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BIOAVAILABILITY AND
BIOEQUIVALENCE
> . Bioavailability: It is the term which means the rate and extent to which the drug is absorbed
from its dosage form and becomes available at the site of action.
>! Absolute bioavailability: It is the measure of the given drug absorbed systematically after
oral administration as compared to ig intravenous administration.
>. Relative bioavailability: It is a measure of the given drug absorbed systematically after oral
administration as compared with that of an oral standard of the same drug.
» © Bioequivalence studies: These are the studies used to compare the bioavailability of the same
drug from different drug products.
> Bioequivalent drug product: This term describes the products that show comparable
bioavailability when studied under similar experimental conditions.
RODUC YI
Cai
nosfusty is defined as the rate and extent of absorption of drug that reaches the
biological system in an active form. This term largely depends on the absorption and the
extent of hepatic metabolism. Bioavailability of a drug can be calculated by testing the drug
from the samples of biological fluids drawn at different intervals. According to the
regulatory authority perspective (21 CFR 320.1) bioavailability is defined as rate and extent
to which the active ingredients or active moiety is absorbed from a drug product and
becomes available at the site of action. Faster absorption is an important consideration whe"
a rapid onset of action is desired whereas slower absorption is desired when the aim is t0
prolong the duration of action or to avoid the adverse effects. Bioavailability studies a¥°
for both approved drug ingredients and therapeutic moieties not yet approved
for marketing by the Food and Drug Administration (FDA). 4.2.1 DEFINITION
Bioavailability refers to the extent and speed with which the active part (drug or metabolite)
enters the systemic circulation, accessing the site of action.
The bioavailability of a drug is determined to a large extent by the properties of the dosage
form, which depend in part on its design and manufacture. The differences in bioavailability
between the formulations of a given drug may have clinical significance; therefore, knowing
if pharmaceutical formulations are equivalent is essential.
4.2.2 OBJECTIVES OF BIOAVAILABILITY STUDIES
1. Bioavailability studies are one of the facies that link in-vivo performance of the drug
product used in clinical studies (for determination of evidence of safety and efficacy)
Bioavailability studies provide useful information important to establish dosage
v
regimen and to support drug labeling.
3, These studies help in determining the influence of excipient, patient related factors and
possible interaction with other drugs on the efficiency of absorption.
4. Bioavailability studies estimates the quality control of a drug product during the early
stages of marketing so that the influence of processing factors, storage and stability on
drug absorption can be determined.
Bioavailable fraction (F) is a term which refers to the fraction of administered dose that
enters the systemic circulation and can be calculated as:
~ “Administered dose
depends upon mainly three major factors.
Bioavailability of a drug
is | factors and formulation factors.
l. Pharmaceutical factors including physiochemical
2 Patient related factors.
3. Route of drug administration.
The above first two factors have been discussed in the chapter of absorption of drug. AECL TE
‘Table 4.1: Bioavailability of the dru;
g is different for the different route of administration
=
pass |
\bsolute bioavailability
Absolute bioavailability is a measure of the given drug absorbed systematically after oral
administration compared to its intravenous administration.
Absolute Bioavailablility (F,%) =
PAN
AUC (Oral))xDose(IV)
‘AUC(IV)xDose (Oral)
«100
Where dose (IV) is the dose administered intravenously, dose (oral) is the dose administered
orally and AUC (Oral) and AUC (IV) are the area under the plasma drug concentration-time
curve after oral and IV administration respectively.
gnificance of absolute bioavailability
The drug is completely Bioavailable when F=1, for the drugs given by intravenous
inleticel:
+ Fe1 is for the drugs which are poorly absorbed or metabolized by first pass effect. E.g.
Insulin solution shows zero bioavailability as it is extensively degraded in GI tract.
Sr.No. | Route of administration Bioavailability (%) Property
1 _ | Intravenous (IV) 100 Most rapid onset
Large volume often feasibie
2 | intramuscular (IM) mony be palale
75 to-s100 ———
‘Smaller volume than IM. may
3 | Subcutaneous (SC) be peiedal
= Most convenient, first pase
oe cto effect may be significant
5 | Rectal 30 to <100 Less first pass effect than oral
6 | Inhalation 5 to <100 Often very rapid onset
Used for bypassing first
7 | Transdermal 80 to <100 effect, prolonged duration of
action
4. - Poses and Bowaivaionce ee
Relative bioavailability
Relative bioavailability is a measure of the given dug absorbed systematically after oral
administration compared with that of an oral standard of the same drug. e.g- comparison
between Amoxicillin capsule and Amoxicillin suspension.
Relative Bioavailability (F, 9») = AUC(Tes0))x Dose (Std) so
"AUC (td) xDose(Test)
Significance of relative bioavailability:
* In comparison to absolute bioavailability, it is used to characterize absorption of a
drug from its formulation.
Both absolute and relative bioavailabilities are expressed in percentages.
LOAVAILABI
1. Pharmacokinetics methods: These are indirect methods based on the assumption that
pharmacokinetics profile reflects the therapeutic effectiveness of a drug. The two major
pharmacokinetics methods are:
a. Plasma/blood level time profile:
i. Time for peak plasma concentration (tax)
ii. Peak plasma drug concentration (Cma)-
iii, Area under the plasma drug concentration time curve (AUC).
b. Urinary excretion studies:
«Cumulative amount of drug excreted in the urine (Dj).
d
ii. Rate of drug excretion in the wsine( 4, } $
iii. Time for maximum urinary excretion w.
2 Pharmacodynamics methods: These involve direct measurement of pharmacologic or
therapeutic end point. The two pharmacodynamics methods involve determination of
bioavailability from:
@. Acute pharmacologic response
Maximum pharmacodynamics effect En.
{Time for maximum pharmacodynamics effect
“Area under the pharmacodynamics effect time curve.
iv. Onset time for pharmacodynamics effect.
». Therapeutic response
© Clinical Observations (oo te ree emery
Plasma/blood level time profile
The measurement of drug concentration in biood, plasma or serum after drug administration
is the most direct and objective way to determine systemic drug bioavailability. It is based on
the assumptions that two dosage forms that exhibit super-imposable plasma level-time
profiles in a group of subjects should result in identical therapeutic activity. An accurate
description of the plasma drug concentration-time profile of the therapeutically active drug
substance can be obtained from three parameters which are considered important for
determining bioavailability are:
|, Time for peak plasma concentration (tna): It corresponds to the time required to reach
maximum drug concentration after drug administration. tmax gives an indication of the rate
of absorption. At tmx peak drug absorption occurs and the rate of drug absorption exactly
equals the rate of drug elimination. After tmax, absorption occurs but at a slower rate. The
value for tmax will become smaller (indicating less time required to reach peak plasma
concentration) as the absorption rate for the drug becomes more rapid. It is expressed in
hours or minutes.
Cmax
Plasma conc.
(ug/ml)
Tmax
Time of sample collection (hr)
Fig. 4.1: Time for peak plasma concentration (tax)
2. Peak plasma concentration (CmaJ: It corresponds to the maximum plasma drug
concentration obtained after oral administration of drug. Cmax provides indications that the
drug is sufficiently systemically absorbed to provide a therapeutic response. In addition,
peak plasma concentration provides warning of possible toxic levels of drug. It is expressed
in mg/ml or pg/ml units. Cmax is often used in bioequivalence studies as a surrogate
measure for the rate of drug availability.
“ elimination Processes do not change. The unit for AUC is
etermined by following methods:
yg-hr/ml. The AUC can be d
Trapezoid method:This method is based on divid
ling the plasma drug concentration time
curve into several trapezoids and calculating the AUC by adding the area of these
trapezoids.
Area of trapezoid = (Cy +Cy-1)(ty ~ty-1)
2
Where,
Cy = Plasma drug concentration at time ty.
C.1 = Plasma drug concentration at time tn.
AUC = Z(Area of each trapezoid).
By this method, one can calculate the AUC from tome 0 to any time “t”. But for calculation of
AUC from 0 to 09, following formula can be used:
AUCs =[AUC], +[AUC]”
For calculation of [AUC], , trapezoid method can be used and
=
[auc] ="
Where,
C; = Plasma drug concentration at the last time point
k= first order elimination rate constant.
Counting Square method:In this method, the total number of squares enclosed by the
Plasma ein time curve is counted. The area of each square is determined using the
Telationship; Area of the square = Height x Width. The height and width are measured in the
unit : is and time on x-axis. |
i of copeearationy ears vacma drug level time profiles plotted on a smooth graph
gen ts tana i contours of the plots and weigh on an electronic balance.
Ber. The paper is cut 6 known weight from the same graph paper. The AUC can
Similarly cut a reference area
calculated as follows:
ue, Dy eee
meter is a precision instrument that allows the calculation of areas
It requires additional instrumentation. The disadvantage of this
0 instrument and human error.
By using planimeter:Plani
by tracing their outlines.
method is that the degree of errors is high due t ; ,
The extent of bioavailability can be determined by the following equations:
For single dose study:
_ AUC (Oral)xDose(IV) 100
~AUC(IV)xDose (Oral)
And
_ AUC(Test)xDose(Std)
= x 100
‘AUC (Std) xDose (Test)
For multiple dose study
_ AUC (Test)xDose(Std)xt(Test)
~ AUC(Std)xDose(Test)xt(Std)
Where, AUC values are area under of one dosing interval in a multiple dosage regimen, after
reaching the steady state and t is the dosing interval.
Bioavailability can also be determined from the peak plasma concentration at steady state
Co
C,. (Test) x Dose (Std) x t(Test)
Ms Cy. (Std) x Dose (Test) x t(Std)
«100
Urinary excretion studies
_ Urinary drug excretion data is an indirect method for estimating bioavailability. This
method is based on the fact that the urinary excretion of unchanged drug is directly
Proportional in the plasma concentration of drug. Urine samples must be collected and the
total amount of urinary drug excretion must be obtained. At each sample collection, total
emptying of the bladder is necessary to avoid error resulting from addition of residual
amounts to the next urine sample. The three major parameters used in urinary drug
excretion data obtained with a single dose study are:
1. Cumulative amount of drug excreted (Ds); It is directly related to the total amount of
drug absorbed. Experimentally, urine samples are collected periodically after administration
of a drug product. Each urine sample is analyzed for free drug using a specific assay. When
the drug is almost completely eliminated, the plasma concentration approaches to zero and
the maximum amount of drug excreted in the itrine is obtained. It increases as the extent of
absorption increases. sos eeeeeeesme 7
i te
2, Rate of drug excretion in the wsine{ 4, } : The rate of drug excretion is dependent on
the first order elimination rate constant “k” and the concentration of drug in the plasma (C>)
It is analogous to the Cmax derived from plasma level studies since the rate of appearance of
drug in the urine is proportional to its concentration in systemic circulation. [ts value
increases as the rate and extent of absorption increases.
(3) nm
Rate of
excretion
B c
Time of sample collection
d
Fig. 4.2: Rate of drug excretion in the srine{ £D, }
3. Time for maximum urinary excretion (#): This is analogous to the tnax of plasma level
studies. The value of tmax decreases as the absorption rate increases.
The extent of bioavailability is calculated by:
Ds (Oral)xDose(IV) ,
Dg (IV) xDose (Oral)
Da (Test)xDose(Std) 45
* ~ De (Std)xDose(Test)
F=
With multiple dose study, the equation is as follows:
Dy (Test) xDose(Std)x*(Test) |
ae De (Std) xDose (Test) 7(Std)
Acute pharmacological response: An acute pharmacological effect, such as an effect on
forced expiration volume, inhaled bronchodilators or skin blanching can be used as an index
° drug bioavailability. In this case, the acute pharmacodynamics effect is measured over a
ind." tian” ater adéninistration of the drug: product. The. use: of an’ acute pharmacodynamics effect to determine bioavailability generally requires demonstration of a
dose-response curve. Effects such as change in ECG or EEG readings, pupil diameter are
reflected to the time course of a given drug. Bioavailability can be determined by
construction of pharmacologic effect time curve as well as dose response graph. The
drawback of this method is that, the response tends to be more variable.
Therapeutic response: This method is most definite among all. It is based on observing
clinical response to a drug formulation given to a patient suffering from disease for which
the drug is intended to be used. A major drawback is that quantification of observed
response is unreliable for assessment of bioavailability.
Clinical observation: This approach isgghe least accurate, least sensitive and least
reproducible of the general approaches for determining in-vivobioavaibility. Well controlled
clinical trials in humans establish the safety and effectiveness of drug products and may be
used to determine bioavailability. Clinical studies have been used to establish
bioequivalence for topical anti-fungal drug products (eg: Ketoconazole) and for topical acne
Preparations. The FDA considers this method only when analytical method and
pharmacodynamics method are not available to permit use of one of the approaches.
Dissolution performance is influenced by physiochemical properties of the substance and
Physiological conditions in the GIT. The technique which assure about the biologic
availability of a drug is its in vitro dissolution test.
Table 4.2: Different in vitro dissolution apparatus are developed to mimic the environment offered
by the biological system
usP BP IP
Drug products
a
| Rotating basket | Rotating basket | Paddle type | Beads, capsules, floating
| type dosage forms
| Paddle type Paddle type Rotating basket | Tablet, capsules, enteric
type coated dosage forms
Reciprocating | Flow through Controlled release drug
cylinder cell products
Low solubility drugs
| Transdermal drug products
Transdermal drug products
Apparatus 7 | Reciprocating disk Non disintegrating
| controlled release drug
i products Bioavailability and Bioc
» |
Apparatus 1 (Rotating basket type); In this apparatus rotating basket acts as a stirrer located
in a cylindrical glass vessel with hemispherical bottom. This assembly is immersed in a
water bath to maintain the temperature at 37C. The ing speed
. The most common rotat
basket method is 100 rpm. = ms hes
Basket Shaft
Sampling Point
Vessel
Basket
Fig, 4.3: Apparatus 1 (Rotating basket type)
Advantages
«Full pH change can be made during the test.
«It can be easily automated which is important for routine work,
Disadvantages
« Hydrodynamic dead zone is created under the basket.
+ Disintegration-dissolution interaction occurs.
«Sink conditions for poorly soluble drugs.
Apparatus-2 (Paddle type): In this apparatus rotating basket is replaced with a paddle
which acts as a stirrer. The paddle is attached vertically to a speed motor that rotates at a
controlled speed. This method is very sensitive to tilting. Improper alignment may
drastically affect the dissolution results. The most common operating speed for apparatus 2
are 50 rpm for solid oral dosage forms and 25 rpm for suspension. Paddle
Capsule Sinker
Fig. 4.4: Apparatus-2 (Paddle type)
Advantages
* It is easy to use and robust.
« It can be easily adapted to apparatus 5.
* It can be easily automated which is important for routine investigation.
Disadvantages
* pH/media changes is difficult.
* Hydrodynamics are complex.
USP apparatus 3 (Reciprocating cylinder): It is considered as the first line apparatus in
Product development of controlled release preparations. The assembly consists of cylindrical
flat bottomed glass vessels, a set of glass reciprocating cylinder, stainless steel fitting screen
and a motor. Dosage form unit is placed in each of the six reciprocating cylinders. Sample is
withdrawn from the surface of the dissolution medium and the bottom of each vessel.
(a) (b)
Fig. 4.5: USP apparatus 3 (Reciprocating cylinder) Advantages
It exposes the products to mechanical as well as a variety of physiochemical conditions
which may influence the release of products in the Gl tract.
This apparatus is the technically easy and problem free use of test solutions with
different pH values for each time interval.
Italso avoids cone formation for disintegrating (immediate release) products, which can
be encountered with the USP apparatus 2.
+ Feasibility of drug release testing of chewable tablets.
Apparatus 4 (Flow through cell): It consists of a reservoir for the dissolution medium and a
pump that force dissolution medium through the cell holding the test sample. This
apparatus is of two types:
1. Open flow cell: This system has a configuration where fresh medium is pumped through
the cell and the fractions are collected every 30 to 60 minutes which result in rather high
fraction volume. This is not practicable for the laboratory and therefore a volume splitting
device (splitter) is used.
2. Close flow cell: This system has a configuration in which medium is pumped in circle
and not replaced by fresh medium. Elute is collected in a beaker which is stirred by a
magnetic stirrer. Readings can be taken on-line with spectrophotometer which measures the
cumulative drug release.
Fig. 4.6: Apparatus 4 (Flow through cell)
Advantages
* Open type flow cell offers the advantages of ability to change the pH conveniently
during the test.
Closed flow cell is used for drug products having very low dosage strength and
essentially it can be performed with very small volumes. PRT ee
Apparatus 5 (Paddle over disk): This apparatus consists of disk assembly that hold the
product in such a way that release surface is parallel with paddle. Paddle is directly attached
over disk assembly for holding transdermal dosage form. Samples are withdrawn away
from the surface of medium and top of paddle blade. The disk assembly is designed to
minimize any dead volume between the disk assembly and the bottom of the vessel.
Dissolution vessel
Paddle
— extraction cal
Membrane
‘Support
Fig. 4.7: Apparatus 5 (Paddle over disk)
Apparatus 6 (Cylinder type): This apparatus is a modified form of apparatus 1. In place of
the basket, a stainless steel cylinder is used to hold the sample. Transdermal patches can be
studied but cannot be cut into small size.
Dosage Form
Fig. 4.8: Apparatus 6 (Cylinder type)
Apparatus 7 (Reciprocating disk): In the reciprocating disk method for testing transdermal
products a motor driven assembly is used to reciprocate the system vertically and the
samples are placed on disk-shaped holders using cuprophan supports. The solution
containers are partially immersed in a suitable water bath and maintained at 3210.5°C. The FDA defines IVIVC as “a predictive mathematical model describing the relationship
between an invitro property of an extended release dosage form and a relevant in vivo
response. E.g. plasma drug concentration or amount of drug absorbed.” Correlations
between in vitro and in vivo data are used to reduce development time and optimize the
formulation. A good correlation is a tool for predicting in vivo results based on in vitro data.
IVIVC can be used as a surrogate for further bioequivalence studies. Correlation allows
dosage form optimization with the lowest possible trials in men, fixes dissolution acceptance
criteria, It is a relationship between in vitro dissolution rate and in vivo input as used in
bioequivalence guidance. When correlations are excellent, in vivo bioequivalence studies are
not essential. If the dissolution rate data are not adequate to ensure bioequivalence, then the
bioequivalence studies must be attempted. Based on the types of data used to establish the
telationship, there are three main levels defined by the FDA:
int linear relationship between in vitro dissolution and
be directly super-imposable or may be made to be
factor. Level A involves 1:1 relationship in which
d to plasma level time curve (bioavailability). It is
dissolution time curve is directly compares ee ; ; 7
applicable to extended release products and essentially independent of dissolution medium.
Human studies are not required as i” vitro curves serve as surrogate for in vivo performance
of formulation.
2 Level B: This level uses the principle
1. Level A: it represents a point-to-P
the in vivo input rate, ie. curves may
Super-imposable by the use of a scaling
«5 of statistical moment analysis. The mean in vitro
solution tim ared either to the mean residence time or to the mean in vivo
stlution time par ne vel B does not reflect the actual in vf plasma level
Curve as similar 1 a eres time values will be produced by number of different in vivo
ir mean 2) 9+ aaa EO oe
curves. Though in vitro and in vivo data are used, point to point correlation is attempted
Hence, it is less than 1:1 correlation.
3. Level C: This IVIVC level involves a single point relationship between a dissolution
Parameter. Level C correlation does not reflect the complete shape of the plasma drup
concentration time curve, which is an important factor for defining the performance op
extended release products. A multiple level C correlation relates one or several
pharmacokinetic parameters of interest to the amount of drug dissolved at several time
points of the dissolution profile.
Table 4.3: Various pharmacokinetic parameters can be used for the establishment of a correlation as
described in the FDA guidance
Sr.No. | Level Invitro |
1 A Dissolution curve Input (absorption curves)
2 B Statistical moment, MDT _| Statistical moments, MRT, MAT ete.
5 E Disintegration time, Dissolution | Cnax, tmax, ks, AUC, time to achieve |
rate 10%, 50% and 90% drug absorbed
There are various examples shows the failure of IVIVC indicating poor correlations of
dissolution to drug absorption. The reason behind for such a poor IVIVC are:
* Drug absorption is complex which cannot be mimicked in in vitro.
* Dissolution design weaknesses like physics of tabletting that operate during dissolution
are not clear.
Bioequivalence studies are the studies used to compare the bioavailability of the same drug
from various drug products. These studies are required during the course of development of
new drugs or when a patent of innovator’s drug product expires.
Need for bioequivalence studies
1. Bioequivalence studies provide a link between the pivotal and early clinical trial
formulation.
Bicequivalence studies are made mandatory for all drug products by FDA before
approving them for marketing.
Bioequivalence studies provide assurance given by the manufacturers to the patients that
their product gives the labeled therapeutic effect and safety.
np ——— rs 3 |
| Applications of bioequivalence studies
| 4, Bioequivalence studies allow substitution
equally effective.
2. Efficiency and safety of product from batch
reduced.
3. Bioequivalence studies also reduce the formulation variables.
' Limitations of bioequivalence studies
of one product by another product which is
to batch produced by same company are
1. Itis very difficult, time consuming and expensive process.
2. Therapeutically equivalent drug products may not be equally suitable for a particular
patient.
5. Bioequivalence studies are not necessary for the following cases:
a. An aqueous solution for parenteral use.
b.A solution for oral use.
c. A powder for reconstitution as a solution for oral or parenteral use.
d.An ophthalmic solution.
e. An inhalation product or nasal spray as an aqueous solution.
Types of equivalence
1. Equivalence: It is a relative term that compares one drug product with another or with a
set of established standards.
2. Chemical equivalence: Chemical equivalence indicates that two or more drug products
are containing the same labeled quantities of drug in the same amount.
3. Pharmaceutical equivalence: It indicates that two or more drug products are identical in
strength, quality, disintegration time and dissolution rate characteristics, but may differ
in excipients. ie
4. Therapeutic equivalence: it indicates that two or more drug products containing same
therapeutic ingredients, elicit identical pharmacological effects, FDA consider drug
Products to be therapeutically equivalent if they meet the following criteria;
a. Approved as safe and effective.
b. Pharmaceutically equivalent.
©. Adequately labeled.
d. Manufactured in compliance with cGI
Bivequivalence: Bioequivalence indicates
Teach the systemic circulation to the same
Clinical equivalence: When the same drug for
in vivo effect (measured by pharmacological
equivalent.
MP.
that drug in two or more similar dosage forms
lative rate and extent.
from two or more dosage forms give identical
response) are said to be clinically c
4.7.4 METHODS TO STUDY BIOEQUIVALENCE
1. In vivo bioequivalence study
This study requires determination of relative bioavailability. The reference product may be
previously approved product or usually an innovator’s product. The study is performed in
fasting, young, healthy, adult male volunteers to assure homogeneity in the population. This
study comprises of different types of design and then evaluation of data by different
methods.
Types of design
Cross over design: In a cross over design each subject receives two or more different
treatments on successive occasions.
Parallel group design:In a parallel group design, subjects are divided randomly into groups,
each group receiving one treatment randomly.
Comparison of designs
Table 4.4: Differentiate in between Cross over design and Parallel group design
Cross over design Parallel group design
‘Subject variability is not much and is not Subject variability is much and is included
| included into the error variability. into the error variability.
‘Numbers of subjects required are more.
Numbers of subjects required are less,
‘There is a fear of sequence or period effect. | There is no fear of sequence or period effect.
re
| Due to long wash out periods, subjects may | No fear of drop out.
| drop out.
Evaluation of the data
The data is evaluated by following methods:
* By using analyti
y be assessed by the use of in vitro dissoluti i changed
product d ion testing to confirm un B
2 quality and performance characteristics with minor formulation or manufacturing
“= 7 J
a pharmacodynamics studies
pharmacodynamics parameters may be used for establishing equivalence between two
rmaceutical products.
{, Comparative clinical trials
‘hese trials are carried out in following conditions:
+ Plasma drug concentration time profile data may not be suitable to assess equivalence
between two formulations.
+ Pharmacodynamics studies cannot be performed.
« Pharmacodynamics and pharmacokinetics studies are not feasible.
4.8 BIOAVAILABIL
There are different methods which are used to overcome the bioavailability problem:
4.8.1 ENHANCEMENT OF DRUG SOLUBILITY
|. Micronization
Nanonisation
Super critical fluid recrystallization
Spray freezing into liquid (SFL)
Evaporative Precipitation into aqueous soluti
© Use of surfactant
Use of salt form
Eutectic mixtures
Use of precipitation inhibitors
‘0Solid solution
‘Solid dispersion
'2Molecular encapsulation wi
jon (EPAS)
th Cyclodextrins
4.8.2 ENHANCEMENT OF DRUG PERMEABILITY
© Lipid technologies
~ lon pairing
Penetration enhancers
48.3 ENHANCEMENT OF DRUG STABILITY
* Use of metabolic inhibitors 9 Semen oe Ty
4.8.4 OF GASTROINTESTINAL RETENTION
4.8.1 Enhancement of drug solubility
L
Micronization: This technique is called an micro milling. The process involves reducing
the size of the solid drug particles 10 1-10 microns by spray drying or by use of air
attrition methods, fluid energy or jet mill). E.g. Griseofulvin and several steroidal and
sulpha drugs.
Nanonisation: In this technique the drug powder is converted to nano crystals of sizes
200-600 nm. E.g. amphotericin B. There are three technologies which are used to prepare
nano particles.
i. Pearl milling.
'. Homogenisation in water.
‘Homogenization in non aqueous media or in water with water miscible liquid.
Super critical fluid recrystallization:Super critical fluids are fluids whose temperature
and pressure are greater than its critical temperature (T.) and critical pressure (T;),
allowing it to assume the properties of both are liquid and a gas.Once the drug particles
are solubilizes within SCF, they may be recrystallize at greatly reduced particle size.
Spray freezing into liquid (SFL): This technique involves atomizing an aqueous
solution or suspension containing a drug and pharmaceutical excipients directly in to a
compressed gas or the cryogenic liquid (nitrogen). The frozen particles are then
lyophilized to obtain dry and free flowing micronized powders.
Evaporative Precipitation into aqueous solution (EPAS): This process utilizes rapid
Phase separation to nucleate and grow nano particles and microparticles of lipophilic
drugs. The drug is first dissolved in a low boiling point organic solvent which is pumped
through a tube where it is heated above the solvent boiling point and then spread
through a fine atomizing nozzle into a heated aqueous solution. Surfactant are added to
the, this [process facilitates dissolution rate.
Use of surfactant: Surfactant enhances both dissolution rate and permeability of drug:
They enhance dissolution rate primarily by promoting, wetting and penetration of
dissolution fluid into the solid drug particle. Nonionic surfactant like polysorbate Te
widely used. Bioavailability of steroids like spironolactone drugs have been increased bY
use of surfactant. /
Use of Salt forms: Sait has improved solubility and dissolution characteristics in
comparison to the original drug. It is generally accepted that a minimum difference of
three units between the pK, value of the group and that of the counter ion is required ©
form stable salt. Alkyl metal salt of acidic drugs like Penicillin and strong acid salts 0
‘basic drugs like atropine are more water soluble than the parent drug. 4, Eutectic Mixture: These systems are prepared by fusion method. When the eutectic
mixture is exposed to water, the soluble carrier dissolves leaving the drug in a
microcrystalline aa which solublizes rapidly. Such systems are basically intimately
blended physical mixture of two crystalline components.
9, Use of precipitation inhibitors: Increase in free drug concentration above equilibrium
solubility results in super absorption,which can lead to drug precipitation or
crystallization. This can be prevented by use of inert polymers such as HPMC, PVP, PEG
etc, Precipitation inhibitors act by one or more mechanism:
Inhibit crystallization three specific intermolecular interactions on growing crystal
surface.
* Adsorbs onto faces of host crystals, reduce the crystal growth rate of the host.
| Solid Solution: These are generally prepared by fusion method where by a physical
mixture of solute and solvent are melted together followed by rapid solidification. Solid
solutions show together followed by rapid solidification. Solid solution show greater
aqueous solubility and faster dissolution than eutectic and solid dispersion because of
reduction in particle size to the molecular level. The griseofulvin form such solid
solution dissolves 6-7 times faster than pure griseofulvin.
11, Solid Dispersion: Solid dispersion refers to the dispersion of one or more active
ingredients in an inert carrier in a solid state frequently prepared by hot melt method,
solvent evaporation method, hot melt extrusion method and co-precipitation techniques
where both the gas solute and the solid carrier solvent are dissolved in a common
volatile liquid which is removed and results in amorphous precipitation of guest in a
crystalline carrier. Such dispersion are often called co-evaporates.
2 Molecular encapsulation with Cyclodextrins: ‘Molecularly encapsulated drug. has
greatly improved aqueous solubility and dissolution a These cyclodextrin molecules
are versatile in having a hydrophobic cavity of size suitable engush to accommodatls ae
de of the host molecules is relatively hydrophilic.
lipophilic drug as guest; the outsi h
Tete dit S ean sand number of NSAIDs re the examples of drugs with
improved bioavailability by this method.
$82 ENHANCEMENT OF DRUG PERMEABILITY
© Lipid Technologies: Lipid base formulation have
ena , ism like:
Sees ane ner ee there by increasing the time available for
ion in gas!
dissolution and absorption.
Increased intestinal membrane P©?
“ Increased intestinal blood flow:
been designed to improve the their
rmeability-
an | 10 a 7 Ty
d. Increased luminal degradation.
e. Increased uptake from the intestinal lumen in to the lymphatic system.
2. Ion pairing: This approach involves co--“ministration of a hydrophilic or polar
with a suitable lipophilic counter ion, which improves the partitioning of the resultage
ion pair into the intestinal membrane. Ion pairing increase the oral bioavailability of the
ionizable drug by two folds.
3. Penetration enhancer: It acts by interaction its lipid part with the polar component of
membrane phospholipids. These facilitate the transport of drug across the biomembrane
This method is used for hydrophilic drugs which have difficulty in penetrating the
liquid structure of the biomemebrane. E.g. Fatty acids, salicylates, EDTA.
4.8.3 ENHANCEMENT OF DRUG STABILITY
1. Enteric Coating: This technique retards the release of drug in stomach example
Erythromycin, Penicillin-V etc.
2, Complexation; This technique is used to increase the stability of drug in GIT. Examples
ester drugs thus enhance their bioavailability.
3. Use of metabolism Inhibitor: Metabolism inhibitor selectively inhibits any of the
contributing processes which would result in increased fractional absorption and
enhance the bioavailability.
4.8.4 ENHANCEMENT OF GASTROINTESTINAL RETENTION
Excipients that are bio adhesive or that swell on hydration when incorporated in an oral
dosage forms can promote gastro retention and absorption by:
a. Increased contact with epithelial surfaces.
b. Prolonging residence time in the stomach.
c. Delaying intestinal transit. Ene ner
2 101
@ REVIEW QUESTIONS
MULTIPLE CHOICE QUESTIONS
(4. The comparison of bioavailability between two dosage forms.
A, Bioequivalence B. Bioavailability
(Bib bam ceutice D. Biological
Q2 The relative amount of an administered dose that reaches the general circulation and the rate
at which this occurs.
A. Biological B. Bioavailability
C. Biopharmaceutics D. Bioequivalency
Q3 Bioavailability of an intravenous drug is always 100% by definition because:
A. Bioavailability measures the amount of substance that reaches the bloodstream.
B.Absolute bioavailability is 50%, for any drug taken intravenously
C.Absolute bioavailability is a much more important measure than relative bioavailability
D. Intravenous administration gets the drug into your bloodstream the fastest.
Q4 Comparison of the rate and extent of the absorption of drug from the formulation under study
to the data of a reference standard that is given intravenously, is known as:
B. Relative bioavailability
A. Biopharmaceutics
C. Absolute bioavailability D. Bioavailability
Q5 Ifthe Relative Bioavailability is 1, it indicates:
A. Bioavailability of dosage form of one drug is same as that of the other dosage form
B. Complete binding of the drugs to the proteins as compared to the standard drug
C. Complete bioavailability of the drug
D. Complete distribution of the drug .
Q6 What would be the order of greater or lesser bioavailability of the dosage forms?
A Intravenous > rectal > oral > topical
B. Intravenous > oral > rectal > topical
C. Intravenous > topical > rectal > oral
D. Oral > intravenous > rectal > topical
KEYS ce
ara 028, 030,04, 054,268, | BY A Test Book of Biopharmaceutics and Pharmacokinevcs |
SHORT ANSWER TYPE QUESTIONS
1. _ Define bioavailability and bioequivalence.
Ans.:Bioavailability: It is the term which means the rate and extent to which the drug is
absorbed from its dosage form and becomes available at the site of action.
Bioequivalence: It may be defined as compare the bioavailability of the same drug from differen:
drug products.
2. Define bioavailable fraction and give its formula.
Ans.: Bioavailable fraction (F) is a term which refers to the fraction of administered dose that
enters the systemic circulation and can be calculated as:
p= Bivavailable dose
Administered dose
Q3_ Give the Significance of relative bioavailability:
Ans. Itis used to characterize absorption of a drug from its formulation.
Q-4. A drug is administered by oral and IV routes having following data:
For IV; Dose = 500 mg, AUC = 13.1pghr/ml.
For oral; Dose = 1000 mg, AUC
= 20.9 pghr/ml.
Calculate the absolute bioavailability for the above drug.
Ans.:
As we know;
Absolute Bioavailability (F, 9) = AUC (Oral) xDose(IV),
AUC(IV)x Dose (Oral)
Replacing the values in the equation;
100
Q
Calculate the relative bioavailability of capsule and SR tablet against oral solution.
Ans:
Relative bioavailability (F,) of capsule against oral solution:
As per equation; Relative Bioavailability (F,,%) = ee
‘Std)x
