about the factors affecting drug absorption

1. RATE LIMITING STEPS IN DRUG ABSORPTION
Presented By
C.Prakash
M.Pharm Ceutics

2. Drug absorption
It is defined as the process of movement of unchanged drug
from the site of administration to systemic circulation.
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.
A drug that is completely but slowly absorbed may fail to show
therapeutic response as the plasma concentration for desired
effect is never achieved. On the contrary, a rapid absorbed drug
attains the therapeutic level easily to elicit pharmacological effect.

3. Drugs that have to enter the systemic circulation to exert
their effect can be administered by 3 major routes:-
The Enteral Route
The Parenteral Route
The Topical Route

4. Rate Limiting Steps In Drug Absorption
In a series of kinetic or rate processes, the rate at which the drug
reaches the systemic circulation is determined by the slowest of
various steps involved in the sequence. Such a step is called as
the rate limiting step.
Systemic drug absorption from a drug product consists of a
succession of rate processes. For solid oral, immediate-release
drug product (tablets, capsules) the rate processes include.
 Disintegration of the drug product and subsequent release of
the drug,
 Dissolution of the drug in an aqueous environment and
 Absorption across cell membranes into the systemic
circulation.

5. DISINTEGRATION
 For immediate- release, solid oral dosage forms, the drug
product must disintegrate into small particles and release
the drug.
 To monitor uniform tablet disintegration, United States
Pharmacopeia (USP) has established an official
disintegration test.
 Solid drug products exempted from disintegration tests
include troches, tablets that are intended to be chewed, and
drug products intended for sustained release or prolonged or
repeat action.
 The process of disintegration does not imply complete
dissolution of the tablet and/or the drug.

6.  Complete disintegration is defined by the USP-NF as ‘’that
state in which any residue of the tablet, except fragments
of insoluble coating, remaining on the screen of the test
apparatus in the soft mass have no palpably firm core’’.
 The official apparatus for the disintegration test and
procedure is described in the USP-NF.
 Separate specifications are given for drug products that are
designed not to disintegrate.
 These products include troches, chewable tablets, and
modified release drug products.
 Although disintegration tests allow for measurement of the
formation of fragments, granules, or aggregates from solid
dosage forms, no information is obtained from these tests
on the rate of dissolution of the active drug.

7.  However, there has been some interest in using only the
disintegration test and no dissolution test for drug products
that meet the Biopharmaceutical Classification System
(BCS) for highly soluble and highly permeable drugs. In
general, the disintegration test serves as a component in the
overall quality control of tablet manufacture.
Class Solubility Permeability
Absorption
Pattern
Rate limiting step in
absorption
Examples
I High High Well Absorbed Gastric emptying Diltiazem
II Low High Variable Dissolution Nifedipine
III High Low Variable Permeability Insulin
IV Low Low Poorly Absorbed Case By Case Taxol

8. DISSOLUTION AND SOLUBILITY
Dissolution is the process by which a solid drug substance
becomes dissolved in a solvent. Solubility is the mass of solute
that dissolves in a specific mass or volume of solvent at a
given temperature (Eg, 1g of NaCl dissolves in 2.786 mL of
water at 25oC )
 Solubility is a static property, whereas dissolution is a
dynamic property. In biologic systems, drug dissolution in
an aqueous medium is an important prior condition for
predicting systemic drug absorption.

9.  The rate at which drugs with poor aqueous solubility dissolve
from an intact or disintegration solid dosage form in the
gastrointestinal tract often controls the rate of systemic
absorption of the drug.
 Thus, dissolution tests may be used to predict bioavailability
and may be used to discriminate formulation factors that
effect drug bioavailability. The dissolution test is required for
all US Food and Drug Administration (FDA) approved solid
oral drug products.
 Noyes and Whitney (1897) and other investigation studied the
rate of dissolution of solid drugs.
 According to their observations, the steps in dissolution
include the process of drug dissolution at the surface of the
solid particle, thus forming a saturated solution around the
particle.

10. The dissolved drug in the saturated solution, known as the
stagnant layer, diffuses to the bulk of the solvent from
regions of high drug concentration to regions of low drug
concentration.
The overall rate of drug dissolution may be described by the
Noyes-Whitney equation
𝑑𝐶
𝑑𝑡
=
𝐷𝐴
ℎ
(𝐶𝑠 − 𝐶)
Where ,
𝑑𝐶
𝑑𝑡
= rate of drug dissolution at time t,
D = diffusion rate constant,
A = surface area of the particle,
Cs = concentration of drug (equal to solubility of drug) in the stagnant layer,
C = concentration of drug in the bulk solvent, and
h = thickness of the stagnant layer.

11.  The rate of dissolution, dC/dt, is the rate of drug
dissolved per time expressed as concentration change in
the dissolution change in the dissolution fluid.
 The Noyes-Whitney equation shows that dissolution in a
flask may be influenced by the physicochemical
characteristics of the drug, the formulation, and the
solvent. The dissolution of drug in the body, particularly
in the gastrointestinal tract, is considered to be
dissolving in an aqueous environment.
 Permeation of drug across the gut wall is affected by the
ability of the drug to diffuse (D) and to partition between
the lipid membranes.
 A favourable partition coefficient (Koil/water) will facilitate
drug absorption.

12. Factors that affect drug dissolution of a solid oral dosage form
include
(1)The physical and chemical nature of the active drug substance
(2) The nature of the excipients
(3)The method of manufacture
(4) The dissolution test conditions.
Physical and chemical nature of the active drug substance
1) 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.

13. 2 ) SALT FORMATION
o It is one of the common approaches used to increase drug solubility and
dissolution rate.
o It has always been assumed that sodium salts dissolve faster than their
corresponding insoluble acids.
o E.g. sodium and potassium salts of Penicillin G, phenytoin, barbiturates,
tolbutamide etc.
o While in case of Phenobarbital dissolution of sodium salt was slower than that of
weak acid. Due to decreaseddisintegration of sodium salt.
o Hydrochlorides and sulphates of weak bases are commonly used due to high
solubility.
o E.g. epinephrine, tetracycline.
3) PARTICLE SIZE
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.
Micronization of sparingly soluble drug to reduce particle size, there is no
guarantee of better dissolution and bioavailability.

14. Nature of the excipients
1)DILUENTS
Studies of starch on dissolution rate of salicylic acid tablet by dry double
compression process shows three times increase in dissolution rate when
the starch content increase from the 5 – 20 %.
Here starch particles form a layer on the outer surface of hydrophobic
drug particles resulting in imparting hydrophilic character to granules &
thus increase in effective surface area & rate of dissolution.
2)DISINTEGRANTS
Disintegrating agent added before & after the granulation affects the
dissolution rate.
Studies of various disintegrating agents on 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.

15.  Starch is not only an excellent diluent but also superior disintegrant
due to its hydrophilicity and swelling property.
3)BINDERS AND GRANULATING AGENTS
The hydrophilic binder increase dissolution rate of poorly wettable
drug.
Large amt. of binder increase hardness & decrease
disintegration/dissolution rate of tablet.
Non aqueous binders such as ethyl cellulose also retard the drug
dissolution.
4)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.

16. Method of manufacture
1) METHOD OF GRANULATION
Granulation process in general enhances dissolution rate of poorly soluble
drug.
Wet granulation is traditionally considered superior.
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.
2)DRUG EXCIPIENT INTERACTION
These interactions occur during any unit operation such as mixing, milling
,blending, drying, and/or granulating result change in dissolution.
The dissolution of prednisolone found to depend on the length of mixing time
with Mg-stearate
Similar as increase in mixing time of formulation containing 97 to 99%
microcrystalline cellulose or another slightly swelling disintegrant result in
enhance dissolution rate.

17. 3)COMPRESSION FORCE
The compression process influence density, porosity, hardness,
disintegration time & dissolution of tablet.
A)Higher compression force increases the density
and hardness of tablet, decreases porosity which
results in tighter bonding between the particles,
which result in the slower dissolution rate of
tablet.
B) Higher compression forces cause deformation,
crushing or fracture of drug particles into
smaller one which increase in the surface area
thus increase in dissolution rate of tablet.
C&D) The influence of compression force on
dissolution rate is difficult to predict and a
thorough study on formulation should be made
to ensure better dissolution and bioavailability

18. Dissolution test conditions
1) AGITATION
Relationship between intensity of agitation and rate of dissolution varies
considerably acc. to type of agitation used, the degree of laminar and turbulent
flow in system, the shape and design of stirrer and
physicochemical properties of solid.
Speed of agitation generates a flow that continuously changes the liq/solid
interface between solvent and
drug. In order to prevent turbulence and sustain a reproducible laminar flow,
which is essential for
obtaining reliable results, 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

19. 2) TEMPERATURE
Drug solubility is temperature dependent, therefore careful temperature
control during dissolution process is extremely important.
Generally, a temp of 37º ± 0.5 is maintained during dissolution of oral
dosage forms and suppositories. However, for topical preparations temp
as low as 30º and 25º have been used.
3) DISSOLUTION MEDIUM
 Addition of Na – sulfate decrease the dissolution rate.
 Addition of urea increase dissolution rate.
 Volume generally 500, 900 or 1,000 ml.
 Simulated gastric fluid(SGF) - pH 1.2.
 Simulated intestinal fluid (SIF)- pH 6.8.
 If drug is poorly soluble, a relatively large amount of fluid should be
used if complete dissolution is to be expected.

20. Gastric Emptying
Apart from dissolution of a drug and its permeation through the bio
membrane, the passage from stomach to the small intestine, called as gastric
emptying, can also be a rate limiting step in drug absorption because the
major site of absorption is intestine.
Rapid gastric emptying is advisable where:
 A rapid onset of action is desired e.g. sedatives
 Dissolution of drug occurs in the intestine e.g. enteric coated tablets
 The drugs are not stable in gastric fluids e.g. penicillin G and erythromycin
For better dissolution and absorption, the gastric emptying can be promoted
by taking the drug on empty stomach.
Delay in gastric emptying is recommended in particular where:
• The food promotes dug dissolution and absorption e.g. griseofulvin
• Disintegration and dissolution of dosage form is promoted by gastric fluids
• The drugs irritate the gastric mucosa e.g. aspirin, phenylbutazone

21. A Large number of factors influence gastric emptying as discussed
below
 Volume of meal
 Composition of meal
 Physical state and viscosity of meal
 Temperature of the meal
 Gastrointestinal pH
 Body posture
 Emotional state
 Exercise
 Drugs

22. Refernces
Applied Biopharmaceutics and Pharmacokinetics by Shargel. Pg
No:363-365
Biopharmaceutics and pharmacokinetics A Treatise, D.M.
Brahmankar and Sunil B. Jaiswal., VallabhPrakashan Pg No:27-
29, 35-41, 52-56, 67-69.

23. THANK YOU