1. Experimental & Clinical Validation of
Classical and Proprietary Ayurvedic
Formulations
K V GOPINATH M Pharm PhD,CPhT
Tirumala Tirupati Devasthanams
TIRUPATI
e-mail:gopinath.karnam@gmail.com

2. Definitions
 Proprietary Name : It is the trade name/brand name of the drug
given by the manufacturer.
- designate the drug’s source of manufacture and
- to differentiate it from the similar drug from the other
manufacture.
 Chemical Name: It is the name used to indicate the chemical
structure of the drug.
 Generic Name: It is the established, non proprietary or common
name or official name of the active drug in a drug product used in
official compendium.
– The generic product must be a therapeutic equivalent to the reference drug
product .
 Drug Product: It means a finished dosage form, e.g., tablet, capsule,
or solution, that contains the active drug ingredient, generally, but
not necessarily, in association with inactive ingredients.

3. Definitions
 Bioequivalent drug product: A drug is said to be bioequivalent to the
reference generally brand drug if both products are pharmaceutical
equivalents and its rate and extent of systemic drug absorption do not show
a statistically significant difference when administered in the same dose of
the active ingredient in the same chemical form, in a similar dosage form,
by the same route of administration and under the same experimental
conditions.
-If two drugs are bioequivalent, there is no clinically significant difference in their
bioavailability
 Pharmaceutical Equivalents: Drug products that contain the same
therapeutically active drug ingredients(s), same salt, ester, or chemical
form; are of the same dosage form; and are identical in strength and
concentration and route of administration. It may differ in characteristics
such as shape, scoring configuration, release mechanisms, packing, and
excipients ( including colors, flavors , preservatives).

4. Definitions
 The reference drug product: It is usually the currently marketed,
brand name product with a full New Drug Application(NDA)
approved by the FDA
 Pharmaceutical alternatives: These are drug products that contain
the same therapeutic moiety but are different salts, esters, or
complexes(Tetracycline HCl vs Tetracycline PO4) or are different
dosage forms( tablets vs capsule; immediate release dosage form vs
controlled release dosage form); or strengths.
 Clinical Trial: A clinical study is a systemic study of pharmaceutical
products in human subjects to evaluate safety and efficacy of the
product (pharmacological action i.e. pharmacokinetic /and
pharmacodynamic /toxic effect of the drug).
 Pharmacokinetics: It is a science dealing with absorption,
distribution, metabolism ,excretion, and toxic study of the drug
product in a biological system.

5. Definition
 Bioavailability :It is a measurement of the rate and extent (amount)
of therapeutically active drug which reaches the general circulation.
 Relative bioavailability: It is important for generic drug studies. It
is the systematic availability of the drug from a dosage form as
compared to a reference standard given by the same route of
administration.
 Absolute bioavailability: It is the fraction of drug systematically
absorbed form the dosage form.
_ It is calculated as the ratio of the AUC for the dosage form
given orally to the AUC obtained after IV drug administration.
 Supra – Bioavailability: This is a term used when a test product
displays an appreciably larger bioavailability than the reference
product.

6. Proprietary/ Classical Drug Evaluation ?
 There are a number of examples of drugs
products which have exhibited bioavailability
problems in the past.
-Chlorpropamide: With three products tested the
peak plasma concentration after one brand was less than 1/2
the peak after the other two products
-Digoxin: The text reports a number of bioavailability
problems with digoxin due to change in formulation to
enhance dissolution.
- Phenytoin : intoxication due to change in diluents
from Calcium sulfate to Lactose
 This is an indication that more attention is now
being given to formulation development during drug
development.
Fig : Plot of Cp versus Time of
Chlorpropamide of A,B, C Brands

7. Reasons for Bio equivalence
 The FDA may decide to require bioavailability studies for a variety
of reasons including:
-Results from clinical studies indicate that different drug
products produce different therapeutics results.
-Results from bioavailability studies indicate that different
products are not bioequivalent.
-Drug has a narrow therapeutic range.
-Low solubility and/or large dose.
-Absorption is considerably less than 100%

8. Bioavailability & Bioequivalence
Determination
 Plasma Drug Concentration VS Time Profile
 Urinary Drug Excretion Studies
 Measurements of an acute Pharmacological effect
 Clinical studies (or)
 In vitro measurements of Bioequivalence

9. Measurement of an Acute Pharmacological
effect
 A good correlation exists between the Pharmacologic
response and plasma concentration. Over at least a limited
concentration range, the intensity of pharmacologic effects
should increase with plasma concentration. This
relationship allows us to predict pharmacologic effects with
changing plasma drug concentrations
 Wide inter subject variation in plasma drug concentrations
results from a given dose.
 When pharmacologic effects relate to plasma drug
concentrations, the latter can be used to predict the former.
 The drug’s desired pharmacologic effects cannot be
assessed readily by other simple means (e.g., blood
pressure measurement for anti hypertensives).

10. Measurements of an Acute Pharmacological
effect
 Acute Pharmacological effects such as changes in heart rate, blood
pressure, ECG, clotting time or FEV1 can be used to measure
bioavailability
or
When the plasma drug concentration does not relate to the
pharmacological response (Albuterol inhalation).
 Quantitation of the pharmacological effect VS time profile can be
used as a measure of bioavailability or bioequivalence.
 The parameters used to known as Pharmacodynamic Parameters
 Pharmacodynamics : It is the study of the relation of the drug
concentration or amount at the site of action (receptor) and its
pharmacological response

11. Pharmacodynamic Parameters : Onset of
Action
 Onset time
 Intensity
 Duration of Action
 Therapeutic window
Onset Time
It is the time required for the drug to start producing
pharmacological response. It corresponds to the time for the plasma
concentration to reach MEC after administration of drug.
Onset of Action
The beginning of pharmacological response is called as on set
of action. It occurs when the plasma drug concentration just exceeds
the required MEC.

12. Pharmacodynamic Parameters
Minimum Effective Concentration (MEC)
 It is defined as the minimum concentration of drug in plasma
required to produce the therapeutic effect.
 It reflects the minimum concentration of drug at the receptor site to
elicit the desired pharmacological response. The concentration of
drug below MEC is said to be in the sub therapeutic level.‐
 In case of antibiotics, the term minimum inhibitory
concentration(MIC) is used. It describes the minimum concentration
of antibiotic in plasma required to kill or inhibit the growth of
microorganisms.

13. Pharmacodynamic Parameters
Intensity
 It is the maximum pharmacological response produced by the peak
plasma concentration of drug. It is also called as peak response.
 It is proportional to the number of receptors occupied by the drug up
to a maximum pharmacological effect.
Duration of Action
 The time period for which the plasma concentration of drug remains
above the MEC level is called as duration of drug action.
 It is also defined as the difference between on set time and time for
the drug to decline back to MEC.
Maximum Safe Concentration (MSC) / Minimum Toxic
Concentration (MTC) :It is the concentration of drug in plasma
above which adverse or unwanted effects are precipitated.
Concentration of drug above MSC is said to be in the toxic level.

14. Pharmacodynamic Parameters
Therapeutic Range/therapeutic window
 The drug concentration between MEC and MTC
Therapeutic Index
 The ratio of MTC to MEC is called as therapeutic index.
 It is also defined as the ratio of dose required to produce toxic or
lethal effects to do so required to produce therapeutic effect.
- The therapeutic index of a drug is a relative measure of the
safety and effectiveness in laboratory studies.
- The therapeutic index is the ratio of the minimum dose that is
toxic for 50% of the population (TD 50 or median toxic dose) to the
minimum dose that is effective for 50% of the population (ED 50%or
median effective dose)
Margin of safety: Ratio of the minimum toxic for 0.1% of the
population to the minimum effective dose for 99.9% of the

15. Plasma Drug Concentration Vs Time Curve
 It is most often to measure the systemic bioavailability of a drug
from a drug product
 Pharmacokinetic parameters used to define the plasma drug
concentration vs time curve
-Time for peak plasma drug concentration (T max)
- Peak plasma drug concentration (C max ) and
-Area under the plasma drug concentration (AUC)

16. Pharmacokinetic Parameter
Peak plasma drug concentration (C max) : The peal plasma drug concentration at
Time T. It relates to the intensity of the pharmacological response. Ideally ,
C max should be within the therapeutic window
Area under the plasma drug concentration (AUC):
- It relates to the amount or extent of drug absorption.
-The amount of systemic drug absorption is directly related to the AUC.
-The AUC is usually calculated by the Trapezoids rule and expressed in
units of concentration multiplied by time (mg * hr/ml)
-The AUC is directly proportional to the dose when the drug follows
linear kinetics.
-The AUC is inversely proportional to the clearance of the drug.
Time for peak plasma drug concentration (T max):
It relates to the rate constant for systemic absorption and elimination.
If two oral drug products contain the same amount of active drug but
different excipients, the dosage form that yields the faster rate of drug
absorption has the shorter T Maxbecause the elimination rate constant for the

17. Urinary Drug Excretion
 Urinary Drug Excretion :Measurement of urinary drug excretion
can determine bioavailability from a drug product. This method is
more accurate if the active therapeutic moiety is excreted unchanged
in significant quantity in the urine
 The cumulative amount of active drug excreted in the urine(DU
∞
)
is directly related to the extent of systemic drug absorption.
 The rate of drug excretion in the urine ( dDU/dt) is directly related
to the rate of systemic drug absorption
 The time for the drug to be completely excreted (t∞) :corresponds
to the total time for the drug to be systemically absorbed and
completely excreted after administration.

18. Clinical (Pharmacodynamic) response & In
vitro measurements of bioequivalence
 Clinical responses to a drug can be used to measure bioavailability
quantitatively: however they are less precise than other methods and
are highly variable because of individual differences in drug
pharmacodynamics and subjective measurements.
 In vitro measurements of bioequivalence: Especially when an in
vitro test has been correlated with human in vivo bioavailability
data.
_ For e.g., the rate of drug dissolution in vitro for certain drug
products correlates with drug bioavailability in vivo. If the
dissolution test in vitro is considered statistically adequate to predict
drug bioavailability, then dissolution may be used in place of an in
vivo bioavailability study.

19. Evaluation of a drug product bioavailability
 The study involves
consideration of
various factors
– Drug
– Drug product
– Subjects
• Health
• Age
• Weight
• Enzyme status
• Number
– Assay
– Design
– Data Analysis
 Drug: Bioavailability studies are conducted to compare
two or more products/dosage form containing the same
chemical substance.
 The apparent volume of distribution and kel can be
quite different for different drug substances, thus no
interpretation of the results is possible.
 The only time that this rule is relaxed is in the case of
pro-drug administration.
- In this case it may be appropriate to compare the delivery of a
dosage form containing the drug with another dosage form containing
a pro-drug. This testing is generally conducted to evaluate the
usefulness of the pro-drug, rather than a strict comparison of the drug
products.

20. Evaluation of a drug product bioavailability
 The study
involves
consideration of
various factors
– Drug
– Drug product
– Subjects
• Health
• Age
• Weight
• Enzyme status
• Number
– Assay
– Design
– Data Analysis
 Drug Product: Usually the comparison is made
between two (or more) similar products, containing
exactly the same chemical substance.
 However, different dosage forms can be compared
(when they contain the same drug). For example we
could compare an IM dosage form with IV dosage
form.
 Subjects: health, age, weight, enzyme status,
number.
– Health: Healthy Volunteers, some times diseased population
– Age: subjects between the ages of 18 to 35 years are preferred.
Kinetic changes usually aren't important until age greater than
60.
– Weight: The apparent volume of distribution is usually
proportional to weight in subjects of normal weight for height
– Enzyme Status: Smokers/poly pharmacy

21. Evaluation of a drug product bioavailability
 The study
involves
consideration of
various factors
– Drug
– Drug product
– Subjects
• Health
• Age
• Weight
• Enzyme status
• Number
– Assay
– Design
– Data Analysis
 Assay: The same assay method should be used for all
phases of the study . The assay method should be
sensitive and specific.
 Design: Usually a complete cross-over design is used.
With this design each subject receives all products
with a wash-out period between each dose
administration.
 Data Analysis: ANOVA
 Acceptance Criteria for Bioequivalence: There must
be no more than 20% difference in AUC and C max of
brand name vs generic. But narrow therapeutic drugs
have different range of acceptance i.e. 90% 112%