYMORPHS
MOLECULAR
ADDUCTS
ENANTIOTROPIC MONOTROPS
NON STOICHOMETRIC
STOICHOMETRIC(PSEUDOPOLYMORPHS)
ORGANIC
SOLVATES
HYDRATES
INTERNAL STRUCTURE OF A
COMPOUND

Hydrates and solvates
SOLVATES
 Adducts where solvent molecule incorporated in crystal lattice
of solid
 High solubility
 Eg. Solvates of Cortisone , Griseofulvin
HYDRATES
 If solvent is water - called as hydrate
 Anhydrous forms more soluble than hydrates
 Eg. Anhydrous ampicillin , Theophylline
34

DRUG PERMEABILITY AND ABSORPTION
 Most orally administered drugs enter the systemic circulation
by passive diffusion
 Three major characters that determine the permeability of the
drug across the intestinal epithelium are:
(A) Lipophilicity of the drug
(b) Polarity
(c) Molecular size
35

 The net effect of above three properties is given as RULE
OF FIVE by Lipinski which is written as:
Molecular weight of drug <=500
Lipophilicity of drug <=5
Number of H-bond receptors <=10
Number of H-bond donors <=5
 If any two of these values are greater than specified limits,
the oral absorption of a drug may be a significant problem.
36

DRUG STABILITY
 A drug for oral use may destabilized either during its shelf
life or in the GIT.
 Two major stability problems resulting in poor
bioavailability of an orally administered drug are -
degradation of the drug into inactive form, and interaction
with one or more different component(s) either of the
dosage form or those present in the GIT to form a complex
that is poorly soluble or is unabsorbable.
37

Pharmaceutical factors
 Disintegration time
 Dissolution time
 Manufacturing and processing variables
 Method of granulation
 Compression force
 Pharmaceutical ingredient/excipients
38

Disintegration time
 Rapid disintegration is important to have a rapid
absorption so lower disintegration time is required.
 Disintegration time of tablet is directly proportional to
amount of binder and compression force.
 Dissolution is a process in which a solid substance
solubilises in a given solvent i.e, mass transfer from
the solid surface to the liquid phase.
 Dissolution time is also an important factor which
affect the drug absorption .
39
Dissolution time:

Manufacturing variables:
 Several manufacturing processes influence drug
dissolution from solid dosage forms.
For example: For tablet it is
 Method of granulation
 Compression force
Method of granulation:
 Different methods like wet granulation , dry
granulation and direct compression etc. yields
product with different dissolution.
40

 Compression force
The compression force employed in tableting process
influence density, porosity, hardness, disintegration time and
dissolution rate of tablets.
Pharmaceutical ingredients/excipients:
 More the number of Excipients in the dosage form, more
complex it is & greater the potential for absorption and
Bioavailability problems.
A) Vehicle
 Rate of absorption – depends on its miscibility with
biological fluid.
 Miscible vehicles (aqueous or water miscible vehicle) causes
rapid absorption e.g. propylene glycol.
41

Immiscible vehicles – Absorption depends on its
partitioning from oil phase to aqueous body fluid.
B) Diluents
 Hydrophilic diluents – Imparts Absorption
 Hydrophobic diluents – Retards Absorption
 Also, there is a drug-diluent interaction, forming
insoluble complex and retards the absorption. E.g.
Tetracycline-di calcium phosphate
C) Disintegrants
 Mostly hydrophilic in nature.
 Decrease in amount of disintegrants – significantly
lowers B.A.
42

D) Binders & granulating agent -
 Hydrophilic binders – Imparts hydrophilic
properties to the granule surface – gives better
dissolution properties of the poorly wettable drugs.
E.g. Starch, Gelatin,PVP.
 But more amount of binder increases the hardness
of the tablet and retards the absorption rate.
E) Suspending agents/viscosity agent
 Stabilized the solid drug particles and thus affect
drug absorption.
 Macromolecular gum forms un-absorbable complex
with drug eg. Na CMC.
 Viscosity imparters – act as a mechanical barrier to
diffusion of drug from its dosage form and retard GI
transit of drug.
43

F) Surfactants
 May enhance or retards drug absorption by interacting with
drug or membrane or both.
 Physiologic surfactants – bile salts – promotes absorption –
e.g. Griseofulvin, steroids
 It may decrease absorption when it forms the un-absorbable
complex with drug above CMC.
G) Coating
 In general, deleterious effects of various coatings on the drug
dissolution from a tablet dosage form are in the following
order.
 Enteric coat > sugar coat > non-enteric coat.
 The dissolution profile of certain coating materials change on
aging; e.g. shellac coated tablets, on prolonged storage,
dissolve more slowly in the intestine. This can be however,
be prevented by incorporating little PVP in the coating
formulation.
44

H) Lubricants
 Commonly hydrophobic in nature – therefore
inhibits penetration of water into tablet and their
dissolution and disintegration.
I) Colourants
 Even a low concentration of water soluble dye can
have an inhibitory effect on dissolution rate of
several crystalline drugs.
 The dye molecules get absorbed onto the crystal
faces and inhibit the drug dissolution. Eg:Brilliant
blue retards dissolution of sulfathiazole.
45

Nature and type of dosage form
 Apart from the proper selection of the drug, clinical
success often depends to a great extent on the proper
selection of the dosage form of that drug.
 As a general rule, the bio-availability of a drug form
various dosage forms decrease in the following order:
Solutions > Emulsions > Suspensions > Capsules >
Tablets > Coated Tablets > Enteric Coated Tablets >
Sustained Release Products.
46

PRODUCT AGING AND STORAGE
CONDITIONS:
 Product aging and storage conditions can adversely
affect the bio-availability by change in especially
the physico-chemical properties of the dosage
forms.
For example:
 Precipitation of the drug in solution
 Hardening of tablet
 Change in particle size of suspension.
47

Dosage forms
 Order of bioavailability of drugs.
 Solutions>suspensions>capsules>tablets>coated tablets
SOLUTIONS
 Drugs absorbed more rapidly in this form.
 When this formulation is taken after meal gastric emptying
is the rate limiting step.
Factors influencing are
 Nature of the solvent(aqueous, water miscible) viscosity,
surfactant, solubilisers, stabilizers.
 Drugs which are poorly soluble can be converted to water
soluble by the addition of co solvents such as alcohol,
propylene glycol, polyethylene glycol 400 etc…
48

ELIXIRS SYRUPS
1. Elixirs are sweetened
aromatic hydro-alcoholic
preparations.
2. Less effective and less
sweeter than syrup
3. Less viscous due to
containing low
proportion of sugar.
E.g:Chlorpheniramine
elixir
1. Syrups are concentrated
aqueous preparation of
sugar.
2. More effective and more
sweeter than elixir.
3. More viscous than
elixirs.
E.g Paediatric Paracetamol
syrup
49

Suspensions
 Dissolution is the rate limiting step for the
absorption the drug from suspension.
Factors to considered are
 Particle size ,
 Wetting agents,
 Viscosity of the medium,
 Suspending agent
 E.g: Chloramphenicol suspension
50

Capsules
 For hard gelatin capsules the shell should disrupt
quickly and expose the contents to the GI fluids.
 Factors influencing are particle size, density, crystal
form of the drug, selection of diluents.
 soft elastic capsule dissolve faster than hard gelatin
capsule & tablets. Which shows better bioavailability
from oily solutions, emulsions, or suspensions.
51

Tablets
 This is the most widely used dosage form.
 Problem with this arises from reduction in the effective surface
area due to granulation & subsequent compression in to dosage
form.
 Tablet disintegration and granule disintegration are the important
steps in absorption process.
 Compression force also may be an important factor.
 Disintegration is the rate limiting step for this.
E.g: Riboflavin tablet.
52

Coated tablets
 Coat is generally used to mask unpleasant taste &
odor & to protect the ingredients from decomposition
during storage.
 This adds an additional barrier between GIT & drug.
It should get dissolve before tablet disintegration &
dissolution.
Sugar & film coatings
 Sugar coating will take more time than film coating.
 Ex: methyl cellulose which retards the dissolution
 Now a days film and press coated are mostly used.
53

Enteric coated tablets
 It is a special film coated design to restricts the
gastric fluids & to dissolve in small intestine.
 Protect the drug from the degradation in the stomach
Ex: erythromycin.
 Minimize the gastric distress caused by some drugs.
Ex: aspirin.
 These tablets must empty the stomach before the drug
absorption can begin.
 The polymers with pka values ranging from 4-7 have
been found to use.
 E.g: Diclofenac enteric coated tablet.
54

REFERENCES:
 D.M. Brahmankar, S.B. Jaiswal; “Bio pharmaceutics
& Pharmacokinetics”; first edition, 12th reprint;
VallabhPrakashan;
 MiloGibaldi ; “Bio pharmaceutics and clinical
pharmacokinetics “ fourth edition , Pharma Med
Press.
 “Clinical pharmacokinetics ,concepts and
applications “ 3rd edition by Malcom Rowland and
Thom N .Tozer, Lea febiger.
 “Applied Bio pharmaceutics & Pharmacokinetics”
by Shargel ,Land Yu ABC, 2nd edition.
55

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