Biopharmaceutics Classification

System
Lecture no.4
Dr.Randa
• the BCS is an experimental
model, centrally embracing
permeability and solubility, with
qualifications related to pH and
dissolution.
BIOPHARMACEUTICS CLASSIFICATION SYSTEM

INTRODUCTION
• The biopharmaceutics classification system is guidance for
Predicting the intestinal drug absorption provided by the U.S.
Food and Drug Administration. The fundamental basis for the
BCs was established by Dr. Gordon Amidon.

DEFINITION
• The Biopharmaceutical Classification System is a scientific
framework for classifying a drug substance based on its
aqueous solubility & intestinal permeability & dissolution rate.
 OBJECTIVE OF THE BCS

• To predict in vivo performance of drug product using

solubility and permeability measurements.

• Aid in earliest stages of drug discovery research.

• For research scientist to decide upon which drug delivery

technology to follow or develop.

• Also for the regulation of bioequivalence of the drug

product during scale up and post approval.
 PARAMETERS OF DRUGS CLASSIFIED
IN BCS
The drugs are classified inn BCS on the basis of following
parameters:

1. SOLUBILITY
• The Maximum Amount of solute dissolved in a given
solvent under standard conditions of temperature, pressure
and pH.
• Solubility is the ability of the drug to be solution after
dissolution.
• The higher single unit dose is completely soluble in 250 ml
at pH 1- 6.8 ( 37˚C ).
2. PERMEABILITY

• Permeability of the drug to pass the biological

membrane which is the lipophilic.

• Permeability is indirectly based on the extent of

absorption of a drug substance.

• Drug substance is considered to be highly

permeable,when the extent of absorption in
human determined to be 90% or more of
administered drug or compare to in vivo reference
dose.
• A drug substance is considered “highly
soluble” when the highest dose strength is
soluble in 250 ml or less of aqueous media
over a pH range of 1–7.5 at 37°C.

• A drug substance is considered to be “highly

permeable” when the extent of the
absorption (parent drug plus metabolites) in
humans is determined to be 90% of an
administered dose based on a mass balance
determination or in comparison to an
intravenous reference dose.
 Predicting Routes of Drug Elimination
• Class 1 and Class 2 compounds are eliminated primarily via
metabolism, whereas Class 3 and Class 4 compounds are
primarily eliminated unchanged into the urine and bile .

• the high permeability of the Classes 1 and 2 compounds allows

ready access to the metabolizing enzymes within hepatocytes, it is
noted that more permeable lipophilic compounds make good
substrates for cytochrome P450 (CYP) enzymes.

• Note that the differential permeability characteristics defined

under BCS do not necessarily reflect differences in permeability
into hepatocytes, as a number of Class 3 and Class 4 compounds
are eliminated into the bile. Rather, the high vs. low permeability
designation reflects differences in access to the metabolizing
enzymes within the hepatocytes.
• Mebendazole
• are eliminated predominantly in the unchanged form by
the renal or biliary route.
• We suspect that mebendazole is misclassified, as it is
extensively metabolized,Lindenberg et al.
• most recently listed mebendazole as either Class 2 or Class
4.
• So that means the BCS classification can used for
predicting drug disposition, the extent of metabolism may
be a better predictor than the 90% absorption
characteristic
• One might suspect that the high-permeability compounds (Class 1
and Class 2) should have higher volumes of distribution than the
low-permeability Class 3 and Class 4 compounds.
• BUT Many highly protein bound acidic Class 1 and Class 2
compounds exhibit very low volumes of distribution (e.g., valproic
acid, ibuprofen).
• so this correlation would be incorrect, however, to conclude that
correction for protein binding would give a better prediction of
the relative size of the volume of distribution in comparing
Classes 1 and 2 compounds with Classes 3 and 4 drugs.
• In fact, analysis demonstrates that the generally larger volumes of
distribution for Class 1 and Class 2 compounds when compared to
Class 3 and Class 4 compounds is independent of the degree of
protein binding.
• New molecular entities (NMEs) today are frequently large-molecular-
weight, lipophilic, poorly water-soluble compounds that most often fall
into BCS Class 2.
• Lipinski’s Rule of 5 was developed to set “drugability” guidelines for
NMEs. In the drug discovery setting, the Rule of 5 predicts that poor
absorption or permeation is more likely when there are more than 5 H-
bond donors, 10 H-bond acceptors, the molecular weight is greater than
500, and the calculated Log P (CLog P) is greater than 5.
• However, Lipinski specifically states that the Rule of 5 only holds for
compounds that are not substrates for active transporters.
• When the Rule of 5 was developed, information about drug
transporters was very limited. Studies to date have not been able to
show this because we are just beginning to gain the knowledge and tools
that allow investigation of substrates for uptake transporters. In
addition, unless a drug molecule can passively gain intracellular access, it
is not possible to simply investigate whether the molecule is a substrate
for efflux transporters.
 DISSOLUTION

• A drug product is considered to be RAPIDLY DISSOLVING

when > 85% of the labeled amount of drug substance
dissolves within 30 minutes using USP dissolution
apparatus I or II in a volume of 900 ml or less in the following
media:

1.0.1 N HCl or simulated gastric fluid (pH 1.2) without

enzyme.
2. pH 4.5 buffer & pH 6.8 buffer.
3. Simulated intestinal fluid without enzyme.
 In-vitro dissolution testing

• For an in vitro test to be useful, it must predict the in

vivo behavior to such an extent that in vivo bioavailability test
need not be performed.

• the in vitro dissolution technique is till by no means a

perfect approach.

• The efforts are mainly aimed at mimicking the environment

offered by the biological system
 Official and Non-Official dissolution
Methods
• There are basically three general
categories of dissolution apparatus in
Official Methods:

1. Beaker methods
2. Open flow-through compartment system
3. Dialysis concept
 Beaker methods .1

1. Rotating Basket Apparatus.

2. Rotating Paddle Apparatus.
3. The Reciprocating Cylinder Method.
4. Paddle over Disk method.
5. Cylinder method.
6. Reciprocating Holder method
 Rotating and Basket Apparatus

• It is basically a closed-compartment, beaker

type Apparatus
• instead of rotating basket, a paddle used.
• 50 rpm-for oral dosage forms, 25 rpm-
suspensions.
• A small, loose, wire helix may be attached to
the dosage form that would otherwise float.
 The Reciprocating Cylinder
Method
For testing of extended release products.
This method is less suitable for precise
dissolution testing due to the amount of agitation
and vibration involved.
 Paddle over Disk method

For testing the release of drug from

transdermal products.
 Rotating Cylinder method

A stainless steel cylinder is used to hold

the sample.
.
 For testing transdermal preparations.
Reciprocating Disc/Holder
method
 Open flow-through .2
compartment system
For modified release dosage forms, containing active
ingredients with limited solubility.
E.g. lipid filled soft Gelatin capsule.
 Dialysis concept .3

Here, dialysis membrane used as a

selective barrier between fresh solvent
compartment and the cell compartment
containing dosage form.

It can be used in case of very poorly

soluble drugs and dosage form such as
ointments,creams and suspensions.
Dialysis concept .3
 Non-Official Methods

1. The Rotating Filter Method.

2. Rotating Flask Dissolution Method.

3. Rotating and Static Disk Methods.

 PLASMA DRUG CONCENTRATION–TIME
CURVE
•As the drug reaches the systemic circulation,
plasma drug concentrations will rise up to a
maximum if the drug was given by an extravascular
route.
•Usually, absorption of a drug is more rapid than
elimination.
•As the drug is being absorbed into the systemic
circulation, the drug is distributed to all the tissues
in the body and is also simultaneously being
eliminated.
 .…Plasma level-time curve
 Plasma level-time curve is generated by
measuring the drug concentration in plasma taking
samples at predetermined time intervals after the
administration of drug.

 Drug concentration in each plasma sample is

plotted against the corresponding time at which the
plasma sample was withdrawn.
 Drug Product Performance
:
Parameters
1) Minimum effective concentration (MEC): Minimum
concentration of drug needed at the receptor site to
produce the desired pharmacologic effect.

2) Minimum toxic concentration (MTC): Minimum drug

concentration needed to produce a toxic effect.

3) Onset time: The time required for the drug to reach the
MEC.

4) Duration of action: The difference between onset time

and the time for the drug to decline back to the MEC.
5) Tmax: The time at which maximum drug concentration
observed in plasma. It is proportional to the rate of drug
absorption.
6) Cmax: The maximum drug concentration observed in
plasma
at a particular time. It is usually related to the dose and the
rate constants for absorption and elimination of the drug.
7) AUC: It is related to the amount of drug absorbed
systemically.
8)TERMINATION OF ACTION
The time when the medicinal agents stop showing the therapeutic
action and go down to the minimum effective concentration (MEC) in
the systemic circulation.

9)THERAPEUTIC RANGE
The range of the drug concentration in systemic circulation within
which medicinal agent shows the therapeutic effect.
 Relationship between the
administered dose and amount of
drug in the body
• Only the bioavailable drug will produce the therapeutic activity

Intravenous solution Extravascular route

• (AUC)0 - area under curve of plasma drug concentration versus

time (AUC) from time zero to time infinity
• K – First order elimination rate constant
• V (or Vd) – drug’s volume of distribution
• F – Bioavailable fraction
Plasma concentration versus time plot
– extravascular route
•The therapeutic window is the concentrations between
the MEC and the MTC.

•Drugs with a wide therapeutic window are generally

considered safer than drugs with a narrow therapeutic
window.

•Sometimes the term therapeutic index is used. This term

refers to the ratio between the toxic and therapeutic
doses.
Plasma concentration versus time plot
– Intravenous route
Comparisons between Intravascular
and Extravascular routes
INTRAVASCULAR EXTRAVASCULAR
ROUTE ROUTE

-no absorption phase -absorption phase is exist

- immediate onset of -Therapeutic action is
action regulated by factors such as
- 100 % dose available to formulations, dosage form,
show the therapeutic etc
action - entire administered dose
-Adverse reactions are may not reach target site
difficult to reverse ( poor absorption)
 CONCLUSION
• Biopharmaceutical classification system aims to provide
regulatory tools for replacing certain bio-equivalence studies
by accurate in vivo dissolution tests.

• The in vivo pharmacokinetics of drug depends largely on

the solubility and permeability.

• Many laboratories are engaged to find better means to

estimates in vivo behavior of the drug after oral
administration by using simple in vitro dissolution tests