Drug absorption from GIT

DRUGABSORPTIONFROM THE
GASTROINTESTINAL TRACT
1

GASTROINTESTINAL TRACT
 The gastrointestinal tract (digestive tract, alimentary canal, digestion tract, GI
tract, GIT) is an organ system within humans and other animals which takes in
food, digests it to extract and absorb energy and nutrients, and expels the
remaining waste as feces.
 The gastrointestinal tract (GIT) consists of a hollow muscular tube starting from
the oral cavity, where food enters the mouth, continuing through the pharynx,
oesophagus, stomach and intestines to the rectum and anus, where food is
expelled.
3

 The gastrointestinal tract is a muscular tube lined by a special layer of cells,
called epithelium. Although each section of the tract has specialised functions,
the entire tract has a similar basic structure with regional variations.
4

Upper gastrointestinal tract
 The upper gastrointestinal tract consists of the esophagus,
stomach, and duodenum.
 Some sources also include the mouth cavity and pharynx.
Lower gastrointestinal tract
 The lower gastrointestinal tract includes most of the small
intestine and all of the large intestine. According to some
sources, it also includes the anus.
7

Small intestine, which has three parts:
 Duodenum: The digestive enzymes break down proteins and
bile emulsifies fats into micelles. Duodenum contains Brunner's
glands which produce bicarbonate and pancreatic juice contains
bicarbonate to neutralize hydrochloric acid of stomach
 Jejunum : It is the midsection of the intestine, connecting
duodenum to ileum. Contain plicae circulares, and villi to increase
surface area.
 Ileum - It has villi, where all soluble molecules are absorbed into
the blood .
Large intestine, which has three parts:
• Cecum
• Colon.
• Rectum and Anus
8

DIGESTION AND ABSORPTION
 The gastrointestinal system is primarily involved in reducing food for
absorption into the body.
 This process occurs in 4 main phases:
i) Fragmentation
ii) Digestion
iii) Absorption
iv) Elimination of waste products
 Initial fragmentation of food occurs along with the secretions of the
salivary glands, in the oral cavity forming a bolus.
 Bolus of food is then carried to the esophagus by the action of the
tongue and pharynx (deglutition).
9

 Esophagus carries food from mouth to stomach, where
fragmentation is completed and digestion initiated.(Eg: protein
to polypeptides followed by small peptides and amino-acids).
 In the stomach food is converted into semi-digested liquid
(chyme) which passes through the pylorus, into the
duodenum.
 Unabsorbed liquid residue enters the cecum through ileo-
cecal valve where water is absorbed and become
progressively more solid as it passes into the anus
10

Introduction of Absorption
 The process of movement of unchanged drug from the site
of administration to systemic circulation.
 There always exist a correlation between the plasma
concentration of a drug & the therapeutic response & thus,
absorption can also be defined as the process of movement
of unchanged drug from the site of administration to the site
of measurement. i.e., plasma.
12

MECHANISM OF DRUG ABSORPTON
There three broad categories are
1.Transcellular / intracellular transport
A.Passive Transport Processes
i. Passive diffusion
ii. Pore transport
iii. Ion- pair transport
iv. Facilitated or mediated diffusion
B.Active transport processes
i. Primary
ii. Secondary
a) Symport (Co-transport)
b) Antiport (Counter transport)
2.Paracellular / Intercellular Transport
A.Permeation through tight junctions of epithelial cells
B.Persorption
3.Vesicular or Corpuscular Transport (Endocytosis)
A.Pinocytosis
B.Phagocytosis
13

1. Transcellular/intracellular transport
 Defined as the passage of drugs across GI epithelium
 Steps involved
o Permeation of GI epithelial barrier
o Movement across intracellular space (cytosol)
o Permeation of lateral or basolateral membrane
A. Passive Transport Processes –Not require energy Further
classified into following types –
i. Passive diffusion.
ii. Pore transport.
iii. Ion-pair transport.
iv. Facilitated- or mediated-diffusion. 14

i. Passive diffusion
 Defined as difference in drug concentration on either side of membrane.
 Also called as non ionic diffusion
 Driving force is the concentration or electrochemical gradient
 Explained by Fick’s first law of diffusion
 Drug molecules diffuse from a region of higher concentration to one of lower concentration
until equilibrium is attained and rate of diffusion is directly proportional to the concentration
gradient across the membrane
𝐝𝐐
𝐝𝐭
=
𝐃𝐀𝐊𝐦/𝐰
𝐡
(CGIT –C)
Where,
dQ/dt - rate of drug diffusion
D - diffusion coefficient of drug
A - surface of absorbing membrane
Km/w- partition coefficient of drug between lipoidal membrane and GI fluids
(CGIT –C) - Difference in concentration of drug in GI fluid and plasma
h - thickness of membrane
15

Characteristics of passive diffusion
 Movement indicate Downhill transport
 Energy independent and non saturable
 Greater the surface area & lesser the thickness of the membrane,
faster the diffusion.
 Equilibrium is attained when the Rate of transfer is proportional to
concentration gradient between GI fluid and blood compartments
 Equilibrium is attained when concentration on either side of
membrane is equal
 Greater the membrane/ water partition coefficient of drug, faster the
absorption.
 Transfer of unionised species is 3-4 times the rate of ionised
 Drug diffuses rapidly when the volume of GI fluid is low
 Drugs having molecular weight between 100-400 Daltons are
absorbed passively. Diffusion decreases with increase in molecular
weight. 18

 The equation of Fick’s first law can be explained in terms of
permeability coefficient and given by
𝑑𝑄/𝑑𝑡 = PCGIT
 Which shows that it is a first order process. i.e; the rate of drug
absorption is rapid than the rate of elimination.
19

ii. Pore transport
 It is Also called as convective transport, bulk flow or filtration.
 Transport of molecules into the cell through the protein channels present in the
cell membrane take place via this mechanism.
Characteristics of pore transport :
 The driving force is the hydrostatic pressure or the osmotic differences
across the membrane due to which bulk flow of water along with small
solid molecules occurs through such aqueous channels.
 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 drugs through narrow, aqueous-filled channels or
pores in the membrane structure—for example, urea, water and sugars.
 Chain-like or linear compounds of molecular weight up to 400 Daltons can
be absorbed by filtration. For example, the straight-chain alkanes.
 Drug permeation through water-filled channels is importance in renal
excretion, removal of drug from the cerebrospinal fluid and entry of drugs
into the liver. 20

iii. Ion-Pair Transport
 Absorption of drugs like quaternary ammonium compounds (Examples
are benzalkonium chloride, benzethonium chloride) and sulphonic acids
(sulfonic acid), which ionise under all pH conditions, is ion-pair transport.
 Drugs which ionise under all pH conditions, despite their low o/w partition
coefficient values, penetrate the membrane by forming reversible neutral
complexes with endogenous ions of the GIT.
 Such neutral complexes have both the required lipophilicity as well as
aqueous solubility for passive diffusion.
 Such a phenomenon is called as ion-pair transport eg: Propranolol, a
basic drug that forms an ion pair with oleic acid, is absorbed by this
mechanism.
23

Ion-pair transport of a cationic drug
24

 Transport of charged molecules due to the formation of a
neutral complex with another charged molecule carrying an
opposite charge.
 Drugs have low o/w partition coefficient values, yet these
penetrate the membrane by forming reversible neutral
complexes with endogenous ions.
 e.g. mucin of GIT.
 Such neutral complexes have both the required lipophilicity
as well as aqueous solubility for passive diffusion.
 E.g. propranol
25

Carrier mediated diffusion
 Some polar drugs cross the membrane more readily than can be
predicted from their concentration gradient and partition
coefficient values. Like monosaccharides, amino acids and
vitamins will be poorly absorbed.
 The mechanism is involved is carrier that binds reversibly or
non-covalently with the solute molecules to be transported.
 This carrier-solute complex traverses across the membrane to
the other side where it dissociates and discharges the solute
molecule.
 The carrier then returns to its original site to complete the cycle
by accepting a fresh molecule of solute.
 Carriers in membranes are proteins (transport proteins) and may
be an enzyme or some other component of the membrane.
 They are—
• facilitated diffusion and
• active transport.
26

 Since the system is structure-specific, drugs having
structure similar to essential nutrients, called as false
nutrients, are absorbed by the same carrier system.
27

iv. Facilitated Diffusion
 It is a carrier-mediated transport system that operates down the
concentration gradient (downhill transport) but at a much a faster rate
than simple passive diffusion.
 The driving force is concentration gradient. E.g: GI absorption of vitamin
B12.
 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.
28

 Limited importance in the absorption of drugs. e.g. Such a
transport system include entry of glucose into RBCs & intestinal
absorption of vitamins B1 & B2.
 A classical example of passive facilitated diffusion is the gastro-
intestinal absorption of vitamin B12.
 An intrinsic factor (IF), a glycoprotein produced by the gastric
parietal cells, forms a complex with vitamin B12 which is then
transported across the intestinal membrane by a carrier system.
30

B.Active transport
 This transport process requires energy from ATP to move drug
molecules from extracellular to intracellular milieu.
 mechanisms are further subdivided into –
i. Primary active transport –the process transfers only
one ion or molecule and in only one direction, and hence called
as uniporter e.g. absorption of glucose.
31

The charge on membrane influences the permeation of
drugs.
32

a) Ion transporters – are responsible for transporting ions in or out
of cells. A classic example of ATP-driven ion pump is proton pump.
Two types of ion transporters which play important role in the
intestinal absorption of drugs have been identified –
 Organic anion transporter – which aids absorption of
drugs such as pravastatin and atorvastatin.
 Organic cation transporter – which aids absorption of
drugs such as diphenhydramine.
b) ABC (ATP-binding cassette) transporters – are responsible for
transporting small foreign molecules (like drugs and toxins)
especially out of cells (and thus called as efflux pumps).
 A classic example of ABC transporter is P-glycoprotein (P-gp).
ABC transporters present in brain capillaries pump a wide range
of drugs out of brain. 33

ii. Secondary active transport – In these processes, there is no direct
requirement of ATP i.e. it takes advantage of previously existing concentration
gradient.
 The energy required in transporting an ion aids transport of another ion or molecule
(co-transport or coupled transport) either in the same direction or in the opposite
direction.
Accordingly this process is further subdivided into –
a) Symport (co-transport) – involves movement of both molecules in the same
direction
e.g. Na+-glucose symporter uses the potential energy of the Na+ concentration
gradient to move glucose against its concentration gradient. A classic example of
symporter is peptide transporter called as H+-coupled peptide transporter (PEPT1)
which is implicated in the intestinal absorption of peptide-like drugs such as -lactam
antibiotics.
b) Antiport (counter-transport) – involves movement of molecules in the opposite
direction
e.g. expulsion of H+ ions using the Na+ gradient in the kidneys. 35

2 . Paracellular/intercellular
transport
 Paracellular/intercellular transport is defined as the transport of
drugs through the junctions between the GI epithelial cells.
 mechanisms involved in drug absorption are –
A. 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.
B. Persorption – is permeation of drug through temporary
openings formed by shedding of two neighbouring epithelial cells
into the lumen.
37

3. Vesicular or Corpuscular Transport
(Endocytosis)
 These are also energy dependent processes
 Transport mechanism which involves engulfing extracellular materials within
a segment of the cell membrane to form a saccule or a vesicle (hence also
called as corpuscular or vesicular transport) which is then pinched-off
intracellularly .
 The only transport mechanism whereby a drug or compound does not have
to be in an aqueous solution in order to be absorbed.
 It is responsible for the cellular uptake of macromolecular nutrients like fats
and starch, oil soluble vitamins like A, D, E and K, water soluble vitamin like
B12 and drugs such as insulin.
 Another significance of such a process is that the drug is absorbed into the
lymphatic circulation thereby bypassing first-pass hepatic metabolism.
 Endocytosis includes two types of processes:
A. Phagocytosis (cell eating): adsorptive uptake of solid particulates, and
B. Pinocytosis (cell drinking): uptake of fluid solute.
38

FACTORS INFLUENCING ABSORPTION OF
DRUGS
41

FACTORS INFLUENCING ABSORPTION OF
DRUGS
A) PHARMACEUTICAL FACTORS:
I. Physicochemical properties of drug substances
1) Drug solubility and dissolution rate
2) Particle size and effective surface area
3) Polymorphism and amorphism
4) Salt form of drug
5) Lipophilicity of drug
6) Pseudopolymorphism
7) pka of drug and pH
8) Drug stability
42

II. Dosage Form Characteristics and Pharmaceutical Ingredient.
1) Disintegration Time.
2) Dissolution Time.
3) Manufacturing variables.
4) Pharmaceutical Ingredient.
5) Nature /type of dosage form.
6) Product age and storage condition.
43

B) PATIENT RELATED FACTORS
1)Age.
2)Gastric emptying time
3)Intestinal transit time
4)Gastrointestinal pH.
5)Disease state
6)Blood flow through the GIT
7)Gastrointestinal content-
a)Other drug
b)Food
c)Fluid
d)Other normal GI content
8)Presystemic metabolism by
a)Luminal enzyme
b)Gut-wall enzyme
c)Bacterial enzyme
d)Hepatic enzyme
44

1.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
A)PHARMACEUTICAL FACTORS:
I. Physicochemical properties of drug substances
45

 If drug is hydrophilic with high aqueous solubility e.g.
cromalin sodium or neomycin, 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.
46

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:
1) Film theory (Diffusion layer model).
2) Permeation or Surface renewal theory (Danckwart’s model).
3)Double barrier or Limited solvation theory (interfacial barrier model).
47

DIFFUSION LAYER MODEL
 Also called ‘film theory’.
 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
a.Solution of the solid to form stagnant film or diffusive layer at the
solid /liquid interface which is saturated with the drug.
b.Diffusion of the soluble solute from the stagnant layer to the bulk of
the solution; this is r.d.s in drug dissolution. 48

 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
50

 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.
51

 This is first order dissolution rate process, for which the driving
force is concentration gradient
 This is true for in-vitro dissolution which is characterized by
non-sink conditions.
 The in-vivo dissolution is rapid as sink conditions are
maintained by absorption of drug in systemic circulation i.e.
Cb=0 and rate of dissolution is maximum.
 Under sink conditions, if the volume and surface area of the
solid are kept constant, then
 This represents that the dissolution rate is constant under sink
conditions and follows zero order kinetics.
52

DISSOLUTION RATE UNDER NON-SINK
AND SINK CONDITIONS.
53

The Hixson-Crowell Cube Root Law
 Major assumptions in Noyes-Whitney relationship is that
the surface area remains constant throughout dissolution
process.
 However, size of drug particles will decrease as drug
dissolves. and thus changes the effective surface area.
Thus, Hixson & Crowell modified the equation to represent
rate of appearance of solute by weight in solution.
where,
M0 = initial mass of powder
M = mass of powder dissolved in time, t
k = cube root dissolution rate constant
54

DANCKWERT’S MODEL:
 Also called “Penetration or Surface Renewal Theory”.
 Danckwert’s takes into account the eddies or packets that are
present in the agitated fluid which reach the solid- liquid interface,
absorb the solute by diffusion and carry it into the bulk of solution.
 These packets get continuously replaced by new ones and expose
to new solid surface each time, thus the theory is called as surface
renewal theory.
 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
55

Where,
m = mass of solid dissolved,
and
γ = rate of surface renewal
(or the interfacial tension)
56

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 .
 Drug dissolution is a function of solubility rather than diffusion.
 Intermediate concentration exist at the interface as a result of
solvation.
 Dissolution rate per unit area, G is given by,
where,
Ki = effective interfacial transport
constant.
57

2.Particle size and effective surface
area
 Particles size plays a major role in drug absorption.
 Dissolution rate of solid particles is proportional to surface area.
 Smaller particle size , greater surface area then higher will be
dissolution rate , because dissolution is thought to take place at
the surface area of the solute(drug).
 Particle size reduction has been used to increase the absorption
of a large number of poorly soluble drugs..
E.g. Bishydroxycoumarin,digoxin .
58

Two types of surface area
 Absolute surface area
 Effective surface area
 To increase the effective surface area, we have o reduce the
size of particle up to 0.1 micron. So these can be achieved by
“Micronisation process”.
 But in these case one most important thing to be keep in mind
that which type of drug is micronised it is :
 Hydrophilic--- Increase in ESA
 Hydrophobic--- Decrease in ESA
59

a)HYDROPHILIC DRUGS :
 In hydrophilic drugs the small particles have higher energy
than the bulk of the solid resulting in an increased
interaction with the solvent.
 E.g. 1.Griesiofulvin – dose reduced to half due to
micronisation.
 2.Digoxin – the bioavailability was found to be 100% in
micronized tablets.
 After micronisation it was found that the absorption
efficiency was highly increased.
b)HYDROPHOBIC DRUGS:
 In this micronisation techniques result in decreased
effective surface area & thus fall in dissolution rate.
60

Reason for these :
 1.The hydrophobic surface of the drugs adsorbed air on to
their surface which inhibits their wettability.
 2.The particles reaggregates to form large particles due to
their surface free energy , which either float on the surface
on the bottom of the dissolution medium.
 Such hydrophobic drugs can be converted to their effective
surface area
a) use of surfactant as a wetting agent .
b)add hydrophilic diluent like PEG , PVP, dextrose etc.
61

3.Polymorphism and amorphism:
 Depending upon the internal structure , a solid can exist either
in a crystalline or amorphous form. When a substance exist in
more than one crystalline form, the different forms are
designated as polymorphs ,and the phenomenon as
polymorphism.
 Polymorphs are of two types
 Enantiotropic polymorph: is one which can be reversibly
changed in to another form by altering the temperature or
pressure.
e.g. sulfur
 Monotropic polymorph: is one which is unstable at all
temperature and pressures
e.g. glyceryl stearate
62

 Stable : lower energy state, higher melting point and least
aqueous solubility
 Metastable : Higher energy state, low melting point and higher
aqueous solubility.
AMORPHISM :some drugs can exist in amorphous form (i.e.having
no internal crystal structure). Such drugs represent the highest
energy states.
 They have greater aqueous solubility than the crystalline form
because a energy required to transfer a molecule from the crystal
lattice is greater than that required for non-crystalline.
Amorphous > Metastable > Stable
63

4. Pseudopolymorphism:
 When the solvent molecules are entrapped in the crystalline structure of
the polymorph, it is known as pseudo-polymorphism.
SOLVATES: the stoichiometric type of adducts where the solvent
molecules are incorporated in the crystal lattice of the solid are called as
the solvates , and the trapped solvent as solvent of crystallization .
HYDRATES: when the solvent in association with the drugs is water , the
solvates in known as a hydrates.
 Hydrate are pseudo-polymorphs where hydrates are less soluble and
solvent are more soluble and thus affect the absorption accordingly.
 For example: n-pentanol solvates of fludrocortisone and succinyl-
sulfathiazole have greater aqueous solubility than the non-solvates.
64

5. Salt form of the drug
 While considering the salt form of drug, pH of the diffusion layer is
important not the pH of the bulk of the solution.
 Example of salt of weak acid. - It increases the pH of the diffusion
layer, which promotes the solubility and dissolution of a weak acid
and absorption is bound to be rapid.
 Other approach to enhance the dissolution and absorption rate of
certain drugs is the formation of in – situ salt formation
 i.e. increasing in pH of microenvironment of drug by incorporation of
a buffering agent. E.g. aspirin, penicillin
 But sometimes more soluble salt form of drug may result in poor
absorption. e.g. sodium salt of phenobarbitone viz., its tablet swells
and did not get disintegrate, thus dissolved slowly and results in poor
absorption.
65

 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 )
66

6 & 7 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.
68

a) Drug pKa and GI pH:
 Amount of drug that exists in un-ionized form and in ionized
form is a function of pKa of drug and pH of the fluid at the
absorption site, and it can be determined by Handerson-
Hasselbach equation:
70

 If there is a membrane barrier that separates the aqueous
solutions of different pH such as the GIT and the plasma,
then the theoretical ratio R of drug concentration on either
side of the membrane can be given by the following
equations:
71

Presence of virtual membrane pH
72

b) Lipophilicity and drug absorption:
 The lipid solubility of the drug is determined form its
oil/water partition co-efficient (Ko/w) value, whereby the
increase in this value indicates the increase in percentage
drug absorbed.
73

8. Drug Stability :
 A drug for oral use may destabilize 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.
74

II. Dosage form characteristics &
pharmaceutical ingredients
1) 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 & Compression force.
 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.
 E.g. COATED TABLETS: they have long disintegration time.
 Fast dispersible tablets have short disintegration time
75

2) Dissolution time:
 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.
3) Manufacturing variables:
 Several manufacturing processes influence drug dissolution from
solid dosage forms.
 For example: For tablet it is
• Method of granulation
• Compression force 76

a) Method of granulation:
 The wet granulation process is the most conventional technique
 The tablets that dissolve faster than those made by other
granulation methods.
 But wet granulation has several limitations like formation of crystal
bridge or chemical degradation.
 The method of direct compression force has been utilized to yield
the tablets that dissolve at a faster rate.
77

b) Compression force:
 The compression force employed in tableting process
influence density, porosity, hardness, disintegration time
and dissolution rate of tablets.
 Higher compression force increases the density and
hardness of the tablet, decreases porosity and hence
penetrability of the solvent into the tablet and thus in
slowing of dissolution and absorption
78

 On the other hand, higher compression force causes
deformation, crushing or fracture of drug particles into
smaller ones and causes a large increase in effective
surface area. This results in an increase in dissolution rate
of tablets (Fig B)
 A combination of both the curves A and B is also possible
as shown in curves C & D.
Influence of compression force on the
dissolution rate of tablets
79

4) Pharmaceutical ingredients
(excipients/adjuvants):
 More the number of Excipients in the dosage form, more
complex it is & greater the potential for absorption and
Bioavailability problems.
 Commonly used excipients in various dosage forms are,
a) Vehicle:
 Rate of absorption – depends on its miscibility with biological
fluid
 Miscible vehicles causes rapid absorption e.g. propylene glycol.
 Immiscible vehicles – Absorption depends on its partitioning
from oil phase to aqueous body fluid.
80

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-DCP
c) Binders & granulating agent:
 Hydrophilic binders – Imparts hydrophilic properties to the granule
surface – gives better dissolution properties. E.g. Starch, Gelatin.
PVP.
 More amount of binder increases the hardness of the tablet and
retards the absorption rate.
d) Disintegrants:
 Mostly hydrophilic in nature.
 Decrease in amount of disintegrants – significantly lowers
bioavailability.
81

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 un-absorbable 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.
g) Surfactants:
 May enhance or retards drug absorption by interacting with drug
or membrane or both.
 e.g. Griseofulvin, steroids
 It may decrease absorption when it forms the un-absorbable
complex with drug above CMC.
82

h) 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.
i) Buffers:
 Buffers are sometimes useful in creating the right atmosphere for
drug dissolution as was observed for buffered aspirin tablets.
 However, certain buffer systems containing potassium cations inhibit
the drug absorption as seen with Vitamin B2 and sulfanilamide.83

j) Colorants:
 Even a low concentration of water soluble dye can have an inhibitory
effect on dissolution rate.
 The dye molecules get absorbed onto the crystal faces and inhibit the
drug dissolution.
 For example: Brilliant blue retards dissolution of sulfathiazole.
k) Complexing agents:
 Complex formation has been used to alter the physicochemical &
biopharmaceutical properties of a drug.
Example
 1)Enhanced dissolution through formation of a soluble complex.
 E.g. ergotamine tartarate-caffeine complex & hydroquinone-digoxin
complex.
 2)Enhanced lipophilicity for better membrane permeability.
 E.g. caffeine-PABA complex.
84

5) Nature & 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.
85

6) Product age & storage condition:
 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:
 1.Precipitation of the drug in solution
 2.Hardening of tablet
 3.Change in particle size of suspension.
87

B) Patient- related factors
1) Age:
 In infants, the gastric pH is high and intestinal surface and blood flow
to the GIT is low resulting in altered absorption pattern in compare to
adults.
 In elderly persons, gastric emptying altered, decreased intestinal
surface area and GI blood flow, higher incidents of achlorhydria so
impaired drug absorption.
2) Gastric emptying time:
 The process by which food leaves the stomach and enters the
duodenum.
 Rapid gastric emptying is required when the drug is best absorbed
from distal part of the small intestine.
88

 Delayed gastric emptying is required when drugs are absorbed
from proximal part of the small intestine and prolonged drug
absorption site contact is desired.
 Gastric emptying is a first order process.
Gastric emptying rate: This is the speed at which the stomach
contents empty into the intestine.
Gastric emptying time: Which is the time required for the gastric
contents to the SMALL INTESTINE.
Gastric emptying half-life: which is the time taken for half the
stomach contents to empty.
89

3) Intestinal transit time:
 Intestinal transit time is the major site of absorption of most of
drugs.
 The mixing movement of the intestine that occurs due to peristaltic
contractions promotes drug absorption, firstly, by increasing the
drug intestinal membrane contact and secondly by enhancing drug
dissolution of especially of poorly soluble drugs, through induced
agitation.
 Delayed intestinal transit is desirable for
A) Drugs that dissolve or release slowly from their dosage form
(sustained release products)
B) Drugs that dissolve only in intestine (enteric coated formulations)
C) Drugs absorbed from specific sites in the intestine (several B
vitamins)
91

 Intestinal transit time is influenced by various factors such
as food, diseases and drugs
 E.g. metoclopramide which promotes intestinal transit,
enhance absorption of rapidly soluble drugs while
anticholinergic retards intestinal transit and promotes the
absorption of poorly soluble drugs.
92

5) Disease states:
Gastric diseases (Achlorhydric patients):
 They may not have adequate production of acids in the stomach;
stomach HCl is essential for solubilizing insoluble free bases.
 Many weak-base drugs that cannot form soluble salts & remain
undissolved therefore unabsorbed. Salt forms of these drugs
cannot be prepared because the free base readily precipitates
out.
 E.g. Dapsone, itraconazole, and ketoconazole .
Cardio-vascular diseases:
 Several changes associated with congestive cardiac failure
influence bio-availability of a drug viz., edema of the intestine,
decreased blood flow to the GIT and gastric emptying rate and
altered GI pH, secretions and microbial flora.
94

6) Blood flow through the GIT:
 It plays a major role in absorption by continuously maintain the
concentrtion gradient across the epithelial membrane.
 The GIT is extensively supplied by blood capillary network.
 Blood flow is imp for actively absorption of drugs.
 Absorption of polar molecules doesn’t depends on the blood flow but
lipid soluble molecules highly depends on the blood flow.
 Food influences blood flow to the GIT. Perfusion increases after
meals & persist for few hours but absorption is not affected.
95

7) Gastrointestinal contents:
a) Food- drug interactions: The presence of food in the GI
tract can affect the bioavailability of the drug .
 Digested foods contain amino acids, fatty acids, and many
nutrients that may affect intestinal pH and solubility of
drugs.
 Some effects of food on the bioavailability of a drug from a
drug product include:
• Delay in gastric emptying
• Stimulation of bile flow
• A change in the pH of the GI tract
• An increase in splanchnic blood flow
96

 Presence of food will affect absorption in following way
 Decreased absorption: ex. Penicillin, erythromycin, ethanol,
tetracycline, levodopa etc.
 Increased absorption: ex grieseofulvin, diazepam, vitamins etc.
b) Fluid volume:
 Large fluid volume results in better dissolution, rapid gastric emptying
and enhanced absorption-
 Ex. Erythromycin is better absorbed when taken with a glass of water
under fasting condition than when taken with meals.
c) Interaction of drug with normal GI constituents:
 The GIT contains a number of normal constituents such as mucin
which is a protective mucopolysaccharides that lines the GI mucosa,
interact with streptomycin.
97

8) Presystemic metabolism:
 The loss of drugs through bio-transformation by such eliminating
organs during the passage to systemic circulation is called as
firstpass or pre-systemic metabolism.
 complete absence of the drug in plasma after oral administration is
indicative of the first-pass effects. The four primary systems which
affect the pre-systemic metabolism of a drug
a) Lumenal Enzymes
b) Gut wall enzymes/mucosal enzymes
c) Bacterial enzymes
d) Hepatic enzymes
98

a) Lumenal Enzymes:
 The primary enzyme found in gastric juice is pepsin. Lipases,
amylases and proteases are secreted from the pancreas into the
small intestine in response to ingestion of food.
 Pepsins and the proteases are responsible for the degradation of
protein and peptide drugs in the lumen.
b) Gut wall enzymes:
 These also called mucosal enzymes, they are present in stomach,
intestine and colon. Alcohol dehydrogenase (ADH) is an enzyme of
stomach mucosa that inactivates ethanol.
 E.g. sulfation of ethinyl estrdiol & isoprenaline.
99

c) Bacterial enzymes:
 Which are mainly localized within the colonic region of the
gastrointestinal tract, also secrete enzymes which are
capable of a range of reactions.
 E.g. Sulphasalazine, is a prodrug of 5- aminosalicylic acid
linked via an azo bond to sulphapyridine.
100

d) Hepatic enzymes:
 Several drugs undergo first –pass hepatic metabolism, the
highly extracted ones being Isoprenaline, propanolol,
diltiazem, etc.
101

DRUG DISSOLUTION
 Dissolution is a process in which a solid substance
solubilizes in a given solvent to yield a solution i.e. mass
transfer from the solid surface to the liquid phase.
 It depends on the affinity between the solid substance and
solvent. 103

 Rate of dissolution is the amount of drug substance that goes into
solution per unit time under standardized conditions of liquid/solid
interface, temperature and solvent composition. The rate of
dissolution is given by Noyes and Whitney
Where,
 dc/dt= dissolution rate of the drug
 K= dissolution rate constant
 Cs= concentration of drug in stagnant layer
 Cb= concentration of drug in the bulk of the solution at time t105

Mechanism of dissolution
 Initial mechanical lag.
 Wetting of dosage form.
 Penetration of dissolution medium.
 Disintegration.
 De-aggregation.
 Dissolution.
 Occlusion of some particles.
106

Application of dissolution
studies
 For optimization of formulation and quality control.
 To identify the manufacturing variable, like the binding agent
effect, mixing effects, granulation procedure, coating parameters
and comparative profile studies.
 To show that the release of drug from the tablet is close to 100%.
 To show that the rate of drug release is uniform batch to batch.
 And to show that release is equivalent to those batches proven
to be bioavailable and clinically effective.
107

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:
1) Film theory (Diffusion layer model).
2) Permeation or Surface renewal theory (Danckwart’s model).
3)Double barrier or Limited solvation theory (intefacial barrier
model).
108

DIFFUSION LAYER MODEL
 Also called ‘film theory’.
 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
a.Solution of the solid to form stagnant film or diffusive layer at the
solid /liquid interface which is saturated with the drug.
b.Diffusion of the soluble solute from the stagnant layer to the bulk of
the solution; this is r.d.s in drug dissolution. 109

 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
111

 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.
112

 This is first order dissolution rate process, for which the driving
force is concentration gradient
 This is true for in-vitro dissolution which is characterized by
non-sink conditions.
 The in-vivo dissolution is rapid as sink conditions are
maintained by absorption of drug in systemic circulation i.e.
Cb=0 and rate of dissolution is maximum.
 Under sink conditions, if the volume and surface area of the
solid are kept constant, then
 This represents that the dissolution rate is constant under sink
conditions and follows zero order kinetics.
113

DISSOLUTION RATE UNDER NON-SINK
AND SINK CONDITIONS.
114

The Hixson-Crowell Cube Root Law
 Major assumptions in Noyes-Whitney relationship is that
the surface area remains constant throughout dissolution
process.
 However, size of drug particles will decrease as drug
dissolves. and thus changes the effective surface area.
Thus, Hixson & Crowell modified the equation to represent
rate of appearance of solute by weight in solution.
where,
M0 = initial mass of powder
M = mass of powder dissolved in time, t
k = cube root dissolution rate constant
115

DANCKWERT’S MODEL:
 Also called “Penetration or Surface Renewal Theory”.
 Danckwert’s takes into account the eddies or packets that are
present in the agitated fluid which reach the solid- liquid interface,
absorb the solute by diffusion and carry it into the bulk of solution.
 These packets get continuously replaced by new ones and expose
to new solid surface each time, thus the theory is called as surface
renewal theory.
 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
116

Where,
m = mass of solid dissolved,
and
γ = rate of surface renewal
(or the interfacial tension)
117

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 .
 Drug dissolution is a function of solubility rather than diffusion.
 Intermediate concentration exist at the interface as a result of
solvation.
 Dissolution rate per unit area, G is given by,
where,
Ki = effective interfacial transport
constant.
118

Factors affecting dissolution
rate
119

Factors affecting dissolution
rate
1. Factors related to Physicochemical Properties of Drug
2. Factors related to Drug Product Formulation
3. Processing Factor
4. Factors Relating Dissolution Apparatus
5. Factors Relating Dissolution Test Parameters
120

1) Factor related to physicochemical
properties of drug
a. Particle size of drug
 There is a direct relationship between surface area of drug and its
dissolution rate. Since, surface area increases with decrease in particle
size, higher dissolution rates may be achieved through reduction of
particle size.
 E.g. Micronisation of non-hydrophobic drug like griseofulvin leads to
increase in dissolution rate.
 Micronisation of hydrophobic powders can lead to aggregation and
floatation, when powder is dispersed into dissolution medium.
 E.g. hydrophobic drugs like aspirin, phenacetin and phenobarbital
shows decrease in dissolution rate, as they tend to adsorb air at the
surface and inhibit their wettability.
121

b) DRUG SOLUBILITY
 Solubility of drug plays a prime role in controlling its dissolution
from dosage form. Aqueous solubility of drug is a major factor that
determines its dissolution rate.
 Minimum aqueous solubility of 1% is required to avoid potential
solubility limited absorption problems.
 Studies on several compound of different chemical classes and a
wide range of solubility revealed that initial dissolution rate of these
substances is directly proportional to their respective solubility.
 -E.g. Poorly soluble drug :griseofulvin, spironolactone
 Hydrophilic drug :neomycin
122

c) Solid state characteristics
 Solid phase characteristics of drug, such as amorphicity,
crystallinity, state of hydration and polymorphic structures have
significant influence on dissolution rate.
 Anhydrous forms dissolve faster than hydrated form because they
are thermodynamically more active than hydrates. E.g. Ampicillin
anhydrate faster dissolution rate than trihydrate.
 Amorphous forms of drug tend to dissolve faster than crystalline
materials. E.g. Novobiocin suspension, Griseofulvin.
 Metastable(high activation energy)
 polymorphic form have better
dissolution than stable form. 123

 Where in the dissolution rate of amorphous erythromycin
estolate is markedly lower than the crystalline form of
erythromycin estolate.
 Metastable(high activation energy) polymorphic form have
better dissolution than stable form. Eg. Methyl prednisone. 124

d) Salt formation
 It is one of the common approaches used to increase drug
solubility and dissolution rate.
 It has always been assumed that sodium salts dissolve
faster than their corresponding insoluble acids.
E.g. sodium and potassium salts of Penicillin G, phenytoin,
barbiturates etc.
 While in case of Phenobarbital dissolution of sodium salt
was slower than that of weak acid. Due to decreased
disintegration of sodium salt.
 hydrochlorides and sulphates of weak bases are commonly
used due to high solubility.
E.g. epinephrine, tetracycline.
125

2) Factors related to drug
product formulation
a) Binders and granulating agents:
 The hydrophilic binders like gelatin increase dissolution rate of
poorly wettable drug.
 Non aqueous binders such as ethyl cellulose retard the drug
dissolution.
 Phenobarbital tablet granulated with gelatin solution provide a
faster dissolution rate in human gastric juice than those
prepared using Na – carboxymethyl cellulose or polyethylene
glycol 6000 as binder.
126

 Large amount of binder increase hardness & decrease
disintegration /dissolution rate of tablet.
 In Phenobarbital tablet, faster dissolution rate was observed with
10% gelatin whereas decrease in dissolution rate with 20%
gelatin.
 This was due to higher concentration which formed a thick film
around the tablet.
128

b) Disintegrants
 Disintegrating agent added before & after the granulation affects the
dissolution rate.
 E.g. Phenobarbital tablet showed that when copagel (low viscosity
grade of Na CMC) added before granulation decreased dissolution
rate but if added after did not had any effect on dissolution rate.
 Microcrystalline cellulose is a very good disintegrating agent but at
high compression force, it may retard drug dissolution.
 Starch is not only an excellent diluent but also superior disintegrant
due to its hydrophilicity and swelling property. 129

Effect of starch content on dissolution rate of salicylic
acid tablet, ○ 5 %, ● 10 % and × 20 % starch in granules. 130

c) Effect of lubricants / anti-frictional
agents
 The nature, quantity, and quality of lubricants added can affect the
dissolution rate.
 Lubricants are hydrophobic in nature (several metallic stearate &
waxes) which inhibit wettability, penetration of water into tablet so
decrease in disintegration and dissolution.
 The use of soluble lubricants like SLS and Carbowaxes promote
drug dissolution.
 E.g. Magnesium stearate, a hydrophobic lubricant, tend to retard
the dissolution rate of salicylic acid tablet, whereas sodium lauryl
sulfate enhances its dissolution, due to its hydrophobic but surface
activity, which increases wetting and better solvent penetration into
tablet.
131

d) SURFACTANTS
 They enhance the dissolution rate of poorly soluble drug. This is
due to lowering of interfacial tension, increasing effective surface
area, which in turn results in faster dissolution rate.
 E.g Non-ionic surfactant Polysorbate 80 increase dissolution rate
of phenacetin granules.
 The increase was more pronounced when the surfactant was
sprayed on granules than when it was dissolved in granulating
agent.
133

e) COATING POLYMERS
 Tablets with MC coating were found to exhibit lower
dissolution profiles than those coated with HPMC at 37ºC.
The differences are attributed to thermal gelation of MC at
temp near 37º, which creates a barrier to dissolution
process & essentially changes the dissolution medium.
 This mechanism is substantiated by the fact that at temp
below the gel point & at increased agitation, the effect
disappears.
 In general, the deleterious effect of various coatings on
drug dissolution from a tablet dosage form is in the
following order:
Enteric coat > Sugar coat > Non- enteric film coat.
134

f) COMPLEXING AGENTS
 A complexed drug may have altered stability, solubility,
molecular size, partition coefficient and diffusion coefficient.
 E.g. Enhanced dissolution through formation of a soluble
complex of ergotamine tartarate-caffeine complex and
hydroquinone-digoxin complex.
g) BUFFERS
 Buffers are sometimes useful in creating the right
atmosphere for drug dissolution, e.g. buffered aspirin
tablets. 135

3) PROCESSING FACTORS
a) METHOD OF GRANULATION
 Wet granulation has been shown to improve the dissolution
rate of poorly soluble drugs by imparting hydrophilic
properties to the surface of granules.
 A newer technology called as APOC “Agglomerative Phase
of Comminution” was found to produce mechanically
stronger tablets with higher dissolution rates than those
made by wet granulation. A possible mechanism is
increased internal surface area of granules produced by
APOC method.
136

b) COMPRESSION FORCE
 The compression process influence density, porosity,
hardness, disintegration time & dissolution of tablet.
 The curve obtained by plotting compression force versus
rate of dissolution can take one of the 4 possible shapes
1. tighter bonding increases hardness
2 . higher compression force cause
deformation crushing or fracture of
drug particle or convert a
spherical granules into disc Shaped
particle
3.& 4. both condition
137

c) DRUG EXCIPIENT INTERACTION
 These interactions occur during any unit operation such as
mixing, milling, blending, drying, and/or granulating result
change in dissolution.
 Increase in mixing time of formulation containing 97 to 99%
microcrystalline cellulose (slightly swelling disintegrant)
result in enhance dissolution rate of prednisolone.
 Polysorbate-80 used as excipient in capsules causes
formation of formaldehyde by autoxidation which causes
film formation by denaturing the inner surface of capsule.
This causes decrease in dissolution rate of capsules.
138

d) STORAGE CONDITIONS
 Dissolution rate of Hydrochlorthiazide tablets granulated
with acacia exhibited decrease I dissolution rate during 1 yr
of aging at R.T. A similar decrease was observed in tablets
stored for 14 days at 50-80ºC or for 4 weeks at 37ºC.
 Tablets with starch gave no change in dissolution rate either
at R.T. or at elevated temperature.
139

4) FACTORS RELATED TO DISSOLUTION
APPARATUS
a) AGITATION
 Rate of dissolution depends on type of agitation used, the
degree of laminar and turbulent flow in system, the shape
and design of stirrer.
 Speed of agitation should be such that it prevent turbulence
and sustain a reproducible laminar flow, which is essential
for obtaining reliable results. So, agitation should be
maintained at a relatively low rate.
 Thus, in general relatively low agitation should be applied.
I. BASKET METHOD- 100 rpm
II. PADDLE METHOD- 50-75 rpm 140

b) SAMPLING PROBE POSITION & FILTER
 Sampling probe can affect the hydrodynamic of the system.
(concentration varies at different places of the system ).
 USP states that sample should be removed at approximately half the
distance from the upper surface of basket or paddle and surface of
dissolution medium and not closer than 1 cm to the side of the flask.
c) STIRRING ELEMENT ALIGNMENT
 The USP / NF states that the axis of the stirring element
must not deviate more than 0.2 mm from the axis of the
dissolution vessel.
 Studies indicate that significant increase in dissolution
rate up to 13% occurs if shaft is offset 2-6 mm from the
center axis of the flask.
 Tilt in excess of 1.5◦ may increase dissolution rate from 2 141

5) FACTORS RELATED TO DISSOLUTION
TEST PARAMETERS
a) TEMPERATURE:
 Drug solubility is temperature dependent, therefore
careful temperature control during dissolution process is
extremely important.
 Generally, a temperature of 37º ± 0.5 is maintained
during dissolution determination of oral dosage forms and
suppositories. However, for topical preparations
temperature as low as 30º and 25º have been used. 142

b) VIBRATION
 The excessive vibration of dissolution apparatus increases
dissolution rates.
c) VESSEL DESIGN AND CONSTRUCTION
 Plastic vessels provide more perfect hemisphere than glass
vessels.
d) pH OF DISSOLUTION MEDIUM
 Weak acids, dissolution rate increases with increase in pH
where as for weak bases, increase with decrease in pH.
143

DISSOLUTION APPARATUS
 Based on the absence or presence of sink conditions, there are two
principal types of apparatus:
1 . Closed- compartment apparatus:
 It is basically a limited volume apparatus operating under non sink
conditions. e.g. beaker type apparatuses such as the rotating basket
and the rotating paddle apparatus.
2 . Open- compartment ( continuous flow- through ) apparatus:
 It is the one in which the dosage form is contained in a column which is
brought in continuous contact with fresh, flowing dissolution medium (
perfect sink condition ).
3 . A third type called as dialysis systems are used for very poorly
 aqueous soluble drugs for which maintenance of sink conditions would
otherwise require large volume of dissolution fluid.
145

USP COMPENDIAL APPARATUS
1. Basket type (USP apparatus 1)
2. Paddle type (USP apparatus 2)
3. Reciprocating cylinder type (USP apparatus 3)
4. Flow - through cell type (USP apparatus 4)
5. Paddle over disc type (USP apparatus 5)
6. Cylinder type (USP apparatus 6)
7. Reciprocating holder type (USP apparatus 7)
146

BASKET TYPE (USP APPARATUS 1)
Design:
Vessel:- Made up of transparent, inert material (borosilicate
glass)
Semi hemispherical bottom
Capacity: 1000ml
Shaft:- Stainless steel 316
Rotates smoothly without significance wobble
Basket:- Stainless steel 316
Gold coatings up to 0.0001 inch (2.5 μm)
Water bath:- Maintained at 37± 0.5˚c 147

 Dosage form contained within basket
 Dissolution should occur within Basket
 pH change by media exchange
Uses:- Capsules, tablets, delayed release dosage form,
suppositories, floating dosage forms.
Agitation:- Rotating stirrer
Usual speed: 50 to 100 rpm
Disadvantage:- Formulation may clog to 40 mesh screen
148

PADDLE TYPE (USP APPARATUS 2)
Design:
Vessel:- Made up of transparent, inert material (borosilicate
glass)
Semi hemispherical bottom
Capacity: 1000ml
Shaft:- The blade passes through shaft so that bottom of
blade fuses with bottom of shaft.
Stirring elements:- Made of Teflon for laboratory purpose
Stainless steel 316
Water bath:- Maintain at 37± 0.5˚c.
Sinkers:- Small loose wire helix used to prevent
capsule/tablet from floating. Dissolution 37 149

 Dosage form should remain at the bottom center of the
vessel.
 pH change by media change.
 Useful for:- Tablets
Capsules
 Agitation:- Rotating stirrer
Usual speed: 25 to 100 rpm
 Advantages:- Easy to use and robust
pH change possible
Can be easily adapted to apparatus 5
 Disadvantages:- Floating dosage forms require sinker
Positioning of tablet. 150

RECIPROCATING CYLINDER TYPE
(USP APPARATUS 3)
Design:
Vessel:- Cylindrical flat bottom glass vessel.
Agitation:- Reciprocating
Generally 6-35 cycles/min
Volume of dissolution fluids:- 200-250 ml
Water bath:- Maintain at 37 ± 0.5˚C
Use:- Extended release
152

 The apparatus consist of a set of cylindrical flat– bottomed
glass vessel equipped with reciprocating cylinders.
 The vessels are partially immersed in a suitable water bath
of any convenient size that permits holding the temperature
at 37 º C ± 0.5 º C during the test.
 The dosage unit is placed in reciprocating cylinder & the
cylinder is allowed to move in upward and downward
direction constantly.
 Total distance it travels during stroke is 9.9- 10.1 cm.
Useful for:- Tablets, Beads, controlled release Formulations.
Advantages:- Easy to change the pH-profiles Hydrodynamics
can be directly influenced by varying the dip rate.
Disadvantages:- Small volume (max. 250 ml)
153

FLOW-THROUGH CELL TYPE (USP
APPARATUS 4)
 The apparatus consist of a reservoir for the dissolution medium and a
pump that forces medium through the cell holding the test sample.
 Dissolution fluid is collected in separate reservoir.
 Temperature is maintained at 37 º C ± 0.5 º C.
Useful for:- Low solubility drugs, powders and granules, micro particles,
implants.
Advantages:- Easy to maintain sink condition.
Easy to change media pH
Disadvantages:-De-aeration necessary
High volumes of media
Labor intensive 154

PADDLE OVER DISC TYPE (USP
APPARATUS 5)
 This uses the paddle apparatus 2 with a stainless steel disk
designed for holding transdermal system at the bottom of
the vessel.
 The disk holds the system flat and is positioned such that
the release surface is parallel with the bottom of the paddle
blade.
 Media volume used is 900 ml which is maintained at 37 º C
± 0.5 º C.
 Useful for transdermal patches.
Disadvantages:- Disk assembly restrict
the size of patch.
Transdermal patch retainer ( Hanson style)
155

CYLINDER TYPE (USP APPARATUS 6)
 This is a modification of Basket apparatus 1, in which the
basket is replaced with a stainless steel cylinder as a
stirring element.
 Sample is mounted to cuprophan (inner porous cellulosic
material) and entire system is adhere to cylinder.
 The dosage unit is placed on the cylinder with release side
out.
 Useful for testing of transdermal patches.
Cylinder stirring element
156

RECIPROCATING HOLDER TYPE (USP
APPARATUS 7)
 The assembly consist of a set of calibrated solution
containers, a motor and drive assembly to reciprocate the
system vertically.
 The sample holder may take the form of disc, cylinder or a
spring or acrylic rod, or it may simply be the rod alone.
 Capacity is 50– 200 ml.
 Reciprocating frequency is 30 cycles/ min.
 Useful for transdermal patches and solid dosage forms.
157

IVIVC (In vitro- in vivo correlation)
159

IVIVC (In vitro- in vivo correlation)
IVIVC is an approach to describe the relationship
between an in-vitro property of dosage form ( rate and
extent of drug release) and a relevant in- vivo response
( plasma drug conc. or amount of drug absorbed )
160

IVIVC - DEFINITION
FDA :
 A predictive mathematical model describing the relationship between
an in vitro property of dosage form (usually the rate or extent of drug
dissolution or release) and a relevant in vivo response, e.g., plasma
drug concentration or amount of drug .
USP :
 The establishment of a relationship between a biological property or a
parameter derived from a biological property (Cmax, AUC) produced
by a dosage form, and a physicochemical characteristic (in vitro
release) of the same dosage form.
161

PURPOSE OF IVIVC
 Serves as a surrogate for in- vivo bioavailability and to
support biowaiver.
 Used in optimization of formulation.
 To reduce the number of human studies during formulation
development.
162

Level A correlation
 The % of drug dissolved at a given time is correlated to % absorbed.
 Highest category of correlation.
 Represents point to point correlation between in vitro dissolution time course
and in vivo response time course.
 Utilizes all the dissolution and plasma level data available to develop
correlation.
 The major advantage of a Level A correlation is that a point to- point
correlation is developed. All in vitro dissolution data and all in vivo plasma
drug concentration–time profile data are used .
 Once a Level A correlation is established, an in vitro dissolution profile can
serve as a surrogate for in vivo performance.
 A change in manufacturing site, method of manufacture, raw material
supplies, minor formulation modification, and even product strength using
the same formulation can be justified without the need for additional human
164

Level B correlation
 The mean in vitro dissolution time (MDT) is compared either to
the mean residence time (MRT) or to the mean in vivo
dissolution time.
 Uses the principles of statistical moment analysis.
 Is not a point-to-point correlation.
 Reason - because a number of different in vivo curves will
produce similar mean residence time values.
 Is not a point-to-point correlation.
 Does not reflects the actual shape of in- vivo plasma level curve.
 Level B correlations are rarely seen in NDAs.
165

Level C correlation
 A Level C correlation is not a point-to-point correlation. A Level C
correlation establishes a single-point relationship between a dissolution
parameter such as percent dissolved at a given time and a
pharmacokinetic parameter of interest such as AUC and Cmax. Level C
correlation is useful for formulation selection and development but has
limited application .
 Several examples of Level C correlation are given below.
1. Dissolution rate versus absorption rate.
2. Percent of drug dissolved versus percent of drug
absorbed.
3. Maximum plasma concentrations versus percent of drug
dissolved in vitro.
4. Serum drug concentration versus percent of drug
dissolved.
167

ROLE OF DOSAGE FORM
 The main purpose of incorporating a drug in a delivery
system is to develop a dosage form that possesses the
following attributes·
 contains the labeled amount of drug in a stable form until
its expiration date ·
 consistently delivers the drug to the general circulation at
an optimum rate and to an optimum extent is suitable for
administration through an appropriate route is acceptable
to patients.
169

 All the physicochemical properties of drugs (i.e. particle size,
pH, pKa, salt form, etc.) will contribute to the dosage form
design.
 Additionally, additives incorporated into the dosage form (e.g.
diluents, binders, lubricants, suspending agents) often may
alter the absorption of a therapeutic agent from a dosage form
 Recognizing the fact that drug must dissolve in the
gastrointestinal (GI) fluid before it can be absorbed, the
bioavailability of a drug would be expected to decrease in the
following order
 solution> suspension >capsule>tablet > coated tablets
170

Solution as a dosage form
 Solutions such as syrups and elixirs show fast and often complete
absorption of drug because they do not have dissolution problem.
 However, dilution of the drug solution with gastric fluid may result in
precipitation that may re-disperse rapidly due to extremely fine
nature of precipitate.
 The factors that affect drug absorption from solution include
viscosity, reversible complexation , chemical stability and micellar
solubilization.
 The vehicle used in syrups , elixirs and emulsions may be aqueous
or nonaqueous( e.g., PEG, PG, alcohol ) or non-water miscible(e.g.,
vegetable oils).
 The rate of drug absorption from non-aqueous or non-water
miscible vehicle based solution is less than the rate of drug
absorption from water based solution.
171

 The selection of vehicle for solution dosage form depends on the
physiochemical properties of the drug.
 Ex. Paracetamol drop is prepared with PEG 400 as it is sparingly
soluble in water.
 Certain materials such as sorbitol or hydrophilic polymers are
added to a solution dosage form, to improve pourability and
palatability by increasing the viscosity of the preparation.
 Due to good systemic availability, solutions are frequently used as
bioavailability standards against which other dosage forms are
compared.
172

 Rapid and complete absorption may be observed in some
instances, particularly if the oil is administered in emulsified
form.
 Administration of indoxole dissolved in the oil phase of
Lipomul-Oral(o/w).
 Resulted in a three fold improvement in the extent of
absorption compared to that observed after administration
of an aqueous suspension and a nine fold improvement
compared to a hard gelatin capsule.
173

SUSPENSIONS
 Suspension may be defined as preparation containing finely divided drug particles
distributed somewhat uniformly throughout a vehicle in which the drug exhibits a
minimum degree of solubility.
 Adjusting the dose to a patient’s needs is easier with solutions and suspensions
than with solid dosage forms.
 Several studies have demonstrated the superior bioavailability characteristics of
suspensions compared to those of solid dosage forms.
 Ex. the blood levels of trimethoprim and sulfamethoxazole were
compared in 24 healthy subjects following oral administration of 3
forms, The absorption rate of each drug was significantly greater with
the suspension than with the tablet or capsule.
 Penicillin blood conc. following oral administration of various dosage
forms show higher level with suspension of Phenoxymethyl penicillin
174

 Finally divided solid particles in suspension are stabilized with
suspending agents.
 Suspending agents retard the rate sedimentation of dispersed particles.
 Absorption of drug in suspension form is not greatly affected by
stomach emptying rate.
 But suspending agent may increase the viscosity of drug vehicle and
thereby may diminish rate of drug dissolution.
 Other critical factors that affect drug absorption include particle size,
crystal forms and formation of non-absorbable complexes
 Suspending agent may form non-absorbable complexes with drug eg.,
divalent metals form in suspension of multivitamins and essentials
elements form complex with sodium carboxymethylcellulose that poorly
get absorb in body.
 As dissolution is taking place at the surface of solute smaller particle
having larger surface area may dissolve rapidly. 175

 Bioavailability studies with drugs suspended in oi1-in-waier emulsions have
yielded some promising results.
 One study compared the absorption of micronized griseofulvin after its
administration to healthy subjects in a corn oil-in-water emulsion, an aqueous
suspension, and two different commercial tablets.
 The extent of absorption of the drug after administration of the emulsion was
about twice that observed after administration of the aqueous suspension or
tablets.
 MOA ; based on the ability of fatty acids, liberated during the digestion of corn
oil, to inhibit gastrointestinal motility (which would increase the residence time of
the drug in the small intestine) and to stimulate gallbladder evacuation
176

Role of Capsule as a dosage form:
A capsule is a medication in a gelatin container.
 Advantage: mask the unpleasant taste of its contents.
The two main types of capsules are:
1- hard-shelled capsules, which are normally used for dry,
powdered ingredients, The hard gelatin shell encapsulating the
formulation should disrupt quickly and expose the contents to the
GI fluid,
2- soft-shelled capsules, primarily used for oils and for active
ingredients that are dissolved or suspended in oil.The capsule has
the potential to be an efficient drug delivery system.
177

 Unlike the tablet dosage form, drug particles in a capsule are not
subjected to high compression forces.
 Hence, upon disruption of the shell, the encapsulated powder mass
should disperse rapidly to expose a large surface area to the GI fluid.
 This rate of dispersion, in turn, influences the rate of dissolution and,
therefore, bioavailability.
 It is important to have suitable diluents and/or other excipients in a
capsule dosage form, particularly when the drug is hydrophobic.
178

 In capsule on disruption of the shell, the encapsulated powder
mass should disperse rapidly to expose a large surface area to the
gastrointestinal fluids.
 Diluents added to capsules dosage form may affect the dissolution
of filled drug in capsule shell.
 Hydrophilic diluents are added in the capsule of a poorly water
soluble drug as they enhance the dispersion rate of the aqueous
fluid to the contents of the shell.
 This results in better dissolution of the drug in the biological fluid.
 Sometimes wetting agents are also added to improve dispersion
rate
179

 Further, drug absorption from capsule may also be affected by
particle size and chemical and physical incompatibility of the
drug with a filler and other ingredients.
 Certain drugs are formulated in soft gelatin capsule as a solution
from which drug disperses and dissolves more rapidly as
compared to hard gelatin capsule.
 Moreover, soft gelatin capsule leaves less residual drug in gut
and hence causes minimal irritation.
 This approach is more useful for the drugs that causes local
irritation
180

 The use of dicalcium phosphate as a diluent in tetracycline capsules
has been found to significantly impair absorption because a poorly
soluble calcium tetracycline complex is formed in the powder mass or
during dissolution.
 Factors that influence drug absorption from capsule dosage forms
include- particle size and crystal form of the drug, and selection of
diluents and fillers.
 A soft elastic capsule containing 0.4 mg of digoxin is about
equivalent to a tablet containing 0.5 mg of the drug i.e; mean
absorption was 75% of the dose from the tablet and 97% from the
capsule.
181

Tablet as a dosage form
 A tablet is a hard, compressed medication in round, oval or
square shape.
The excipients include:
 Binders, glidants (flow aids) and lubricants to ensure efficient
tabletting.
 Disintegrants to ensure that the tablet breaks up in the digestive
tract.
 Sweeteners or flavours to mask the taste of bad-tasting active
ingredients.
 Pigments to make uncoated tablets visually attractive.
182

 Many factors related to the formulation or production of tablets may affect
drug dissolution and absorption.
 Most formulations require the incorporation of hydrophobic lubricants, such
as magnesium stearate, to produce an acceptable tablet. In general, the
larger the quantity of lubricant in a formulation the slower is the dissolution
rate.
 Compression force may also be an important factor in drug bioavailability
from compressed tablets.
 The in vitro disintegration time of tablets has been shown to be directly
proportional to compression force and tablet hardness.
 High compression forces may also increase the strength of the internal
structure of the granules and retard dissolution of drug from the granules
and disintegration of the granules.
184

 A novel approach to enhance the availability of poorly water-
soluble drugs from tablets has been used in a marketed
griseofulvin product.
 A molecular dispersion of the drug in
 polyethylene glycol 6000,
 a water-soluble waxy polymer that congeals at about 60C, is
prepared and suitably modified for incorporated into a tablet
dosage form.
 The absorption of griseofulvin from this product appears to be
complete and about twice that observed from commercial tablets
containing micronized drug.
185

COATED TABLET :
 The coating must dissolve or disrupt before tablet disintegration and
drug dissolution can occur.
 The disintegration of certain coated tablets appears to be the rate-
limiting process in drug absorption.
 Film-coated tablets are compressed tablets that are coated with a thin
layer or film of a material that is usually water soluble or dispersible.
 A number of polymeric substances with film forming properties may be
used including hydroxypropyl methylcellulose and
carboxymethylcellulose.
 The film coat should disrupt quickly in the fluids of the gastrointestinal
tract, independent of pH.
 Sugar coating may affect the bioavailability of a drug. Alternatives
include the film-coated tablet and the press coated tablet.
186

Enteric coated Tablets:
 Enteric coated is special film coated tablet which are
used to bypass gastric fluid so that the drug gets dissolve
in intestine.
 They show a delayed absorption and therefore a delayed
onset of action.
 They also show high inter and intra subject variability due
to difference in gastric emptying rate.
 The modern approach to enteric-coating makes use of
polymer like cellulose acetate phthalate that are
''insoluble' at pH I to 3 but 'soluble" at pH5 to 7.
187

 The thickness of the coating may also affect bioavailability.
 Studies with quinine tablets coated with cellulose acetate
phthalate show a decrease in both rate and extent
absorption with increasing thickness of the coating.
188

Permeability-Solubility charge
state & The pH partition Hypothesis.
 Fick’s first law applied to a membrane shows that passive diffusion of a
solute is the product of the diffusivity and the concentration gradient of
the solute inside the membrane. For an ionizable molecule to permeate
by passive diffusion most efficiently, the molecule needs to be in its
uncharged form at the membrane surface.
 Consider a vessel divided into two chambers, separated by
homogeneous lipid membrane. The left side is the donor compartment,
where the sample molecules are first introduced; the right side is the
acceptor compartment, which at the start has no sample molecules.
190

Transport model diagram, depicting two aqueous
cell separated by a membrane barrier. 191

PROPERTIES OF THE GASTROINTESTINAL
TRACT (GIT)
 Oral Drug Absorption :The oral route of administration is the most common
and popular route of drug dosing. The oral dosage form must be designed to
account for extreme pH ranges, the presence or absence of food, degradative
enzymes, varying drug permeability in the different regions of the intestine, and
motility of the gastrointestinal tract.
 Anatomic and Physiologic Considerations : The normal physiologic
processes of the alimentary canal may be affected by diet, contents of the
gastrointestinal (GI) tract, hormones, the visceral nervous system, disease, and
drugs. Thus, drugs given by the enteral route for systemic absorption may be
affected by the anatomy, physiologic functions, and contents of the alimentary
tract. Moreover, the physical, chemical, and pharmacologic properties of the
drug and the formulation of the drug product will also affect systemic drug
absorption from the alimentary canal
192

 Drugs administered orally pass through various parts of the enteral
canal, including the oral cavity, esophagus, and various parts of the
gastrointestinal tract. Residues eventually exit the body through the
anus. The total transit time, including gastric emptying, small intestinal
transit, and colonic transit, ranges from 0.4 to 5 days.
 The small intestine, particularly the duodenum area, is the most
important site for drug absorption. Small intestine transit time (SITT)
ranges from 3 to 4 hours for most healthy subjects.
 Oral Cavity : Saliva is the main secretion of the oral cavity, and it has
a pH of about 7. Saliva contains ptyalin (salivary amylase), which
digests starches. Mucin, a glycoprotein that lubricates food, is also
secreted and may interact with drugs. About 1500 mL of saliva is
secreted per day. 194

Esophagus :
 The esophagus connects the pharynx and the cardiac orifice of the
stomach. The pH of the fluids in the esophagus is between 5 and 6.
The lower part of the esophagus ends with the esophageal sphincter,
which prevents acid reflux from the stomach. Tablets or capsules
may lodge in this area, causing local irritation. Very little drug
dissolution occurs in the esophagus.
Stomach :
 The stomach is innervated by the vagus nerve. However, local nerve
plexus, hormones, mechanoreceptors sensitive to the stretch of the
GI wall, and chemoreceptors control the regulation of gastric
secretions, including acid and stomach emptying. The fasting pH of
the stomach is about 2–6. In the presence of food, the stomach pH is
about 1.5–2, due to hydrochloric acid secreted by parietal cells
.Generally Basic drugs are solubilized rapidly in the presence of
stomach acid.
195

 If the stomach pH is too high, the enteric-coated drug product may
release the drug in the stomach, thus causing irritation to the stomach.
Duodenum :
 A common duct from both the pancreas and the gallbladder enters into
the duodenum. The duodenal pH is about 6–6.5, because of the
presence of bicarbonate that neutralizes the acidic chyme emptied from
the stomach. The duodenum is the major site for passive drug
absorption due to both its anatomy, which creates a high surface area,
and high blood flow.
Jejunum :
 The jejunum is the middle portion of the small intestine, between the
duodenum and the ileum. Digestion of protein and carbohydrates
continues after addition of pancreatic juice and bile in the duodenum.
196

Ileum :
 The ileum is the terminal part of the small intestine. This site also
has fewer contractions than the duodenum and may be blocked off
by catheters with an inflatable balloon and perfused for drug
absorption studies. The pH is about 7, with the distal part as high
as 8. Due to the presence of bicarbonate secretion, acid drugs will
dissolve in the ileum. Bile secretion helps dissolve fats and
hydrophobic drugs.
Colon :
 The colon lacks villi and has limited drug absorption due to lack of
large surface area, blood flow, and the more viscous and semisolid
nature of the lumen contents. The colon is lined with mucin that
functions as lubricant and protectant. The pH in this region is 5.5–
7. A few drugs, such as theophylline and metoprolol, are absorbed
in this region. Drugs that are absorbed well in this region are good
candidates for an oral sustained-release dosage form.
197

Rectum :
 The rectum is about 15 cm long, ending at the anus. In the
absence of fecal material, the rectum has a small amount of
fluid (approximately 2 mL) with a pH of about 7.
198

pH Microclimate :
 The absorption of short-chain weak acids in the rat intestine, as a
function of pH, does not appear to conform to the pH partition hypothesis
. Similar anomalies were found with weak bases . The apparent pKa
values observed in the absorption– pH curve were shifted to higher
values for acids and to lower values for bases, compared with the true
pKa values. Such deviations could be explained by the effect of an acid
layer on the apical side of cells, the so-called acid pH microclimate.
Intracellular pH environment :
 Intracellular pH (pHi) is the measure of the acidity or basicity (i.e., pH) of
intracellular fluid. The pHi plays a critical role in membrane transport and
other intracellular processes. Physiologically normal intracellular pH is
most commonly between 7.0 and 7.4. Intracellular pH is typically lower
thanextracellular pH due to lower concentrations of HCO3 −.
199

Tight junction complex:
 Tight junctions, also known as occluding junctions or
zonulae occludentes (singular, zonula occludens) are
multiprotein junctional complexes whose general function is
to prevent leakage of transported solutes and water and
seals the paracellular pathway.
 Tight junctions may also serve as leaky pathways by
forming selective channels for small cations, anions, or
water. Tight junctions are present mostly in vertebrates
(with the exception of Tunicates. The corresponding
junctions that occur in invertebrates are septate junctions
200

Structure of tight junction:
 Tight junctions are composed of a branching network of sealing strands,
each strand acting independently from the others. Therefore, the
efficiency of the junction in preventing ion passage increases
exponentially with the number of strands.
 Each strand is formed from a row of transmembrane proteins embedded
in both plasma membranes, with extracellular domains joining one
another directly. There are at least 40 different proteins composing the
tight junctions.
 These proteins consist of both transmembrane and cytoplasmic proteins.
The three major transmembrane proteins are occludin, claudins, and
junction adhesion molecule (JAM) proteins.
 These associate with different peripheral membrane proteins such as
ZO-1 located on the intracellular side of plasma membrane, which
anchor the strands to the actin component of the cytoskeleton. Thus,
tight junctions join together the cytoskeletons of adjacent cells
202

Function of tight junction
 Tight junctions help to maintain the polarity of cells by preventing the
lateral diffusion of integral membrane proteins between the apical
and lateral/basal surfaces, allowing the specialized functions of each
surface (for example receptor-mediated endocytosis at the apical
surface and exocytosis at the basolateral surface) to be preserved.
This aims to preserve the transcellular transport.
 Tight junctions prevent the passage of molecules and ions through
the space between plasma membranes of adjacent cells, so
materials must actually enter the cells (by diffusion or active
transport) in order to pass through the tissue. 203

REFERENCE
 Tortora G.J.;Derrickson B.H.;Principles of Anatomy And Physiology,12th
Edition,Volume 2,p.921-966
 Brahmankar D.M., Jaiswal S.B., First edition, “Absorption of Drugs”
Biopharmaceutics and Pharmacokinetics – A treatise, Vallabh
Prakashan, Delhi 1995.
 The theory and the practice of Industrial pharmacy by Lachman L,
Liberman HA, Indian edition 2009. Pg. no. 302- 303.
 Leon Shargel, Andrew B.C.YU “Applied biopharmaceutics and
pharmacokinetics”Seventh edition,Mc Graw Hill Education, pg no.390-
393,429-431.
 Avdeef alex “Absorption and drug development ’’A john Wiley & sonc
Inc publication, pg no.7-18.
204

Drug absorption from GIT

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