Absorption Mechanism through GIT and Factors Influencing drug absorption through GIT

1. INTRODUCTION TO
BIOPHARMACEUTICS
(ABSORPTION)
Presented By:
Maneesh Banyal (Asst. Prof.)
Swati Joshi (Asst. Prof.)
( Pharmaceutics)

2. CONTENT:
 Introduction
 Mechanisms of drug absorption
 Factors affecting absorption
 References
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3. Introduction:
Biopharmaceutics:
 Study of factors influencing the rate and amount of drug that reaches the systemic circulation &
the use of this information to optimize the therapeutic efficacy of drug product
 It is combination of two terms
1) Pharmacokinetics(ADME)
2) Pharmacodynamics
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4. Absorption:
Process of movement of unchanged drug from the site of administration to systemic circulation.
The rate and extend of absorption depends on the route of administration , the formulation and
chemical properties of the drug.
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5. Drug absorption mechanisms through GIT:
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6. Passive Diffusion:
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 It is defined as the difference in the drug concentration on either side of the membrane.
 Best expressed by Fick's first law of diffusion.
 Fick’s first law of diffusion: states that the molecule diffuse from the region of higher concentration to one of
lower concentration until equilibrium is attained and that the rate of diffusion is directly proportional to the
concentration gradient across the membrane.
 Can be written as:
Where: dq/dt = rate of drug diffusion
D = diffusion coefficient of drug through membrane
A = surface area of the absorbing membrane for drug diffusion
Km/w = partition coefficient b/w the lipoidal membrane and the aqueous GI fluids
(Cgit-C) = difference in the concentration of drug in the GI fluids and the plasma, called as concentration
gradient
h = thickness of the membrane

7. 
Also called as non-ionic diffusion.
Major process for absorption of more than 90% of the drugs.
Driving force for this process is the concentration or electrochemical gradient.
The drug moves down the concentration gradient indicating downhill transport.
The process is energy independent and non-saturable.
Greater the area and lesser the thickness of the membrane, faster the diffusion.
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8. Pore transport:
 Also called as connective transport, bulk flow or filtration.
 This mechanism is responsible for transport of molecules into the cell through the protein channels present in
the cell membrane.
 The process is important in the absorption of low molecular weight (less than 100), low molecular size (smaller
than the diameter of the pore) and generally water soluble drug through narrow, aqueous filled channels or pores
in the membrane structure. for example urea, water and sugars.
 Drug permeation through water filled channels is of particular important in renal excretion, removal of drug
from the cerebrospinal fluid and entry of drug into the liver.
Ion Pair Transport: Ion pair transport is the mechanism that explains the absorption of drugs like quaternary
ammonium compounds, sulphonic acids, which ionize under all pH conditions.
 These agents penetrate the membrane by forming reversible neutral complex with endogenous ions of GIT.
 These neutral endogenous ions have both lipophilicity and aqueous solubility for passive diffusion.
 Propranolol, a basic drug, that forms an ion pair with oleic acid, is absorbed by this mechanism.
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10. Facilitate Diffusion:
 It is a carrier mediated transport system that operates down the
concentration gradient (downhill transport) but at a much
faster rate than can be accounted by simple passive diffusion.
 It involves a “carrier molecule” in the membrane for the
movement of certain drug molecules across the membrane.
 It involves no energy expended by the cell to move the drug
molecules.
 Vit. B12 is absorbed from the gut by this process.
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11. Active Transport:
Requires energy in the form of ATP.
a) Primary active transport: In this transport, there is direct ATP requirement.
The process transfer only one ion or molecule and in only one direction, and hence called as uniporter e.g. absorption
of glucose.
b) Secondary active transport: there is no direct requirement of ATP.
The energy required in transporting an ion aids transport of another ion or molecule either in the same direction or in
the opposite direction.
Symport: involves movement of both the molecules in the same direction
Ex- peptide transporter called as H-coupled peptide transporter (PEPT1) which is implicated in the intestinal
absorption of peptide like drugs such as beta lactum antibiotics.
Antiport: involves movement of molecules in the opposite direction.
Ex- explusion of H+ ions using the Na+ gradient in the kidneys.
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13. Endocytosis:
 It is a minor transport mechanism which involves engulfing
extracellular materials within a segment of the cell membrane to
to form a saccule or a vesicle which is then pinched-off
intracellulary.
 This is the only transport mechanism whereby a drug or compound
does not have to be in an aqueous solution in order to be absorbed.
Two types:
a) Phagocytosis (cell eating): adsorptive uptake of solid particulates.
b) Pinocytosis (cell drinking): uptake of fluid solute.
Ex. Cellular uptake of macromolecular nutrients like fat and starch,
oil soluble vitamins like A, D, E, K, water soluble vitamins like B12 etc.
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15. A) Drug solubility and dissolution rate:
Dissolution Rate: amount of drug in solution / time(at specific pH, temp and solvent composition)
Two slowest rate-determine processes in the orally administered drugs are:
Rate of dissolution
Rate of drug permeation through biomembrane
Dissolution is the RDS for hydrophobic, poorly aqueous soluble drugs e.g. griseofulvin and spironolactone. these drug
are dissolution rate limited
If drug is hydrophilic with high aqueous solubility e.g. cromalin sodium or neomycine, then dissolution is rapid
and the RDS in the absorption of such drugs is rate of permeation through the biomembrane. In other word,
absorption of such drug is said to be permeation rate limited or transmembrane rate limited.
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THEORIES OF DISSOLUTION:
Dissolution: Dissolution is process in which a solid substance solubilizes in a given solvent i.e. mass transfer
from the solid surface to the liquid phase.
The three basic theories of dissolution involves:
i. Film theory (Diffusion layer model).
ii. Permeation or Surface renewal theory (Danckwart’s model).
iii. Double barrier or Limited solvation theory (interfacial barrier model).
1) Diffusion layer model
 proposed by Nernst
 According to this theory dissolution process completes in two steps -
A)formation of stagnant layer
B) diffusion of drug from this layer
It involves two steps :-
a. Solution of the solid to form stagnant film or diffusive layer at the solid /liquid interface which is saturated with the
drug

17. b. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is r.d.s in drug
dissolution.
The equation to explain the rate of dissolution when the process is diffusion controlled and involve no chemical
reaction was given by Noyes and Whitney:
dc/dt = k(Cs-Cb)
Where , dc/dt= dissolution rate of drug K=dissolution rate constant
Cs=concentration of drug in the stagnant layer Cb=concentration drug in bulk of solution
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18. Modified Noyes-Whitney’s Equation:
Where,
D= diffusion coefficient of drug.
A= surface area of dissolving solid.
Kw/o= water/oil partition coefficient of drug.
V= volume of dissolution medium. h= thickness of stagnant layer.
(Cs – Cb )= conc. gradient for diffusion of drug
2. Danckwert’s Model:
 Danckwert suggested that , the turbulence in dissolution medium exists at the solid-liquid interface.
 As a result ,the agitated fluid consisting of solvent packets reaches the interface in a random fashion due to eddy
current, absorb the solute and carry it to the bulk of the solution.
 Such solute containing packets are continuously replaced with new packets of fresh solvent
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3) Interfacial barrier model :
According to interfacial barrier model ,an intermediate concentration can exist at the interface as a result of solvation
mechanism and is a function of solubility rather than diffusion.
While considering the dissolution of a crystal each face of the crystal will have a different interfacial barrier
G= Ki (Cs-Cb)

20. B) Particle size and effective surface area
•Absolute surface area :
•Effective surface area:
particle size = 1/surface area from the modified Noyes and Whitney equation it is clear that larger the surface area
higher the dissolution rate.
Micronisation Hydrophilic--- Increase in ESA
Hydrophobic--- Decrease in ESA
C. Polymorphism and amorphism:
 Existence of substance in a more than one crystalline form, the different forms are designated as polymorphism
and the phenomenon as polymorphism.
 two types are…..
i. Enantiotropy polymorph: is one which can be reversibly changed in to another form by altering the
temperature or pressure. e.g. sulfur
ii. Monotropic polymorph: is one which is unstable at all temperature and pressures e.g. glyceryl stearate
Stable : lower energy state, higher melting point and least aqueous solubility
Metastable : Higher energy state, low melting point and higher aqueous solubility
Amorphous > Metastable > Stable
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21. D) Pseudopolymorphism:
 Solvate: The stoichimetric type of adducts where solvent molecules are incorporated in crystal lattice of solid are
called as solvates and trapped solvent as solvent of crystallization. The solvates can exist in different crystalline
form called as Pseudo polymorph
 Hydrate:- When solvent in association with the drug is water is known as hydrates
E) Salt form of the drug:
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22. F.Drug pKa and liphophilicity and GI pH:
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24. pH partition Hypothesis:
 Brodie et al. proposed the pH partition Hypothesis .
 The theory states that 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 of the drug.
The lipid solubility of the unionized drug.
The pH at absorption site.
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25. H. Drug Stability :
Poor B.A due to destabilization of drug during its shelf life due to:
• Degradation of the drug in to inactive form
• Interaction with one or more different components
2) Formulation factors:
a) Disintegration time:
 Rapid disintegration is important to have a rapid absorption so lower D.T is required.
 Now D.T of tablet is directly proportional to – amount o f binder - Compression force.
 And one thing should be remembered that in vitro disintegration test gives no means of a guarantee of drugs
bioavailability because if the disintegrated drug particles do not dissolve then absorption is not possible
b) Manufacturing variables: -
i) Method of granulation: Wet granulation yields a tablet that dissolves faster than those made by other granulating
methods.
But wet granulation has several limitations like formation of crystal bridge or chemical degradation.
ii) Compression force:
 Higher compression force yields a tablet with greater hardness and reduced wettability & hence have a long D.T.
but on other hand higher compression force cause crushing of drug particles into smaller ones with higher
effective surface area which in decrease in D.T.
 So effect of compression force should be thoroughly studied on each formulation.
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26. 3. Nature and type of dosage form:
 Aqueous solution, syrups, elixirs and emulsions do not cause
Dissolution problem and show fast and complete absorption as
Compared to solid dosage forms
Solutions > Emulsions > Suspensions > Capsules > Tablets >
Coated Tablets > Enteric coated tablets > Sustained Release Products.
4. Pharmaceutical ingredients / Excipients:
 More the no. of excepients in dosage form, more complex it is & greater the potential for absorption and
Bioavailability problems.
 Changing an excipient from calcium sulfate to lactose and increasing the proportion of magnesium silicate,
increases the activity of oral phenytoin.
Vehicle: Rate of absorption – depends on its miscibility with biological fluid. Miscible vehicles (aq or water miscible
vehicle) –rapid absorption e.g. propylene glycol.
Immiscible vehicles - absorption –depends on its partitioning from oil phase to aqueous body fluid.
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27. b) Diluents: Hydrophilic diluents-form the hydrophilic coat around hydrophobic drug particles –thus promotes
dissolution and absorption of poorly soluble hydrophobic drug.
c) Binders & granulating agent : Hydrophilic binders – imparts hydrophilic properties to granule surface – better
dissolution of poorly wettable drug. e.g. starch, gelatin, PVP. More amount of binder – increases hardness of
tablet – decrease dissolution & disintegration rate.
d) Disintegrants : Mostly hydrophilic in nature.
Decrease in amount of disintegrants – significantly lowers B.A.
e)Lubricants : Commonly hydrophobic in nature – therefore inhibits penetration of water into tablet and thus
dissolution and disintegration.
f) Suspending agents/viscosity agent :
Stabilized the solid drug particles and thus affect drug absorption.
Macromolecular gum forms unabsorbable complex with drug e.g. Na CMC.
Viscosity imparters – act as a mechanical barrier to diffusion of drug from its dosage form and retard GI transit of
drug.
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28. Surfactants :
 May enhance or retards drug absorption by interacting with drug or membrane or both.
 In general, unionic surfactants have little effect on membrane structure but cationic
 Surfactants have been associated with reversible cell loss and loss of goblet cells.
 Physiologic surfactants – bile salts – promotes absorption e.g. Griseofulvin, steroids It may decrease absorption
when it forms the unabsorbable complex with drug above CMC.
Colorants:
 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. e.g: Brilliant blue retards
dissolution of sulfathiazole.
Product age and storage conditions :
 Product aging and improper storage conditions adversely affect B.A.
 e.g: precipitation of drug in solution decrease rate of Change in particle size of suspension drug dissolution &
Hardening of tablet & absorption.
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29. Patient related factors:
a) Gastric emptying: apart from the dissolution of drug and its permeation through the bio membrane, the
passage from stomach to small intestine, called as gastric emptying, can also be a rate limiting step in absorption
because the major site of drug absorption is intestine. It is advisable where:
 Rapid onset of drug is desired eg: sedatives
 Drug not stable in gastric fluids eg: pencillin G
 Dissolution occurring in intestine eg: enteric coated forms
 Delay in gastric emptying is recommended in particular where: Food promotes drug dissolution and absorption
eg: griseofulvin. The drugs dissolve slowly.
 Disintegration and dissolution of dosage form is promoted by gastric fluids.
 Gastric emptying is first order process.
Gastric emptying rate: speed at which stomach contents empties into intestine.
Gastric emptying time: time required for gastric contents to empty into small intestine
Gastric emptying t1/2 : time taken for half of the stomach contents to empty
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30. b) Gastro intestinal pH : The GI ph generally increases as one moves down the stomach to the colon and rectum.GI
ph influence absorption in several ways.
Disintegration: Enteric coated formulations: coat dissolves only in intestine followed by disintegration.
Dissolution: weakly acidic drugs: dissolve rapidly in alkaline ph of intestine Weakly basic drugs: dissolve in acidic ph
of stomach
c) Pre systemic metabolism : For a drug administration orally, the 2 main reasons for its decreased bioavailability
are:
 Decreased absorption and
 First pass metabolism
The loss of drug through biotransformation by such eliminating organs during its passage to systemic circulations
called as first pass or presystemic metabolism. The 4 primary systems which effect presystemic metabolism of a
drug are:
a. Luminal enzymes b. Gut wall enzymes
c. Bacterial enzymes d. Hepatic enzymes
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31. d) Disease states: various disease like malabsorption, thyrotoxicosis, achlohydria, cirrhosis of liver and billiary
abstruction can influence the absorption and bioavailability of drugs.
Achlorhydia: acidic drugs can’t be absorbed
Cirrhosis of liver: drug is more metabolized and produces toxic effects.
e) Splanchnic Blood Flow: the presence of food in the GIT can influence the bioavailability of the drug from an oral
drug product. This is because food increase splanchnic blood flow.
drugs are achieved higher plasma concentration after food like propranalol, chloramphenicol, lithium carbonate etc.
Drug absorption is reduced due to presence of food are: ampicillin, aspirin, L-dopa etc.
f) Intestinal transit : Since small intestine is the major site for absorption of most drugs, long intestinal transit time
is desirable for complete drug absorption.
Intestinal region Transit time
Duodenum 5 min
Jejunum 2 hrs
Ileum 3to 6 hrs
Caecum 0.5 to 1hr
Colon 6 to 12 hrs
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32. Delayed transit time is desirable for:
Drugs that dissolve their dosage form.
Drugs that dissolve only in intestine.
Drugs absorbed from specific sites in the intestine.
Laxatives promote the rate of intestinal transit.
Anticholinergic drugs: retard gastric and intestinal transit promote absorption of poorly soluble drugs eg:
propantheline
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33. References:
 Brahmankar D.M. ,Jaiswal S.B. ,Biopharmaceutics and pharmacokinetics ;A Treatise ,2nd ed. ,Vallabh
Prakashan ,p. 116-136.
 2.Tipnis H.P. ,Bajaj A. ,Principle and application of Biopharmaceutics and pharmacokinetics ,1st ed. ,Carrier
Publication ,p. 73-84.
 3.Shargel L. ,Wa-Pong S. ,Andrew B.C. Yu. ,Applied Biopharmaceutics and pharmacokinetics ,5th ed. ,Mc Graw
Hill company ,p. 267-298.
 4.Tipnis H.P. ,Nagarsenkar M.S. ,Introduction to Biopharmaceutics and pharmacokinetics ,1st ed. ,Nirali
Prakashan ,p. 30-35.
 5.Paradkar A. ,Bakliwal S. ,Biopharmaceutics and pharmacokinetics ,2nd ed. , Nirali prakashan , p. 3.12-3.15.
 6.Madan P.L. ,Biopharmaceutics and pharmacokinetics ,1st ed. ,Jaypee brothers Medical publisher Ltd. ,p. 82-85.
 7.Tripati K.D. ,Essential of Medical pharmacology ,6th ed. , Jaypee brothers Medical publisher Ltd. ,p. 20-23.
 8.Barar F.S.K , ,Essential of Pharmacotherapeutics ,5th ed. ,S.Chand and Company Ltd. ,p. 43-48.
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