ivivc is a great concept of interest it tells about the BCS classification and biowaiver also tells about the dissolution studies.

1. Presentation Title

2. INTRODUCTION
• IVIVC can be used in the development of new pharmaceuticals to reduce
the number of human studies during the formulation development.
• In recent years, the concept and application of the in vitro-in vivo
correlation (IVIVC) for pharmaceutical dosage forms have been a main
focus of attention of pharmaceutical industry, academia, and regulatory
sectors.
• IVIVC could also be employed to establish dissolution specification and to
support and/or validate the use of dissolution methods.

3. DEFINITIONS
• Acc. to FDA:
It is defined as a predictive mathematical model describing
the relationship between an in-vitro property(rate or extent of drug
dissolution or release) of a dosage form and an in vivo response(plasma
drug concentration or amount of drug absorbed.)
• Acc. To USP:
The establishment of the relationship b/w a biological
property, or a parameter derived form a biological property produced
from a dosage form, and a physicochemical property of same dosage
form.

4. CORRELATION LEVELS
• Level A correlation: Highest category of correlation and represent a point
to point relationship b/w in-vitro dissolution rate and in-vivo input rate of
the drug from the dosage form. Percent of drug absorbed may be
calculated by means of model dependent technique such as Wagner-
Nelson Procedure or Loo-Riegelman method or by Model independent
numerical deconvolution.

5. CORRELATION LEVELS(contd.)
• Level B correlation: In this level of correlation, the mean in-
vitro dissolution time(MDT vitro) of the product is compare to
either mean in vivo residence time MRT or in vivo dissolution
time (MDT vivo). It uses all of the in vivo or in vitro data and
not to be considered a point to point correlation.

6. CORRELATION LEVELS(contd.)
• Level C Correlation: In this level one dissolution time point ( t50% , t90%, etc) is
compare to one mean pharmacokinetic parameter such as AUC, tmax or cmax. It is
weakest level of correlation as partial relationship b/w absorption and
dissolution is established and represents a single point correlation and
doesn’t reflect the entire shape of plasma drug conc. curve.

7. CORRELATION LEVELS(contd.)
• Multiple Level Correlation: It relates one or several pharmacokinetic
parameters of interest (cmax, AUC or any other suitable parameters) to the
amount of drug dissolved at several time points of the dissolution profile.
It should be based on at least three dissolution time points covering the
early, middle, and late stage of the dissolution profile.
• Level D Correlation: It is rank order and qualitative analysis and is not
considered useful for regulatory purposes. It is not formal correlation but
serve as an aid in the development of a formulation or processing
procedure.

8. THE CORRELATION BETWEEN IN VITRO DRUG DISSOLUTION AND
IN VIVO DRUG ABSORPTION

9. Biopharmaceutics Classification System (BCS)
• The (BCS) has been developed to provide a scientific approach to allow for
the prediction of in vivo pharmacokinetics of oral immediate release (IR)
drug products by classifying drug compounds based on their solubility
related to dose and intestinal permeability in combination with the
dissolution properties of the dosage form.

10. BCS Classification
According to the BCS, drug substances are classified as
follows:
• Class I - High Permeability, High Solubility
• Class II - High Permeability, Low Solubility
• Class III - Low Permeability, High Solubility
• Class IV - Low Permeability, Low Solubility

11. BCS (Contd.)
• The BCS is a scientific framework for classifying drug substances based on
their aqueous solubility and intestinal permeability. When combined with
the dissolution of the drug product, the BCS takes into account three
major factors that govern the rate and extent of drug absorption from IR
solid oral dosage forms: dissolution, solubility, and intestinal permeability.

12. CLASS BOUNDARIES
• A drug substance is considered HIGHLY SOLUBLE when the highest dose
strength is soluble in < 250 ml water over a pH range of 1 to 7.5.
• A drug substance is considered HIGHLY PERMEABLE when the extent of
absorption in humans is determined to be > 90% of an administered dose,
based on mass-balance or in comparison to an intravenous reference
dose.
• A drug product is considered to be RAPIDLY DISSOLVING when > 85% of
the labeled amount of drug substance dissolves within 30 minutes using
USP apparatus I or II in a volume of < 900 ml buffer solutions.

13. The benefits of knowing the BCS category of a compound
• It can save both time and money—if the immediate -release, orally
administered drug meets specific criteria, the FDA will grant a waiver for
expensive and time-consuming bio-equivalence studies.
• The aim of the BCS is to provide a regulatory tool for the replacement of
certain BE studies by conducting accurate in vitro dissolution tests.
• Combined with the dissolution, the BCS takes into account the three
major factors governing bioavailability viz. dissolution, solubility and
permeability.

14. Key Parameters Controlling Drug Absorption
• Absorption number (An) :-
defined as the ratio of the mean residence time to
mean absorption time.
Radius of GI
Residence time in GI
( )
ABS
GI
GI
eff
T
T
T
R
P
An =





=
Effective permeability
Time required for complete absorption

15. Key Parameters Controlling Drug Absorption (contd.)
• Dissolution number (Dn) :-
defined as the ratio of mean residence time to
mean dissolution time.
( ) 





=











=
DISS
GI
GI
S
T
T
T
C
r
D
Dn
ρ2
3
Diffusivity
5x10-6
cm2
/s
Particle Radius
25 µm
Solubility
mg/mL
Density
1.2 mg/cm3
Residence time in GI
180 min
Time required forcomplete dissolution

16. Key Parameters Controlling Drug Absorption (contd.)
• Dose number (D0) :-
defined as the mass (Dose) divided by the product
of (uptake volume (250 ml) and solubility of drug).










=
S
Water
C
V
D
Do
Highest Dose Unit 250 mL
Solubility

17. Class I
• Class I drugs exhibit a high absorption number and a high
dissolution number. The rate limiting step is drug dissolution.
• If dissolution is very rapid, then gastric emptying rate becomes the
rate determining step.
• e.g. Metoprolol, Diltiazem, Verapamil, Propranolol.

18. Class II
• Class II drugs have a high absorption number but a low dissolution
number. In vivo drug dissolution is then a rate limiting step for
absorption except at a very high dose number. The absorption for
class II drugs is usually slower than class I and occurs over a longer
period of time.
• In vitro- In vivo correlation (IVIVC) is usually excepted for class I and
class II drugs.
• e.g. Phenytoin, Danazol, Ketoconazole, Mefenamic acid,
Nifedinpine.

19. Class III
• For Class III drugs, permeability is rate limiting step for drug
absorption. These drugs exhibit a high variation in the rate and
extent of drug absorption.
• Since the dissolution is rapid, the variation is attributable to
alteration of physiology and membrane permeability rather than the
dosage form factors.
• e.g. Cimetidine, Acyclovir, Neomycin B, Captopril.

20. Class IV
• Class IV drugs exhibit a lot of problems for effective oral administration.
Fortunately, extreme examples of class IV compounds are the exception
rather than the rule and are rarely developed and reach the market.
Nevertheless a number of class IV drugs do exist. e.g. Taxol.

21. Applications of BCS in oral drug delivery technology
• Once the solubility and permeability characteristics of the drug are known
it becomes an easy task for the research scientist to decide upon which
drug delivery technology to follow or develop.

22. CLASS I DRUGS
• The major challenge in development of drug delivery system for class I
drugs is to achieve a target release profile associated with a particular
pharmcokinetic and/or pharmacodynamic profile.
• Formulation approaches include both control of release rate and certain
physicochemical properties of drugs like pH-solubility profile of drug.

23. CLASS II DRUGS
• The systems that are developed for class II drugs are
based on micronisation, lyophilization, addition of
surfactants, formulation as emulsions and
microemulsions systems, use of complexing agents like
cyclodextrins.

24. CLASS III DRUGS
• Class III drugs require the technologies that address to
fundamental limitations of absolute or regional permeability.
Peptides and proteins constitute the part of class III and the
technologies handling such materials are on rise now days.

25. CLASS IV DRUGS
• Class IV drugs present a major challenge for development of
drug delivery system and the route of choice for
administering such drugs is parenteral with the formulation
containing solubility enhancers.

26. IN VITRO-DISSOLUTION
• Purpose of the in vitro dissolution studies in the early stage of
the drug development is to select the optimum formulation,
evaluate the active ingredient and excipient, and assess any
minor changes for drug products.
• For the ivivc perspective, dissolution is proposed to be a
surrogate of drug bioavailability.

27. Why do we study dissolution?
Disintegration Dissolution Absorption Drug in
the blood
and the
body

28. TYPES OF DISSOLUTION APPARATUS
Apparatus
Name
Apparatus 1 Rotating basket
Apparatus 2 Paddle
Apparatus 3 Reciprocating cylinder
Apparatus 4 Flow cell
Apparatus 5 Paddle over disk
Apparatus6 Cylinder
Apparatus7 Reciprocating disc

29. Apparatus 1 (ROTATING BASKET)
• In case of none-disintegrating dosage forms
this apparatus is superior to apparatus 2
since it constraints the dosage form in a
steady state fluid flow
• It is inferior for testing dosage forms which
contains gums due to clogging of screen
matrix

30. Apparatus 2 (ROTATING PADDLE)
• This apparatus is identical to apparatus
1 except that the paddle is substituted
for the rotating basket
• Frequently used for both disintegrating
and non-disintegrating dosage forms

31. Apparatus 3 (RECIPROCATING CYLINDER)
• One advantage of the reciprocating
cylinder is that the gastrointestinal
tract conditions can be easily
simulated, as it is easy to make time
dependent pH changes
• This apparatus is most suitable for
nondisintegrating (extended release) or
delayed release (enteric coated)
dosage forms

32. Apparatus 4 (FLOW CELL)
• The advantage of flow through cell
apparatus is the ability to test drugs of
very low aqueous solubility and the
ability to change the pH conveniently
during the test

33. Apparatus 5 (PADDLE OVER DISK)
• In paddle over the disc apparatus
the disc is placed and above that
the paddle is rotated .
• Mainly use in case of trandermal
preperations.

34. Apparatus 6 (CYLINDER)
• The cylinder method (Apparatus 6) for
testing transdermal preparation is
modified from the basket method
(Apparatus 1). In place of the basket, a
stainless steel cylinder is used to hold
the sample.

35. Apparatus 7 (RECIPROCATING DISK METHOD )
• In the reciprocating disk method for
testing transdermal products, a motor
drive assembly (Apparatus 7) is used to
reciprocate the system vertically, and
the samples are placed on disk-shaped
holders using cuprophan supports

36. DISSOLUTION MEDIUM
• Water or simulated gastric fluid(pH1.2) or intestinal
fluid( pH6.8 or 7.4) without enzyme, Buffer with a pH
range(4.5-7.5)
• For sparingly water soluble drugs surfactant may be added in
dissolved medium

37. SAMPLING TIME POINTS
Time Points
IR products
• Test duration : 15 to 60 minutes
Specifications
• Dissolution profile : sampling at 5-, 10-or 15-minute
intervals

38. SAMPLING TIME POINTS(contd.)
• Extended-Release Products
Test time : at least 3 test times
• Early time point : 1-2 hours : potential dose
dumping
• Intermediate time point : define the release
profile
• Final time point : show complete release of the
drug

39. IN VIVO ABSORPTION
• FDA requires in-vivo bioavailability test for NDA
• Bioavailability studies performed in young healthy male
volunteers. under some restriction conditions like :-
• fasting
• Non smoking
• No intake of other medications

40. APPROACHES FOR DETERMINING IN-VIVO ABSORPTION
Wagner-Nelson - One
compartment
Loo-Riegelman - Multi
compartment
Numerical Deconvolution - Both model
independent
method

41. BIOAVAILABILITY STUDIES FOR DEVELOPMENT
OF IVIVC
• A bioavailability study should be performed to characterize
the plasma concentration versus time profile for each of the
formulation.
• Bioavailability studies for IVIVC development should be
performed with sufficient number of subjects to characterize
adequately the performance of the drug product under study

42. EVALUATION OF PREDICTABILITY OF IVIVC
• An IVIVC should be evaluated to demonstrate that predictability of in vivo
performance of a drug product from its in vitro dissolution characteristics
is maintained over a range of in vitro dissolution release rates and
manufacturing changes
• Depending on the intended application of an IVIVC and the therapeutic
index of the drug, evaluation of prediction error internally and/or
externally may be appropriate.

43. EVALUATION OF PREDICTABILITY OF IVIVC
(contd.)
External predictability evaluation is not necessary unless the
drug is a narrow therapeutic index, or only two release rates
were used to develop the IVIVC, or, if the internal predictability
criteria are not met i.e. prediction error internally is inconclusive

44. INTERNAL PREDICTABILITY
All IVIVCs should be studied regarding internal
predictability. One recommended approach involves
the use of the IVIVC model to predict each
formulation’s plasma concentration profile (or Cmax
and/or AUC for a multiple Level C IVIVC) from each
respective formulation’s dissolution data.

45. EXTERNAL PREDICTABILITY
• Therefore, it may be important to establish the external
predictability of the IVIVC. This involves using the IVIVC to
predict the in vivo performance for a formulation with known
bioavailability that was not used in developing the IVIVC
model.

46. EXTERNAL PREDICTABILITY(contd.)
• Most important when using an IVIVC as a surrogate
for bioequivalence is confidence that the IVIVC can
predict in vivo performance of subsequent lots of the
drug product.

47. CONCLUSION
• IVIVC includes in vivo relevance to in vitro dissolution
specifications and can serve as surrogate for in vivo
bioavailability and to support biowaivers.
• Furthermore, IVIVC can also allow setting and validating of
more meaningful dissolution methods and specifications.

48. CONCLUSION(contd.)
• It can also assist in quality control for certain scale-up and
post-approval changes

49. REFERENCES
• Venkateswarlu V. , “Biopharmaceutics and Pharmacokinetics”, edition
2004, PharmaMed press, Hyderabad.
• Brahmankar D.M., Jaiswal B. Sunil, “bipharmaceutics and
pharmacokinetics- a treatise”, first edition 1995, Vallabh prakashan, New
Delhi.
• Sharge leon , yu pc andrew, applied biopharmaceutics and
pharmacokinetics, third edition.

50. THANK YOU